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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
Resting
hypermetabolism
Malnutrition
Inflammation
Cardiovascular
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
Interventional
Yes
NE
NE
Mak et al. (2000)
82
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 2004
RR
95% CI
Age at entry (yr)
1.03
1.02 to 1.05
Male gender
0.84
0.64 to 1.10
Davies’ comorbidity score at entry
high
intermediate
low
Primary kidney disease
diabetes
glomerulonephritis
renal vascular disease
others
Albumin baseline
(for each 0.1 g/dl
increase)b
SGA (scale 1–7) at baseline
BMI (kg/m2)
P Value
<0.0001
0.2098
4.74
2.35
1.00 ref
3.04 to 7.40
1.63 to 3.39
<0.0001
1.43
0.67
1.18
1.00 ref
0.98
0.98 to 2.09
0.38 to 1.20
0.86 to 1.62
0.0855
0.95 to 1.01
0.1355
0.89
0.96
0.80 to 0.99
0.93 to 0.99
0.0389
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
<0.0001
The residual renal function (rKt/Vurea) and dose of dialysis (sp-dKt/Vurea)
werLe included as time-dependent variables. RR, relative risk; CI, confidence interval.
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
4 17
Renal-PD and
renal
4 10
Creatinine
6 16
6 11
Para aminohippuric acid
Inulin
20 26
20 23
5 5.4
5 8
B2microglobulin
5 5.7
5 6
Krediet, KI 2006
Clearance L/w 1.73m2
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
Cardiac
hyperthyrophy
 Clearence
of urea
and
creatinine

Inflammation
 Sodium
and fluid
removal

Atherosclerosis
and
arteriosclerosis


malnutrition
P
removal
 EPO
production
 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?
5
4.5
4
3.5
3
PD n:25
HD n:25
2.5
2
CCr
ml/min
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
PD
HD
A
HD
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
HD/PD
Difference in
patients (n) 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 Trial
Group 1
SPDF (n =
36)
Group 1 P
balance
(n = 36)
Group 2
balance
(n = 35)
Group P
2 SPDF
(n = 35)
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
NS
Williams et al KI 2004
Dialysis adequacy, residual renal function and nutritional indices
Control group
4 weeks
52 weeks
6.42 ± 0.83
Balance group
4 weeks
52 weeks
PD exchange
volume (l/day)
6.08 ± 0.40
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 fluids
Pts
Study Type
46 CAPD-Prosp,Rand., paral..
Month (PDF)
2 (Physioneal)
RRF
=
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 al
1998
30
CAPD-Prosp.,
Rand., crossover
6(BicaVera)
=
28
ped.
APD-Prosp.,
Rand., crossover
6(BicaVera)
=
Coles et al. 1994
Haas et al.2003
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
Exclusion
-Age: 18-80 with ESRD
-Pregnancy or lactating subjects
-GFR ≥ 3mL/min or CrCl ≥ 6mL/min
-Several peritonitis episodes
-HBV, HCV, HIV negative
-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
Standard
P- value
Clinical
Signifi
cance
1.5 %
4.3 %
p=0.0437
SIG
12mL/month
38mL/month
p= 0.0241
SIG
p=0.0381
SIG
P=0.90
NS
P=0.42
NS
Low GDP
RRF
24 Hr. Urine Decline
Difference: 26mL/month (0.86mL/day)
Phosphate Level
Increased by 0.0135mg/dL/month
Increased by 0.0607mg/dL/month
( 0.004 mmol/L )
( 0.02 mmol/L )
Difference: 0.016 mmol/L per month
3.74 g/dL
3.72 g/dL
(37.4 g/L)
(37.2 g/L)
0.78 mg/dL
1.28 mg/dL
(7.8 mg/L)
(12.8 mg/L)
61.2U/mL
18.7U/mL
p<0.001
SIG
21699± 5485 cm/1.73m2
20028±6685cm/1.73m2
No important changes
NS
1 per 36.4 patient months
1 per 39.7 patient months
P= 0.815
NS
11 of 43 (25.6%)
6 of 26 (23.7%)
Albumin
CRP
CA125
PDC
Peritonitis Episode
Clinical Significance
• RRF: Treatment group higher by 2.3 ml/min/1.73 m2
• 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
Retrosp.
CPvsPS/PMMA/C
A
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/synthetic
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
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
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