Biocompatible Peritoneal Dialysis fluids

Santosh Varughese

PD through the ages

Peritoneum Greek peritonaion 1862 cellular structure of peritoneum 1st described
Friedrich Daniel von Recklinghausen

1877 - Animal experiments

Injecting solutions into rabbits! Sugar solution ultrafiltration
Wegner

PD through the ages

1894 Fluid removal by peritoneal blood vessels
Starling & Tubby

1923 1st PD
Georg Ganter

Salt soln into peritoneal cavity of lady with post-renal AKI

PD through the ages

Intermittent PD Porcelain / metal / latex / glass Catheters: metal needles polyethylene tubes side holes 1968 catheter PERMANENT access
Tenckhoff

Silicone with cuff/s Plastic bags

Oreopoulos

PD through the ages

Y-system; Double bags; flush before fill
Buoncristiani

1975 - CAPD in patients unable to undergo HD

Popovich & Moncrief

APD 40 L container Cycler

After over 4 decades of fidelity

Is the nephrologists love affair with conventional glucose based fluid over?

Conventional Fluid

Disruption of vascular BM

RAGE activation

Glucose degradation products Conventional Fluid

Mesothelial cells
Injury / apoptosis
VEGF
TGF IL-6 H2O2 / free radicles

Fibrosis / Neovascularization

Inflammation

JASN 2002

Compact submesothelial collagenous band

loose adipose connective tissue

Normal peritoneum

Chronic PD

Normal

Grade I

JASN 2002

Grade II

Grade III

Subendothelial hyaline zone

Glucose & UF failure

Systemic inflammation

Peritonitis Peritoneal inflammation

Bioincompatible PD fluid

Altered membrane transport

Increased glucose absorption

use of hypertonic fluid Osmotic gradient

UF

Adapted from Chung, et al PDI 2000

The story so far..

Key determinant of patient survival on PD is residual renal function Decline of residual renal function HD > PD Recent evidence - newer biocompatible PD fluids
neutral pH + low in GDPs

may be superior for preserving residual renal function

improved clinical outcomes

Determinants of biocompatibility
pH Buffer System Osmolality Concentration of Glucose Potential for formation of advanced glycation end products (AGE) Presence of glucose degradation products (GDPs)

Combination of these factors for a particular PD fluid defines its biocompatibility profile

Whats the difference anyway?

Randomized crossover trial 86 prevalent PD patients

Small in renal urea & creatinine clearances

Retrospective Observational Study 1162 patients

Perit Dial Int 2005; 25:248255

But.
No stratification / statistical adjustment for CVD, HTN, socioeconomic status Potential selection bias with residual confounding
Pts on Balance YOUNGER & treated at large centers

Center effect bias

25 centers exclusively contributed Balance patients 25 exclusively contributed Staysafe patients Only 33 - mixture of both

BalNet study group

91 incident CAPD pts - 12 month 48=LF (Balance) or 43=CF Non-significant slower GFR Statistically significant only after multivariable adjustment for age, sex, comorbidity& GFR at 1 month

However, peritoneal UF in
Balance group ?? volume-driven renal functional improvement

Diurest study

Multicentre, prospective, randomized, controlled, open, parallel study 80 patients low GDP fluid vs or std PD fluid Followed for 18months

Diurest study

Diurest study

But.
No information on peritoneal ultra-ltration volume Approx two-fold higher ACE inhibitor use Rx group High drop-out rates - Control > Rx group

Several RCTs - benecial / no-benefit Underpowered / short term follow-up only / high drop-out rates Poor methodologic quality / prevalent patients enrolled / single-center

Evidence-based Nephrology

AIM
Multicenter, multi-country [Aus / NZ / Singapore] Randomized Controlled Trial

Does neutral pH, low GDP dialysate better preserve residual renal function in PD patients over a 2-year period compared with conventional dialysate?

Methods
Protocol previously published Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000044527) Study protocol approved by ethics committees at all participating centers Written informed consent before trial participation

Methods
Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000044527) Study protocol approved by ethics committees at all participating centers Written informed consent before trial participation

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival Adverse events

91

91

Slopes of GFR [ml/min/1.73m2/mo] B: -0.22 S: -0.28 in the 1st year ([95% CI], -0.05 to 0.17; P=0.17) B: -0.09 S: -0.10 in the 2nd year ([95% CI], -0.18 to 0.2; P=0.9)

10 outcome
No difference in GFR

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival Adverse events

Time to Anuria
B group - 6 (7%) vs 18 (20%) in S group Time to anuria - significantly longer in B group (P=0.01)

B
S

After adjusting for diabetic nephropathy, baseline GFR & APD vs CAPD B group lower hazard of anuria (aHR 0.36; 95% CI, 0.130.96).

Time to Anuria
B group - 6 (7%) vs 18 (20%) in S group Time to anuria - significantly longer in B group (P=0.01)

After adjusting for diabetic nephropathy, baseline GFR & APD vs CAPD B group lower hazard of anuria (aHR 0.36; 95% CI, 0.130.96).

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival Adverse events

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival Adverse events

Peritonitis
Number of patients with peritonitis
B: 27 (30%; 95%CI, 20%40%) S: 45 (49%; 95%CI, 39%59%) (P=0.006)

Overall peritonitis rate [episodes per patient-year]

B: 0.30 S: 0.49 (P=0.01)

Incidence rate ratio for peritonitis B group 0.64 (95% CI, 0.420.98)
after adjustment for age, sex, BMI, DM, CVD, baseline GFR, and peritoneal transport status

Time to First Peritonitis Episode

B

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival Adverse events

Patient Survival
B: 9 patients (10%)
Cardiovascular (n=6), Infectious (n=1), others (n=2)

S: 8 (9%)
Cardiovascular (n=5), Infectious (n=1), others (n=2)

KaplanMeier analysis No survival advantage

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival Adverse events

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival ---------------Adverse events

More than just GDPs

Additional explanation for renoprotective effect reduced risk of peritonitis Numerous studies peritonitis &/or nephrotoxic antibiotics major risk factors for residual renal function

Study Outcomes
10 outcome:
Slope of decline over time of residual renal function
Arithmetic mean of 24-hour urinary urea & creatinine clearances at 0, 3, 6, 9, 12, 18, and 24 months

20 outcomes:
Time to occurrence of anuria (urine volume <100 ml/d) Indices of fluid balance
Wt, BP, urine vol, peritoneal UF vol, albumin, Hemoglobin

Peritonitis-free survival Technique survival Patient survival ---------------Adverse events

BalNet study group

91 incident CAPD pts - 12 month 48=LF (Balance) or 43=CF Non-significant slower GFR Statistically significant only after multivariable adjustment for age, sex, comorbidity& GFR at 1 month

However, peritoneal UF in
Balance group ?? volume-driven renal functional improvement

S
B

Merchant of Venice Act II:Scene VII

All that glisters is not gold;
Often have you heard that told: Many a man his life hath sold But my outside to behold: Gilded tombs do worms enfold. Had you been as wise as bold, Young in limbs, in judgment old, Your answer had not been inscroll'd: Fare you well; your suit is cold.