Proteinuria as a surrogate outcome in CKD UKPDS

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. M and/or RRT) § Aggregate microvascular (above +/or vitreous haemorrhage +/or photocoagulation. ) § Surrogate endpoints (new MAU, CP, doubling plasma creatinine) § Latterly estimated creatinine clearance (e. Cr. Cl – CG formula) < 60 ml/min/1. 73 m 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 : 837 -53

Glycaemic Control Trial 1 Baseline MAU UAC > 50 mg/L Uncorrected Baseline CP UAC > 300 mg/L Uncorrected Conventional N = 1138 Intensive N = 2729 12. 4 % (127) 11. 3 % (273) 2. 1 % (21) 1. 7 % (40)

Glycaemic Control Trial 2 Hb. A 1 c Median Conv’l Intensive RR p 7. 9 % 7. 0 % - < 0. 0001 10 y ? t test Microvascular endpoints 8. 6 11. 4 0. 75 < 0. 01 1000 pt yrs (0. 60 -0. 93)# Log rank MAU 9 y % 25. 4% 19. 2% 0. 76 < 0. 001 ( number) (183/721) (338/1759) (0. 62 -0. 91)* c 2 CP 9 y % 6. 5% 4. 4% 0. 67 < 0. 03 (number) (47/721) (77/1759) (0. 42 -1. 07)* c 2 x 2 PCr 0 -9 y% 1. 76% 0. 71% 0. 40 < 0. 03 (number) (11/625) (11/1547) (0. 14 -1. 20)* c 2 x 2 PCr = doubling plasma creatinine (# 95 % CI ; * 99 % CI)

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

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

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

Blood Pressure Trial 2 Less Tight RR p Mean BP 6 y 156 / 85 142 / 80 - < 0. 0001 (estimated) mm. Hg Microvascular endpoints 19. 2 12. 0 0. 63 < 0. 01 1000 pt yrs (0. 44 -0. 89)# ? test MAU 6 y % 28. 5% 20. 3% 0. 71 < 0. 01 ( number) (78/274) (110/543) (0. 51 -0. 99)* ? test CP 6 y % 8. 6% 5. 3% 0. 61 0. 06 (number) (24/274) (29/543) (0. 31 -1. 21)* ? test x 2 PCr 9 y % NS NS ? t test (# 95 % CI ; * 99 % CI)

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

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 : 867 MAU 264 CP 71 Plasma Creatinine > 175 m. M 14 Renal Replacement Therapy 17 Renal 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 2 MAU or worse CP or worse PCr > 175 m. M or RRT Baseline 5 yrs 10 yrs 15 yrs N = 5097 N = 4791 N = 2799 N = 435 7. 3 % 17. 3 % 24. 9 % 28. 0 % (370) (830) (696) (122) 0. 7 % 3. 1 % 5. 3 % 7. 1 % (37) (149) (148) (31) 0 0. 4 % 0. 8 % 2. 3 % (19) (22) (10)

UKPDS Progression 3 Proportion alive at 10 yrs No nephropathy 87. 1 % MAU 70. 8 % CP 65. 1 % PCr > 175 m. M or RRT 8. 5 % Years spent in stage (IQR) 18. 9 (7. 8 – 37. 8) 10. 9 (4. 5 – 21. 8) 9. 7 (4. 0 – 19. 4) 2. 5 (1. 0 – 5. 0)

UKPDS Progression 4 § 38 % of 4031 developed MAU at 15 yrs § 64 % had e. Cr. Cl > 60 ml/min/1. 73 m 2 § 24 % had e. Cr. Cl < 60 ml/min/1. 73 m 2 after MAU § 12 % had e. Cr. Cl < 60 ml/min/1. 73 m 2 pre MAU § 29 % of 5032 developed reduced e. Cr. Cl < 60 ml/min/1. 73 m 2 at 15 yrs § 51 % had UAC < 50 mg/L § 16 % had UAC > 50 mg/L after reduced e. Cr. Cl § 33 % had UAC > 50 mg/L pre reduced e. Cr. Cl § Thus MAU does not always precede declining renal function

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

UKPDS Progression 5 Age at D MAU CP Cr. Cl 756 events 219 events 584 events _ _ 2. 15 Per 5 y Male sex (1. 98 -2. 31) 1. 18 1. 47 0. 55 (1. 01 -1. 39) (1. 06 -2. 02) (0. 42 -0. 75) 2. 02 2. 07 1. 93 (1. 59 -2. 60) (1. 36 -3. 15) (1. 38 -2. 72) Waist 1. 016 0. 95 cm (1. 004 -1. 016) (1. 006 -1. 026) (0. 94 -0. 96) Smoking 1. 20 _ 1. 25 Indo Asian (1. 01 -1. 42) (1. 03 -1. 52) Stepwise proportional hazards regression model. HR with 95 % CI

UKPDS Progression 6 MAU CP Cr. Cl 756 events 219 events 584 events UAC 1. 004 1. 009 Per 20 mg/L (1. 002 -1. 007) (1. 005 -1. 012) (1. 002 -1. 015) Plasma Cr _ 1. 087 1. 34 (1. 005 -1. 175) (1. 28 -1. 40) Per 10 m. M Systolic BP 1. 15 1. 107 Per 10 mm. Hg (1. 11 -1. 20) (1. 07 -1. 24) (1. 06 -1. 16) LDLC _ 1. 17 _ m. M (1. 02 -1. 18) Triglyceride 1. 09 1. 15 m. M (1. 04 -1. 14) (1. 09 -1. 21) _ 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 T 2 DM § Discordance between e. Cr. Cl and UAC

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