I would like to tell you somethingWill you listen to me?

Hanan Fathy
Pediatric Nephrology Unit

University Of Alexandria

 Excretion
Homeostasis Osmoregulation Regulation of salts in the body Regulation of pH Production of a hormone (EPO)

 0.4% of body weight vs 25% of cardiac output each minute High metabolic demand
High oxygen consumption High substrate delivery

High surface area

Glomerular basement membrane Tubular microvilli

Renal injury Results from Hemodynamic changes Direct injury to cells and tissue Inflammatory tissue injury Obstruction of renal excretion

Acute renal failure

Acute kidney injury

Biochemical test

Biomarkers

Sudden causes affecting

Renal Perfusion

Called
Pre-renal

Parenchymal Structures

Induce GFR

Parenchymatous (intrinsic)

Urine output

Post-renal

ARF

 One of the most striking characteristics of the renal circulation is the ability of the kidney to maintain a constant renal blood flow (RBF) and glomerular filtration rate (GFR) as renal perfusion pressure is altered.

Thus renal protection is lost when renal autoregulation fails.

Conditions that Lead to Pre-renal Azotemia-Ischemic AKI

Intravascular Volume Depletion Large-vessel Renal Vascular Disease Decreased Effective Circulating Volume
CHF Cirrhosis Nephrosis Generalized or Localized Reduction in Renal Blood Flow Renal Artery Thrombosis Renal Artery Embolism Renal Artery Stenosis or Crossclamping

Medications
CYA, Tacrolimus ACE inhibitors NSAIDS Radiocontrast Amphotericin B Aminoglycosides

Sepsis

Small-vessel Renal Vascular Disease

Vasculitis Atheroemboli Thrombotic Microangiopathies Transplant Rejection

Hepatorenal Syndrome
Ischemic Acute Kidney Injury

A 6-month old infant, Was admitted to the hospital for: Fever and vomiting.
Family history revealed young and apparently healthy parents. He was the third child, with normal gestational age, Birth weigh 3300g, 2 months breast feeding and then artificial feeding with cow milk.

Two days before admittance, the child was hospitalized in another pediatric department for bronchopneumonia being treated with association of antibiotics.
Based on an ultrasound examination, a suspicion of polycystic kidney was established. No information regarding diuresis before admittance was available.

Clinical examination showed an infant with 3850g, fever (T=390C), bad general state, no appetite, severe pallor, warm extremities, enlarged abdomen, liver with inferior margin 2 cm below the right rib.. Biologic tests showed: Oligo-anuria was present during the entire evolution. Hb=6,6g%. urea=178mg%. creatinine=1,4mg%. uric acid=9,7mg%. Na=146135119mEq/l. K=6,5mEq/l. ph=7,07. BE=-19,7mmol/l. albuminura, leucocytouria, Uroculture with E. Coli>100,000/ml. U/S bilateral hydroureteronephrosis.

 Conclusions: 1. The case represents a diagnosis error. 2. The delayed diagnosis was determined by multiple factors: few clinical signs at the domicile, ambiguous results at ultrasound examinations, and the rapid evolution of pyelonephritis ,in the absence of therapy, to acute renal failure.

3. Voiding urogram performed in due time would have been allow a timely diagnosis and a appropriate treatment

A 20-day-old male infant with a body weight of 2.5 kg, transferred from the neonatal unit on the ninth day after the surgical correction of Fallot's tetralogy and pulmonary atresia.

On admission to the pediatric intensive care unit, the infant required mechanical ventilation, an infusion of vasoactive drugs (dopamine 6 mcg/kg/minute, dobutamine 10 mcg/kg/minute and milrinone 0.5 mcg/kg/minute) and furosemide in a continuous infusion of 0.4 mg/kg/hour. The patient had received treatment with vancomycin and amikacin up to 2 days earlier. On examination, there was marked generalized edema. The initial blood tests revealed a creatinine level of 0.5 mg/dL, urea 75 mg/dL, albumin 2.8 g/dL, sodium 132 mmol/L, potassium 4.6 mmol/L and chloride 96 mmol/L. In order to decrease the doses of intravenous vasoactive drugs, It was decided to administer digitalis to the patient, prescribing a dose of digoxin of 10 mcg/kg enterally.

 Four hours after the administration of the drug, the child presented with progressive oliguria, with a fall in diuresis from 4 to 1.5 mL/kg/hour, and with no change in the hemodynamic situation (blood pressure 65/40 mmHg, lactate 1.1 mmol/L, heart rate 140 bpm). Blood tests revealed a rise in creatinine to 0.7 mg/dL and in urea to 89 mg/dL and a fall in sodium to 121 mmol/L. There were no neurological clinical symptoms or alterations in the cerebral echography that suggested cerebral edema. The urinalysis was normal. Initially, to exclude hypovolemia, volume expansion was performed with 5% albumin (20 mL/kg). Intravenous sodium replacement was started according to the equation (135 - 121) 0.6 weight (kg) in 24 hours and the dose of dopamine was increased from 7.5 to 15 mcg/kg/minute in order to raise the mean blood pressure and improve renal perfusion.

Subsequently, on persistence of the oliguria, the infusion of furosemide was increased from 0.4 to 1 mg/kg/hour, though no improvement in the diuresis was achieved. The medication chart was reviewed and the error was detected. Instead of digoxin, indomethacin had been prescribed at a dose of 25 mg (10 mg/kg), which is 50 to 100 times higher than the therapeutic dose.

 What are risk factors of this patient developing acute renal failure?

What are the possible preventable human errors?

Decreased Effect Renal Blood Flow Sepsis Systemic inflammation Impaired cardiac output

Nephrotoxins Aminoglycosides Amphotericin Foscarnet Rhabdomyolysis Iodinated radiocontrast

Pre-renal Azotemia Nephrotoxic tubular injury

Ischemic tubular injury

Acute tubular necrosis

Volume

Perfusion

Microcirculation

Tissue Hypoxia Inflammation

Multi Organ Failure

Early reversal of pediatric-neonatal septic shock by community physicians is associated with improved outcome

A, Shock reversal resulted in 96% survival versus 63% survival among patients who remained in persistent shock state. B, Resuscitation consistent with the new ACCM-PALS Guidelines resulted in 92% survival versus 62% survival among patients who did not receive resuscitation consistent with the new ACCM-PALS Guidelines.

Han YY et al. Pediatrics 2003; 112: 793-799

A common adverse consequence of fluid resuscitation is fluid overload and pulmonary oedema leading to a significant reduction in lung Organ preference function and oxygenation.
Prefer the lung to the kidneys do not fill the kidneys A threshold mayexist beyond which the perceivedand flood the lungs benefit of additional fluid therapy after

resuscitation may be detrimental.

A positive cumulative fluid balance has been shown in several studies to independently predict hospital morbidity and mortality.

 Sepsis is a frequent cause of AKI in children. Sepsis increases the mortality of AKI AKI increases the mortality of sepsis More than half of children with septic AKI presents renal dysfunction at discharge and 1/3 develops abnormalities in the long term. Follow-up of these patients is recommended. Genetic risk factors may be involved in the individual susceptibility to septic AKI

Methods of Attenuating or Preventing Sepsis-Related Acute Renal Failure

Arginine vasopressin
Hydrocortisone Early directed resuscitation

Maintenance of blood glucose < 145 mg/dl (8.0 mmol/l)

Activated protein C

Schrier RW et al. NEJM 2004; 351: 159-69

 Ensure adequate renal perfusion. Avoid / minimize use of nephrotoxic drugs including radio contrast. Early recognition and aggressive management of sepsis. Early recognition and timely mangement of shock

Blood pressure Intravascular volume Cardiac output Other markers of perfusion

No drug produces a single effect!!!

Characteristic Age 0 to 3 years Male 1 to 4 additional meds 5 or more additional meds No clinic visit

Odds Ratio (95 CI)* 1.6 (1.1 to 2.5) 1.7 (1.1 to 2.4) 1.4 (1.0 to 2.0) 3.4 (1.4 to 8.0) 1.8 (1.3 to 2.6)

McPhillips et al, Journal of Pediatrics, 2005

1. Pediatric prescribing is complex

2. Off-label medication use is common 3. Lack of standardization of recommended doses

4. Lack of guidelines regarding use of adult dosing regimens

 Radiocontrast Agents

Aminoglycosides Nonsteroidal Anti-Inflammatory Drugs (NAIDs) Angiotensin-Converting Enzyme Inhibitors (ACEIs) Lithium Crystal-Induced Acute Renal Failure Calcineurin inhibitors (Cyclosporine, Tacrolimus) Amphothericin B Chemotherapy

Proximal convoluted tubule (s1/s2 segment) Aminoglycoside Cephaloridine Cadmium Cl K dichromate

Glomeruli
Interferon- Gold Penicillamine

Renal vessel
NSAIDs ACE Inhibitor

Cyclosporin A
Interstitium

Cephalosporin
Pappillae Phenacetin Cadmium NSAIDs

Acute renal failure Chronic renal failure Nephrotic syndrome (Acute/Chronic) Fluid and Electrolyte disturbances Acid-base disorders

Most episodes of drug-induced renal disorders are reversible discontinue drug renal fn. return to baseline. Chronic renal injury (due to medication) Chronic tubulointerstitial inflammation, pallillaly necrosis or prolonged proteinuria.

Amikacin Gentamicin Neomicin Netilmicin Kanamicin Streptomycin Tobramycin

[AMIKIN ] [GARAMYCIN ] [NETROMYCIN ] [KANTREX ] [TOBREX, NEBCIN ]

Lysosomal overload Inhibition of intralysosomal phospholipase activity Intralysosomal phospholipidosis Altered phosholipase signalling mechanisms PROXIMAL TUBULE NECROSIS

Related to AMG dosing Large total cumulative dose

Related to Predisposing condition in the patient Preexisting renal insufficiency Increased age Poor nutrition Shock Gram negative bactermia Liver disease Hypoalbuminemis Obstructive jaundice K+ or Mg++ deficiency

Prolong therapy
High peak or trough conc. Recent previous AMG therapy Related to synergistic nephrotoxicity

AMG combination with

Cyclosporin Amphotericin B Vancomycin Diuretics

Irreversible Damage!

Prevention
Switching to alternative antibiotics Avoid volume depletion, concomitant therapy with other nephrotoxic drugs Limit total dose

Management
Monitor Scr, concentration, renal fn and electrolytes Discontinue AMG if changes are seen.

Decreasing the frequency of AMG dosing to at least daily (as direct by renal clearance)

1. Fever is a symptom not a disease

1.

Fever is a symptom not a disease

2. A child can have meningitis with a low fever or a viral URTI with a high fever

1. 2.

Fever is a symptom not a disease A child can have meningitis with a low fever or a viral upper respiratory tract infection with a high fever

3. The difference is in how sick the child is!!

1. 2. 3.

Fever is a symptom not a disease A child can have meningitis with a low fever or a viral upper respiratory tract infection with a high fever The difference is in how sick the child is!!

4. MINIMAL CLOTHES & COOL ENVIRONMENT 5. FLUIDS

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Hemodynamically- Induced ARF

Acute Interstitial Nephropathy + Proteinuria Papillary necrosis and chronic renal failure (Analgesic nephropathy) Salt and water retention; Hyperkalemia; Hypertension

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Papillary necrosis

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Patients at risk:
Preexisting renal disease (glomerular disease nephrotic syndrome ,lupus);

Hypercalcemia;
Congestive Heart Failure, Cirrhosis, Volume depletion (vomiting, diarrhea, diuretics)

 Acyclovir (antiviral agent )

Indinavir (antiretroviral agent, protease inhibitor) Methotrexate (antineoplastic agent, antimetabolite) Sulfonamide antibiotics Triamterene

Sulfonamide crystals

Indinavir sulfate urinary crystals

Gagnon et al. 1998, Ann Intern Med 128-321

 Know the potential nephrotoxicity of drug and therapeutic pharmacologic agents. Compare the potential risks and expected benefits for each course of treatment. Consider alternative diagnostic and therapeutic approaches. Use the lowest dose and shortest course of therapy that is efficacious.

Monitor appropriately for potential toxicity.

Monitor therapy if toxicity is occurs.

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

Recognise and assess the patient at risk Avoid nephrotoxic agents Maintain effective circulatory volume Recognise and treat hypoxia Early recognition of rising BUN and Cr. Treat infection, avoid nosocomial infection Pharmacological manipulation to maintain RBF, perfusion pressure and GFR

8. Awareness of signs and symptoms of different renal

diseases for early detection and timely referral. 9. Spread of health education information to parents as regards what is normal and what is abnormal concerning their children's renal system. 10. Timely referral to a pediatric nephrologist in cases with suspected renal disease or insult