The Importance of Residual Renal Function
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Transcript of The Importance of Residual Renal Function
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
MalnutritionCardiovascular
Disease
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
Clearence effect on outcomes
n Study Type Total Peritoneal
Renal
Maiorca et al. (1995)
68 Observational
Yes, NE Yes
Fung (1996) 31 Observational
Yes NE Yes
Davies (1998) 210 Observational
Yes, no
NE Yes
Diaz-Buxo et al. (1999)
673 Observational
NE No Yes
Merkus (2000) 106 Observational
NE No Yes
Jager et al. (1999) 118 Observational
NE No Yes
Szeto et al. (1999) 168 Observational
Yes NE NE
Szeto et al. (2000) 270 Observational
Yes No Yes
Mak et al. (2000) 82 Interventional
Yes NE NE
Rocco et al. (2000) 873 Observational
NE No Yes
Szeto et al. (2001) 140 Observational
NE Yes NE
Bargman (2001) 601 Observational
NE No Yes
Patient survival Termorshuizen et al. J Am Soc Nephrol 2004RR 95% CI P Value
Age at entry (yr) 1.03 1.02 to 1.05 <0.0001
Male gender 0.84 0.64 to 1.10 0.2098
Davies’ comorbidity score at entry
high 4.74 3.04 to 7.40 <0.0001
intermediate 2.35 1.63 to 3.39
low 1.00 ref
Primary kidney disease
diabetes 1.43 0.98 to 2.09 0.0855
glomerulonephritis 0.67 0.38 to 1.20
renal vascular disease 1.18 0.86 to 1.62
others 1.00 ref
Albumin baseline (for each 0.1 g/dl increase)b
0.98 0.95 to 1.01 0.1355
SGA (scale 1–7) at baseline 0.89 0.80 to 0.99 0.0389
BMI (kg/m2) 0.96 0.93 to 0.99 0.0252
Dialysis sp- rKt/Vurea (L/wk)) 0.76 0.64 to 0.92 0.0035
Residual rKt/Vurea (L/wk) 0.44 0.30 to 0.65 <0.0001The residual renal function (rKt/Vurea) and dose of dialysis (sp-dKt/Vurea)
werLe included as time-dependent variables. RR, relative risk; CI, confidence interval.
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)
Potential mechanisms of benefit of RRF in dialysis
Effects of additional of dialysis clearences to a glomerular filtration rate of 5ml/min
Solute Clearence
RenalHD and renal
Renal-PD and renal
Urea 4 17 4 10
Creatinine 6 16 6 11
Para amino-hippuric acid
20 26 20 23
Inulin 5 5.4 5 8
B2-microglobulin
5 5.7 5 6Krediet, KI 2006
0
20
40
60
80
100
UN Cr P B2M p-cresol
Cle
aran
ce L
/w 1
.73m
2
Peritoneal
Renal
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
Resting energy
expenditure
Removal of middle
moleculer uremic toxins
Toxins, such as p-cresol
Inflammation
Clearence of urea
and creatinine
Sodium and fluidremoval
P removal
EPOproduction
Cardiac hyperthyrophy
Atherosclerosis
andarteriosclerosis
malnutrition Vascular and
valvularcalcification
Overall and cardiovascular mortality
Quality of life
Residual renal function
Wang and Lai KI 2006
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 and >2 ml/min
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
Menon, M. K. et al. Nephrol. Dial. Transplant. 2001 16:2207-2213;
Mean arterial pressure and RRF over time from initiation of peritoneal dialysis
Suda, T. et al. Nephrol. Dial. Transplant. 2000 15:396-401
Nutritional parameters in patients with and RRF
Is the rate of decline of RRF between HD and PD different?
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
start 6 mo 12 mo 18 mo
PD n:25
HD n:25
Residual renal function is preserved longer in peritoneal dialysis (PD)
CCrml/min
Rottembourg J. Perit Dial Bull 1986
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
Decline of residual renal function is faster on HD than on PD
Study Type HD/PD patients (n)
Difference in rate of decline
Rottembourg Prospective 25/25 80%
Lysaght et al Retrospective 57/58 50%
Misra et al. Retrospective 40/103 69%
Lang Prospective 30/15 69%
Jansen et al Prospective 279/243 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 TrialGroup 1 SPDF (n = 36)
Group 1 balance (n = 36)
P Group 2 balance (n = 35)
Group 2 SPDF (n = 35)
P
P Urea Cl L/day 8.1 7.8 NS 8.2 8.4 NS
U Urea Cl L/day 3.8 3.9 S 3.7 2.7 S
Kt/V 2.23 2.33 NS 2.31 2.22 S
P Cr Cl L/day 6.1 6.2 NS 6.1 5.9 NS
U Cr Cl L/day 4.9 5.2 Ns 4.5 3.5 S
T Cr Cl L/wk/1.73m2
76.5) 78.6 NS 75.4 67.1 S
UF 24 hours mL 1350 995 S 1025 1185 S
U Volume mL/day 875 925 NS 919 660 S
D/PCr 4hrs 0.59 0.63 S 0.60 0.56 S
Weight kg 70.0 71.25 NS 78.0 78.0 NS
Systolic BP mm Hg 135 130 Ns 130 133 NS
Diastolic BP mm Hg 80 81 NS 80 81 NSWilliams et al KI 2004
Dialysis adequacy, residual renal function and nutritional indices
Control group Balance group4 weeks 52 weeks 4 weeks 52 weeks
PD exchange volume (l/day)
6.08 ± 0.40 6.42 ± 0.83 6.08 ± 0.41 6.17 ± 0.57
Glucose load (g/day)
100.9 ± 17.7 106.7 ± 24.9 100.7 ± 14.6 106.2 ± 23.7
Total Kt/V 2.23 ± 0.62 2.12 ± 0.32 2.28 ± 0.35 2.16 ± 0.56
Ultrafiltration (l/day)
0.56 ± 0.69 0.77 ± 0.59 0.56 ± 0.60 0.83 ± 0.56
Urine output (l/day) 0.90 ± 0.71 0.69 ± 0.52 0.87 ± 0.62 0.80 ± 0.60
Residual GFR (ml/min/1.73 m2)
3.67 ± 2.27 2.81 ± 2.87 3.91 ± 2.09 2.72 ± 2.08
Serum albumin (g/l) 36.5 ± 4.1 35.7 ± 3.2 32.8 ± 4.4 34.3 ± 4.2
Szeto et al. NDT 2007
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
New multicompartmental PD fluidsPts Study Type Month (PDF) RR
FColes et al. 1994
46
CAPD-Prosp,Rand., paral..
2 (Physioneal)
=
Tranaeus et al 1998
106
CAPD-Prosp.,Rand., paral.
6(Physioneal)
=
Fan et al 2008 12 APD-Prosp.,Rand., paral.
12(Physioneal)
=
Rippe et al. 2001
20 CAPD-Prosp.,Rand., paral.
24(Gambrosol trio)
=
Williamset al 2004
86 CAPD-Prosp.,Rand., crossover,paral.
6 (Balance)
Szeto et al. 2007
50 CAPD-Prosp.,Rand., paral.
12 (Balance) =
Feriani et al1998
30 CAPD-Prosp.,Rand., crossover
6(BicaVera) =
Haas et al.2003
28 ped.
APD-Prosp.,Rand., crossover
6(BicaVera) =
Preserving residual renal function in peritoneal dialysis: volume or biocompatibility?
Davies, Simon NDT 23, June 200924, 2620-2622
Majority of studies indicate RRF is relatively well preserved with PD in comparison to HD
Davies, Simon NDT 23, June 200924, 2620-2622
Davies, Simon NDT 23, June 200924, 2620-2622
Studies Reviewed
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 200924, 2620-2622
Low-GDP Fluid (Gambrosol Low-GDP Fluid (Gambrosol Trio) Attenuates Decline of Trio) Attenuates Decline of Residual Renal Function Residual Renal Function (RRF) in PD Patients: A (RRF) in PD Patients: A
Prospective Randomized Prospective Randomized StudyStudy
(DIUREST Study)(DIUREST Study)NDT March 2010NDT March 2010
BackgroundBackground
• Clinical study in PD patients regarding content of GDP Clinical study in PD patients regarding content of GDP on PD fluid and its influence on the decline of RRFon 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 Morbidity, poor nutrition & fluid overload associated with decline of RRFdecline of RRF
• Glucose degradation products (GDPs):Glucose degradation products (GDPs):– Affect cell system and tissuesAffect cell system and tissues– Act as precursors of advanced glycosylation endproducts Act as precursors of advanced glycosylation endproducts
(AGEs) locally and systemically (AGEs) locally and systemically
MethodsMethods• Study designStudy design
– A Multicentre, prospective, randomized, controlled, A Multicentre, prospective, randomized, controlled, open, parallel, 18 month studyopen, parallel, 18 month study
• 80 patients randomized 80 patients randomized – through stratification for the presence of diabetesthrough 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:Study centers in:– Germany(15)Germany(15)– France (7)France (7)– Austria (1)Austria (1)
• SolutionsSolutions– Treatment solutionTreatment solution
• Gambrosol trioGambrosol trio– Control (Standard) solution: 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)
• Follow-upFollow-up
– 4 - 6 weeks4 - 6 weeks• Serum U & Cr, CRP, T. Protein, albumin, lytes, Serum U & Cr, CRP, T. Protein, albumin, lytes,
phosphatephosphate• 24 Hr. Urine: CrCl & UrCl24 Hr. Urine: CrCl & UrCl• BP & WtBP & Wt• UFUF
– At 1, 6, 12, 18 monthsAt 1, 6, 12, 18 months• CA125CA125• Personal Dialysis Capacity (PDC)Personal Dialysis Capacity (PDC)
Medications:Medications:• ACE & ARBsACE & ARBs• DiureticsDiuretics• Phosphate bindersPhosphate binders
ResultsResults
• SubjectsSubjects
44 (Treatment: 1 was intend-to-treat)44 (Treatment: 1 was intend-to-treat)
– Recruited: 80Recruited: 80
36 (Standard)36 (Standard)
– Median exposure time: Treatment solution 17.8 mMedian exposure time: Treatment solution 17.8 m
Standard solution 16.3 mStandard solution 16.3 m
– Dropout: 11 before first RRF measurementDropout: 11 before first RRF measurement
– N=69 with 2.4% /month dropout rate N=69 with 2.4% /month dropout rate
Low GDP Standard P- valueClinical
Significance
RRF 1.5 % 4.3 % p=0.0437 SIG
24 Hr. Urine Decline
12mL/month 38mL/month
p= 0.0241 SIGDifference: 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
Albumin3.74 g/dL
(37.4 g/L)
3.72 g/dL
(37.2 g/L)P=0.90 NS
CRP0.78 mg/dL
(7.8 mg/L)
1.28 mg/dL
(12.8 mg/L)P=0.42 NS
CA125 61.2U/mL 18.7U/mL p<0.001 SIG
PDC 21699± 5485 cm/1.73m2 20028±6685cm/1.73m2 No important changes NS
Peritonitis Episode1 per 36.4 patient months
11 of 43 (25.6%)
1 per 39.7 patient months
6 of 26 (23.7%)P= 0.815 NS
Clinical SignificanceClinical Significance
• RRF: Treatment group higher by 2.3 ml/min/1.73 mRRF: Treatment group higher by 2.3 ml/min/1.73 m22 • 24 H Urine volume: less decline in Treatment group by 24 H Urine volume: less decline in Treatment group by
three-foldthree-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 D/P & PDC parameters no significant changes, possibly
due to patient dropout & missing datadue to patient dropout & missing data
LimitationsLimitations
• Inconsistency in control group (?)Inconsistency in control group (?)
• Patients’ selection: incident & prevalent Patients’ selection: incident & prevalent patients 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 Effects of different antihypertensive use with their potential effect on RRFwith 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 Retrosp. CPvsPS/PMMA/CA
A faster rate with CP
Hakim et al 1996
159 Prosp.,Rand.
UC vs PMMA NS
Hartmann et al. 1997
20 Prosp.,Rand.
CA vs PS A faster rate with CA
McCarthy et al 1997
100 Retrosp. CA vs PS A faster rate with CA
Mois et al.2000
814 Retrosp. UC vsMC/synthet
ic
NS
Lang et al.2001
30 Prosp.,Rand.
CP vs PS A faster rate with PS
Jansen et al. 2002
270 Prosp. MC vs synthetic
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
ConclusionThe 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
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.
Questions? Comments?
Thank You