best ever lecture on diabetic nephropathy

5. Etiologies of ESRD

8. Diabetes, diabetic nephropathy and the epidemic raging in the U.S.

10. ESRD CV Mortality

11. Finne, P. JAMA 2005; 294:1782-87.

14. 5-10 years 15-20 years 20 years

15. Ritz E, et al. N Engl J Med 1999;341 :1127-33.

17. nodular glomerulosclerosis Kimmelstiel-Wilson lesions

19. Type I Diabetes Type II Diabetes No difference in glycemic control between people who get nephropathy and those who don’t Ritz E, et al. N Engl J Med 1999;341 :1127-33. Incidence of proteinuria at 25 years after diagnosis

21. Transforming Growth Factor Beta Angiotensin II Hyperglycemia Extracellular matrix Fibrosis Scientific studies on TGFß and renal disease Huang Y, Et al. Kidney International 2006; 69: 1713-4. TGFß

23. Pathology

25. A B C 0 years 5 years 10 years

27. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Diabetes Microalbuminuria Dipstick negative Macroalbuminuria Dipstick positive 30 300 mg/d 0  MI, CVA, CV Death  All-cause mortality  CHF hospitalization Gerstein, H. C. et al. JAMA 2001;286:421-426. Albuminuria (mg/d)

28. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Cholesterol < 198 Triglycerides < 145 Glycemic control (hgb a1c <8) Blood pressure (sbp<115) ACEi Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I

29. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type II Diagnosis Diagnosis Diagnosis

31. When is proteinuria not diabetic nephropathy? When does a diabetic need a biopsy?

39. Microvascular Endpoints Any Diabetes Related Endpoint Favors conventional 0.5 1 2 0.88 0.90 0.94 0.84 1.11 0.75 0.029 0.34 0.44 0.052 0.52 0.0099 Any diabetes related endpoint Diabetes related deaths All cause mortality Myocardial infarction Stroke Microvascular RR p Favors intensive Relative Risk 0 10 20 30 40 50 0 3 6 9 12 15 Proportion of patients (%) Years from randomisation Hypoglycemia: any episode 0 1 2 3 4 5 0 3 6 9 12 15 Hypoglycemia: major episodes Proportion of patients (%)

40. Blood pressure: Tight vs less tight control 60 80 100 140 160 180 0 2 4 6 8 mmHg Years from randomisation 144 154 87 82 Blood pressure: Bad vs worse control

41. Any diabetes-related endpoints 0% 10% 20% 30% 40% 50% 0 3 6 9 % of patients with events Tight blood pressure control (758) Less tight blood pressure control (390) risk reduction 24% p=0.0046 Years from randomisation risk reduction 32% p=0.019 Diabetes-related deaths Stroke 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 44% p=0.013 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 37% p=0.0092 Microvascular endpoints

48. Home blood pressure is the hemoglobin A1c of blood pressure management. Dr Whitey routinely checks Hgb A1c to make sure my diabetes is on track. Dr Whitey asks me check my home BP to verify my BP is on track.

50. Lewis, E. J. et al. N Engl J Med 1993;329:1456-1462 Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups

51. RENAAL Trial 1513 type II DM with nephropathy Cr 1.9 Randomized to placebo or losartan Primary outcome: composite of doubling serum Cr, ESRD, or death Brenner BM, Et al. NEJM 2001; 343: 861-9.

52. Picture of world with/without electricity

53. ACEi are good, ARB are good… in patients with albuminuria. What about in normotensive patients without albuminuria?

54. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

56. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

57. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

58. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51. Progression of diabetic retinopathy (2 steps) Odds ratio vs placebo Placebo 38% 1 Enalepril 25% 0.35 (65% reduction) Losartan 21% 0.30 (70% reduction)

59. ACEi are good ARB are good What about both together?

62. Problem: Too short Wrong target

67. Primary outcome ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

70. Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008 0.037 0.038 0.020

71. Increased renal outcomes despite better proteinuria

72. Cooperate Trial: ACEi+ARB in non-diabetics 263 patients with non-diabetic renal disease Average GFR 37.5 mL/min Average protein excretion 2.5 g/day Randomized to losartan 100mg, trandolapril 3mg, or both Nakao N, Et al. Lancet 2003; 361: 117-24. Endpoint: doubling of serum creatinine or dialysis

73. Potassium Potassium

77. Theory: reduce proteinuria, reduce cardiovascular events High  High | High  Low | Low  High | Low  Low Ibsen H, Et al. Hypertension 2005; 45: 198-202. Pre-specified subanalysis of the LIFE trial 8206 men and women ages 55-80 with hypertension and LVH 13% were diabetics Primary analysis was Atenolol vs Losartan Composite endpoint (CEP) was CV death, non-fatal stroke, or non-fatal MI … Reduction in albuminuria during treatment translates to a reduction in cardiovascular events…

78. Theory: reduce proteinuria, reduce cardiovascular events and renal end-points Reanalysis of the RENAAL trial. Instead of the intension to treat analysis, patients were analyzed by baseline proteinuria or reduction in proteinuria. The reduction in albuminuria at 6 months predicted outcomes at 42 months … Interestingly, suppression of albuminuria was the strongest predictor of long-term protection from cardiovascular events… De Zeeuw D, Et al. Circulation 2004; 110: 921-927.

79. Conclusion: reduction in proteinuria reduces CV complications and renal complications Implications: reduction in proteinuria can be used as an intermediate end-point, i.e. interventions which reduce proteinuria are good.

84. Run-in ACEi or ARB ACEi + ARB Atorvastatin Group A Placebo Group B Randomization Bianchi S, Et al. Am J Kidney Dis 2003; 41:565-570. A Controlled, Prospective Study of the Effects of Atorvastatin on Proteinuria and Progression of Kidney Disease 56 men and women with non-diabetic GN CrCl 53 mL/min and proteinuria = 2.5 g/d

85. GREACE Study 1541Greek men and women Age < 75, LDL > 100 and hx CHD 20% DM 3 year follow-up CHD events: Study:12% vs control: 24.5% Athyros VG, Et al. J Clin Pathol 2004; 57: 728-34.

89. Incidence of ESRD due to diabetic nephropathy IDNT RENALL

90. fin