Download - 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