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

2. 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

3. 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

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

5. UKPDS Patient Randomisation for Glycaemic Control Study Lancet 1998; 352 : 837-53

6. 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)

7. Glycaemic Control Trial 2 Conv’lIntensiveRRp HbA1c Median 10y HbA1c Median 10y 7.9 % 7.0 % - < 0.0001 ? t test Microvascular endpoints 8.6 1000 pt yrs 11.4 0.75(0.60-0.93)# < 0.01 < 0.01 Log rank MAU 9 y % ( number) 25.4%(183/721)19.2%(338/1759)0.76(0.62-0.91)* < 0.001  2 CP 9 y % (number)6.5%(47/721)4.4%(77/1759)0.67(0.42-1.07)* < 0.03  2 x2 PCr 0 -9y% (number) 1.76%(11/625)0.71%(11/1547)0.40(0.14-1.20)* < 0.03  2 (# 95 % CI ; * 99 % CI)x2PCr = doubling plasma creatinine

8. Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317:703-713 UKPDS Patient Randomisation to BP Study

9. 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

10. Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317:703-713 Achieved Blood Pressure in UKPDS BP Study

11. Blood Pressure Trial 2 Less Tight TightRRp Mean BP 6y Mean BP 6y(estimated) 156 / 85 mmHg 142 / 80 mmHg- < 0.0001 ? t test Microvascular endpoints 19.2 1000 pt yrs 12.0 0.63(0.44-0.89)# < 0.01 < 0.01 ? test MAU 6 y % ( number) 28.5%(78/274)20.3%(110/543)0.71(0.51-0.99)* < 0.01 ?  test CP 6 y % (number)8.6%(24/274)5.3%(29/543)0.61(0.31-1.21)* 0.06 0.06 ?  test x2 PCr 9y % NSNS (# 95 % CI ; * 99 % CI)

12. Copyright ©1998 BMJ Publishing Group Ltd. UK Prospective Diabetes Study Group, BMJ 1998;317:703-713 Surrogate outcomes in UKPDS BP Study

13. 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

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

15. UKPDS Progression 2 Baseline N = 5097 5 yrs N = 4791 10 yrs N = 2799 15 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 0 0.4 % (19) 0.8 % (22) 2.3 % (10)

16. 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)

17. 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

18. 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

19. UKPDS Progression 5 MAU 756 events CP 219 events CrCl 584 events Age at  Per 5 y __2.15(1.98-2.31) Male sex 1.18(1.01-1.39)1.47(1.06-2.02)0.55(0.42-0.75) Indo Asian 2.02(1.59-2.60)2.07(1.36-3.15)1.93(1.38-2.72) Waistcm1.01(1.004-1.016)1.016(1.006-1.026)0.95(0.94-0.96) Smoking1.20(1.01-1.42)_1.25(1.03-1.52) Stepwise proportional hazards regression model. HR with 95 % CI

20. UKPDS Progression 6 MAU 756 events CP 219 events CrCl 584 events UAC Per 20 mg/L 1.004(1.002-1.007)1.009(1.005-1.012)1.009(1.002-1.015) Plasma Cr Per 10  M _1.087(1.005-1.175)1.34(1.28-1.40) Systolic BP Per 10 mmHg 1.15(1.11-1.20)1.15(1.07-1.24)1.107(1.06-1.16) LDLCmM_1.17(1.02-1.18)_ TriglyceridemM1.09(1.04-1.14)1.15(1.09-1.21)_ Stepwise proportional hazards regression model. HR with 95 % CI

21. 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

22. 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

23. Bibliography  Intensive blood-glucose control with SUs or insulin …. UKPDS 33. Lancet 1998 : 352 : 837-53  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 : 225-32  Risk Factors for renal dysfunction …. UKPDS 74. Retnakaran R et al Diabetes 2006 : 55 : 1832 - 9