Proteinuria as a surrogate outcome in CKD UKPDS Rudy Bilous Middlesbrough, UK

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

UKPDS - Outcomes  Fatal / non fatal renal failure (plasma creatinine > 250  M and/or RRT)  Aggregate microvascular (above +/or vitreous haemorrhage +/or photocoagulation.)  Surrogate endpoints (new MAU, CP, doubling plasma creatinine)  Latterly estimated creatinine clearance (eCrCl – CG formula) < 60 ml/min/1.73m 2  Reported per triennium, or B/L to year, or event rate per number at a given time point

UKPDS Outcomes  No impact on primary renal outcomes of either intensive glycaemic or tight blood pressure control  Combined microvascular outcome heavily weighted by photocoagulation

UKPDS Patient Randomisation for Glycaemic Control Study Lancet 1998; 352 :

Glycaemic Control Trial 1 Conventional N = 1138 Intensive N = 2729 Baseline MAU UAC > 50mg/L Uncorrected 12.4 % (127) 11.3 % (273) Baseline CP UAC > 300mg/L Uncorrected 2.1 % (21) 1.7 % (40)

Glycaemic Control Trial 2 Conv’lIntensiveRRp HbA1c Median 10y HbA1c Median 10y 7.9 % 7.0 % - < ? t test Microvascular endpoints pt yrs ( )# < 0.01 < 0.01 Log rank MAU 9 y % ( number) 25.4%(183/721)19.2%(338/1759)0.76( )* <  2 CP 9 y % (number)6.5%(47/721)4.4%(77/1759)0.67( )* < 0.03  2 x2 PCr 0 -9y% (number) 1.76%(11/625)0.71%(11/1547)0.40( )* < 0.03  2 (# 95 % CI ; * 99 % CI)x2PCr = doubling plasma creatinine

Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317: UKPDS Patient Randomisation to BP Study

Blood Pressure Trial 1 Less Tight <180/105mmHg N = 390 Tight <150/85 mmHg N = 758 Baseline MAU UAC > 50 mg/L Corrected 16 % (53) 18 % (114) Baseline CP UAC >300 mg/L Corrected 4 % (13) 3 % (18) UAC corrected to urine creatinine concentration of 8mM

Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317: Achieved Blood Pressure in UKPDS BP Study

Blood Pressure Trial 2 Less Tight TightRRp Mean BP 6y Mean BP 6y(estimated) 156 / 85 mmHg 142 / 80 mmHg- < ? t test Microvascular endpoints pt yrs ( )# < 0.01 < 0.01 ? test MAU 6 y % ( number) 28.5%(78/274)20.3%(110/543)0.71( )* < 0.01 ?  test CP 6 y % (number)8.6%(24/274)5.3%(29/543)0.61( )* ?  test x2 PCr 9y % NSNS (# 95 % CI ; * 99 % CI)

Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317: Surrogate outcomes in UKPDS BP Study

UKPDS Progression 1  5097 at baseline  4727 (92.7%) No nephropathy  333 (6.5 %) MAU (UAC > 50 mg/L)  37 (0.7 %) CP (UAC > 300 mg/L)  At 10.4 yrs median follow up :  867MAU  264CP  71Plasma Creatinine > 175  M  14Renal Replacement Therapy  17Renal Deaths

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

UKPDS Progression 2 Baseline N = yrs N = yrs N = yrs N = 435 MAU or worse 7.3 % (370) 17.3 % (830) 24.9 % (696) 28.0 % (122) CP or worse 0.7 % (37) 3.1 % (149) 5.3 % (148) 7.1 % (31) PCr > 175  M or RRT % (19) 0.8 % (22) 2.3 % (10)

UKPDS Progression 3 Proportion alive at 10 yrs Years spent in stage (IQR) No nephropathy 87.1 % 18.9 (7.8 – 37.8) MAU 70.8 % 10.9 (4.5 – 21.8) CP 65.1 % 9.7 (4.0 – 19.4) PCr > 175  M or RRT 8.5 % 2.5 (1.0 – 5.0)

UKPDS Progression 4  38 % of 4031 developed MAU at 15 yrs  64 % had eCrCl > 60 ml/min/1.73m 2  24 % had eCrCl < 60 ml/min/1.73m 2 after MAU  12 % had eCrCl < 60 ml/min/1.73m 2 pre MAU  29 % of 5032 developed reduced eCrCl < 60 ml/min/1.73m 2 at 15 yrs  51 % had UAC < 50 mg/L  16 % had UAC > 50 mg/L after reduced eCrCl  33 % had UAC > 50 mg/L pre reduced eCrCl  Thus MAU does not always precede declining renal function

Proportion of patients reaching a renal event in UKPDS 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 :

UKPDS Progression 5 MAU 756 events CP 219 events CrCl 584 events Age at  Per 5 y __2.15( ) Male sex 1.18( )1.47( )0.55( ) Indo Asian 2.02( )2.07( )1.93( ) Waistcm1.01( )1.016( )0.95( ) Smoking1.20( )_1.25( ) Stepwise proportional hazards regression model. HR with 95 % CI

UKPDS Progression 6 MAU 756 events CP 219 events CrCl 584 events UAC Per 20 mg/L 1.004( )1.009( )1.009( ) Plasma Cr Per 10  M _1.087( )1.34( ) Systolic BP Per 10 mmHg 1.15( )1.15( )1.107( ) LDLCmM_1.17( )_ TriglyceridemM1.09( )1.15( )_ Stepwise proportional hazards regression model. HR with 95 % CI

UKPDS Caveats  Primary renal outcomes too infrequent  Mix of therapeutic and pathological microvascular outcomes  Surrogate renal outcome used urinary albumin concentration with high cut off  No allowance of impact of antihypertensive therapies on UAC

UKPDS Conclusions  Strong evidence of effectiveness of glycaemic and BP control in prevention of increases in albuminuria  Significant reduction in those doubling plasma creatinine (albeit small numbers)  Demonstration of poor prognosis for those with worsening renal function  Relatively slow progression of albuminuria toward renal impairment in T2DM  Discordance between eCrCl and UAC

Bibliography  Intensive blood-glucose control with SUs or insulin …. UKPDS 33. Lancet 1998 : 352 :  Tight blood pressure control….UKPDS 38 BMJ 1998: 317 : 703 – 13  Development and progression of nephropathy… UKPDS 64. Adler AI et al KI 2003 : 63 :  Risk Factors for renal dysfunction …. UKPDS 74. Retnakaran R et al Diabetes 2006 : 55 :