1. Diabetic Nephropathy Yiming Lit, M.D. May 5, 2009

18. Epidemiology Diabetic nephropathy is the leading cause of ESRD in the US. It accounts for 43% of all patients on dialysis Cost to Medicare > $ 2 billion per year

19. Definition A microvascular complication of diabetes marked by albuminuria and a deteriorating course from normal renal function to ESRD.

20. Albuminuria 30 - 300 mg/day got called “Microalbuminuria” it predicts the development of clinical nephropathy one “positive” is not enough in the low range detected by measuring the albumin/creatinine ratio on a spot urine sample

21. Epidemiology About 20-30% of patients with type I DM develop microalbuminuria, less than half progress to overt nephropathy Incidence of ESRD is 16% at 30 years. 5-60% of type II DM patients develop DN, depending on ethnicity

22. Epidemiology 63% of patients with diabetic nephropathy have type II DM The risk of developing diabetic nephropathy is not constant over the duration of diabetes

23. Epidemiology Risk factors: –Hypertension –Hyperglycemia –Microalbuminuria –Ethnicity –Male gender –Family history –Cigarette smoking

24. Natural History

26. Pathology Expansion of mesangial matrix with diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) Thickening of glomerular and tubular BM Arteriosclerosis and hyalinosis of afferent and efferent arterioles Tubulointerstitial fibrosis

30. Pathogenesis Exposure to the diabetic milieu Hyperglycemia –Induce mesangial expansion and injury –Increased activity of growth factors –Activation of cytokines –Formation of ROS –accumulation of advanced glycosylation endproducts in tissues Accumulation of ECM components, such as collagen

31. Pathogenesis Genetic predisposition to or protection from diabetic nephropathy –Differences in prevalence of microalbuminuria, ESRD in different patient populations –Only half of patients with poor glycemic control will develop diabetic nephropathy –Family studies Multiple genes may be involved

32. Diagnosis/Screening Spot urine albumin : creatinine ratio 24 hour urine collection dipstick

33. Treatment Glycemic control Hypertension control Dietary protein restriction RAS blockade

34. “ Insulin was first isolated from the pancreas in 1922 by Banting and Best, and almost overnight the outlook for the severely diabetic patient changed from one of rapid decline and death to that of a nearly normal person.” Guyton, 1991

36. Elizabeth Hughes (1907 - 1981)

38. Treatment Glycemic control –DCCT 1441 patients with type I DM randomly assigned to intensive therapy vs. conventional therapy Intensive therapy reduced microalbuminuria by 39% Reduced albuminuria by 54%

41. Treatment Hypertension control: –Lower the BP, slower the decline in GFR in patients with diabetic nephropathy –JNC VI recommended BP < 130/85 mmHg in patients with renal insufficiency –Patients with CKD and > 1g proteinuria, BP goal should be < 125-130/75-80 mmHg

43. Treatment ACE inhibitors: –Type I diabetes with nephropathy: Lewis et al. NEJM, 1993. captopril vs. placebo 50% RR of combined end points of death, dialysis and transplantation in ACEI group independent of BP

45. Treatment Angiotensin-receptor blockers: –RENAAL study(2001) 1513 pts with type II DM and nephropathy. Losartan vs. placebo. Losartan reduced the rate of doubling of cr by 16% but no effect on the rate of death. –IDNT(2001) 1715 type II DM pts with nephropathy. Irbesartan vs. amlodipine vs. placebo. Irbesartan has 20% lower risk of reaching endpoints compared to placebo and 23% lower incidence than that in the amlodipine group

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47. Treatment Conclusions: ACE inhibitors or ARB have a strong antiproteinuric effect apart from their antihypertensive actions Increasing the dose of the ACEI or ARB beyond the optimum antihypertensive doses further reduces proteinuria Antiproteinuric effect is enhanced by a low Na diet or diuretic

48. Treatment Early screening Tight glycemic control HTN management Use ACEI as first line, if not tolerated, use ARB. Use the maximum dose as tolerated If still hypertensive or proteinuric, consider using combination ACEI and ARB, or ACEI and diuretics