1. Diabetic Nephropathy Joel Michels Topf, MD Clinical Nephrologist

7. Diabetes has gone from being one of 3 major causes of ESRD to the single most important cause

11. ESRD CV Mortality

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

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

14. Finne, P. JAMA 2005; 294:1782-87. The risk of ESRD is dwarfed by the risk of death

16. 5-10 years 15-20 years 20 years

17. Diabetic nephropathy is relatively rare before 10 years, peaks at 15-20 years and if the patient has not been affected by 20 years, is unlikely to get the disease 5-10 years 15-20 years 20 years

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

20. nodular glomerulosclerosis Kimmelstiel-Wilson lesions

23. 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

25. 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

27. Pathology

28. Pathology Two biopsies from the same patient, the patient had unilateral RAS on the left. The RAS prevented hyper-filtration on the left and protected that kidney.

29. 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)

32. 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

33. 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

34. 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

35. 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

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

40. Randomized prospective trial of treatment strategies in type two diabetes Protocol written in 1976 Recruitment from 1977 - 1991 End of study 1997 Type 2 diabetic patients 5,102 Person years follow-up 53,000 ukpds

42. 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

43. Microvascular Endpoints Any Diabetes Related Endpoint 0 10 20 30 40 50 0 3 6 9 12 15 Proportion of patients (%) Years from randomization Hypoglycemia: any episode 0 1 2 3 4 5 0 3 6 9 12 15 Hypoglycemia: major episodes Proportion of patients (%)

44. 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

45. 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

46. 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

47. 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

52. Don’t worry about the glucometer get the BP under control

53. Microalbumin is the Hemoglobin A1c of blood pressure management. Dr Whitey routinely checks A1c to make sure my diabetes is on track.

54. Microalbumin is the Hemoglobin A1c of blood pressure management. Dr Whitey routinely checks Hgb A1c to make sure my diabetes is on track. Dr Whitey routinely checks µAlb to verify my blood pressure is on track.

56. 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

57. 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.

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

61. 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

62. Potassium Potassium

66. 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

67. 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…

68. 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 De Zeeuw D, Et al. Circulation 2004; 110: 921-927.

69. 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.

70. 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.

74. 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

75. 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.

77. Incidence of ESRD due to diabetic nephropathy IDNT RENALL

78. fin