Proteinuria as a surrogate Proteinuria as a surrogate outcome in CKDoutcome in CKD

UKPDSUKPDS

Rudy BilousRudy Bilous

Middlesbrough, UKMiddlesbrough, UK

UKPDS - DefinitionsUKPDS - Definitions

Microalbuminuria (MAU)Microalbuminuria (MAU) > 50 mg/L> 50 mg/L Clinical Proteinuria (CP)Clinical Proteinuria (CP) >300 mg/L>300 mg/L Spot urine sample annuallySpot urine sample annually Albumin concentration (ACR not reported)Albumin concentration (ACR not reported) Immunoturbidimetry 1988 (RIA previous)Immunoturbidimetry 1988 (RIA previous) Lower limit 2 mg/L Lower limit 2 mg/L CV 3.1 – 6.5% over range 4.4–136.7 mg/LCV 3.1 – 6.5% over range 4.4–136.7 mg/L

UKPDS - OutcomesUKPDS - Outcomes

Fatal / non fatal renal failure Fatal / non fatal renal failure (plasma creatinine > 250 (plasma creatinine > 250 M and/or RRT)M and/or RRT)

Aggregate microvascular (above +/or vitreous Aggregate microvascular (above +/or vitreous haemorrhage +/or photocoagulation.)haemorrhage +/or photocoagulation.)

Surrogate endpoints Surrogate endpoints (new MAU, CP, doubling plasma creatinine)(new MAU, CP, doubling plasma creatinine)

Latterly estimated creatinine clearance Latterly estimated creatinine clearance (eCrCl – CG formula) < 60 ml/min/1.73m(eCrCl – CG formula) < 60 ml/min/1.73m22

Reported per triennium, or B/L to year, or event Reported per triennium, or B/L to year, or event rate per number at a given time pointrate per number at a given time point

UKPDS OutcomesUKPDS Outcomes

No impact on primary renal outcomes of No impact on primary renal outcomes of either intensive glycaemic or tight blood either intensive glycaemic or tight blood pressure controlpressure control

Combined microvascular outcome heavily Combined microvascular outcome heavily weighted by photocoagulationweighted by photocoagulation

UKPDS Patient Randomisation for Glycaemic Control Study

Lancet 1998; 352 : 837-53

Glycaemic Control Trial 1Glycaemic Control Trial 1

ConventionalConventional

N = 1138N = 1138

IntensiveIntensive

N = 2729N = 2729

Baseline MAUBaseline MAU

UAC > 50mg/LUAC > 50mg/L

UncorrectedUncorrected

12.4 %12.4 %

(127)(127)

11.3 %11.3 %

(273)(273)

Baseline CPBaseline CP

UAC > 300mg/LUAC > 300mg/L

UncorrectedUncorrected

2.1 %2.1 %

(21)(21)

1.7 %1.7 %

(40)(40)

Glycaemic Control Trial 2Glycaemic Control Trial 2Conv’lConv’l IntensiveIntensive RRRR pp

HbA1c HbA1c Median Median 10y10y

7.9 %7.9 % 7.0 %7.0 % -- < 0.0001< 0.0001? t test? t test

Microvascular Microvascular endpointsendpoints

8.68.61000 pt yrs1000 pt yrs

11.411.41000 pt yrs1000 pt yrs

0.750.75(0.60-0.93)#(0.60-0.93)#

< 0.01< 0.01Log rankLog rank

MAU 9 y % MAU 9 y % ( number)( number)

25.4%25.4%(183/721)(183/721)

19.2%19.2%(338/1759)(338/1759)

0.760.76(0.62-0.91)*(0.62-0.91)*

< 0.001< 0.00122

CP 9 y %CP 9 y %(number)(number)

6.5%6.5%(47/721)(47/721)

4.4%4.4%(77/1759)(77/1759)

0.670.67(0.42-1.07)*(0.42-1.07)*

< 0.03< 0.0322

x2 PCr 0 -9y% x2 PCr 0 -9y% (number)(number)

1.76%1.76%(11/625)(11/625)

0.71%0.71%(11/1547)(11/1547)

0.400.40(0.14-1.20)*(0.14-1.20)*

< 0.03< 0.0322

(# 95 % CI ; * 99 % CI)x2PCr = doubling plasma creatinine

Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

UKPDS Patient Randomisation to BP Study

Blood Pressure Trial 1Blood Pressure Trial 1

Less TightLess Tight

<180/105mmHg<180/105mmHg

N = 390N = 390

TightTight

<150/85 mmHg<150/85 mmHg

N = 758N = 758

Baseline MAUBaseline MAU

UAC > 50 mg/LUAC > 50 mg/L

CorrectedCorrected

16 %16 %

(53)(53)

18 %18 %

(114)(114)

Baseline CPBaseline CP

UAC >300 mg/LUAC >300 mg/L

CorrectedCorrected

4 %4 %

(13)(13)

3 %3 %

(18)(18)

UAC corrected to urine creatinine concentration of 8mM

Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

Achieved Blood Pressure in UKPDS BP Study

Blood Pressure Trial 2Blood Pressure Trial 2Less TightLess Tight TightTight RRRR pp

Mean BP 6yMean BP 6y(estimated)(estimated)

156 / 85156 / 85mmHgmmHg

142 / 80142 / 80mmHgmmHg

-- < 0.0001< 0.0001? t test? t test

Microvascular Microvascular endpointsendpoints

19.219.21000 pt yrs1000 pt yrs

12.012.01000 pt yrs1000 pt yrs

0.630.63(0.44-0.89)#(0.44-0.89)#

< 0.01< 0.01? test? test

MAU 6 y % MAU 6 y % ( number)( number)

28.5%28.5%(78/274)(78/274)

20.3%20.3%(110/543)(110/543)

0.710.71(0.51-0.99)*(0.51-0.99)*

< 0.01< 0.01? ? testtest

CP 6 y %CP 6 y %(number)(number)

8.6%8.6%(24/274)(24/274)

5.3%5.3%(29/543)(29/543)

0.610.61(0.31-1.21)*(0.31-1.21)*

0.060.06? ? testtest

x2 PCr 9y %x2 PCr 9y % NSNS NSNS

(# 95 % CI ; * 99 % CI)

Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317:703-713

Surrogate outcomes in UKPDS BP Study

UKPDS Progression 1UKPDS Progression 1 5097 at baseline5097 at baseline 4727 (92.7%) 4727 (92.7%) No nephropathy No nephropathy 333 (6.5 %) 333 (6.5 %) MAU MAU (UAC > 50 mg/L)(UAC > 50 mg/L) 37 (0.7 %) 37 (0.7 %) CP CP (UAC > 300 mg/L)(UAC > 300 mg/L) At 10.4 yrs median follow up :At 10.4 yrs median follow up : 867867 MAUMAU 264264 CPCP 7171 Plasma Creatinine > 175Plasma Creatinine > 175MM 1414 Renal Replacement TherapyRenal Replacement Therapy 1717 Renal DeathsRenal Deaths

Progression rates for 5097 newly diagnosed Type 2 diabetic patients in UKPDS. Adler AI et al Kidney Int 2003 ; 63 : 225 - 32

UKPDS Progression 2UKPDS Progression 2

BaselineBaselineN = 5097N = 5097

5 yrs5 yrsN = 4791N = 4791

10 yrs10 yrsN = 2799N = 2799

15 yrs15 yrsN = 435N = 435

MAU or worseMAU or worse 7.3 %7.3 %(370)(370)

17.3 %17.3 %(830)(830)

24.9 %24.9 %(696)(696)

28.0 %28.0 %(122)(122)

CP or worseCP or worse 0.7 %0.7 %(37)(37)

3.1 %3.1 %(149)(149)

5.3 %5.3 %(148)(148)

7.1 %7.1 %(31)(31)

PCr > 175PCr > 175M M or RRTor RRT

00 0.4 %0.4 %(19)(19)

0.8 %0.8 %(22)(22)

2.3 %2.3 %(10)(10)

UKPDS Progression 3UKPDS Progression 3

Proportion alive Proportion alive at 10 yrsat 10 yrs

Years spent in Years spent in stage (IQR)stage (IQR)

No nephropathyNo nephropathy 87.1 %87.1 % 18.9 18.9

(7.8 – 37.8)(7.8 – 37.8)

MAUMAU 70.8 %70.8 % 10.9 10.9

(4.5 – 21.8)(4.5 – 21.8)

CPCP 65.1 %65.1 % 9.7 9.7

(4.0 – 19.4)(4.0 – 19.4)

PCr > 175PCr > 175M or M or RRTRRT

8.5 %8.5 % 2.5 2.5

(1.0 – 5.0)(1.0 – 5.0)

UKPDS Progression 4UKPDS Progression 4

38 % of 4031 developed MAU at 15 yrs38 % of 4031 developed MAU at 15 yrs 64 % had eCrCl > 60 ml/min/1.73m64 % had eCrCl > 60 ml/min/1.73m22

24 % had eCrCl < 60 ml/min/1.73m24 % had eCrCl < 60 ml/min/1.73m2 2 after MAUafter MAU 12 % had eCrCl < 60 ml/min/1.73m12 % had eCrCl < 60 ml/min/1.73m22 pre MAU pre MAU

29 % of 5032 developed reduced eCrCl 29 % of 5032 developed reduced eCrCl < 60 ml/min/1.73m < 60 ml/min/1.73m22 at 15 yrs at 15 yrs

51 % had UAC < 50 mg/L51 % had UAC < 50 mg/L 16 % had UAC > 50 mg/L after reduced eCrCl16 % had UAC > 50 mg/L after reduced eCrCl 33 % had UAC > 50 mg/L pre reduced eCrCl33 % had UAC > 50 mg/L pre reduced eCrCl

Thus MAU does not always precede declining Thus MAU does not always precede declining renal function renal function

Proportion of patients reaching a renal event in UKPDS. 4032 with no albuminuria, 5032 with normal plasma creatinine at baseline. Microalbuminuria >50mg/L, macroalbuminuria > 300 mg/L, reduced CrCl < 60 ml/min. Retnakaran et al Diabetes 2006 ; 55 : 1832 - 9

UKPDS Progression 5UKPDS Progression 5MAUMAU

756 events756 events

CPCP219 events219 events

CrClCrCl584 events584 events

Age atAge atPer 5 yPer 5 y

__ __ 2.152.15(1.98-2.31)(1.98-2.31)

Male sexMale sex 1.181.18(1.01-1.39)(1.01-1.39)

1.471.47(1.06-2.02)(1.06-2.02)

0.550.55(0.42-0.75)(0.42-0.75)

Indo AsianIndo Asian 2.022.02(1.59-2.60)(1.59-2.60)

2.072.07(1.36-3.15)(1.36-3.15)

1.931.93(1.38-2.72)(1.38-2.72)

WaistWaistcmcm

1.011.01(1.004-1.016)(1.004-1.016)

1.0161.016(1.006-1.026)(1.006-1.026)

0.950.95(0.94-0.96)(0.94-0.96)

SmokingSmoking 1.201.20(1.01-1.42)(1.01-1.42)

__ 1.251.25(1.03-1.52)(1.03-1.52)

Stepwise proportional hazards regression model . HR with 95 % CI

UKPDS Progression 6UKPDS Progression 6MAUMAU

756 events756 events

CPCP219 events219 events

CrClCrCl584 events584 events

UACUACPer 20 mg/LPer 20 mg/L

1.0041.004(1.002-1.007)(1.002-1.007)

1.0091.009(1.005-1.012)(1.005-1.012)

1.0091.009(1.002-1.015)(1.002-1.015)

Plasma CrPlasma CrPer 10 Per 10 MM

__ 1.0871.087(1.005-1.175)(1.005-1.175)

1.341.34(1.28-1.40)(1.28-1.40)

Systolic BPSystolic BPPer 10 mmHgPer 10 mmHg

1.151.15(1.11-1.20)(1.11-1.20)

1.151.15(1.07-1.24)(1.07-1.24)

1.1071.107(1.06-1.16)(1.06-1.16)

LDLCLDLCmMmM

__ 1.171.17(1.02-1.18)(1.02-1.18)

__

TriglycerideTriglyceridemMmM

1.091.09(1.04-1.14)(1.04-1.14)

1.151.15(1.09-1.21)(1.09-1.21)

__

Stepwise proportional hazards regression model . HR with 95 % CI

UKPDS CaveatsUKPDS Caveats

Primary renal outcomes too infrequentPrimary renal outcomes too infrequent Mix of therapeutic and pathological Mix of therapeutic and pathological

microvascular outcomesmicrovascular outcomes Surrogate renal outcome used urinary Surrogate renal outcome used urinary

albumin concentration with high cut offalbumin concentration with high cut off No allowance of impact of antihypertensive No allowance of impact of antihypertensive

therapies on UACtherapies on UAC

UKPDS ConclusionsUKPDS Conclusions

Strong evidence of effectiveness of Strong evidence of effectiveness of glycaemic and BP control in prevention of glycaemic and BP control in prevention of increases in albuminuriaincreases in albuminuria

Significant reduction in those doubling Significant reduction in those doubling plasma creatinine (albeit small numbers)plasma creatinine (albeit small numbers)

Demonstration of poor prognosis for those Demonstration of poor prognosis for those with worsening renal functionwith worsening renal function

Relatively slow progression of albuminuria Relatively slow progression of albuminuria toward renal impairment in T2DMtoward renal impairment in T2DM

Discordance between eCrCl and UAC Discordance between eCrCl and UAC

BibliographyBibliography Intensive blood-glucose control with SUs or Intensive blood-glucose control with SUs or

insulin …. UKPDS 33. insulin …. UKPDS 33. Lancet 1998 : 352 : 837-53Lancet 1998 : 352 : 837-53

Tight blood pressure control….UKPDS 38 Tight blood pressure control….UKPDS 38 BMJ 1998: 317 : 703 – 13BMJ 1998: 317 : 703 – 13

Development and progression of Development and progression of nephropathy… UKPDS 64. Adler AI et al nephropathy… UKPDS 64. Adler AI et al KI 2003 : 63 : 225-32KI 2003 : 63 : 225-32

Risk Factors for renal dysfunction …. Risk Factors for renal dysfunction …. UKPDS 74. Retnakaran R et al UKPDS 74. Retnakaran R et al Diabetes 2006 : 55 : 1832 - 9Diabetes 2006 : 55 : 1832 - 9