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RENAL REPLACEMENT THERAPY

CLINICAL PRACTICE GUIDELINES 2nd Edition

Editors
Dr Ghazali Ahmad Dr Hooi Lai Seong Dr Lim Yam Ngo Dr Ong Loke Meng Dr Rozina Ghazalli Dr Tan Chwee Choon Dr Wan Shaariah Wan Yusof Dr Wong Hin Seng Dato Dr Zaki Morad bin Mohd Zaher

Ministry of Health, Malaysia 2004

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PREFACE (1st Edition) In recent years clinical practice guidelines (CPG) have become a regular feature in clinical practice. Their advocate includes the clinicians, healthcare managers, patients and funding agencies. CPGs were developed for a number of reasons. They help in promoting more efficient use of resources. They may reduce inappropriate variation in clinical practice. For the practicing clinicians well developed and evidenced based guidelines offers concise, easy to follow guide, which are useful in daily clinical practice. While CPGs have generally found wide acceptance, a number of concerns remain. One major issue is the perception that guidelines limit clinical freedom and doctors are restricted to practicing cookbook medicine. Another issue is the concern that guidelines may be used as a standard against which to judge a complaint. Guidelines are not new; they have been in existence since clinical practice began. In the Ministry of Health guidelines were already available for many years. Very often they are department or hospital derived and reflects the practice of the consultants in the department or sometimes the view of just one senior clinician. Few are based on evidence from randomized clinical trials or other forms of scientific inquiry. The Department of Nephrology first developed its Clinical Practice Guidelines in 1984, the Hemodialysis Manual and the Ward Manual. They were developed by the doctors and paramedical staff together. These manuals served to guide doctors and others in managing routine clinical problems. In 1995 the Department together with other Nephrologists in the Ministry started developing a new set of evidence based guidelines in Renal Replacement Therapy (RRT). These were completed in 1996 and subsequently revised in 1997/8. Where evidence were available they were incorporated in the guidelines; however many aspects of the guidelines were consensus of opinion on contemporary practice with no clear or strong evidence. The process of developing the guidelines was a major learning experience even for those who worked many years in the field. For the first time long standing practices were subjected to critical review. The development of the guidelines went through various stages. Initially a consultant or specialist was given a particular area to review and he/she was expected to do an exhaustive literature search as well as study contemporary practices in a number of well-1-

known centers. He/She then prepared a draft proposal which was presented to the whole group for discussion. Amendments made were necessary before the proposal were adopted. The discussions were generally before the proposals were adopted. The discussions were generally exhaustive and comprehensive. While emphasis was given to adopting guidelines which were supported by strong evidence, consideration was also given to practical issues such as costs and other resource constraints. Where a particular recommendation based on evidence could not be adopted due to resource constraints in the next best line of action derived from consensus of opinion was accepted. The revision in 1997/8 was made following suggestions from the various nephrologists as well as based on new evidence in the literature. It is hoped that in the year 2000 a formal revision will be carried out. How well are these guidelines used and adhered to? Data from the National Renal Registry showed there is little variation in practice in Haemodialysis, CAPD and Renal Transplantation in the Ministry of Health. The practice in these particular areas has always been protocol based. To some extent compliance to guidelines in the field of RRT has been enforced through budget and other resource allocations. It is hoped that with these new guidelines, compliance will extend beyond these considerations. We trust users will find these guidelines adequate, informative and practical in their day to day practice.

DATO DR. ZAKI MORAD

DEPARTMENT OF NEPHROLOGY, HOSPITAL KUALA LUMPUR

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PREFACE (2nd Edition) This second edition of the Practice Guidelines on Renal Replacement Therapy came more than five years after the first. During the period there has been a number of developments in the field of Nephrology, Dialysis and Transplantation. There are new evidences on the outcome of various interventions in the field. Where appropriate they are included in this edition. The format for this edition has been the same as before and we hope users will find it as useful as the previous edition. This guideline now adds to the long list of Practice Guidelines developed by the Ministry of Health in association with the Academy of Medicine and the professional societies. Most of these guidelines are available on line as well as in hard coies which have been distributed widely. Nonetheless there are many practitioners who are unaware of the existence of these guidelines. The usage of these guidelines varied widely and in general is not optimum. It is hoped that this guideline on Renal Replacement Therapy will be better utilized. The target audience for this guideline is limited and thus it is possible to promote its effective use. We also hope to place these guidelines in both its forms (electronic and hard copies) at various point of care to make it readily accessible. Renal Replacement Therapy continues to consume a disproportionate share of the healthcare budget. Minimising practice variation and at the same time achieving the desired outcomes is important to contain costs. Practice guidelines are important tools in trying to achieve this.

DATO DR. ZAKI MORAD

DEPARTMENT OF NEPHROLOGY, HOSPITAL KUALA LUMPUR

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CONTRIBUTORS HAEMODIALYSIS SECTION


Section Editors: Dato Dr Zaki Morad, Dr Ghazali Ahmad, Dr Ong Loke Meng & Dr Rozina Ghazalli Dr Foo Siu Mei Dr Goh Bak Leong Mr Husin Harun Dr Indralingam Vaithilingam Dr Lynster Liaw Mr Mohd Sulaiman Dalimi Dr Moy Chee Hoou Dr Ong Loke Meng Mr T.S. Singam Dr Sukeri Mohamed Mr Tam Chong Chiang Dr Teo Sue Mei

CRITICAL CARE NEPHROLOGY SECTION


Section Editor: Dato Dr Zaki Morad, Dr Wan Shaariah Wan Yusuf Dr Ravindran Visvanathan Dr Zawawi Nordin

PERITONEAL DIALYSIS SECTION


Section Editors: Dato Dr Zaki Morad, Dr Lim Yam Ngo & Dr Tan Chwee Choon Dr Lee Meng Lee Dr Parameswaran Krishnan Dr Ramli Seman Dr Sunita Bavanandan Dr Clare Tan Ms Tan Poh Choo Dr R. Tharmaratnam

RENAL TRANSPLANTATION SECTION


Section Editors: Dato Dr Zaki Morad, Dr Hooi Lai Seong & Dr Wong Hin Seng Dr Anthony Chan Dr Goh Bak Leong Dr Liew Boon Seng Dr Liu Wen Jiun Dr Rosnawati Yahya Dr Susan Pee Dr Wan Jazilah Wan Ismail

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CONTENTS
Page HAEMODIALYSIS SECTION 1. Patient Selection And Preparation For Haemodialysis 2. Vascular Access 3. Anticoagulation In Haemodialysis 4. Intradialytic Complications 5. Long Term Complications 5.1 Anaemia 5.2 Bone Disease 5.3 Aluminium Toxicity 6. Management Of Cardiovascular Risk Factors 7. Management Of The Infective Patient 8. Nutritional Management 9. Haemodialysis Adequacy 10. Surgery And The Dialysis Patient 11. Use Of Drugs In Dialysis Patients And Treatment Of Acute Poisoning 12. Rehabilitation 13. Pregnancy During Dialysis 14. Quality Assurance Program In Haemodialysis 15. Paediatric Haemodialysis 16. Technical Aspects Of Haemodialysis 17. The Haemodialysis Procedure 18. Water Treatment Glossary CRITICAL CARE NEPHROLOGY SECTION 19. Principles And Technique In Crrt 20. Vascular Access 21. Anticoagulation 22. Replacement Fluid And Dialysate 23. Drugs And Dosage In Crrt 24. Dialysis Prescription PERITONEAL DIALYSIS SECTION 25. Patient Selection 26. Pre Dialysis Preparation 27. CAPD Systems 28. CAPD Access 29. CAPD Procedures -51 5 12 15 23 31 37 45 50 56 59 67 70 79 82 83 84 89 97 101 125 127 133 135 137 140 143 152 154 156 158 160

30. Complications Of CAPD 31. Malnutrition 32. CAPD Adequacy 33. Peritoneal Dialysis In Children 34. Automated Peritoneal Dialysis 35. Intermittent Peritoneal Dialysis Glossary RENAL TRANSPLANTATION SECTION 36. Living Related Donor Workup 37. Living Related Recipient Workup 38. Perioperative Management 39. Cadaveric Transplantation 40. Malaysian Organ Sharing System (Moss) 41. Immunosupressive Protocol 42. Management Of Graft Dysfunction 43. Management Of Infection Post Kidney Transplantation 44. Renal Transplantation And Nutrition 45. Long Term Complications After Renal Transplantation 46. Paediatric Renal transplantation Glossary

168 195 199 202 207 209 213 215 222 234 239 243 245 250 261 273 277 285 292

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HAEMODIALYSIS

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1. PATIENT SELECTION AND PREPARATION FOR HAEMODIALYSIS 1.1 Patient selection and screening The decision to choose haemodialysis as the mode of treatment for end stage renal disease (ESRD) should be made after a thorough discussion with the patient and other family members and parties (e.g. employer). The final decision is made after considering coexisting medical and socio-economic factors. 1.1.1 Chronic haemodialysis is relatively contraindicated in the following conditions: a. Haemodynamic or circulatory instability b. Advanced malignancy c. Incapacitating end stage organ failure: Dementia Advanced cirrhosis with encephalopathy d. Severe vascular access problems e. Advanced AIDS 1.1.2 Socio-economic factors which have to be considered include: a. Access to haemodialysis facilities b. Family support c. Financial support d. Patients preference Screening for haemodialysis should include physical examination to exclude unfavourable medical conditions. Visual acuity and hand dexterity is important for self- care haemodialysis. An assessment of the suitability for vascular access as well as screening for HbsAg, anti-HIV and anti-HCV should also be made. 1. 2 Preparation for haemodialysis Timely placement of a permanent vascular access is important to: obviate the need for temporary access and reduce catheter related complications allow better maturation of native fistula 1.3 Timing of vascular access placement A permanent vascular access should be created when creatinine clearance is: < 20mls/min for diabetics < 15 mls/min for non diabetics

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Any suitable veins should be preserved regardless of arm dominance. The dorsum of the hand is the preferred site for intravenous lines. 1.4 Temporary access A cuffed tunnelled catheter should be considered if the requirement for a catheter is anticipated to be > 6 weeks. Whenever possible, ultrasound guided insertion of catheter should be practised. Table 1.1 Sites of temporary access SITE Internal jugular Femoral COMMENTS The right is preferred 1. Daily exit site care 2. < 7 days duration of HD 3. Should be at least 19 cm long to prevent recirculation 4. Avoid in potential renal transplant recipients Avoid to prevent subclavian vein stenosis

Subclavian

1.5 Care of temporary vascular access Strict adherence to aseptic techniques should be practised at each catheter contact The exit site should be inspected at each haemodialysis session The use of dry gauze dressing + mupirocin at the catheter exit site should be practised The patient should be educated on catheter care 1.6 Catheter related infections 1.6.1 When catheter-associated bacteraemia is recognised, catheters should be removed. If an alternative site for vascular access is not available, the catheter may be retained.In addition: a. blood cultures should be taken from both catheter lumens and a peripheral site b. a two day trial of antibiotics and observation is reasonable c. the catheter should be removed if the patient remains febrile or condition deteriorates 1.6.2 Antibiotics should be started if there is an exit site infection and the catheter removed if infection is not resolving 1.6.3 Patients who remain febrile or still retain a positive culture after catheter removal should be evaluated for metastatic complications (e.g. endocarditis, vertebral abscess, osteomyelitis)

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1.6.4 First line empirical antibiotics for catheter related infections: a. IV cloxacillin 500mg 1 gm 6 hourly + aminoglycoside or 3rd generation cephalosporin b. IV vancomycin in MRSA nasal carriers or recent episode of MRSA infections (15 mg/kg every 5-7 days depending on blood levels) c. Duration of treatment should be at least 2 weeks 1.7 Selection of a permanent vascular access In the order of preference, the choice of a permanent vascular access should be: Radiocephalic AVF Brachiocephalic AVF Transposed brachiobasilic AVF AV graft (PTFE) Cuffed tunnelled CVC 1.8 Patient evaluation prior to access placement To determine the type of access most suitable, a history must be taken and physical examination of the patients venous, arterial and cardiopulmonary systems must be performed. 1.8.1 History Note any previous central venous catheter insertion. This is associated with central venous stenosis. Arm dominance: non dominant arm is preferred for AVF Diabetes mellitus Severe congestive cardiac failure. Fistulae may alter haemodynamics and cardiac output Previous vascular access Previous arm, neck or chest surgery/trauma Anticipated renal transplant from living donor: temporary access may be sufficient 1.8.2 Physical examination Physical examination of the patients venous, arterial and cardiopulmonary systems is important, looking specifically at: Venous calibre and patency Character of peripheral pulses Blood pressure of upper limbs will determine suitability of vascular access Allens test Difference in arm size - 10 -

Scars of previous SVC placement, arm, neck and chest surgeries Presence of collateral veins may indicate venous obstruction Evaluate for oedema Tourniquet venous palpation with vein mapping Signs of cardiac failure

1.9 Initiation of dialysis Dialysis should be initiated to promote wellness and not to rescue from illness. 1.9.1 Dialysis should be started when: a. Uraemic signs and symptoms are present b. The weekly renal Kt/V falls < 2.0 (table 1.2) and/or c. Indices of malnutrition (table 1.3) develop in the absence of other causes 1.9.2 Dialysis should be initiated earlier in diabetics Table 1.2 KT/V equivalents Kt/V of 2.0 = 1. Renal urea clearance of 7 mls/min 2. Renal CrCl of 9-14 mls/min/1.73m2 3. GFR of 10.5 mls/min/1.73m2 Table 1.3 Indices suggestive of malnutrition Plasma albumin < 40g/L Total cholesterol < 3.9 mmol/L Dietary protein intake < 0.8g/kg/day Transferrin level < 200 mg/dL Weight loss

References: 1. National Kidney Foundation DOQI guidelines for vascular access 2000 2. Bander; Seminars in dialysis 1992:5:121 3. Jaques; J. Vasc. Intern. Radio. 1992:3:427 4. Schwab; The haemodialysis catheter conundrum; Kidney Int 1999 5. Marr; Management of infected cuffed CVC for HD: UpToDate 2000 6. Pearson; Hospital infection control practises advisory committee, Guidelines for prevention of intravascular device related infections; Am J Infection Control 1996;24:262-293 7. Bonomini; Kidney International 1985;28: S57-S59 8. Hakim RM; JASN 1995: 6:1319-1328. - 11 -

2. VASCULAR ACCESS 2.1 Patient assessment prior to access placement should include: 2.1.1 History and physical examination see Section 1.8.1 and 1.8.2 2.1.2 Diagnostic evaluation: a. Doppler ultrasound/venography should be done if venous stenosis is suspected b. Arteriography may be indicated in patients with arterial insufficiency planned for AVF. This is to avoid extremity ischaemia. 2.2 Selection of permanent vascular access and order of preference for placement of AV fistula 2.2.1 The order of preference for placement of AV fistula: a. A wrist (radial-cephalic) primary AV fistula b. An elbow (brachial-cephalic) primary AV fistula (Level C) 2.2.2 If it is not possible to establish either of these types of fistulae, access may be established using: a. A transposed brachial basilic vein fistula (Level C) b. An arteriovenous graft of synthetic material (eg PTFE) 2.3 Vascular access catheter Cuffed tunnelled central venous catheters should be discouraged as permanent vascular access unless patients have exhausted all other options Tunnelled cuffed venous catheters are the method of choice for temporary access of longer than 6 weeks duration. Tunnelled cuffed catheters should not be placed on the same side as a maturing AV access, if possible. (Level C) The preferred insertion site for tunnelled cuffed venous dialysis catheters is the right internal jugular vein. Other options include: the right external jugular vein, the left internal and external jugular veins. Subclavian access should be used only when jugular options are not available All cuffed dialysis catheters should ideally be inserted under fluoroscopy. The catheter tip should be adjusted to the level of the caval atrial junction or into the right atrium to ensure optimal blood flow. (Atrial positioning is only recommended for catheters composed of soft compliant material, such as silicone. (Level C) Real-time ultrasound-guided insertion is recommended to reduce insertion- related complications. (Level C) - 12 -

2.4. Timing of Access Placement 2.4.1 Patients with chronic kidney disease should be referred for surgery of primary AV fistula when: a. creatinine clearance is <25 mL/min b. serum creatinine level is >350 mol/L or c. within 1 year of an anticipated need for dialysis 2.4.2 The patient should be referred to a nephrologist prior to the need for access and for counseling about renal replacement therapy. (Level C) 2.4.3 A new primary fistula should be allowed to mature for at least 1 month, and ideally for 3 to 4 months, prior to cannulation. (Level C) 2.4.4 Dialysis AV grafts should be placed at least 3 to 6 weeks prior to an anticipated need for hemodialysis in patients who are not candidates for primary AV fistulae. (Level C) 2.4.5 Hemodialysis catheters should not be inserted until hemodialysis is needed. (Level C) 2.5. Access Maturation 2.5.1 A primary AV fistula is mature and suitable for use when the veins diameter is sufficient to allow successful cannulation, but not sooner than 1 month (and preferably 3 to 4 months after construction) 2.5.2 If adequate flow (>250mls/min) is not achieved by 4 months, reassess for revision or a new access will have to be created. (Level D) 2.5.3 The following procedures may enhance maturation of AV fistula: a. Fistula hand-arm exercise (eg squeezing a rubber ball)will increase blood flow and speed maturation of a new native AV fistula (Level C) b. Selective obliteration of major venous side branches will speed maturation of a slowly maturing AV fistula (Level C) c. When a new native AV fistula is infiltrated (ie presence of hematoma with associated induration and edema), it should be rested until swelling is resolved (Level C) 2.5.4 PTFE dialysis AV grafts should not routinely be used until 14 days after placement. Cannulation of a new PTFE dialysis AV graft should not routinely be attempted, even 14 days or longer after placement, until swelling has gone down enough to allow palpation of the course of the graft. Ideally, 3 to 6 weeks should be allowed prior to cannulation of a new graft. (Level C)

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2.5.5 Patients with swelling that does not respond to arm elevation or that persists beyond 2 weeks after AV access placement should receive a venogram or other non contrast study to evaluate central veins (Level C) 2.5.6 Cuffed and non cuffed hemodialysis catheters are suitable for immediate use and do not require maturation time (Level C) 2.6. Monitoring of vascular access 2.6.1 Monitoring of vascular access should include clinical examination and measurement of venous pressure, blood flow, access recirculation (if indicated) & access flow (if available) 2.6.2 Further investigations are indicated if there is evidence of : a. Persistent swelling of the arm, clotting of the AVF, prolonged bleeding after needle withdrawal, or altered characteristic of pulse or thrill in the AVF (Level C) b. Persistently elevated venous pressure (> 150mmHg with G16 needle and > 125mmHg with G15 needle at Qb 200mls/min in 3 consecutive readings) c. Elevated negative arterial pre-pump pressures that prevent increase to acceptable blood flow d. Unexplained decrease in the measured amount of haemodialysis delivered (URR, Kt/V) (Level C) e. Additional investigations include: Access recirculation Venogram / fistulogram Access flow (e.g. Transonic method) f. For selected high risk groups (e.g. graft, previous thrombosis), regular dynamic venous pressure, access recirculation or access flow (Transonic) monitoring should be done 2.7 Method for access recirculation study Blood samples must be drawn within the first hour of dialysis Three samples are required Draw samples from arterial and venous port simultaneously, then quickly stop ultrafiltration. Reduce blood flow to 25-50 ml /min Raise venous pressure alarm limit to maximum. Clamp venous line between patient and drip chamber. Wait 30 seconds (or until alarm sounds). Stop pump (manually or by alarm). Sample blood from arterial port.

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2.8 Skin preparation for cannulation of permanent AV access a. Locate and palpate the needle cannulation sites prior to skin preparation b. Wash access site using an antibacterial soap or scrub (eg 2% chlorhexidine) and water c. Cleanse the skin by applying 70% alcohol and/or 10% povidone iodine using a circular rubbing motion Notes: Alcohol has a short bacteriostatic action time and should be applied in a rubbing motion for 1 minute immediately prior to needle cannulation Povidone iodine needs to be applied for 2 to 3 minutes for its full bacteriostatic action to take effect and must be allowed to dry prior to needle cannulation Clean gloves should be worn by the dialysis staff for cannulation Gloves should be changed if contaminated at any time during the cannulation procedure New clean gloves should be worn by the dialysis staff for each patient Table 2.1 Technique for AV Fistula/Graft Cannulation Technique After skin preparation, pull skin taut in opposite direction of needle insertion Rationale Compresses peripheral nerve endings between epidermis and dermis Facilitates smoother incision of skin with less surface area contacting cutting edge of needle Enables better stabilization of graft or vessel to be cannulated Less steep angles increase risk of dragging cutting edge of needle along surface of vessel Steeper angles increase risk of perforating underside of vessel

Use approximately 45 degree angle of insertion for AV graft and approximately 25 degree angle for AV fistula

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Table 2.1 Technique for AV Fistula/Graft Cannulation (contd). Technique Rationale Once the vessel has been Any manipulation may penetrated, there are basically traumatize the intima of the three methods employed in vessel Rotating the axis avoids existing practice: traumatizing the intima 1. Advance the needle slowly Waiting to rotate axis avoids with cutting edge facing top traumatizing top of vessel of vessel and do not rotate while needle is taped in place axis 2. Immediately rotate the axis of the needle 180 degrees and advance slowly with cutting edge facing bottom of the vessel 3. Advance the needle to desired position, then rotate the axis 180 degrees Tape the needle at the same Pressing the needle shaft flat angle or one similar to the angle against the skin moves the of insertion needle tip from the desired position within the vessel lumen Remove needle at same or angle Avoid trauma to the intima by similar to angle of insertion, and dragging cutting edge along it. Avoid pressing cutting edge into NEVER APPLY PRESSURE intima when applying pressure BEFORE NEEDLE IS to venepuncture site for COMPLETELY OUT haemodialysis. 2.9 Monitoring for limb ischaemia All patients, particularly those in high-risk groups, should be monitored for the development of limb ischaemia following AV access construction. These include sensations of coldness, numbness, tingling, and impairment of motor function (not limited by postoperative pain) and objective assessment of skin temperature, gross sensation, and movement and distal arterial pulses in comparison to the contralateral side.

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References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. National Kidney Foundation. NFK-DOQI clinical practice guidelines for vascular access. 2000 Windus DW: Permanent vascular access: A nephrologist's view. Am J Kidney Dis 21:457-471, 1993 Depner TA: Techniques for prospective detection of venous stenosis. Adv Ren Replace Ther 1:119-130, 1994 Older RA, Gizienski TA, Wilkowski MJ, Angle JF, Cote DA: Hemodialysis access stenosis: Early detection with color Doppler US. Radiology 207:161-164, 1998 Schwab SJ, Raymond JR, Saeed M, Newman GE, Dennis PA, Bollinger RR: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36:707-711, 1989 Besarab A, Sullivan KL, Ross RP, Moritz MJ: Utility of intra-access pressure monitoring in detecting and correcting venous outlet stenoses prior to thrombosis. Kidney Int 47:1364-1373, 1995 Strauch BS, O'Connell RS, Geoly KL, Grundlehner M, Yakub YN, Tietjen DP: Forecasting thrombosis of vascular access with Doppler color flow imaging. Am J Kidney Dis 19:554-557, 1992 Krivitski NM: Theory and validation of access flow measurement by dilution technique during hemodialysis. Kidney Int 48:244-250, 1995 Depner TA, Krivitski NM: Clinical measurement of blood flow in hemodialysis access fistulae and grafts by ultrasound dilution. ASAIO J 41:M745-M749, 1995 . Bosman PJ, Boereboom FT, Smits HF, Eikelboom BC, Koomans HA, Blankestijn PJ: Pressure or flow recordings for the surveillance of hemodialysis grafts. Kidney Int 52:1084-1088, 1997 Safa AA, Valji K, Roberts AC, Ziegler TW, Hye RJ, Oglevie SB: Detection and treatment of dysfunctional hemodialysis access grafts: Effect of a surveillance program on graft patency and the incidence of thrombosis. Radiology 199:653657, 1996 May RE, Himmelfarb J, Yenicesu M, Knights S, Ikizler TA, Schulman G, Hernanz Schulman M, Shyr Y, Hakim RM: Predictive measures of vascular access thrombosis: A prospective study. Kidney Int 52:1656-1662, 1997 Middleton WD, Picus DD, Marx MV, Melson GL: Color Doppler sonography of hemodialysis vascular access: Comparison with angiography. Am J Roentgenol 152:633-639, 1989 Schwab SJ, Raymond JR, Saeed M, Newman GE, Dennis PA, Bollinger RR: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36:707-711, 1989 Safa AA, Valji K, Roberts AC, Ziegler TW, Hye RJ, Oglevie SB: Detection and treatment of dysfunctional hemodialysis access grafts: effect of a surveillance program on graft patency and the incidence of thrombosis. Radiology 199:653657, 1996 Strauch BS, O'Connell RS, Geoly KL, Grundlehner M, Yakub YN, Tietjen DP: Forecasting thrombosis of vascular access with Doppler color flow imaging. Am J Kidney Dis 19:554-557, 1992 Schwab S, Raymond J, Saeed M, Newman GE, Dennis P, Bollinger R: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36:707-711, 1989 Bosman PJ, Boereboom FTJ, Bakker CJ, et al: Access flow measurements in hemodialysis patients: in vivo validation of an ultrasound dilution technique. J Am Soc Nephrol 7(6):966-969, 1996

12. 13. 14. 15.

16. 17. 18.

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19. Harter H, Burch J, Majerus P, et al: Prevention of thrombosis in patients on hemodialysis by low-dose aspirin. N Engl J Med 301:577-579, 1979 20. Kaegi A, Pineo G, Shimizu A, Trivedi H, Hirsh J, Gent M: Arteriovenous-shunt thrombosis: prevention by sulfinpyrazone. N Engl J Med 290:304-306, 1974 21. Kobayashi K, Maeda K, Koshikawa S, Kawaguchi Y, Shimizu N, Naito C: Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis: a multicenter collaborative double blind study. Thromb Res 20:255-261, 1980 22. Fiskerstrand C, Thompson I, Burnet M, Williams P, Anderton J: Double-blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for hemodialysis. Artif Organs 9:61-63, 1985 23. Grontoft K-C, Larsson R, Mulec H, Weiss LG, Dickinson JP: Effects of ticlopidine in AV-fistula surgery in uremia. Scand J Urol Nephrol 32:276-283, 1998 24. Ell S, Mihindukulasuriya J, O'Brien J, Polak A, Vernham G: Ticlopidine in the prevention of blockage of fistulae and grafts [abstract]. Haemostasis 12:180, 1982 25. Randolph AG, Cook DJ, Gonzales CA, Andrew M: Benefit of heparin in central venous and pulmonary artery catheters: a meta-analysis of randomized controlled trials. Chest 113:165-171, 1998 26. Bern MM, Bothe A Jr, Bistrian B, Champagne CD, Keane MS, Blackburn GL: Prophylaxis against central vein thrombosis with low-dose warfarin. Surgery 90:216-220, 1986 27. Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized prospective trial. Ann Intern Med 112:423-428, 1990 28. Boraks P, Seale J, Price J, et al: Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies. Br J Haemat 101:483-486, 1998

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3. ANTICOAGULATION IN HAEMODIALYSIS Haemodialysis requires anticoagulation to prevent extracorporeal clotting which is contributed by several factors (see table 3.1) 3.1 General principles The most commonly used anticoagulant in haemodialysis is unfractionated heparin. Table 3.1 Factors which favour clotting of the extracorporeal circuit Low blood flow High hematocrit High ultrafiltration rate Dialysis access recirculation Intradialytic blood, blood products and lipid transfusion Use of drip chambers (Adapted from Daugirdas Handbook of dialysis 3rd edition) Table 3.2 Measures to assess coagulation during dialysis 1. Visual inspection Extremely dark blood Black streaks in the dialyser Foaming with clots in the drip chamber and venous trap Tethering b. Changes in the arterial and venous pressure readings depending on the location of the clot c. Clotting time tests : ACT and PTT Table 3.3 Standard anticoagulation with heparin: Constant-infusion method a. Bolus dose of heparin at 50u/kg; this dose should be reduced in extremely uraemic patients b. Wait 3-5 minutes to allow heparin dispersion c. Start heparin infusion at a rate of 10-20 units/kg per hour d. Stop the heparin infusion 1 hour before the end of dialysis

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3.2 Anticoagulation in haemodialysis patients at risk for bleeding A number of alternative modalities have been used: 3.2.1 Heparin free dialysis: a. No heparin during priming b. Set the blood flow rate as high as possible c. 100-250 mls of saline flushes are administered every 15-30 minutes into the arterial limb d. The volume of saline administered must be removed during dialysis to prevent fluid overload e. Careful monitoring of the arterial and venous pressure alarms will be required to detect early clotting f. Indications for heparin free dialysis: Pericarditis (tight heparin is also acceptable) Recent surgery with bleeding complications Post renal/liver biopsy Coagulopathy Thrombocytopenia Intracerebral haemorrhage Active bleeding 3.2.2 Tight heparin A bolus dose of heparin at 20 units per kg followed by continuous infusion at 5-10 units/kg/hour with ACT monitoring half hourly (Refer table 3.4 for ACT values) Table 3.4 Target clotting times during dialysis Routine heparin Tight heparin Test Baseline (Desired range) (Desired range) value During End of During End of dialysis dialysis dialysis dialysis ACT 60 -150s 1.8 times 1.4 times 1.4 times 1.4 times (Adapted from Daugirdas `Handbook of dialysis 3rd edition) 3.2.3 Other forms of anticoagulation a. Low molecular weight heparin is expensive and there is no additional benefit compared to heparin in terms of dialysis related bleeding or other complications b. Regional anticoagulation with citrate c. Prostacyclin regional anticoagulation

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3.3 Side effects of heparin a. Bleeding complications b. Hypertriglyceridaemia c. Thrombocytopenia. The options for these patients are: Heparin free dialysis Change to CAPD Regional citrate anticoagulation LMWH is not a safe substitute due to crossreactivity in >90% Danaparoid (a heparinoid) or recombinant hirudin d. Pruritis. Consider switching to LMWH e. Hyperkalaemia. Consider switching to LMWH f. Osteoporosis

References
1. Handbook of Dialysis Third edition: John T. Daugirdas 2. Haemodialysis anticoagulation- 2002 UpToDate 9.3 3. Lohr JW. Minimizing haemorrhagic complications in dialysis patients. J Am Soc Nephrol 1991;2:961 4. Henny CP. The effectiveness of a low molecular weight heparinoid in chronic intermittent haemodialysis. Thromb. Haemost 1985; 54:460 5. Fischer KG. Recombinant hirudin as anticoagulant in continous haemodialysis. Kidney Int Suppl 1999; 72: S46

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4. INTRADIALYTIC COMPLICATIONS In spite of advances in haemodialysis treatment and technology, intradialytic complications still occur.

4.1 Causes of intradialytic complications include: Hypotension Disequilibrium syndrome Bleeding Air embolism Dialyser reaction Muscle cramps Technical: incorrect dialysate composition and microbiological contamination

4.2 Hypotension This is the commonest intradialytic complication. Hypovolaemia has been implicated as a major causal factor, manifesting as hypotension, nausea, vomiting, muscle cramps, fits and cardiac arrhythmias. However, hypovolaemia is not consistently reflected by blood pressure changes. Hypovolaemia is sometimes asymptomatic. Impairment of specific compensatory response will lead to hypotension. Factors causing intradialytic complications include: a. Impaired plasma refilling rate due to: high ultrafiltration (UF) rate low predialysis haematocrit low sodium dialysate acetate dialysate b. Inappropriate increase in venous capacity due to: intradialytic ingestion of food high body temperature low sodium dialysate acetate dialysate c. Decreased vascular resistance due to: anaemia high temperature food ingestion acetate dialysate d. Cardiac dysfunction

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e. Uncommon causes including: pericardial tamponade arrhythmia dialyser reaction haemolysis air embolism myocardial infarction occult haemorrhage septicemia 4.3 Management of hypotension Lie patient in the Trendelenburg position Reduce or stop ultrafiltration depending on severity Infuse normal saline 100-250cc at a time to a maximum of 500cc Reduce blood flow rate Oxygen therapy Haemodialysis is terminated if hypotension remains after infusion of 500cc of saline If hypotension persists exclude gastrointestinal bleeding, acute myocardial infarction or ischaemia, cardiac arrythmias,cardiac tamponade, pulmonary embolism and electrolyte disturbances Carry out the following investigations : ECG,urea and electrolytes, blood glucose,arterial blood gases

4.4 Measures to prevent hypotension Reassessment of dry weight when indicated Avoid rapid and excessive ultrafiltration On-line monitoring of blood volume using haematocrit sensor Avoid excessive interdialytic weight gain (IDWG), maintain it <3% of dry weight Consider higher sodium concentration or sodium/UF profiling Avoid heavy meals prior to/during dialysis in hypotension-prone patients Consider use of a cooler dialysate temperature (34-36 oC) Avoid acetate dialysate Omit the predialysis dose of antihypertensive drugs Use sequential ultrafiltration Ensure haematocrit remains stable at 30% or greater prior to dialysis 4.5 Dialysis Disequilibrium Syndrome a. The disequilibrium syndrome is a set of systemic and neurologic symptoms that can occur either during or following dialysis - 23 -

b. Individuals with preexisting neurologic disorders, such as recent stroke, head trauma, subdural haematoma, or malignant hypertension are at increased risk. This syndrome has become rare in recent years due to improvement of dialysis delivery technology. c. The signs and symptoms are nausea, vomiting, headache, blurred vision, restlessness, obtundation, seizure and coma. Symptoms of nausea, vomiting and headache are non specific. d. The immediate treatment is symptomatic as the problem is self limiting e. The following measures may avoid disequilibrium: Avoid aggressive dialysis. The first few haemodialysis sessions should be gentle, using low blood flow rates (150 mls/min) and short hours. 2 The dialyser should be of a small surface area (0.8-1.0 m ) Use of high dialysate sodium of at least 140 mEq/L may be useful Use of sodium profiling 4.6 Bleeding a. Dialysis patients have a higher incidence of bleeding. The causes include: platelet dysfunction / impaired platelet-endothelium interaction use of anticoagulation during haemodialysis platelet-dialyser membrane interaction leading to thrombocytopenia b. Presenting features include: bleeding from venepunctures sites subdural haematoma subarachnoid haemorrhage gastrointestinal bleeding haemopericardium c. Management minimal heparinisation-monitor activated clotting time (ACT) hourly; keeping ACT between 150-180 seconds or heparin-free haemodialysis- this requires increased blood flow rate and frequent flushing with isotonic saline blood transfusion for severe blood loss FFP, cryoprecipitate, DDVAP (0.3-0.4 g/kg) may be required protamine when haemostasis is poor in heparinised patients avoid catheter removal within 4-6 hours after dialysis

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4.7 Air Embolism a. Sources of air entry into the dialysis circuit include: prepump tubing segment, intravenous infusion set, other parts of the dialysis tubing, air from the dialysate and from an inadvertently opened end of a central venous catheter. b. The signs and symptoms depend on the volume of air entering the vascular system and the position of the patient. If the patient is sitting upright air will enter the central nervous system causing fits. If the patient is recumbent, air enters the heart causing decreased cardiac output and sudden onset of dyspnoea, cough and central cyanosis. c. Management of air embolism Stop haemodialysis, clamp the venous return. Do not return blood to the patient. Place the patient in the left lateral Trendelenburg position Give 100% oxygen with or without mechanical ventilation d. Prevention Dialysis should never be performed with the air alarm system inactivated IV solution should be in collapsible bags Catheter should be aspirated for return of blood and flushed with saline before connection to the dialysis circuit Dialyser should be rinsed thoroughly with saline to expel air bubbles 4.8 Haemolysis a. Acute haemolysis is usually caused by: dialyser/dialysate contamination with formaldehyde, bleach, copper, nitrate or chloramine faulty dialysis equipment or procedure kinked catheter/tube hypoosmolar dialysate patient- related factors b. The presenting feature is a change in colour of the blood returning to the patient from dark to brighter red. The symptoms of acute haemolysis are back pain, chest tightness and shortness of breath c. Management of haemolysis Stop haemodialysis, clamp the venous return. Do not return blood to the patient Blood transfusion may be necessary Treat hyperkalemia

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Document haemolysis by inspection of the serum sample (red),

send the blood for lactate dehydrogenase (LDH), peripheral blood film, serum haptoglobulin and serum haemoglobin Sample of dialysate solution should be analysed, unless mechanical cause is suspected d. Prevention Water quality to follow standard recommendation Thorough rinsing of re-use dialysers Care in preparation of dialysate to avoid hypoosmolarity Monitor dialysate temperature 4.9 Dialyser Reactions 4.9.1 Type A (Anaphylactic type) a. Those with a history of atopy are at risk. Occurs usually during the first few minutes of dialysis. Mild: Itching, urticaria, cough, sneezing, coryza, watery eyes, abdominal pain and diarrhoea Severe: Anaphylactic reaction b. Management Stop dialysis Clamp blood lines- disconnect extracorporeal circulation Assess severity Drugs- anti-histamine/ steroid Cardiovascular support c. Prevention Proper dialyser rinsing prior to use Re-use procedures prior to first use Avoid ETO sterilised dialyser for those with history of type A dialyser reaction Predialysis anti-histamine for those with persistent mild reaction 4.9.2 Type B (non-specific dialyser reaction) a. Typically manifestes with chest pain, may or may not be accompanied by back pain. Less severe and generally dialysis can be continued. Onset of symptom may be within several minutes of starting dialysis. b. Management Supportive Exclude myocardial ischaemia/ subclinical haemolysis c. Prevention Reuse procedure on new dialyser Try different dialyser membrane - 26 -

4.10 Muscle cramps a. Dialysis-induced muscle cramps are due to decreased muscle perfusion and contraction of intravascular volume that occurs in response to excessive ultrafltration. In some patients, leg cramps are chronic, occur during inter-dialytic interval. b. Management Reduce ultrafltration rate Infuse normal saline c. Prevention Reduce interdialytic weight gain Reduce ultrafitration rate Reassess dry weight Use bicarbonate dialysate Increase dialysate Na+ Drugs- oral Quinine sulphate 300mg ON, short or medium acting benzodiazepine. Vit E 400IU ON and carnitine have been tried Stretching exercises 4.11 Complications due to technical faults a. This is usually due to incorrect proportioning of water and dialysate component, leading to incorrect concentration of dialysate sodium, potassium, calcium and pH. This may happen as a result of: empty dialysate container improper dialysate concentrate connection machine malfunction faulty or inactivated conductivity alarm interrupted water supply b. Presenting features: Hypo/ Hyponatremia can cause haemolysis, cerebral hypernatremia oedema, hyperkalemia & abdominal pain Acidosis/alkalosis Acidosis causes hyperventilation & predisposes to ventricular arrhythmias Alkalosis causes hypoventilation, confusion, obtundation, stupor or coma, tetany & seizures The hard water syndrome is due to hypercalcemia in water that has been inadequately prepared - 27 -

Hypercalcemia

Hyperchloraemic acidosis

This occurs with bicarbonate dialysis due to incorrect mixing of acid/base if no pH meter is included in the system. The conductivity meter does not detect this.

c. The management is according to the underlying cause. Check urea and electrolytes, full blood count, arterial blood gas, calcium, magnesium and phosphate. 4.12 Microbial/Endotoxin contamination The presenting features are fever and hypotension Contamination is caused by reuse of improperly processed dialysers or contaminated dialysate Microbial contamination can occur during any of the reprocessing steps (rinsing, cleaning, testing, and sterilising hollow fibre dialysers), but most commonly, use of contaminated water is implicated The use of bicarbonate dialysate and high-flux dialysis is associated with an increased risk of pyrogenic reaction 4.13 Pyrogenic Reaction a. Differential diagnosis includes: improperly sterilised dialyser contaminated water or bicarbonate dialysate cannulation of infected fistulae or grafts dialyser reaction early septicaemia b. Management is largely supportive and empirical: antipyretic if hypotensive, discontinue ultrafiltration and continue dialysis with caution. Saline infusion may be necessary. hospitalisation may be required a cluster of similar cases should prompt a review of the water used for reprocessing and water distribution and dialysate, the reprocessing procedures, and the bicarbonate system

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References
1. Daurgidas. Dialysis hypotension. A haemodynamic analysis. Kidney Int (1991) 39: 233-246 2. Daurgidas. Handbook of dialysis. 3rd Edition. Lippincott Williams & Wilkins 3. Steur R. Reducing symptoms during haemodialysis by continuously monitoring the haematocrit. Am. Jour. of Kidney Dis (1996) 27(4): 525-532. 4. Van der Sarde FM. Energy transfer is the single most important factor for the difference in the vascular response between isolated UF and haemodialysis. J.Am Soc. Nephrol (2000) 11: 1512-1517. 5. Maggiore Q. Multicentre randomised study on the effect of thermal balance on vascular stability in haemodialysis patient. J.Am Soc. Nephrol Abstract A 1473. 6. Nisselsen. Clinical Dialysis 3rd Edition (1995) Appleton & Lange. 7. M.K.Steward. Muscle cramps during maintenance haemodialysis Lancet (1992): 1049-1051. 8. Sweet SJ. Haemolytic reaction mechanically induced by kinked haemodialysis lines. Am Jour Kidney Dis. (1996) 27: 263. 9. Ahmad. Multicenter trial of L-Carnitine in maintenance haemodialysis patient.Clinical and biochemical effect. Kidney Int (1990) 38: 912-918.

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5. LONG TERM COMPLICATIONS 5.1 ANAEMIA Anaemia is a common manifestation in patients with ESRD and is normochromic normocytic. 5.1.1 Assessment of anaemia Evaluation of anaemia in patients on dialysis should include a thorough clinical assessment to determine the cause as well as clinical impact of anaemia. 1-2 The primary cause of anaemia in chronic renal failure is erythropoietin deficiency but other factors may contribute. a. Causes of anaemia include: erythropoietin (Epoeitin) deficiency iron deficiency blood loss e.g. gastrointestinal and uterine loss shortened red cell survival effects of uraemic inhibitors on bone marrow severe hyperparathyroidism leading to myelofibrosis aluminium overload nutritional deficiencies hypothyroidism infection and/or inflammation haemoglobinopathies b. The following evaluation should be made prior to Epoetin therapy: Full blood picture and peripheral film Absolute reticulocyte count Iron status serum ferritin transferrin saturation (serum iron x 100/TIBC) and/or % hypochromic red cells if available (Level B) 1-2 The following work-up may be included if indicated (Level B) 1-2 assessment of occult gastrointestinal blood loss serum (or red cell) folate and Vit B12 level C-reactive protein tests for haemolysis serum and/or urine protein electrophoresis assess for aluminium toxicity bone marrow examination intact PTH - 30 -

5.1.2 Treatment of anaemia Identify and correct underlying causes of anaemia Assess clinical impact of anaemia Ensure adequate nutrition and adequate dialysis Iron supplementation (see Section 5.1.4) Folate and Vitamin B supplementation Blood transfusion should be used only when the patient is symptomatic and rapid correction of anaemia is required. Blood transfusion is discouraged because it carries the risk of transmission of viral infections, sensitisation to donor HLAs (human leucocyte antigens) thus jeopardising transplantation prospects, iron overload and depression of endogenous erythropoietin production. Epoetin should be used when all other causes have been excluded and haemoglobin concentration remains below the target level (refer to Section 5.1.3)

5.1.3 Administration of Epoetin a. Indications for Epoetin therapy Persistent Hb concentration < 10g/dl after evaluation for other causes of anaemia (Level C) b. Priority for epoietin therapy should be considered for the following: patients preparing for transplantation anephric patients symptomatic anaemia despite Hb above target patients with co-morbidities such as ischaemic heart disease children (Level C) c. Pre-treatment evaluation Clinical evaluation to exclude other causes of anaemia Hypertension should be controlled Assessment of iron status and treatment of iron deficiency prior to initiation of Epoetin to achieve target iron levels (Refer to Section 5.1.4) Ensure dialysis is adequate (Level C)

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d. Initiation of Epoetin i. Dosage Starting dose: iv 4000 units weekly in one or two divided doses (or 50-150 IU/kg/week) Children less than 5 years may require up to 300 units/kg/ week in divided doses (Level B) ii. Method of administration Intravenous injection is the preferred route for administration of Epoetin although subcutaneous administration is more cost effective 3-11 the risk of pure red cell aplasia is higher with this route 12 (Level C) if administered subcutaneously alpha epoetin should not be used (Level C) Insulin syringe (and not tuberculin syringe) should be used to reduce wastage due to dead space when Epoetin is not available in pre-filled syringes IV injection should be delivered perpendicularly to the injection port at the end of dialysis The smallest needle (e.g. gauge 29) should be used to minimise pain with subcutaneous injection Site of subcutaneous injection should be rotated iii. Monitoring during Epoetin therapy Blood pressure Blood pressure should be monitored closely during initiation or increase in dose of Epoetin and antihypertensive medication increased if necessary Dosage interruption should be minimised Hb response Hb level should be checked every 2 weeks at initiation or change in Epoetin dosage until Hb stabilises then every 3 months (Level C) Iron status Serum ferritin, transferrin saturation (serum iron and TIBC) and % hypochromic red cells should be monitored every 3 months. Adequate iron levels should be maintained (refer to Section on 5.1.4) Target haemoglobin Target Hb should be 10 to 12 g/dL (Level A) 13-21 Target rise in Hb is 1 2 g/dl per month and target should be reached within 2 to 4 months

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e. Titration of Epoetin dosage If Hb rise is < 0.5g/dl over 2-4 weeks, Epoetin dose should be increased by 2000 units to 4000 units every 2 to 4 weeks If Hb rise is > 2.5 g/dl per month or Hb exceeds the target, reduce dose of Epoetin by 25 50% (Level C) f. Resistance to Epoetin Resistance to Epo is arbitrarily defined as failure to achieve or maintain target haemoglobin with > 300 units/kg/week (20,000 units/week) subcutaneously In patients with resistance to Epoetin, the following conditions should be evaluated and treated: iron deficiency (absolute or functional) is the most common reason for resistance to Epoetin chronic blood loss inflammation e.g. chronic allograft rejection, SLE, rheumatoid arthritis infections e.g. tuberculosis, access infection, AIDS malignancies inadequate dialysis drugs e.g. ACE inhibitors aluminium toxicity hyperparathyroidism haemoglobinopathies e.g. thalassemias folate or Vit B12 deficiency bone marrow disorders e.g. mutiple myeloma, myelofibrosis, myelodysplastic syndrome, pure red cell aplasia haemolysis hypothyroidism g. Side effects of Epoetin include: hypertension access thrombosis Except for fits due to hypertensive encephalopathy, there has been no evidence of increased risk of seizures. History of seizure is not a contraindication to Epoetin therapy.

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5.1.4 Iron supplementation a. Iron supplementation should be given to: achieve and maintain Hb > 10g/dl achieve and maintain adequate iron stores (refer to Section 5.1.6) (Level A) b. Route of administration Oral iron It is reasonable to start with oral supplementation: At least 100mg to 200mg (2 3mg/kg for paediatric patients) of elemental oral iron daily should be given Oral iron should not be taken with food and other medications particularly phosphate binders Oral iron is often insufficient to maintain target haemoglobin and iron levels in haemodialysis patients especially those receiving erythropoietin (Level B) 22-27 Intravenous iron Intravenous iron has been shown to improve haemoglobin levels and reduce requirement for Epoetin in patients with and without iron deficiency 28-34( Level A) Intramuscular iron injection is not recommended due to the risk of haematoma. Oral iron should be stopped in patients who require maintenance intravenous iron. 5.1.5 Administration of intravenous iron a. Resuscitation equipment should be available during administration of iv iron b. Patients receiving iv iron for the first time should receive a 25mg test dose c. Method of administration Iron dextran should be given by iv infusion over 1 hour Iron sucrose may be given by iv slow bolus (20mg/min) or by infusion d. Suggested iv iron schedule Haemodialysis patients: Absolute iron deficiency : 100mg iron dextran or 100mg iron sucrose every HD session for 10 sessions then check iron status no earlier than 7 days Functional iron deficiency : iv iron dextran 100mg every week for 10 weeks Maintenance: 25mg to 100mg per week

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CAPD patients: 200mg to 500mg of iron dextran infused in 250mls saline over 1-2 hours or iron sucrose 200 to 500 mg in 100 to 500 ml saline over 1 to 4 hours The manufacturers recommended maximum single dose is 1000mg of iron dextran and 500mg of iron sucrose 5.1.6 Assessment of iron status a. Indices of iron status There has been no single measure of iron which accurately indicate the patients iron status 21. The best available tests are serum ferritin, % hypochromic red cells and transferrin saturation: Serum ferritin reflects iron stores serum ferritin should be interpreted with care in the presence of infection, inflammation or hepatitis and 1 2 weeks following blood transfusion or adminstration of intravenous iron Transferrin saturation (TSAT) reflects availability of iron ratio of serum iron to total iron binding capacity multiplied by 100 Percentage of hypochromic red cells also reflects availability of iron red cells with Hb concentration < 28g/dl or Hb < 26pg b. Definitions of iron deficiency absolute iron deficiency : serum ferritin < 100 ng/ml functional iron deficiency : serum ferritin > 100 ng/ml and TSAT < 20% or % hypochromic rbc >10% c. Iron targets Table 5.1 Target iron measurements Test Minimum target Serum ferritin TSAT % hypochromic red cells > 100 ng/ml > 20% < 10%

Optimal target 200-500 ng/ml 30-40%

Maximum level > 800 ng/ml > 50% < 2.5%

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References
1. 2. 3. European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Guideline 2: Evaluation of anaemia in uraemic patients in. Nephro Dial Transplant 1999:14(Suppl 5):6-7 NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 2001; 37 Suppl 1:S182-S236 Kaufman JS, Reda DJ, Fye CL, Goldfarb DS, Henderson WG, Kleinman JG, Vaamonde CA. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med 1998; 339(9):578-83 Virot JS, Janin G, Guillaumie J, Michel P, Dubot P, Chevet D, Rifle G. Must erythropoietin be injected by the subcutaneous route for every hemodialyzed patient? Am J Kidney Dis 1996; 28(3):400-8 Taylor JE, Belch JJ, Fleming LW, Mactier RA, Henderson IS, Stewart WK. Erythropoietin response and route of administration. Clin Nephrol 1994;41(5):297-302 European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Guideline 9: Route of administration of epoetin. Nephrol Dial Transplant 1999;14 Suppl 5:19-20 Schaller R, Sperschneider H, Thieler H, Dutz W, Hans S, Voigt D, Marx M, Engelmann J, Schoter KH, Scigalla P, et al. Differences in intravenous and subcutaneous application of recombinant human erythropoietin: a multicenter trial. Artif Organs 1994;18(8):552-8 Muirhead N, Churchill DN, Goldstein M, Nadler SP, Posen G, Wong C, Slaughter D, Laplante P. Comparison of subcutaneous and intravenous recombinant human erythropoietin for anemia in hemodialysis patients with significant comorbid disease. Am J Nephrol 1992;12(5):303-10 Paganini EP, Eschbach JW, Lazarus JM,Van Stone JC, Gimenez LF, Graber SE, Egrie JC, Okamoto DM, Goodkin DA. Intravenous versus subcutaneous dosing of epoetin alfa in hemodialysis patients. Am J Kidney Dis 1995;26(2):331-40 De Schoenmakere G, Lameire N, Dhondt A, Van Loo A, Van der Goten J, Duym P, Vanholder R. The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration (i.v. or s.c.). Nephrol Dial Transplant 1998;13(7):1770-5 Jensen JD, Madsen JK, Jensen LW. Comparison of dose requirement, serum erythropoietin and blood pressure following intravenous and subcutaneous erythropoietin treatment of dialysis patients. IV and SC erythropoietin. Eur J Clin Pharmacol 1996;50(3):171-7 Casadevall N et al. Pure red-cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Eng J Med 2002;346(7):46975 European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Target Guideline 5: Target haemoglobin concentration for the treatment of the anaemia of chronic renal failure. Nephro Dial Transplant 1999:14(Suppl 5):11-13 Locatelli F, Conte F, Marcelli D. The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity the experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 1998;13:1642-4 Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low

4. 5. 6. 7.

8.

9. 10.

11.

12. 13.

14.

15.

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16. 17. 18. 19. 20.

21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998 Aug 27;339(9):584-90 Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 1999;10(3):610-9 Madore F, Lowrie EG, Brugnara C, Lew NL, Lazarus JM, Bridges K, Owen WF. Anemia in hemodialysis patients: variables affecting this outcome predictor. J Am Soc Nephrol 1997;8(12):1921-9 Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 1999;10(6):1309-16 Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ 1990;300(6724):573-8 McMahon LP, Johns JA, McKenzie A, Austin M, Fowler R, Dawborn JK. Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin. Nephrol Dial Transplant 1992;7(12):1199-206 McMahon LP, Dawborn JK. Subjective quality of life assessment in hemodialysis patients at different levels of hemoglobin following use of recombinant human erythropoietin. AmJ Nephrol 1992;12(3):162-9 Fishbane S, Maesaka JK. Iron management in end-stage renal disease. Am J Kidney Dis 1997;29(3):319-33 Kooistra MP, van Es A, Struyvenberg A, Marx JJ. Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin. Br J Haematol 1991;79(4):634-9 Dunea G, Swagel MA, Bodiwala U, Arruda JA. Intra-dialytic oral iron therapy. Int J Artif Organs 1994;17(5):261-4 Wingard RL, Parker RA, Ismail N, Hakim RM. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin. Am J Kidney Dis 1995;25(3):433-9 Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995;26(1):41-6 Anastassiades EG, Howarth D, Howarth J, Shanks D, Waters HM, Hyde K, Geary CG, Yin JA, Gokal R. Monitoring of iron requirements in renal patients on erythropoietin. Nephrol Dial Transplant 1993;8(9):846-53 Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995;26(1):41-6 Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 1996;50(5):1694-29. Sunder-Plassmann G, Horl WH. Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant 1995; 10(11):2070-6 Sepandj F, Jindal K, West M, Hirsch D. Economic appraisal of maintenance parenteral iron administration in treatment of anaemia in chronic haemodialysis patients. Nephrol Dial Transplant 1996;11(2):319-22 Silverberg DS, Blum M, Peer G, Kaplan E, Iaina A. Intravenous ferric saccharate as an iron supplement in dialysis patients. Nephron 1996;72(3):413-7 Taylor JE, Peat N, Porter C, Morgan AG. Regular low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients. Nephrol Dial Transplant 1996;11(6):1079-83 Allegra V et al. Iron deficiency in maintenance hemodialysis patients: assessment of diagnosis criteria and of three different iron treatments. Nephron 1991;57(2):175-82

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5.2 BONE DISEASE With the prolongation of life by dialysis the morbidity associated with renal bone disease will assume greater significance. 5.2.1 Categories of bone disease Bone disease in the patient with ESRD falls into three categories: High turnover bone disease (HTBD): Secondary or tertiary hyperparathyroidism Low turnover bone disease: Osteomalacia and adynamic bone disease Mixed Bone Disease 5.2.2 Objectives of treatment a. To maintain serum calcium and phosphate levels as near normal as possible Target range of serum phosphate in dialysis patients should be 0.8-1.6 mmol/l (K/DOQI 1.13-1.78 mmol/l ; EBPG 0.81.8mmol/l) Target range of serum calcium in dialysis patients should be 2.2-2.6 mmol/l (K/DOQI 2.1-2.37 mmol/l) The calcium x phosphate product should be < 4.5 1,2(K/DOQI & EBPG < 55mg2/dl2 = 4.4 mmol2 /l2).Higher values have been shown to increase cardiovascular morbidity and mortality (Level B) b. To prevent or suppress the development of parathyroid hyperplasia c. To prevent and reverse the development of extra skeletal calcification d. To prevent or reverse the accumulation of aluminium in bone e. To reduce cardiovascular risk 5.2.3 Diagnosis of renal bone disease a. Intact parathyoid hormone (iPTH) assay -measures both the mid region and N-terminal fragments of the parathyroid hormone molecule. It should be carried out at least twice a year. For selected patients treated with DFO/pulse calcitriol/low calcium dialysate iPTH should be measured 3 monthly. The cold chain must be maintained for iPTH sampling from point of blood taking right up to the lab. 3 b. Serum calcium/phosphate/albumin should be done every 3 months but more frequently if receiving high dose phosphate binders/high dose calcitriol/low calcium dialysate. 4

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c. Serum alkaline phosphatase may not reflect bone turnover status; however increasing levels may correlate with HTBD, thus should be measured 3 monthly. 5 (Level B) d. Serum aluminium should be screened yearly in high risk patients eg. home HD/patients on long-term aluminium exposure. If the aluminium level is above 30ug/l on a repeat test (and serum ferritin is above100ng/ml) a desferrioxamine test should be done.6 (Level B) e. Desferrioxamine (DFO) test should be done if the above criteria are met (refer to Section 5.3) The test is positive if the increase in serum Al level is above 50 ug/l. 7 (Level B) f. X-ray of hands and lumbar spine - the characteristic finding in osteitis fibrosa is bone loss (resorption) in the subperiosteal area, best seen on the radial side of the second and third phalanges. When severe, associated erosion of the tuft of the distal phalanges leads to blunting of the fingertips. g. Bone biopsy is desirable but this test is presently not available locally. 8 h. Ultrasound of the parathyroid glands may be done with a high resolution transducer (7.5MHz) in severe hyperparathyroidism or for patients planned for parathyroidectomy. 9 (Level C) i. Additional imaging techniques (CT neck and thorax, Thallium subtraction scan, MR scan, MIBI scan) may be required to look for ectopic parathyroid glands and in cases of recurrent hyperparathyroidism. 10 (Level B) 5.2.4 Medical treatment for secondary hyperparathyroidism a. Control of hyperphosphataemia A multidisciplinary approach is required to counsel patients regarding a low phosphate diet (reduce dietary PO4 to 0.81.2g/day) Check compliance with PO4 binders (should be taken crushed or chewed with meals and titrated to the amount of food eaten) Calcium carbonate and calcium acetate are the preferred PO4 binders (total daily amount of 6 gram should probably not be exceeded) 11 (K/DOQI 1.5g elemental Ca) Aluminium hydroxide should not be used. However if unavoidable should not exceed 2-3 gm/day and used for the shortest possible duration only (4 weeks) Increase PO4 clearance in dialysis by increasing dialysis frequency if feasible 12 (Level B) Also use high efficiency dialysers 13 and ensure adequate dialysis - 39 -

b. Calcium control Maintain target with calcium supplements (refer 5.2.2) If hypercalcaemia develops reduce or withdraw calcium supplements and/or calcitriol Care should be exercised when using low calcium dialysate especially in cardiac patients and ensure hypocalcaemia does not subsequently develop to cause ventricular arrythmias or rebound increase in PTH 14-16 (Level B) c. Vitamin D3 The aim is to keep serum PTH at 100-200 pg/ml (i.e. 2-3 times above the normal range) 17, 18 (Level B) (DOQI 150-300 pg/ml) Starting dose of calcitriol is 0.25-0.5 ug/dialysis thrice weekly and increased every month up to 2-4 ug/dialysis, monitoring iPTH and other parameters to exclude hypercalcaemia, hyperphosphataemia and refractory hyperparathyroidism 17 If PO4 is above 1.5 or Ca X PO4 product is more than 4.5, Vit D3 should not be started. Patients already on Vit D3 should have the dose adjusted or stopped if Ca x PO4 > 4.5 IV calcitriol is required only in the non-compliant patient or if hypercalcaemia develops with oral calcitriol as there is no good evidence to support IV over oral in the treatment of severe hyperparathyroidism 19 (Level B) Newer Vitamin D analogues may be considered 20 d. Other drugs Calcium acetate , non-hypercalcaemic Vitamin D analogues, second generation PO4 binders (Sevelamer,Lanthanum) and calcimimetics may be added to our armamentarium in the management of calcium and phosphate and PTH in the future21, 22 5.2.5 Parathyroidectomy a. Indications: Calcific uraemic arteriolopathy (calciphylaxis) 23 Therapy resistant hyperCa and hyperPO4 in the presence of very high PTH levels (> 800 pg/ml) 24 Failure to reduce PTH levels after adequate trial of high dose calcitriol 24 Intractable pruritus Progressive extraskeletal calcification that is associated with Ca PO4 product of more than 5 Severe and progressive skeletal pain or fractures

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b. DFO test should be done to exclude aluminium bone disease and treated if positive prior to parathyroidectomy c. The preferred procedure is currently not established. In patients on the waiting list for transplant, total parathyroidectomy without autoimplantation is contraindicated in the opinion of most experts24. (Level C) d. To avoid 'hungry bone syndrome' (post-op hypocalcaemia) in patients with severe osteitis fibrosa, IV calcitriol may be required before and after surgery and Pamidronate may be needed to control calcium to allow for more intensive calcitriol use 5.2.6 Preparation for Parathyroidectomy a. Ensure patient is well dialysed (see Section 10) b. Ensure DFO is negative (see Section 5.3) e. Administer IV Calcitriol 2 ug at the end of each HD treatment, or oral calcitriol 2-6 ug daily beginning 3 to 5 days prior to surgery and continuing postoperatively to prevent hungry bone syndrome 25 (Level C). f. Some authors also suggest starting oral calcium 2 to 3 grams per day 2 days prior to surgery, even in patients who are hypercalcaemic 26 (Level C) g. The patients at highest risk of hungry bone syndrome are those with the most severe hyperparathyroidism, very high preoperative alkaline phosphatase levels, those patients not well dialysed with high preoperative BUN, and the elderly 27 2. A few case reports have suggested a possible role for the preoperative administration of bisphosphonates as a means to prevent the hungry bone syndrome. 28,29 However there is not enough evidence to justify the use of bisphosphonates routinely prior to parathyroidectomy. If bisphosphonate is indicated, then IV pamidronate infusion 60 mg should be given 2 weeks before surgery.

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References
Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium-phosphate product with mortality risk in chronic haemodialysis patients: a national study. Am. J Kidney Dis 1998;4:607-617 2. Ferreira MA. Diagnosis of renal osteodystrophy: when and how to use biochemical markers and non-invasive methods; when bone biopsy is needed. Nephrol Dial Transplant 2000;15(Suppl 5):8-143.opez J. 3. Qi Q, Monier-Faugere MC, Geng Z, Malluche HH. Predictive value of Serum PTH levels for Bone Turnover in Patients on Chronic Maintenance Dialysis. Am. J Kidney Disease 1995;4:622-631 4. Ferreira A. Biochemical markers of bone turnover in the diagnosis of renal osteodystrophy: what do we have, what do we need? Nephrol Dial Transplant 1998;13(Suppl 3):29-32 5. Cannata-Andia JB. Pathogenesis, prevention and management of low-bone turnover. Nephrol Dial Transplant 2000:15 (Suppl5):15-17 6. DeBroe ME et al. New insights and strategies in the diagnosis and treatment of aluminium overload in dialysis patients. Nephrol Dial Transplant 1993;8(Suppl1):47-50 7. D'Haese et al. Use of the low-dose desferrioxamine test to diagnose and differentiate between patients with aluminium-related bone disease, increased risk for aluminium toxicity, or aluminium overload. Nephrol Dial Transplant 1995;10:1784-1884 8. Ferreira MA. Diagnosis of renal osteodystrophy: when and how to use biochemical markers and non-invasive methods; when bone biopsy is needed Nephrol Dial Transplant 2000 15(Suppl5):8-14 9. Coakley AJ. Parathyroid Imaging. Nucl Med Commun 1995: 16 522-533 10. Torregrosa JV, Palomar MR, Pons F, Sabater L, Gilabert R, Llovera J, Fernandez- Cruz L. Has double-phase MIBI scintigraphy usefulness in the diagnosis of hyperparathyroidism? Nephrol Dial Transplant (1998) 13 (Suppl 3) 37-4 11. Drueke TB.Renal Osteodystrophy: management of hyperphosphataemia. Nephrol Dial Transplant (2000) 15 (Suppl 5) 32-33 12. Mucsi I, Hercz G, Uldall R, Ouwendyk M, Francoeur R, Pierratos A. Control of serum phosphate without any phosphate binders in patients treated with nocturnal haemodialysis. Kidney Int 53 (1998) 1399-1404 13. Chauveau P, Poignet JL, Kuno T, Bonete R, Kerembrun A et al. Phosphate removal rate: A comparative study of five high-flux dialysers. Nephrol Dial Transplant 1991;2(Suppl) 114-115. 14. Ritz E, Passlick-Deetjen J, Lippert J. What is the appropriate dialysate calcium concentration for the dialysis patient? Nephrol Dial Transplant (1996) 11 (Suppl 3): 91-95 15. Argiles A, Kerr PG, Canaud B, Flavier JL, Mion C. Calcium kinetics and the long-term effects of lowewring dialysate calcium concentration. Kidney Int 1993:43; 630-640 16. Nappi SE, Vittanen VK, Saha HT, Mustonen JT, Pasternack AI. QTc dispersion increases during haemodialysis with low -calcium dialysate. Kidney Int 57 (2000) 2117-2122 17. Schomig M, Ritz E. Management of disturbed calcium metabolism in uraemic patients: use of vitamin D metabolites. Nephrol Dial Transplant (2000): 15 (Suppl5): 18-24

1.

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between Intact PTH 1-84 and Bone Histomorphometric Parameters in Dialysis Patients Without Aluminium Toxicity. Am J Kidney Dis1995; 26; 836-844 19. Quarles LD, Yohay DA, Carroll BA, Spritzer CE, Minda SA, Bartholomay D, Lobaugh BA. Prospective trial of pulse oral versus intravenous calcitriol treatment of hyperparathyroidism in ESRD Kidney Int 1994;45;1710-1721 20. Brown AJ, Dusso A et al. Selective vitamin D analogs and their therapeutic applications Semin in Nephrol. 1994 14 (2) 156-174 21. Chertow GM, et al. Long term effects of sevalamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 1999;14:2907-14 22. Schomig M, Ritz E. Management of disturbed calcium metabolism in uraemic patients: 3. Potential perspectives-calcimimetics Nephrol Dial Transsplant 2000;15 (Suppl 5):30-31 23. Llach F. Calcific uraemic arteriolopathy (calciphylaxis): An evolving entity? Am J Kidney Dis 1998 32:514-518 24. Schomig M, Ritz E. Management of disturbed calcium metabolism in uraemic patients: Indications for parathyroidectomy. Nephrol Dial Transplant (2000):15(Suppl5) 25-29 25. Shinoda T, Aizawa T, Shirota T, et al. Hypocalcaemia after parathyroidectomy in a long-term haemodialysis patient. Nephron 1992;60:482 26. Cruz DN, Perazella MA. Biochemical aberrations in a dialysis patient following parathyroidectomy. Am J Kidney Dis 1997;29:759 27. Brasier AR, Nussbaum SR. Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. Am J Med 1998; 84:654 28. Shpitz B, Korzets Z, Dinbar A et al. Immediate postoperative management of parathyroidectomised haemodialysis patients. Dial Transplant 1986;15:507 29. Llach F. Parathyroidectomy in chronic renal failure:Indications, surgical approach ant the use of calcitriol, bisphosphonates. Kidney Int Suppl 1990;29:S62

18. Wang M. Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y. Relationship

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5.3 ALUMINIUM TOXICITY Aluminium (Al) toxicity is becoming less common now with the use of reverse osmosis for treatment of dialysate water and decline in use of Al-based phosphate binders. Nevertheless it may still occur as Al is present in many substances including medications. 5.3.1 Sources of Aluminium drinking water pickled foods beer baking powder frozen food water for HD (e.g. home/school/office HD) processed cheese commercial tea/coffee Al-based phosphate binders Gelusil, Sucralfate IV albumin Note : Citrate (e.g. fruit juices, Shohls solution, Mist. potassium citrate) increases Al absorption from food Although Al level in water is very low, continued exposure over a prolonged period of time leads to significant accumulation. As the kidney fails, it is no longer capable of excreting absorbed Al efficiently. 5.3.2 Consequences of Al overload Bone disease Encephalopathy Iron & Epoetin resistant anaemia 5.3.3 Screening (see Fig. 5.1) a. Serum Al screening Serum Al screening (with serum ferritin) should be done yearly in the following selected cases 1,2 (Level C): home/office/school dialysis long-term aluminum hydroxide treatment history of Al toxicity If the level is above 30ug/l, repeat the test one month later. (Level C). If repeated level is also > 30ug/l & serum ferritin is >100ng/ml, proceed to desferrioxamine (DFO) test 1,2 (Level B) b. Serum Al sampling technique

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Sample collection containers and caps should be made of colourless plastic, and must be subjected to a special acidsoaking and ionised-water rinsing process before being sterilized Blood should be collected from the venous line by dripping directly into the specimen bottle. Heparinise the venous line only after sample collection. This procedure is recommended to avoid contamination of the sample as plastic syringes without rubber plunger is not available. 5 to 7 mls of nonheparinized blood is required for each sample. For HD patients, draw blood from the arterial needle line without pre-filling with heparin saline or normal saline. The specimen should be sent to the lab as soon as possible to avoid contamination Al assays should be sent to reliable labs that have facilities for Flameless Atomic Absorption Spectrophotometry. 1 (Level C) 5.3.4 Desferrioxamine (DFO) test a. Indications for low dose DFO test: i. Diagnosis of Al overload in patients: planned for parathyroidectomy (Level C) with se. Al >30ug/l on 2 successive occasions & serum ferritin >100ng/ml & iPTH <650pg/ml, or se. Al <30ug/l but se. ferritin >800ng/ml 1 suspected of Al toxicity ( Level C) ii. Assessment of adequacy of DFO treatment b. DFO test procedure Withold Al-containing medications for at least 48 hours before test 2,3 (Level C) Positive DFO is defined as rise in (delta) Aluminum > 50 ug/l. i. Procedure in Hemodialysis patients A baseline serum Al level is obtained before a HD session. 5 mg/kg DFO* in 150 ml of 5% dextrose is infused into the venous blood line during the last hour of the same HD session Just before the start of the next HD session (44 h after DFO administration), a 2nd serum Al level is obtained * Vital signs should be closely monitored during DFO infusion. 1,6 (Level B)

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ii. Procedure in Peritoneal dialysis patients A baseline serum Al is measured at any time of the day 5 mg/kg DFO in 150 ml of 5% dextrose is given intravenously during the last 60 mins of a CAPD exchange. Alternatively, 5 mg/kg DFO is added to the nocturnal exchange for CAPD patients or the long daytime exchange for CCPD patients. A 2nd serum Al level is obtained 44h after termination of the DFO infusion or the DFO-containing exchange. * Vital signs should be closely monitored during DFO infusion. 1,6 (Level B) 5.3.5 Bone biopsy Bone biopsy with tetracycline labeling is the gold standard for diagnosing aluminium-related bone disease but this test is not presently available locally. 5.3.6 Prevention a. Use reverse osmosis for water treatment b. Monitor dialysate water Al level 6-monthly 1,8. Al level in treated water should be kept <5g/l (AAMI standard) c. Monitor serum Al levels yearly in selected patients (see Section 5.3.3a) d. Avoid foods with high Al content. Patients on aluminium tablets should avoid concomitant citrate ingestion 1 e. Avoid Al-based phosphate binders if possible. They may be used temporarily for 4-8 weeks if: serum phosphate is very high despite high dose CaCO3 high serum calcium despite low-calcium dialysate precludes use of CaCO3 Maximum allowable daily dose of Alutab is 2-3g (6 tablets) (Level C)

Conversion factor for serum aluminium : 1 umol/l = 26.95 ug/l - 46 -

5.3.7 Desferrioxamine treatment 1,8 a. Indications for DFO treatment 1: i. Biopsy-proven aluminium related bone disease (ARBD) ii. DFO-test positive with clinical evidence of Al toxicity iii. DFO-test positive without clinical evidence of Al toxicity in high risk patients iv. DFO-test positive & patient planned for parathyroidectomy b. Administration of DFO i. Ear & eye review should be documented before start of treatment ii. Dose = 5mg/kg weekly for 3 months iii. Infuse over 1 hour (at a rate not exceeding 1g/hour): during the last hour of HD if post-DFO serum Al<300ug/l or 4 hours before HD if post-DFO serum Al >300ug/l iv. To enhance removal of DFO-Al chelate, high-flux membranes (e.g. F60, F80, polyflux), or Alukart cartridges should be used during the HD session after each dose of DFO. 9 v. Repeat DFO test 1 month after completing treatment if repeat DFO-test is negative, stop DFO treatment and monitor serum Al level if repeat DFO-test is positive, give 2nd course of DFO treatment 1 (Level C) c. Side effects of DFO treatment: i. Acute aluminium encephalopathy To avoid this, DFO is given 4 hours before HD if patients post-DFO SAl is above 300 ugl/l ii. Hypotension Treat by temporarily stopping the infusion and giving a volume expander if needed. However, if hypotension is very severe and fails to respond to above measures or other signs of anaphylaxis/allergy e.g. wheezing, angioedema, rash is present, inform the doctor and consider s.c.adrenaline 1mg. iii. Allergic reaction (rash, anaphylaxis) iv. Infections (Yersinia, Mucormycosis) v. Deafness vi. Cataract, retinopathy vii. Arrhythmia viii. Gastrointestinal disturbances

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Fig 5.1 Strategy for monitoring & diagnosis of aluminium related bone disease 10

DFO- test + treatment before PTX or high dose Vit D

DFO- treatment before PTX or high dose Vit D

PTX: parathyroidectomy SAI: serum aluminium

Conversion factor for serum aluminium : 1 umol/l = 26.95 ug/l - 48 -

Fig 5.2 Strategy for low dose DFO treatment

10

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Table 5.1 Aluminium content in drugs & solutions Drug Dried gel Amphogel Maalox Alutab Alucap Sucralfate Solution Sodium chloride Dextrose 5% TPN solution (amino acids) 25% albumin Calcium gluconate Stated Al 5 mg 320mg/5ml 225mg/5ml 600mg/tab 475mg/tab 1g Calculated Al 0.35 mg 112mg/5ml 78mg/5ml 210mg 166mg 207mg Measured Al 0.347 mg 106mg/5ml 60mg/5ml 174mg 111mg Al (mg/l) 6 72 72 1822 5

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. DHaese PC et al. NDT (1996) 11 [Suppl 3]: 74-79 Kausz AT et al. AJKD Vol 34, No 4 (Oct 1999): 688-693 Ostric V et al. JASN 1994 Vol 5: 469 Andia JBC. NDT (1996) 11 [Suppl 3]: 69-73 Pei Y et al. KI Vol 41 (1992): 1374-1382 DHaese PC et al. NDT (1995) 10: 1874-1884 Barata JD et al. NDT 1996 Fernandez-Martin JL et al. NDT (1998) 13 [Suppl 3]: 78-81 Vasilakakis DM et al. KI 1992 Vol 41: 1400-1407 Daugirdas : Handbook of dialysis, 3rd Ed.

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5.4 Dialysis-related Amyloidosis 5.4.1 Introduction a. Beta-2-microglobulin amyloidosis (2 M), is a unique type of amyloidosis affecting patients with renal failure, either before or during dialysis. b. This condition is defined as a disabling disease in which the accumulation of amyloid fibrils consisting of 2 M deposits lead to bone and joint destruction. c. A variety of osteoarticular complications have been associated with 2 M amyloid deposition in patients on long-term dialysis including: carpal tunnel syndrome (CTS), chronic arthropathy, cystic bone lesions, subchondral bone cysts and/or articular erosions are a pathognomonic finding of dialysis related amyloid (DRA). These changes are not true cysts, but rather eroded cavities. destructive spondyloarthropathy pathologic fractures 5.4.2 Risk factors for Dialysis-related Amyloidosis a. more than 40 years of age at the onset of dialysis therapy b. those treated with bioincompatible dialysis membranes c. on dialysis for > 10 years d. the degree of bacteriologic quality of the dialysis fluid may also play a role, possibly by endotoxin contamination of dialysate e. metabolic acidosis may stimulate 2 M production 5.4.3 Prevention & Management a. Successful kidney transplantation normalizes plasma 2 M levels, may prevent disease progression and can alleviate symptoms b. Convective treatments were associated with reduced DRA morbidity and postponed the need for carpal tunnel syndrome surgery compared to diffusive treatments. The following membrane properties are particularly important with regard to 2 M accumulation: Highly permeable membranes provide better 2 M clearance Adsorptive capacity. Membrane adsorption appears to an important mechanism of 2 M removal Biocompatibility membrane-induced cell activation with subsequently generated proinflammatory mediators has been incriminated in the stimulation of 2 M synthesis and in contributing to the formation of amyloid deposits and joint lesions

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6. MANAGEMENT OF CARDIOVASCULAR RISK FACTORS Cardiovascular events are the major cause of morbidity and mortality in ESRD patients on long term haemodialysis. 1,2,3,4 Various factors exist which increase the risk of ischaemic heart disease, left ventricular hypertrophy and heart failure. These include factors that are not amenable to intervention, as well as those that are treatable and proven effective in the general population. Newer treatable risk factors that are being increasingly recognised in haemodialysis patients should also be targetted even though the effect on survival has not been clearly established. (See table 6.1) Table 6.1 Cardiovascular risk factors in patients on long term haemodialysis Intervention Should be treated Should be is not Intervention is possible considered possible Efficacy Effect on Effect of treatment proven in survival not not proven general proven population Age Hypertension Uraemia Hyperrelated homocysteinemia Gender Diabetes dyslipidemia Hypoalbuminemia mellitus Lipo Increased protein(a) Smoking Hyperserum fibrinogenaemia Physical phosphorus inactivity Raised Advanced Increased Glycation End Hyperserum Ca Products lipidemia PO4 product Increased Uraemic Hyperoxidative stress anaemia volaemia Increased acute phase response 6.1 Hypertension 6.1.1 In the general population, hypertension has been shown to be a major CV risk factor 5,6,7 (Level A). In dialysis patients, hypertension has clearly been shown to be a risk factor for LVH, coronary artery disease and congestive heart failure 8 (Level A). At least 80% of patients have hypertension at the commencement of regular haemodialysis.

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6.1.2 The majority of hypertension in this population is salt and volume dependant 9-13 (Level A).Control can be achieved by adequate dialysis, fluid and salt restriction, achievement and maintenance of dry weight and the addition of antihypertensive medications as necessary. Less than 20 percent of hypertension in haemodialysis patients are renin dependant. These patients may require antihypertensive medications despite adequate dialysis and ultrafiltration. a. Management Thorough history and physical examination is carried out to assess for possible target organ damage (retinopathy, left ventricular hypertrophy, ischaemic heart disease & heart failure). Correct and control the volume status using the following strategies: Achieve target dry weight over 4-6 weeks of starting haemodialysis. Antihypertensive medication is often required at the initiation of haemodialysis until the dry weight is achieved. If the patient is already on antihypertensive medication, subsequent dosage may need to be reduced or stopped depending on the blood pressure response to the dialysis and ultrafiltration. As the blood pressure is expected to decrease with fluid removal on haemodialysis it is generally recommended to omit the predialysis dose of anti hypertensive medication unless indicated. Some drugs are dialysable and dose adjustment may need to be made accordingly. b. Target blood pressure Current target is extrapolated from the general population. The aim is to keep BP < 140/90. There is no consensus on whether target BP is based on pre or post dialysis readings. 14 (Level C) c. Antihypertensive medications The choice of antihypertensive agents should be individualised based on the presence of other comorbidities e.g ischaemic heart disease, heart failure etc. Most of the major classes of antihypertensive medications may be used. Diuretics are not useful as monotherapy in patients with residual renal function and clearly has no role in anuric patients. d. Refractory hypertension or dialysis resistant hypertension refers to the patients at `dry weight requiring at least two antihypertensive medications for control. Management of such patients include: reassess dry weight

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assess drug compliance consider drug effect eg NSAIDs, sympathomimetics, alcohol, erythropoeitin consider other causes (eg native kidneys) 6.1.3 Dry weight Definition : dry weight is the post dialysis weight below which hypotension develops when the patient has no evidence of volume overload ie free of oedema, and normal cardiac size on chest radiograph 15 ( Level C). Maintain dry weight once this is achieved Consider prolonged or more frequent dialysis if adequate BP control is not achieved 16-17( level B). Revise the set dry weight when lean body mass changes. Fluid intake should be controlled to match the urine output and insensible losses. Salt intake must be limited to < 6g daily 18 (level B). Interdialytic weight gain should be < 3% of the set dry weight. 6.2 Hyperlipidemia 6.2.1 Introduction a. In the general population, hyperlipidemia had been clearly shown to be a significant CV risk factor and drug therapy in this population has convincingly shown effective reduction in cardiovascular mortality. 19,20 (Level A) b. A third of patients on haemodialysis have dyslipidemia. Serum cholesterol may be normal but triglyceride, IDL and Lipoprotein(a) are elevated and HDL cholesterol may be reduced . Since haemodiaysis patients constitute a high CV risk group and treatment with lipid lowering drugs have been shown to be safe and effective in reducing hyperlipidemia, serum lipids should be regularly monitored and treated accordingly 1,21-24 6.2.2 Measurement and monitoring 24: Measurement of serum lipid should be made from blood sample taken pre dialysis before heparinisation after a 12 hour fast. Once known and controlled, continue to monitor six monthly. 6.2.3 Treatment 24: a. Treatment is initiated if the concentrations exceed the following: LDL- Chol > 100mg /dl (> 2.6mmol/l) TG > 180 mg/dl (> 2.1mmol/l) HDL -Chol < 40mg/dl (< 1mmol/l) - 54 -

b. Provide counseling on dietary modification including alcohol restriction, optimal weight and physical activity/exercise. If hyperlipidaemia remains consider drug therapy. c. Statins should be used for hypercholesterolemia and combined hyperlipidemia d. In hypertriglyceridaemia use of fibrate (gemfibrozil) is recommended e. Combination therapy is not recommended due to the high risk of rhabdomyolysis f. Liver enzymes should be monitored within six weeks of drug therapy to detect hepatotoxicity and rhabdomyolysis 6.2.4 Target concentration 24: LDL-Cholesterol < 100mg/dl (< 2.6mmol/l) Triglyceride < 180mg/dl (< 2.1mmol/l) 6.3 Anaemia see section 5.1

References 1. 2. 3. 4. 5. 6. 7. 8. 9.
Levey AS, Beto JA, Parfrey PS et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? Am J Kidney Dis 1998;32: 85-906 US Renal Data System. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD. Annual Report. Am J Kidney Dis 1998; 32 [Suppl 1]: S81-88 Raine AEG, Margreiter R, Brunner FP et al. Report on management of renal failure in Europe, XXII, 1991. Nephrol Dial Transplant 1991; 7[ Suppl 2]: 7-35 Parfrey PS etal. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999;10:1606-15 MacMahon S, Peto R, CutlerJ et al Blood pressure, stroke and coronary heart disease. Part 1,prolonged differences in blood pressure: prospective observational studies corrected for the regressioin dilution bias. Lancet 1990;335:765-74 Prospective Studies Collaboration. Cholesterol, diastolic blood pressure and stroke: 13000 strokes in 45,000 people in 45 prospective cohorts. Lancet 1995;346:1647-53 Kannel WB, Castelli WP, McNamara PM et al.Role of blood pressure in the development of congestive heart failure.The Framingham Study. N Eng J Med 1972;287:781-7 Foley RN, Parfrey PS, Harnet JD et al. Impact of hypertension on cardiomyopathy, morbidity and mortality in end stage renal disease. Kidney Int 1996;49:1379-85 Leunissen KML et al. How important is volume excess in the etiology of hypertension in dialysis patients. Semin Dial 1999;12(5):299-301

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B. How important is volume excess in the etiology of hypertension in dialysis patients. Semin Dial 1999;12(5):297-9 11. Ritz E. How Important Is Volume Excess in the Etiology of Hypertension in Dialysis Patients. Semin Dial 1999;12(5):296-7 12. Zuchello PC et al. How important is volume excess in the etiology of hypertension in dialysis patients. Semin Dial 1999;12(5):304-6 13. Fink JC et al. How important is volume excess in the etiology of hypertension in dialysis patients. Semin Dial 1999;12(5):303-4 14. Clinical Algorithms On Cardiovascular Risk factors In Renal Patients.Medical Expert Group. Nephrol Dial Transplant 2000;15[Suppl 5]:134-5 15. Charra B, Laurent G, Chazot C et al. Clinical assessment of dry weight. Nephrol Dial Transplant 1996;11[Suppl 2]:16-9 16. Katzarski KS, Charra B, Luik AJ et al. Fluid state and blood pressure control in patients treated with long and short haemodialysis. Nephrol Dial Transplant 1999; 14: 369-75 17. Raj DS et al. In search of ideal haemodialysis: is prolonged frequent dialysis the answer? Am J Kidney Dis 1999;34:597-610 18. Krautzig S et al. Dietary salt restriction and reduction of dialysate sodium to control hypertension in maintenance haemodialysis patients. Nephrol Dial Transplant 1998;13:552-3 19. Scandinavian Simvastatin Survival Study Group. Randomised Trial of Cholesterol Lowering in 4444 Patients With Coronary Artery Disease: the Scandinavian Simvastatin Survival Study (4s). Lancet 1994;344:1383-9 20. Lowrie EG, Law NL. Commonly measured laboratory variables in haemodialysis patients: relationship among them and to death risk . Semin Nephrol1992;12: 276-83 21. Prichard S. Dyslipidemia as a Risk Factor For Cardiac Disease in Dialysis Patients. Semin Dial 1999;12(2):87-90 22. Wanner C. Importance of hyperlipidemia and therapy in renal patients. Nephrol Dial Transplant 2000;15 [Suppl 5]:92-6 23. Clinical Algorithms On Cardiovascular Risk factors In Renal Patients.Medical Expert Group. Nephrol DialTransplant 2000;15[Suppl 5]:128-9

10. Charra

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7. MANAGEMENT OF THE INFECTIVE PATIENT Due to the nature of haemodialysis treatment and the likelihood of receiving multiple blood transfusions, long term haemodialysis patients have a higher risk of acquiring Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection compared to the normal population. In the past, HBV was the major cause of viral hepatitis in end-stage renal disease. The introduction of rigorous infection-control strategies has led to a decline in the spread of HBV infection in the dialysis units. 1, 2 Hepatitis C infection is now a major problem in the Malaysian haemodialysis scene. In 2000, 29% of patients in the government centres were positive for anti-HCV antibody. The chronically infected person is central to the epidemiology of HCV transmission. 3,5 Studies have indicated that HCV transmission most likely occurs because of breakdown in standard infection control practices. 6, 7 Nosocomial transmission within the dialysis centre is the principal route of HCV dissemination in the dialysis population. 4,8,9 HCV transmission within the dialysis environment can be prevented by strict adherence to infection control precautions. 10 7.1 Measures to reduce risk of transmission of virus or other infectious agents include: 7.1.1 Universal precaution for the care of all haemodialysis patients: a. Wear disposable gloves when caring for the patient or touching the patients equipment at the dialysis station; remove gloves and wash hands between each patient or station b. All machines should be cleaned after each use c. Sharing of ancillary supplies such as tray, BP cuffs, clamps, scissors and other nondisposable items among patients should be discouraged d. Nondisposable items should be cleaned or disinfected appropriately between uses e. Medication and supplies should not be shared among patients and medication carts should not be used f. Medication should be prepared and distributed from a centralised area g. There should be separate clean and contaminated areas (e.g. handling and storage of medication). Hand washing should not be done in or near an area where used equipment or blood samples are handled.

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7.1.2 Serological testing a. HbsAg and anti-HCV antibody should be checked 3 monthly and anti-HIV antibody yearly b. For those with negative HbsAg, negative anti-HCV antibody, repeat serologic tests every 3 months c. In newly infected HBV patient, repeat HbsAg testing and test for anti-HBs six months later to determine clinical outcome d. Patients with chronic HBV infection require annual HBsAg testing to detect the small percentage of those who might lose their HbsAg e. In HbsAg negative patient, vaccination should be given for those with negative anti-HBs antibody status f. Confirmed positive anti-HCV patients do not require repeated serologic test 7.2 Hepatitis B vaccine Larger vaccine doses, an increased number of doses or both may be required to produce protective anti-HBs concentrations in adult haemodialysis patients. For children with progressive chronic renal failure, hepatitis B vaccine is recommended early in the disease course to provide protection and potentially decrease the need for larger doses once dialysis is initiated. Table 7.1 Recommended dosages of hepatitis B vaccines Target Group Recombivax HB Engerix-B Dose, ug (ml) Dose ug, (ml) Infants, children and 5 (0.5) 10 (0.5) adolescents < 20 yrs of age Adults 20 yrs of age or older 10 (1.0) 20 (1.0) Patients undergoing dialysis 20 40 (2.0) and other (1.0ml-special immunocompromised adults formulation for dialysis patients ) 7.2.1 Schedule Dosing schedule for dialysis patients: 4 dose schedule at 0, 1, 2, and 6 to 12 months 7.2.2 Repeat serologic testing Serum anti-HBs-antibody should be checked 1-2 months after completing the vaccination course

Formatted: Ge

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7.2.3 Management of non-responders a. Vaccine recipients who do not develop a serum anti-HBsantibody response (> 10 mIU/ml) after a primary vaccine series should be re-immunised (unless they are confirmed to be HbsAgpositive) b. Re-immunisation consists of 1 to 3 doses. Those who remain antiHBs-negative after a re-immunisation series of 3 doses are unlikely to respond to additional doses of vaccine. 7.2.4 Booster doses a. For haemodialysis patients, the need for booster doses should be assessed by annual anti-HBs testing b. A booster dose should be given if the anti-HBs concentration is less than 10 mIU/ml 7.2.5 Staff of haemodialysis units should be routinely immunised 7.3 Isolation Patients positive for HbsAg or anti-HCV antibody should be dialysed on separate machines not shared by seronegative patients. A separate area is recommended. 11,12 7.4 Management of patients with hepatitis B/C infection Patients positive for HbsAg and/or anti-HCV should be monitored for evidence of chronic liver disease and its complications; 3 monthly LFT, yearly -fetoprotein and liver ultrasound Hepatology referrral for possible interferon (IFN) therapy may be considered in patients who are positive for anti-HCV, persistent ALT elevation and HCV RNA-positive 7.5 Management of patients with HIV infection For anti-HIV positive patients, disposables should not be reused. The disposal of bloodlines and dialysers should be made according to the recommendations of the Ministry of Health. For anti-HIV positive patients who acquire the virus whilst on regular haemodialysis or newly accepted patients for haemodialysis who are asymptomatic, the decision to continue the treatment will be based on similar grounds as those for nonHIV infected patients.

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References
J. Alter. Impact of infection control strategies on the incidence of dialysisassociated hepatitis in the United States. J. Infection Disease (1986) 153: 1549 2. Tokars JI. National surveillance of haemodialysis associated disease in the United States. ASAIO J. (1998) 44:98. 3. Loureiro A. Portuguese Society of Nephrology. Trend in the incidence of hepatitis C infection in haemodialysis unit: J Am Soc Nephrol (abstract 1995) 6: 547. 4. Sampietro M. High prevalence of a rare hepatitis C virus in patients treated in the same hemodialysis unit: Evidence for nosocomial transmission of HCV: Kidney Int (1995) 47:911-7 5. Annmarie W. Epidemiology of hepatitis C: Geographic differences and temporal trends : Seminar in liver disease (2000) 20:1-16. 6. Gill. Multi dose heparin vial, non-A, non-B and anti-HCV antibody in dialysis patients: IJAO (1990) 13: 737 7. Okuda K. Mode of hepatitis C infection not associated with blood transfusion among chronic haemodialysis patients. J. Hepatology (1995) 23: 28 8. H. Taskapan. Patient to patient transmission of Hepatitis C virus in haemodialysis units in Turkey. Clinical Nephrology (2000) 55: 477-481. 9. M Cendorogio. Incidence of and risk factors for hepatitis B virus and hepatitis C virus infection among haemodialysis and CAPD patients: Evidence for environmental transmission. Nephrol Dialysis Transplantation (1995) 10: 240246. 10. Jodoul M. Universal precautions prevent hepatitis C virus transmission. The Universitaies Clinique St-Luc (UCL) Collaborative Group. Kidney Int (1998) 53: 1022-5. 11. dos Santos. Impact of dialysis room and reuse strategies on the incidence of hepatitisC virus in haemodialysis units. Nephrol DialTransplant (1996) 11: 201722. 12. Units. A prospective study. Nephrol Dial Transplant (1995) 10:230-233. 13. Jorge M.Hepatitis C in dialysis and Transplantation. Current opinion in Nephrology and Hypertension (1996) 5:497-503. 14. M. Espinosa. Interferon therapy in haemodialysis patients with chronic hepatitis C virus infection induces a high rate of long-term sustained virological and biological response. Clinical Nephrology. (2000) Vol 55-No:3/2001:220-226.

1.

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8. NUTRITIONAL MANAGEMENT Malnutrition is a well recognised comorbid condition in dialysis patients that contributes to the increased mortality seen in these patients. 8.1Causes of protein energy malnutrition Increased net protein catabolism Anorexia, nausea and vomiting Inter-current illness e.g.infection Increased circulating levels of catabolic hormones e.g. glucagons, PTH Dialytic loss of amino acids and vitamins Intradialytic hypercatabolism dialyser bioincompatability 8.2 Nutritional changes in uraemia a. Protein metabolism Increased degradation of protein and amino acids Increase in non-essential amino acids and decrease in essential amino acids b. Carbohydrate metabolism Impaired glucose tolerance due to: increased peripheral resistance to insulin decreased beta cell sensitivity to glucose levels increased hepatic gluconeogenesis c. Lipid metabolism Moderate increase in triglyceride levels Normal or slight increase in cholesterol 8.3 Evaluation of Nutritional status a. Nutritional status in maintenance dialysis patients should be assessed with a combination of valid, complementary measures rather than any single measure alone b. Nutritional status should be routinely assessed. This may include predialysis serum albumin, body mass index (BMI), subjective global assessment, dietary interview, diaries and protein nitrogen appearance (PNA) c. Serum albumin, creatinine and cholesterol are valid and clinically useful markers of protein energy nutritional status. The following levels suggest protein-energy malnutrition: i. Albumin < 40g/L ii. Creatinine < 880umol/L iii. Cholesterl < 3.8 mmol/L

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d. PNA and protein catabolic rate (PCR) are valid and clinically useful measures of net protein degradation and protein intake in maintenance dialysis patients e. Anthropometric measurements including % usual body weight, % standard body weight, BMI, skinfold thickness, estimated % body fat, mid arm muscle area, circumference or diameter are valid and clinically useful indicators of protein energy nutrition status 8.4 Nutrition in the haemodialysis patient 8.4.1 Carbohydrate intake a. Dialysis improves the abnormalities of glucose metabolism. The insulin requirement of diabetic patients may be reduced on dialysis days due to improvement of the tissue sensitivity to insulin. The response of the diabetic patient to hypoglycaemia is blunted during haemodialysis. These patients should reduce their insulin intake on dialysis days and eat before dialysis. One important aim in supplying adequate calories is to reduce protein breakdown for gluconeogenesis. b. The total daily calorie requirement is about 35 kcal/kg/day. Carbohydrate should consist of more complex carbohydrates to avoid frequent peaks of glycaemia. 8.4.2 Protein intake a. An adequate nitrogen balance is important for patients on dialysis. There is significant correlation between serum albumin and mortality. During hemodialysis, patients lose 1.5 to 3 gram of amino acids per hour of dialysis. The losses are increased when glucose-free dialysate is used. b. It is important that pre-dialysis patients should not be subjected to severe protein restriction that may deplete their protein stores. c. The amount of protein needed for positive nitrogen balance is 1.0 to 1.2g/kg/day. The protein should be derived from animal source and they should account for at least 50% of the total protein intake. 8.4.3 Fat intake a. The lipid abnormalities of patients on chronic haemodialysis have been correlated with cardiovascular mortality. The reason for the abnormalities include: Impaired catabolism of VLDL - retention of a lipoprotein lipase inhibitor dialysate (conversion of acetate to long chain fatty acids and cholesterol)

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b. Lipid intake should be 25% of the total should be in the form of vegetable fats which contains polyunsaturated oils. hyperlipidemia includes the reduction of and reduction in carbohydrates.

energy requirement. It (maize, sunflower oil) Dietary control of intake of saturated fat

8.4.4 Calcium and phosphorus a. Uraemia is associated with accumulation of phosphorus and low calcium level. In haemodialysis the removal of phosphate is less efficient than in CAPD. b. The dietary intake of phosphate should be limited to 800mg to 1200 mg daily c. The serum phosphate should be kept below 1.6 mmol/l d. Patients on dialysis require calcium supplements if they are hypocalcaemic. A total of 1200 mg/day may be needed. Table 8.1 Foods rich in phosphate Liver Nuts and nut products Kidney Legumes e.g. peas, beans Heart Butter/peanut butter Brain Baked beans Canned meat Bean products Sardines Egg yolk Crabs Coconut & all coconut products Prawns Kaya Mussels Dried fruit Scallops Keropok Shellfish Ikan Bilis Mushrooms Cauliflower

Evaporated milk Condensed milk Yoghurt Cheese Cocoa Chocolate Foods with chocolate Instant coffee Horlicks Ovaltine Cereals e.g. oats Wholemeal bread Bovril, Marmite Cola drinks Beer

8.4.5 Vitamins Supplements of water soluble vitamins are recommended as they are lost during dialysis. Vitamin B1 4mg/day Vitamin B6 10mg/day Vitamin C 100 mg/day Folic acid 0.5-1mg/day Iron supplement 200 mg /day

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8.4.6 Sodium and water a. The amount of water allowed varies with residual urine output b. If the patient has residual urine output sodium intake should be restricted to 130-170 mmol/day (3-4 g/day) c. If the patient is anuric sodium intake should be reduced to 40-80 mmol/day (1-2g/day). Interdialytic weight gain should not be > 3% of dry weight. 8.4.6 Potassium Hyperkalemia may result from excessive intake of fruits and vegetables. If the patient is anuric potassium intake should be restricted to 50 mmol/day. Those with adequate urine output require mild dietary restriction. Table 8.2 Foods rich in potassium Pure fruit juices Bran Dried fruit Bran cereal Ribena Muesli Tomato juice Nuts Tomato sauce Peanut butter Vegetables Crisps

Bovril, Marmite Brown sauce Salt substitutes Curry powder Beer, lager, wine

8.5 Management of acid base status Predialysis serum bicarbonate levels should be maintained at or above 22mmol/l and measured regularly 8.6 Nutritional support Individuals on hemodialysis who are unable to meet their protein and energy requirements with food intake for an extended period of time should receive nutritional support. Complete nutritionl assessment should be done and reversible or treatable conditions should be identified. Oral diet may be started , proceeding to tube feeding if unsuccessful. Intradialytic parenteral nutrition or daily total or partial parenteral nutrition should be considered if the former fails. 8.7 Recommended nutritional intake in patients on haemodialysis The nutritional prescription should be individualised and the motivation of the patient plays a vital role in ensuring compliance: a. Dietary protein intake 1.2 g/kg/day b. Total energy intake > 35 kcal/kg/day c. Water and salt as allowed by fluid balance

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d. Potassium 50 mmol/day + 25 mmol/day for each litre of residual urine e. Calcium 1.2 g/day f. Phosphate 0.8-1.2g/day References 1. K/DOQI Clinical Practice Guide for Nutrition in Chronic Renal Failure. 2. Handbook of Dialysis. 3rd Edition. John B. Daugirdas. Todd S.Ing

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9. HAEMODIALYSIS ADEQUACY 9.1 Measurement of Haemodialysis Adequacy 9.1.1 Regular Measurement of the Delivered Dose of Haemodialysis The dialysis care team should routinely measure and monitor the delivered dose of haemodialysis at least 3 monthly 9.1.2 Method of Measurement of Delivered Dose of Haemodialysis The delivered dose of haemodialysis in adult and pediatric patients should be measured using formal urea kinetic modelling (UKM), employing the single pool, variable volume model. Other methods include URR (urea reduction ratio), natural log Kt/V and the Daugirdas second generation formula: a. URR URR = (Co Ct) x 100 Co (Ct = post dialysis BUN, Co = pre dialysis BUN) b. Kt/V natural logarithm formula Kt/V = -Ln(R - 0.008 x t) + (4 3.5 x R) x UF/W c. Formal urea kinetic modelling Formal urea kinetic modeling provides a quantitative method for developing a treatment prescription for a specific patient. Computational software is necessary to compute Kt/V using formal UKM. d. The single pool Kt/V (spKt/V) is a dimensionless ratio representing fractional urea clearance. K is the dialysis blood water urea clearance (L per hour), t is dialysis session length (hours, hr), and V is the distribution volume of urea (liters, L). If we deliver an spKt/V of 1.0, this implies that K x t, or the total volume of blood cleared during the dialysis session, is equal to V, the urea distribution volume. e. Formal UKM requires accurate measures of: predialysis and post dialysis blood urea for the second dialysis treatment of the week in a thrice weekly haemodialysis schedule. predialysis and postdialysis weights at the time of the second haemodialysis treatment of the week. f. The actual treatment time, i.e. the exact number of minutes during which the haemodialysis treatment was delivered on the second dialysis treatment of the week (not the prescribed length of treatment time or the time elapsed between putting the patient on the machine and taking him or her off).

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g. Changes in the dialysis treatment time, choice of dialysers, or operating conditions such as blood and dialysate flows can be calculated to meet the selected prescription goal. h. Formal UKM permits calculation of the normalized protein catabolic rate (nPCR). The volume of distribution term may be used to calculate the nPCR as follows: nPCR (g/kg/day) = (PCR, g/day)x (mean V/0.58) i. Use of the nPCR enables the dialysis team to perform longitudinal analysis of the patients nutritional status. The nPCR can be used to identify patients who might benefit from counseling about their dietary protein intake. Furthermore, it can be used to determine whether the haemodialysis dose needs to be increased because of sustained high protein intake. 9.1.3 Uniformity of Method of Measurement All patients receiving haemodialysis in the same dialysis facility should have the delivered dose of haemodialysis measured using the same method. (Level C) 9.2 Haemodialysis Dose 9.2.1 Minimum Delivered Dose of Haemodialysis (Adults Level B) The dialysis team should deliver a Kt/V of at least 1.2 (single pool, variable volume) for both adult and pediatric haemodialysis patients. For those using the URR, the delivered dose should be equivalent to a Kt/V of 1.2, i.e. an average URR of 65%. The HEMO study did not show major benefit from higher dialysis dose (Kt/V 1.7) over current recommended guidelines. (Level A) 9.2.2 Prescribed Dose of Haemodialysis To prevent the delivered dose of haemodialysis from falling below the recommended minimum dose, the prescribed dose of haemodialysis should be Kt/V 1.3. In terms of URR, a Kt/V of 1.3 corresponds to an average URR of 70%, but the URR corresponding to a Kt/V of 1.3 can vary substantially as a function of ultrafiltration. (Level C) 9.2.3 Discrepancies in Kt/V Formal UKM provides a mechanism to check for errors in the delivered dose of haemodialysis. By comparison, the value of V derived from patients anthropometric features is only an estimate of urea distribution volume based on body composition analysis.

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Reasons for discrepancies between the kinetically derived and anthropometric distribution volume (v) a. Kinetically Derived V Larger Than Anthropometric V Low blood flow from the access Inadequate dialysis performance Dialysate flows less than prescribed Dialysis machine programmed incorrectly Premature completion of treatment Pre-Dialysis BUN sample drawn after initiation of haemodialysis b. Kinetically Derived V Smaller Than Anthropometric V Post-dialysis BUN sample drawn from the venous blood line Post-dialysis BUN sample drawn in the setting of significant fistula recirculation Post-dialysis BUN sample drawn following a very efficient haemodialysis in a patient with a small V (high K/V) Post-dialysis BUN sample inadvertently diluted with saline 9.2.4 Reasons for Underdelivery of Prescribed Dose of Haemodialysis a. Compromised Urea Clearance Access recirculation Inadequate blood flow from the vascular access Inaccurate estimation of dialysis performance Inadequate dialysis reprocessing Dialyser clotting during dialysis Blood pump/dialysate flow calibration errors Errors in prescribed blood and dialysate flow rates due to variability in blood pump tubing Dialysate flow rate that is inappropriately set too low Dialysate flow miscalibration Dialysis leaks b. Reductions in Treatment Time Incorrect assumption of continuous treatment time because of failure to account for interruptions. Premature discontinuation of haemodialysis for staff or unit convenience Premature discontinuation of haemodialysis to honour patient request or adherence. Delay in starting dialysis session due to patient tardiness Time on dialysis calculated incorrectly

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c. Laboratory or Blood Sampling Errors Dilution of pre-dialysis BUN blood sample with saline Pre-dialysis BUN blood sample drawn after the start of dialysis Post-dialysis BUN blood sample drawn before the end of dialysis Laboratory error due to calibration or equipment problems Post-dialysis BUN blood sample drawn more than 5 minutes after dialysis completed 9.2.5 Frequency of Measurement of Haemodialysis Adequacy (Level C) The delivered dose of haemodialysis should be measured at least 3 monthly in all adult and pediatric haemodialysis patients. The frequency of measurement of the delivered dose of haemodialysis should be increased when: patients are noncompliant with their haemodialysis prescriptions frequent problems are noted in delivery of the prescribed dose of haemodialysis wide variability in urea kinetic modeling results is observed in the absence of prescription changes the haemodialysis prescription is modified 9.3 Blood Urea Sampling 9.3.1 Blood Urea Sampling Predialysis and postdialysis blood samples for measurement of blood urea levels must be drawn at the same haemodialysis session. 9.3.2. Acceptable methods for blood urea sampling a. Predialysis BUN samples should be drawn immediately prior to dialysis, using a technique that avoids dilution of the blood sample with saline or heparin. b. Postdiaylsis BUN sampling: Stop flow method Stop ultrafiltration after completing haemodialysis Reduce blood pump to 25-50 ml/min Wait for 30 seconds Widen pressure alarm limit to maximum Clamp venous line in between patient and venous chamber If pump does not stop automatically, stop pump after 30-50s Draw blood sample from ARTERIAL port

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9.4 Duration of dialysis treatment session There are no randomized control trials comparing short with long hours. Many observational studies have suggested lower mortality associated with longer duration of treatment. Consideration should be given to the observational studies suggesting a minimum of 4 hours for each treatment session (frequency three per week) with low flux dialysers. Longer hours of dialysis may facilitate fluid and blood pressure control and reduce consequences of excess small and middle molecule accumulation 9.5 Dialysers The characteristics of the dialysers may influence the outcome of the dialysis process in several ways, e.g. molecular weight of cleared solute, biocompatibility and transmission of bacterial products from the dialysate. Much debate remains regarding the importance, the cause and the outcome ensuing from the use of individual membranes. Use of high flux compared to low flux membrane did not confer additional survival advantage .(Level A) 9.6 Inadequate Delivery of Haemodialysis: Troubleshooting 9.6.1 The delivered dose of haemodialysis measured by Kt/V or URR can be affected primarily by: a. clearance of the dialysers b. treatment duration c. blood flow rate d. dialysate flow rate Refer to Figure 9.1 9.6.2 If Kt/V < 1.2 or a URR < 65% on a single determination, consider the following interventions: a. Repeat the measurement of Kt/V or URR more often b. Investigate potential errors (Refer Figure 9.1) In the interim, increase the prescribed dose of haemodialysis 9.7 Clearance Less Than Assumed 9.7.1 Elements of the haemodialysis procedure affecting clearance (K) include dialyser permeability (KoA), effective dialyser surface area, blood flow and dialysate flow a. Assess fistula integrity to determine whether recirculation is present Review arteriovenous needle placement, proximity, and direction Verify the direction of blood flow through vascular access. - 70 -

b. Review written documentation of haemodialysis treatment, when Kt/V or URR was measured c. Review the hemodialysis reuse log to evaluate fibre bundle volume (FBV) of the dialysis d. Review the maintenance log for the dialysis machine to check the last calibration date and results e. Review the following: Blood flow rate (Qb) Dialysate flow rate (Qd) Type of dialyser Extracorporeal pressures compared with previous sessions at prescribed Qb Were pre-pump arterial pressures 200 mm Hg or higher? Were pre-pump arterial or venous pressures close to upper limit per dialysis unit policy? f. Review the haemodialysis log for clinical events that may have resulted in a change in treatment parameters, such as the Qb (hypotension, muscle cramps, chest pain, or problems with needle placement) g. Review pattern of dialyser clotting (review of the patients anticoagulation may be warranted) h. Determine whether dialyser clearance is overestimated by reviewing formal urea kinetic modeling results in other patients using the same model of dialyser with the same prescribed Kt/V i. For delivery systems with computers, review the total liters of blood processed 9.7.2 Effective Haemodialysis Treatment Time Less Than Prescribed. Haemodialysis treatment time (t) is the total time at the prescribed blood and dialysate flow rates with the prescribed dialysis, or it is the dialysis time determined to provide an equivalent Kt/V at the prevailing blood and dialysate flow rates for a particular dialyser. Review actual total duration of the dialysis treatment and any intradialytic events 9.6.2 Errors in Blood Sampling or measurement for calculating delivered dialysis dose. Review sampling procedures with dialysis staff 9.6.3 Consider repeating pre-dialysis and post-dialysis BUN sampling to determine Kt/V or URR again.If the above still do not reveal the problem, then assess for possible recirculation in the vascular access.

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Figure 9.1 Inadequate Delivery of Haemodialysis: Troubleshooting Low URR or Kt/V

Adequate prescription?

No

Correct prescription

Yes

Completed prescribed time?

Yes

No

Check dialyser integrity Clotting Fibre bundle volume

Access function Needle placement Recirculation

Isolated

Recurrent

Monitor

Assess reasons Noncomplia Intradialytic symptoms

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References
1. Handbook of Dialysis (3rd Edition) 2001 (pg. 15 45) John T. Daugirdas, Peter G. Blake, Todd S. Ing Lippincott Williams & Wilkins 2. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Haemodialysis Adequacy, 2000 Am J Kidney Dis 2001 (supp/1), 37 : 57 564 3. Effect of dialysis dose and membrane flux in maintenance hemodialysis. (HEMO) study group N Engl J Med 2002;347:2010-9 4. The CARI Guidelines : Caring for Australian with Renal Impairment. 5. Dialysis & Transplantation : A Companion To Brenner And Rectors THE KIDNEY William F. Owen, Brian J.G. Pereira, Mohamed H. Sayegh. W. B. Saunders Company 2000.

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10. SURGERY AND THE DIALYSIS PATIENT Patients with ESRD may need to undergo surgery either as an emergency or elective procedure. They are at higher risk of perioperative complications. 10.1Preoperative management: 10.1.1 Fluid status a. Ideally patients going for surgery should be well dialysed with no significant fluid overload. However, patients should not be overultrafiltrated to avoid perioperative haemodynamic instability. b. Tranfusion of blood or blood products should be given during dialysis/ ultrafitration. c. Intravenous fluids should be given judiciously. d. For patients going for renal transplantation, see Guideline on Renal Transplant Section 38 10.1.2 Electrolytes a. Serum potassium should preferably be normal at the time of surgery b. Measurement of serum potassium should not be done within an hour post-dialysis to allow time for equilibration.4 10.1.3 Acid-base status a. Blood gases may be required for patients going for emergency surgery b. If pH < 7.25 and serum HCO3 < 12-15 mEq/l, haemodialysis is required to correct acidosis 1 (Level C) 10.1.4 Dialysis a. For elective surgery dialysis should preferably be done within 24 hours before surgery b. If dialysis is required before an emergency surgery it should be heparin-free 10.1.5 Anaemia a. There is no conformity of opinion as to the safe haemoglobin level for surgery b. Blood transfusion may be needed depending on the type of surgery and co-morbidity c. Patients with cardiovascular disease should have Hb > 10 g%

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10.1.6 Bleeding Coagulopathy is common in ESRD patients, especially when blood urea is >35 mmol/l, and is multifactorial in origin. Haemodialysis within 24 hours of surgery is effective in partially reversing platelet dysfunction. Other adjunctive treatment includes use of cryoprecipitate, desmopressin. 10.1.7 Blood pressure a. A blood pressure of 140/90 mmHg or less is preferred. b. However, attempts to aggressively reduce blood pressure to normal within 24 hours of surgery are associated with intraoperative haemodynamic lability and hypotension and the risk of significant cardiovascular complication c. Anti-hypertensive medication should be served on the morning of elective surgery 101.8 Cardiovascular disease a. Basic cardiovascular assessment (history, physical examination, ECG, CXR) should be done for adult ESRD patients planned for general anaesthesia b. Patients with unexplained cardiorespiratory symptoms, abnormal signs, ECG or with multiple cardiovascular risk factors planned for elective major surgery should be referred for cardiac assessment 10.1.9 Dialysis access A label with the words NO BP TAKING OR NEEDLING should be clearly taped to the limb with the vascular access. 10.2 Intra-operative management 10.2.1 Anaesthesia Most anesthetic agents can be used in ESRD patients 1 a. Premedication with commonly used drugs e.g. benzodiazepine & atropine can be given in normal doses. b. Induction can be accomplished with iv barbiturate & succinylcholine. (Succinylcholine increases serum potassium by 0.5 mmol/l, thus repeated dosing is best avoided) c. Maintenance of anaesthesia is achieved with nitrous oxide or halothane d. Muscle relaxant of choice is atracurium as its pharmacokinetics & duration of action is unchanged in renal failure. e. Other agents (including vecuronium which is cleared by the liver) may be used in reduced dosage as their half-life is increased in renal failure. - 75 -

10.2.2 Dialysis access This must be protected during surgery. Blood pressure cuff & iv lines must never be placed in the same limb as the access. Padding should be placed around the limb with the access. 10.3 Postoperative management 10.3.1 Patients should be closely monitored during the immediate post-operative period. Post-op complications to watch out for in dialysis patients: a. Hyperkalaemia: Urea and serum electrolytes should be repeated after major surgery/ when blood transfusions have been given. b. Fluid overload: this can be prevented by careful fluid management guided by strict input-output charts, CVP/ PCWP. If patient becomes fluid overloaded, heparin-free sequential ultrafiltration should be done. c. Bleeding: check FBC, PT, APTT; Cryoprecipitate/ desmopressin packed cells may be given if indicated. d. Hypertension: Avoid intravenous nitroprusside in the treatment of severe hypertension to avoid thiocyanate toxicity. e. AVF thrombosis: may occur due to undetected prolonged pressure on AVF intraoperatively, hypotension or dehydration. Feel for thrill immediately post-operatively & periodically thereafter. f. Hypoventilation: may occur due to prolonged sedation from side effects of drugs and uraemia in hypercatabolic state. Blood gases may be required following major surgery. g. Analgesia: opiate usage should be reduced to avoid overdosage. h. Infection e.g. pneumonia, wound sepsis: higher risk than nonESRD patient. Chest physiotherapy & breathing exercises, mobilisation of patient should be started as soon as possible. 10.3.2 Dialysis with tight or no heparin is usually done the day following surgery.

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11. USE OF DRUGS IN DIALYSIS PATIENTS AND TREATMENT OF ACUTE POISONING 11. 1 The Use Of Drugs In Dialysis Patients 11.1.1 General Principles a. Effects of renal failure on pharmacokinetics of drugs: Effects of renal failure Altered bioavailability Altered volume of distribution (Vd) Comments Changes in gastric transit time Vomiting due to uraemia Oedema increases the Vd of water soluble or protein bound drugs resulting in low plasma levels as the drug stays in the extracellular space Acidic drugs are less protein bound in renal failure but basic drugs are unaffected by uraemia. Reduces the nonrenal elimination of drugs by decreasing hepatic hydroxylation Higher incidence of adverse drug reaction due to accumulation of active metabolites of the drug Elimination of drugs excreted mainly by the kidneys will be affected

Altered drug metabolism

Reduced renal excretion

The Cockroft-Gault formula (figure 11.1) may be used for the estimation of GFR:

Creatinine clearance = (140-age) x body weight (kg) 0.814 X Creatinine (umol/L) (For women: multiply by 0.85)

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b. Principles of drug therapy in renal failure Drugs with extensive renal elimination will require dosage adjustment. Loading drug dosage is similar to that of a patient with normal renal function. (If oedema is present a larger dose is needed, in dehydration a smaller dose is needed) Interval extension method: The usual dose is given at increased intervals Dose reduction method: The dose is reduced with a normal dosing interval 3-4 doses should be given before the plasma levels are measured to ensure that the steady state has been achieved. 11.1.2 Drug Prescribing In Haemodialysis Drugs which are dialysable will need to be given post dialysis If no information is available regarding the drug, the maintenance dose can be given after each dialysis. Refer to the Table 11.1 for drug dosing of antimicrobial agents. For other drugs, refer to drug insert or books on drug dosing in renal failure

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Table 11.1 Dosing of antimicrobial agents in renal failure

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Table 11.1 Dosing of antimicrobial agents in renal failure (contd.)

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Table 11.1 Dosing of antimicrobial agents in renal failure (contd.)

Abbreviations: D = Dose adjustment, I = Dosage interval adjustment Dose after = dose as for GFR < 10 mls/min should be held until after dialysis No supplement = This means that the dose given is the same as for GFR < 10 mls/mi Nd = No data, N/a = Not applicable

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11.2 Treatment of acute poisoning 11.2.1 Treatment of the patient with acute poisoning is based on 3 main approaches: a. Removal of the offending agent b. Administration of antidotes c. Supportive therapy eg cardiorespiratory support Peritoneal dialysis, haemodialysis and hemoperfusion are be useful adjuncts in the management of acute poisoning. 11.2.2 Forced Alkaline Diuresis This should only be used when specifically indicated eg. poisoning with weak acids (salicylate and phenobarbitone) as this is associated with risk of: a. acid-base disturbances b. electrolyte abnormalities eg. hypokalaemia, hypocalcaemia, hypomagnesaemia c. pulmonary oedema d. cerebral oedema Note : Use with caution in the presence of: impaired renal function cardiac disease 11.2.3 Management includes bladder catheterisation, CVP line, iv infusion, correction of fluid deficit and correction of acidosis with iv sodium bicarbonate a. Infuse in rotation at a rate of 1.5L per hour during the first hour and adjust subsequent rate accordingly 500ml of Dextrose 5% with 50ml of 8.4% Sodium bicarbonate 500 mls of 0.9% Saline 500ml of Dextrose 5% b. Measure urine volume If urine flow < 200 mls/hour reassess fluid balance with the help of a CVP line. Give iv furosemide 20-80 mg If urine output does not improve, abandon forced alkaline diuresis c. Maintain urine pH 7.5-8.5 by giving 50mls boluses of intravenous sodium bicarbonate 8.4% d. Replace potassium as indicated Note: Close monitoring is mandatory including dextrostix, serum electrolytes etc - 82 -

11.2.4 Extracorporeal elimination a. Clinical indications for the use of extracorporeal elimination methods: Severe clinical intoxication eg. Grade 4 coma, hypotension, hypothermia and hypoventilation in those who have ingested hypnotic drugs Progressive clinical deterioration despite the best supportive management Impairment of normal drug excretory function in the presence of hepatic, cardiac or renal insufficiency Intoxication with an extractable poison which can be removed at a rate exceeding endogenous elimination by the liver or kidneys b. The use of extracorporeal elimination methods is not indicated in the following situations: When an antidote is available eg. N-acetyl-cysteine for paracetamol poisoning The toxic substance is irreversibly acting eg. organophosphorus insecticide The substance is a rapidly acting metabolic poison eg. paraquat The drug ingested is relatively non toxic eg. benzodiazepines The drug has a large Vd eg. digoxin c. Extracorporeal methods: Peritoneal dialysis (PD) -efficiency is lower than haemodialysis or hemoperfusion Haemodialysis does not eliminate short and medium acting barbiturates and non-barbiturate hypnotics A high efficiency dialyzer should be used and for larger molecular weight drugs, a high flux dialyser should generally be used Hemoperfusion - This is a process whereby blood passes through a cartridge packed with activated charcoal or carbon. This method will remove many lipid soluble and highly protein bound drugs more efficiently than HD. The advantage of this system lies in the larger adsorbent surface compared to conventional hollow fiber dialyzer 11.2.5 Haemoperfusion - Treatment and complications a. The hemoperfusion circuit is similar to the blood side of a HD circuit without the use of a dialysate. The priming procedures depend on the manufacturer. The cartridge should be primed with D5% in order to load the charcoal with glucose first. This may also prevent hypoglycaemia. - 83 -

b. The duration of the haemoperfusion depends on the amount of sorbent. Generally prolonged haemoperfusion beyond 3 hours is unnecessary especially if the sorbent amount is less than 150 gm (see Table 11.2). c. More heparin is generally required than the conventional HD: bolus 2000-3000u followed by infusion to maintain ACT twice normal d. The complications of this technique include: leucopaenia loss of clotting factors thrombocytopaenia hypophosphataemia hypouricaemia hypoglycaemia hypocalcaemia

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Table 11.2 Hemoperfusion devices: Manufacturer Sorbent type Asahi Charcoal Clark Charcoal Gambro Charcoal Braun XAD-4 Smith and Nephew Charcoal

Amount of sorbent 170 gm 50,100,250 gm 100,300 gm 350 gm 100,300 gm

11.3 Summary of indications for elimination techniques: Different elimination techniques should be considered in adults depending on plasma concentration of the following drugs. Table 11.3 Drugs and elimination techniques Drugs Other findings Level Salicylates Mixed respiratory alkalosis with Metabolic acidosis, Renal failure Coma in severe cases 500 mg/l 750 mg/l 900 mg/l Method of elimination FAD HD/HP HD/HP (2-3 x more efficient than FAD or PD) HP

All barbiturates (except phenobarbitone & barbitone) Phenobarbitone or barbitone Drugs Methanol, ethylene glycol Other findings Metabolised to formic acid and lactic acid which causes optic nerve toxicity and lactic acidosis. Antidote is 4-

75-100 mg/l 100 mg/l Level

FAD HD/HP Method of elimination Dialysis (HD) is indicated if > 30 gm is ingested or if there is metabolic acidosis or mental and

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methylpyranole fundoscopic which inhibits changes the formation of lactate and formic acid. Isopropanol Significant 0.4 gm/l HD hypotension is an important clinical indication for HD Lithium Dialysis reduces 5 mmol/l HD the levels rapidly but a rebound phenomenon may occur 60 mg/l HP Theophylline Correction of hypokalaemia is most important and may obviate the need for HP FAD = forced alkaline diuresis, HD = haemodialysis, HP = haemoperfusion, PD = peritoneal dialysis Adapted from Seyffart G. Potson index. Dialysis and hemoperfusion in Poisonings For further information contact Poison Centre : Tel: 04-6570099 fax: 04-6568417 Email: prnnet@prn.usm.my

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12. REHABILITATION ESRD patients undergoing haemodialysis are typically sedentary and functionally limited as a consequence of their condition. Rehabilitation attempts to restore an optimal quality of life. Renal rehabilitation is defined broadly in terms of optimal functioning of individual patients and restoration to productive activities. This requires the integration of excellent medical care, psychosocial and psychiatric care and occupational rehabilitation services. 12.1 Psychological stresses of dialysis Regimentation of dietary fluid and medication intake Dialysis procedure The illness itself Multiple losses and threats of loss: job, freedom, life expectancy, self image and self esteem Associated sexual dysfunction Impaired activities of daily living and social function Anxieties about vascular access, transplantation, medical complication and fear of death 12.2 Manifestation of psychiatric morbidity 12.2.1 As a result of the stresses, patients have substantial psychiatric morbidity manifesting as: anxiety disorders including phobic disorders (e.g. needle phobia) depressive disorders (often situational and reactive) panic attacks treatment regimen non compliance suicidal crises other behaviour problems such as violent behaviour towards own family, other patients and dialysis staff 12.2.2 Depression is the most common psychological complication in dialysis patients. Exercise and antidepressants such as the newer selective serotonin reuptake inhibitors can play a potentially large role in the treatment of depressive symptoms. 12.3 The 5 es of total rehabilitation: Employment Exercise Education Encouragement Evaluation

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In patients who are employed, efforts should be made to maintain employment and vocational counseling should be provided to unemployed patients who are capable of working. 12.4 Fundamental methods to achieve optimal psychosocial rehabilitation include: Social worker to provide assessment, counseling and other basic services Availability of a Consultant Psychiatrist and/or Psychologist to the dialysis program Regular case management meetings of a multidisciplinary dialysis team that includes all professional staff 12.5 Exercise: Exercise and physical training can add to increased physical well being and should begin at the start of the dialysis period or preferably in the pre-dialysis period. Aerobic exercise is an excellent means of improving the physical condition of these patients, restoring a substantial degree of strength, endurance and flexibility. 12.5.1 Potential benefits of exercise include: Heightened sense of well-being Lessening of stress, anxiety and depression Cardiovascular and muscle conditioning Improvement of lipid profile and lowering of blood pressure 12.5.2 Precautions Cardiac evaluation should ideally be done prior to the start of an exercise program. Initial stages of exercise should be started under observation and prescription of a specialist. Exercise with the least physical stress on muscles, bones and tendons such as walking, cycling and swimming is preferred

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12.6 Sex, fertility, contraception and pregnancy in chronic dialysis patients: 12.6.1 Chronic dialysis patients commonly experience sexual problems such as: diminished sexual desire impaired sexual response 12.6.2 Contributing factors to sexual dysfunction include: psychological factors anaemia hindrance of CAPD catheter and AV fistula endocrine dysfunction drugs 12.6.3 Management: Counseling and psychosocial rehabilitation Correct anaemia Sexual counseling - emphasise the non-physical aspects of demonstration of love. Alteration of sexual techniques and positions to overcome problems related to impotence, CAPD catheter and AV fistula. Encourage the healthy spouse to act as the active partner in love making. Review of the use of drugs that contribute to sexual dysfunction Consider non-pharmacological aids and potency drugs e.g. sildenafil, MUSE References 1. Exercise, Rehabilitation and the Dialysis Patient. Dialysis & Transplantation. Vol 3 No.3 March 1999 2. Life Options Rehabilitation Advisory Council. Exercise and the ESRD patient. Cont Dial Nephrol April 1995 3. The socioeconomic impact of rehabilitation. CR Blagg. AJKD Vol 24 4. The Life Readiness Program: A Physical Rehabilitation Program for Patients on Hemodialysis. AJKD Vol 36, No 3 (September 2000) 5. Renal Rehablitation: Obstacles, Progress and Prospects for the future. AJKD Vol 35 ,Suppl.1 (April) 2000

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13. PREGNANCY DURING DIALYSIS Incidence of pregnancy in woman of childbearing age on dialysis is 0.75 to 7%. Infant survival is about 40%. Available data suggests that there is no increased risk of death in the dialysis patient who becomes pregnant. 13.1 Prescription of dialysis during pregnancy Six sessions per week Minimise fluid shifts Avoid hypotension and abrupt osmolality changes Aim to keep predialysis blood urea < 17.7 mmol/l Avoid hypokalaemia and alkalosis (Level C) 13.2 Targets First trimester: minimal weight gain of 1 to 1.5 kg After 1st trimester expected weight gain of 0.45 kg/week Target Hb 10 12g% Consider elective delivery between 34 to 36 weeks 13.3 Additional prescription Daily protein intake of 1.8 g/kg/day 13.4 Birth control & contraception a. Women of reproductive age on dialysis should be counselled regarding pregnancy b. Birth control is advisable: Barrier methods are the contraceptive methods of choice Combined OCP is an alternative in the absence of hypertension, diabetes or active SLE References
1. Giatras I, Levy DP, Malone FD, Carlson JA, Jungers P. Pregnancy during dialysis: case report and management guidelines. Nephrol Dial Transplant. 1998;13(12):3266-72. 2. Okundaye I, Abrinko P, Hou S. Registry of pregnancy in dialysis patients. Am J Kidney Dis. 1998;31(5):766-73. 3. Davison JM. Dialysis, transplantation, and pregnancy. Am J Kidney Dis. 1991;17(2):127-32. 4. Hou SH. Frequency and outcome of pregnancy in women on dialysis. Am J Kidney Dis. 1994 Jan;23(1):60-3. 5. Bagon JA et al. Pregnancy and dialysis. Am J Kidney Dis. 1998;31(5):756-65.

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14. QUALITY ASSURANCE PROGRAM IN HAEMODIALYSIS (In compliance with the requirements of ISO 9002 for Ministry of Health Haemodialysis programme) 14.1 Quality Policy Commitment to achieve and maintain the highest possible standards of quality, commensurate with available resources and consistent with current scientific evidence Commitment to ensure all future patients with ESRD will be able to access the same high quality HD treatment service delivered at a cost that is affordable to even the poorest in our community 14.2 Quality objectives: Annual patient risk-adjusted mortality rate < 15 per 100 patientyears Life expectancy no worse than 50% expected for normal persons 30% of patients between age of 20 and 55 who were employed premorbidly could return to paid employment 75% of patients have serum albumin > 40g/l 50% of patients have serum PO4 < 1.6 mmol/l 95% of patients have prescribed KT/V > 1.3 % of patients have delivered KT/V > 1.2 95% of patients have discrepancy between prescribed and delivered KT/V that is < 20% 60% of patients have BP< 140/90 70% patients have Hb > 8g% No avoidable life threatening intradialytic event 90% of reuse dialysers perform within 80% of specification 90% of patients expressed confidence in competence of staff and satisfaction with service provided in annual Customer Satisfaction survey Chronic HD capacity to patient ratio < 2 Cost effectiveness ratio < RM 25,000 per life year saved Publicly funded dialysis acceptance rate of 50 per million population by year 2003 No gender bias in dialysis acceptance, as measured by male to female acceptance ratio < 1.5 Geographical equity in dialysis acceptance, as measured by highest state to lowest state acceptance ratio < 3

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15. PAEDIATRIC HAEMODIALYSIS 15.1 Introduction Children comprise less than 1% of the total haemodialysis population. The preferred mode of dialysis is peritoneal dialysis but chronic haemodialysis is viable in older children and in places where PD is not available. They should ideally be dialysed in a paediatric unit with facilities and personnel relevant to the child. In areas where the population is not sufficient to justify a separate unit, good care can be given in integrated paediatric and adult units with specialised staff. 15.2 Patient selection Generally all children can be accepted for chronic haemodialysis except those who have no potential for rehabilitation. 15.3 Indications for starting dialysis Fluid overload resulting in cardiovascular instability Restriction of fluid intake resulting in inadequate nutrition School absenteeism from uraemic symptoms GFR < 10ml/min/1.73m2 Reduced growth velocity Reduced head circumference Neurological developmental delay despite adequate nutrition Calculated GFR (ml/min/1.73m2) = 40 x height (cm) creatinine (umol/l) 15.4 HD machine The pump for maintaining and controlling blood flow should be accurate at low flow rates (up to 20ml/min) 15.5 Haemodialysers Should have a low priming volume and compliance, safe UF coefficient, high degree of biocompatibility and a predictable relationship between clearance and blood flow rates Total extracorporeal circuit volume is < 10% of childs estimated blood volume (80ml/kg) i.e. extracorporeal volume is < 8ml/kg childs body weight Dialyser surface area (m2) = 70 100% of childs body surface area (BSA) BSA =

height (cm) x weight (kg) 3600

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or refer to normogram Table 15.1 Locally available paediatric dialysers Manufacturer Material Model No. Surface (m2) Fresenius Polysulfone F3 0.4 F4 0.7 F5 1.0 F6 1.3 Asahi AM-SD 300 0.6 AM-SD 400M 0.8 AM-SD 400U 0.8

Volume (line)/ml 30 42 63 82 40 49 49

15.6 Blood lines Volume capacity of blood lines range from 13ml (neonatal) to 30ml (paediatric) to 120ml (adult) 15.7 Needles - as in adults (18G 14G) 15.8 Vascular access 15.8.1 Temporary Appropriately down-sized venous cannulas (single or double-lumen) can be inserted percutaneously into vena cava via internal jugular, femoral or subclavian approach. 15.8.2 Permanent Refer to adult section 15.9 Method of dialysis Blood pump flow = 5ml/kg/min Priming of the blood lines is necessary if the child is anaemic, if extracorporeal blood volume exceeds the recommended amounts. Whole blood or 5% albumin can be used. Heparinisation: bolus 20 - 50 units /kg followed by 10 - 20 units/kg/hour. Activated clotting time (if used) should be kept 150 - 180 seconds Ultrafiltration rate: maximum fluid removal per session should be < 5% of dry weight and rate of removal < 0.2ml/kg/min 15.10 Nutrition Refer to Chapter 31

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15.11 Growth Children with CRF are growth retarded especially if renal failure starts in infancy and if the aetiology is congenital renal disease. Growth rates based on age and sex are higher than expected in the youngest patients who are transplanted. Aim to transplant early especially if young. 15.11.1 The treatment goal for children on dialysis should include: a. normal height velocity for age b. catch-up growth for those who are short at onset of dialysis 15.11.2 Children with short stature at onset of dialysis (height standard deviation score SDS < -1.88): a. optimise dialysis b. control renal osteodystrophy c. control acid-base balance d. correct anaemia e. ensure adequate nutrition f. recombinant human growth hormone (rhGH) (Level C) 15.12 Adequacy Currently no published outcome data in children with ESRD to suggest that any measure of dialysis adequacy is predictive of well-being, morbidity or mortality Achievement of numeric targets should not be the sole determinant of adequacy of care (Level C) 15.13 Differences with adults: Greater size differences and dietary variations with resultant larger variations in PCR and urea generation rate Prescription of dialysis changes with growth In small children with relatively high clearances, the 2-pool model is preferred 15.14 Kt/V In the absence of specific data, it is recommended that delivered dose of HD should be equivalent to a single pool Kt/V urea of at least 1.3 Higher Kt/V values which are relatively easy to achieve (relatively low V) may facilitate growth Measured dose of dialysis delivery should be done 3-monthly

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15.15 Problems of patients on long-term HD As for adults plus: growth retardation delayed sexual maturation psychosocial problems

References 1.
Handbook of Dialysis (3rd edition), 2001, 562-579. Daugirdas JT, Blake PG, Ing TS. Lippincott Williams and Wilkins 2. National Kidney Foundation. K/DOQI Clinical practice guidelines for hemodialysis adequacy, 2000. Am J Kidney Dis 2001(suppl 1); 37: S7-S64 3. Warady BA, Alexander SR, Watkins S, Kohaut E, Harmon WE. Optimal care of the pediatric end-stage renal disease patient on dialysis. Am J Kidney Dis 1999; 33: 567-583 4. Al-Hermi BE, Al-Saran K, Secker D, Geary DF.Hemodialysis for end-stage renal disease in children weighing less than10kg. Pediatr Nephrol 1999; 13: 401-403 5. Warady B, Watkins SL Current advances in the therapy of chronic renal failure and end stage renal disease. Semin Nephrol 1998; 18: 341-354. 6. Warady BA, Bunchman TE An update on peritoneal dialysis and hemodialysis in the pediatric population. Curr Opin Pediatr 1996; 8: 135-140 7. Bunchman TE .Pediatric hemodialysis: lessons from the past, ideas for the future. Kidney Int Suppl 1996; 53: S64-S67 8. Donckerwolcke RA, Bunchman TE. Hemodialysis in infants and small children. Pediatr Nephrol 1994; 8: 103-106 9. K/DOQI Clinical Practice Guidelines for nutrition in chronic renal failure. Am J Kidney Dis 2000(suppl 2); 35: S105-S136 10. Sharma AK Reassessing hemodialysis adequacy in children: the case for more. Pediatr Nephrol 2001; 16: 383-390 11. Sharma A, Espinosa P, Bell L, Tom A, Rodd C Multicompartment urea kinetics in well-dialyzed children. Kidney Int 2000; 58: 2138-2146 12. Van Hoeck KJM, Lilien MR, Brinkman DC, Schroeder CH. Comparing a urea kinetic monitor with Daugirdas formula and dietary records in children. Pediatr Nephrol 2000; 14: 280-283 13. Goldstein SL, Brewer ED. Logarithmic extrapolation of a 15-minute postdialysis BUN to predict equilibrated BUN and calculate double-pool Kt/V in the pediatric hemodialysis population. Am J Kidney Dis 2000; 36: 98-104 14. Jiravuttipong A, Jones CL Natural logarithmic formula: not an alternative method for estimating Kt/V in paediatric haemodialysis. Nephrology 2000; 5: 167-171 15. Goldstein SL, Sorof JM, Brewer ED Evaluation and prediction of urea rebound and equilibrated Kt/V in the pediatric hemodialysis population. Am J Kidney Dis 1999; 34: 49-54 16. Goldstein SL, Sorof JM, Brewer ED Natural logarithmic estimates of Kt/V in the pediatric hemodialysis population. Am J Kidney Dis 1999; 33: 518-522

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17. Verrina

E, Brendolan A, Gusmano R, Ronco C Chronic renal replacement therapy in children; which index is best for adequacy? Kidney Int 1998; 54: 1690-1696 18. Harmon WE Kinetic modeling of hemodialysis in children. Semin Dial 1994; 7: 392-397 19. Hokken-Koelega A, Mulder P, De Jong R, Lilien M, Donckerwolcke R, Groothof J Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency. Pediatr Nephrol 2000; 14: 701-706 20. Tom A, McCauley L, Bell L, Rodd C, Espinosa P, Yu G, Yu J, Girardin C, Sharma A Growth during maintenance hemodialysis: impact of enhanced nutrition and clearance.J Pediatr 1999; 134: 464-471 21. Berard E, Crosnier H, Six-Beneton A, Chevallier T, Cochat P, Broyer M Recombinant human growth hormone treatment of children on hemodialysis. Pediatr Nephrol 1998; 12: 304-310 22. Turenne MN, Port FK, Strawderman RL, Ettenger RB, Alexander SR, Lewy JE, Jones CA, Agodoa LYC, Held PJ Growth rates in pediatric dialysis and renal transplant patients. Am J Kidney Dis 1997; 30: 193- 203 23. Fine RN Growth retardation in children with chronic renal insufficiency. Nephron 1997; 76: 125-129 24. Hanna JD, Krieg RJ, Scheinman JI, Chan JCM Effects of uremia on growth in children. Semin Nephrol 1996; 16: 230-241

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16. TECHNICAL ASPECTS OF HAEMODIALYSIS 16.1 Haemodialysis Machines Over the years haemodialysis machines have evolved from a simple mechanistic model to one with sophisticated microprocessor controlled processes incorporating digital displays and many features that allow individualisation of treatment. 16.1.1 The main functions of haemodialysis machines include: a. Blood related functions: To transport blood from the patient via the blood pump to the artificial kidney and back to the patient safely b. Dialysate related functions: To prepare the dialysis fluid by heating, deaerating and appropriate proportioning of dialysate and treated water. This must be done safely by constantly measuring conductivity and temperature of the dialysate 16.1.2 The main components of haemodialysis machines The standard dialysis machine consists of a blood pump, heparin infusion pump, dialysis solution delivery system and appropriate safety monitors. a. Blood pump: The blood pump moves blood from the access site (AVF) through the dialyser and back to the patient. The usual flow rate is at least 250-300 ml/min and has a direct effect on the quality of dialysis. b. Heparin infusion pump: This is a continuous infusion pump used to infuse a certain volume of heparin into the predialyser segment of the blood line to prevent clotting in the extracorporeal circuit. c. Dialysis solution delivery system: Central versus individual proportioning There are two types of dialysis solution delivery systems, namely central delivery and individual proportioning system. The haemodialysis machines available in all the haemodialysis units in MOH facilities are of the latter type. Two different methods of proportioning are used: Fixed proportioning 1:1.83:34, where one part of acid concentrate is mixed with 1.83 parts of HCO3 and 34 parts of treated water, e.g Drake Willock 480, Baxter 450/550. (Different ratios are used in different models).

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Servo assisted or feedback system where conductivity can be adjusted by the use of concentrate pumps and printed circuit boards, e.g. AK 90 , AK 95 Heating and degassing Incoming water has to be heated to body temperature so that dialysate sent to the artificial kidney does not cool down the blood resulting in chills and discomfort to the patient. Heated water has to be free of bubbles and deaeration chambers are used. Negative pressure: Negative pressure is used to achieve ultrafiltration or removal of excess water from the patients blood. A negative pressure pump and pressure regulators have been incorporated in the haemodialysis machine. TMP monitoring is utilised in many machines to maintain accuracy of fluid removal. TMP (Transmembrane pressure) = Venous pressure dialysate pressure d. Monitoring devices: Blood circuit Pressure monitors. T tubes attached to the blood line permit monitoring of pressure at various points in the blood circuit: Arterial pressure monitoring: Arterial pressure guard monitors the adequacy of arterial blood supply, and detects clotting of the dialyser when pressure monitoring is after the blood pump Venous pressure monitoring: To detect any kink or clot in the venous line distal to the venous chamber To help in calculation of TMP To detect accidental separation of the blood line from the fistula needle Air bubble detector (ABD). This is located distal to the venous pressure monitor. The purpose of the ABD is to prevent air which may have inadvertently entered the blood circuit from being introduced into the patient. The ABD is attached to a relay switch which automatically clamps the venous blood lines and shuts off the blood pump if air is detected. Dialysis solution circuit Conductivity: If the proportioning system that dilutes the concentrate with water malfunctions, an excessively dilute or concentrated dialysis solution can be produced. High or low conductivity

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can result in high or low blood pressure and this affects the patient severely. The machine should be able to monitor the conductivity continuously. Temperature: Malfunction of the heater element in the dialysis machine can result in production of excessively cool or hot dialysis solution. Use of cold dialysate causes patients to complain of cold and shivers (chills). The use of dialysis solution greater than 42C can lead to haemolysis. Thus temperature sensors are used for continuous monitoring and the dialysate is bypassed when out of safety limits. Bypass valve: This valve is solely responsible for diverting dialysis solution directly to the drain whenever temperature/conductivity are out of set safe limits. Blood leak detector (BLD): This device is placed in the dialysate outflow line and detects any blood leak from the dialyser and activates an alarm. Negative pressure / TMP regulator: This consists of negative pressure pumps and regulators and continuously monitors the total TMP to achieve the desired goal for fluid removal 16.1.3 Options available for haemodialysis machines a. Bicarbonate: Bicarbonate dialysate is preferred. The two concentrate approach in preparation of bicarbonate dialysate is standard. Use of Bicarbonate cartridges is an alternative. b. Sodium profiling: This option permits rapid alteration of the dialysis solution sodium concentration and is useful in haemodynamically unstable patients. c. Ultrafiltration controllers (UFC): Two common methods used are volumetric method and electromagnetic flow sensors. It is standard in all new haemodialysis machines. d. Single needle dialysis: This is not commonly used but is useful in patients with poor vascular access. Only one vascular access line (needle) is needed and the arterial and venous lines are kept either closed/opened one at a time. Time settings or pressure settings can be used to control inflow/outflow of blood.

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e. Haemodiafiltration (HDF): Haemodiafiltration combines the advantages of haemodialysis and haemofiltration to provide the largest amount of blood purification over a wide molecular weight spectrum achievable with present renal replacement therapy. HDF can be thought of as haemodialysis in which massive fluid removal (20-30 litres) far exceeds the desired weight loss, and fluid balance is maintained by replacement of ultra-pure solution. With modern HDF machines e.g. Gambro Ak100/Ak200 Ultra System ultrapure water can be produced continuously by 3filter ultrafiltration. Ultrapure water meets stringent criteria and contains <0.1 CFU/ml and < 0.03 EU/ml endotoxin). It is used for on line preparation of (i) Replacement fluid and (ii) Dialysis solution by proportionating ultrapure water with Bicarbonate powder cartridge. Volume of replacement fluid = 0.3 (ultrafiltration ratio) x Qb.If Qb=350 ml/min, the volume of replacement fluid over 4 hours = 0.3 x 350 x 4 x 60 = 25 Liters The advantages of HDF are: greater blood purification less 2 microglobulin related symptoms by convective clearance of 2 microglobulin e.g reduces joint pain and carpal tunnel syndrome, increases mobility better treatment comfort-the incidence of hypotensive episodes, muscle cramps, post treatment fatigue is reduced improved response to Epoetin better haemodynamic stability improved nutritional status f. Blood temperature monitor g. Blood volume monitor 16.1.4 Sterilisation of haemodialysis machines Machines should be bleached/sterilised and decalcified after each dialysis or at least after the last dialysis of the day. This is to minimise spread of infection. Common methods are: a. Heat b. Chemical Formaldehyde Sodium Hypochlorite Peracetic acid

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16.1.5 Preventive maintenance All machines should have a check list for preventive maintenance and this must be adhered to strictly. Purpose: a. To ensure machine is safe for use b. To detect malfunctioning parts early and cut down mean breakdown time c. To check all calibrations which include blood pump flow rate, temperature, conductivity, blood leak detector, air bubble detector, negative pressure etc d. To cut down cost 16.1.6 The following is a set of criteria to determine if a haemodialysis machine is safe for use: a. The air bubble detector should be in good working condition and able to detect microbubbles/air passing through the device and clamp immediately b. All audible and visual alarms should be in good working order c. The heparin pump should be able to infuse the prescribed volume of anticoagulant at the set flow rate d. The blood flow rate and the dialysate flow rates should be accurate at all times e. The dialysate pressure/TMP/UFC calibrations must be correct to facilitate removal of fluid according to set targets f. The conductivity and temperature readings should be within acceptable limits and stable all the time to avoid loss in effective dialysis time g. Venous monitor including alarm limits must be in good working order to facilitate TMP calculation and detection of positive pressure on venous lines h. The dialysate lines should be free of air bubbles i. There should be no leakage of fluid from the hydraulics of the machine j. The blood leak detector should be able to perform its function accurately within set limits k. For on line HDF, the ultrapure water for replacement and sterile dialysate should have < 0.1 CFU/ml and < 0.03 EU/ml

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16.2. Dialysers 16.2.1 Dialyser description The dialyser is a tube with four ports. Two ports communicate with the blood compartment and the other two with dialysate compartment. The two compartments are separated by a semipermeable membrane. The types of dialysers are parallel plate dialysers, coil and hollow fibre dialysers. Currently all of the dialysers in the Ministrys dialysis units are hollow fibre dialysers. The following define the characteristics of a dialyser: a. Membrane material b. Ultrafiltration coefficient (Kuf) c. Surface area and priming volume d. Clearance of urea, creatinine, uric acid, phosphate and Vit B12 e. Sterilisation method 16.2.2 Membrane material: There are 3 three types of membrane currently used cellulose, substituted cellulose and synthetic membrane. a. Cellulose This first generation membrane used to be the most common type. It is commonly named as regenerated cellulose, cuprammonium rayon, cuprammonium cellulose (cuprophane) and saponified cellulose ester b. Substituted cellulose: The most commonly used is cellulose acetate. Cellulose acetate being a substituted cellulose membrane reduces complement activation thus increasing the biocompatibility of the dialyser. c. Synthetic membrane These membranes are not cellulose based. They are manufactured from synthetic materials which include polyacrylonitrile (PAN), polysulfone (e.g. F6, F8, F60), polyamide (e.g. POLYFLUX 17 S) and polymethylmethaacrylate (PMMA). 16.2.3 Ultrafiltration rate (KUf) The permeability of the membrane to water is determined by the ultrafiltration rate coefficient (KUf). In most MOH dialysers (e.g. F6, F8) the KUf is between 6-12 ml/mmHg/hour. The KUf for high flux dialyser is more then 20 ml/mmHg/hour (e.g.F60, HF80) 16.2.4 Surface area and priming volume

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The membrane surface area of a dialyser determines the blood volume in the dialyser. For adults the dialyser surface area is between 1.2-1.8 m2 with a priming volume of 60-120 ml. 16.2.5 Clearance of urea, creatinine, uric acid, phosphate and Vit B12 The clearance of a dialyser is determined by the surface area, membrane thickness and design (refer to manufacturers specifications) 16.2.6 Sterilisation method The most common method of dialyser sterilisation is by exposure to ethylene oxide (ETO) gas. This form of sterilisation causes hypersensitivity reactions in patients who are allergic to ETO; this includes anaphylactic reactions although this is rare. Other forms of sterilisation include gamma irradiation and steam sterilisation. 16.3 Bloodlines 16.3.1 In our practice universal blood lines are used. The components of the bloodlines are: a. Blood pump segment b. Artery and venous blood chambers (without filters-for easy reuse procedure) c. Heparin line d. Artery and venous pressure monitor lines e. Infusion line 16.3.2 The priming volume of the bloodline in adults is between 100-150 ml. 16.4 Artery and venous fistula needles Artery and venous fistula needles range from 14 18G. The commonly used size for adults is 15G. 16.5 Dialyser Reuse and Reprocessing System 16.5.1 Dialysers are reused for the following reasons: To reduce cost of treatment To reduce hypersensitivity reaction to ethylene oxide gas To reduce complement activation. This is achieved through protein coating of the membrane surface. Dialysers can be reprocessed either by a semi-automated or a fully automated system.

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16.5.2 Semi automated reprocessing system consists of solenoid valves and timer relays a. The process is activated manually b. The cleaning cycle consists of Fast Rinse and Reverse Ultrafiltration (RUF) modes; it ends automatically 10 minutes after being activated c. The disinfection cycle has to be manually activated and 2-3 % formalin is filled in over a period of 2 minutes. d. No fibre bundle volume (FBV) or pressure leak test is available 16.5.3 Automated dialyser reprocessing system a. rinses and cleans the dialyser of residual blood and blood products with RO water b. tests the dialyser for leaks and performance parameters (fibre bundle volume). Reject dialyser if FBV <80%. c. fills the dialyser with an appropriate concentration of a germicide. 16.5.4 Policies and Procedures in reprocessing dialysers There should be policies and procedures to ensure safety and effective operation of a reuse programme 16.5.5 Precautions when using dialyser reprocessing systems. a. Separate machines should be used for the following patients: Hep B negative & Hep C negative Hep B positive & Hep C negative Hep B negative & Hep C positive b. Always ensure that the correct strength of sterilant is used for disinfection c. Reverse osmosis water should be used d. All working areas in the reuse bay should be kept clean of blood and other biohazard materials e. There should be proper care in handling formalin or any other germicide that is being used. Eye goggles or face shields, face mask, apron and gloves should be used. f. Sterilisation and calibration of the dialyser reprocessing machine should be done regularly g. A good ventilation system is required

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17. THE HAEMODIALYSIS PROCEDURE 17.1 Pre and post procedure checks 17.1.1 General observation on receiving the patient: Greet patient Is he/she comfortable? Is he/she able to walk into the unit? Any signs of fluid overload? Any signs of being unwell? Is there any unusual reaction? 17.1.2 Vital signs observation: a. Sitting and standing blood pressure Hypotension (e.g. BP < 90/60 mmHg) or severe hypertension (e.g. BP > 200/120 mmHg) requires medical attention Countercheck with the patient regarding the antihypertensive drugs prescribed, the dosages and the time of the last dose b. Pulse rate Any abnormalities in rhythm, volume and rate may require medical attention. ECG monitoring may help to confirm the findings. c. Body temperature Hyperpyrexia requires medical attention to determine the source of infection and may require antibiotics d. Body weight Interdialytic weight gain should not be more than 3% of the dry weight No weight gain may indicate good urine output, poor oral intake or gastrointestinal loss Excessive weight gain requires a check on oral intake of salt, fluid, diet and iv therapy if any 17.2 Starting the patient on dialysis 17.2.1 Before commencing treatment note the haemodialysis orders: hepatitis B, hepatitis C and HIV status blood access dialysate regime e.g. bicarbonate, acetate, low calcium heparin regime e.g. normal, tight or free amount of fluid removal required duration of treatment special orders e.g. sequential ultrafiltration, blood transfusion, iv therapy

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17.2.2 Check the function of the haemodialysis machine temperature conductivity blood leak detector air detector blood pump dialysate flow rate arterial, venous, TMP monitors

17.2.3 Preparation of the required items Choose the correct dialyser e.g. type of membrane, surface area, KUf, clearance Use the correct haemodialysis concentrate Ensure correct heparin dilution 17.2.4 On commencing treatment: Aseptic procedure must be observed during needling Record starting time Record blood flow rate Check all monitors are properly set Set required ultrafiltration rate Set up heparin infusion as required Set air bubble detector 17.3 Observations while on treatment 17.3.1 On the patient: To ensure that patients remain comfortable and in stable condition, close monitoring will help to reduce unwanted incidents e.g. hypotension, clotting dialyser and unnecessary blood loss Check vital signs at least 2 hourly 17.3.2 On the machine: Two hourly monitoring of the progress of treatment remaining treatment time venous pressure arterial pressure blood flow rate TMP heparin extracorporeal blood condition e.g. blood clots

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17.4 Isolated/sequential ultrafiltration 17.4.1 Definition It is a process of removing excessive body fluid before or after the actual dialysis procedure. It is best performed before haemodialysis. The advantages are: it gives fast relief of pulmonary oedema it maintains a constant blood pressure in sipte of a large amount of fluid removed rapidly better tolerance by the patient due to constant blood electrolytes as the dialysate does not flow through the dialyser 17.4.2 There are two methods of performing this therapy: a. by using an external vacuum pump The disadvantages of using an external vacuum pump are: negative pressure is set between 400 to 780 mmHg and the danger of dialyser rupture is high there is no blood leak detector. If blood leak occurs there is significant amount of blood loss. b. by using the automatic device which is incorporated in the haemodialysis machine the negative pressure is kept within 450 mmHg to prevent the risk of dialyser fibre rupture the ultrafiltration rate depends on the KUf on the dialyser used the blood leak detector is functioning and this detects 0.001ml of blood concentrate is saved during sequential ultrafiltration therapy due to inactivation of the concentrate pump

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18 WATER TREATMENT 18.1 Introduction From the early days of dialysis it is known that water used for hemodialysis must be purified. The role of microbial contamination of dialysis water has been greatly underestimated in the last three decades. The possibilities of dialysis patients exposed to greater levels of bacterial and endotoxin has increased tremendously during the last two decades with the increase in reuse, the use of bicarbonate dialysis fluid, high flux dialysis and on-line replacement fluid. The consequences of bacterial contamination besides acute pyrogenic reaction, is a state of chronic inflammation that may contribute to progressive inflammatory diseases in chronic renal failure such as 2-microglobulin amyloidosis, protein catabolism, malnutrition, and accelerated atherosclerosis. To help prevent these events from occurring, standards for maximum allowable bacterial and endotoxin contamination must be established, and all dialysis centers should develop good surveillance policies. Water quality however is not limited to microbiological quality, but also chemical quality. The water quality standards for hemodialysis must be more stringent than drinking water since the largest contact material that the blood is exposed to during hemodialysis is the dialysis fluid. 18.2 Quality standards for microbial purity 18.2.1 Introduction Water use for conventional haemodialysis should be at least complied with the minimum requirements of AAMI (European Pharmacopoeia standard should be adopted if possible). AAMI stated that water used for diluting concentrated haemodialysis solution should have a total viable microbial count of no more than 200 cfu/ml, and that the concentration of endotoxin should be no more that 2 EU/ml. While the action level are 50 cfu/ml for total viable microbial count and 1 EU/ml for endotoxin levels. Action level denotes the concentration of a contaminant at which steps should be taken to interrupt the trend toward higher, unacceptable levels.

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Standard fluid

Water Concentrate Viable counts (VC) ET VC (CFU/ml) (CFU/ml) (EU) 2000 200 (bicarb) 200

Dialysis Endotoxin (ET) ET (EU) 2 1 0.25 0.5 VC (CFU/ml)

AAMI Action level* 50 European 100 1.25

In ultrapure dialysis fluid, the limits are <0.1 cfu/ml for total viable microbial count and <0.03 IU/ml for endotoxin levels. However, the use of ultrapure water is strongly recommended for conventional and high-flux dialysis to prevent and/or delay the occurrence of dialysis related complications. Level B 18.2.2 Biofilm The treatment system must be regularly disinfected. Filters and resins must be periodically cleaned, regenerated and changed, and precautions should be taken against the formation of biofilms. They form easily in any crevice or corner of containers, pipes, treatment devices, storage tanks and dialysis machines, and are extremely difficult to remove. 18.2.3 Material The materials of any components of water treatment systems that contact the purified water should be unreactive in nature to prevent contamination of the product water. These include such materials as plastics (acrylonitrile-butadienestyrene, polyethylene, polypropylene, polyvinylidine fluoride, polyvinyl chloride) or appropriate stainless steel. 18.2.4 Design Steps in preventing biofilm formation include the use of pipe work with linear configuration, small diameter with loop system favouring continuous high speed water recirculation even when dialysis facility is closed, a smooth surface that resist corrosion, and does not crack with age. Avoidance of uneven surfaces such as ridges or grooves particularly at the joints is recommended. Dead spaces and area of slow flow and turbulence such as sharp bends should be eliminated. Storage tanks should be avoided where possible. If unavoidable, then an option to switch to direct feed by

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bypassing the tank is recommended. Storage tanks should be designed to minimize bacterial growth and facilitate routine disinfection (e.g. cone shape base). Level C 18.2.5 Ultrafilter In order to minimize chronic inflammation, use of ultrapure water is strongly recommended for all dialysis modalities. Ultrapure dialysate is a prerequisite for on-line haemofiltration or haemodiafiltration. The production of UPD, prevention of microbial proliferation and biofilm formation relie on: the use of two ultrafilters placed in series on the dialysis fluid pathway regular disinfection and hygienic maintenance of the water treatment system, pipe distribution system, dialysisproportioning machine, and the electrolyte concentrate, which include: o regular cleaning of the tubing with detergent to remove organic deposits o descaling with acid solution o disinfection with chemical/or heat-sterilizing agent o a good quality assurance programme that involves all dialysis staff, require strict protocol, good documentation of results and prompt corrective actions when necessary 18.3 Quality standards for chemical purity 18.3.1 Introduction Water use for conventional haemodialysis should comply with the requirements of AAMI/European Pharmacopoeia standard. (refer Appendix 1) Drinking regulation standards for water are based on a weekly exposure of 14 L with a selective gut barrier, while hemodialysis patients are regularly exposed to 300-400 L per week through nonselective dialyzer membrane. Furthermore dialysis patients having no urinary excretion ability are exposed to high risks of toxic substances accumulation. Hence water used for dialysis must comply with more stringent criteria. A combination of a variety of water treatment devices is needed to produce water that fulfills the established standard for chemical purity for dialysis.

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18.3.2 Treatment devices The decision making process requires three key input parameters: the purity of the water required the quality of the municipal water supply (chemical and microorganism levels) the amount of water required Water treatment systems can be divided into three sections: Pre-Treatment consisting of raw water storage tanks, sediment filters, softener, activated carbon filter and microfilters Primary Treatment involving one or more Reverse Osmosis devices The Distribution Loop for reverse osmosis water supply to the HD stations. a. Pre-treatment i.) Raw water storage tanks The material used should be of stainless steel (grade 304) or High density polyethylene (HDPE). The tank should be placed in a clean and safe environment with direct feed from the nearest main supply. The minimum size should be 1500 Litres to 2000 Litres and come complete with cover. The tank should be regularly inspected for dirt particles etc and cleaned at least once a year. ii) Filters Pre-filters, also known as sediment filters or sand filters, remove large particles ranging from 500 micron down to about 5 micron and are generally employed to remove particles and prevent fouling of devices further downstream. iii) Softeners Softening of the incoming water is necessary to avoid the hard water syndrome suffered by dialysis patients due to dialysis water contamination with calcium and magnesium, and to prevent calcium carbonate scale formation on other water treatment devices downstream. iv) Activated carbon filters Activated carbon filter is usually used as pre-treatment for removing dissolved organic contaminants, chlorine, and chloramines from water supply. Carbon adsorption beds (tanks) should be sized for the

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maximum of two tanks in a series configuration (one tank feeding the next) A sample port for testing the water after the first tank and before the next tank should be in place. Upon exhaustion (chlorine/chloramines breakthrough) of the first tank, the carbon media should be discarded and replaced with new, virgin carbon. The second tank should be moved to the first position, and the new tank placed in the last position. A formula is used to determine Empty Bed Contact Time (EBCT), and the goal is 6-12 minutes (3-6 minutes per working and polishing tank(s)). v) Microfilters Microfilters remove intermediate sized particles of 5-1 micron in diameter and are situated in the pre-treatment and primary treatment sections of the system in order of decreasing particle size cut-off. b. Primary treatment i) Reverse osmosis units RO units are the most effective method of treating water. They also prevent bacteria and endotoxin passage. Dissolved solids are unable to pass through the membranes enclosed, and pure water forms on the product side. All RO membranes are designed for cross-flow filtration so the feed water is separated into two streams: (a) permeate (RO water) of purified water which has passed through the membrane, and (b) concentrate which has a high concentration of contaminants. Conductivity is the vital measurement for an RO. The RO should provide AAMI quality water, and minimum rejection levels should be set. The RO membrane should be regularly flushed to prevent layering of contaminants on the membrane surface as these would reduce the effectiveness of the membrane. c. Distribution loop The product water distribution system should not contribute chemicals such as aluminium, copper, zinc and lead, or bacterial contamination to the final product water. It is advisable to use either stainless steel or crosslinked polyethylene (PEX) material for the piping system. Both direct (no storage tank) and indirect (storage tank system) water distribution systems should be configured as a continuous recirculating loop designed with the proper flow and velocity to minimize bacterial proliferation and biofilm. No dead

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ends or multiple branches should exist in the piping system, and the use of simple wall outlets with the shortest possible fluid path and minimum pipe fittings are recommended. 18.4 Maintenance and Quality Control 18.4.1 Control of Microbial Quality a. System Disinfection (refer 18.3.2.a, 18.3.2.b and 18.3.2.c) The water treatment system should be designed to allow routine disinfection of the entire system, including the distribution system and the connections to the dialysis machine. The entire system should be disinfected at least once a month. To disinfect the RO membrane a separate clean disinfectant tank is usually needed. The RO should be disinfected separately. Disinfection times should be according to the disinfectant instruction for use and the membrane manufacturers instructions for use. Germicides for disinfecting water systems include Formaldehyde (2-3 %), Sodium Hypochlorite (500ppm) ,Peracetic Acid (2-3%), Hydrogen Peroxide, Ozone, Chlorine dioxide and Hot water (> 80oC) To disinfect the RO water distribution Loop, a separate chemical tank with pump facility should be used. The disinfectant is introduced post RO membrane at the permeate side, through to all supply outlets and diverted back to the chemical tank via the RO return loop, before it enters the water system. The disinfectant should be distributed to all lines and tested positive for presence of disinfectant. After the required dwell time, ensure removal of disinfectant from the system before use and verify with a test strip.

b. Frequency of microbial testing (refer 18.4.2.c) For a newly installed water treatment system and distribution system, the microbial testing should be done at least once a week as part of the validation procedure for the disinfection programme. After completion of the validation, microbial testing ideally should be carried out at least once a month. Testing must also be frequent enough to pick up changes in the trend.

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c. Sampling location, timing and technique i). Daily test for chlorine Sampling location o Pre R.O sampling valve. Technique Colorimetric (Using HANNA Free Chlorine Test Kit) o Run the R.O system at least 10 to 15 minutes. o Open the Free Chlorine Test kit and check for damage. o Add 5 drops of reagent 1 and 3 drops of reagent 2 to the colour comparator cube. o Fill the colour comparator cube with water sample from POINT A (See diagram 1) o Replace the cap and mix by carefully swirling the cube in tight circles and inverting it several time. o Determine which colour band best matches the solution in the vessel and record the results in mg/L (ppm) free chlorine. (Refer figure 18.4.1.c.i)

ii). Daily test for hardness (Total Dissolve Solids) Sampling location o Pre R.O sampling valve Technique Using HANNA Hardness Kit o Collect water sample from sampling point into a 50 ml plastic container supplied (See diagram 2 below). o Add 5 drops of solution A. o Add 1 drop of solution B. o Titrate water with reagent supplied from a 1 ml syringe. o Observed colour change from purple to blue while adding reagent from syringe drop by drop. o Note volume of reagent used after the colour change. o Calculate total hardness : o Volume of titre x 30 = _________mg CaCO3 (Refer figure 18.4.1.c.i) iii). Monthly water analyses Water for microbial analyses Samples shall be collected at a point where water enters the equipment or any point where product water is dispensed. Sampling Site o Point A Feed water (raw water)

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o Point B o Point C o Point D o Point E o Point F

Pre treated water R.O water First distribution point Middle distribution point Last distribution point

Sampling technique (refer figure 18.4.1.c.iii)

o o o o o o

Flush sampling valve for a few second. Swab sampling valve nozzle with 70% alcohol or povidone iodine. Flush sampling valve for another few second. Repeat step 2 and 3. Collect mid stream water from sampling valve into a sterile container. Samples shall be assayed within 30 minutes of collection or shall be immediately stored at 4-6 C and assay within 24 hours of collection.

iv). Six monthly Water Analysis (refer figure 18.4.1.c.iii) Chemical contaminants analyses Collect sample from point C and send to analytical laboratory d. Technique of culturing water-borne microorganisms i). Many factors influencing the detection and quantification of micro-organism Factor
Sampling place Sampling hygiene Sample storage

Recommendations
Direct access to the stream to be sampled, avoidance of stagnant flow, flushing of the port Cleaning of the sample port with a bactericidal agent, sterile sample tube etc. Immediate storage of the sample at 4 C and plating of the samples within 24 hours ( to avoid additional growth) Sufficient sample volume Appropriate culture medium ( e.g. nutrient for Reasoners 2A agar or standard methods agar for water bacteria ) Appropriate length and temperature of incubation ( e.g. 24-28 C up to 7 days for water bacteria)

Sample size Choice of culture medium

Conditions of incubation

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Proper sampling procedures involving sampling process, sample storage and transportation are all of importance. Implement aseptic conditions during sampling o disinfect hands and sampling ports with disinfectants (alcohol swab/spray) o do not use ports which cannot be properly disinfected or rinsed o rinse tap ports with an adequate volume of sample medium prior to sampling. Samples must be transported/stored in sterile and pyrogen-free containers. Take an adequate sample volume: this is at least 10 ml for the determination of microbial counts and 3 ml for determining the endotoxin concentration. As microorganisms can continue to grow in samples it is necessary to cool samples in the fridge and analyze microbial counts within 24 hours. Endotoxin samples can be frozen and stored for a longer period of time. Standardize and document all procedures including: o sampling technique o sampling time points, e.g. on Monday/Saturday after a long shut-down period o personnel responsible for sampling o sample storage and transport o methods for laboratory analysis o data interpretation and action protocol Document the cleaning and disinfection procedure for the water treatment and delivery system, as well as any changes made. ii). Determination of colony forming units (CFU) Viable microorganisms are assayed by three different methods with subsequent culturing on plates. Spread plate technique 0.1 to 1 ml of the aseptically collected sample are distributed over the surface of 15 ml dried culture agar on 9-10 cm culture plate with a sterile glass spreading rod. The plates are then incubated at 24 C for 7 days and colonies are counted at 48, 72 and 168 hours. Pour plate technique 1 ml of undiluted sample and samples in different dilutions are added to 10 ml of the appropriate medium agar and mixed. The agar

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should be held at 43 C in a water bath before use. The sample/agar mixed is poured onto 9-10 cm culture plates and incubated under the same conditions as described for the spread plate technique. Disadvantages of the method are that the organisms are submerged in the agar and the colonies tend to be smaller and do not show colony morphology characteristics. Recoveries of bacteria compared to the counts obtained with the spread plate method may, therefore, be decreased. Membrane filter method Sample volumes greater than 1 ml is filtered through a sterile membrane with a pore size not greater than 0.45 m and effective in retaining microorganisms. This filter is transferred under sterile conditions onto the appropriate culture medium on plates, whereby it should be ensured that the filter is not inverted. Nutrients diffuse through the filter so that colonies can grow on the filter surface. iii). Media for culturing water/ dialysate samples Nutrient-poor agar o Reasoners 2- Agar ( R2A) o Standard Method Agar ( SMA) o Tryptone Glucose Extract ( TGE) Sample incubation o At lower temperature (24-28 C ) o Duration: 7 days

e. Measuring endotoxin levels i). Why Endotoxin, or lipopolysaccharides, is essential components of the cell wall of gram negative bacteria, which when enters the patients blood stream it can cause pyrogenic reactions. It can be more important to test water and dialysis fluid for endotoxin than for bacteria as bacteria do not pass through intact dialyzer membrane readily. The possibilities of dialysis patients exposed to greater levels of these microbial products has increased with the increase in reuse, the use of bicarbonate dialysis fluid and high flux dialysis. The consequence of microbial contamination besides acute pyrogenic reaction, is a state of chronic inflammation that may contribute to progressive inflammatory diseases in chronic renal failure such as

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2-microglobulin amyloidosis, protein catabolism, and accelerated atherosclerosis. ii). How Bacterial endotoxin levels should be monitored using the Limulus Amoebocyte Lysate (LAL) assay. The simplest form of LAL assay is the gel-clot test which can be performed in the dialysis unit, provided staff has received the necessary training. In the gel-clot method, when a fluid sample containing ET is mixes with lysate from the blood of the horseshoe crab (Limulus polyphemus), a complex enzymatic reaction occurs. If sufficient ET is present, and the pH of the sample is 6 to 7.5, and there are no inhibiting substances, the solution will turn into a gelatinous clot. It is necessary to run appropriate assay control samples. Chemical germicides with low pH (<6.0) or dialysate concentrates with high salt content will inhibit formation of gel clot and give false negative results. The procedure described by the particular LAL manufacturer must be followed exactly. Hands on training of personnel are important. Other LAL tests include the colorimetric and turbidimetric assays. iii). When Dialysis fluid should be tested routinely for endotoxin to monitor the efficacy of the dialysis machine disinfection procedure. If the endotoxin levels in the dialysis fluid are significantly higher than in the water feeding the machine, the disinfection schedule or the method used should be modified. Dialysis fluid samples should also be tested if a patient experiences a pyrogenic reaction during dialysis. However the LAL assay will not detect all pyrogenic substances derived from bacteria. 18.4.2 Control of chemical quality a. Filter and resin maintenance i). Water softener In typical water treatment configurations, a water softener removes calcium and magnesium by ion exchange from the feed water before it reaches the RO system. The excess calcium and magnesium in "hard" water must be removed to prevent patient injury. However,

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the primary practical reason for removing these ions is to prevent them from "plating" on the RO membranes, resulting in deterioration of performance. The following risks are associated with the water softener: failure of the softener, resulting in high calcium or magnesium content in the water improper sizing or improper regeneration scheduling of the softener, resulting in increased hardness late in the cycle before regeneration; and regeneration of the water softener without bypass during treatment time, resulting in a large sodium concentration in the softener effluent stream and potentially causing severe patient injury or death due to hypernatremia

These risks can be minimized by the following monitoring and maintenance activities: Cheek the clock on the regeneration timer daily to ensure the proper setting. Record this information on the daily water treatment log sheet. Check the hardness of the water softener effluent daily before beginning dialysis. Confirm daily that there is an adequate supply of salt in the brine tank. Validate the appropriate sizing of and regeneration schedule for the softener by periodically checking the hardness of the water softener effluent at the end of the treatment day. Use only salt designed for water softeners.

ii). Carbon filtration Granular activated carbon (GAC) is used in water treatment systems to remove chlorine, chloramines, and some organic substances. While little has been published regarding the risks associated with organic materials in dialysis water supplies, the results of excessive chlorine or chloramines are well known. There are several literature reports of patient injury or death due to hemolysis when facilities did not adequately remove chloramines before initiating dialysis (FDA 1988). The AAMI -recommended maximum contaminant level for chloramine is 0.1 milligrams per liter (mg/L). Two tanks filled with granular activated carbon should be used in series. Each

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of these tanks should have a minimum empty-bed contact time (EBCT) of 3 to 5 minutes. The effluent of the first tank should be monitored before every patient shift to ensure that the chloramine content is below the AAMI standard level. If the level of chloramine exiting the first tank exceeds 0.1 mg/L, a sample should immediately be drawn from the water exiting the second tank. If that water meets the AAMI standard, dialysis can proceed; however, arrangements should be made to replace the first tank. If the chloramine level in the effluent of the second tank also exceeds 1 mg/L, that water must not be used for dialysis. iii). Sediment filters The sediment filter is usually placed just before the RO system to prevent dirt, suspended materials, pieces of water softener resin, carbon fines, or other matter from damaging or plugging the RO membranes. Risks associated with sediment filters include algae growth in the filter housing and clogging of the filter, resulting in excessive pressure build up and filter failure and thus the flushing downstream of dirt and other debris trapped by the filter. The risks associated with sediment filters can be minimized by the following design, maintenance, and surveillance practices: To prevent algae growth, use only opaque housings on sediment filters. Incorporate pressure gauges before and after all sediment filters, and monitor pressures at least daily. Whenever the pressure drop between the two gauges exceeds 10 pounds per square inch (psi) or the value recommended by the manufacturer, the filter should be changed. To prevent excess bacterial growth and to prophylactically guard against other contaminant build up, many manufacturers recommend that the filter be changed monthly even if the pressure drop does not exceed 10 psi. iv). Reverse osmosis systems Reverse osmosis systems use pressurized filtration (pressures capable of overcoming the osmotic pressure of solutes) to remove chemical contaminants at a rate of 95% to 99% and microbiological contaminants (bacteria, bacterial endotoxins, viruses) at a rate of

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approximately 99%. The following risks are associated with the use of RO systems: membrane failure, allowing large amounts of chemical or microbiological contaminants to pass downstream, progressive membrane failure, resulting in either reduced flow rates or some passage of chemical contaminants; and, bacterial colonization, resulting in possible pyrogenic reactions or septicaemia. These risks can be minimized by the following design, maintenance, and monitoring practices: Employ appropriate pre-treatment components to protect the RO system and optimize its performance (e.g., a water softener to remove excess calcium and magnesium, which would "scale" on the RO membrane; carbon filtration to remove excess chlorine, which would also damage the RO membrane; particulate filtration for removal of silt, which could clog the RO system; a temperature-blending valve to assure a feed-water temperature for optimum RO system performance). Equip the RO system with a continuous monitor for conductivity, which can be set to activate visible and audible alarms if the percent salt passage exceeds two times that validated when the membranes were initially installed. Such alarms indicate to the facility that cleaning or other service of the RO system may be necessary to maintain proper operation and cost-effectiveness. Such alarms also alert the dialysis staff to any massive failure of the system, which could result in a percent rejection level lower than that needed to produce "chemically safe" water for hemodialysis. Performing a reduction ratio analysis on "worst-case" tap water will allow the dialysis staff to estimate that minimum percent rejection level. Periodically perform a quantitative analysis of the chemical contaminants listed in the AAMI standard (table 1). Monitor other RO system parameters daily, and document the results. Data on such parameters as pressure and flow rate are important in evaluating the safe and effective operation of the system. Whenever any significant change occurs in pressure or flow rate, the cause of the change should be determined and addressed. 1998 Association for the Advancement of Medical Instrumentation AAMI WQD

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b Frequency of maintenance and testing i). Daily 15 minutes after starting R.O. Document in R.O. Water daily log sheet o Raw Water pump pressure (30-90 psi) o Guard filter in / out (diff. pressure < 15 psi) o Product water pressure (20-40 psi) o RO filter pre / post (max. diff. 15 psi) o Product water flow rate. o Reject water flow rate o Product conductivity o Test hardness of post-softened water o Test the chlorine/chloramines of the product water ii). Weekly Maintenance Multimedia Sand Column Manual / Auto regeneration (backwash) 3x/week (Monday, Wednesday & Friday)* Carbon Column Manual /Auto regeneration (backwash) 3x/week (Tuesday, Thursday & Saturday)* Softener resin Manual /Auto regeneration once per week (Sunday)* Municipality water Frequency depends on pre and post pressure difference of column, chlorine and hardness test. iii) Monthly Change guard filter if the pressure difference is more than 15 psi Change bacteria filter at the R.O. storage tank if pressure difference is more than 15 psi. Check the UV light at the R.O. storage tank. R.O. water for bacteria culture and endotoxin level.*

iv). 3 Monthly Chemical wash of the R.O. membranes with Citric Acid and NaOH. (40gm in 10 liters of water)

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v). 6 Monthly Inspection of the Raw water tank o physical examination of the raw water tank o ball float valve o presence of impurities in the water o cleaning of the tank if necessary Pre and post R.O. water for analysis inclusive of TBC and Endotoxins o AAMI standards Disinfection of R.O. water distribution piping o peroxide base disinfectant 3% o formaldehyde 4%

vi). Multimedia Sand Column o change as recommended in the service manual o depending on the usage but usually once in 2-4 years. vii). Carbon Column o change as recommended in the service manual which is usually once in 2-4 years. o indication: chlorine/chloramine test positive or traces after a few regeneration of carbon column for a few days. viii). Softener Resin change as recommended in the service manual which is usually once in 2-4 years. o Indication: hardness test positive after a few regeneration of softener resin for a few days. c. Sampling location, timing and technique (refer 18.4.1.c)

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18.5 Checklist
FDA- Recommended Features of Water Purification Systems Component/System Feature

A Total Dissolve Solids (TDS) indicator should be provided for product quality as well as percent rejection The TDS alarm should be temperature-compensated
Reverse osmosis

Whenever the product quality alarm is activated, there should be an audible and visible alarm and permeate flow should divert to drain. All water-contact materials should be appropriate for this use and should pass a leachables test. A temperature-compensated, audible and visible alarm should be provided to indicate bed exhaustion. Ultrafilters or submicron filters should be provided on the product water output line for removal of bacteria and endotoxin.

Deionization

If used for primary purification, flow should divert to drain in the event of bed exhaustion, or an alarm should sound. Deionization should only be used when carbon filters are installed for pretreatment (to prevent formation of nitrosamines). All water-contact materials should be appropriate for this use and should pass a leachables test There should be a 6-minute empty-bed contact time (EBCT) for chlorine removal and a 10-minute EBCT for chloramines removal.

Carbon filters Water softeners

Two tanks should be installed in series (i.e. worker/polisher configuration), and chlorine/chloramines should be monitored after every shift. Regeneration lockouts should be included Product water must meet all applicable industry and government standards and should pass a leachables test. Failure analysis of the complete system must demonstrate safe operation in the event of a single component failure. Each component of the system must be labeled with the name and address of the supplier. The user must be supplied with clear and adequate instructions for startup, monitoring, maintenance, and troubleshooting of the system.

Complete system

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WATER TREATMENT SYSTEM LOG Mon DATE VALVES OPEN Water Supply Raw water tank inlet Raw water pump inlet/outlet Sand/Carbon/Softener Guard filter inlet SERVICE MODE / TIMER CHECK Multimedia Sand column Softener resin Carbon column 1 Carbon column 2 Brine tank (adequate salt) GAUGE READINGS Pressure pre multimedia sand Pressure pre softener Pressure pre carbon 1 Pressure pre carbon 2 Pressure Guard filter in Pressure Guard filter out Pressure pre RO filter Pressure post RO filter Permeate pressure Permeate flow Reject flow Permeate conductivity WATER TESTS Post Softener Hardness LOGGED BY: CHLORAMINES TESTS (<0.1 mg/L) Before 1st patient shift (initials) Before 2nd patient shift (initials) Before 3rd patient shift (initials) AUDITS (initials) * Suggested daily water treatment system log Tue Wed Thu Fri Sat

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Figure 18.4.1.c.i: Pre R.O sampling valve (daily test for chlorine and hardness)

Raw water

Dialysis machines

Sediment filter

Carbon Filter (x2)

Softener Sampling

R.O membrane

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Figure 18.4.1.c.iii: Sampling sites for water for microbial analyses

E
Dialysis machines

Raw water

Sediment filter

Carbon Filter (x2)

Softener

R.O membrane

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Appendix 1 Table 1 AAMI standard for hemodialysis water quality MICROBIOLOGICAL MONITORING Should be performed at least monthly. Total viable microbial counts shall not exceed 200/ml in water used to prepare dialysate, or 2000/ml in proportional dialysate exiting the dialyzer. CHEMICAL CONTAMINANTS MONITORING Should be performed at least yearly if prepared by DI or RO, more frequently if prepared with lesser level of treatment. AAMI maximum levels of contaminants* Contaminant Calcium Magnesium Potassium Sodium Fluoride Free chlorine Chloramines Nitrate (as N) Sulfate Copper, Barium, Zinc Aluminum Arsenic, Lead, Silver Cadmium Chromium Selenium Mercury Suggested Maximum Level (mg/L) 2 (0.1 mEq/L) 4 (0.3 mEq/L) 8 (0.2 mEq/L) 70 (3.0 mEq/L) 0.20 0.50 0.10 2.00 100.00 0.10 0.01 0.005 0.001 0.014 0.09 0.0002

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a) The physician has the ultimate responsibility for ensuring the quality of water used for dialysis. b) 230 mg/L (10 mEq/L) where sodium concentration of the concentrate has been reduced to compensate for the excess sodium in the water, as long as conductivity of water is being continuously monitored.

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Appendix 2
Recommendation ERA-EDTA Best Practice Guidelines for Haemodialysis: Section IV. Dialysis fluid purity
Bacteria: < 100 cfu/ml Endotoxin: < 0.25 IU/ml Fungi and yeast: < 10 cfu/ml

EDTNA/ERCA Guidelines for the control and Monitoring of microbiological contamination in water for dialysis
Total viable count:<100 cfu/ml (action level 25 cfu/mi) Endotoxin: <o0.25 IU/ml (action level 0.125 IU/ml) Suggested limit for fungi and yeast: 10 cfu/ml At least weekly during validation phase At least monthly during normal maintenance

Minimum requirement for water used for production of dialysis fluid Frequentcy of monitoring water used for production of dialysis fluid for microbiological contamination Frequency of monitoring dialysis fluid for microbiological contamination Requirements for ultrapure dialysis fluid (UPD)

Weekly during validation phase At least quarterly during normal use (more frequently if used for online production of substitution fluid) Regular checks to optimize disinfection cycles

A representative sample of machines should be tested for endotoxin each month

Undetectable bacteria level Undetectable endotoxin level UPD can be used as substitution fluid Tryptone Glucose Extract Agar or Reasoners 2A Culture at 20 to 220C for 7 days Tryptone Glucose Extract Agar or Reasoners 2A Culture at 20 to 220C for 7 days Limulus Amoebocyte Lysate (LAL) assay (gelclot, turbidimeter or chromogenic) with detection limit of 0.03 IU/ml

< 0.1 cfu/ml < 0.03 IU/ml UPD must be further purified for used as substitution fluid Tryptone Glucose Extract Agar or Reasoners 2A Culture at 20 to 220C for 7 days Malt Extract Agar or Sabourauds Dextrose Agar Culture at 20 to 220C for 7 days LAL assay (gel-clot, turbidimeter or chromogenic) or other validated techniques. Dialysis fliuid samples must be diluted to prevent interference

Incubation conditions for bacteria Incubation conditions for fungi and yeast Endotoxin test method

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References: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. E.Bonnie-Schorn: Water Quality in Hemodialysis. Good dialysis practice; Vol 1-1998 Pabst Science Publisher Robert A Laurence: Quality of hemodialysis water, A 7-year Multicenter study. Am Jour of Kidney Disease, Vol 25,No 5(May), 1995;pp 738-750 Arvanitidou A: Microbiological quality of water and dialysate in all haemodialysis centers in Greece, Nephrol Dial Transplant (1998) 13:949-954. Lonnemann G :assessement of the quality of dialysate,Nephrol dial transplant(1998) 13 (Supp 5):17-20. Lonnemann G :The quality of dialysate: An integrated approach,Kidney International,Vol. 58,Suppl, 76(2000)pp. S-112-119. Pass T: Culture of dialysis fluids on nutrient-rich media for short periods at elevated temperatures underestimate microbial contamination,Blood Purification, 14(2):136-45,1996. Harding GB: Bacteriology of hemodialysis fluids:are current methodologies meaningful?, Artificial organ,16(5):448-456,1992 Oct. Klein E. Microbial and endotoxin contamination in water and dialysate in the central United State,Artif Organs,14(2):85-94, 1990 Apr. Brunet P, Berland Yvon: Water quality and complications of haemodialysis. Nephrol Dial Transplant 15:578-580, 2000 Lonnemann G: Should ultra-pure dialysate be mandatory? Nephrol Dial Transplant 15(Suppl 1):55-59, 2000 Ward RA: Ultrapure dialysate: A desirable and achievable goal for routine hemodialysis. Semin Dial 13(6):378-380, 2000 Lonnemann G: Chronic inflammation in hemodialysis: The role of contaminated dialysate. Blood Purif 18(3):214-223, 2000 Lonnemann G: The quality of dialysate: An integrated approach. Kidney Int 76(S112-119), 2000 Tielemans C: Are standards for dialysate purity in hemodialysis insufficiently strict? Semin Dial 14(5):328-329, 2001 AAMI Dialysis Monograph 3rd Edition

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Glossary AVF BP BUN CAPD CRF DFO EBPG EPO ESRD GFR Hb HD HDF K/DOQI Kt/V KUf LMWH PCR PD PO4 RO URR Arteriovenous fistula blood pressure Blood urea nitrogen continuous ambulatory peritoneal dialysis chronic renal failure Desferrioxamine European Best Practice Guidelines erythropoeitin end stage renal disease glomerular filtration rate haemoglobin haemodialysis haemodiafiltration Kidney Disease Outcomes & Quality Initiatives K = urea clearance t = time on dialysis V = total body water volume Ultrafiltration coefficient Low molecular weight heparin protein catabolic rate peritoneal dialysis phosphate Reverse osmosis Urea reduction ratio

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CRITICAL CARE NEPHROLOGY

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19: PRINCIPLES AND TECHNIQUE IN CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT) CRRT is any extracorporeal blood purification therapy intended to substitute for renal function over an extended period of time and applied for, or aim at being applied 24 hours a day.1 There is insufficient evidence for the effectiveness of CRRT over intermittent haemodialysis in patients with acute renal failure. Most observational studies have reported improved survival with CRRT.2,3 However, some reported poor outcome. 4,5 19.1 Definitions 19.1.1 Convection : flow of solute across a semipermeable membrane with solvent which is dependent upon transmembrane pressure. 19.1.2 Diffusion: flow of solute across a semipermeable membrane driven by a concentration gradient. 19.1.3 Replacement fluid: special solution used to replace ultrafiltrate during haemofiltration or haemodiafiltration 19.1.4 Post dilution: replacement fluid infused post filter. 19.1.5 Predilution: replacement fluid infused prefilter. 19.1.6 Ultrafiltrate: plasma water and ultrafiltered solute produced during ultrafiltration or haemofiltration of blood. 19.1.7 Ultrafiltration control system (UFC): technique whereby ultrafiltrate production is controlled by volumetric pump. 19.2 Types of CRRT 19.2.1 Continuous Venovenous Haemofiltration (CVVH) Blood is driven through a highly permeable membrane by a pump via an extracorporeal circuit originating from a vein and terminating in a vein. The ultrafiltrate produced is replaced in part or completely with appropriate replacement solution to achieve blood purification and volume control. Ultrafiltration in excess of replacement fluid results in weight loss. The replacement fluid can be infused either before(predilution) or after the filter(post-dilution). 19.2.2 Continuous Venovenous haemodialysis(CVVHD) Slow countercurrent dialysate flows into the dialysate compartment of the dialyser. Blood flow is pump driven, beginning and terminating in a vein. Fluid replacement is not administered. Solute clearance is mostly diffusive. Solute removed may vary depending on the choice of membrane.

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19.2.3 Continuous Venovenous Haemodiafiltration (CVVHDF) Combines both the process of CVVHD and CVVH. Fluid replacement is routinely administered to maintain desired fluid balance. Fluid replacement can be infused either before or after the filter. Solute removal is both diffusive and convective. 19.2.4 Slow Continuous Ultrafiltration (SCUF) Similar to CVVH but no fluid replacement required. Volumetric control of ultrafiltration is necessary to maintain the ultrafiltration rate. Table 19.1 Mechanism of function and membrane type.6,7,8
CVVH CVVHD CVVHDF

SCUF Low Low No Poor 100-200 0 High flux

Diffusion Clearance Convective Clearance Fluid Replacement Middle Molecule clearance Blood Flow mls/min Dialysate l/hr Membrane type

Low High Yes Good 100-200 0 High flux

High Low No Poor 100-200 1-2.5 Low flux

High High Yes Good 100-200 1-2.5 High flux

19.3 19.3.1 19.3.2 a. b.

Recommendation for Clinical Practice: Arteriovenous therapy should be reserved for settings in which venovenous therapy cannot be provided because of absence of adequate equipment or personnel.8 (Level D) Choice of treatment Studies have shown relative equivalence between convective (CVVH) and diffusive (CVVHD) clearance for low molecular weight solutes.2,9,10,11 (Level A). Convective transport provides higher clearance for middle /high molecular weight molecules. 3,10,11 There is considerable variability based on membrane type.1

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(Level A) c. Data is inconclusive on adsorptive ability of membranes for proinflammatory mediators and its clinical impact.4 (Level D) d. There is no data comparing patient outcome between convective and diffusive therapies. 19.3.3 Recommendations for clinical practice: No recommendations regarding use of convective therapies compared to diffusive therapies can be made. 19.4 Indications for CRRT in patients with ARF There is no consensus on exact indications of CRRT.12 Some criteria for the decision to start CRRT have been proposed. 13

19.4.1 Non obstructive oliguria (urine output < 200mls/12hr) or anuria. 19.4.2 Severe metabolic acidosis 19.4.3 Azotaemia (blood urea > 30 mmol/l) 19.4.4 Hyperkalaemia (K+ > 6.5mmol/l) 19.4.5 Suspected ureamic organ involvement (pericarditis, encephalopathy) 19.4.6 Progressive severe dysnatraemia (Na > 160 or< 115mmol/l) 19.4.7 Hyperthermia (core temperature > 39.5oC) 19.4.8 Clinically significant cerebral or pulmonary oedema 19.4.9 Coagulopathy requiring large amounts of blood products in patients with pulmonary oedema 19.4.10 Overdose with dialysable drugs 19.5 Non-renal indication for CRRT There is insufficient evidence to recommend the use of CRRT for non renal indications. 12,14 19.6 Patient Selection CRRT is usually used in 19.6.1 Severely ill patients in intensive care. 19.6.2 Haemodynamic instability. 19.6.3 For continuous removal of fluid, toxic substances eg. in septic shock, ARDS, cerebral oedema. 19.7 Timing of initiation of CRRT No recommendation on the timing of initiation of CRRT but treatment should be started early before complications develop.15,16

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19.8

Decision to stop CRRT Decision is influenced by 19.8.1 Haemodynamic status 19.8.2 Urine output 19.8.3 Volume status 19.8.4 Staff availability 19.8.5 Cost 19.8.6 Circuit clotting.
.

Figure 19.2.1 CRRT techniques: CVVH R V P Uf Qb = 100- 200 ml/min Qf = 10-20 ml/ min V

Figure 19.2.2 CRRT techniques: CVVHD

V V
Dialysate Out Qb = 100- 200 mls/ min Dialysate In Qf = 1-5 ml/ min

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Figure 19.2.3 CRRT techniques: CVVHDF

P R V
Dialysate out + Uf Dialysate in

P
Qb = 100-200mls/ min Qd = 16-40 ml/ min Qf = 8-15mls/min

Figure 19.2.4 CRRT techniques: SCUF

P V
UFC

Uf
Qb = 100- 200 ml/min Qf = 2-8 ml/min

Key: V= Vein Qb= Blood flow Qd= Dialysate flow UFC= Ultrafiltrate controller

R= Replacement fluid Qf= Ultrafiltration rate P = Blood pump

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References.
1. 2. 3. 4. 5. 6. 7. 8.

9.
10. 11.

12. 13. 14.

15.
16. 17. 18.

ADQI: Workgroup 1,2001. Definition and Nomenclature, Reporting of CRRT Techniques. Kruezynski K, Irvine-Bird K, Toffelmire EB, et al: A Comparison of continuous arteriovenous haemofiltration and intermittent hemodialysis in acute renal failure patients in the intensive care unit. ASAIO Journal 1993:39; 778-781. Bellomo R, Farmer M, Parkin G, et al: Severe acute renal failure: A comparison of acute continuous haemodiafiltration and conventional dialytic therapy. Nephron 1995:71;59 -64. Bosworth C, Paganini EP, Cosentino F, et al; Long term experience with continuous renal replacement therapy in intensive care unit; acute renal failure, Contrib Nephro 1991 : 93:13-16. Van Bommel, Bouvy ND , So KL. et al: Acute dialysis support for critically ill: intermittent hemodialysis versus continuous arteriovenous haemodiafiltration . American Journal of Nephrology 1995;15:192-200. ADQI, 2001: Workshop 5, Operational Characteristic . Rinaldo Bellomo, Claudio Ronco, Critical Care Nephrology, Kluwer Academic Publishers,1998 ,1169-1176. Rinaldo Bellomo, Claudio Ronco, Ravindra Mehta, Nomenclature for Continuous Renal Replacement Therapies. Am Journal of Kidney Disease, Nov 1996,, Vol 28;no 5,Suppl 3, S2-7. Robert Udhall; Vascular Access for Continuous Renal Replacement Therapy: Seminar in Dialysis, March-April 1996, Vol 9, No. 2, 93-97. Davenport A, Will EJ, Davison AM et al, Changes in intracranial pressure during haemofiltration in oliguric patients with Grade V Hepatic Encephalopathy. Nephron,89:53;142-146. Ronco C, Bellomo R, Brendolan A, et al, Brain density changes during renal replacement in critically ill patients with acute renal failure. Continuous haemofiltration versus intermittent hemodialysis. J Nephrology, 1999:12 :173178. ADQI:2001,Workshop 2, Selection of patients for acute extracorporeal renal support in general and CRRT in particular. Bellomo R, Ronco C: Continuous haemofiltration in the intensive care unit. Critical Care 2000:4:339. Miet Schetz, Non renal indications for renal replacement therapy, Kidney International, Nov 1999, Vol 56; Suppl 72,S88-99. Lettering LG, Reynolds HN, Scalea: Outcome in post traumatic acute renal failure when continuous renal replacement therapy is applied early versus late: Intensive Care Medicine, 1999; 25; 805-813. Proceedings of 2nd International Course on Critical Care Nephrology May 2225; 2001. Mehta RI, Letteri JM: Current Status of renal replacement therapy for acute renal failure. American Journal of Nephrology 1999:19:377-382. Rinaldo Bellomo; Choosing a Therapeutic Modality; Hemofiltration versus Haemodiafiltration; Seminar in Dialysis Vol 9, No. 2, March April 1996, 88-92.

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20. VASCULAR ACCESS

20.1 Introduction 20.1.1 Central venous catheter provide rapid and easy access in the critically ill patients 20.1.2 CRRT can be operated with the use of a single double lumen catheter inserted in any central vein but require the use of a blood pump to circulate the blood through the extra corporeal circuit. An air bubble detector monitoring system is required to avoid air embolism.1,2
20.2 The placement of catheter can be at: 20.2.1Femoral vein a. The insertion is located approximately 1-2 cm below the inguinal ligament and 1 cm medial to femoral artery. b. Cannulation of femoral vein for central access is the primary choice in critically ill patients. c. Usage of femoral catheter should be restricted to 2 weeks.3,4 (Level C). 20.2.2 Internal jugular vein(IJV) a. IJV cannulation has become more popular. b. The right IJV is preferred, offering a shorter distance to reach the right atrium. 5 20.2.3 Subclavian vein a. Cannulation of subclavian is associated with subclavian vein stenosis and thrombosis, especially when a semirigid or poorly haemocompatible catheter is used. 5,6 b. The right subclavian is preferred to reduce the distance from insertion site to right atrium. c. The left subclavian is more difficult to cannulate and is exposed to higher risk of thrombosis. 7 d. A straight tipped guide wire should never be used in the subclavian or jugular veins as they may perforate the apex of the right ventricle and cause cardiac tamponade. Jtipped guide wires should be used. 7,8 . Movement of the patient is made easier if catheters are Inserted in the IJV or subclavian compared to if they are in the femoral area. 20.3 Catheter length used. 3,7 (Level C) 13.3.1 (R) Subclavian or internal jugular vein 13.3.2 (L) Subclavian or internal jugular vein 13.3.3 Femoral (R + L) 15 cm 19-20cm 25-35cm

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20.4 Ideal position of tip of central venous catheter.3,7 20.4.1 Subclavian or Internal jugular: Just above junction between superior vena cava and right atrium. 20.4.2 Femoral Vein: In the inferior vena cava. (Level C) References:
1. 2. 3. Robert Udhall, Vascular Access for Continuous renal Replacement Therapy, Seminar In Dialysis, 1996: Vol 9; No 2: 93-97. ADQI ,2001,Workgroup 5, Operational Characteristic. C Ronco, K. Bellomo, G La Greca, Proceeding of the 2nd International Course in critical care nephrology Vienna May 22-25 ; 2001. Blood purification in intensive care . Karger Publisher. W Weyde, I Wikiere, M Klinger; Prolonged cannulation of femoral vein is a safe method of temporary vascular access for hemodialysis. Nephron, 1998; 80; 86. George E. Cimochowski, Edward Worly, E.E Rutherford, et al, Superiority of internal jugular over the subclavian access for temporary dialysis, Nephron; 1990; 54;154-161. BB.De Moor, R. Vanholder, S. Ringoir , Subclavian vein hemodialysis catheters; Advantages and disadvantages. .Artificial Organ 1994, No.4, 293-297 William T. Mcgee, Barbara L, Ackerman, R. Rouben, et al, Accurate placement of central venous catheters; A prospective randomized multicenter trial. Critical Care Med. Vol 21; No 8; 1118-1123. John Stephen Tapson, Robert Udhall. Fatal hemothorax caused by subclavian hemodialysis catheter. Arch Intern Med; 1984, Vol 144, 1685-1687. Rita A Mankus, Stephen R. Ash, James M Sutton, Comparison of Blood Flow and Hydraulic Resistance between the Mahukar catheter, the Tesio Twin catheter and the Ash Split catheter, ASAIO Journal, 1998; m532-m534. Leblanc Martin, Bosc JY, Vaussenat F, et al, Effective blood flow and recirculation rate in internal jugular vein catheter; Measurement by ultrasound velocity dilution. Am J Kidney Dis, 1998; 31; 87-92. Bambauer R, Mestres P, Pirrung KJ. Frequency, therapy and prevention of infection associated with large bore catheter. ASAIO, 1992; 38 :96-101. Micheal Wanscher, Jens Jorgen Frifelt, Christian Smith, et al, Thrombosis caused by polyurethane double lumen subclavian catheter and hemodialysis, Critical Care Medicine, 1998, Vol 16, No 6, 624-628. Jean Francois Timsit, Fabrice Bruneel, Christine Cheval. Use of tunnel femoral catheters to prevent catheter related infection. Ann Intern Med. 1991;130 ;729735. Leonard Mermel; Catheter related infections and their prevention. Is there enough evidence to recommend tunneling for short term use. Critical Care Med; 1998; Vol 26; No 8; 1315-1316. Theodore F. Saad, Bacteraemia associated with tunneled, cuffed hemodialysis catheters. Am J Kidney Dis, 1999; Vol 34; No 6(December),1114-1124. Vanita Jarssal, Adreas Pierratos, Vascular Access for renal replacement therapy, Critical Care Nephrology, 1998, Kluwer Publisher, 1177-1

4.

6 7

8
9 10 11 12

13
14

15

16

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21: ANTICOAGULATION One of the major drawback of CRRT is frequent filter clotting. This increases the cost of treatment, reduces efficiency of therapy and may affect patients outcome. Anticoagulation is therefore routinely used to optimize filter life. Unlike intermittent haemodialysis, in CRRT the patients exposure to anticoagulation is much more prolonged, thus increasing the risk of bleeding and other side effects. 21.1 Bleeding risk stratification:1.2.3 21.1.1 High risk Group a. Platelet count <100,000/ul with coagulopathy. b. Liver failure c. Immediate post-operation d. Patient with bleeding. 21.1.2 Moderate risk group a. Platelet count >100,000/ul with coagulopathy. 21.1.3 Low risk group a. Normal platelets and no coagulopathy. 21.2 Priming: 1-2 liter normal saline containing 2,000-5,000unit/L heparin (except in severe bleeding or heparin induced thrombocytopaenia) is flushed into the extracorporeal system and drained out prior to connection. 4
21.3 Normal Heparin 4 For those without contraindication, initial dose of 1,0002,000unit heparin bolus is given into inflow limb (prefilter), followed by continuous infusion 5-10unit/kg/hour. 21.3.1 Monitoring of anticoagulation profile should be done one hour after starting CRRT and every 4-6 hourly unless there is a change in heparin dose, which requires a repeat ACT/ PTT one hour after dose alteration. 5 21.3.2 Partial thromboplastin time is aimed at 1.5-2.0 X control or ACT at 150-200 second { Normal ACT value for uraemic patients: 100 seconds (62-138sec); Non uraemic: 90seconds.6 21.3.3 Post- filter blood sampling is preferred in patients without bleeding risk and prevention of filter clotting is the main goal. 21.3.4 Systemic sampling is used in patients with bleeding risk, or requiring systemic anticoagulation for other reasons.7 21.3.5 Heparin infusion should be stopped once there is evidence of bleeding or severe heparin induced thrombocytopaenia.

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21.4 Low Dose Heparin: 1 21.4.1 Used in patients with moderate risk of bleeding. 21.4.2 No data available regarding bolus dose at initiation. 21.4.3 Maintenance dose:5 unit/kg/hour. 21.5 Heparin Free: 21.5.1 For high risk patients. 21.5.2 Priming with saline is appropriate 1. 21.5.3 Flushing of the system (prefilter) with 100ml-250ml saline every hour or more frequent if necessary. 21.6 Low Molecular Weight Heparin(LMWH) 21.6.1 LMWH may have a role in CRRT, but so far the reported experience in continuous dialysis is insufficient for us to make a strong recommendation. 1,8-13 (Level D) 21.6.2 Types of LMWH available : a. Fraxiparin b. Enoxaparin 21.6.3 Recommended dosage: a. Fraxiparin : 0.4ml( <50kg) or 0.6ml (>50kg) every 12hourly. b. Enoxaparin: Initial dose: 40mg. Maintenance: 10-14mg every 4-6 hours or infusion at the rate of 0.4 -0.6 mg/kg/day. 21.6.4. Monitoring: a Measure anti Xa level, b. Target : 0.25 U/ml ( Level of >0.45 U/ml have been shown to be associated with bleeding complication. 14,15 21.7 Regional Heparinisation 21.7.1Heparin is infused into inflow limb and protamine is infused on the return line. 21.7.2Dosage: 1mg of protamine will neutralizes approximately 100units of heparin. 21.7.3In CVVHD it has not been shown to prolong filter life nor to reduce bleeding complications compared with low dose UH36 . (Level B) 21.8 Alternatives For Anti-coagulation in CRRT: 21.8.1 Prostacyclin. 6,7,8,9,10. 21.8.2 Citrate References: Please refer to chapter 23

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22 : REPLACEMENT FLUID AND DIALYSATE To maintain fluid balance in haemofiltration or haemodiafiltration the replacement fluid used during CRRT should contain physiological concentrations of electrolytes, except in patients with extreme electrolyte imbalance. Most commercially available solutions do not contain phosphate and supplementation is generally required at some stage during CRRT. 16The serum concentration of phosphate and magnesium should be monitored and replaced accordingly.17 Fluid with high glucose content results in hyperglycaemia and should be avoided. During CVVH/CVVHD there is a loss of bicarbonate up to 1,000 mmol/day and these needs to be replaced.18 22.1 Types of replacement fluid: 22.1.1Lactate based solution: Ringers lactate (caution in hyperkalaemia) a. Lactate based replacement fluid is safe and effective for reversal of acidosis in the majority of ICU and acute renal failure patients. b. Lactate is converted to bicarbonate in the liver on an equimolar basis at rate of 100 mmol/hour.13 c. Controlled trials (not all randomized) have shown that during CRRT, lactate or bicarbonate buffered solutions have similar efficacy for correction of metabolic acidosis.19-23. d. Lactate levels are generally higher with lactate solutions and may confuse the interpretation of blood lactate level. 22.1.2Bicarbonate based solution e.g. Haemasol 32 mmol/l HCO3 a. Indications are: hepatic failure, lactic acidosis and high volume haemofiltration. Data does not show any survival benefit, but it provides better control of acidosis and cardiovascular stability. b. If Haemasol is not available the following formula can be used: 17 i) Single Bag Formulation: 1L 0.45% saline + 35ml 8.4% NaHCO3 (35meq) + 10ml 23.4% NaCl (40meq) +2ml 10% CaCl2 (2.8meq). ii) Two-bag Formulation: Solution A: 1L 0.9% saline + 5ml 10% CaCl2 (7mEq) Solution B: 1L 0.45% saline + 75ml 8.4% NaHCO3 (75meq) iii) Four Bag Formulation: Solution A: 1L 0.9% Saline + 7.5ml 10% CaCl2 (10.5meq)

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Solution B: 1L 0.9%Saline + 1.6ml 50% MgSO4 (6.4meq) Solution C: 1L 0.45%Saline Solution D: 1L 0.45% Saline + 150ml 8.4% NaHCO3 It is not advisable to use saline solution as the sole replacement fluid as it does not contain buffer 7. 22.2 Recommendations 22.2.1 Replacement fluid can be given either pre-filter (pre-dilution) or post filter (post-dilution) with their own advantages and disadvantages. 22.2.2 Pre-dilution fluid replacement is believed to enhance filter patency during CRRT and to reduce need for anticoagulant. 22.2.3 Pre-dilution enhances achievable ultrafiltration rate (important in high volume CVVH) and may be considered in patients with frequent clotting. 22.2.4 Combination of pre-dilution and post-dilution is needed when extracorporeal clearance is limited by achievable blood flow. 22.2.5 In patients who have no contraindication for anticoagulation, post-dilution is preferred.24 22.2.6 In CVVH (for post-dilution mode) ultrafiltration rate should not exceed 25% of blood flow; CVVH is generally performed with an average UF rate between 1 and 2 liters per hour.25 Table 22 : Advantages and disadvantages of pre and post filter replacement fluid Advantages Pre-filter - Reduced use of anticoagulant - allow high UF rate - solute clearance can be increase by increase UF rate - Reduce solute clearance because of dilutional effect -Required large amount of replacement fluid -Require more porous membranes and larger surface area in high volume UF Post filter -Higher solute clearance

Disadvantages

-Efficiency is limited by filtration fraction (25 % from Qb).

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22.3 Dialysate Types: 22.3.1 Lactate based e.g Peritoneal dialysis solution 1.5% dextrose. a. Although lactate metabolism may be impaired in acutely ill patients, the use of lactate buffered solution (PD 1.5%) has been shown to be safe and effective in both continuous haemodialysis and haemodiafiltration. b. As a result of the large glucose load (5.8gm 7.3 g/hour absorption) an increase in the mean serum glucose is seen especially at higher dialysate flow rates.26-28 c. Sodium concentration in PD solution is 132mmol/l which is lower than optimal may result in mild hyponatraemia. 29 22.3.2 Bicarbonate based solution (Haemosol) a. Bicarbonate buffered dialysate is required for patient with impaired lactate metabolism. Sources: Haemosol solution: Content Na: 140mmol/l , K: 0, Cl: 109.5meq/l, Ca:1.75mmol/l, Mg: 0.5mmol/l, Lactate: 3mmol/l, HCO3: 32.0mmol/l, Glucose: 0 22.4 Dialysate Flow Rate 22.4.1 With increasing Qd from 500ml/hour to 2500ml/hour in CVVHD, the clearance of small solute is increase from 8.6 ml/min to 40 ml/min.30-31 22.4.2 The efficiency of small solute removal during high dialysate flow rate in CVVHD is enhanced by using a large surface area filter (0.6-0.9m2).30 22.5 Recommendation: In hypercatabolic ARF patients on CVVHD/CVVHDF, the dialysate flow rate can be increased from 1000 ml/hour to a maximum of 2500 ml/hour. 22.6 Physical properties (temperature & sterility) of replacement fluid and dialysate 46 22.6.1 Most patients undergoing CRRT show a decrease of body temperature, the clinical consequences of which are illdefined. However a reduction of body temperature below 35oC should be avoided. (Level D) 22.6.2 Whereas the use of sterile substitution fluid is imperative, the bacteriological requirements for CRRT dialysate are less clear, except in high flux dialysis where dialysate should be sterile because of back-filtration. References: Please refer to chapter 23

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23: DRUGS AND DOSAGE IN CRRT 23.1 Drug remove by CRRT that requires a dose adjustment has: 23.1.1 Low protein binding 23.1.2 Low volume distribution 23.1.3 Low non-renal clearance Examples are aminoglycoside, Vancomycin, Fosfomycine and flucytocine 23.2 Twenty liters of daily ultrafiltrate correspond to a urea clearance of 14ml/min. Thus, the dosage of a drug should be calculated as for a patient with GFR of 14ml/min. Drug Dosing in CRRT
Drugs Amikacin Gentamicin Netilmicin Cefaclor Cefoperazone Cefotaxime Ceftazidime Ceftriaxone Cefuroxime Aztreonam Chloramphenicol Ciprofloxacin Clindamycin Erythromycin Imipenem Meropenem Metronidazole Sulphamethoxazole Teicoplanin Tetracycline Trimethoprim Vancomycin Amoxycillin Ampicillin Penicillin G Piperacillin Amphotericin B Fluconazole Itraconazole Ketoconazole T1/2 GFR<15 30-90hr 20-60 35-75 3 3 15-35 13-25 12-24 17 6-8 3-7 6-9 4 6 4 7 7-21 20-50 60-230 60-100 20-50 200-500 * 7-20 6-20 3-5 24 100 25 8 Usual dose 5mg/kg q8h or 15mg/kg q24h 1mg/kg q8h or 4mg/kg q24h As for amikacin 250-500mg q8h 1-2g q12h 1g q6h 1-2g q8h 1g q12h 0.75-1.5g q8h 1-2g q6-8h 12.5mg/kg q6h 0.5-0.75g q12h 150-300mg q6h 0.5-1g q6h 0.5-1g q6h 0.5-1g q6h 7.5mg/kg q8h 1g q8h 6mg/kg q24h 250-500mg q6h 100-200mg q12h 1g q12h 500mg q8h 0.5-1g q6h 0.6-2.4g q4-6h 3-4g q4h 20-60mg q24h 200-400mg q24h 100-200mg q12h 200mg q24h Dose in CVVH 2l/hr, Equal GFR:30ml/min 5mg/kg q12-18h or 15mg/kg q48-72h 1mg/kg q12-18h or 4mg/kg q48-72h As for amikacin 250-500mg q8h 1-2g q12h 1g q8-12h 1-2g q24h 1g q12h 0.75-1.5g q8-12h 0.5-1g q8h 12.5mg/kg q6h 0.25-0.5g q12h 150-300mg q6h 250-500mg q6h 0.5g q8h 0.5 q12 7.5mg/kg q8h 1g q18h 6mg/kg q48h 250-500mg q12-24h 100-200mg q18h 1g q24-48h 500mg q8-12h 0.5-1g q6-12h 0.6-1.8g q4-6h 3-4g q6-8h 20-60mg q24h 200-400mg q24-48h 100-200mg q12h 200mg q24h

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Co-trimoxazole Pentamidine Ethambutol Ethionamide Pyrazinamide Rifampicin Acyclovir Ganciclovir Zidovudine Amiadarone Carbamazepine Chlorpromazine Cimetidine Cyclophosphamide Cyclosporin Digoxin Flecainide Frusemide Haloperidol Hydrocortisone Ibuprofen Indomethacin Insulin Isosorbide dinitrate Isosorbide mono Lignocaine Mexiletine Metoclopramide Metoprolol Midazolam Morphine Naloxone Omeprazole Pancuronium Paracetamol Pethidine Phenobarbitone Phenytoin Prednisolone Procainamide Propranolol Pyridostigmin Quinidine Ranitidine Sotalol Theophylline Valproate Vecuronium Verapamil Warfarin

* 118 20 * 9 9 20 30 2 600 15 30 5 3.7 12 100 20 * 20 1.8 * * * 0.8 4.4 2 16 10 * 2.5 * 0.1-2mg * * 2.5 * 140 24 3.5 5.5 3.5 * * 6 * 12 15 * 5 *

160mg/400mg 12h 4mg/kg q24h 15mg/kg q24h 250-500mg q12h 25mg/kg q24h (max 2.5g qd) 600mg q6h 5mg/kg q8h 5mg/kg q12h 200mg q8h 10-15mg/kg/24h 200-400mg q8-12h 10-50mg q8h 200-400mg q6h * 2-5mg/kg/24h 250ug q24h 1-2mg/kg q8-12h 20-80mg q8h 0.5-5mg q8-12h 50-250mg q6h 400mg q8h 25-50mg q8h 0.5-10units/h 5-15mg q2-3h 40mg q8h 2g/24h 100-200mg q6-8h 10mg q8h 50-100mg q8-12h 2-8mg/hr 5-10mg q5-6h unchanged 10-20mg q24h 1-4mg/hr 0.5-1g q4-6h 50-100mg q3-4h 100-400mg q8-12h 250-500mg q24h 1mg/kg q24h 250-500mg q6h 10-40mg q6-8h 60-180mg q4h 200-400g q12h 100-150mg q12h 160mg q6-12h 10mg/kg q8-12h 0.3-1g q12h 40-80ug/kg/h 40-80mg q8h 0.5-8mg q24h

160mg/400mg q18h 4mg/kg q24h 15mg/kg q24-36h 250-500mg q12h 25mg/kg q24h (max.2.5g qd) 300-600mg q6h 5mg/kg q12-24h 5mg/kg q24-48h 200mg q8h unchanged unchanged unchanged 100-200mg q6h 50-75% usual dose unchanged 62.5mcg q24h 0.5-1.5mg/kg q8-12h 80-250mg q12h unchanged unchanged Not recommended Not recommended Unchanged Unchanged Unchanged Unchanged 50-150mg q6-8h 5mg q8h Unchanged Unchanged Unchanged Unchanged Unchanged 50% 0.5-1g q6-8h Unchanged 100-200mg q8-12h Unchanged Unchanged 250-500mg q12h Unchanged 60-120mg q6-8h Unchanged 50-75mg q12h 80mg q8h Unchanged Unchanged Unchanged Unchanged Unchanged

*data not available

148

References:
1. 2. 3. 4. 5. 6. 7. 8. Mehta, R.L. Critical Care Nephrology, 1998; 1199-1211. Herve. Anticoagulation: Seminar in Dialysis: April 1996; Vol. 9: 112-118. Ronco, C. Blood purification in intensive care: 2001; Vol.132. Mann, M. Continuous Renal Replacement Therapy: An Update; AJKD: 1998; 32(2): 8 Palevsky, PM. Continuous venovenous hemodialysis: Technical considerations : Up to date ACTest System, manufacture guideline. Ronco, C. Blood purification in Intensive Care. Contrib. Nephrology: 2001; Vol. 132,313-322. Reeves, JH et al. A control trial of low molecular weight heparin (dalteparin) versus unfractionated heparin as anticoagulation during venovenous hemodialysis with filtration. Critical Care Med. 1999; 27: 2224-2228. Jeffrey, RF et al. Anticoagulation with low molecular weight heparin (fragment)During continuous hem dialysis in the intensive care unit. Artif. Organ, 1993; 17:717-720. Hory, B et al. Continuous arteriovenous hemofiltration with a low- molecular weight heparin (letter). Nehru, 1985; 41: 125. Lorenzini JL et al. Continuous haemofiltration with a low molecular weight heparin enoxaparine: Report on two cases: Int. J Clin Pharmacol Theraphy Toxicol: 1991; 29:89-91 Wynckel, A et al. Guidelines to the use of enoxaparin in slow continuous hemodialysis: Contrib. Nephrol. Basel, Karger, 1991; Vol. 93, 221-224. De pont, ACJ et al. Nadroparin versus daltaparin anticoagulation in high volume continuous venovenous hemofiltration double blind randomized cross- over study. Blood Purif, 1997; 15, 123. .Hirsh, J et al. Heparin and LMWH, Mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficiency and safety. Chest, 1998; 114: S498-S510. Jeffrey, RF et al. Anticoagulation with Low Molecular Weight Heparin during continuous hemodialysis in intensive care unit. Artif Organs, 1993; 17, 717-720 Bellomo, R et al. Continuous arterivenous hemofiltration: Optimal therapy for renal failure in an intensive care setting? Autralia NZ L Med. 1990; 20, 237-242. Poul, M. Continuous Renal Replacement Therapy Component Selection: Replacement fluid and dialysis solutions. Seminars in dialsysis, 1996; Vol. 9, No.2(Mar- Apr), 107-111. Singler, MH. Solute transport in continuous hemodialysis, a new treatment for acute renal failure, Kidney Int., 1987; 32, 562-571. Leblane, M et al. Bicarbonate dialysate for continuous renal replacement therapy in intensive care unit patients with acute renal failure. Am J Kidney Dis. 1995; 26, 910-917. Kierdorf, H et al. Continuous venovenous hemofiltration in ARF, is bicarbonate or lactate buffered solution better ? Contrib Nephrol., 1995; 116, 38-47. Morgera, S et al. Comparison of lactate versus acetate base hemofiltration replacement fluid in patient with acute renal failure, Ren Fail, 1997; 19, 155164. Thomas, AN et al. Comparison of lactate and bicarbonate buffered hemofiltration fluids: use in critically ill patients. Nephrol Dial Transplant, 1997; 12, 1212-1217. Heering, P et al. Acid Base balance and substitution fluid during continuous hemofiltration, 1999; 56 suppl 72, S37-40. Brunet, S et al. Am J Kidney Disease, 1999; 34(3) Sept: 486-497.

9.

10. 11. 12. 13. 14 15 16 17 18 19 20 21 22 23 24

149

25 26 27 28 29 30 31 32

Ronco, C. CRRT, Evaluation in technology and nomenclature, Kidney Int., 1998;Vol. 53, suppl 66, suppl 160-164. Bellomo, R et al. Acute continuous hemofiltration with dialysis, effect on insulin concentration and glycemic control in critically ill patients. Crit. Care Med, 1992;20, 1672-1676. Bellomo, R et al. Continuous AV hemofiltration in the critically ill, influence on major nutrition balance. Intensive Care Med, 1991; 17, 399-402. Paleevsky, P et al. Slow continuous UF and dialysis for the treatment of acute renal failure, J Am Soc Neprhol, 1991; 2, 343. Paleevsky, P et al. Seminar in dialysis, 1996; Vol.9, No. 2, 107-111. Brunet, S et al. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rate, Am. J Kidney, 1999; Dis 34(3): 486- 492. Bonnardeaux et al. Solute clearances with high dialysate flow rates and glucose absorption from the dialysate in continuous arterioveneous hemodialysis. Am J Kidney 1992; Dis 19: 31-38. Bellomo, R et al. A prospective comparative study of continuous arteriovenous hemodialfiltration and continuous venovenous hemodialfiltration in critically ill patients. Am. J Kidney, 1993; Dis 21: 400- 404.

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24: DIALYSIS PRESCRIPTION 24.1 Membranes for CRRT 24.1.1 Membrane characteristics determine solute removal and water permeability 24.1.2 Based on hydraulic permeability, they can be classified into a. Low flux: ultrafiltration coefficient (Kuf) 4-8 ml/hr/mmHg b. High flux: Kuf > 20ml/hr/mmHg Kuf: is defined as the coefficient of hydraulic permeability of the membrane. 24.1.3 High flux membranes also have higher porosity and increased sieving coefficients for larger molecules 1,2 24.1.4 Most membranes in CRRT are high flux membranes made of synthetic polymers. These are also called haemofilters. 24.1.5 There is inconclusive evidence that the biocompatibility of the membrane affects mortality in critically ill patients with acute renal failure.3, 4,5,6 24.2 Recommendations for clinical practice 24.2.1 Based on current evidence, the use of synthetic membranes with high hydraulic permeability is appropriate.7 (Level D) 24.3 Optimisation of CRRT therapies 24.3.1 Small solute clearance is proportional to hemofilter or haemodialyser effluent flow rate i.e (QD or QD +QUF) 24.3.2 Solute clearance can be increased by a. increasing dialysate flow b. increasing ultrafiltrate flow rate or both c. using a hemodialyser with greater surface area 24.3.3 Higher molecular weight clearance can be achieved by increasing ultrafiltration rate using a haemofilter/ haemodialyser with high UF coefficient 24.3.4 Fluid removal can be maximized by using a haemofilter with high ultrafiltration coefficient .7(Level D) Examples of haemofilters/haemodialysers suitable for CVVH, CVVHD and CVVHDF include: a. Multiflow 60 or100 b. AN 69 c. F40 d. PAN-50 24.4 Assesment of menbrane function7 24.4.1 No accepted method to assess filter function in CRRT 24.4.2 Some useful indicators of filter function include:

151

Urea sieving coefficient ( ultrafiltrate urea /blood urea) > 0.6 (CVVH) b. Urea equilibration ratio ( dialysate urea /blood urea) > 0.6 (CVVHD/HDF) c. Filtration fraction < 0.2 (CVVH).7( level D) 24.5 Recommendations for clinical practice 24.5.1 Transmembrane pressure monitoring, urea sieving coefficient, urea equilibration ratio and filtration fraction may be used to assess filter function although there is no proven benefit.7 (Level D). 24.5.2 Duration of filter use should not exceed 48 hours. 24.6. Dialysis dose in CRRT 24.6.1. Recent data suggest renal replacement therapy dose may affect outcome in critically ill patients with ARF. 16,17 One study 18 suggests higher doses of clearance improved survival.22 (level A) 24.6.2 Various methods for dialysis quantification and prescription including urea kinetic Modeling and direct quantification techniques have been described. 22,23 There is no consensus on which approach is best. Markers of clearance have been suggested to be used as a basis of CRRT dosing (e.g urea clearance)23 24.6.3 For CRRT modalities (except predilutional CVVH, CVVHDF, SCUF), urea clearance may be equated to Qeff, effluent flow rate from the filter.This is equal to the sum of QD, dialysate flow rate and Quf, ultrafiltration rate for CVVHDF, or Quf for CVVH provided the Qeff < 50% Qb for CVVHD / CVVHDF.22 a.

Table 24:Variables used to measure clearance for the different forms of CRRT
Variable Qb Qd Quf CVVH ++ CVVHD ++ CVVHDF + +

(Qb) blood flow. (Qd) dialysate flow rate, (Quf) Ultrafiltration rate (-) not recommended, (+) Recommended, (++) Best

24.6.4.Data also suggests that adequate metabolic control is achieved when urea clearances equal or exceeds 2 l/hr. However the appropriate target clearance is not clear22,23 24.7 Recommendation for clinical practice: 24.7.1 The optimal technique for CRRT quantification in ARF remains to be determined.

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24.7.2 Based on the lack of data currently, specific target levels of azotaemia control cannot be recommended 24.7.3 Markers of clearance should be used for CRRT dosing.22 (Level D) 24.7 For CVVH, ultrafiltration of at least 35 ml/hr/kg is advocated. 24.8 Initiation of CRRT 24.8.1 Primary service should contact Nephrology Referral team to evaluate patient for CRRT 24.8.2 If appropriate, the Referral Team/ICU specialist will notify Critical Care Nephrology/ Haemodialysis Unit to set-up the CRRT system. Vascular access should be inserted 24.8.3 Prescription orders should be written up by Referral Team before the procedure is started and this should be reviewed every 8-12 hourly. 24.8.4 Baseline parameter required: a. Full blood count count b. Renal profile, random blood sugar c. Liver function tests d. PT, APTT, activated clotting time e. Serum calcium, phosphate, magnesium f. Hepatitis screen g. Arterial blood gas 24.8.5 Haemodynamic parameters required a. Central venous pressure b. Pulmonary artery wedge pressure if available c. Blood pressure d. Heart rate 24.8.6 Monitoring Parameters: a. ACT/APTT: 1 hour after initiation then 4 6 hourly and after 1 hour of any change in anti-coagulation b. Blood urea / serum electrolytes 6 hourly initially then bd once stable c. Daily serum calcium, magnesium, phosphate d. Daily full blood count e. Daily serum lactate f. Filtrate urea/blood urea ratio daily. Change filter if ratio < 0.6 g. arterial blood gases four hourly then prn when stable

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24.9 Sample of CRRT prescription form (Hospital Kuala Lumpur) Date Time

Start Finish

NAME AGE: SEX: Aquarius DIAGNOSIS Prisma Hospal INDICATION: RN:

TYPE OF THERAPY SCUF CVVHDF CVVH CVVHD

DIALYSATE: BICARBONATE: Bicaflac / Hemosol LACTATE: 1.5%PDSolution (Prisma/Hospal only) (Potassium addition see Table)

154

DIALYSATE FLOW RATE: REPLACEMENT: BICARBONATE RINGER`S LACTATE SALINE REPLACEMENT FLOW RATE: Pre-filter Post-filter

BLOOD FLOW RATE: ANTICOAGULATION: SALINE FLUSH: HEPARIN: BOLUS (units/hr) (See Table) ACCESS: FEMORAL SUBCLAVIAN Reason for Termination : Filter clotting Change of Modality Procedure Name of Doctor: Low BP Renal recovery Death MAINTAINANCE:

IJC

155

Potassium Replacement in Dialysate Serum K (mmol/l) K addition (per 5L bag) 50 mmol/l < 3.5 3.5- 3.9 40 mmol/l 4.0- 4.4 30 mmol/l 4.5- 4.9 15 mmol/l 5.0 or more 0 mmol/l ANTICOAGULATION Start @ 5-10 u/kg /hr ( intial bolus) Check APTT @ 4 hrs then 6 hrs followed by every 24 hrs APTT Heparin dosage Increase by 400u/hr < 40s 40-60s Increase by 200u/hr 61-80s No change Inform Doctor > 80s

References

156

1. 2. 3. 4. 5. 6.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17. 18. 19. 20. 21. 22. 23.

Clark WR, Hamburger RJ, Lysaght MJ : Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Kidney International 1999; 56: 2005-2015. Ronco C : Hemodialysis filters, What`s new: Current Opinion in Nephrology and Hypertension 1999; 8(6):709 -713. Hakim RM, Wingard RL, Parker RA. Effect of the dialysis membrane in the treatment of patients with acute renal failure. N Engl J Med 1994; 331:1338 1342. Himmelfarb J, Tolkoff RN, Chandran P, Parker RA, Wingard: .Hakim R: A multicenter comparison of dialysis membranes in the treatment of acute renal failure J Am Soc Nephrol, 1998; 9:257266. Schiffl H, Lang SM, Konig A, Strasser T, Haider MC, Held E. .Biocompatible membranes in acute renal failure: prospective case-controlled study. Lancet 1994; 344:570572. Jorres A, Gahl GM, Dobis C, et al. Haemodialysis-membrane biocompatibility and mortality of patients with dialysis-dependent acute renal failure: A prospective randomised multicentre trial. International Multicentre Study Group. Lancet 1999; 354:13371341. ADQI: Workgroup 4: Membranes 2001. Relton S, Greenberg A, Palevsky P: Dialysate and blood flow dependence of diffusive solute clearance during CVVHD, ASIO J, 1992; 38: 691-696. Brumet S, Leblanc M: Diffusive and Convective solute clearance during CRRT at various dialysate and ultrafiltrate rates: Am J Kidney Dis 1999; 34:486-492. Kellum J Diffusive vs Convective: Effect of mediators of inflammation in patients with severe systemic inflammatory response syndrome. Critical care Med 1998; 26:1995-2000. Maxvold NJ.: Prospective comparison between hemofiltration and hemofiltration with dialysis. Critical Care Med 2000; 28:1161-1165. Ronco C. Removal of platelet activating factor in experimental arteriovenous hemofiltration. Crtical Care Med 1995; 23:99-107. Van Bommel EF.Cytokine kinetics during continuous hemofiltration. Contribution Nephrology 1995; 116:62-65. ADQI. Working group 5: Operational Characteristics 2001. Storck M: Comparison of pump driven and spontaneous hemofiltration in postoperative ARF: Lancet 1991: 337:452. Van Bommel: Acute dialytic support for critically ill: intermittent hemodialysis vs continuous arterovenous hemodiafiltration: American J of Nephro 1995:15(3):192-200. Rondo C, Bloom R, Homely P: Effect of different doses in Continuous venomvenous haemofiltration on outcome in acute renal failure: a prospective randomized trial: Lancet, 2000: 56:26-30. Clark WR: Extra corporeal therapy requirements for patients with ARF: J Am Soc Nephi (in press) Chime CS: Protein catabolic rate in patients with ARF on CAVH: J Am Soc Nephrology 1993; 3:1516 1521. Kraus MA Acute dialysis catheter recalculation studies, Blood purification 1995: 14:255. Laurie Gnarred: Urea Kinetic Modeling for CRRT: Am J Kidney Dies 1997:30(5 Supply 4: S2-S9). ADQI: Workgroup 3: Solute Control (Treatment Dose) 2001. Clark W: Role of renal replacement therapy quantification in Acute renal failure: Am J Kidney Dies 1997:30(5 Supply 4: S 10-S14)

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PERITONEAL DIALYSIS

25. PATIENT SELECTION

158

Ideally continuous ambulatory peritoneal dialysis (CAPD) is best suited to patients who are independent, disciplined and motivated to care for themselves. They should be physically and mentally capable of performing the procedure. When the above characteristics are not available particularly in the very young and old patients, a fully committed and reliable trained assistant must be available. In new patients starting dialysis, the following factors may influence the choice of CAPD: 25.1. Psychosocial factors Patient preference and motivation Concern with body image Occupation Economic considerations Home and workplace environment Family support and availability of assistant Distance from nearest haemodialysis (HD) centre

25.2. Medical Factors Age Cerebro and cardiovascular disease Diabetes mellitus Blindness Peripheral vascular disease Severe pulmonary disease Lumbar disc problems Inflammatory bowel disease Previous extensive abdominal surgery Timing of referral Vascular access

In adults, medical factors play a role in the choice of modality only in a minority of patients.1 Once other psychosocial factors are eliminated, patient preference should determine the modality of therapy. Although the evidence is controversial, some diabetics and other high risk patients with severe cerebro- and cardiovascular disease

159

may be better managed on CAPD. The rapid change in solute transport and rapid shifting of volume within compartments during HD may result in HD being potentially more hazardous in these situations. CAPD is the dialysis modality of choice for children (vascular access is often problematic in this group of patients). For patients already on haemodialysis, CAPD may be indicated in the following circumstances: 1. Vascular access problems 2. Unstable cardiovascular status on HD 25.3. Absolute Contraindications Extensive peritoneal fibrosis and adhesions arising from previous surgery or inflammatory bowel disease. 25.4. Relative Contraindications 1. 2. 3. 4. 5. 6. 7. 8. Abdominal hernias. Hernias may need to be repaired before CAPD is started. Colostomy, ileostomy, nephrostomy and ileal conduits. These can lead to contamination of the catheter exit site. Poor vision, neurological and rheumatological disorders resulting in physical disability can make CAPD impossible to perform unless assisted. Psychological problems A psychotic, belligerent or uncooperative patient cannot be expected to succeed in CAPD. Chronic obstructive airways diseases. Severe diverticular disease of the colon. Chronic backache from preexisting lumbar disc disease. Morbid obesity.

26. PRE-DIALYSIS PREPAPARATION

160

26.1. Counselling and education Pre-dialysis counselling, careful psychological preparation and assurance can alleviate fear, anxiety and stress associated with the insertion of the Tenckhoff catheter, subsequent CAPD procedures and changes to their lifestyle. CAPD Units should have a formal educational plan and checklist to ensure consistency. However such teaching plans should also be flexible and adaptable to patient needs. 26.2. Early Start of CAPD Evidence that an early start of dialysis will improve outcome has been derived from studies showing that late referral to the nephrologist has detrimental effect on ESRD patients. 2,3 The PD committee of the NKF-DOQI recommends that some form of chronic dialysis be initiated once the weekly Kt/Vurea drops below 2.0.4 A weekly Kt/V of 2.0 approximates a renal creatinine clearance of 9-14 mL/min/1.73 m2 . The conditions that may indicate that dialysis is not yet necessary even though weekly Kt/V is below 2.0 include: 1. Stable or increased oedema free body weight. 2. Dietary protein intake as estimated by urea kinetics > 0.8 g/kg per day (nPNA 0.8 g/kg/d) 3. Complete absence of clinical signs and symptoms attributable to uraemia. The dose of dialysis should be gradually increased to the recommended minimal targets of total weekly Kt/V. 26.3. Timing of catheter insertion It is important that the catheter is inserted on an elective basis preferably before dialysis needs to be initiated. Repeated percutaneous insertion of temporary dialysis catheters should be avoided. Local data has shown that CAPD technique survival is adversely affected if the antecedent renal replacement therapy was intermittent peritoneal dialysis by repeated percutaneous insertion of temporary dialysis catheters.5 The catheter break-in should be delayed for 10 to 14 days after the insertion.

161

26.4. Pre catheter insertion preparation 1. 2. The patient is briefed regarding the operation including risks and possible complications, and all questions answered in a reassuring way. On the day prior to the surgery, patients should have a good bath with soap, water and hibiscrub. The belt line of the patient is identified preferably in the sitting and standing position. The tunnel site is marked on the skin in such a way that the exit hole will be created at least 2 cm below the belt line. Prior to the operation, the patient should empty the bladder and an enema may be given to patients who are constipated. One dose of parenteral cephalosporin is given intra-operatively.

3. 4.

26.5. Indications for switching from CAPD to HD4 1. 2. 3. 4. 5. Inadequacy of dialysis on CAPD with consistent failure to achieve target Kt/Vurea and creatinine clearance. Inadequate solute or fluid removal. High transporters may have poor ultrafiltration and/ or excessive protein losses. Unmanageably severe hypertriglyceridaemia Unacceptably frequent peritonitis or other PD-related complications. Development of mechanical and technical problems.

References 1. 2. 3. 4. 5. Prichard SS. Treatment modality selection in 150 consecutive patients starting ESRD therapy. Perit Dial Int. 1996; 16:69-72. Jungers P, Zingraff J, Page B. et al. Detrimental Effects of late referral in patients with chronic renal failure: a case control study. Kidney Int. 1999 (suppl. 41): S170-3 Obrador GT, Pereira BJ. Early referral to the nephrologist and timely initiation of renal replacement therapy: a paradigm shift in the management of patients with chronic renal failure. Am J Kidney Dis 1998; 31(3): 398-417 NKF-DOQI Clinical Practice Guidelines Initiation of dialysis. Am J Kidney Dis 1997: 30(supp.2): S70-3 Lim TO. First Report of the Malaysian Dialysis and Transplant Registry 1993.

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27. CAPD SYSTEMS 27.1. CAPD Solutions Several types of solutions are available in clinical practice in different volumes and glucose concentrations. They are formulated with electrolytes including sodium chloride, calcium, magnesium, and lactate as a precursor of bicarbonate. As dextrose is the osmotic agent, various strengths are available i.e. 1.5%, 2.5% and 4.25%. The volumes available are 1.0, 1.5, 2.0, 2.5 and 5.0 litres. Table 27.1: Composition per 100ml PD solutions Dextrose strength 1.5% 2.5% Glucose 1.36 2.27 Osmolarity (mmol/L) 346 396 pH 5.2 5.2 Ionic Concentration (mmol/L) Sodium 132-134 132-134 Calcium 1.0-1.75 1.0-1.75 Magnesium 0.25-0.75 0.25-0.75 Chloride 96 96 Lactate 35-40 35-40 4.25% 3.86 485 5.2 132-134 1.0-1.75 0.25-0.75 96 35-40

27.2. New PD Solutions The long term use of standard PD solutions may be responsible for some of the complications of PD namely ultrafiltration failure, peritonitis and sclerosing peritonitis. Factors of concern are unphysiological pH, hypertonicity and formation of advanced glycosylation end products (AGE) and glucose degradation products (GDP).1 27.2.1. Role of new PD solutions Improved UF Prolonged technique survival Improved membrane viability Nutritional management Reduced glucose load.

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27.2.2. Amino Acid solution A high percentage of patients treated with PD are malnoursished due to continued loss of amino acids and proteins. Substitution with amino acids in PD fluids may correct this loss. A 2% amino acid solution produces equivalent UF to 4.25% dextrose. Recent trials showed that once daily intraperitoneal amino acid solution leads to positive nitrogen balance.2 (Level B) Disadvantages of amino acid: Due to rapid absorption its use as an osmotic agent is limited. Metabolic acidosis may be seen in 50% of patients, alkaline supplements may be needed. Associated with loss of appetite, nausea and vomiting 27.2.3. Icodextrin It is a 7.5% mixture of glucose polymers that is isosmolar. As it is removed from the peritoneum by lymphatic absorption the osmotic gradient is better preserved than glucose and its ultrafiltration capacity is equivalent to dextrose 4.25%. It is safe and efficacious and especially useful for patients with UF failure.3 (Level B)

27.2.4. Bicarbonate solution Bicarbonate solutions have been shown to reduce infusion pain and should also provide a more physiological environment for the peritoneal membrane. Unfortunately, it is difficult to prepare and store and is incompatible with calcium, magnesium and glucose. Thus it has to be stored in double chamber bags to be mixed immediately before use. References
1. 2. 3. Gokal R, Khanna R, Krediet R and Nolph K eds. Textbook of Peritoneal Dialysis. 2nd Ed 2000, Kluwer Academic Publishers Jones MR, Gehr TW, Burkart JM et al. Replacement of amino acid and protein losses with 1.2% amino acid peritoneal dialysis solution. Perit Dial Int 1998; 18:210 Peers E, Gokal R. Icodextrin overview of clinical experience. Perit Dial Int 1997; 17:22-26

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28. PD ACCESS Chronic PD catheters are made of soft materials like silicone rubber or polyurethane. The standard two cuff straight Tenckhoff catheter is still the most widely used access device because it satisfies the needs of most patients and there is no conclusive evidence that other catheters are superior1. 28.1. Catheters available in Malaysia. 1. Straight Tenckhoff Catheter:Double cuffed straight catheter with perforations of 1 mm over the inner-most ten cm. Swan Neck Catheter:Dual cuff with a pre-formed 150-degree bend in the tubing between the cuffs designed so that the catheter can be placed in an arcuate tunnel. Both internal and external segments are directed downwards. The downward directed exit is associated with decreased incidence of exit site associated peritonitis.

2.

28.2. CAPD Connectology Some of the systems currently available are as follows: 28.2.1. The Y-Disconnect System2,3 In the Y-set method, the exchange is initiated by spiking a new dialysate bag, followed by flushing of the Y-set lines from the new bag to the empty drainage bag. Then the previous peritoneal exchange is drained followed by inflow of fresh dialysate. (Flush before fill). The exchange is completed by disconnecting the Y-set (and both dialysate bags) from the peritoneal catheter which is then capped off. 28.2.2. Double Bag System This system is similar to the Y-disconnect system except that the two bags are permanently connected to the upper two branches of a long Y-set while the short branch is connected to the PD catheter only during exchanges.

165

This has been shown to significantly reduce peritonitis rate as it eliminates the need for spiking of the dialysate bag.4,6 (Level A) This system is particularly suitable for those with impaired dexterity. 28.2.3. A.N.D.Y. (A-non-disconnect Y) This is also a double-bag system closed with a special irreversible clamp which is removed at the next exchange. 28.2.4. The Stay-Safe system This is another double-bag system in which the drainage bag and the dialysate bag are connected to the tubing lines by a special disc.5 By turning the disc all the exchange phases can be performed i.e. outflow, flush, inflow and automatic closing of the system with a pin.

References
1. 2. 3. 4. 5. 6. Burkatt JM. Comparison of peritonitis rates using standard spike versus Y- sets in CAPD. Trans ASAIO 1988; 34: 433. Prospective controlled trial of a Y- connector and disinfectant to prevent peritonitis in CAPD. Lancet 1983;2:642. Canadian CAPD trial group. Peritontis in CAPD: a multicenter randomized clinical trial comparing the Y- connector disinfectant to standard system. Perit Dial Int 1989; 9:159. Tielens E, Nube MJ, et al. Major reduction of CAPD peritonitis after introduction of twin bag system. Nephrol Dial Transplant 1993;8: 1237. Van Biesen W, Krichgessner J, Schilling H. Stay safe a new PVC free system for peritoneal dialysis: results in a multicentre trial. Int J Artif Organs 1998; 21: 596. Daly C, Campbell M, Cody J, Grant A, Donaldson C, Vale L, Lawrence P, MacLeod A, Wallace S, Khan I. Double bag or Y-set versus standard transfer systems for continuous ambulatory peritoneal dialysis in endstage renal disease (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford: Update Software.

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29. CAPD PROCEDURES 29.1. Catheter Insertion Ideally, catheter insertion should be undertaken under operating theatre, sterile conditions, usually on an inpatient basis. Although several techniques have been used, the common practice is by surgical implantation under direct vision. The implantation technique has a significant influence on the complications and outcome of the chronic peritoneal catheter.1 29.1.1. Recommendations2 a. The implantation must be performed by a competent and experienced operator, in a planned manner. The procedure must be regarded as an important surgical intervention demanding care and attention to detail equal to any other surgical procedure. Peritoneal entry should be lateral (deep cuff in or below the rectus musculature), or paramedian (deep cuff at the medial edge of the rectus musculature) to give good deep-cuff fixation and minimise herniation and fluid leaks. The deep cuff should be placed in the musculature of the anterior abdominal wall or in the preperitoneal space. Good results have also been obtained with the cuff placed within the posterior rectus fascia. The deep cuff should never be placed within the peritoneal cavity. After proper positioning of the catheter tip, the peritoneum is closed tightly around the catheter below the level of the deep cuff using a pursestring suture.3 The subcutaneous cuff should be located near the skin surface and at a distance of at least two cm from the exit site. Care should also be taken to avoid mechanically stressing the cuff material. Check for catheter patency. The catheter should be tested to ensure that there is adequate inflow and outflow without leakage. Techniques to accomplish this include infusing one litre of peritoneal fluid over 5 minutes and allowing an equal time for drainage, or injecting 60 ml of 0.9% saline and observing if 30-40 ml is easily aspirated. The exit site should be facing downwards or laterally. This has been found to decrease the risk of peritonitis associated

b.

c.

d.

e.

f.

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g.

with exit site or tunnel infection. Upward-directed exit sites should, in general, be avoided. (Level B evidence) The intra-abdominal portion of the catheter should be placed between the visceral and the parietal peritoneum towards the pouch of Douglas and should not be placed within loops of bowel or directed in omental tissue. This can be facilitated by the use of a bent stylet or any device that will add rigidity to the catheter.

29.2. Post operative catheter care. There is little evidence to support the superiority of one approach over the others. The approach given below is adapted from current Malaysian CAPD practice which has been found to be similar to ISPD practice. a. b. c. d. e. The Tenckhoff catheter and the extension tubing is soaked in 1% povidone iodine for 5 minutes. The catheter is clamped and disconnected from the tubing and re-soaked in povidone iodine for another 5 minutes. A titanium adapter is attached to the end of the catheter. The catheter is then flushed with 5000 units of heparin in 8 ml of distilled water and capped. Clean the exit site and surgical wound with 1% povidone iodine and rinse with normal saline. Cover with sterile gauze and non-occlusive dressing. The dressing should not be changed for at least 7 days unless there is obvious bleeding or signs of leakage or infection.

Initial exit site dressing changes are done by properly trained nursing staff. Only sponge baths are advocated during the initial healing period. Showers should only be advised 4 6 weeks after implantation. 29.3. Catheter break-in and post implantation dialysis. Optimally, CAPD should not be initiated for 10-14 days after catheter implantation. If peritoneal dialysis is required during this period, small volume exchanges of 500 ml, preferably by automated cycler may be carried out with the patient in the recumbent position. The volume per exchange can be gradually increased over the next few days to a maximum of one litre.

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29.4. Chronic care of the healed exit site. Exit site care includes a. assessment of the exit site b. cleansing the exit site c. anchoring and immobilising the catheter d. protecting the tunnel and exit site from trauma. Optimal care of the exit site has not been determined. However certain recommendations are given below based on evidence if available, or current practice.2 a. b. c. d. The exit site should be inspected and cleansed daily or every other day. The exit site should be cleaned with povidone iodine and rinsed with saline. If patient is sensitive to iodine, normal saline dressing can be used after bathing using liquid soap. The exit site should be patted dry after cleansing. Mupirocin cream should be applied at the exit site after cleansing.4 (Level B) Use of dressing has not been shown to affect the incidence of exit site infections. However, dressings may help keep the exit site clean, protect it from trauma and immobilise the catheter. It is important not to forcibly remove crusts or scabs during cleansing because this may cause a break in the skin and increase exit site infection. Only showers and not long baths are recommended.

e. f.

29.5. CAPD Training Program When CAPD is decided on:1. 2. 3. 4. Speak to patient and spouse or other family members about what CAPD involves i.e self care and being trained to do so. Decide who is to be trained with the patient. Assess patient's domestic environment. Start exit care training on the tenth post-catheter insertion day. a. Familiarise the patient on the components of PD catheter. b. Educate the patient on:

169

5.

the rules to follow when handling/touching the catheter. catheter exit site care. catheter complications, their causes, prevention and management. hand washing procedure and its importance. c. Hand out "shopping list" of essential equipment to patient to make purchase. Check when training is to be started and let the patient and partner know about it.

29.6. Schedule of Training For CAPD Patients DAY 1 Objectives Nursing management 1. 2. 1. 2. 3. Provide adequate dialysis. Introduce patient to CAPD. Evaluate patient's dialysis requirements and set the time for the exchanges (usually 4 exchanges daily). Assess patient's anxiety and learning capacity. Impress on importance of record keeping of exchanges, blood pressure, weight and temperature.

Patient/Partner

1.

Demonstrate taking blood pressure, temperature and body weight. 2. Observe first exchange procedure and do subsequent exchanges under close supervision. 3. Learn to record all exchanges. 1. 2. 3. 4. 5. 6. Normal kidney function. Basic theory of PD. Emergency phone numbers. Aseptic technique (clean/dirty/sterile). Record keeping. Personal hygiene.

Teaching Topics

170

DAY 2 Objectives

1. 2. 3.

Provide adequate dialysis according to patient's needs. Enforce self care. Understand principles of CAPD. Evaluate patient's dialysis treatment. Supervise exchange procedure. Explain the following terms clean and dirty, aseptic & sterile disinfection contamination areas which are considered sterile & non-sterile in PD Learn to take blood pressure, weight and temperature. Carry out exchanges as stipulated. Learn exit site care. Record all exchanges correctly. Define how fluid & waste products are removed in CAPD. Describe the importance of keeping to dialysis prescription to achieve adequate dialysis (i.e. not omitting any exchanges). Describe fluid removal and how to regulate ultrafiltration with different dextrose concentrations

Nursing management

1. 2. 3.

Patient/Partner

1. 2. 3. 4.

Teaching Topics

1. 2.

3.

171

DAY 3 Objectives

1. 2. 3.

Provide adequate dialysis according to patient's needs. Participation of patient in exchange procedures Inform patients about CAPD complications Evaluate effectiveness of exchange schedule and dextrose concentration used Supervise exchange procedures. Monitor blood pressure, weight and temperature. Carry out exchanges as stipulated. Carry out exit site care under supervision. Record all exchanges correctly. Review fluid management Dietary management Complication - peritonitis -exit site infection - leakage/hernia. Contamination

Nursing management

1. 2.

Patient/Partner

1. 2. 3. 4.

Teaching Topics

1. 2. 3.

4.

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DAY 4 Objectives

1. 2.

Provide adequate dialysis according to patient's needs Encourage patient's independence Assess patients independence & proficiency in performing exchange procedure Monitor vital signs. Perform catheter & exit site care independently. Perform exchanges as stipulated. Problem solving (troubleshooting). Medication/diet. Disconnect system.

Nursing management

1.

Patient/Partner

1. 2. 3.

Teaching Topics

1. 2. 3.

DAY 5 Objectives

1. 2. 3.

Encourage patient independence. Evaluate dialysis schedule effectiveness. Re-educate on symptoms & signs peritonitis. Evaluate patient's independence and proficiency in procedures Retrain procedures where necessary Perform procedures independently Peritonitis a) Symptoms and signs b) Causes c) Prevention d) Early detection & reporting e) Treatment protocols Follow up care Disposable & dialysate indenting & storage

Nursing management

1. 2.

Patient/Partner Teaching Topics

1. 1.

2. 3.

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End of Training 1. Training should not end until both the staff & patient are comfortable with the patient / carers ability to care for himself/ herself independently. 2. Schedule a return appointment, one to two weeks after completion of training to assess progress & discuss problems.

References
1. 2. 3. 4. Golper TA, Brier ME, et al. Risk factors of peritonitis in long term peritoneal dialysis: The Network 9 peritonitis and catheter survival studies. Am J Kidney Dis 1996; 28(3):428-436 Gokal R, Alexander S, Ash S, Chen TW, et al. Peritoneal catheters and exit-site practices toward optimum peritoneal access: 1998 update.( Official report from the ISPD). Perit Dial Int 1998; 18(1):11-33 Stegmayr BG, Hedberg B, Norrgard O. Stylet with a curved tip to facilitate introduction of new Tenckhoff catheters and reposition of displaced ones. Eur J Surg 1993;159(9):495-7 Thodis E, Passadakis P, Panagoutsos S, Bacharaki D, Euthimiadou A, Vargemezis V. The effectiveness of mupirocin preventing staphylococcus aureus in catheter-related infections in peritoneal dialysis. Adv Perit Dialysis, 2000; 16:257-261

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30. COMPLICATIONS OF CAPD 30.1. Technical Complications of CAPD 30.1.1. Hernia a. Incidence: 10-25% b. Predisposing factors Children Older females Multiparity Post-operative leak at time of catheter insertion Previous hernia repair/laparotomy Higher fill volumes: studies so far do not support this to be a factor leading to hernia formation.

c. Common sites Incisional or through catheter placement site Inguinal Umbilical Epigastric

d. Treatment Surgical repair is indicated to prevent strangulation and incarceration especially in small hernias.1 (Level C) Peri-operative management of CAPD patients undergoing hernia repair.2 Pre-operative imaging is only indicated in those in whom diagnosis is unclear. CAPD may be continued till day of operation. Drain peritoneal dialysate immediately prior to surgery. Post-operative management remains controversial and the following have been followed. - HD for 2-4 weeks2 - Immediate resumption of CAPD but on smaller fill volumes 2 - Resumption of CAPD 3 days later3,4 - Cycler PD using small fill-volumes.

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e. Prevention Paramedian incision for PD catheter insertion has been found to reduce the incidence of incisional hernias.5,6 (Level C) 30.1.2. Genital and abdominal wall oedema Oedema of the scrotum/ penis, labia majora or abdominal wall may result in poor ultrafiltration and inadequate dialysis. a. Causes Leak through soft tissue plane from catheter insertion site Patent processus vaginalis to labia/scrotum then leakage into surrounding soft tissue.

To distinguish the cause of genital oedema, the following may be helpful. Technetium 99 dialysate fluid into abdominal cavity. Radiocontrast (preferably non-ionic) into abdominal cavity. CT scan b. Treatment Various options have been practiced. Bed rest and cessation of CAPD Keep intra-abdominal pressure low by cycling PD in supine position, or HD if vascular access is available. Recurrence of abdominal wall oedema HD for 4-6 weeks Resolve Restart CAPD Recur surgical repair Permanent HD Recurrence of Genital oedema Radiologic investigation (refer above section) Patent processus vaginalis Repair Leak Permanent HD 30.1.3. Leakage a. Early leakage (<30 days after insertion of PD catheter) Overt leak Subcutaneous leak or genital swelling

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Recommendations: Can be prevented by a break-in period of about 2 weeks. Withhold PD temporarily for 1-2 weeks HD if patient needs dialysis, small volume PD in recumbent position if HD is not feasible. Persistent leak after resting will need surgical repair. b. Late leakage (>30 days after catheter insertion) This may be difficult to diagnose. Signs & symptoms Diminished drainage Pale patch around catheter or surgical scar. Increasing abdominal girth Genital swelling Diagnosis and treatment (See section on genital swelling) 30.1.4. Inflow and Outflow Obstruction Outflow and inflow obstruction are most frequently observed within 2 weeks after catheter implantation. It can also present later together with a PD related complication such as peritonitis. a. Outflow obstruction

Causes: Intraluminal debris or blood clot Extraluminal - stool filled bowel enwrapping the catheter - occclusion of catheter holes from pressure exerted by adjacent organs - omental wrap - tip entrapment in peritoneal pockets from adhesions - incorrect catheter placement at implantation b. Inflow obstruction Causes: Kinking Intraluminal debris

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Recommendations Establish type of obstruction by examination and evaluation Try non-invasive approaches: - Body position change - Laxatives - Flushing with heparinised saline. - Instillation with fibrinolytic agents urokinase/streptokinase 12,000 u in 2 ml heparin (10,000 units) into catheter for 2 hours Invasive approaches: - Interventions such as fluoroscopically guided stiff wires or stylet manipulation or intraluminal brushing. Caution: increased risk of peritonitis and bowel perforation. - Open surgical revision or replacement.

These various techniques have not been evaluated in randomized clinical trials. Other rare complications include: Sclerosing encapsulating peritonitis Kidney stones Haemoperitoneum Hydrothorax Chyloperitoneum.

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30.2 Exit-Site and Tunnel Infections 7,8,9 30.2.1. Definitions. a. Acute exit site infection Purulent and/or bloody discharge from the exit site which may be associated with erythema of >13 mm in diameter, tenderness, exuberant granulation tissue and oedema. Crusting alone is not indicative of infection. Chronic exit site infection Exit site infection lasting for > 4 weeks. It may be a sequelae of untreated or inadequately treated infection or recurrence of resolved acute infection. Symptoms are similar to acute infection, however granulation tissue is more commonly seen and pain and erythema are frequently absent. Equivocal exit site infection Purulent and/or bloody drainage only in the sinus that cannot be expressed out, accompanied by regression of the epithelium and presence of granulation tissue in the sinus. Erythema may be present but with a diameter <13 mm. Pain, swelling and discharge are absent. It represents low grade infection and most progress to overt infection if untreated. Tunnel infection Erythema, oedema and/or tenderness over the subcutaneous pathway and may be characterised by intermittent or chronic, purulent bloody or gooey discharge. It is associated with increased risk of peritonitis.

b.

c.

d.

30.2.2. Pathogens Staphylococcus aureus majority Peudomonas aeruginosa Staphylococcus coagulase negative

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Table 30.1. Treatment of exit-site and tunnel infections


Equivocal infection Evaluati on Culture and sensitivities on peri-exit smear. Gram Stain Acute infection Culture and sensitivities on exudate Gram Stain Chronic infection Culture and sensitivities on exudate Gram stain Tunnel infection Palpation of cuff and tunnel Culture and sensitivities and Gram stain of exudate (spontaneous or after pressure on cuff) U/S of cuff/tunnel Cauterise slightly exuberant and exuberant granulation tissue. Initial antibiotic therapy based on Gram stain results

Initial therapy

Cauterise slightly exuberant granulation tissue with copper sulphate crystals or silver nitrate solution. Topical mupirocin

Cauterise slightly exuberant and exuberant granulation tissue. First generation cephalospori n for grampos. organisms, quinolone for gram-neg. organisms, vancomycin for MRSA

Cauterise slightly exuberant granulation tissue. If initial therapy: first generation cephalospori n for grampos. organisms; quinolone for gramneg. organisms; vancomycin for MRSA. If previously treated: add synergistic drug or change antibiotic according to culture and sensitivities.

180

48 Hours

Change to neomycin or gentamicin ointment if gram-neg. organisms on culture. If no response in 2 weeks, change to systemic antibiotic based on initial culture and sensitivities . Continue therapy 7 days past achieving a good appearance. Response to systemic antibiotic therapy is excellent with cure occurring in almost all instances.

Adjust therapy according to culture and sensitivities.

Adjust therapy according to culture and sensitivities.

Adjust antibiotic according to culture and sensitivities

Followup

Evaluate weekly; reculture if no improvement Substitute another appropriate antibiotic or add a second, synergistic antibiotic. Use rifampicin as a second antibiotic for staph infections. Most acute infections respond favourable to therapy. Continue to treat for 7 days after achieving a good appearance. If accompanying peritonitis, consider catheter removal.

Evaluate every 2 weeks; reculture every 2 weeks if no improvement on appropriate therapy. If infection recurs repeatedly after achieving a good appearance: 1. Consider chronic antibiotic suppression, 2. if no improvement after a month of treatment, suspect cuff infection and treat as such. If accompanying peritonitis, remove catheter.

Re-evaluate every 2 weeks, reculture monthly. If no remission: 1. consider cuff shaving 2. consider catheter replacement. If accompanyin g peritonitis, remove catheter.

Adapted from 1998 update on peritoneal catheters and exit site practices toward optimum peritoneal access 7

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30.3. Peritonitis10 Peritonitis is a common clinical problem in patients on CAPD and the main cause of technique failure. 30.3.1. Clinical manifestations of peritonitis Symptoms Cloudy effluent Abdominal pain Fever Nausea/vomiting/chills Drainage problems Signs Abdominal tenderness Fever 30.3.2. Diagnosis In a patient with cloudy fluid and/or abdominal pain and/or fever, an elevated cell count of >100 WBC per mm3 with at least 50% polymorphs is supportive of the diagnosis of peritonitis. 30.3.3. Microorganisms causing CAPD peritonitis Table 30.2. Principal pathogens causing peritonitis in CAPD patients in Hospital Kuala Lumpur Microorganism % total organism isolated 1998 1999 2000 Gram positive bacteria Staph. aureus 3.6 2.3 10.2 Staph epidermis 13.4 6.9 10.2 MRSA 1.2 0 2.5 Gram negative bacteria Pseudomonas 1.2 8.1 6.8 aeruginosa Acinetobacter 3.6 2.3 3.4 Enterobacter 2.4 2.3 3.4 E. coli 3.6 3.4 0 1.2 5.8 7.7 Kelbsiella TB 0 1.1 0

182

Fungal Culture negative

6.1 58

9.3 54.6

5.1 43.6

30.3.4.

Laboratory investigation

a. Diagnostic Workup of Peritonitis Specimen Collection and transport10 The sample should be obtained from the first cloudy bag as it has the greatest probability of yielding a positive culture. 50 100 ml peritoneal effluent should be concentrated and cultured to maximize bacteria recovery rates. For immediate delivery, transport sample at room temperature. For delayed delivery (>1 hour after collection), refrigerate but do not freeze sample. Processing Place effluent sample into two 50 ml tubes and centrifuge for 15 minutes at 3000g. Decant supernatant aseptically. Vortex to re-suspend sediment. Perform Gram stain and microscopy from sediment Materials Blood agar plate Chocolate agar plate EMB agar plate or MacConkey agar IMA agar plate BHI/Blood agar plate or Sabourods plate BacT/Alert fan blood bottle or BACTEC bottle Procedure Microscopic examination Perform gram stain on sediment - Culture Bacteria : Using Pasteur pipette, draw up sediment and place 1 drop on bacteriological culture plates. Place 5 mL of sample into blood culture bottle. Incubate plates in carbon dioxide (5%) at 35 oC for 48 hours and hold the blood bottle for 5-7 days in the BacT/Alert or BACTEC Blood System.

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Fungus : Inoculate BHI/blood agar or Sabourods agar and IMA plates with the sediment. Wrap plates and incubate in 30 oC incubator for 4 weeks. - Haematology Effluent polymorphonuclear leucocyte count Count unspun sample using a counting chamber or haemocytometer. Cell differential Spin peritoneal effluent sample (200 uL) in a cytocentrifuge (1:10-1:100 dilution in physiological saline for leucocyte count > 1000) at 8000g for 7 minutes. Stain sample according to Pappenheim for evaluation. 30.3.5. Management of peritonitis10 Once the diagnosis of peritonitis is suspected and the suggested work-up completed the following steps for treatment are initiated either at home or in the hospital. One to three rapid exchanges in succession are carried out without addition of antibiotics. It is reported to be of symptomatic benefit, but does not appear to offer any specific therapeutic benefits. Dialysate fluid with loading doses of recommended first line antibiotics is instilled and allowed to dwell for at least 6 hours. The usual number of CAPD exchanges is then continued with maintenance doses of antibiotics. Heparin at a dose of 500-1000 U/L may be added to the regular regimen until dialysate effluent clears. This regimen is continued until the results of gram stain, culture and antibiotic sensitivity are available. Appropriate changes in antibiotics are made if necessary. The resolution of peritonitis is monitored clinically and by serial effluent white cell counts. The duration of antibiotic therapy is dependent on the culture and sensitivity results. The CAPD team should review the patients technique in an attempt to determine whether errors in technique have contributed to the episode of peritonitis.

a. Initial Empiric Antibiotic Selection 10

184

Although there is no clear evidence, the expert committee in ISPD recommends a first-generation cephalosporin, cephazolin (1gm daily in the long dwell), in combination with ceftazidime as first line empiric therapy. In patients with residual urine volume of < 100 ml/day, cephazolin in combination with an aminoglycoside can be used. In Malaysia, since first generation parenteral cephalosporin is not yet widely available, cloxacillin is used instead although there is no evidence available in the literature for its use. However, it should be noted that penicillins deactivate aminoglycosides. Table 30.3. Empirical antibiotic selection Residual urine output Antibiotic cephazolin ceftazidime gentamicin amikacin cloxacillin <100ml/day 15 mg/kg BW once daily 1g/bag once daily 0.6mg/kgBW/bag daily 2mg/kgBW/bag daily 250 mg/bag >100ml/day 20mg/kgBW once daily 20mg/kgBW/bag once daily not recommended not recommended 250 mg/bag

* once daily dose should be given in long dwell exchange. *Aminoglycoside given as a single daily dose may result in less ototoxicity and nephrotoxicity and improved bacterial killing in association with prolonged post-antibiotic effect.11

185

Table 30.4. Antibiotic dosing recommendations for CAPD patients with and without residual renal functiona CAPD intermittent CAPD continuous dosing (once/day) dosing (per litre exchange) Drug Anuric NonAnuric Nonanuric anuric Aminoglycosides * (Increase MD 24 mg Amikacin 2 mg/kg (Increase all doses all MD by Gentamicin 0.6 mg/kg MD 8 mg by 25%) 25%) Netilmicin 0.6 mg/kg MD 8 mg Cephalosporins All LD same as anuric Cefazolin 15 mg/kg 20 LD 500 MD mg/kg mg, MD increase 125 mg by 25% Cephalothin 15 mg/kg ND LD 500 MD, ND mg, MD 125 mg Ceftazidime 1000-1500 ND LD 250 MD, ND mg mg, MD 125 mg Penicillins All LD same as anuric Piperacillin 4000 mg ND LD 4 g IV, MD, ND IV, b.i.d. MD 250 mg Ampicillin 250-500 ND MD 125 or MD, ND mg p.o., 250-500 b.i.d. mg p.o., b.i.d. Dicloxacillin 250-500 ND 250-500 MD, ND mg p.o., mg p.o. q.i.d. q.i.d. ND ND LD 250MD, ND Amoxicillin 500 mg, MD 50 mg

186

Quinolones Ciprofloxacin Ofloxacin

500 mg p.o., b.i.d. 400 mg p.o., then 200 mg p.o., q.d. 15-30 mg/kg q.57d 400 mg IP, b.i.d. 1 g b.i.d.

ND ND

LD 50 mg, MD 25 mg As intermittent

ND ND

Others Vancomycin Increase doses by 25% ND MD 30-50 mg/L LD 400 mg, MD 40 mgb LD 500 mg, MD 200 mg LD 1000 mg, MD 250 mg As intermittent As intermittent Increase MD by 25% ND

Teicoplanin

Imipenem/ cilastatin Aztreonam

ND

ND

ND

Metronidazole Rifampin Antifungals

250 mg p.o., b.i.d. 300 mg p.o., b.i.d.

ND ND

ND ND All LD same as anuric NA ND

Amphotericin Flucytosine

Fluconazole Itraconazole Antituberculars

NA 2 g LD, then 1 g q.d., iv 200 mg q.d. 100 mg q.12 hr Isoniazid 300 mg p.o., q.d. + rifampin 600 mg p.o., q.d.

NA ND

MD 1.5 mg As intermittent As intermittent 100 mg q.12 hr As intermittent

ND 100 mg q.12 hr ND

ND 100 mg q.12 hr ND

187

+
pyrazinamide

1.5g p.o, q.d. + pyridoxine 10 mg/d Combinations All LD same as anuric ND

LD 1000 mg, MD 100 mg Cotrimoxazole 1920 mg ND LD 1920 ND p.o., q.1-2 mg p.o., days MD 480 mg p.o. MD = maintenance dose; LD = loading dose; ND = no data; q.i.d. = four times per day; IV = intravenous; q.d. = once per day; b.i.d. = twice per day; IP = intraperitoneally; NA = not applicable. CAPD patients with residual renal function may require increased doses or more frequent dosing, especially when using intermittent regimens. For penicillins: "No change" is for those predominantly hepatically metabolized, or hepatically metabolized and renally excreted; "ND" means no data, but these are predominantly renally excreted, therefore probably an increase in dose by 25% is warranted; "NA" = not applicable, that is, drug is extensively metabolized and therefore there should be no difference in dosing between anuric and non-anuric patients. Anuric = <100 mL urine/24 hours; nonanuric = >100 mL/24 hours. These data for CAPD only.
a

Ampicillin/ sulbactam

2 g q.12 hr

ND

The route of administration is IP unless otherwise specified.. There is no evidence that mixing different antibiotics in dialysis fluid (except for aminoglycosides and penicillins) is deleterious to the drugs or patients. Do not use the same syringe to mix antibiotics.
b

This is in each bag 7 days, then in 2 bags/day 7 days, and then in 1 bag/day 7 days. Therapeutic Drug Monitoring: for vancomycin and aminoglycosides * Avoid if possible in patients with residual renal function

188

Table 30.5. Modification of treatment based on culture and sensitivity Enterococcus Other gram-positive Staphylococcus organism aureus (Coagulasenegative staph) At 24 to 48 hours Stop Stop ceftazidime or Stop ceftazidime or cephalosporins aminoglycoside aminoglycoside Start ampicillin Continue Continue 125 mg/L/bag cephalosporin cephalosporin Consider adding aminoglycoside If ampicillinIf MRSA, start If MRSE and resistant, start vancomycin clinically not vancomycin responding, start vancomycin Duration of therapy 14 days 21 days 14 days At 96 hours If no improvement, re-culture and evaluate for exit-site or tunnel infection, catheter colonization, etc. Choice of final therapy should always be guided by antibiotic sensitivities. VRE = vancomycin-resistant enterococcus; MRSA = methicillinresistant S. aureus; MRSE = methicillin-resistant enterococcus.

189

Table 30.6. Treatment strategies if peritoneal dialysis fluid cultures are negative or not performed Continue initial therapy Duration of therapy If clinical Continue treatment 14 days improvement If no clinical Repeat cell count, Gram improvement stain, and culture at 96 hours Consider change to vancomycin, continue ceftazidime/ aminoglycoside If culture positive, adjust therapy 14 days accordingly If culture negative, consider infrequent 14 days pathogens and/or catheter removal Table 30.7. Treatment recommendations if a gram-negative organism is identified on culture at 24 to 48 hours Duration of therapy Single gramAdjust antibiotics to sensitivity 14 days negative organism < 100 mL urine, aminoglycoside > 100 mL urine, ceftazidime Pseudomonas/ Continue ceftazidime and add 21 days stenotrophomonas < 100 mL urine, aminoglycoside > 100 mL urine, ciprofloxacin 500 mg, p.o. b.i.d. or piperacillin 4 g IV q.12 hours or sulfamethoxazole/trimethoprim 960 mg/day p.o. or imipenam/cilastatin LD 500mg/L, MD 200 mg/L Continue cephazolin/cloxacillin and Multiple gramnegatives and/or ceftazidime and add metronidazole, 500 mg 21 days q.8 hours, p.o., IV, or rectally anaerobes If no change in clinical status, consider surgical intervention IV = intravenously; IP = intraperitoneally.

190

b. Management of fungal peritonitis 10,12,13 (Level C) Fungal peritonitis in CAPD patients accounts for about 5-10% of peritonitis episodes among CAPD patients. Clinical presentation does not differ from bacterial peritonitis but should be suspected in culture negative peritonitis or peritonitis not responding after adequate doses of conventional antibiotics. Type of fungus C.albicans C. non-albicans e.g. C. parapsilosis, C. glabrata , C. .tropicalis, C. Krusei Non-yeast spp Table 30.8. Treatment of fungal peritonitis At 24 to 48 hours Flucytosine Fluconazole At 2-4 days If clinical improvement, duration of therapy 4-6 weeks, If no clinical improvement, remove catheter and continue therapy for 10-14 days after catheter removal with fluconazole 200 PO daily and flucytosine 1 g IV after hemodialysis. Imidazole/triazole plus flucytosine combination is as effective as amphotericin B in treatment of fungal peritonitis. Timing of catheter reinsertion no evidence but current practice recommends catheter reinsertion at least 4 weeks after catheter removal. Mortality at 1 month was 15% in patients in whom the catheter was removed within a week of diagnosis, but 50% in those in whom the catheter was left in place. Therapy with antifungal agents should be continued after catheter removal for at least an additional 10 days longer. Loading dose 2 g IV; maintenance dose 1 g q.d. iv. 200 mg po; or IP 200 mg daily

If organism resistant, consider itraconazole IP 100 mg 12 hourly

191

c. Management Of Tuberculous Peritonitis 10,14 Tuberculous peritonitis is uncommon and accounts for less than 4% of peritonitis episodes among CAPD patients. Isolation of mycobacteria from peritoneal effluent is difficult. Smear and culture may be negative and diagnosis may be from tissue obtained through peritoneoscopy, laparotomy or percutaneous peritoneal biopsy. Early peritoneal biopsy should be considered in the presence of non-resolving peritonitis with lymphocytosis. Chest X-Ray and Mantoux test may not be helpful. Peritoneal membrane biopsy is best obtained at the time of catheter removal. Treatment: Anti-TB drugs should be started with removal of catheter at diagnosis. At least three anti-TB drugs isoniazid, rifampicin and pyrazinamide together with pyridoxine should be prescribed for 9-12 months. Streptomycin should be avoided. There is high risk of optic neuritis with ethambutol..

30.3.6. Catheter removal and reinsertion PD catheter removal should be considered when peritonitis is unlikely to resolve with catheter in-situ. These include: Fungal peritonitis Tuberculous peritonitis Perforated bowel Persistent exit/tunnel infections Peritonitis not responsive to second line antibiotic treatment Relapsing peritonitis not responding to treatment.

The timing of catheter replacement should be 4 weeks following catheter removal although the optimal period is not known. (Level B) 30.3.7. Relapsing Peritonitis Definition: Peritonitis caused by the same organism occurring within 4 weeks of completion of the antibiotic therapy. Inadequate dosing has been found to predispose to relapse. Empirical treatment should be commenced based on previous culture while awaiting culture results.

192

Table 30.9. Management of relapsing peritonitis Organism Management Coagulase neg/pos cephalosporin for 4 weeks staphylococcus MRSA/S.epidermidis vancomycin for 4 weeks. Coagulase pos Search for occult tunnel infection staphylococcus Enterococci Ampicillin plus aminoglycoside Look for intra-abdominal abscess Consider catheter removal if no response after 96 hours Gram negative bacilli Evaluate for intra-abdominal abscess, consider catheter removal and surgical exploration. 30.3.8. Adjunctive therapy for peritonitis In patients who are being treated for peritonitis, adjunctive therapy should be considered on an individual basis and may include the following: a. Antifungal prophylaxis with oral nystatin at a dose of 500 000 u q.i.d. during and for a few days after the course of antibiotics (Level B). 15 b. Thrombolytic therapy may be occasionally useful in patients with recurrent peritonitis (Level C). 30.3.9. Prophylactic Antibiotic use Short term antibiotic prophylaxis may be considered in the following situations: a. Invasive procedures associated with transient bacteraemia (level C) dental procedures amoxycillin 2 g prior to procedure genito-urinary instrumentation: ampicillin plus ceftazidime/aminoglycosides gastrointestinal - ampicillin plus ceftazidime/ aminoglycosides +/- metronidazole b. Technique break Although no data is available, current practice recommends 1-2 day course of antibiotics e.g. cephalosporin

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30.4. METABOLIC COMPLICATIONS IN CAPD16 30.4.1. Metabolic complications of glucose absorption Uraemia per se is associated with hyperinsulinaemia. The average carbohydrate load of 100-150 g of glucose per day through CAPD exchanges amplifies the abnormalities in carbohydrate metabolism and leads to metabolic problems such as obesity, hypertriglyceridaemia and premature atherosclerosis. In some patients, the constant energy source may exacerbate malnutrition. Continuous contact between the peritoneum and glucose-based solutions may induce peritoneal mesothelial damage by nonenzymatic glycosylation leading to the formation of advanced glycosylation end-products ( AGEs). Hence, use of hypertonic glucose-based CAPD solutions should be minimised wherever possible and alternative solutions e.g. Icodextrin may be considered in the event of problems with ultrafiltration although evidence is still lacking. 30.4.2. Hyperlipidaemia Peritoneal dialysis is associated with the following abnormalities.17 increased total and LDL cholesterol concentration increased apolipoprotein B concentration decreased HDL cholesterol concentration decreased apolipoprotein AI concentration increased triglyceride concentration preponderance of small dense LDL particles increased lipoprotein (a) lipid

Hyperlipidaemia (in particular elevated LDL) as well as increased small dense LDL particles and lipoprotein (a) in the general population has a strong association with coronary artery disease (level A evidence). Evidence in the dialysis population is still not available. When compared with a non-uraemic cohort, PD patients have a 15 to 25 fold higher annual rate of cardiovascular mortality.18 In view of this fact, and the proven benefit of lipid-lowering therapy in the general population,

194

Serum cholesterol, triglycerides, HDL and LDL should be measured every 6 to 12 months It may be reasonable to treat hyperlipidaemia with diet and lipid lowering agents (level D evidence). However there are no long term trials with lipid lowering treatment in the dialysis population so the value of this approach is still uncertain. 30.4.3. Hyper/hypokalaemia a. Hypokalaemia Causes: Ongoing losses through dialysis solution Poor nutritional intake Treatment: Oral supplement to raise serum potassium concentration to > 3 mmol/L and 3.5 mmol/L in patients on digoxin or history of cardiac arrhythmias. Serum potassium levels should be monitored regularly.

References
1. 2. 3. 4. 5. 6. 7. Bargman JM. Complications of peritoneal dialysis related to increased intraabdominal pressure. Kidney Int. 1993; 40(Suppl 49) S75-80 Morris-Stiff GJ, Bowrey DJ, Jureqicz WA, Lord RHH. Management of inguinal herniae in patients on CAPD: an audit of current UK practice. Postgrad Med J. 1998; 74:699-670 Wetherington G, Leapman SB, Robison RJ, Filo RS. Abdominal and inguinal hernias in continuous ambulatory peritoneal dialysis patients. Am J Surg 1985;150(3):357-60 OConnor JP, Rigby RJ, Haride IR et al, Abdominal hernias complicating CAPD. Am . J. Nephrol. 1986; 6:271-274 Sepnce PA, Mathews RE, Khanna R, Oreopoulos DG. Improved results with a paramedian technique for the insertion of PD catheters. Surgery, Gynecology & Obstetrics. 1985; 161:585-587 Apostolidis NS, Tzardis PJ, Manouras AJ et al. The incidence of postoperative hernia as related to the site of insertion of permanent peritoneal catheter. Am Surg. 1988;54(5):318-9 Gokal R, Alexander S, Ash S, Chen TW, Danielson A, Holmes C, Joffe P, Moncrief J, Nichols K, Piraino B, Prowant B, Slingeneyer A, Stegmayr B, Twardowski Z, Vas S. Peritoneal catheters and exit-site practices toward optimum peritoneal access: 1998 update.( Official report from the ISPD). Perit Dial Int 1998;18(1):11-33 Bernardini J, Piraino B, Holley J, Johnston JR, Lutes R A randomised trial of Staphylococcus aureus prophylaxis in peritoneal dialysis patients: mupirocin

8.

195

9.

10.

11. 12. 13. 14. 15.

16. 17. 18.

calcium ointment 2% applied to the exit site versus cyclic oral rifampin. Am J Kidney diseases; 1996; 27: 695-700 Thodis E, Passadakis P, Panagoutsos S, Bacharaki D, Euthimiadou A, Vargemezis V. The effectiveness of mupirocin preventing staphylococcus aureus in catheter-related infections in peritoneal dialysis. Adv perit dialysis, 2000; 16:257-261 Keane WF, Bailie GR, Boeschoten E, Gokal R, Golper TA, Holmes CJ, Kawaguchi Y, Piraino B, Riella M, Vas S. Adult peritoneal dialysis-related peritonitis treatment recommendations:2000 update. Perit Dial Bull 2000; 20: 610-624 Barza M, Ioannidis JPA, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. Br Med J 1996;312:338-345. Cheng IKP, Fang GX, Chan TM, Chan PC, Chan MK. Fungal peritonitis complicating peritoneal dialysis: Report of 27 cases and review of treatment. Q J Med 1989;71:407-416. Johnson RJ, Ramsey PG, Gallagher N, Ahmad S. Fungal peritonitis in patients on peritoneal dialysis: incidence, clinical features and prognosis: Am J.Nephrol 1985;5:169-175. Lui SL, Lo CY,B.Y. Choy, Chan TM, Lo WK, .Cheng IKP. Optimal treatment and long-term outcome of tuberculous peritonitis complicating continuous ambulatory peritoneal dialysis. Am J Kidney Dis.1996; 28(5):747-751. Lo WK, Chan CY, Cheng SW, Poon JMP, Daniel Tak-Mao Chan, Cheng IKP. A prospective randomized control study of oral Nystatin prophylaxis for Candida peritonitis complicating continuous ambulatory peritoneal dialysis. Am J Kidney Dis.1996; 28 :549-552. Textbook of Peritoneal Dialysis 2nd edition, eds. Gokal R, Khanna R, Krediet R and Nolph,K, Kluwer Academic Publishers Prichard S. Major and minor risk factors for cardiovascular disease in peritoneal dialysis. Perit Dialysis Int Vol.20 Suppl.2 : S154-S159 Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol. 1998; 9(Suppl Dec):S16-23.

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30.5. Ultrafiltration Failure in CAPD 30.5.1. The Peritoneal Equilibration Test (PET)1 The PET defines the peritoneal membranes clearance and ultrafiltration characteristics by measuring the dialysate to plasma ratios of creatinine and dialysate glucose at specific times under standard conditions. Once the membrane permeability is identified, a PD regime can be more accurately selected to optimise dialysis. Results from the PET classify patients into four basic groups as shown below: Figure 30.5. The peritoneal equilibration test results

Table 30.10. Baseline PET prognostic value Solute transport High High average Low average Low Predicted response to CAPD UF Poor Adequate Good Good Excellent Clearance Adequate Adequate Adequate Inadequate Inadequate APD, DAPD Standard dose PD Standard dose PD High dose PD High dose PD or HD Preferred dialysis prescription

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Standard Peritoneal Equilibration Test (PET) Procedure Initiate after 8 12 hours overnight dwell of standard CAPD. At 0 hour: 1. 2. Drain dialysate completely from patient over 20 minutes and note volume drained. Perform exchange procedure with 2000 ml Dextrose 2.5% dialysate by infusing over 10 minutes. Ask patient to roll from side to side. Record time infusion is completed considered the 0 hour. Using aseptic technique, soak injection port with methylated spirit/povidone iodine for 5 minutes. Then drain 200 mls of effluent into drain bag. Under aseptic technique obtain 10 ml sample of effluent for creatinine, urea and glucose testing. Label the specimen 0 hour PET. Reinfuse the remaining 190 ml of effluent. Advise patient to ambulate or sit.

3. 4. 5. 6. 7.

At 2 hours: 1. Two hours after initial infusion obtain blood sample for blood urea, creatinine and glucose. 2. Using aseptic technique, soak injection port with methylated spirit/povidone iodine for 5 minutes. 3. Then drain 200 ml of effluent into drain bag. 4. Obtain 10 mls sample of effluent for creatinine, urea and glucose. 5. Reinfuse remaining 190 ml of effluent. 6. Label specimens 2 hour PET. At 4 hours 1. 2. 3. 4. At 4 hours after initial infusion, with patient in vertical position, drain exchange over at least 20 minutes. Using aseptic technique, soak injection port with methylated spirit/povidone iodine for 5 minutes. Obtain 10 mls sample of effluent for creatinine, urea and glucose. Measure and record effluent volume.

The following samples are sent for analysis: 1. Dialysate for creatinine, urea and glucose at 0, 2 and 4 hours.

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2.

Blood for creatinine, urea and glucose at 2 hours.

Once the values are obtained, the calculations can be made and the values plotted onto the PET graph as shown below. Note the range in which the patients values fall and use the prognostic value table shown above to select the appropriate PD regime. 30.5.2. Ultrafiltration Failure in CAPD From the Malaysian dialysis and transplant registry, 8-12% of CAPD patients were transferred to HD yearly because of membrane failure. Ultrafiltration (UF) failure in simple terms can be defined as the failure of peritoneal fluid removal to match the volume balance needs of the patient being treated by PD i.e. failure to maintain volume homeostasis. A net UF volume of <100 ml after a 4 hour dwell using 2.5% dextrose solution according to standard PET, or a net UF volume of <400 ml after a 4 hour dwell using 4.25% dextrose solution may be considered abnormal.2,4 a. Causes of UF failure.2 Input dependent cause Excessive salt/water intake Output dependent causes Uncompensated loss of residual renal function. Inadequate provision of ultrafiltration conditions - Long dwells - Inappropriate tonicity - Mismatch of prescription and PET status. Exaggerated contrary mechanisms - Lymphatic/tissue reabsorption Failure of peritoneal response - High transport status - Aquaporin deficiency - Loss of functional peritoneum Mechanical failure of dialysis procedure - Obstruction and other catheter malfunctions

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b. Diagnosis Volume / fluid overload Evaluation for reversible causes - Dietary indiscretion/compliance Deficient education Complex regime Burn-out Appropriate prescription Dwell time Dialysate tonicity Mechanical problems Leaks Obstruction Entrapment Mal-position Evaluation of peritoneal membrane function Ultrafiltration response Modified PET 4.25% 2 Litres drain volume > 2400 ml/4 hrs re-evaluate clinically Low transport D/P Cr < 0.5 High transport D/P Cr > 0.81 drain volume< 2400 ml/4 hrs small solute profile (PET) High average/ low average 0.81 > D/P Cr > 0.5 Mechanical causes Enhanced reabsorption Aquaporin deficiency

Disruption of Inherent high Peritoneal space Recent peritonitis Long term PD c. Treatment General Guidelines (level C)

Routine standardised monitoring, including awareness of PET status Dietary counselling concerning appropriate salt and water intake Protection of residual renal function Loop diuretics if residual renal function present

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Enhanced compliance by education Hyperglycaemia control Preservation of peritoneal membrane function

CAPD Avoid long dwells Use of night- time exchange device Tailoring prescription to transport profile determined by PET Use of icodextrin for long dwells3

APD Avoidance of long dwells with low glucose concentrations Use of short day dwells even when no additional exchange is needed for clearance

References
1. 2. 3. Twardowski ZJ, Nolph KD, Prowant B, Ryan L, Moore H, Nielsen M. Peritoneal Equilibration Test. Perit Dialysis Bul, 1987, 7: 138-147 Mujais S: Ultrafiltration failure. In Ram Gokal, Ramesh Khanna, Raymond Krediet and Karl Nolph eds. Textbook of Peritoneal Dialysis. 2nd Ed 2000 Mistry CD, Gokal R, Peers E. and the MIDAS Study Group. A randomized multicentre clinical trial comparing isosmolar Icodextrin with hyperosmolar glucose solutions in CAPD. Perit Dial Int. 1995;15(6):22630. Roppe B. How to measure ultrafiltration failure: 2.27% or 3.86% glucose? Perit Dialysis Int. 1997, 17: 125-128

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31. MALNUTRITION Evidence from both cross-sectional and longitudinal studies1-3 suggest that up to two-thirds of patients on haemodialysis and CAPD are malnourished (Grade B evidence). Malnutrition is strongly associated with increased morbidity and mortality in patients with end-stage renal failure from both international studies and local renal registry data.4,5,6 (Grade B evidence) Two different types of malnutrition exist in dialysis patients 7. Type 1 - associated with the uraemic syndrome. This may be reversible with adequate dialysis treatment and nutritional support. Type 2 or cytokine-driven malnutrition - marked hypoalbuminaemia, inflammation, co-morbidity e.g. chronic heart failure, and increased protein catabolism. Adequate nutritional support and dialysis treatment alone is insufficient unless the co-morbid and inflammatory conditions are adequately treated. 31.1. Periodic assessment of nutritional status should be part of the routine care of dialysis patients to ensure early recognition of malnutrition and institution of appropriate therapy. There is however, no single measurement that provides a comprehensive indication of protein-energy nutrition status. Hence a combination of measures is recommended as in Table 31.1. below8: Table 31.1. Measures of protein energy malnutrition Category Measure Minimum frequency of measurement in PD patients 3 monthly Predialysis or 1. Measurements stabilized serum that should be albumin performed routinely in all patients Subjective global Every 6 months assessment (SGA) nPNA Every 3-4 months 2. Measures that Skinfold thickness As needed

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may be useful to confirm/ extend the data from measures in Category 1 3. Clinically useful measures which, if low, might suggest the need for a more rigorous examination of protein-energy nutritional status Mid-arm muscle area, circumference/diameter Predialysis or stabilized serum - creatinine - urea nitrogen - cholesterol As needed

As needed As needed As needed

31.2. The recommended dietary protein intake (DPI) for clinically stable CPD patients is 1.2 1.3 g/ kg BW/ day11. (Level C) NB: Both protein and caloric intake recommendations should be based on ideal rather than actual body weight At least 50% of the protein intake should be of high biological value i.e. have a high content of essential amino acids. Patients who do not have an adequate DPI should be managed in a stepwise manner as in the flowchart below: Inadequate DPI

Counseling from a trained dietician Should include - identification of any specific issues e.g. cost/limited access to food - suggestion of alternative food sources if palatability is a concern - regular review modification based on the patients medical and social conditions

If DPI remains inadequate

Oral energy and protein supplements

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Other measures eg enteral feeding, intraperitoneal amino acids and parenteral nutrition should ideally be implemented if above measures fail but this is dependent on availability of resources. 31.3. The recommended daily energy intake for CPD patients is 35 kcal/ kg BW/d for those < 60 years of age and 30-35 kcal/kg BW/d for those 60 years or older10,12 ( Grade C evidence) 31.4. It is recommended that only up to 30% of energy intake is in the form of fat, with preference for mono- and polyunsaturated fats. Carbohydrate should be predominantly in the form of starch. 31.5. Consideration should be given to adequacy of dietary intake of mineral and trace elements. Supplementation of water soluble and not fat soluble vitamins is recommended. High dose folic acid supplementation has been shown to reduce homocysteine levels. 31.6. Specific attention should be given to factors impacting on the patients nutritional status which are independent of nutrient intake. 31.6.1. 31.6.2. 31.6.3. 31.6.4. 31.6.5. 31.6.6. 31.6.7. avoidance of drugs which exacerbate anorexia prevention and control of hyperparathyroidism maintenance of vitamin D homeostasis correction of acidosis optimal treatment of catabolic comorbid conditions provision of adequate dialysis minimisation of the use of hypertonic glucose-based dialysates 31.6.8. prevention of peritonitis 31.6.9. timely initiation of dialysis

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References
Bergstrom J, Lindholm B. Nutrition and adequacy of dialysis. How do haemodialysis and CAPD compare? Kidney Int Suppl 1993;40:S39-S50 2. Marckmann P. Nutritional status of patients on haemodialysis and peritoneal dialysis. Clin Nephrol 1988; 29 : 75-8 3. Young GA, Kopple JD, Lindholm B,Vonesh EF, DeVecchi A, Scalamogna A, et al. Nutritional assessment of continuous ambulatory peritoneal dialysis patients : an international study. Am J Kid Dis 1991;17: 462-71 4. Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15 : 458-82 5. Canada-USA (CANUSA) Peritoneal Dialysis Study Group. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcome J Am Soc Nephrol 1996;7: 198-207 6. Lim TO, Lim YN (Eds). Eleventh Report of the Malaysian Dialysis and Transplant Registry 2003. Kuala Lumpur 2004 7. Steinvinkel P, Lindholm B, Heimburger O. New strategies for the management of malnutrition in peritoneal dialysis patients. Perit Dial Int 2000; 20:271-275 8. National Kidney Foundation DOQI Clinical Practice Guidelines for Nutrition in Chronic Renal Failure. Am J Kidney Dis. 2000;35(6 Suppl 2):S1-140 9. Blumenkrantz MJ, Kopple J, Moran J, Coburn J. Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis. Kidney Int 1982; 21: 849-861 10. Bergstrom J, Furst P, Alvestrand A, Lindholm B. Protein and energy intake, nitrogen balance and nitrogen losses in patients treated with continuous ambulatory peritoneal dialysis. Kidney Int 1993;44: 1048-57 11. Bruno M, Gabella P, Ramello A Use of amino acids in peritoneal dialysis solutions. Perit Dialysis Int 2000;20 Suppl.2 : S166-S171 12. Slomowitz LA, Monteon FJ, Grosvenor M, Laidlaw S Kopple J. Effect of energy intake on nutritional status in maintenance haemodialysis patients. Kidney Int 1989;35:704-11 1.

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32. CAPD ADEQUACY GUIDELINES Delivered dose of CAPD should be routinely measured and monitored as clinical signs and symptoms may be unreliable indicators of adequacy and studies have shown correlation between delivered dose of CAPD and patient mortality and morbidity. (Level B) Dialysis adequacy should be assessed by clinical parameter - dry weight, BP control, correction of anaemia, renal osteodystrophy, measurement of delivered dialysis dose dietary protein intake. 32.1. PD dose and total solute clearance Both total and peritoneal weekly Kt/V urea and total and peritoneal weekly creatinine clearance(CrCl) normalised to 1.73m2 should be used to measure delivered PD dose as each measure provides slightly different information, and both measurements have been shown to be associated with outcomes in studies. (Level B) The K/DOQI guidelines recommends a total Kt/V of > 2.0 per week, and total creatinine clearance > 60L/ 1.73m2 per week. Recent studies have increasingly shown that renal clearance and peritoneal clearance are not equivalent and a lower total Kt/V of 1.8 (peritoneal Kt/V) did not result in poorer outcome. Hence although the target Kt/V value is still not defined, there should be a minimum peritoneal Kt/V of at least 1.6 and peritoneal creatinine clearance of 45 L/week.(Level A).9 Other parameters protein intake, nutritional status, phosphate control, sodium and fluid removal and BP control should be considered in the assessment of adequacy of dialysis treatment. When there is a discordance between weekly Kt/V urea and CrCl, causes for the discrepancy should be sought and patient monitored closely for signs of under-dialysis. Kt/V urea should be the minimum target of adequacy 32.1.1: Reasons for discordance: a. Amount of residual renal function and its relative contribution to Kt/V and CrCl b. Difference in peritoneal transport of urea and creatinine c. Dwell time d.Influence of patient size on normalisation

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32.2. Frequency of measurement 2-4 weeks after initiation of CAPD 6 monthly thereafter Measurement of dialysis dose should be done when the patient is clinically stable, and should be delayed for > 4 weeks after resolution of peritonitis. 32.3. Protocol for Kt/V measurement 32.3.1. 24 hours dialysate a. Patient performs first bag exchange, and discard b. Save all exchanges in the next 24 hours period i.e. exchanges 2, 3 and 4 c. Perform an exchange the next morning and save. d. Bring all 4 bags of effluent to the CAPD unit. e. Weigh all 4 bags separately. Record total volume of effluent per 24 hours. f. Using syringe, aspirate 1 % of dialysate volume from each bag into a container and mix thoroughly g. Draw 10 mls of the above mixed effluent for creatinine and urea. h. Obtain blood sample for urea, creatinine, glucose and albumin 32.3.2. 24 hours urine a. This should be done on the same day as the dialysate collection. b. The 24 hour urine collection should begin in the morning and the first morning specimen should be discarded. Record the time of first urine specimen c. Collect every subsequent urine specimen including the first morning urine sample of the following day. d. Bring urine to the CAPD unit NB. For patients who void > 3 x/day, 24 hr urine collection is sufficient but for patients who void < 3 x/day, 48 hr urine collection is recommended 32.3.3. a. b. c. Sending specimens to the lab 10 mls of mixed effluent for urea and creatinine Blood for urea, creatinine, albumin and glucose 24 (or 48) hours urine for urea and creatinine

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32.4. Nutritional assessment Nutritional status should be monitored regularly as there is a correlation between nutrition and dialysis dose. There is also strong indirect evidence linking survival with nutritional status, both at initiation of dialysis and on follow up 32.4.1. Measurements of nutritional status : a. albumin level ( target > 35 g/L) b. nPNA ( target > 1g/kg/day) c. Subjective global assessment (SGA)

References: 1. Clinical practice guidelines for peritoneal dialysis adequacy. National Kidney Foundation Dialysis Outcomes Quality Initiative. Am J Kidney Dis 1997;30(Suppl 2) : S67-136 2. Adequacy of dialysis and nutrition in continuous peritoneal dialysis: association with clinical outcomes. CANUSA Peritoneal Dialysis Study Group. J Am Soc Nephrol 1996 Feb;7(2):198-207 3. Blake PG. Critique of CANUSA. Perit Dial Int 1996;16:243-5 4. Genestier S; Hedelin G: Schaffer P; Faller B. Prognostic factors in CAPD patients: a retrospective study of a 10-year period. Nephrol Dial Transplant 1995 Oct; 10(10):1905-11 5. Maiorca R; Brunori G; Zubani R . Predictive value of dialysis adequacy and nutritional indices for mortality and morbidity in CAPD and HD patients. A longitudinal study. Nephrol Dial Transplant 1995 Dec;10(12):2295-305 6. Blake PG, Burkart J, Churchill D. Recommended clinical practices for maximizing peritoneal dialysis clearances. Perit Dial Int 1996;16:448-56 7. Oreopoulos DG. The optimization of continuous ambulatory peritoneal dialysis. Kidney Int 1999;55:1131-49 8. Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR, Oreopoulos DG, Page D. Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. The CanadaUSA (CANUSA) Peritoneal Dialysis Study Group. J Am Soc Nephrol 1998;9: 1285-92 9. Paniagua R, Amato D,Vonesh E, Correa-Rotter R, Ramos A, Moran J, Mujais for the Mexican Nephrology Collaborative Study Group. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a Prospective, randomized, controlled trial. J Am Soc Nephrol 13: 13071320, 2002

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33. PERITONEAL DIALYSIS IN CHILDREN CAPD/APD is the preferred form of dialysis for children with ESRD. In children; scaling of intraperitoneal fill volume by body surface area (BSA) is recommended.1,2 A fill volume of 900 1100 mL/m2 is recommended for most paediatric patients to achieve a theoretical weekly target Kt/Vurea of > 1.9. Solutions used are as for adults except that volumes of 1.5L and 1.0L are available. 33.1. Access. Catheters commonly used are as for adults except for the size paediatric and neonatal straight double cuff Tenckhoff catheters are commonly used. 33.2. Catheter insertion. The recommendations for adult patients apply to children as well. In addition; partial omentectomy may be helpful in preventing catheter obstruction3 . 33.3. Chronic peritoneal dialysis prescription 33.3.1. CAPD : usually 4 5 exchanges; using exchange volume of 900 - 1100ml/m2. Theoretically this will result in a weekly target Kt/Vurea of greater than 1.9 for the average patient. 33.3.2. APD : usually 8 10 exchanges over 8 10 hours at night. Higher fill volume used compared to CAPD because of enhanced tolerance to the intraperitoneal fill volume in the supine position in APD.1 33.4. Adequate Dose of Peritoneal Dialysis 33.4.1. Weekly dose of CAPD. There are currently no definitive outcome data in paediatric patients to suggest that any measure of dialysis adequacy is predictive of well being, morbidity or mortality. It is the opinion of the DOQI Work Group that since the nutritional requirements per kg of body weight are higher in children than in adults; the PD doses in children, and especially small infants who have very high protein intakes, may have to be higher than PD doses in adults4 .

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33.4.2. Weekly dose of APD. Again there are no definitive outcome data in paediatrics to suggest that any measure of dialysis adequacy is predictive of well being, morbidity, or mortality. 33.5. Treatment of peritonitis in children5 The Guideline for the treatment of peritonitis in children is similar to that for the adult patients with the exception that aminoglycosides should be avoided unless absolutely indicated. Table 33.1: Paediatric Antibiotic Dosing Recommendations (Administration should be via intraperitoneal route unless specified otherwise.) Loading dose Maintenance Intermittent dose therapy Glycopeptides 500 mg/L 30 mg/L Vancomycin 30 mg/kg q 5-7 days 200 mg/L 20mg/L Teicoplanin 15 mg/kg q 5-7 days Cephalosporins 250 mg/L 125 mg/L Cefazolin/ 15 mg/kg q24H cephalothin 200 mg/L 125 mg/L 15 mg/kg q24H Cefuroxime 500 mg/L 250 mg/L 30 mg/kg q24H Cefotaxime 250 mg/L 15 mg/kg q24H 125 mg/L Ceftazidime 250 mg/L 125 mg/L Ceftizoxime Antifungals __ 1mg/kg/day Amphotericin B 1 mg/kg IV IV __ 3-6 mg/kg IP, __ Fluconazole IV, or PO q 2448H (max dose 200 mg) __ 50 mg/kg IV 25-37.5 Flucytocine or PO (max mg/kg PO q dose 2.0 g) 24H (max 1.0 g) Aminoglycosides 25 mg/L 12 mg/L __ Amikacin 8 mg/L 4 mg/L __ Gentamicin 8 mg/L 4 mg/L __ Netilmycin Penicillins

Formatted: Ge

Formatted: Ge

Formatted: Ge

Formatted: Ge

Formatted: Ge

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Piperacillin Ampicillin Oxacillin Amoxicillin Quinolones Ciprofloxacin Combinations Ampicillin/ Sulbactam Imipenem/ Cilastin TMP/SMZ Others Metronidazole Rifampin

__ __ __ 250 -500 mg/L 50 mg/L 1000 mg/L 500 mg/L 320/1600 mg/L __ __

250 mg/L 125 mg/L 125 mg/L 50 mg/L 25 mg/L 100 mg/L 200 mg/L 80/400 mg/L __ __

150 mg/kg IV q 12 H __ __ __ __ __ __ __

35-50 mg/kg/d PO in 3 doses 20 mg/kg/d PO (max 600 mg/day)

33.6. Quality of Life Issues. 33.6.1. Schooling 33.6.2. Growth and developmental progress measured serially 33.6.3. Minimal restriction of physical activities 33.7. Nutrition. Table 33.2: Nutritional parameters and appropriate minimum schedule of testing or measurement for patients on HD and PD 6 Minimum Interval Parameter Below 2 years 2 years and Over Length 3 Monthly Not applicable *+ Standing height Not applicable 3 mo Head circumference Monthly 3-4 mo until 36 mo+ Estimated dry weight Monthly 3-4 mo + Weight/height index Monthly 3-4 mo+ Z score or SDS height 3 monthly 6 mo for chronological age Serum albumin Monthly 3 Monthly+ Serum bicarbonate Monthly 3 Monthly+ Skinfold thickness No agreement 3-4 mo+ Midarm 3-4 mo 3-4 mo+

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circumference Dietary interview Urea kinetic modelling * evidence, + opinion

Monthly 6 mo

3-4 mo+ 6 mo+

Table 33.3: Daily dietary recommendation for children on CAPD Infants Children / Adolescents Minimum of RDA for Minimum of RDA Energy height age for age 3.0 g/kg ht.age 2-5 year 3-4 g/kg Protein 2.5 g/kg ht age 5-10 years 2.0g/kg ht age 10-12 years 1.5 g/kg ht age >12years Sodium Potassium Calcium Phosphorus Vitamins: Water soluble Fat soluble Trace elements Zinc (mg) Copper (mg) 1 mmol/kg 3 mmol/kg and restriction supplement as necessary may be liberalized supplement avoid supplementation 5 0.4-0.7 26 100 mmol/day if necessary 25-50 mmol/day if necessary supplement as necessary generally 240 ml milk/day supplement avoid supplementation 10-15 0.2-2.0 (<7yr), 1.5-2.5 (>7yr)

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References:
1. 2. 3. 4. 5. Alexander S. Balfe JW, Harvey E. Peritoneal dialysis in children. In: Gokal R, Nolph KD, Eds. The textbook of peritoneal dialysis. Dordecht: Kluwer Academic, 1994:591-637. Kohaut EC, Waldo FB, Bienfeld M. The effects of changes in dialysate volume on glucose and urea equilibration. Perit Dial Int 1994; 14:236-9. Nicholson M, Burton P, Donnelly P, Veitch P, Walls J. The Role of omentectomy in Continuous Ambulatory Peritoneal Dialysis. Perit Dial Int 1990; 11:330-332. NKF-DOQI Peritoneal Dialysis Adequacy Work Group Members (1997) NKFDOQI clinical practice guidelines for peritoneal dialysis adequacy. Am J Kidney Dis 30:S67-S136. Warady BA, Schaefer F, Holloway M, Alexander S, Kandert M, Piraino B, Salusky I, Tranaeus A, Divino J, Honda M, Mujais S, Verrina E; International Society for Peritoneal Dialysis (ISPD) Advisory Committee on Peritonitis Management in Pediatric Patients. ISPD Guidelines/recommendations. Consensus guidelines for the treatment of Peritonitis in Pediatric Patients receiving peritoneal dialysis. Perit Dial Int 2000; 20; 6:610-624 K/DOQI Nutrition in Chronic Renal Failure. Am J Kidney Dis, 2000; 35:6, Suppl 2 (June), S105-S136

6.

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34. AUTOMATED PERITONEAL DIALYSIS (APD) APD includes every type of peritoneal dialysis performed with the aid of a cycler. 34.1. The various APD techniques available are: 34.1.1. NIPD nightly intermittent peritoneal dialysis; APD performed only at night with complete fill and drain of the peritoneal cavity 34.1.2. NTPD nightly tidal peritoneal dialysis; APD performed only at night with partial fill and drain of the peritoneal cavity 34.1.3. CCPD continuous cycling peritoneal dialysis; APD performed at night, but with the addition of one or two daytime dwells 34.1.4. CTPD continuous tidal peritoneal dialysis; APD performed at night (tidal modality), with the addition of one(CTPD1) or two(CTPD2) daytime dwells. These latest two modalities are also called PD plus therapy 34.2. Prescription and delivery of APD 34.2.1. The efficiency of APD is affected by a. Fill volumes 40 mL/kg or 2.5 L/1.73 m2 b. Peritoneal transport characteristics c. Total prescribed dialysate volume per session 34.2.2. Patient selection criteria for APD: a. High average and high transporters b. CTPD may be the only way that some larger or anephric patients can achieve target clearance rates c. Patients with limited self-sufficiency d. Children e. Patients with hernias or leaks 34,3. Modification of APD regimen for treatment of peritonitis: The initial (24 48 hours) treatment of peritonitis should include a prolongation of the dialysate dwell time to 3-6 hours until there is clearing of the peritoneal effluent. This may be preceded by several rapid flushes of dialysis solution at diagnosis to help reduce

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abdominal pain. When the effluent demonstrates clearing which typically occurs within the initial 48 hours; the patient may return to a more standard APD regimen or be converted temporarily to standard CAPD regime. Data on dosing of antibiotics for patients on APD is lacking but generally follows that for single daily dosing for CAPD, or maintenance dosing if patient continues on APD.

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35. INTERMITTENT PERITONEAL DIALYSIS 35.1. Indications 35.1.1. Acute renal failure 35.1.2. Severe fluid overload not responsive to conservative measures 35.1.3. Electrolyte imbalance unresponsive to conservative measures 35.1.4. High blood urea or rapidly rising blood urea with metabolic acidosis 35.1.5. End stage renal disease as temporary treatment 35.1.6. Acute poisoning 35.2. Contraindications 35.2.1. 35.2.2. 35.2.3. 35.2.4. 35.2.5. Congenital absence of diaphragm Large pleuroperitoneal fistula Diffusely infected abdominal wall. Recent major abdominal operation Large abdominal masses e.g. aneurysm, polycystic kidneys, pregnancy

35.3. Procedure 35.3.1. Consent for first peritoneal dialysis 35.3.2 If necessary, shave the area between the umbilicus and pubic symphysis. 35.3.3. The bladder must be emptied. In unconscious or ill patients, the bladder may need to be catheterised. The catheter should be removed as soon as possible. 35.3.4. The puncture site is usually in the midline about one inch below the umbilicus. Avoid puncturing a previously scarred site. 35.3.5. The operator should be masked, scrubbed and gloved. 35.3.6. Under aseptic conditions, the periumbilical area is cleaned with povidone iodine only, then draped. 35.3.7. The area is infiltrated with 3-10 mls of 1-2% lignocaine down to the peritoneum with a 21G or 23G needle. 35.3.8. A small skin incision, slightly smaller than the diameter of the catheter is made using a sharp pointed scalpel blade (No. 11). Do not cut the muscle layer. 35.3.9. The catheter must be checked carefully by withdrawing the stilette from the catheter for any breakages before insertion.

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35.3.10. The catheter and stilette are introduced while controlling the length with the dominant hand until the peritoneum is pierced. The stilette is then withdrawn and the catheter gently pushed in, directed towards either iliac fossae. 35.3.11. Skin sutures are unnecessary if a retaining knob is present. Bleeding from the insertion site can be stopped by a pursestring suture. Gauze with povidone iodine is applied around the puncture site. Cover with plaster. 35.3.12. The required volume of dialysate is instilled into the abdomen. The first 6 cycles are rapid exchanges with heparin. The subsequent cycles are retained for 20-40 minutes per cycle and drained in 10-15 minutes. 35.3.13. Exchange volume: adult 1000 2000 ml Children 20-50 ml/kg body weight 35.3.4. The duration of dialysis depends on the needs of the patient. The current practice is 60 cycles for first PD and 40 cycles for subsequent PDs. At the termination of the procedure, the catheter is removed and the puncture site covered with gauze and plaster. Suturing is not necessary unless there is leakage. N.B. The peritoneal cavity may be pre-filled with dialysate using 14-18G branula before introducing the actual PD catheter. This is to reduce the risk of puncturing any viscus in the peritoneal cavity. 35.4. Reminder: 35.4.1. Ensure strict aseptic techniques at all times and especially when preparing the PD sets of fluids and lines, changing peritoneal dialysis solutions or injecting drugs into bags. 35.4.2. Oversee the first 3 cycles of dialysis to ensure good flow. 35.4.3. Check for turbidity, leakage and ultrafiltration every two hours. 35.4.4. Input and output chart, vital signs monitoring and PD chart should be kept up-to-date. Turbid effluent must be noted to the doctor. 35.4.5. Blood urea, serum electrolytes and creatinine should be requested according to patients needs. In stable patients, once daily should be more than sufficient. 35.4.6. Blood urea and electrolyte results to be reviewed by the doctor and potassium chloride to be added into dialysate if necessary.

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35.4.7. One gram of potassium chloride available in 10 ml ampoule is equivalent to 13.3 mmol of potassium. Hence adding 3 ml to one litre would result in dialysate with 4.0 mmol/l of potassium. 35.4.8. Check blood sugar in diabetic patients. Actrapid may be needed. 35.5. Nursing guidelines in acute peritoneal dialysis. 35.5.1. Ensure asepsis at all times. 35.5.2. Wash hands each time before spiking solution bags. Do NOT touch the part that spikes into the bag. Spike all the way in. 35.5.3. Do not use dialysate solution that is past the expiry date or looks turbid. 35.5.4. Do not add drugs from open medication ampoules that have been left open for some time into the dialysate bag. 35.5.6. Dialysate drainage bag should not touch the floor. The outlet tubing should not dip into the drainage container. 35.5.6. If there is poor drainage: a. Check for kinking of the external drainage tubes. b. Change position of the patient. c. Run rapid cycles with heparinised dialysate solution at 500 U per litre till good flow is obtained. d. Check for fibrin clots. 35.5.7. Inform doctor immediately in the following situations: a. Poor inflow or outflow. b. Leakage of dialysate from the abdomen or anywhere along the dialysis set. c. If dialysate is heavily blood stained Turbid/cloudy Faecal matter present. Stop dialysis immediately. NB. Collect effluent for cell count and culture and sensitivity. d. Patient complains of severe abdominal distension or pain. e. Abnormal vital signs e.g. hypotension, tachycardia, tachypnoea, fever. f. Patient complains of severe/progressive breathlessness after starting PD. 35.5.8. Never flush catheter under non-sterile conditions. 35.5.9. Avoid dismantling any part of the dialysis system once it is set up.

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35.5.10. Send PD fluid for cell count and culture and sensitivity at start and end of PD and when the effluent is turbid. 35.6. Complications: 35.6.1. Mechanical complications a. Damage to viscera. - If there is faecal material in the effluent, stop dialysis immediately, collect specimens for inspection, culture and sensitivity, and remove dialysis catheter. - Start antibiotics ceftazidime plus metronidazole. - Drip and suck. - Convert to HD. b. Bleeding from puncture site. - Purse string suture. c. Leaking dialysate. - Check site of leakage. Exit site - Resuture immediately. Tubings change dialysis set. One to two days of IP antibiotics e.g. cephalosporin group may be needed. d. Poor drainage - Check for kinking - Check for blockage by blood clots and fibrin. - Change position of patient. - Re-insert if necessary. e. Blood stained effluent - If mild observe. It should clear with successive cycles. - If heavy, but vital signs stable, run rapid cycles. Transfuse cryoprecipitate. Consider blood transfusion and DDAVP. If bleeding does not stop after the first few cycles, stop the dialysis. - If heavy, patient in shock, resuscitate as for patient with hypovolaemic shock. Stop dialysis and refer surgeon immediately. 35.6.2. Peritonitis (refer section on CAPD peritonitis)

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GLOSSARY PD APD CAPD IPD CCPD HD ISPD NKF-DOQI PET Kt/Vurea nPNA UF BW BSA AGE GDP MRSA peritoneal dialysis automated peritoneal dialysis continuous ambulatory peritoneal dialysis intermittent peritoneal dialysis continuous cycling peritoneal dialysis haemodialysis International society for peritoneal dialysis National Kidney Foundation Dialysis Outcomes Quality Initiative peritoneal equilibrium test urea kinetic modelling normalised protein nitrogen appearance ultrafiltration body weight body surface area advanced glycation end-products glucose degradation products methicillin resistant staph aureus

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RENAL TRANSPLANTATION

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36. LIVING RELATED DONOR WORKUP 36.1 Patient information 36.1.1 Short term risk a. Surgical risk Mortality rate of 0.03 0.05 %1,2,3 Morbidity (Table 36.1)2 Table 36.1: Summary of the incidence of early complications after donor nephrectomy Complications Incidence Atelectasis 15-30 % Paraesthesia / nerve injury 6% Urinary tract infection 5% Pneumothorax 5% Wound infection 3% Blood transfusion 2% Pneumonia 1% Splenectomy 0.3 % Pulmonary embolism 0.3 % b. Psychological risk1 Minor feelings of depression are common in the immediate post operative period; more so if the graft fails 36.1.2 Long term risk to renal function is minimal4,5,6 (Level B) There is no increase in proteinuria. There was a small increase in blood pressure but this increase was insufficient to result in increased prevalence of hypertension 4 36.1.3 Results of graft and recipient survival is dependent on the centre (refer to Renal Registry) 36.1.4 Assurance that donor may withdraw at any stage of pre transplant assessment 36.2 Selection criteria 36.2.1 Siblings / parents are the best donor1,3 (Level B) In the absence of a relative, consideration can be given to emotionally related donor7 (Level B) 36.2.2 Age

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Exclude those who are < 18 and > 65 years of age8,9,10,11,12 Biological age is more important than chronological age 36.2.3 ABO compatibility1,3,13 (Level A)

36.2.4 HLA A, B, DR phenotypes3 (Level A) Priority should be given to the donor with 1 or 2 haplotype match 36.3 Contraindications to renal donation1,3,6,14 36.3.1 Absolute contraindications a. Proteinuria / haematuria (refer to 36.4.4) b. Impaired renal function (refer to 36.4.4) c. Hypertension > 140/90 mmHg d. Diabetes mellitus e. Family history of type 2 diabetes mellitus with impaired glucose tolerance test f. Transient gestational diabetes 15 g. Psychiatric illness e.g. psychotic disorders h. Coagulopathy i. Systemic illness with potential to develop renal disease j. Drug abuse e.g. amphetamines, heroin and cocaine k. Severe cardiac and pulmonary disease l. Infectious disease eg. HIV m. Pregnancy n. Adult polycystic kidney disease (APKD). For donors who are relatives of recipient with adult polycystic kidney disease use of US kidneys to rule out APKD is according to the following criteria 16 (Level B): Donor of less than 30 years of age, 2 cysts establish APKD. The cysts may be either unilateral of bilateral Between 30 to 59 years of age, at least 2 cysts must be present in each kidney Over the age of 60, 4 cysts must be present in each kidney 36.3.2 Relative contraindications a. Obesity: BMI > 30 15,17,18 b. Living related donor < 30 years old if recipient is type 1 diabetic c. History of nephrolithiasis. Donation is safe if: stone disease is inactive for the last 10 years, donor has only passed 1 stone so far, there is no evidence of stones on current radiographic studies.

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d. Malignancy (donation is possible if tumour is cured) e. Hepatitis B or C infection HBsAg positive and HBeAg negative donor can be accepted if the recipient is HBsAb positive (titre >10mIU/l) Renal donation from HCVAb positive donor to HCVAb positive, HCV RNA positive recipient is relatively safe19,20,21 provided the HCV genotype is similar (Level D). There is no difference in liver disease prevalence over a period of 10 years.21,22 Caution: Superinfection with a new genotype can occur unless HCV genotypes in donor-recipient are matched.22 f. Donors who are relatives of recipient with Alports syndrome 1 Male relatives without haematuria can become a donor Female relatives without haematuria might be a carrier and she should consider that her child may inherit the disease and require future transplantation. Final decision should preferably be based on genotyping Recipient who gets a kidney from someone without Alports syndrome may develop anti glomerular basement membrane disease 36.4 Donor assessment 36.4.1 Motivation and psychosocial status assessment The motive to donate to the potential recipient should be entirely altruistic. The potential donor should not be under duress, coerced or induced to donate. The potential donor should be seen individually and given sufficient time to decide. The rest of the family should also be seen to obtain collateral and feedback information. Other members of the transplant team including the dialysis staff should interact with the potential donor so that a continuous assessment of the motivation can be made and further doubts cleared. In doubtful cases and in cases involving spousal donors, the potential donor should be independently assessed by another person outside the transplant team e.g. social worker, psychiatrist. 36.4.2 Cardiovascular assessment ECG, CXR, fasting triglyceride and cholesterol Referral for cardiology assessment is indicated for: a. male donor who is more than 45 years old b. female donor who is 50 years old or premature menopause. c. donors who are 35 years or older with coronary risk factors e.g. smoking, family history of coronary heart disease, dyslipidaemia, obesity

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36.4.3 Respiratory assessment Potential donor with chronic smoking history and symptoms of chronic lung disease should be referred to a respiratory physician and anaesthetist for assessment. 36.4.4 Assessment of donor renal status A full history and examination should be carried out with particular attention to the recipients primary renal disease and any history of familial renal disease. Investigations include the following: a. Renal profile b. Fasting blood sugar (glucose tolerance test if indicated) c. Serum calcium and phosphate, uric acid d. Urine cystine, uric acid, calcium, phosphate (X3). Abnormally high results should be assessed individually e. 24 hour creatinine clearance (X3). Exclude < 80 mls/min/1.73 m2 or < 2 standard deviations of the mean8,17 Table 36.2: Renal function as determined by creatinine clearance according to age range17 Mean creatinine Standard Mean minus 2 Age clearance deviation standard deviations range mls/min/1.73 m2 (years) 17-24 140 11.7 117 25-34 140 21.4 97 35-44 133 20.0 93 45-54 127 17.3 93 55-64 120 16.5 87 65-74 109 16.5 76 Table 36.3: Renal function as determined by inulin clearance according to age range17 Standard Mean minus 2 Age Mean creatinine deviation standard deviations range clearance (years) mls/min/1.73 m2 24-29 123 16.4 90 30-38 115 10.8 93 40-49 121 23.3 74 51-59 99 14.6 70 61-68 96 25.5 45 70-78 89 19.9 49

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f. 24 hour urine protein (X3). Exclude if > 300 mg /day8 g. Urine microscopy (X3) h. Ultrasonography of the kidneys i. KUB j. IVP k. DTPA renography. If GFR contradicts the 24 hour urine creatinine clearance, proceed to Cr EDTA scan l. Selective renal angiography. Spiral CT angiogram23.24.25 (Level C) or Gadolinium-enhanced magnetic resonance angiography26 (Level C) could be an alternative 36.4.5 Assessment of potential risk of transmitting infection to the recipient a. Screening and treatment of Syphilis Tuberculosis Urinary tract infection b. Screening of HIV HBV (including HBeAg in HBsAg positive cases) HCV antibody Toxoplasmosis Cytomegalovirus (See section on: Prevention of CMV disease post transplantation) 36.5 Laparoscopic donor nephrectomy Laparoscopic donor nephrectomy can be performed with morbidity and mortality comparable to open donor nephrectomy in established centres27,28,29 (Level B) 36.5.1 First introduced in 1991 36.5.2 Benefits of laparoscopic versus open method are: a. Shorter hospital stay b. Less analgesic requirement c. Earlier return to work d. Less blood loss e. Improved cosmetic results f. No deaths reported g. Can be performed on obese patients h. Multiple renal vessels are not a contraindication 36.5.3 Disadvantages of laparoscopic method: a. Longer operating time b. Technically more demanding

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36.5.4 Relative contraindication to laparoscopic method: a. Prior open upper abdominal surgery b. Right sided donor nephrectomy

References
1. Kasiske BL, Ravenscraft M, Ramos EL, et al. The evaluation of living renal transplant donors: clinical practice guidelines. Ad Hoc Clinical Practice Guidelines Subcommittee of the Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol 1996; 7: 2288 Richard DM, Stephen VL, Russell WS. The Living Organ Donor. Jeremy C (eds.). Organ and Tissue Donation for transplantation. Arnold Publication, 1997, 162-199 The EBPG Expert Group on Renal Transplantation. European Best Practice Guidelines for Renal Transplantation (Part 1). Nephrol Dial Transplant 2000; 15 (suppl 7) Kasiske BL et al. Long term effects of reduced renal mass in humans. Kidney Int 1995; 48: 814-819 Narkun-Burgess DM et al. Forty-five years of followup after uninephrectomy. Kidney Int 1993; 43: 1110-1115 Najarian JS et al. 20 years or more of followup of living kidney donors. Lancet 1992; 340: 807-810 Terasaki PI et al. High survival rates of kidney transplants from spousal and living unrelated donors. N Eng J Med 1995; 333: 333-336 Margaret JB et al. Evaluation of living renal donors. Transplantation 1995; 60: 322-327 Kerr SR et al. Living donors > 50 years. To use or not to use? Transplantation 1999; 67: 999-1004 Kim YS et al. Use of elderly living related donors in renal transplantation. Transplant Proc 1992; 24: 1325-1326 Kanematsu A et al. Impact of donor age on long term graft survival in living donor kidney transplantation. Transplant Proc 1998; 30 : 3118-3119 Kumar A et al. Should elderly donors be accepted in a living renal transplant program? Clin Transplantation 1994; 8: 523-526. Cook DJ et al. ABO incompatibility in cadaver donor kidney allografts. Transplant Proc 1987; 16: 4549-4552 Kasiske BL. The evaluation of prospective renal transplant recipients and living donors. Surgical Clinics of North America 1998; 78: 27-39 Morris RD et al. Obesity and hereditary in the etiology of non-insulin dependent diabetes mellitus in 32,662 adult white women. Am J Epidemiology 1989; 130: 112-121 Ravine D et al. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease. Lancet 1994: 343: 824-827 British Transplantation Society and The Renal Association. United Kingdom guidelines for living donor kidney trans-plantation, 2000 Flancbaum L, Choban PS. Surgical implications of obesity. Ann Rev Med 1998; 49: 215-34 Ali MK et al. Donor hepatitis C virus status does not adversely affect short term outcomes in HCV + recipients in renal transplantation. Transplantation 1998; 66: 1694-1697

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

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20. Morales JM et al. Transplantation of kidneys from donors with hepatitis C antibody into recipient with pre-transplantation anti-HCV. Kidney Int 1995; 47: 236-240 21. Dominguez-Gil B et al. Ten years experience in transplantation of kidneys from HCV positive donors into HCV positive recipients. Transplantation 2000; 69: S404 22. Morales JM and Campistol JM. Trasplantation in the patients with hepatitis C. J Am Soc Nephrol 2000; 11: 1343-1353 23. Rubin GD et al. Assessment of living renal donors with spiral CT. Radiology 1995; 195 (2): 457-62 24. Alfrey EJ et al. The use of spiral computed tomography in the evaluation of living donors for kidney transplantation. Transplantation 1995; 59: 643-645 25. Lionel G et al. The use of spiral computed tomography angiography for the assessment of the living kidney donors. Aust N. Z. J. Surg 1999; 69: 217-219 26. Bakker J et al. Preoperative evaluation of living renal donors with gadoliniumenhanced magnetic resonance angiography. Transplantation 1999; 67: 8 27. Kavoussi LR. Laparoscopic donor nephrectomy. Kidney Int 2000; 57: 21752186 28. Flowers JL et al. Comparison of open and laparoscopic live donor nephrectomy. Annals of Surgery 1997; 226 (4): 483-489 29. Ratner LE et al. Laparoscopic assisted live donor nephrectomy- a comparison with the open approach. Transplantation 1997; 63: 229-233

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37. LIVING RELATED RECIPIENT WORKUP 37.1 Contraindications to transplantation 37.1.1 HIV infection1,2 (Level C) 37.1.2 Malignancy (Table 37.1)3

Table 37.1: Guidelines for recommending tumor free waiting periods for common pretransplant malignancies3 Site Waiting period Renal: Incidental, asymptomatic None Large , infiltrating At least 2 years Wilms tumor At least 2 years Bladder : In situ None Invasive At least 2 years Uterus : In situ cervical None Invasive cervical 5 years Uterine body At least 2 years Testis At least 2 years Thyroid At least 2 years Breast At least 5 years Colorectal At least 2 years Prostate At least 2 years Lymphoma At least 2 years Skin : Melanoma At least 5 years Squamous cell 2 years Basal cell None 37.1.3 Severe cardiovascular disease e.g. diffuse disease on coronary angiogram, ejection fraction of < 35 %, valvular heart disease, ventricular arrythmia1 (Level C) 37.1.4 37.1.5 37.1.6 37.1.7 37.1.8 Diabetes mellitus with multiorgan failure Psychiatric illness e.g. psychosis4 Noncompliance1,4 (Level C) Active substance dependence or abuse e.g. alcohol, amphetamines, cocaine, heroin4 Chronic active hepatitis or cirrhosis4,5 (Level C)

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37.1.9 Age: > 55 years old. Patients between the age of 55 and 65 years of age are not at a significantly increased risk of post transplant morbidity as long as they do not have significant vascular disease.3 Consideration should be given on an individual basis. 37.1.10 Any disease with an expected survival of less than 5 years or with a resultant poor quality of life. 37.1.11 Primary renal disease. Patients with end stage renal disease due to the following aetiology may be transplanted with caution: a. Focal segmental glomerulosclerosis b. Antiglomerular basement membrane (Anti GBM) disease. Transplant should be considered one year after end stage renal failure and the circulating anti GBM titre is no longer detectable in the blood. 2 c. Membranoproliferative glomerulonephritis type II (MPGN II). d. Oxalosis. Patients can be treated with orthophosphate and pyridoxine, and preemptive renal transplantation with possible liver transplantation should be considered.6 e. Fabrys disease 37.1.12 Secondary GN a. Systemic Lupus Erythematosus (SLE). Disease should be inactive for at least 6 months prior to transplant as assessed by clinical and serological status. b. Haemolytic Uraemic Syndrome (HUS) or Thrombotic Thrombocytopaenia Purpura (TTP). Delay for at least 1 year prior to transplantation. c. Idiopathic crescentic GN or Wegeners or microscopic polyangiitis. Stable ANCA and asymptomatic for at least 6 months prior to transplantation. 37.2 Dialysis and nutritional status 37.2.1 Potential renal transplant recipients should be adequately dialysed to achieve good control of blood pressure, optimum status of hydration and acquire satisfactory nutritional status 37.2.2 Potential renal transplant recipients should have the following assessment : a. Body weight b. Body mass index c. Triceps skin fold thickness d. Mid arm circumference (MAC.)

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e. Serum albumin Patients on continuous ambulatory peritoneal dialysis (CAPD) may undergo renal transplant without Tenckhoff catheter removal prior to transplantation provided they are free from peritonitis or catheter related infection for at least 4 weeks.4 Similarly, haemodialysis patients may undergo renal transplant with an indwelling central venous dialysis catheter provided there is no evidence of catheter related infection. 37.3 Assessment of medical and psychiatric status In women: breast and pelvic examination, Pap smear. In those over 40 years old or over 35 years old with a family history of breast carcinoma, mammography.6 In men: testicular and per rectal examinations 37.3.1 Assessment of the cardiovascular system Full history and examination, CXR, ECG Further assessment by cardiologist is indicated for the following cases: a. male recipients who are more than 45 years old b. female recipients who are 55 years old or premature menopause c. recipients who are 35 years or older with coronary risk factors e.g. smoking, family history of coronary heart disease, diabetes mellitus, dyslipidaemia, obesity 37.3.2 Assessment of respiratory system Full history and examination, CXR Potential recipients with chronic smoking history and symptoms of chronic lung disease should be referred to a respiratory physician and anaesthetist for assessment 37.3.3 Assessment of the gastrointestinal system Routine upper GI endoscopy should be performed in order to detect subclinical peptic ulcer disease (not routinely done in children unless symptomatic) 37.3.4 Urological evaluation a. The following investigations should be routinely carried out in potential recipients KUB. Ultrasonography of kidneys / ureter. Micturating cystourethrogram (if there is a history of recurrent urinary tract infection, a suspicious renal tract abnormality or an unknown primary renal disease in a young patient).

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b. For patients with suspected urological disorders, referral to urologist is required for further evaluation which may include a urodynamic study c. The following group of potential recipients should be referred earlier to the transplant surgeon All diabetic patients Patients with a history of recurrent urinary tract infections Patients with raised PSA level Patients with adult polycystic kidney disease Patients with severe peripheral vascular disease 37.3.5 Assessment of pelvic vasculature For selected patients e.g. past history of femoral catheterisation, long-term HD or increased iPTH, Doppler US studies, CT scan, MRA/angiogram when indicated 37.3.6 Assessment of the liver status a. Routine assessment include ALT, HBsAg, HCVAb If HBsAg is positive, the patient should have HBeAg and HBV DNA tested. If HBsAg is negative and HBsAb is negative, the patient should be immunised with Hepatitis B vaccine (refer table 7.1) b. Indications for liver biopsy4,8,9,10,11 (Level B) Patients with HCVAb or HCV PCR positive with or without elevation of liver enzymes Patients with positive HBsAg, negative HBeAg with or without raised liver enzymes c. Following liver biopsy the patients should be treated as follows: If there is chronic active hepatitis (CAH), renal transplant is contraindicated.11,12 (Level C) If the liver enzymes is more than twice normal, renal transplant should be deferred until the enzyme has decreased to a level less than twice normal on 3 consecutive occasions separated by two weekly intervals between each reading. If there is chronic persistent hepatitis or milder disease with ALT less than 2X normal renal transplant may be carried out.13 d. Refer hepatologist for treatment of chronic hepatitis B and C Treatment of chronic hepatits B: Treatment is indicated when HBsAg + > 6 months, HBeAg +, HBV DNA +, raised ALT (2X above upper limit), chronic hepatitis on biopsy. Treatment with either Interferon -2b 5

232

million units daily or 10 million units 3X/ week for 3 to 6 months13,14,15 or Lamivudine 100 mg daily for at least 1 year.16,17,18 Treatment of chronic hepatitis C: Treatment is indicated when HCVAb +, HCV RNA +, raised ALT (2X above upper limit), chronic hepatitis (moderate to severe) on biopsy. Treatment is interferon -2b 3 million units 3X per week for 6 to 12 months.19,20,21,22. Pegylated interferon 2a may be considered at a weekly dose of 135ug for 48 weeks with close monitoring for toxicity. 21 37.3.7 Assessment of the haematological system Potential recipients should have haemoglobin of at least 8 g/dl before transplant. Blood transfusion for correction of anaemia is strongly discouraged. Patients should be treated with erythropoeitin after exclusion and treatment of underlying factors which contribute to anaemia 37.3.8 Psychological assessment 4 All potential recipients should be assessed psychologically with particular attention paid to the following areas: a. Noncompliance with dialysis / medications b. Alcohol and substance abuse (at least 6 months of documented abstinence) c. Family support d. Past psychiatric history / treatment e. In children a full developmental assessment should be made If indicated, a referral to a counselor or a psychiatrist should be made prior to further pretransplant evaluation. 37.3.9 Obesity Attempts should be made for the potential recipients to achieve an ideal body weight (weight reduction should be carried out for potential recipient whose BMI> 30). 37.4 Dental evaluation All potential recipients should be assessed by a dentist for dental clearance.

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Figure 37.1: Management of HCV infection in dialysis patient on the waiting list for renal transplantation23
HCV Ab POSITIVE PATIENT ON DIALYSIS HCV RNA -ve HCV RNA +ve LIVER FAILURE / CIRRHOSIS

LIVER BIOPSY

Normal

Chronic Hepatitis

Liver Cirrhosis

IFN for 12 months

RNA -ve

RNA +ve

IFN + Ribavirin

RNA -ve Waiting list for renal transplantation Defer renal Tx ?

RNA +ve

To consider double liver-kidney transplantation

37.5 Management of pretransplant infection (12 weeks pretransplant) 37.5.1 Screening for infection according to organ / system a. ENT Surveillance cultures should be taken from ear, nose and throat. Chronic suppurative otitis media should be excluded b. Respiratory CXR just prior to transplantation should be done

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c. Genitourinary tract Mid stream urine for C & S if potential recipient still having significant urine output d. Miscellaneous CAPD catheter dialysate for cell count and C & S and exit site swab for C & S if indicated Central venous catheter exit site swab for C & S 37.5.2 Screening for specific infection a. Tuberculosis (TB) Any suspicion of active TB (radiological or clinical) should be thoroughly investigated and adequately treated. A six month period of observation after completing anti TB treatment is desirable before transplantation is undertaken b. Toxoplasma IgM antibody of > 1:4 is regarded as significant and the patient should be treated pretransplant c. HCV Screening is done by detecting HCV antibody HCV antibody +ve patients can be considered for renal transplantation, subject to liver histology.24,25,26,27,28,29 Refer to figure 37.1 for details (Level C) d. HIV Screening by ELISA should be done twice during the pretransplant assessment. The first is done at the initial part of the assessment and the second preceding the transplant e. HBV Potential recipient who are HBeAg and HBV DNA positive in spite of treatment are excluded from transplantation f. Cutaneous and genital warts should be treated pretransplant g. Varicella Zoster Ab (refer to table 45.2) h. Herpes Simplex Ab i. Epstein Barr virus Ab j. Cytomegalovirus (CMV) IgG Ab against CMV is used for screening 37.6 Acute rejection prophylaxis 37.6.1 White cell cross match is done at the early stage of donor workup and one week prior to transplant (adapted from Guidelines for lymphocytotoxic cross match procedures, Renal Unit, Singapore General Hospital) 37.6.2 The following 6 cross matches should be performed by complement-dependent cytotoxicity (CDC) method:

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a. T cell cross match (standard) b. B cell cross match (standard) c. Anti human globulin (AHG) enhanced T cell cross match d. AHG enhanced B cell cross match e. Dithiothreitol (DTT) treated T cell cross match f. DTT treated B cell cross match 37.6.3 All T cell positive crossmatches i.e. presence of IgG or IgM anti HLA class I antibodies, contraindicate transplantation. IgG and especially IgM anti HLA class II antibodies indicate a less certain risk. T cell cross match detects anti HLA class I antibodies while B cell cross match detects both anti HLA class I and II antibodies. B cell cross matches are also more sensitive than T cell cross matches in identifying class I antibodies. AHG enhanced cross matches are more sensitive than the standard CDC (SCDC) method in detecting lymphocytotoxic antibodies, usually IgG. Conversion of a positive cross match to negative after pretreatment of recipient serum with DTT indicates the presence of IgM antibodies. 37.6.4 Many studies have confirmed that the historical crossmatch result is not relevant in sensitised recipients of a first transplant. The situation is less certain when the recipient of a historical positive, current negative crossmatch has become sensitised by loss of a first graft. Many centres would ignore a historical crossmatch result in first graft but not in regraft recipients.2,30 There remains considerable doubt about the degree of positive B lymphocyte crossmatch in influencing transplant outcome. Presence of autoantibodies in recipient sera can cause false positive crossmatch.30(Level C) Table 37.2: Standard white cell crossmatch results and their implications Transplant Current Cell Historical (Test done (Test done within 1 week of months before transplant) transplant) T + No Yes + No Yes B No + Yes + No + +

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37.6.5 Panel Reactive Antibodies (PRAs) PRAs are anti HLA antibodies against T & B cells from a panel of donors selected to represent the HLA specificities. The results are expressed as the % of panel cells that show positive antibody reactivity. Patients with PRA>20% should have enhanced immunosuppression. Serum screening determines: a. Percentage of PRAs Its value determines the likelihood of a negative cross match. Those with high % of PRAs are more likely to have a positive cross match and to be excluded from transplant. In international organ sharing algorithms, the PRAs value is used to increase queue points to improve patients chances of receiving a cadaveric transplant. b. Anti HLA specificity of antibodies produced by the patient A sequential record of antibody specificities over time can be used to avoid donors with those specificities and therefore diminish the likelihood of rejection episodes.

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Figure 37.2: Algorithm for white cell cross match


T cell XMatch SCDC + SCDC

AHG +

AHG

B cell XMatch

SCDC + or AHG +

SCDC or AHG

DTT +

DTT

Delay 3 months and repeat T & B cell XMatch

DTT + (IgM has converted to IgG)

DTT

Continue transplant workup. Needs enhanced immunosuppression post transplant Continue transplant workup

Transplantation excluded

238

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Eleanor LR et al. The evaluation of candidates for renal transplantation. Transplantation 1994; 57: 490-497 The EBPG Expert Group on Renal Transplantation. European Best Practice Guidelines for Renal Transplantation (Part 1). Nephrol Dial Transplant 2000; 15 (suppl 7) Danovitch G. Handbook of Kidney Transplantation, 2nd edition. A Little Brown Handbook, 1996. Kasiske BL et al. The evaluation of renal transplant candidates: Clinical practice guidelines. J Am Soc Nephrol 1995; 6: 1-34 Fornairon S et al. The long term virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection. Transplantation 1996; 62: 297-299 Kasiske BL. The evaluation of prospective renal transplant recipients and living donors. Surg Clin North Am 1998; 78: 27-39 Ramos E, Mohamed HS. Evaluation of the potential renal transplant recipient. UpToDate, 1999; 7 (3) Martin P et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000; 69: 1479-1484 Sterling RK et al. Chronic hepatitis C infection in patients with end stage renal disease: characterisation of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999; 94: 3576-3582 Mathurin P et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999; 29: 257-263 Ozdogan M et al. Histological impacts of hepatitis virus infection in haemodialysis patients: Should liver biopsy be performed before renal transplantation? Artif Organs 1997; 21: 355-358 Venkateswara K et al. Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients. Am J Med 1993; 94: 241250 Lok ASF. Interferon therapy for chronic hepatitis B virus infection. UpToDate 2000; 8(3) Wong DKH et al. Effect of alpha interferon treatment in patients with hepatitis Be Ag positive chronic hepatitis B, a meta analysis. Ann Intern Med 1993; 119: 312-323 Lok ASF et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology 1992; 102: 2091-2097 Lok ASF. Lamivudine treatment of chronic hepatitis B virus infection. UpToDate 2000; 8(3) Lai C et al. A one year trial of lamivudine for chronic hepatitis B. N Eng J Med 1998; 339: 61-68 Tassopoulos NC et al. Efficacy of lamivudine in patients with hepatitis Be antigen negative/ hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Hepatology 1999; 29: 889-896 Pereira B. Hepatitis C virus infection and renal transplantation. UpToDate 2000; 8(3) National Health Institiutes (NIH) of Health Consensus Development Conference Panel. NIH consensus development conference panel statement: Management of hepatitis C. Hepatology 26 (supp 1): 2S-10S Chopra S. Treatment of chronic hepatitis C virus infection: Recommendation. UpToDate 2003; 11(2) Campistol JM et al. Efficacy and tolerance of interferon alpha-2b in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Nephrol Dial Transplant 1999; 14: 2704-2709

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23. Morales JM, Campistol JM. Transplantation in the patient with hepatitis C. J Am Soc Nephrol 2000; 11: 1343-1353 24. Hanafusa T et al. Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 1998; 66: 471-476 25. Pereira BJG et al. Effect of hepatitis C infection and renal transplantation on survival in end stage renal disease. Kidney Int 1998; 53: 1374-1381 26. Knoll GA et al. The impact of renal transplantation on survival in hepatitis C positive end stage renal disease patients. Am J Kidney Dis 1997; 29: 608-614 27. Rostaing L et al. Impact of hepatitis C virus duration and hepatitis C virus genotypes on renal transplant patients. Transplantation 1998; 65: 930-936 28. Roth D et al. A prospective study of hepatitis C virus infection in renal allograft recipients. Transplantation 1996; 61: 886-889 29. Kliem V et al. The long term course of hepatitis C after kidney transplantation. Transplantation 1996; 62: 1417-1421 30. Allen RDM, Chapman JR. A manual of renal transplantation. An Edward Arnold publication, 1994, 52-66

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38. PERI-OPERATIVE MANAGEMENT 38.1 Specific issues to be addressed: 38.1.1 Assessment of recipients fluid status (to keep 1-2 kg above dry weight in adults if possible).1 38.1.2 Organise dialysis before transplant. Decision to dialyse a patient depends on the timing of the previous dialysis, volume status, and serum electrolyte levels, particularly serum potassium.1 38.1.3 CAPD patients should have their usual exchanges until day of transplant, then the peritoneal dialysis fluid should be drained from the abdominal cavity, examined and sent for cell count and culture.2 38.1.4 Determination of any intercurrent problems that may preclude or complicate surgery (e.g. fever, URTI, recent onset of cardiac or respiratory disease, uncontrolled BP). 38.1.5 Document residual urine, previous abdominal surgery, obesity (if present), femoral catheter insertion, position of Tenckhoff catheter if on CAPD, CMV status, cytotoxic cross-match result, viral status and infective screen as well as pre-transplant sensitisation. 38.1.6 The site of vascular access should be clearly marked and demonstrated to the OT staff. Protection of the vascular access site is advisable using non-circumferential padding to reduce the risk of occlusion by inadvertent external occlusion. 38.1.7 Knowledge of the donor status is important.

38.2 Immediate pre-transplant investigations: 38.2.1 Renal profile 38.2.2 38.2.3 38.2.4 38.2.5 38.2.6 Ca2+, PO4, LFT FBS/RBS FBC PT/APTT Urine C&S

241

38.2.7 38.2.8 38.2.9

Swabs: nasal, throat, ear CMV serology (if not available) Chest radiography

38.2.10 ECG 38.2.11 Cross match 4 units packed cells 38.2.12 Cyclosporin or tacrolimus level (for LRRT only, before serving cyclosporine or tacrolimus on the morning of operation, EDTA tube) 38.3 Consent for donor nephrectomy: 3 signatures required for LRRT: 38.3.1 Urology or Nephrology consultant 38.3.2 38.3.3 Urology Specialist Nephrology Specialist

38.4 Prophylactic antibiotic is recommended3,4,5,6,7,8 Perioperative prophylactic antibiotic drugs are beneficial in reducing the incidence of wound infections (not UTI), although there is considerable variation in practice. (Level C) The regimen depends on local bacterial epidemiology but should attempt to cover Staph. aureus and common enteric coliform bacteria. Instilling antibiotic into the bladder is of no additional benefit9,10 38.5 Immunosuppressive protocol Refer to chapter 40 for prophylactic/induction therapy 38.6 Intra-operative management 38.6.1 Central line to be inserted in OT 38.6.2 38.6.3 38.6.4 To maintain CVP at 10-15 cmH2O2 (Level D) Urinary catheter to be inserted Anaesthetist to document clamp and release time

38.6.5 Measures to decrease the likelihood of delayed graft function entail maintenance of adequate blood pressure and fluid status with IV colloid or crystalloid (the latter being preferable). In

242

living related transplant, it is common practice to administer mannitol before the kidney is reperfused, which helps to trigger an osmotic diuresis2,9 (Level D) 38.7 Post-operative care 38.7.1 Isolation nursing until all tubes/drains removed 38.7.2 38.7.3 Proper hand wash before and after examining the patient Hourly fluid balance (input, output, CVP), daily weight

38.7.4 Daily investigations: biochemistry, haematology, microbiology, and urinalysis 38.8 Intravenous fluids2 (Level D) 38.8.1 Aggressive replacement, aim to keep patient well hydrated 38.8.2 If patient is adequately hydrated with good graft function, replace previous hours urine output 38.8.3 If patient is adequately hydrated but remains anuric, restrict intravenous fluid to 500-1000 ml/day 38.8.4 Use normal saline alternate with D5%; if K+ < 4, use Hartmanns solution or K+ supplement 38.8.5 CVP line to be removed at the discretion of nephrologist

38.9 Bladder catheter 38.9.1 Indwelling bladder catheter should be inserted in OT 38.9.2 Urine output to be measured hourly

38.9.3 If urine output declines (< 100 ml/hour) or blood clots present to inform doctor immediately 38.9.4 Bladder washout should be only done under strict aseptic technique by urologist if deemed necessary 38.9.5 Catheter usually removed at Day 5 or at the discretion of urologist 38.10 Wound drain To be removed at the discretion of urologist

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38.11 Stents If there is an internal J stent ensure removal by 3 months post transplant or earlier if patient has UTIs 38.12 Investigations 38.12.1 Renal profile twice daily for 48 hours then daily (can be altered at the discretion of nephrologist) 38.12.2 Daily FBC, MSU 38.12.3 Chest radiography 38.12.4 LFT, Mg2+, Ca2+, PO4 3 x a week 38.12.5 Cyclosporin / tacrolimus level 3 x a week or when indicated 38.12.6 Doppler US Day 1, or immediately if primary non-function, delayed graft function or sudden drop in urine output 38.12.7 DPTA scan as indicated (usually done on Day 2 4) 38.13 Other medications 38.13.1 Intravenous ranitidine 50 mg tds for 2 days then change to oral ranitidine 150 mg bd for 3 6 months 38.13.2 Nystatin 250 000 units gargle and swallow qid for 3 months 38.13.3 Cotrimoxazole 480 mg at night, to commence when renal function is stable 38.13.4 CMV prophylaxis in high risk recipients

244

1. 2. 3.

Danovitch G. Handbook of Kidney Transplantation. 1996, 2nd edition Allen R, Chapman J. A Manual of Renal Transplantation. 1994 Cohen J, Rees AJ, Williams G. A prospective randomized controlled trial of perioperative antibiotic prophylaxis in renal transplantation. J Hosp Infect 1988; 11(4): 357-63 4. Lapchik MS, Castelo Filho A, Pestana JO, Silva Filho AP, Wey SB. Risk factors for nosocomial urinary tract and postoperative wound infections in renal transplant patients: a matched-pair case-control study. J Urol 1992; 147(4): 9948 5. Goodman CM, Hargreave TB. Survey of antibiotic prophylaxis in European renal transplantion practice. Int Urol Nephrol 1990; 22(2): 173-9 6. Judson RT. Wound infection following renal transplantation. Aust NZ J Surg 1984; 54(3): 223-4 7. Midtvedt K, Hartmann A, Midtvedt T, Brekke IB. Routine perioperative antibiotic prophylaxis in renal transplantation. Nephrol Dial Transplant 1998; 13(7): 1637-41 8. Townsend TR, Rudolf LE, Westervelt FB Jr, Mandell GL, Wenzel RP. Prophylactic antibiotics therapy with cefamandole and tobramycin for patients undergoing renal transplantation. Infect Control 1980; 1(2): 93-6 9. Morris P. Kidney Transplantation: Principles and Practice. 2001, 5th edition 10. Salmela AD, Ekland B, Kyllonen L et al. The effects of intravesically applied antibiotic solution in the prophylaxis of infectious complication of renal transplantation. Transplant Int 1990; 3: 12

References

245

39. CADAVERIC TRANSPLANTATION 39.1 Selection of donors Any comatose patients with irreversible cerebral damage who appears likely to progress to brain death prior to terminal circulatory failure should be considered as a potential donor, regardless of age. Physicians caring for the potential donors should be encouraged to make early contact with the tissue organ procurement (TOP) team or the HKL transplant coordinator for assistance in the further management of the donor and the donor family (Tel. No: 0326942704 or 03-26942705 during office hours, or 013-3759887) 39.2 Contraindications 39.2.1 Absolute contraindication (Level B) a. Severe untreated septicaemia or septicaemia of unknown origin b. HIV positive serology or a history of activities with high risk for HIV infection c. Acute hepatitis b. History of cancer other then non invasive brain tumor, non melanotic non metastatic skin tumor. The Council of Europe has recently published an international consensus on the prevention of neoplastic disease in transplantation and classified primary brain tumors according to acceptability for organ donation1 Brains tumors that do not exclude the donor from organ donation are: benign meningiomas, pituitary adenomas, acoustic schwannomas, craniopharyngiomas, pilocytic astrocytomas (astrocytomas grade I), epidermoid cysts, colloid cysts of the third ventricle, choroid plexus papillomas, haemangioblastomas, ganglional cell tumors, pineocytomas, low grade oligodendrogliomas, ependymomas and well differentiated teratoma. Tumours where the donor can be considered for organ donation depending on characteristics: low grade astrocytoma (grade II), gliomatosis cerebri Tumours where the donor should not be considered for organ donation: Anaplastic astrocytoma (grade III), glioblastoma multiforme, medulloblastoma, anaplastic oligodendroglioma (Schmidt C & D), malignant ependymomas, pineoblastomas, anaplastic and malignant meningiomas, intracranial sarcomas, germ cell tumours (except well differentiated teratomas), chordamas and primary cerebral lymphomas.

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39.2.2 Relative contraindication (Level C) a. Very elderly donor (>70 years)2 b. Severe vascular disease c. Long term insulin dependent diabetes mellitus d. Hypertension or other condition with impaired renal function e. Suboptimal or non acceptable renal function It is recommended that donors should be evaluated on the basis of renal function (calculated creatinine clearance),3 age and vascular disease. Limit may be set as CrCl >60ml/min as acceptable, 50-60 ml/min as marginal and <50 ml/min as non acceptable for single kidney transplant.4 Non acceptable kidneys may be considered for dual transplant.5 (Level B) Recipients for suboptimal kidneys or dual kidneys should have given their informed consent prior to transplantation 39.3 Special situations 39.3.1 Hepatitis C positive donors Hepatitis C positive donors may be accepted for seropositive recipients if the recipients PCR for HCV is also positive.6,7,8 (Level C) 39.3.2 Hepatitis B positive donor Hepatitis B positive donor may be accepted for transplantation to recipients with Hepatitis Bs antibody. Hepatitis B immunoglobulin should be given prior to transplantation. 39.4 Determination of brain death Any potential donor should be adequately assessed. The clinical neurological examination to confirm brain death should include: 39.4.1 Basic criteria for clinical neurological examination to be used a. Known cerebral disease that can cause total cerebral infarction b. Body temperature > 330C c. Poisoning, sedation, and metabolic, electrolyte or acid/base disturbance are excluded 39.4.2 Clinical criteria a. Unconscious. No reaction to speech, touch or pain b. Spontaneous breathing absent c. Spontaneous muscular movement in area innervated by cranial nerves absent. Spinal reflexes in trunk or extremities may be seen d. Defensive movement of head, extremities and trunk on painful stimuli absent. Spinal reflexes may be present

247

e. Reactions of pupils to light absent f. Corneal reflexes absent bilaterally g. Dolls eye movement absent h. Cardiocerebral reflexes absent (eye bulb pressure) i. Blinking reflexes on sound stimuli absent j. Laryngeal reflexes absent k. Apnoea test shows absence of spontaneous breathing 39.5 Support of the potential donor and optimisation of organ function Any comatose patient with irreversible cerebral disease should be identified as a potential donor and monitored carefully awaiting determination of brain death, evaluation and consent for organ donation. The management of a potential donor should be similar to normal ICU care and simplified goal for management should be to13,14 (Level C): 39.5.1 Maintain a CVP of 10cm H2O. Blood volume can be increased with crystalloids and colloids 39.5.2 A systolic arterial pressure of 100 mmHg.15 If this cannot be reached using fluids alone, dopamine may be added as an inotropic support. 39.5.3 A urine output of 100 ml/hr. (Level C) The best treatment of diabetes insipidus is vasopressin or one of its analogues. 39.5.4 Maintain normal values of blood gas analysis. A positive end expiratory pressure of 5cm H2O is advisable to retard the development of atelectasis.

248

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Council of Europe International Consensus. Committee of experts on the organisational aspects of cooperation in organ transplantation. Standardisation of organ donor screening to prevent transmission of neoplastic diseases. 1997 Karpinski J, Lajoie G, Cattran D et al. Outcome of kidney transplantation from high risk donors is determined by both structure and function. Transplantation 1999; 67: 1162-1167 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41 Sola R, Guirado LL, Lopez Navidad et al. Renal transplantation with limited donors. To what extent should the good results obtained be attributed? Transplantation 1998; 66: 1159-1163 Alfred EJ, Lee CM, Scandling JD et al. When should expanded criteria donor kidneys be used for single versus dual kidney transplants? Transplantation 1997; 64: 1142-1146 Morales JM, Campistol JM, Castellano G et al. Transplantation of kidneys from donors with hepatitis C antibody into recipient with pre transplantation anti HCV. Kidney Int 1995; 47: 236-240 Periera BJ, Wright TL, Schmid CH, Levey AS. A controlled study of hepatitis C transmission by organ transplantation. Lancet 1995; 345: 484-487 Widell A, Mansson S, Persson NH et al. Hepatitis C superinfection in hepatits C virus infected patients transplanted with a HCV infected lidney. Transplantation 1995; 60: 642-647 Eastlund T. Infectious disease transmission through cell, tissue, and organ transplantation: Reducing the risk through donor selection. Cell Transpl 1995; 4: 455-477 Wijnen RMH, Booster MH, Kootstra G et al. Outcome of transplantation of non heart beating donors kidneys. Lancet 1995; 345: 1067-1070 Cho YW, Terasaki PI, Cecka JM, Gjerston DW. Transplantation of kidneys from donors whose hearts have stopped beating. N Eng J Med 1998; 338: 221225 Sanchez-Fructuoso Al, Prats D, Torrente J et al. Renal transplantation from non heart beating donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol 2000; 11: 350-358 Soifer BE, Gleb AW. The multiple organ donor: Identification and management. Ann Int Med 1989; 110: 814-823 Nygaard CE, Townsend RN, Diamond DL. Organ donation management and outcome: a 6 year review from a level 1 Trauma Centre. Trauma 1990; 30: 728732 Caroll RPN, Chisholm GD, Shackman R. Factors influencing early function of cadaver renal transplants. Lancet 1969; 551-552

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40. MALAYSIAN ORGAN SHARING SYSTEM (MOSS) Malaysian Society of Nephrology (MSN) and the Ministry of Health of Malaysia initiated the development of a national organ sharing network in 1999, named the Malaysian Organ Sharing System (MOSS). This system is to ensure an equitable distribution of cadaveric organs. Presently only cadaveric kidneys are distributed based on the criteria drawn up by the MOSS committee. Any Malaysian citizen with end stage renal failure can register with MOSS as a potential renal recipient. 40.1 Exclusion criteria Patients aged less than 2 years old or above 60 years old are disqualified. Patients with any disease or illness with expected survival of less than 5 years or with a resultant poor quality of life are not eligible. This will include the following patients: 40.1.1 Positive HIV serology 40.1.2 40.1.3 40.1.4 40.1.5 40.1.6 Positive hepatitis Be antigen Active liver disease Severe cardiovascular/cerebrovascular/pulmonary disease Dementia or psychosis with no underlying treatable disease Malignancy of limited life expectancy

40.1.7 Oxalosis (not contraindicated for combined liver and kidney transplantation) 40.1.8 Active substance abuse

40.2 Preregisteration assessment 40.2.1 Cardiac assessment (including cardiac stress test and echocardiogram) is required for asymptomatic, nondiabetic patients > 55 years old or diabetic patients > 35 years old. 40.2.2 Symptomatic or asymptomatic patients with positive stress test should be further assessed by a cardiologist and treated appropriately.

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40.3 Criteria for prioritisation With rare exception, the donor and recipient should be the same ABO blood group type. One of the two kidneys will be allocated to the procurement centre. Candidates with limited life expectancy (<1 year) without renal transplant will be placed into the medical emergency list (SOS). This decision can only be made by a nephrologist. Candidates on the SOS list will receive top priority in receiving a cadaveric kidney. Candidates will be selected based on the following scoring system: 40.3.1 HLA antigens (A, B and DR) matching * (12 points) 40.3.2 40.3.3 40.3.4 Panel reactive antigen (10 points) * Waiting time (20 points) Logistic score (6 points)

*Due to logistic reasons, HLA antigens & PRA are presently not used as selection criteria.

Reference
Wong HS. Malaysian Organ Sharing System. Med J Malaysia 1999; 54 : 537-538

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41. IMMUNOSUPPRESSION PROTOCOL 41.1 The standard immunosuppression regimen The standard immunosuppression regimen (adult1,2,3,10,11,12,13,14,15,16 and LRRT in children18) consists of tacrolimus / cyclosporin, mycophenolate mofetil (MMF) and prednisolone. (Level A) 41.1.1 The immunosuppression regimen may be modified in the following situations: a. Polyclonal4,5/monoclonal antibody6 or anti-ILII antibody7,19,20 can be used as induction immunotherapy when acute tubular necrosis or delayed graft function is anticipated and in highly sensitised recipients. (Level A) However Anti-IL II antibody has minimal side effects and is easier to use.4 b. In highly sensitised recipients i.e. multiparous female, multiple blood transfusion and previous history of transplant, PRA >20%, cadaveric transplantation in children, tacrolimus may be used instead of cyclosporin,8,9, and/or the use polyclonal5/monoclonal antibody 6 or anti-ILII antibody7,19,20 as induction immunotherapy. 41.2 Immunosuppressive agents 41.2.1 Corticosteroids a. Hydrocortisone 200 mg IV stat on call to theatre and postoperatively and 8-hourly until patient is tolerating orally b. IV Methylprednisolone 500 mg at anastomosis for cadaveric renal transplant in addition to the above c. Hydrocortisone is replaced by prednisolone 20 mg daily when allowed orally d. Prednisolone is tapered off beginning at 3 months post-transplant, by 2.5 mg per month till the dose of 10 mg daily is reached e. Prednisolone may be reduced to 5 7.5 mg daily in selected patients (e.g. stable recipient with severe steroid toxicity) 41.2.2 Cyclosporin a. For living related renal transplantation, Neoral 8 mg/kg/day to begin 5 days pre-transplant b. For cadaveric transplant, dose of Neoral is 10 mg/kg/day given pre transplant c. Dose of Neoral is adjusted according to trough levels or C2 Trough levels Less than 6 months post-transplant: 250-375 ng/ml 6 months or more post-transplant: 100-250 ng/ml

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C2 levels Less than 1 month: 1.7 ug/ml 1-2 months: 1.5 ug/ml 2-3 months: 1.3 ug/ml 4-6 months: 1.1 ug/ml 712 months: 0.9 ug/ml more than 12 months: 0.8 ug/ml 41.2.3 Tacrolimus a. For living related renal transplantation, tacrolimus 0.2 mg/kg/day to begin 5 days pre-transplant b. For cadaveric transplant, dose of tacrolimus is 0.3 mg/kg/day given per oral when called to operating theatre. c. Post-operatively, tacrolimus is given at 0.2 mg/kg/day in divided doses d. Dose is adjusted according to trough levels: Less than 6 months post-transplant: 10-15 ng/ml 6 months or more post-transplant: 5-10 ng/ml 41.2.4 Mycophenolate mofetil a. On call to theatre, mycophenolate mofetil is given 1 g per oral b. Post-transplant, mycophenolate mofetil is given 1 g twice a day per oral (dose in children 600 mg/m2/dose 12 hourly) c. Dose is reduced or omitted if total white counts are < 4000/mm3 d. When tacrolimus and mycophenolate mofetil are used, administration of these two agents must be spaced apart and the dose of MMF is reduced to 500 mg twice a day. e. Dose reduction is indicated if haematologic or gastro-intestinal side effects develop Dose reduction is done in 30 50% decrements. If leucopaenic mycophenolate mofetil should be stopped It can be safely withheld for a few days up to 2 3 weeks for severe side effects 41.2.5 Azathioprine a. Oral Azathioprine is given at 1.5 mg/kg/day b. Azathioprine will be omitted in the following situations: Recipients who are HBsAg positive and/or Anti-HCV antibody positive Recipients with post-transplant chronic active hepatitis Recipients with chronic hepatitis and progressively rising serum transaminase

253

In the presence of leucopaenia (<4000/mm3). Azathioprine can be resumed at lower dose once counts are normalised 41.2.6 ATG/ALG Refer to Chapter 42 41.2.7 Anti-Interleukin II antibody a. Basiliximab 20 mg IV is given on call to theatre and at day 4 post-transplant b. Daclizumab 1 mg/kg stat IV on call to theatre and at week 2,4,6,8 post-transplant 41.3 Paediatric immunosuppressive regime Immunosuppressive protocol for paediatric kidney transplantation is as follows:41.3.1 Cadaveric Renal Transplantation Day of Transplant D0 IV Basixilimab 10 mg bolus if < 8 yr, 20 mg bolus if > 8 yr Oral MMF 300 mg/m2/dose stat dose before going to OT Tacrolimus 0.1 mg/kg/dose b.d. IV Methyprednisolone 600 mg/m2 BSA just prior to anastomosis of renal vessels D1 IV Hydrocortisone 5 mg/kg/dose tds Oral MMF 300 mg/m2/dose bd Tacrolimus 0.1 mg/kg/dose b.d. D2 Prednisolone 60 mg/m2/day b.d. dosing Oral MMF 300 mg/m2/dose bd Tacrolimus 0.1 mg/kg/dose b.d. D4 Repeat IV Basiliximab 41.3.2 Living Related Renal Transplant D 5 Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d. Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus) D0 IV Methyprednisolone 600 mg/m2 BSA prior to anastomosis of vessels Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d. Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus) D1 IV Hydrocortisone 5mg/kg/dose tds

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D2

Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d. Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus) Prednisolone 60 mg/m2/day bd dosing Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d. Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)

41.3.3 Guidelines for drug dose tapering in paediatric renal transplant recipients a. Cyclosporin / tacroloimus follow adult schedule b. Prednisolone - start tapering the dose 1 week post-transplant and taper 10 mg/week till 10 12.5 mg daily if renal function is stable and cyclosporin / tacrolimus is within the desired range.

References
The Canadian Multicentre Transplant Study Group. A randomised clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983; 309: 809-815 2. The Canadian Multicentre Transplant Study Group. A randomised clinical trial of cyclosporine in cadaveric renal transplantation.Analysis at three years. N Engl J Med 1986; 314: 1219-1225 3. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 1983; 986-989 4. Slakey D, Johnson C, Callaluce R et al. A prospective randomised comparison of quadruple versus triple treatment for the first cadaver transplant with immediate graft function. Transplantation 1996; 56: 827-831 5. Wechter W, Brodie J, Morrell R et al. Antithymocyte globulin (ATGAM) in renal allograft recipients. Transplantation 1979; 28: 294-302. 6. Abramowicz D, Goldman M, De Pauw L et al. The long term effect of prophylactic OKT3 monoclonal antibody in cadaveric kidney transplantation a single centre, prospective ,randomised study. Transplantation 1992; 54: 433-437 7. Nashan B, Moore R, Amlot P et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997; 350: 1193-1198 8. European Tacrolimus Multicentre Renal Study Group. Multicentre randomised trial comparing tacrolimus and cyclosporin in prevention of renal allograft rejection. Transplantation 1997; 64: 436-443 9. Johnson C, Ahsan N, Gonwa T et al. Randomised trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporin (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69: 834-841 10. Shapiro R, Jordan M, Scantlebury V et al. A prospective randomised trial of tacrolimus/prednisolone versus tacrolimus/prednisolone/mycophenolate mofetil in randomised transplant recipients. Transplantation 1999; 67: 411-415 1.

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11. Halloran P, Mathew T, Tomlanovich S et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, doubleblind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Study Groups. Transplantation 1997; 63(1): 39-47 12. Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded randomised clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 10291037 13. Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded long-term randomised multicentre study of mycophenolate mofetil in cadaveric renal transplantation: results at 3 years. Transplantation 1998; 65: 1450-1454 14. European Mycophenolate Mofetil Multicentre Cooperative Study Group. Placebo control study of Mycophenolate Mofetil combined with cyclosporin and steroid for prevention of acute rejection. Lancet 1995; 345: 1321-1325 15. European Mycophenolate Mofetil Multicentre Cooperative Study Group. Mycophenolate Mofetil in renal transplant: 3-year results for placebo controlled trial. Transplantation. 1999; 68: 391-396 16. US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate Mofetil in cadaveric renal transplant. Am J Kidney Dis 1999; 34: 296-303 17. Michael HJ, Francos GC, Burke JF et al. A comparison of the effect of cyclosporin versus antilymphocyte globulin on delayed graft function in cadaveric renal transplant recipients. Transplantation 1999; 48: 805-808 18. Renal transplantation, chronic dialysis and chronic renal insufficiency in children and adolescents. The 1995 annual report of the North Paediatric Renal Transplant Cooperative Study. Paed Nephrol 1997; 11: 49-64 19. Kahan B. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, achimeric anti-chimeric antiinterleukin-2-receptor monoclonal antibody. United States Simulect Renal Group Study. Transplantation 1999; 67(2): 276-84 20. Meier-Kriesche et al. The effect of daclizumab in high risk renal transplant population. Clin Transplant 2000; 14(5): 509-13

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42. MANAGEMENT OF GRAFT DYSFUNCTION 42.1 Primary non function Definition: failure of graft to function immediately post anastomosis 42.1.1 Causes: a. Acute tubular necrosis b. Vascular thrombosis c. Hyperacute rejection Figure 42.1: Approach to primary non-function Primary non-function

Urgent Doppler Flow present Hyperacute rejection ATN Refer urologist No flow

Consider antilymphocyte

Avoid CSA

42.2 Acute graft dysfunction Table 42.1: Causes of acute graft dysfunction First 3 months After 3 months Acute rejection Acute rejection Calcineurin inhibitor toxicity Calcineurin inhibitor toxicity Urinary obstruction Urinary obstruction Recurrence of 1o disease Recurrence of 1o disease Drugs Graft renal artery stenosis Infections Drugs Infections

257

Figure 42.2: Clinical approach to acute graft dysfunction


Acute allograft dysfunction Exclude nongraft related causes e.g. drugs / infection

Obstruction

Doppler US

No obstruction

Refer urologist

Flow present

No flow

Calcineurin inhibitor level

DTPA scan / Angiogram

Raised

Normal

Refer urologist

Response

Reduce dosage

No response

Allograft biopsy

Calcineurin inhibotor toxicity

Disease recurrence

Rejection

ATN

42.3 Obstruction 42.3.1 Causes: a. Ureteric stenosis b. Perinephric collection c. Others

258

42.3.2 Investigations: a. Ultrasound scan b. DTPA scan with frusemide c. Retrograde/antegrade pyelography 42.3.3 Management: Consult urologist. All obstruction must be dealt PROMPTLY to avoid permanent graft dysfunction 42.4 Renal artery stenosis 42.4.1 Consider if: a. Sudden deterioration in BP control b. Recent onset of hypertension c. Graft dysfunction in the presence of hypertension 42.4.2 Diagnosis: a. Angiography Gold standard Invasive b. Doppler US1,2 (Level C) Preferred screening modality Operator dependent c. Magnetic resonance angiography3 (Level C) Increasingly utilised to screen for renal artery stenosis d. Spiral CT angiography e. Renography (DTPA with Captopril)4 (Level C) Perform before and after an ACE inhibitor Useful in predicting the physiological significance of a moderately severe stenotic lesion Negative renography is less likely to respond to intervention 42.4.3 Treatment a. Angioplasty Success rate 80%, 20% recurrence rate 5 Stent deployment results in better results b. Surgery Difficult due to extensive fibrosis and scarring Should only be considered in patients with resistant hypertension or with proximal atherosclerotic disease6 Success rate 60-90%

259

42.5 Acute rejection 42.5.1 Recommendations: a. Acute rejection should be suspected in patient with stable graft function who experience rapid rise of plasma creatinine concentration of more than 20-25% over their baseline with or without decrease urine output, graft tenderness or fever when other causes of acute graft dysfunction has been ruled out. (Level C) b. It is recommended to exclude other causes of graft dysfunction (see figure 41.2) and to do a graft biopsy to confirm clinical diagnosis of acute rejection. The biopsy result can be used to guide the intensity of anti rejection therapy and to assess long term prognosis.7,8,9 (Level B) c. Reporting of biopsies should be standardised according to an internationally agreed scheme to reflect the histopathological pattern and severity of the rejection episode.9 (Level B) 42.5.2 Banff classification of acute rejection

Table 42.2: Banff classification 199710 Class Histopathological Findings Grade I A Interstitial infiltration (>25% parenchyma affected) Foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section/group of 10 tubular cells Interstitial infiltration (>25% parenchyma affected) Foci of severe tubulitis (>10 mononuclear cells /tubular cross section /group of 10 tubular cells Mild to moderate intimal arteritis found in at least one arterial cross section Severe intimal arteritis (>25% loss of the luminal area)

Type I rejection (tubulointerstitial)

Grade I B

Type II rejection (vascular)

Grade II A

Grade II B

260

Class

Histopathological Findings Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells occurring in association with lymphocytic inflammation of the vessels No intimal arteritis Foci of mild tubulitis

Type III rejection

Borderline/ suspicious of rejection

42.5.3 Treatment of acute rejection episodes Treatment of first acute rejection episode a. Corticosteroids11 (Level C) Corticosteroid treatment is most widely used 500 mg of methylprednisolone for 3 days In children 300-600 mg/m2BSA/day IV methylprednisolone for 3 days Response to treatment is identifiable by day 5 of treatment b. Antilymphocyte or Monoclonal Antibody12,13,14,15,16,17 (Level B) Rejection reversal in 67-98% of cases Main problems : cost and adverse events The use of anti-T-lymphocyte antibody therapy are reserved for: i. Severe acute rejection (Banff II B or III) ii. Second rejection episodes within 2 weeks of previous rejection iii. Steroid resistant rejection (Banff I B and above) Response is usually evident after 5 days of treatment Use of polyclonal/monoclonal antibody has to be weighed against risk of infection (e.g. high CMV risk, hepatitis Be antigenaemia) In cases where the acute rejection is resistant to corticosteroid therapy and treatment with anti-T-lymphocyte preparation does not provide optimal response, a change in baseline therapy may be considered.18,19,20,21,22 "Rescue therapy" include replacing cyclosporin with tacrolimus.

261

Figure 42.3: Protocol recommendation for Polyclonal Antibody use Adapted from drug insert Usage : only histologically confirmed acute rejection Dosage : ATG 10-15mg/kg/day for 10 to 14 days (see dosage table for different brands) : ALG for 10 to 14 days (see dosage table for different brands)

Prophylactic treatment: 1 hour prior to each administration IV chlorpheniramine 10 mg (children 0.1 mg/kg) Antipyretic agent: paracetamol 1 g 6 hourly (children 15 mg/kg) Administer via central venous line as an infusion Dose of Azathioprine/MMF should be reduce or stopped according to TWC Monitoring: daily renal profile, FBC

Treatment of Acute Rejection In Children 6 a. Pulse steroids : Remains the mainstay of treatment of acute rejection IV Methylprednisolone : Doses range from 510 mg/kg/day for 3 5 days followed by maintenance corticosteroid dose at prerejection level or recycled back down from the high levels used posttransplant Oral prednisolone: Oral prednisolone pulses 35 mg/kg for 3 days followed by tapering the dose back to baseline levels over 23 days b. OKT3 Approximately 20 30% of rejection episodes will not respond to high-dose steroids but up to 90% of these can be reversed by OKT3 c. Tacrolimus23 This agent has been used successfully to reverse episodes of acute rejection that are refractory to treatment with steroids and OKT3

262

Figure 42.4: Protocol recommendation for OKT3 use

Adapted from Danovitch 1996 / Drug insert - Should only be given for histologically confirmed acute allograft rejection - Before administration of first dose, patient should be oedema free and within 3% of dry weight and have normal CXR - Use high dose diuretics, dialysis or ultrafiltration to achieve euvolaemia in a volume overloaded patient - Dosage: - Adults: 5 mg daily for 10 to 14 days - Children (dosage): body weight < 30 kg : 2.5 mg OKT3 body weight > 30 kg : 5 mg OKT3 - Contraindication: 1. Hypersensitivity e.g. serum sickness 2. Fluid overload (>3% above dry weight) 3. Use with caution in patients with past history of seizures - Administer premedication 15-60 min before first and second dose: - IV methylprednisolone 5-8 mg/kg - IV chlorpheniramine 10 mg (children 0.1 mg/kg) - Oral paracetamol 0.5 to 1 g (children 15 mg/kg) Premedication is not required for remainder of the course, use paracetamol prn for fever - Administer as a bolus injection through a peripheral line - Dosage adjustment for other immunosuppressive treatment: - Stop cyclosporin / tacrolimus and restart 3 days before completion of the course - Continue MMF, reduce dosage if patient is leucopaenic. - Monitoring: daily FBC, renal profile; CXR before OKT3

263

Figure 42.5: Flow diagram of management strategy for acute graft rejection
Suspected Rejection

Pulse IV Methylpred No or partial response Response

Allograft biopsy

Maintain Immunosuppression

Biopsy proven

Cellular Rejection IA IB

Vascular rejection Cellular Rejection (>IIA / + IB)

Monoclonal Antibody/ Polyclonal antibody

Suboptimal response

Rescue therapy

42.6 Chronic allograft nephropathy 42.6.1 Usually occurs after 6 months 42.6.2 Characterised by a gradual and irreversible deterioration in renal function 42.6.3 No proven effective specific treatment at present. However general measures to retard the progression of the renal failure should be instituted 42.6.4 Start withdrawing immunosuppression when allograft function is severely impaired

264

42.6.5 No controlled prospective studies have been performed to determine the best method for withdrawing immunosuppression. Recommendation24 (Level D): a. Late graft failure (> 1 year) Stop Azathioprine/MMF when in advanced renal failure Withdraw Cyclosporin / Tacrolimus on starting dialysis Taper Prednisolone by 1 mg/month until drug is discontinued watching for adrenal insufficiency If patient develop symptoms of allograft rejection, start a 5-7 days of prednisolone at dose of 0.5 to 1.0 mg/kg and refer patient for graft nephrectomy b. Early graft failure (< 1 year) To consider graft nephrectomy with withdrawal of immunosuppression 42.7 Calcineurin inhibitor (Cyclosporin / Tacrolimus) toxicity Calcineurin inhibitor` toxicity is one of the causes of renal allograft dysfunction and it is difficult to differentiate from acute rejection clinically 42.7.1 Cyclosporin toxicity There are two forms of cyclosporine toxicity i.e. acute toxicity and chronic toxicity. a. Acute toxicity Clinical features suggestive of acute cyclosporin toxicity include : i. Increased cyclosporin blood level (Note: nephrotoxicity can occur with normal cyclosporin level) ii. Hyperkalaemia iii. Hypertension iv. Tremor There is no characteristic feature of cyclosporin toxicity on histopathological examination of allograft biopsy. Acute cyclosporin toxicity: histology may be normal. The absence of cellular or vascular rejection strongly suggests cyclosporin toxicity.25 Acute toxicity is usually reversible with cessation of therapy Some commonly used drugs can interact with cyclosporin metabolism resulting in toxicity Cyclosporin blood monitoring is useful adjunct in preventing nephrotoxicity. The frequency of monitoring should be guided by the following factors: i. Time interval post-transplant ii. Deterioration in graft function iii. Change in cyclosporin dosing

265

iv. The possibility of drug interaction In patient with suspected cyclosporin nephrotoxicity the dosage should be reduced. Improvement in graft function usually noted in 48-72 hours. If this is not seen, allograft biopsy is indicated b. Chronic cyclosporin toxicity Leads to chronic allograft failure26 Chronic cyclosporin toxicity: stripe fibrosis, glomerular ischaemia, microcalcification Reduction of cyclosporin dose and replacement with nonnephrotoxic immunosuppressive drugs (e.g. mycophenolate mofetil) may ameliorate renal dysfunction in patients with cyclosporin induced nephrotoxicity.27,28 (Level C) At present, there is no effective treatment modalities that have been shown to be effective in preventing chronic cyclosporin nephrotoxicity 42.7.2 Tacrolimus toxicity a. As nephrotoxic as cyclosporin 28 b. May cause hyperglycaemia, hyperkalaemia and hyperuricaemia

References
Baxter GM et al. Colour Doppler ultrasound in renal transplant artery stenosis: Which Doppler index? Clinical Radiology 1995; 50: 618 2. Loubeyre P et al. Transplanted renal artery: Detection of stenosis with colour Doppler. Radiology 1997; 203: 661 3. Johnson DB et al. Gadolinium enhanced magnetic resonance angiogram of renal transplant. Magnetic Resonance Imaging 1997; 15: 13 4. Shamlou et al. Captopril renography and the hypertensive renal transplant patient-predictive test of therapeutic outcome. Radiology 1994; 190: 153 5. Sierre SD, Raynauds AC. Treatment of recurrent transplant renal artery stenosis with metallic stents. J Vasc Interv Radiol 1998; 9: 639 6. Danovitch G. Handbook of Kidney Transplantation 2nd Ed, Little, Brown and Company, Boston 1996 7. Pascual M et al. The clinical usefulness of renal allograft biopsy in the cyclosporin era. A prospective study. Transplantation 1999; 67: 737-741 8. Solez K, Axelsen RA, et al. International Standardization of criteria for the histologic diagnosis of renal allograft rejection. The Banff working classification of transplant pathology, Kidney Int 1993; 44: 411-422 9. Dean De, Kamath S et al. A blinded retrospective analysis of renal allograft pathology using Banff schema. Transplantation 1999; 68: 642-645 10. Racusen, Solez et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55; 713-723 11. Mazucchi, Lucon et al. Histological outcome of acute cellular rejection in kidney transplantation after treatment with methylprednisolone. Transplantation 1999; 67: 1430-434 1.

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12. Ortho Multicentre Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337-342 13. Uslu A, Tokat Y. ATG versus OKT3 in the treatment of steroid resistant rejection following living related donor renal transplantation. Transplant Proc 1997; 29: 2805-2806 14. Schroedrer TJ, Weiss MA. The efficacy of OKT3 in vascular rejection. Transplantation 1991; 51: 312-315 15. Kamath S, Dean D, Peddi VR et al. Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection. Transplantation 1997; 64: 1428-1432 16. Norman D, Shield C. et al. Effectiveness of second course of OKT3 monoclonal anti T cell antibody for treatment of renal allograft rejection. Transplantation 1988; 46: 523-529 17. Gaber AO, First MR. Results of double blind, randomized multicentre phase III clinical trial of Thymoglobulin versus ATGAM in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998; 66: 29-37 18. Woodle ES, Thistlewaite JR et al. A Multicenter Trial of TACROLIMUS (Tacrolimus) Therapy Refractory Acute Renal Allograft Rejection. Transplantation 1996; 62: 594-599 19. Jordan M,Shapiro R et al. FK506 "Rescue" For Resistant Rejection Of Renal Allografts Under Primary Cyclosporine Immunosuppression. Transplantation 1994; 57 :860-865 20. The Mycophenolate Mofetil Renal Refractory Rejection Study Group. Rescue therapy with Mycophenolate Mofetil. Clinical Transplant 1996; 10: 131-135 21. Pascual M, Saidman S. et al. Plasma Exchange and Tacrolimus - Mycophenolate Rescue for Acute Humoral Rejection in Kidney Transplantation. Transplantation 1998; 66 (11): 1460-1464 22. Woodle ES, Jordan ML. Refractory rejection Metaanalysis Group. Metaanlysis of TACROLIMUS and mycophenolate refractory rejection trials in renal transplantation. Transplant Proc. 1998; 30: 1297-1298 23. Howard E. Corey. Improved renal allograft survival in children treated with FK506 (tacrolimus) rescue therapy. Paedr Nephrol 1996; 10: 720-722 24. Miller BW, Brennan. Withdrawal of Immunosuppression after renal transplant failure. Up To Date 2000; 8 (3) 25. Mihatsch et al. Histopathology of cyclosporine nephrotoxicity. Transplant Proc 1988; 20: 759 26. Myers et al. Cyclosporine induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol 1991; 2: S45 27. Houde et al. Prednisone-mycophenolate mofetil double therapy for cyclosporine A toxicity in kidney transplantation. Transplantation 1998 ; Suppl: 139 28. Ducloux et al. Mycophenolate Mofetil in renal transplant recipient with cyclosporine associated nephrotoxicity. Transplantation 1998; 65: 1504 29. The US Multicenter Liver FK 506 Study Group. A comparison of tacrolimus and cyclosporin for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110

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43. MANAGEMENT OF TRANSPLANTATION

INFECTION

POST

KIDNEY

Infections related to transplantation procedure and opportunistic pathogens can adversely affect the outcome of kidney transplantation. 43.1 General guidelines for infection recognition1 The following factors may assist in the identification of the causative pathogen and initiation of therapy (Table 43.1) 43.1.1 The temporal occurrence of presumed infectious episode relative to the date of transplantation (see Figure 43.1) 43.1.2 43.1.3 Pretransplantation donor screening Pretransplantation recipient screening

43.1.4 Acquisition of community and hospital acquired pathogens e.g. pneumococcus, pseudomonas species, MRSA, VRE 43.1.5 Net state of immunosuppression a. Prophylactic immunosuppressive protocol employed and treatment for acute rejections b. Neutropaenia c. Open wounds, foreign bodies (catheters, stents), fluid collections and devitalised tissues d. Metabolic abnormalities (malnutrition, hyperglycaemia, ureamia) e. Infection with immunomodulatory viruses (CMV, EBV) Table 43.1: Risk factors for infection post kidney transplantation1
Pretransplantation (Recipient) Medical Condition a. Immunosuppression for chronic conditions eg steroid, cytotoxics b. Diabetes mellitus c. Suboptimal nutritional status d. Unrecognised or inadequately treated infection Perioperative Post-transplantation

Surgery a. Prolonged procedure or anaesthesia b. Graft injury or prolonged ischaemia c. Bleeding or multiple blood transfusions

Post-op management a. Catheters, stents, and intubation b. Anastomotic breakdown or leak c. Fluid collections or devitalized tissue d. Early re-exploration or retransplantation e. Leukopaenia

268

Pretransplantation (Recipient) Altered bacterial colonisation a. Pre-op antibiotic exposures b. Duration of hospitalisation

Perioperative Graft ( donor) a. Bacteraemia or sepsis b. Unrecognised infection in allograft c. Microbial contamination of preservation fluid

Post-transplantation Nosocomial infection a. Prolonged antibiotic therapy b. Increased antibiotic resistance

Immunosuppression a. Multiple agents b. Antibody induction and treatment for acute rejection. c. Steroid pulse and maintenance dose

43.2 Diagnosis of infection Diagnosis of infections post kidney transplantation can be difficult due to attenuation of the usual clinical signs and symptoms of infection by alterations in the immune response. Fever may be absent in the presence of infection due to immunosuppression. In transplant recipients, fever also has a more expanded differential diagnosis which in addition to infections, may include: 43.2.1 Graft rejection 43.2.2 Adverse effect of medication Treatment with antibodies (OKT3 and polyclonal antibodies) for acute rejection may cause fever and signs and symptoms suggestive of aseptic meningitis and pulmonary infiltrates. 43.2.3 Systemic inflammatory response The presence of more than one causative agent must be considered e.g. CMV disease facilitating other opportunistic infections.

269

Fig 43.1: Time table for occurrence of infection post transplantation2

43.3 Diagnosis of pneumonia Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy. Specific pathogens should be sought in addition to common bacteria, 43.4 Diagnosis of pneumonia Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy. Specific pathogens should be sought in addition to common bacteria, such as: 43.4.1 Legionella pneumophila direct fluorescent antibodies of antigens in respiratory specimens. 43.4.2 Pneumocystis carinii fluorescein labeled antibody of BAL or sputum. 43.4.3 Nocardia modified acid-fast staining.

43.4.4 Cytomegalovirus (CMV) antigen detection using DEAFF from respiratory fluid and blood. 43.4.5 43.4.6 Mycobacterium tuberculosis Fungi

270

43.5 Diagnosis of urinary tract infection Clean catch mid-stream urine specimen for culture. If suspected, tips of ureteric stents should be cultured. 43.6 Diagnosis of wound and other infections Wound infections, skin nodules or necrotic tissues should be swabbed and biopsied when appropriate. Aspiration and drainage of any collections, either percutaneously with ultrasound guidance or surgically should be performed. Intravascular access and catheter tips should be cultured. Patients with diarrhoea should have stool examination done including detection for clostridium difficile. 43.7 Treatment of infection In severe infection, immunosuppressive therapy may need to be reduced or stopped. A number of antibiotics interact with cyclosporin metabolism and the level has to be monitored and adjusted accordingly. Antibiotic dosage also needs to be adjusted for renal impairment. The implementation of anti-microbial therapy can be considered under the categories of prophylaxis therapy, empirical therapy and definitive therapy. 43.7.1 Prophylaxis therapy Peri-operative antibiotics prophylaxis may reduce the incidence of wound infection. However, prolonged course of antibiotics may promote emergence of resistance organisms and increase the risk for Clostridium difficile colitis. The choice of broad spectrum antibiotics should have good Gram negative coverage according to local bacteriological and susceptibility pattern. The duration of treatment should be minimised. 43.7.2 Empirical therapy For patients with suspected bacterial infections, empirical therapy may be started while waiting for results of bacteriological studies. The choice of therapy should be guided by the available clinical information such as: a. Suspected anatomical site of infection b. Probable organism c. Local antibiotic susceptibility pattern d. Previous anti-microbial therapy e. Time since transplantation (see fig 42.1) f. Net state of immunosuppression Initial empirical treatment for suspected severe bacterial infection should be broad spectrum, and effective against Gram positive and

271

Gram negative bacteria. The duration of therapy is based on the resolution of clinical signs and symptoms of bacterial infections, usually of 10 to 14 days duration. If a specific pathogen is isolated, and sensitivities are available, treatment is changed to appropriate narrow spectrum agent (see specific therapy). If patient deteriorates or did not improve, aggressive search for source of infection should be performed, including search for MRSA, ESBL producers, mycobacterium and fungal infections. At the same time consider changing antibiotics (e.g. Imipenem). Table 43.2: Pathogens and recommended antibiotics. Pathogens (suspected/proven) Antibiotics 3rd generation cephalosporins Gram negative Gram positive: Aerobic: Staph aureus (MSSA) Staph aureus (MRSA) Staph epidermidis (MRSE) Streptococcal Listeria Anaerobic: Clostridium perfringens Clostridium difficile Legionella Pneumocystis Norcadia Cloxacillin Vancomycin Vancomycin Penicillin + Gentamicin Ampicillin + Gentamicin Penicillin Oral Vancomycin or Metronidazole Erythromycin* + Rifampicin* Cotrimoxazole + Pentamidine Dapsone+Trimethoprim

Cotrimoxazole , Minocycline, Amikacin, Ceftriazone, Imipenem * cyclosporin dosage needs to be adjusted 43.7.3 Specific therapy Therapy is focused on the specific organism isolated to avoid superinfection. 43.8 Mycobacterial infection3 Can occur as early as one month post-transplantation. Unusual presentation of mycobacterium tuberculosis and non tuberculous mycobacterial disease may delay diagnosis.

272

Patients with previous mycobacterial infection are at risk of reactivation. Patients may have disseminated disease, and may involve skin, joints and bones, and central nervous system. Rifampicin (R) Isoniazid (H) Pyrazinamide (Z) Vitamin B6 * Then if susceptible, Rifampicin Isoniazid

daily for 2 months

daily# for 4 to 10 months

*In certain situations, ethambutol (E) or ciprofloxacin may be added. # Daily dosing to avoid fluctuating cyclosporin level. If intolerant of rifampicin, combination of daily isoniazid, pyrazinamide and ethambutol is given for 18 to 24 months, or 12 months after cultures are negative, whichever is longer. If intolerant to isoniazid, combination of ERZ daily for 2 months then ER for 12 to 16 months, or 12 months after cultures are negative, whichever is longer. Caution: With the use of rifampicin, the dose of cyclosporin should be doubled and the cyclosporin dose should be adjusted with close monitoring of cyclosporin level. The dose of cyclosporin may need to increase by 3 to 5 folds with the use of rifampicin. Chemoprophylaxis for mycobacterial is currently not given routinely. 43.9 Pneumocystis carinii infection Occurs from 1 month post-transplantation onward. Presents with fever, non-productive cough, breathlessness, hypoxia and diffuse interstitial infiltration or focal consolidation on chest radiography. Bronchial alveolar lavage and transbronchial biopsy are good diagnostic methods. 43.9.1 Treatment Treatment is intravenous cotrimoxazole (20 mg/kg/day trimethoprim and 100 mg/kg/day sulphamethoxazole) given 6 hourly for at least 2 weeks. If there is no improvement after 4 to 5 days, add in pentamidine infusion at 4 mg/kg/day. Alternatively Dapsone (100 mg/day) and Trimethoprim (15 mg/kg/day) may be used but caution on the use of dapsone and

273

cotrimoxazole combination which may cause haemolysis in G6PD deficiency. Chemoprophylaxis with oral co trimoxazole 80/400 daily or inhaled pentamidine 300 mg/month may be required for at least 3 months post treatment. 43.9.2 Chemoprophylaxis Chemoprophylaxis for pneumocystis carinii pneumonia with co trimoxazole 80/400 daily is recommended for the first 6 months after renal transplantation and during treatment for acute rejection.4 (Level A) However the duration of chemoprophylaxis is unclear.5 (Level B) 43.10 Fungal infection 43.10.1 Candidiasis Oral nystatin may be helpful as prophylaxis during period of intensified immunosuppression (first 3 months after transplant). Culture of candida from the mouth, urinary catheter and vaginal swab may be sufficient to justify local or topical treatment. Evidence of candida in the blood or disseminated infection of the lungs or other organs must be treated with intravenous amphotericin B or fluconazole. 43.10.2 Aspergillosis Usually presents with pneumonia but may disseminate to gastrointestinal, skin and central nervous system. Treatment is with intravenous amphotericin B. Itraconazole is an alternative. 43.10.3 Cryptococcosis May cause meningitis, pulmonary, dermatological, and other organ specific disease. Treatment of meningitis is with intravenous amphotericin B followed by fluconazole. Less severe disease can be treated with fluconazole alone 43.10.4 Histoplasmosis Usually causes acute pulmonary syndrome. Treatment is with intravenous amphotericin B or itraconazole. 43.11 Hepatitis B virus (HBV) infection The outcome of HBV hepatitis is unfavourable in renal transplant recipients as it may lead to progressive liver damage. This can be prevented by careful pre-transplant donor and recipient screening, and by vaccination of the recipient.6 The routine use of OKT3 and polyclonal antibodies for induction should be avoided in transplant recipients who are positive for

274

hepatitis B surface antigen (HBsAg). Such patients should be monitored for raised liver enzymes and viral replication by HBVDNA PCR.7 (Level D) Azathioprine is omitted from HBV carriers undergoing kidney transplantation. (Level D) In HBV seroconverted recipients, azathioprine withdrawal had been shown to reduce the incidence of progression of viral hepatitis to cirrhosis in a small study.8 (Level D) Treatment of active HBV hepatitis is limited. The biggest concern regarding the use of interferon-alpha is precipitation of acute rejection. Two small studies demonstrated clearance of HBV DNA in renal transplant recipients by Lamivudine 100mg daily. However, viral replication recurred when therapy was discontinued and one patient developed lamivudine resistant viral mutant.9,10 (Level D) Early referral to hepatologist is desirable. 43.12 Hepatitis C infection HCV hepatitis may develop progressive liver disease in the long term but at a slower rate than HBV hepatitis. In HCV positive recipients, the use of OKT3 and polyclonal antibodies should be avoided. Early reduction of immunosuppression may be useful in preventing severe liver disease. Azathioprine is omitted from HCV carriers undergoing kidney transplantation. (Level D) Azathioprine should be stopped in HCV seroconverted recipients and in those with hepatitis.8 (Level D) Currently there is no effective treatment for HCV hepatitis. Interferon-alpha may precipitate acute rejection. 43.13 Cytomegalovirus (CMV) infection and disease CMV infection occurs primarily after the first month of transplantation and the risk is dependent on the serological status of the donor and recipient. CMV infection is the presence of CMV viraemia with mild fever without evidence of tissue invasion. It may be asymptomatic. CMV disease refers to symptomatic or tissue-invasive acute CMV infection eg pneumonitis, hepatitis, haematological, nervous system and gastrointestinal involvement. The risk of CMV infection is greatest in donor-positive, recipientnegative (D+R-) kidney transplant patients, particularly after the use of anti-lymphocyte antibodies. CMV is associated with immunomodulatory derangements that can lead indirectly to opportunistic superinfections, allograft rejection, and development of post transplant lymphoproliferative disease. 43.13.1 Diagnosis

275

a. Direct early antigen fluorescent foci (monoclonal antibody against pp65, DEAFF), in urine, blood, throat washing b. CMV DNA PCR c. Upper and lower GI endoscopy and biopsy d. Bronchio-alveolar lavage e. Serology (IgM and IgG) is less helpful 43.13.2 Treatment of CMV disease11 (Level C) a. Intravenous ganciclovir for at least 2 to 4 weeks, dosage according to renal function Table 43.3: Dosing of ganciclovir
Serum Creatinine (umol/l) GFR (ml/min) Dose (mg/kg/dose) <130 70 5 bd 130 220 50-69 2.5 bd 220 - 400 25-49 2.5 daily >400 10-24 1.25 daily On dialysis <10 1.25 3x/wk after HD

b. Foscarnet 180mg/kg/day may be used instead of ganciclovir especially in ganciclovir resistant CMV Note: Acyclovir has no role in treating CMV disease while CMV immunoglobulins and intravenous immunoglobulin have uncertain value. 43.13.3 Monitor during treatment a. Daily full blood count, renal profile, liver enzymes b. CMV DNA if available c. Repeat cultures for CMV as necessary Overall, given that life threatening disease is difficult to treat successfully once it is established, prevention by either prophylaxis or pre-emptive therapy is the most effective approach. 43.13.4 Prophylaxis therapy Modalities of prophylaxis therapy (dose adjustment required for renal impairment)13 a. IV ganciclovir 5 mg/kg bd for at least 14 days, followed by oral 1000 mg tds for 2 to 12 weeks b. Oral ganciclovir 1000 mg tds for 2 to 12 weeks In children14,15: > 50 kg 1000 mg tds 37.5 50 kg 750 mg tds 25 37.5 kg 500 mg tds

276

c. d.

Oral valacyclovir 2000 mg qds for 90 days Oral acyclovir 800 mg qds for 12 weeks.

Table 43.4: Definitions of prophylaxis and pre-emptive therapy 11 Strategy Definition Advantages Disadvantages
Prophylaxis Treatment administered before and at transplantation to prevent CMV disease Easy to administer Risk of unnecessary exposure of low risk individual to a drug. Prolonged exposure may result in development of resistance Requires sensitive, predictive test to detect infection Depending on test sensitivity may not identify all individuals at risk of disease

Preemptive therapy

Treatment administered for a brief period if laboratory tests indicate a high risk for CMV disease

Exposure of fewer individuals to drug Reduce duration of exposure Minimizes emergence of resistant CMV

Table 43.5: Prophylaxis therapy12 Donor (D) Immunosuppression recipient (R) regime serological status D-/R+/-antilymphocyte therapy D+/RConventional D+/RD+/R+ D+/R+ D-/R+ D-/R+ Antilymphocyte therapy Conventional Antilymphocyte therapy Conventional Antilymphocyte therapy

Recommendations

Not needed Prophylaxis (Level B) Prophylaxis (Level A) Discretionary (Level C) Prophylaxis (Level A) Discretionary (Level C) Prophylaxis (Level A)

277

43.13.5 Pre-emptive Currently there is insufficient data to recommend routine screening for CMV infection (presence of viraemia).11 Therefore, there is no guideline on pre-emptive therapy. 43.14 Varicella-zoster (Level C) The most commonly seen manifestation in older paediatric transplant recipients is dermatome-restricted herpes zoster. In younger children, primary varicella infection can result in rapidly progressive and overwhelming infection with encephalitis, pneumonitis, hepatic failure, pancreatitis and disseminated intravascular coagulation. 43.14.1 Prophylaxis on exposure Prophylactic varicella-zoster immune globulin (VZIg) given to seronegative children within 72 hours of accidental exposure can modify the disease in 75% of cases. 43.14.2 Treatment Chickenpox: intravenous acyclovir 500 mg/m2/dose tds should be instituted immediately. Zoster: oral acyclovir 400 mg/dose 5x/day (< 2 yr) , 800 mg/dose 5x/day (> 2 yr) (dosage adjustment will be needed in renal impairment) In chicken pox discontinue azathioprine until 2 days after the last new crop of vesicles has dried up. The dose of other immunosuppressive agents will depend on the clinical situation and response to therapy.

278

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Kubak BM, Pegues DA, Holt CD. Infectious complications of kidney transplantation and their management. In: Handbook of Kidney Transplantation (Danovitch GM) 3rd ed, Lippincott Williams & Wilkins. 2001;pp 221-262 Rubin RH, Young LS, eds, Clinical approach to infection in the compromised host. Plenum,1994. Practice Guidelines for the Control and Management of Tuberculosis. 2nd edition. 2002 Ioannidis JPA, Cappelleri JC, Skolnik PR, Lau J, Sacks HS: A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regiments. Arch Intern Med 1996; 156: 177-188 Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S49-50 Recommendations for the Outpatient Surveillance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S50-51 The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7): 75 David-Neto E, Da Fonseca JA, et al. The impact of azathioprine on chronic viral hepatitis in renal transplantations: a long term, single center, prospective study on azathioprine withdrawal. Transplantation 1999; 68: 976-980 Rostaing L, Henry S et al. Efficacy and safety of lamivudine on replication of recurrent hepatitis B after cadaveric renal transplantation. Transplantation 1997; 64: 1624-1627 Goffin E, Horsman Y et al. Lamivudine inhibits hepatitis B virus replication in kidney graft recipients. Transplantation 1998; 66: 407-409 Recommendations from the IHMF Management Strategies Workshop: The Challenge of CMV Infection and Disease in Transplantation, 2000. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15); S45-46 The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7); 71-74 CMV infections following renal transplantation effects of antiviral prophylaxis : a report of NAPRTCS. Paedr Nephrol 1997; 11: 665-667 Guido Filler. Prophylactic oral ganciclovir after renal transplantation dosing and pharmacokinetics. Paedr Nephrol 1998; 12: 6-9

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44.

RENAL TRANSPLANTATION AND NUTRITION

44.1 Dietary modification The first 21 days after successful transplantation should focus on a diet of optimal protein and energy intake as well as restrictions of total fat, saturated fat, cholesterol and simple sugars to restore nitrogen balance and minimise clinical symptoms of post-transplant diabetes and hyperlipidaemia.1 (Level C) 44.1.1 Calorie intake Adequate calorie intake of at least 35kcal/kg/day (range of 35 to 50 kcal/kg/day) a. 40%-50%: Carbohydrate b. < 30%: Fat Calorie intake is aimed at achieving or maintaining desired body weight. 44.1.2 Protein Protein intake is recommended at 1.2 1.5 gm/kg/day. 44.1.3 Fat The ratio of polyunsaturated fatty acids, mono-unsaturated fatty acids and saturated fatty acids should be 1:1:1. Dietary cholesterol should be < 300mg/day. 44.1.4 Sodium intake Sodium intake is restricted to 2-4 gm/day. A diet with moderate sodium restriction to 1 2 gm/day is recommended if there is hypertension. 44.1.5 Potassium intake Patients who have normal functioning graft will usually not encounter problems with serum potassium. Potassium supplementation or restriction is necessary in some cases. 44.2 Nutritional complications post-transplantation 44.2.1 Obesity a. Incidence: Approximately 40% of renal transplant recipients are obese one-year post transplant.2 Detected by height, weight and body mass index (weight in kg divided by height in metres squared) b. A desired body mass index of 20 25 kg/m2 is considered healthy, > 25 kg/m2 is overweight and >30kg/m2 is obese. c. Increased caloric intake may occur after transplantation primarily because of enhanced appetite associated with steroid use.3 d. May have adverse effect on coronary vascular disease.

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44.2.2 Malnutrition Incidence: 10% of patients exhibit low serum albumin levels at 1 year and 20% at 10 year after transplantation.4 Suspect malnutrition in the presence of low serum albumin (although factors other than calorie intake may contribute to hypoalbuminaemia). Diagnosed by the presence of low serum albumin levels. Corticosteroid accelerates the protein catabolic rate and frequently creates a negative nitrogen balance. Malnutrition is associated with increased risk of infection, delayed wound healing and general debility. 44.2.3 Post transplantation hyperlipidaemia Incidence: 60% of patients exhibit total cholestrol levels > 240mg/dl (high risk).5 Reported changes in serum lipid levels are: triglyceride total cholestrol LDL cholesterol apolipoprotein B a. Pathogenesis of hyperlipidaemia in renal transplant patients: (multifactorial)6,7,8 Age Body weight Sex Pretransplantation lipid levels Renal dysfunction Proteinuria Drugs eg. Sirolimus, Blockers, Diuretics, Prednisolone, Cyclosporin etc b. Consequences of hyperlipidaemia Correlation with chronic allograft nephropathy Development of cardiovascular and peripheral vascular disease c. Treatment Weight reduction Increase exercise Dietary modification as recommended for non transplant population (National Cholesterol Education Programme) Step 1 Intake of saturated fat 8% to 10% of total calories Fat intake of 30 % of total calories Saturated fat intake < 300mg/day

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If Step 1 fails, then proceed to Step 2 Step 2 Intake of saturated fat to 7% of total calories Saturated fat intake < 200mg/day Drug therapy Drug therapy is indicated if dietary modification fails (Refer to chapter 45) 44.2.4 Post transplantation diabetes mellitus (PTDM) Incidence : Peak incidence in the first year post-transplant affecting 3% to 4% of patients.10 a. Predisposing factors: Tacrolimus Family history of diabetes mellitus Prednisolone Cyclosporin b. Management Diet modification Exercise Weight loss Cessation of smoking Metformin Sulfonylureas Insulin - half of patients with PTDM may require insulin. Treatment with insulin is also required during periods of stress and intercurrent illness.11

282

References
Edwards MS, Doster S. Renal transplantation diet recommendations: results of a survey or renal dietitians in the United States J Am Diet Assoc 1990; (6): 843-6 2. Modlin CS Flechner SM Goormastic M. Should obese patients lose weight before receiving a kidney transplant? Transplantation 1997; 64: 597-604 3. Johnson CP Gallagher-Lepak S, Zhu YR et al. Factors influencing weight gain after renal transplantation. Transplantation 1993; 56: 822-27 4. Guijarro C, Massy ZA, Ma JZ et al. Serum albumin and mortality after renal transplantation Am J Kid Dis 1996; 27: 117-123 5. Aakhus S, Dahl K, Wideroe TE Hyperlipidaemia in renal transplant patients. J Int Med 1996; 239: 407-415 6. Cattran DC, Steiner G, Wilson D et al. Hyperlipidaemia after renal transplantation: natural history and pathophysiolology. Ann Inter Med 1991; 79: 554 7. Vathsala A, Weinberg RB, Schoenberg L et al. Lipid abnormalities in cyclcosporin prednisolone treated renal transplant recipients. Transplantation 1989; 48: 37 8. Massy ZA, Kasiske BL: Post transplantation hyperlipidaemia: Mechanisms and management, J Am Soc Nephrol 1996; 7: 971 9. Summary of the second report of the National Cholestrol Education Program (NCEP) Expert Panel on Detection, Evaluation and treatment of high blood cholesterol in adults(Adult Panel 11). JAMA 1993; 269: 3015 10. Roth D, Milgrom M, Esquenazi V et al. Posttransplantation hyperglycaemia: Increased incidence in cyclosporin treated renal allograft recipients Transplantation 1989; 47:278-281 11. Sumrani N, Delaney V, Ding Z et al. Diabetes mellitus after renal transplantation in the cyclosporin era : analysis of risk factors. Transplantation 1991; 51: 343-47 1.

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45.

LONG-TERM COMPLICATIONS TRANSPLANTATION

AFTER

RENAL

45.1 Cardiovascular disease 17% of deaths in renal transplant are due to cardiovascular disease.1 The death rate from cardiovascular disease is 10 20 times increased in the younger age groups. Table 45.1: Risk factors for IHD post renal transplant2,3,4,5,6,7,8,9 family history of left ventricular age IHD hypertrophy male sex hypertension acute rejection smoking high LDL levels diabetes mellitus low HDL levels Elevated body mass index, hyperhomocysteinaemia, increased lipoprotein A and increased circulating inflammatory factors (CRP, fibrinogen) are associations.5,10,11 It is recommended to aggressively modify identifiable risk factors to lower cardiovascular risk. (Level B) All renal transplant patients are considered at high risk of IHD.1,9,11,12 If they had an old myocardial infarction (MI) they are considered very high risk.8 45.1.1 The following steps may be taken to lower the IHD risk in patients (Level B): a. Decrease LDL cholesterol (refer to 44.1.3 on lipid lowering therapy) b. Blood pressure < 125/75 mmHg if proteinuria > 1 g/day and < 130/85 mmHg if < 1 g/day13 c. ACEI and beta blockers for hypertension13 d. Low dose aspirin* (75 150 mg/day)14,15 e. Control diabetes mellitus (HbA1C < 7% and FBS < 7 mmol/l) f. Stop smoking14,16 g. Exercise 30 minutes 3 4 times a week16 h. Weight kept at body mass index < 30 i. Other suggestions (Level C)6: Treat polycythaemia when PCV > 55%14 Folic acid supplement (5 mg/day) to reduce homocysteine levels8,14,16,17 * caution in patients at risk of bleeding

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45.1.2 Hypertension The incidence of hypertension post renal transplant is 60 80% with the use of cyclosporine and tacrolimus.13,18 Treatment is to protect from cardiovascular complications and injury to the allograft.13 It is assumed the patient has no acute rejection, is on the lowest steroid and cyclosporine dose, has decreased salt intake and is limiting weight gain. The management is similar to other cases of hypertension. Comorbid factors e.g. cardiovascular disease, left ventricular hypertrophy, diabetes mellitus, hypercholesterolaemia, obesity are taken into account. Table 45.2: The following anti-hypertensives may be used in renal transplant recipients19 Agent Notes Calcium Headache, oedema common. Diltiazem, channel verapamil and amlodipine elevate cyclosporine blockers levels. Nifedipine causes gum hypertrophy.13 Beta blockers Lipid side effects. Worsens peripheral vascular disease, asthma, heart block. Useful in IHD. Vasodilators Postural hypotension, palpitations. Alpha blockers useful in benign prostatic hypertrophy. Methyl dopa Sedation, liver damage. Minoxidil Hirsutism and fluid retention. Useful in uncontrolled hypertension. Table 45.3: The following anti-hypertensives are used with caution Agent Notes Decreased GFR, hyperkalaemia, anaemia, ACE inhibitors and AII receptor cough. Contraindicated in renal artery stenosis. antagonists13,20 Renal function should be closely monitored. Useful in HT with proteinuria or posttransplant erythrocytosis. Diuretics Metabolic side effects, dehydration. Useful in fluid overload a. Suspect a secondary cause of HT if: Hypertension is poorly controlled despite good compliance and maximum anti-HT drugs Malignant hypertension Recent onset hypertension Hypertension with progressive graft dysfunction b. Secondary causes include20,21:

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Graft renal artery stenosis Chronic allograft nephropathy Recurrent or de novo glomerulonephritis (active urine sediment with CRF) Chronic cyclosporine toxicity

45.1.3 Lipid lowering therapy Lowering LDL cholesterol in patients with IHD or in high risk patients for primary prevention leads to clinical benefit beyond a doubt.2,22,23,24,25,26,27,28 (Level A) a. Patients should be screened at least once during the first 6 months and again at 1 year after renal transplant with fasting total cholesterol, LDL, HDL and TG. Thereafter annual screening with fasting lipid profile. Changes in immunosuppressive therapy, graft function or IHD risk may warrant additional screening.14 (Level A) b. Cholesterol lowering in renal transplant recipients: (Level A) For primary prevention start with HMG CoA reductase inhibitor (statin) if total cholesterol is 7 or LDL > 5 mmol/l.22,26 With IHD, start if total cholesterol is 4 or LDL > 3 mmol/l.23,25 Primary prevention: target LDL < 3.37 mmol/l9 Secondary prevention: target LDL < 2.59 mmol/l 13 Further guidelines are to start if HDL < 0.91 mmol/l29 (>1.55 mmol/l is protective) *(Conversion from mg/dl to mmol/l cholesterol: x 0.02586) (Conversion from mmol/l to mg/dl cholesterol: x 38.67) Cholesterol usually will not change with diet modification. Statins are the drugs of first choice for decreasing LDL.2,9 Statins reduced the incidence of cardiac deaths and non fatal myocardial infarction in renal transplant recipients.30,31,32 There are 2 classes of statins: hydrophilic (pravastatin and fluvastatin) which do not cause myopathy and lipophilic (lovastatin, simvastatin and atorvastatin) which cause myopathy.2,33,34,35 In the former class maximum dose can be used; in the latter reduce the dose to half, e.g. 5 10 mg/day simvastatin and 20mg/day lovastatin. Caution as statins may interact with cyclosporin. Fibrates may be used for hypertriglyceridaemia and decreased HDL: target TG < 2.1 mmol/l (180 mg/dl). Fibrates should not use in combination with statins. In postmenopausal women with IHD there was no effect of HRT on decreasing IHD.16.36

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45.2 Prevention and treatment of osteoporosis Patients at highest risk of osteoporotic fractures are those with established osteoporosis, insulin dependent diabetes, old age or who are post-menopausal.6 Osteoporosis (bone mineral density > 2.5 SD below the young adult mean value; t score) may be diagnosed with dual energy Xray absorptiometry (DEXA) at the time of renal transplant, after 6 months and then every 12 months if results are abnormal.14 (Level B) Intravenous pamidronate 0.5 mg/kg given at the time of renal transplant and one month later reduces bone loss.6,37,38,39,40 (level B) This drug prevents bone resorption and may cause transient hypocalcaemia and hypophosphataemia. Oral alendronate and etidronate are alternatives.6,41,42 Calcium supplements (500 1000 mg/day elemental calcium) and calcitriol 0.25 ug/day may reduce long term bone loss.6,37,43,44,45,46 (Level D) The side effect is hypercalcaemia. Hormone replacement therapy is recommended for post-menopausal women.6,37 45.3 Recurrence of primary disease All reports are from observational studies. (Level D) Table 45.4: Recurrence of primary disease post renal transplant
Type of GN
Focal glomerulosclerosis
47

Recurrence rate
8/16 children, 3/27 adults ; renal transplant (Tx) within 3 years of nephrotic syndrome and rapid progression to ESRF are associated with recurrence 20 30%; 50% in children < 5 years; 80 100% in children < 15 years with ESRF within 3 years of FSGS; 10 15% in adults 48,49,50 10 - 30% 49,51,52,53

Graft loss
60% compared to 23% if no recurrence 75 85% second graft failure in children if first graft is lost to FSGS; 40 50% in adults 30 50% 30 40%

De novo rate

5 10% Associated with hepatitis C

Membranous GN Membranoproliferativ e GN Type I 20 30%, higher in children; 80% recur in second graft (48,54)

287

Type of GN Membranoproliferativ e GN Type II IgA nephropathy

Recurrence rate 50 100%48,53,54 50%; usually > 5 years post renal transplant49,53,55 Recurrence correlates with disease activity and Tx only after activity subsides 12 months48 Delay transplant till circulating anti-GBM AB undetectable for 12 months;48,49,56 50% but asymptomatic;

Graft loss 10 20% < 10%, 75% graft survival at 5 years

De novo rate

Henoch-Schonlein purpura Anti-GBM antibody positive glomerulonephritis

Rare

Haemolytic uraemic syndrome

Idiopathic crescentic glomerulophritis or Wegeners or microscopic polyangitis Lupus nephritis

25 50%; typical HUS caused by diarrhoae does not recur; increased in atypical HUS, autosomnal recessive HUS, older age onset, short duration disease pre-ESRF, use of living donors, cyclosporine47,57; Transplant after activity subsides 12 months 16%; stable ANCA and no symptoms transplant after 6 months; increasing ANCA or active do not transplant48 Low recurrence rate49,53

10 50%

From CSA toxicity do not use CSA next renal transplant

40%

45.4 Surveillance for malignancy The evidence is from retrospective case studies, single centre series and registry data. The incidence of cancer is 100 times that of the general population.58 It tends to be aggressive with mortality 4.5 times that of cancer in the general population. The incidence is dependent on viral infections pre- and post-transplant, policies for their prevention, detection and therapy. It is dependent on the type and dose of immunosuppressants, age, sex of the patients, genetic

288

factors and time after renal transplantation (incidence increases with time).6,59 45.4.1 Skin cancer There is increased incidence of squamous cell cancer but not basal cell cancer. It occurs at younger age (30 years) compared to general population (60 years), at multiple sites, is aggressive and tends to recur after resection. The mean time of appearance is 69 months after renal transplantation; up to 40% incidence at 20 years with a 250 times increased risk. The mortality rate is 5% compared to 2% in the general population. There is an association with human papillomavirus infection. In places with less sun exposure the incidence decreases. Cancer is found in body areas exposed to the sun and the incidence increases with time.6,60 Recommendations are to avoid and limit sun exposure, wearing sunscreen and protective clothing.6,14 (Level B) Self examination of the skin should be done monthly (Level B) and skin inspection by physician yearly14 (Level B), more often for patients at risk. Premalignant lesions should be treated aggressively. 45.4.2 Cancer of the cervix There is a 3 16 times increased risk with human papillomavirus infection having a 3.2 relative risk.14 The incidence of dysplasia is 9%. The recommendations are for yearly pelvic examination and Pap smear in sexually active females > 18 years old.14 (Level A) 45.5 Post transplant lymphoproliferative disorder (Level C) The incidence of post transplant lymphoproliferative disorder (PTLD) is more common in transplanted children compared to adults (10.1% versus 1.2%) especially in presence of vigorous immunosuppression. 80% of PTLD are in transplants with EBV +ve donor to EBV ve recipients. In 30%, acute rejection are observed before diagnosis of PTLD. 45.5.1 Treatment The treatment of PTLD consists of: a. marked decrease or cessation of immunosuppression b. a small percentage (~ 2%) may require chemotherapy In children the outcome of PTLD is more favourable than adult in terms of patient and graft survival. 45.6 Other cancers There is no increased incidence of lung, prostate, colon and uterine cancer6. The incidence of breast cancer is decreased 25 30%. However colon and breast cancers are common. 45.6.1 Screening include:

289

a. Breast: Mammography every 1 2 years at age 50 69 years.14 (Level A) b. Colon: Faecal occult blood yearly and flexible sigmoidoscopy every 5 years in patients > 50 years old.14 (Level A)

References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Foley R, Parfrey P, Sarnak M. NKF: Controlling the epidemic of CV disease in CRD: V. Part I. Clinical epidemiology of cardiovascular disease in chronic renal disease. UpToDate 2000; Vol 8 No 2 Stewart G, Jardine A, Briggs J. Ischaemic heart disease following renal transplantation. Nephrol Dial Transplant 2000; 15 (2) : 269 277 Kasiske B, Harini A, Chekkera, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11 : 1735 1743. Wheeler D. Ischaemic heart disease after renal transplantation: how to assess and minimize the risk. Nephrol Dial Transplant 1999; 14 : 1075 1077. Vella J, Sayegh M. Risk factors for cardiovascular disease in the renal transplant recipient. UpToDate 2000; Vol 8 No 2 Silkensen J. Long-term complications in renal transplantation. JASN 2000; 11 : 582 588. Roodnat J, Mulder P, Zietse R et al. Cholesterol as an independent predictor of outcome after renal transplantation. Transplantation 2000; 69 : 1704 1710 Levey A. NKF: Controlling the epidemic of CV disease in CRD: II. Executive summary. UpToDate 2000; Vol 8 No 2 Kasiske B. NKF: Controlling the epidemic of CV disease in CRD: V. Part III. Hyperlipidemia in patients with chronic renal disease. UpToDate 2000; Vol 8 No 2. Meyer K, Levey A. Controlling the epidemic of cardiovascular disease in chronic renal disease: report from the National Kidney Foundation task force on cardiovascular disease. J Am Soc Nephrol 1998; 9 : S31 S42. I.V. Recommendations for the management of cardiovascular risk factors. Nephrol Dial Transplant 2000; 15 (Suppl 5) : S58 S154. Foley R, Parfrey P, Sarnak M. Epidemiology of cardiac disease in chronic renal disease. J Am Soc Nephrol 1998; 9 : S16 S23 Mailloux L, Levey A. NKF: Controlling the epidemic of CV disease in CRD: V. Part II. Hypertension in patients with chronic renal disease. UpToDate 2000; Vol 8 No 2. Kasiske B, Vazquez M, Harmon W et al. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000; 11 : S1 S86 Murphy S, Foley R, Parfrey P. NKF: Controlling the epidemic of CV disease in CRD: V. Part VI. Screening and treatment for cardiovascular disease in patients with CRD. UpToDate 2000; Vol 8 No 2. Beto J, Bansal V. NKF: Controlling the epidemic of CV disease in CRD: V. Part V. Tobacco use; physical activity; menopause; and homocysteine. UpToDate 2000; Vol 8 No 2. Sunder-Plassmann G, Floth A, Fodinger M. Hyperhomocysteinemia in organ transplantation. Current Opinion in Urology 2000; 10 : 87 94. Rosenkrantz A, Mayer G. Mechanisms of hypertension after renal transplantation. Current Opinion in Urol 2000; 10 (2) : 81 86.

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19. Olyaei A, deMattos A, Bennett W. A practical guide to the management of hypertension in renal transplant recipients. Drugs 1999; 58 (6) : 1011 1027. 20. Sayegh M, Vella J. Hypertension after renal transplantation. UpToDate 2000; Vol 8 No 2. 21. Zeier M, Mandelbaum A, Ritz E. Hypertension in the transplanted patient. Nephron 1998; 80 (3) : 257 268 22. Sheperd J, Cobbe S, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Eng J Med 1995; 333 (20) : 1301 1307. 23. Sacks F, Pfeffer M, Moye L et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Eng J Med 1996; 335 (14) : 1001 1009 24. Scandinavian simvastatin survival study group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival study (4S). Lancet 1994; 344 : 1383 1389. 25. The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Eng J Med 1998; 339 (19) : 1349 1357. 26. Downs J, Clearfield M, Weis S. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS / TexCAPS. JAMA 1998; 279 (2) : 1615 1622. 27. Law M, Wald N, Thompson S. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease. Br Med J 1994; 308 : 367 372 28. Ansell B, Watson K, Fogelman A. An evidence-based assessment of the NCEP adult treatment panel II guidelines. JAMA 1999; 282 (21) : 2051 2057. 29. Ministry of Health Malaysia, Academy of Medicine Malaysia. Second consensus statement on management of hyperlipidemia. 1998. 30. Holdaas H, Fellstrom B, Jardine AG, Holme I et al. Effect of fluvaswtatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361 :2024 2031 31. Wanner C, Quaschning T, Weingartner K. Impact of dyslipidaemia in renal transplant recipients. Current Opinion in Urology 2000; 10 : 77 80. 32. Wheeler D. Statins and the kidney. Current Opinion in Nephrology & Hypertension 1998; 7 (5) : 579 584 33. Jardine H, Holdaas H. Fluvastatin in combination with cyclosporin in renal transplant recipients: a review of clinical and safety experience. Journal of Clinical Pharmacy & Therapeutics 1999; 24 (6) : 397 408. 34. Arnadottir M, Berg A. Treatment of hyperlipidemia in renal transplant recipients. Transplantation 1997; 63 : 339 345. 35. Castro R, Queiros I, Fonseca J et al. Therapy of post-transplant hyperlipidaemia: comparative study with simvastatin and fish oil. Nephrol Dials Transplant 1997; 12 : 2140 2143 36. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280 (7) : 605 - 613. 37. Rodino M, Shane E. Osteoporosis after organ transplantation. Am J Med 1998; 104 (5) : 459 469. 38. Rosen H, Rosenblatt M. Osteoporosis after transplantation. UpToDate 2000; Vol 8 No 2. 39. Fan S, Almond M, Ball E et al. Pamidronate therapy as prevention of bone loss following renal transplantation. Kid Int 2000; 57 : 684 690. 40. Butterly D, Quarles L. Parathyroid and mineral metabolism after renal transplantation. UpToDate 2000; Vol 8 No 2.

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41. Adachi J, Bensen W, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Eng J Med 1997; 337 : 382 387. 42. Saag K, Emkey R, Gruber B et al. Alendronate for the management of glucocorticoid-induced osteoporosis: results of the multicenter US study. (Abstract). Arthritis & Rheumatism 1997; 40 : S136. 43. Cueto-Manzano A, Konel S, Freemont A, et al. Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation. J Am Soc Nephrol 2000; 35 (20):227-236 44. Amin S, Simms W, Felson D. A meta-analysis evaluating the efficacy of calcium and vitamin D for corticosteroid-induced osteoporosis. (Abstract). Arthritis & Rheumatism 1997; 40 : S136. 45. Sambrook P, Birmingham J, Kelly P et al. Prevention of corticosteroid osteoporosis a comparison of calcium, calcitriol and calcitonin. N Eng J Med 1993; 328 : 1747 1752. 46. Diamond T, McGuigan L, Barbagallo S et al. Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in post-menopausal women. Am J Medicine 1995; 98 (5) : 459 - 463. 47. Niaudet P. Complications of renal transplantation in children. UpToDate 2000; Vol 8 No 2. 48. Kotanko P, Pusey C, Levy J. Recurrent glomerulonephritis following renal transplantation. Transplantation 1997; 63 (8) : 1045 1052. 49. The EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation (part 1). Nephrol Dial Transplant 2000; 15 Suppl 7. 50. Sayegh M, Kaplan A. Focal glomerulosclerosis: recurrence after transplantation. UpToDate 2000; Vol 8 No 2. 51. Cosyns J, Couchoud C, Pouteil-Noble C et al. Recurrence of membranous nephropathy after renal transplantation: probability, outcome and risk factors. Clin Nephrol 1998; 50 (3) : 144 153. 52. Sayegh M. Membranous nephropathy and renal transplantation. UpToDate 2000; Vol 8 No 2. 53. Hariharan S. Recurrent and de novo diseases after renal transplantation. Seminars in Dialysis 2000; 13 (3) : 195 199 54. Sayegh M. Membranoproliferative glomerulonephritis: recurrence after transplantation. UpToDate 2000; Vol 8 No 2. 55. Sayegh M. IgA nephropathy: recurrence after transplantation. UpToDate 2000; Vol 8 No 2. 56. Sayegh M. AntiGBM antibody disease: recurrence after transplantation. UpToDate 2000; Vol. 8 No.2. 57. Sayegh M.TTP-HUS: recurrence after transplantation. UpToDate 2000; Vol 8 No 2. 58. Sayegh M. Development of malignancy following solid organ transplantation. UpToDate 2000; Vol 8 No 2. 59. Jamil B, Nicholls K, Becker G, Walker R. Impact of acute rejection therapy on infections and malignancies in renal transplant recipients. Transplantation 1999; 68 (10) : 1597 1619. 60. Sheil R. Patterns of malignancies following renal transplantation. Transplant Proc 1999; 31 (12) : 1263 1265

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46.

PAEDIATRIC RENAL TRANSPLANTATION

46.1 Pretransplant Work-up Obstructive uropathy accounts for approximately 20% ESRF and needs to be fully evaluated before transplantation. Outcome of transplant in patients with obstructive uropathy is not significantly different from others though there may be an increased incidence of post-transplantation urological complications and urinary tract infection.1,2,3 (Level C) 46.1.1 Cadaveric kidneys from young donors Cadaveric kidneys from young donors yield poorer graft survival and should be used with caution. Donors < 2 years should not be routinely used en bloc or singly. Table 46.1: Graft survival with respect to donor age Donor age 1 yr graft survival 5 yr graft survival < 2 years 2 5 years en bloc single kidney 6 15 years > 16 years 20% 82% 64% 70% comparable to adult kidneys 70% 40% comparable to adult kidneys

a. Long-term results with single paediatric donor (< 6 year) kidney transplants into adult recipients: increase incidence in requirement for early dialysis (45% vs 24%) higher incidence of proteinuria > 0.8 g/24 hr (67% vs 48%) higher incidence of rejection within 6 months (80% vs 60%) Recommendations (Level C): Kidneys < 6 cm employ en-bloc transplantation Lighter patients generally given preference for receiving paediatric kidneys 46.1.2 Immunisation As information about the use of live virus vaccines after solid organ transplantation is limited, it is advisable to avoid live vaccines post transplantation. Children who are scheduled for transplant should have their immunisation completed at least one month prior to transplantation.

293

a. Varicella vaccination Varicella vaccine for those patients who are seronegative. Table 46.2: Dosing for varicella vaccine Age Dose of vaccine 12 months to 13th birthday one dose of varicella vaccine Adolescents and adults two doses of vaccine 4 to 8 weeks apart b. Hepatitis B vaccination Potential recipients who are seronegative for Hepatitis B should be vaccinated with double the recommended dose of Hepatitis B vaccination at month 0, 1, 2, and 6. Check the antibody response after one month on completing the immunisation. Vaccinees whose serum anti-HBsAb is < 10 mIU/ml after a primary vaccine series should be revaccinated. Revaccination consists of three doses. Those who remain anti-HBs negative after a revaccination series of 3 doses are unlikely to respond to additional doses of vaccine. 46.1.3 Immunosuppression Immunosuppressive protocol for paediatric kidney transplantation at Paediatric Nephrology Hospital Kuala Lumpur (Refer to chapter 41) 46.2 Peritransplant management issues in children3 46.2.1 Intraoperative Fluid Management (Level D) Precise intraoperative fluid management and maintenance of adequate vascular volume are essential to minimise post-transplant delayed graft function particularly when placing an adult kidney in a relatively small child. a. Administer estimated amount of blood sequestered by an adult kidney of isotonic crystalloid or colloid solutions before renal vessels are unclamped. b. Maintain central venous pressure at 10 14 cm H2O c. Maintain mean arterial pressure above 70 mmHg before vascular clamps are removed. d. Frusemide (0.5-1mg/kg) and mannitol (0.5-1.0g/kg) may be given during the creation of the vascular anastomosis to facilitate urine output. Urine output must be replaced to prevent hypovolaemia. 46.2.2 Postoperative fluid management (Level D) a. Maintain central venous pressure in the range of 6 10 cm H2O and mean arterial pressure above 70 mmHg

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b. Insensible fluid losses (400 ml/m2) should be administered as 0.18% dextrose saline c. Urine output should be replaced ml for ml with 0.45% saline. The target urine output should be more than 1ml/kg/hr 46.2.3 Acute allograft dysfunction in children (Level C) The differential diagnosis of an algorithm for working-up acute graft dysfunction in children is generally similar to that of adult. (refer to chapter 41) Particular emphasis however should be made in the following circumstances: a. small rise or no recognisable rise in serum creatinine can occur in acute rejection especially in small children who receive large kidneys b. urinary tract infections in young children can be clinically indistinguishable from acute rejection c. CMV infection may manifest as only modest fever and a minimal rise in serum creatinine level in situations where aggressive antiCMV prophylactic therapies are employed 46.3 Problems encountered in children post transplant 46.3.1 Infections a. Viral Infections The herpes group viruses (CMV, herpesvirus, varicella-zoster virus and EBV) pose a special problem in view of their common occurrence in children. Many young children have not yet been exposed to these viruses and because they lack protective immunity, their predisposition for serious primary infection is high. Cytomegalovirus4,5 (Level B) The younger the child, the greater is the potential for serious infection when a CMV positive donor kidney is transplanted. (Refer to chapter 42) Herpes Simplex The typical perioral herpetic ulcerations are common in immunosuppressed children and will usually respond to oral acyclovir therapy (dose 200 mg 5x/day). 46.3.2 Growth (Level C) Growth retardation remains a major concern in children with chronic renal failure. Catch-up growth occurs in only 30 50 % of children after transplantation, often in children less than 6 years old. Efforts should focus on the normalisation of height before transplantation or before the onset of puberty. a. Determinants of post-transplant growth : Age at transplant

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Table 46.3: Height gained post renal transplant in relationship to age of transplant Age at Tx Height gained 1 2 yrs post-transplant < 6 yrs + 1.0 SDS 6 12 yrs + 0.1 SDS > 13 yrs may be no mean increase The fact that younger children benefit the most in statural growth from early transplantation provides a strong argument for expedited transplantation in an attempt to optimise and perhaps normalise stature. Early transplantation allows less time for growth failure on dialysis and therefore less requirement for catch-up growth. b. Strategies for improving growth include: Using low dose steroids Maintain good graft function Using human recombinant growth hormone6,7,8, 46.3.3 Hypertension and cardiovascular disease Persistent post-transplant hypertension is seen in 50% of living related transplant and 70% of cadaveric transplant. Hypertension has been shown to be associated with poorer graft function. (Level C) The incidence of post-transplant hyperlipidemia is high (approximately 50%) in long-term paediatric graft recipients. Dietary measures to reduce hyperlipidaemia are advocated. There is currently no consensus to make firm recommendations for the use of pharmacologic measures in children. (Level C) 46.3.4 Non compliance Non-compliance has been estimated to be the principal cause of graft loss in 10 15% of all paediatric kidney transplants.9,10 a. Non-compliance should be suspected when any of the following are observed diminution in cushingnoid features sudden unexplained weight loss and unexplained swings in the patients kidney function or cyclosporin trough blood level b. Management of non-compliance Ongoing counseling should be undertaken in high-risk patients pre-transplant. Modified medication by using medications with less cosmetic side effect and daily dosing regime. Prospective introduction of behaviour modification programs.

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46.3.5 Malignancy The incidence of post-transplant malignancy in children has been reported to be 1.4%. Of these, 60% were PTLDs and lymphoma.3 46.4 Preemptive transplantation (Level C) Pre-emptive transplantation should be considered if creatinine clearance reduced to 10 20 ml/min or severe growth failure 46.4.1 Advantages of preemptive transplantation a. Preemptive transplantation eliminates complications and inconvenience of dialysis as well as transfusion requirements and its associated morbidity. b. Preemptive transplantation demonstrated longer graft survival compared to conventional transplantation (rate ratio of allograft failure 0.48 first year, 0.18 second year, 0.14 subsequent year). 46.5 Transplantation in infants and young children1,11,12,13 (Level C) Compared with adults and larger paediatric patients, infants with end stage renal disease are the most challenging subgroup of patients undergoing renal transplantation. the highest risk for early graft loss a higher mortality rate. With dialysis and without transplantation, however, there is even higher mortality rate (14% at 1 year and 25% at 2 years) with accompanying co-morbid factors difficulty maintaining long-term dialysis access.

Recipients who survived the first year with good renal allograft function, however exhibited the best long-term graft survival with graft half-life of 18 years compared with adults (11 years) and adolescents (7 years). 46.5.1 Special problems pertaining to infants and young children a. vascular thrombosis (23%) b. primary non-function (delayed graft function: 12%) c. technical error d. irreversible acute rejection e. various inherited and sporadic syndromes with multiorgan involvement f. high incidence of obstructive uropathy and other anomalies of the genitourinary system that pose challenging anatomical and

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functional problems and require special approaches in preparation for transplant. 46.5.2 Special precautions in transplants involving infants a. dedicated paediatric urological team b. tight immunosuppressive management c. aggressive fluid management d. careful integration of urologic and transplant surgery

References
1. Millan et al. A 100% 2-year graft survival can be attained in high risk 15 kg or smaller infant recipients of kidney allografts. Arch Surg. 2000; 135(9): 1063-1068 2. Renal Transplantation, chronic dialysis and chronic renal insufficiency in children and adolescents. The 1995 Annual Report of the North Paediatric Renal Transplant Cooperative Study. Paedr Nephrol.1997; 11: 49-64 3. Samhar I. Al-Akash , Robert B. Ettenger. Kidney transplantation in children. Danovitch - Handbook on Renal Transplantation 4. Scott J. Schurmann. Center volume effects in paediatric renal transplantation. A report of the NAPRTCS. Paedr Nephrol 1999; 13: 373-378 5. CMV infections following renal transplantation effects of antiviral prophylaxis: a report of NAPRTCS. Paedr Nephrol 1997; 11: 665-667 6. Sven Arvid Birkeland. Paediatric renal transplantation without steroids. Paedr Nephrol 1998;12: 87-92 7. Richard Fine. The impact of recombinant human growth hormone treatment on final adult height. Paedr Nephrol 2000; 14: 679-681 8. Dominique Simon. Post-graft development of short children treated with growth hormone before kidney graft. Paedr Nephrol 1999; 13: 723-729 9. Douglas M. Silverstein. Risk factors for hyperlipidemia in longterm paediatric renal transplant recipients. Paedr Nephrol 2000; 14:105-110 10. Alan R. Watson. Non-compliance and transfer from paediatric to adult transplant unit. Paedr Nephrol 2000; 14: 469-472 11. Mahmoud A. Outcome of preemptive renal transplant and pre-transplant dialysis in children. Paedr Nephrol 1997; 5: 537-41 12. Haeley et al. Transplantation of adult living donor kidneys into infants and small children. Arch Surg. 2000; 135(9): 1035-1041 13. Jameela A. Kan. Renal transplantation in children under 5 years of age. Paedr Nephrol 1999; 13: 730-736

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Glossary HLA Ab ACE ACEI AHG AII ALG ALT ANCA Anti IL-II APKD APTT ATG ATN BAL BMI BP C&S Ca2+ CAPD CDC CMV Cr EDTA CrCl CRF CRP CSA CT CVP CXR DEAFF DNA DTPA DTT EBV ECG EDTA ELISA ENT Human leucocyte antigen Antibody Angiotensin converting enzyme ACE inhibitor Anti human globulin Angiotensin 2 Anti-lymphocyte globulin Alanine transaminase Anti-neutrophil cytoplasmic antibody Anti-interleukin 2 Adult polycystic kidney disease Activated partial thromboplastin time Anti-thymocyte globulin Acute tubular necrosis Broncho-alveolar lavage Body mass index Blood pressure Culture and sensitivity Calcium Continuous ambulatory peritoneal dialysis Complement-dependent cytotoxicity Cytomegalovirus Chromium EDTA Creatinine clearance Chronic renal failure C reactive peptide Cyclosporin Computer axial tomography Central venous pressure Chest Xray Direct early antigen fluorescent foci Deoxyribonucleic acid Diethylenetriaminepentaacetic acid Dithiothreitol Epstein Barr virus Electrocardiogram Ethylene diamine tetraacetic acid Enzyme linked immunosorbent assay Ear nose throat

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ERZ ESBL ESRF FBC FBS FSGS G6PD GBM GFR GI GN H20 HbA1c HBeAg HBsAb HBsAg HCV HD HDL HIV HKL HMG CoA HT HUS ICU IFN IgA IgG IgM IHD iPTH IVP KUB LDL LFT LRRT Mg2+ MI MMF mmHg MOSS MRA

Ethambutol, rifampicin, pyrazinamide Extended spectrum beta lactamase End stage renal failure Full blood count Fasting blood sugar Focal segmental glomerulosclerosis Glucose-6-phosphate deficiency Glomerular basement membrane Glomerular filtration rate Gastrointestinal Glomerulonephritis Water Haemoglobin A1C Hepatitis B e antigen Hepatitis B surface antibody Hepatitis B surface antigen Hepatitis C Haemodialysis High density lipoprotein Human immunodeficiency virus Hospital Kuala Lumpur 3-hydroxy-3-methyl-glutaryl coenzyme A Hypertension Haemolytic uraemic syndrome Intensive care unit Interferon Immunoglobulin A Immunoglobulin G Immunoglobulin M Ischaemic heart disease Intact parathyroidhormone Intravenous pyelogram Kidney ureter bladder Low density lipoprotein Liver function test Living related donor renal transplant Magnesium Myocardial infarction Mycophenolate mofetil Millimetres of mercury Malaysian organ sharing system Magnetic resonance angiography

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MRSA MRSE MSSA MSU OT PCR PCV PO4 PRA PSA PT PTDM PTLD RBS RNA SCDC SOS TB TG Tx URTI US UTI

Methicillin resistant staph. aureus Methicillin resistant staph. epidermidis Methicillin sensitive staph. aureus Mid stream urine Operating theatre Polymerase chain reaction Packed cell volume Phosphate Panel reactive antibodies Prostatic specific antigen Prothrombin time Post transplant diabetes mellitus Post transplant lymphoproliferative disorder Random blood sugar Ribonucleic acid Standard CDC Save our souls Tuberculosis Triglyceride Transplant Upper respiratory tract infection Ultrasound Urinary tract infection

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