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