Download - Biocompatible PD Fluids
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Biocompatible Biocompatible Peritoneal Dialysis fluidsPeritoneal Dialysis fluids
Santosh Varughese
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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
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PD through the ages
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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
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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
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After over 4 decades of fidelity…
Is the nephrologist’s love affair with conventional glucose based fluid over?
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Conventional Fluid
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Glucose degradation products
Mesothelial cells
Injury / apoptosis
H2O2 / free radiclesIL-6
VEGFTGF β
Fibrosis / Neovascularization
RAGE activation
Disruption of vascular BM
Inflammation
Conventional Fluid
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Compact submesothelial collagenous band
loose adipose connective tissue
Normal peritoneum Chronic PD
JASN 2002
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NormalJASN 2002
Subendothelial hyaline zone
Grade I
Grade IIIGrade II
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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
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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
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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’
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What’s the difference anyway?
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Small in renal urea & creatinine clearances
Randomized crossover trial86 prevalent PD patients
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Retrospective Observational Study1162 patients
Perit Dial Int 2005; 25:248–255
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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
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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
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Diurest study
Multicentre, prospective, randomized, controlled, open, parallel study 80 patients – low GDP fluid vs or std PD fluid Followed for 18months
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Diurest study
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Diurest study
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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
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Evidence-based Nephrology
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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?”
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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
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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
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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
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91 91
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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
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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
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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
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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).
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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
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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
?
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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
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Time to First Peritonitis EpisodeB
S
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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
?
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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
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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
?
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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----------------
?
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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
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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----------------
?
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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
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B
S
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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
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