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The Importance of Residual Renal Function
Dr Paul Tam June 11, 2010
RRF, an important predictor of survival in dialysis patients Loss of RRF Inflammation Resting hypermetabolism Cardiovascular Disease Malnutrition Increased Mortality and Cardiovascular Death
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
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
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
Clearance effect on outcomes in PD Maiorca et al. (1995) Fung (1996) Davies (1998) n 68 31 210 Study Type Observational Clearence effect on outcomes Total Yes, Peritoneal Renal NE Yes Observational Observational Yes Yes, no NE NE Yes Yes Diaz-Buxo et al. (1999) 673 Observational Merkus (2000) Jager et al. (1999) Szeto et al. (1999) Szeto et al. (2000) Mak et al. (2000) Rocco et al. (2000) Szeto et al. (2001) Bargman (2001) 106 118 168 270 82 873 140 601 Observational Observational Observational Observational Interventional Observational Observational Observational NE NE NE Yes Yes Yes NE NE NE No No No NE No NE No Yes No Yes Yes Yes NE Yes NE Yes NE Yes
Patient survival Termorshuizen et al. J Am Soc Nephrol 2004 RR 95% CI Age at entry (yr) 1.03
1.02 to 1.05
Male gender Davies’ comorbidity score at entry high intermediate low Primary kidney disease diabetes glomerulonephritis renal vascular disease 0.84
4.74
2.35
1.00 ref 1.43
0.67
1.18
0.64 to 1.10
3.04 to 7.40
1.63 to 3.39
0.98 to 2.09
0.38 to 1.20
0.86 to 1.62
others Albumin baseline (for each 0.1 g/dl increase) b SGA (scale 1 –7) at baseline BMI (kg/m 2 ) Dialysis sp- rKt/V urea (L/wk)) 1.00 ref 0.98
0.89
0.96
0.76
0.95 to 1.01
0.80 to 0.99
0.93 to 0.99
0.64 to 0.92
P Value <0.0001
0.2098
<0.0001
0.0855
0.1355
0.0389
0.0252
0.0035
Residual rKt/V urea (L/wk) 0.44
0.30 to 0.65
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.
<0.0001
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) Termorshuizen, F. et al. J Am Soc Nephrol 2004
Potential mechanisms of benefit of RRF in dialysis
Effects of additional of dialysis clearences to a glomerular filtration rate of 5ml/min Solute Clearence Urea Renal
HD and renal Renal-PD and renal 4
17 4
10 Creatinine Para amino hippuric acid Inulin B2 microglobulin 6
16 20
26 5
5.4
5
5.7
6 20 5 Krediet, KI 2006
11 23 8 5
6
100 80 60 Peritoneal Renal 40 20 0 UN Cr P B2M p-cresol 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
Residual renal function
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
Wang and Lai KI 2006
Fig.
ECW in patients with rGFR <2 and >2 ml/min
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).
Konings, C. J. A. M. et al. Nephrol. Dial. Transplant. 2003 18:797-803;
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
Mean arterial pressure and RRF over time from initiation of peritoneal dialysis Menon, M. K. et al. Nephrol. Dial. Transplant. 2001 16:2207-2213;
Nutritional parameters in patients with and RRF Suda, T. et al. Nephrol. Dial. Transplant. 2000 15:396-401
Is the rate of decline of RRF between HD and PD different?
CCr ml/min 5 4.5
4 3.5
3 2.5
2 1.5
1 0.5
0 start 6 mo 12 mo 18 mo Residual renal function is preserved longer in peritoneal dialysis (PD ) Rottembourg J. Perit Dial Bull 1986 PD n:25 HD n:25
PD HD HD PD A B 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.
Jansen et al KI 2002
Decline of residual renal function is faster on HD than on PD Study Type Rottembourg Prospective HD/PD patients (n) 25/25 Difference in rate of decline 80% Lysaght et al Retrospective 57/58 Misra et al.
Retrospective 40/103 Lang Jansen et al Prospective Prospective 30/15 279/243 50% 69% 69% 24%
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
Do biocompatible PD solutions or biocompatible dialyser membranes have any advantage in relation to RRF?
The Euro-Balance Trial P Urea Cl L/day U Urea Cl L/day Kt/V P Cr Cl L/day U Cr Cl L/day T Cr Cl L/wk/1.73m
2 UF 24 hours mL U Volume mL/day D/PCr 4hrs Weight kg 1350 875 0.59
70.0
Systolic BP mm Hg Diastolic BP mm Hg 135 80 Group 1 SPDF (n = 36) 8.1
3.8
2.23
6.1
4.9
76.5) Group 1 balance (n = 36) P 7.8
NS 3.9
2.33
S NS 6.2
5.2
78.6
NS Ns NS 995 925 0.63
71.25
130 81 Group 2 balance (n = 35) 8.2
3.7
2.31
6.1
4.5
75.4
Group 2 SPDF (n = 35) P 8.4
NS 2.7
2.22
S S 5.9
3.5
67.1
NS S S S NS S NS 1025 919 0.60
78.0
1185 660 0.56
78.0
Ns 130 133 NS 80 81 Williams et al KI 2004 S S S NS NS NS
Dialysis adequacy, residual renal function and nutritional indices Control group 4 weeks 52 weeks Balance group 4 weeks 52 weeks 6.08 ± 0.40
6.42 ± 0.83
6.08 ± 0.41
6.17 ± 0.57
PD exchange volume (l/day) Glucose load (g/day) 100.9 ± 17.7 106.7 ± 24.9 100.7 ± 14.6
106.2 ± 23.7
Total Kt/V Ultrafiltration (l/day) Urine output (l/day) 2.23 ± 0.62
0.56 ± 0.69
0.90 ± 0.71
2.12 ± 0.32
0.77 ± 0.59
0.69 ± 0.52
2.28 ± 0.56 ± 0.87 ± 0.35
0.60
0.62
2.16 ± 0.56
0.83 ± 0.56
0.80 ± 0.60
Residual GFR (ml/min/1.73 m 2 ) Serum albumin (g/l) 3.67 ± 2.27
36.5 ± 4.1
2.81 ± 2.87
35.7 ± 3.2
3.91 ± 2.09
2.72 ± 2.08
32.8 ± 4.4
Szeto et al. NDT 2007 34.3 ± 4.2
Effect of biocompatible (B) vs standard (S) PD solutions on RRF (mean of urea and nCrCl)
Fan et al KI 2008
Effect of biocompatible (B) vs standard (S) PD solutions on 24-h Uvol (mean/s.e.m.).
Fan et al KI 2008
Coles et al. 1994 New multicompartmental PD fluids Pts Study Type 46 CAPD-Prosp,Rand., paral..
Month (PDF) 2 (Physioneal) RRF = Tranaeus et al 1998 Fan et al 2008 Rippe et al. 2001 106 CAPD-Prosp.,Rand., paral.
12 20 Williamset al 2004 Szeto et al. 2007 Feriani et al 1998 Haas et al.2003
86 50 30 28 ped.
APD-Prosp.,Rand., paral.
CAPD-Prosp., Rand., crossover APD-Prosp., Rand., crossover 6(Physioneal) 12(Physioneal) CAPD-Prosp.,Rand., paral.
CAPD-Prosp.,Rand., crossover,paral.
CAPD-Prosp.,Rand., paral.
24(Gambrosol trio) 6 (Balance) 12 (Balance) 6(BicaVera) 6(BicaVera) = = =
= = =
Preserving residual renal function in peritoneal dialysis: volume or biocompatibility?
Davies, Simon NDT 23, June 2009 24, 2620-2622
Majority of studies indicate RRF is relatively well preserved with PD in comparison to HD
Davies, Simon NDT 23, June 2009 24, 2620-2622
Studies Reviewed
Davies, Simon NDT 23, June 2009 24, 2620-2622
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
Low-GDP Fluid (Gambrosol Trio) Attenuates Decline of Residual Renal Function (RRF) in PD Patients: A Prospective Randomized Study
(DIUREST Study) NDT March 2010
Background
• Clinical 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 patients • Morbidity, poor nutrition & fluid overload associated with decline of RRF • Glucose degradation products (GDPs): – Affect cell system and tissues – Act as precursors of advanced glycosylation endproducts (AGEs) locally and systemically
Methods
• Study design – A Multicentre, prospective, randomized, controlled, open, parallel, 18 month study • 80 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
• Study centers in: – Germany(15) – France (7) – Austria (1) • Solutions – Treatment solution • Gambrosol trio – Control (Standard) solution: • Gambrosol (50% of patients) • Stay-safe (31% of patients) • Dianeal (19% of patients)
• Follow-up –
4 - 6 weeks
• Serum U & Cr, CRP, T. Protein, albumin, lytes, phosphate • 24 Hr. Urine: CrCl & UrCl • BP & Wt • UF –
At 1, 6, 12, 18 months
• CA125 • Personal Dialysis Capacity (PDC) Medications: • ACE & ARBs • Diuretics • Phosphate binders
Results
• Subjects 44 (Treatment: 1 was intend-to-treat) – Recruited: 80 36 (Standard) – Median exposure time: Treatment solution 17.8 m Standard solution 16.3 m – Dropout: 11 before first RRF measurement – N=69 with 2.4% /month dropout rate
Low GDP Standard P- value RRF 24 Hr. Urine Decline Phosphate Level Albumin CRP CA125 PDC Peritonitis Episode
1.5 % 4.3 % 12mL/month 38mL/month Difference: 26mL/month (0.86mL/day) Increased by 0.0135mg/dL/month ( 0.004 mmol/L ) Increased by 0.0607mg/dL/month ( 0.02 mmol/L ) Difference: 0.016 mmol/L per month 3.74 g/dL (37.4 g/L) 3.72 g/dL (37.2 g/L) 0.78 mg/dL (7.8 mg/L) 61.2U/mL 1.28 mg/dL (12.8 mg/L) 18.7U/mL 21699± 5485 cm/1.73m
2 20028±6685cm/1.73m
2 p=0.0437
p= 0.0241
p=0.0381
P=0.90
P=0.42
p<0.001
No important changes 1 per 36.4 patient months 11 of 43 (25.6%) 1 per 39.7 patient months 6 of 26 (23.7%) P= 0.815
SIG NS NS SIG NS NS
Clinical Signifi cance
SIG SIG
Clinical Significance
• RRF: Treatment group higher by 2.3 ml/min/1.73 m 2 • 24 H Urine volume: less decline in Treatment group by three-fold • Phosphate control: better in Treatment group by five-fold • CA125: higher levels in Treatment group • UF volumes not conclusive due to unreliability of data • D/P & PDC parameters no significant changes, possibly due to patient dropout & missing data
Limitations
• Inconsistency in control group (?) • Patients’ selection: incident & prevalent patients • Large dropout rate • Unreliability of data on UF & D/P properties • Consistency issue with testing of CA125 • Effects of different antihypertensive use with their potential effect on RRF
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
In HD patients
• Prevention of intradialytic
hypotensive episodes
• Developing a highly biocompatible
HD system including a synthetic membrane and ultrapure dialysis fluid.
Biocompability of dialyser membranes n Study Type Predictor Decline in RRF Caramelo et al. 1994 22 Prosp.Rand.
CPvsPAN/PS NS Van Stone. 1995 334 159 Retrosp.
CPvsPS/PMMA/C A UC vs PMMA A faster rate with CP NS Hakim et al 1996 Hartmann et al. 1997 McCarthy et al 1997 Mois et al.2000
Lang et al.2001
Jansen et al.
2002 20 100 814 30 270 Prosp.,Rand .
Prosp.,Rand .
Retrosp.
Retrosp.
Prosp.,Rand .
Prosp.
CA vs PS CA vs PS UC vsMC/synthetic CP vs PS MC vs synthetic A faster rate with CA A faster rate with CA NS A faster rate with PS NS at 3 months
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
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