biocompatible pd fluids

Biocompatible Biocompatible Peritoneal Dialysis fluidsPeritoneal Dialysis fluids

Santosh Varughese

PD through the ages

Peritoneum – Greek peritonaion1862 – cellular structure of peritoneum 1st described

Friedrich Daniel von Recklinghausen

1877 - Animal experimentsInjecting solutions into rabbits!Sugar solution ultrafiltration

Wegner

PD through the ages

PD through the ages

Intermittent PDPorcelain / metal / latex / glassCatheters:

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 fillBuoncristiani

1975 - CAPD in patients unable to undergo HDPopovich & Moncrief

APD – 40 L container Cycler

After over 4 decades of fidelity…

Is the nephrologist’s love affair with conventional glucose based fluid over?

Conventional Fluid

Glucose degradation products

Mesothelial cells

Injury / apoptosis

H2O2 / free radiclesIL-6

VEGFTGF β

Fibrosis / Neovascularization

RAGE activation

Disruption of vascular BM

Inflammation

Conventional Fluid

Compact submesothelial collagenous band

loose adipose connective tissue 

Normal peritoneum Chronic PD

JASN 2002

NormalJASN 2002

Subendothelial hyaline zone

Grade I

Grade IIIGrade II

Peritonitis

Increased glucoseabsorption

Osmotic gradient use of

hypertonic fluid

UF

Systemic inflammation

Altered membrane transport

Peritonealinflammation

Adapted from Chung, et al PDI 2000

Glucose & UF failure

Bioincompatible PD fluid

The story so far…..

Key determinant of patient survival on PD is residual renal function

Decline of residual renal function – HD > PDRecent 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 (GDP’s)

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

What’s the difference anyway?

Small in renal urea & creatinine clearances

Randomized crossover trial86 prevalent PD patients

Retrospective Observational Study1162 patients

Perit Dial Int 2005; 25:248–255

But….

No stratification / statistical adjustment for CVD, HTN, socio-economic status

Potential selection bias with residual confounding Pts on Balance YOUNGER & treated at large centers

Center effect bias25 centers exclusively contributed Balance patients25 exclusively contributed Staysafe patientsOnly 33 - mixture of both

91 incident CAPD pts - 12 month 48=LF (Balance) or 43=CF Non-significant slower GFR Statistically significant only aftermultivariable adjustment for age, sex,

comorbidity& GFR at 1 month

BalNet study group

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-filtration volume

Approx two-fold higher ACE inhibitor use – Rx group

High drop-out rates - Control > Rx group

Several RCTs - beneficial / 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 publishedRegistered with the Australian New Zealand Clinical

Trials Registry (ACTRN12606000044527)Study protocol approved by ethics committees at all

participating centersWritten 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 survivalTechnique survivalPatient survivalAdverse events

91 91

10 outcome

No difference in GFR

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

B: -0.09S: -0.10 in the 2nd year ([95% CI], -0.18 to 0.2; P=0.9)

B

S

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 survivalTechnique survivalPatient survivalAdverse events

Time to Anuria

B group - 6 (7%) vs 18 (20%) in S groupTime 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, 0.13–0.96).

B

S

Time to Anuria

B group - 6 (7%) vs 18 (20%) in S groupTime 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, 0.13–0.96).

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 survivalTechnique survivalPatient survivalAdverse 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 survivalTechnique survivalPatient survivalAdverse events

?

PeritonitisNumber 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, 0.42–0.98)after adjustment for age, sex, BMI, DM, CVD, baseline GFR,

and peritoneal transport status

Time to First Peritonitis EpisodeB

S

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 survivalTechnique survivalPatient survivalAdverse 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)

Kaplan–Meier 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 survivalTechnique survivalPatient survivalAdverse 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 survivalTechnique survivalPatient survivalAdverse 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 survivalTechnique survivalPatient survivalAdverse events----------------

?

91 incident CAPD pts - 12 month 48=LF (Balance) or 43=CF Non-significant slower GFR Statistically significant only aftermultivariable adjustment for age, sex,

comorbidity& GFR at 1 month

BalNet study group

However, peritoneal UF in

Balance group

?? volume-driven renal

functional improvement

B

S

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 soldBut 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.

Thank

you