1. The Importance of Residual Renal Function Dr Paul Tam June 11, 2010

2. RRF, an important predictor of survival in dialysis patients Loss of RRF Inflammation Resting hypermetabolism Malnutrition Cardiovascular Disease Increased Mortality and Cardiovascular Death

3. Importance of RRF Average GFR at dialysis initiation : 6.6 to 8.0 ml/min (USRDS 99 Annual Data Report Each 1ml/min of residual renal GFR translate into CCr of 10 L/Week and Kt/v urea of 0.25 to 0.3/Week (70kg male) Improved clinical outcomes with better small solute clearences

4. Importance of RRF Reanalysis of CANUSA study: For each 5L/wk/1.7.73 m increment in GFR; there was 12% decrease in RR of death. (RR0.88; Cl 0.83-0.94) No association with peritoneal creatinine clearance (RR 1.0, Cl 0.9-1.10) Peritoneal and renal clearance not equivalent 24 h urine volume is even more important than GFR (250ml/day 36% in RR of deaths) Bargman et al. J am Soc Nephrol 12:2158-2158-2162, 2001

5. ADEquacy of Peritoneal Dialysis in MEXico (ADEMEX) study Residual renal and peritoneal dialysis clearance are not equivalent and thus not simply additive. Increasing peritoneal solute clearence showed no beneficial effect on survival in PD patients. Residual renal function was predictive of outcome. Paniagua et al. Am Soc Nephrol, 2002

6. Clearance effect on outcomes in PD Clearence effect on outcomes nStudy TypeTotalPeritonealRenal Maiorca et al. (1995) 68ObservationalYes,NEYes Fung (1996) 31ObservationalYesNEYes Davies (1998)210ObservationalYes, noNEYes Diaz-Buxo et al. (1999)673ObservationalNENoYes Merkus (2000)106ObservationalNENoYes Jager et al. (1999)118ObservationalNENoYes Szeto et al. (1999)168ObservationalYesNE Szeto et al. (2000)270ObservationalYesNoYes Mak et al. (2000) 82InterventionalYesNE Rocco et al. (2000)873ObservationalNENoYes Szeto et al. (2001)140ObservationalNEYesNE Bargman (2001)601ObservationalNENoYes

7. Patient survival Termorshuizen et al. J Am Soc Nephrol 2004 RR95% CIP Value Age at entry (yr)1.031.02 to 1.05<0.0001 Male gender0.840.64 to 1.100.2098 Davies’ comorbidity score at entry high 4.743.04 to 7.40<0.0001 intermediate2.351.63 to 3.39 low 1.00 ref Primary kidney disease diabetes 1.43 0.98 to 2.090.0855 glomerulonephritis0.670.38 to 1.20 renal vascular disease1.180.86 to 1.62 others1.00 ref Albumin baseline (for each 0.1 g/dl increase) b 0.980.95 to 1.010.1355 SGA (scale 1–7) at baseline0.890.80 to 0.990.0389 BMI (kg/m 2 )0.960.93 to 0.990.0252 Dialysis sp- rKt/V urea (L/wk))0.76 0.64 to 0.92 0.0035 Residual rKt/V urea (L/wk)0.440.30 to 0.65<0.0001 The residual renal function (rKt/V urea ) and dose of dialysis (sp-dKt/V urea ) werLe included as time-dependent variables. RR, relative risk; CI, confidence interval.

8. Termorshuizen, F. et al. J Am Soc Nephrol 2004 The effect of single-pool Kt/Vurea (sp-dKt/Vurea) on mortality by presence of residual renal function (rKt/Vurea = 0 ["anurics'" versus rKt/Vurea >0)

9. Potential mechanisms of benefit of RRF in dialysis

10. Effects of additional of dialysis clearences to a glomerular filtration rate of 5ml/min Solute Clearence Renal  HD and renal Renal-PD and renal Urea 4  174  10 Creatinine 6  166  11 Para amino- hippuric acid 20  2620  23 Inulin 5  5.45  8 B2- microglobulin 5  5.75  6 Krediet, KI 2006

11. Peritoneal, renal, and total clearances of urea nitrogen (UN), creatinine (Cr), phosphate (P),  2 -microglobulin ( B2M), and p-cresol. Bammens et al. Kidney International (2003) 64, 2238–2243

12.  Resting energy expenditure  Removal of middle moleculer uremic toxins Toxins, such as p-cresol  Inflammation  Clearence of urea and creatinine  Sodium and fluid removal  P removal  EPO production  Cardiac hyperthyrophy  Atherosclerosis and arteriosclerosis  malnutrition  Vascular and valvular calcification  Overall and cardiovascular mortality  Quality of life  Residual renal function Wang and Lai KI 2006

13. Konings, C. J. A. M. et al. Nephrol. Dial. Transplant. 2003 18:797-803; ECW:extracellular volume determined by bromide dilution, corrected for height. the 25th–75th percentile range (line across box=median). Capped bars: minimum and maximal values (with exception of outliers). Fig. ECW in patients with rGFR 2 ml/min

14. Left Ventricular Mass in Chronic Kidney Disease and ESRD “A new paradigm of therapy for CKD and ESRD that places prevention and reversal of LVH and cardiac fibrosis as a high priority is needed.” Richard J. Glassock et al, CJASN 4: s79-91s

15. Menon, M. K. et al. Nephrol. Dial. Transplant. 2001 16:2207-2213; Mean arterial pressure and RRF over time from initiation of peritoneal dialysis

16. Suda, T. et al. Nephrol. Dial. Transplant. 2000 15:396-401 Nutritional parameters in patients with and RRF

17. Is the rate of decline of RRF between HD and PD different?

18. Residual renal function is preserved longer in peritoneal dialysis (PD) CCr ml/min Rottembourg J. Perit Dial Bull 1986

19. Figure:Unadjusted (A) and adjusted (B) residual glomerular filtration rate (rGFR) values SE at the start of dialysis treatment, and at 3, 6 and 12 months after the start of dialysis treatment. PD HD PD HD A B Jansen et al KI 2002

20. Decline of residual renal function is faster on HD than on PD StudyTypeHD/PD patients (n) Difference in rate of decline RottembourgProspective25/2580% Lysaght et alRetrospective57/5850% Misra et al.Retrospective40/10369% LangProspective30/1569% Jansen et alProspective279/24324%

21. Does PD have a protective effect on RRF? Less abrupt fluctuations in volume and osmotic load in PD Intradialytic hypotension and volume fluctations in HD Patients on PD are in slightly volume-expanded state Bioincompatible membranes in HD PD might delay the progression of advanced renal failure

23. Do biocompatible PD solutions or biocompatible dialyser membranes have any advantage in relation to RRF?

24. The Euro-Balance Trial Group 1 SPDF (n = 36) Group 1 balance (n = 36) PGroup 2 balance (n = 35) Group 2 SPDF (n = 35) P P Urea Cl L/day8.17.8NS8.28.4NS U Urea Cl L/day3.83.9S3.72.7S Kt/V2.232.33NS2.312.22S P Cr Cl L/day6.16.2NS6.15.9NS U Cr Cl L/day4.95.2Ns4.53.5S T Cr Cl L/wk/1.73m 2 76.5)78.6NS75.467.1S UF 24 hours mL1350995S10251185S U Volume mL/day875925NS919660S D/PCr 4hrs0.590.63S0.600.56S Weight kg70.071.25NS78.0 NS Systolic BP mm Hg 135130Ns130133NS Diastolic BP mm Hg 8081NS8081NS Williams et al KI 2004

25. Dialysis adequacy, residual renal function and nutritional indices Control groupBalance group 4 weeks52 weeks4 weeks 52 weeks PD exchange volume (l/day) 6.08 ± 0.406.42 ± 0.836.08 ± 0.416.17 ± 0.57 Glucose load (g/day) 100.9 ± 17.7106.7 ± 24.9100.7 ± 14.6106.2 ± 23.7 Total Kt/V2.23 ± 0.622.12 ± 0.322.28 ± 0.352.16 ± 0.56 Ultrafiltration (l/day)0.56 ± 0.690.77 ± 0.590.56 ± 0.600.83 ± 0.56 Urine output (l/day)0.90 ± 0.710.69 ± 0.520.87 ± 0.620.80 ± 0.60 Residual GFR (ml/min/1.73 m 2 ) 3.67 ± 2.272.81 ± 2.873.91 ± 2.092.72 ± 2.08 Serum albumin (g/l)36.5 ± 4.135.7 ± 3.232.8 ± 4.434.3 ± 4.2 Szeto et al. NDT 2007

26. Effect of biocompatible (B) vs standard (S) PD solutions on RRF (mean of urea and nCrCl) Fan et al KI 2008

27. Effect of biocompatible (B) vs standard (S) PD solutions on 24-h Uvol (mean/s.e.m.). Fan et al KI 2008

28. New multicompartmental PD fluids PtsStudy TypeMonth (PDF) RRF Coles et al. 1994 46CAPD-Prosp,Rand., paral..2 (Physioneal) = Tranaeus et al 1998 106CAPD-Prosp.,Rand., paral. 6(Physioneal) = Fan et al 200812APD-Prosp.,Rand., paral. 12(Physioneal) = Rippe et al. 200120CAPD-Prosp.,Rand., paral. 24(Gambrosol trio) = Williamset al 2004 86 CAPD-Prosp.,Rand., crossover,paral. 6 (Balance)  Szeto et al. 200750CAPD-Prosp.,Rand., paral.12 (Balance) = Feriani et al 1998 30 CAPD-Prosp., Rand., crossover 6(BicaVera) = Haas et al.200328 ped. APD-Prosp., Rand., crossover 6(BicaVera) =

29. Preserving residual renal function in peritoneal dialysis: volume or biocompatibility? Davies, Simon NDT 23, June 2009 24, 2620-2622

30. Majority of studies indicate RRF is relatively well preserved with PD in comparison to HD Davies, Simon NDT 23, June 2009 24, 2620-2622

31. Davies, Simon NDT 23, June 2009 24, 2620-2622 Studies Reviewed

32. Hypothesis???? Relative stability of volume in PD, where as HD fluctuations in volume are common Biocompatibility of the dialysis fluids “The new biocompatible solutions may help preserve RRF, but the mechanisism is not certain and an inadvert effect on fluid status seems likely – at least in some of the studies.” Davies, Simon NDT 23, June 2009 24, 2620-2622

33. Low-GDP Fluid (Gambrosol Trio) Attenuates Decline of Residual Renal Function (RRF) in PD Patients: A Prospective Randomized Study (DIUREST Study) NDT March 2010

34. Background Clinical study in PD patients regarding content of GDP on PD fluid and its influence on the decline of RRFClinical study in PD patients regarding content of GDP on PD fluid and its influence on the decline of RRF RRF impacts outcome & survival of PD patientsRRF impacts outcome & survival of PD patients Morbidity, poor nutrition & fluid overload associated with decline of RRFMorbidity, poor nutrition & fluid overload associated with decline of RRF Glucose degradation products (GDPs):Glucose degradation products (GDPs): –Affect cell system and tissues –Act as precursors of advanced glycosylation endproducts (AGEs) locally and systemically

35. Methods Study designStudy design –A Multicentre, prospective, randomized, controlled, open, parallel, 18 month study 80 patients randomized80 patients randomized –through stratification for the presence of diabetes Inclusion -Age: 18-80 with ESRD -GFR ≥ 3mL/min or CrCl ≥ 6mL/min -HBV, HCV, HIV negative Exclusion -Pregnancy or lactating subjects -Several peritonitis episodes -Cancer

36. Study centers in:Study centers in: –Germany(15) –France (7) –Austria (1) SolutionsSolutions –Treatment solution Gambrosol trioGambrosol trio –Control (Standard) solution: Gambrosol (50% of patients)Gambrosol (50% of patients) Stay-safe (31% of patients)Stay-safe (31% of patients) Dianeal (19% of patients)Dianeal (19% of patients)

37. Follow-upFollow-up –4 - 6 weeks Serum U & Cr, CRP, T. Protein, albumin, lytes, phosphateSerum U & Cr, CRP, T. Protein, albumin, lytes, phosphate 24 Hr. Urine: CrCl & UrCl24 Hr. Urine: CrCl & UrCl BP & WtBP & Wt UFUF –At 1, 6, 12, 18 months CA125CA125 Personal Dialysis Capacity (PDC)Personal Dialysis Capacity (PDC)Medications: ACE & ARBsACE & ARBs DiureticsDiuretics Phosphate bindersPhosphate binders

39. Results SubjectsSubjects 44 (Treatment: 1 was intend-to-treat) –Recruited: 80 36 (Standard) –Median exposure time: Treatment solution 17.8 m Standard solution 16.3 m Standard solution 16.3 m – Dropout: 11 before first RRF measurement –N=69 with 2.4% /month dropout rate

41. Low GDPStandardP- value Clinical Signifi cance RRF1.5 %4.3 %p=0.0437SIG 24 Hr. Urine Decline 12mL/month38mL/month p= 0.0241SIG Difference: 26mL/month (0.86mL/day) Phosphate Level Increased by 0.0135mg/dL/month ( 0.004 mmol/L ) Increased by 0.0607mg/dL/month ( 0.02 mmol/L ) p=0.0381 SIG Difference: 0.016 mmol/L per month Albumin 3.74 g/dL (37.4 g/L) 3.72 g/dL (37.2 g/L) P=0.90NS CRP 0.78 mg/dL (7.8 mg/L) 1.28 mg/dL (12.8 mg/L) P=0.42NS CA12561.2U/mL18.7U/mLp<0.001SIG PDC21699± 5485 cm/1.73m 2 20028±6685cm/1.73m 2 No important changesNS Peritonitis Episode 1 per 36.4 patient months 11 of 43 (25.6%) 1 per 39.7 patient months 6 of 26 (23.7%) P= 0.815NS

42. Clinical Significance RRF: Treatment group higher by 2.3 ml/min/1.73 m 2RRF: Treatment group higher by 2.3 ml/min/1.73 m 2 24 H Urine volume: less decline in Treatment group by three-fold24 H Urine volume: less decline in Treatment group by three-fold Phosphate control: better in Treatment group by five-foldPhosphate control: better in Treatment group by five-fold CA125: higher levels in Treatment groupCA125: higher levels in Treatment group UF volumes not conclusive due to unreliability of dataUF volumes not conclusive due to unreliability of data D/P & PDC parameters no significant changes, possibly due to patient dropout & missing dataD/P & PDC parameters no significant changes, possibly due to patient dropout & missing data

43. Limitations Inconsistency in control group (?)Inconsistency in control group (?) Patients’ selection: incident & prevalent patientsPatients’ selection: incident & prevalent patients Large dropout rateLarge dropout rate Unreliability of data on UF & D/P propertiesUnreliability of data on UF & D/P properties Consistency issue with testing of CA125Consistency issue with testing of CA125 Effects of different antihypertensive use with their potential effect on RRFEffects of different antihypertensive use with their potential effect on RRF

44. Strategies for preservation of RRF Avoidance of hypovolemia Avoidance of potentially nephrotoxic drugs The use of high dose of loop diuretics The use of an ACE inhibitor or A-II reseptor antogonist Starting dialysis with PD

45. In HD patients Prevention of intradialytic hypotensive episodes Developing a highly biocompatible HD system including a synthetic membrane and ultrapure dialysis fluid.

46. Biocompability of dialyser membranes nStudy TypePredictorDecline in RRF Caramelo et al. 1994 22Prosp.Rand.CPvsPAN/PSNS Van Stone. 1995 334Retrosp.CPvsPS/PMMA/C A A faster rate with CP Hakim et al 1996 159Prosp.,Rand. UC vs PMMANS Hartmann et al. 1997 20Prosp.,Rand. CA vs PSA faster rate with CA McCarthy et al 1997 100Retrosp.CA vs PSA faster rate with CA Mois et al.2000814Retrosp.UC vsMC/synthetic NS Lang et al.200130Prosp.,Rand. CP vs PSA faster rate with PS Jansen et al. 2002 270Prosp.MC vs syntheticNS at 3 months

47. In PD patients Prevention of hypotension and fluid volume depletion Optimization of blood pressure control Usage of biocompatible and smoother ultrafiltration profile Preservation of peritoneal permeability capacity Prevention of peritoneal dialysis-related peritonitis

48. Conclusion The potential benefits of RRF Better clearence of middle and larger molecular weights toxins, Better volume and blood pressure control Improved appetite and nutritional status Relative preservation of renal endocrine functions Improved phosphate control Improved quality of life

49. Conclusion Beneficial effect of RRF has been reported both in PD or HD patients. One potential strategy to preserve RRF may be to preferentially use PD over HD in incident patients with RRF.

50. Questions? Comments? Thank You