1. Diabetic Nephropathy

2. Diabetic Nephropathy A clinical syndrome DM + Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure

3. Diabetic nephropathy (DN) is a major cause of ESRD, and the incidence of diabetes mellitus is rising rapidly.

4. Objectives n Prevalence of diabetic kidney disease n Pathogenesis of diabetic nephropathy n Clinical course of diabetic nephropathy n Slowing the progression of nephropathy n Screening for early nephropathy

5. Causes of End Stage Renal Disease USRDS 1993 Annual Data Report

6. Diabetic Nephropathy n The most common cause of ESRD in USA. n However one needs to keep in mind all diabetic patients with ESRD do not have DN as underlying cause of ESRD.

7. Diabetic Nephropathy n Mortality of ESRD patients with Diabetes Mellitus is higher than in ESRD patients without Diabetes. n This higher mortality is due to increase in Cardiovascular, cerebro-vascular, peripheral vascular and infection related morbidity.

8. Patient Survival on Dialysis by Cause of Renal Failure From UpToDate v 6.2; Data from USRDS 1995 Annual Report

9. Diabetic Nephropathy n DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15- 20% of patients with type II diabetes (NIDDM). n Definition or Criteria for diagnosis of DN u Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.

10. D.N.- Pathogenesis n Familial - Genetic u Only 35-40% patients with IDDM develop DN. u There is an increased risk of DN in a patient with family member having DN.

11. D.N.- Pathogenesis n Glycemic Control-in both expt & human F DN does not occur in euglycemic patients. F Confirmed role of hyperglycemia in pathogenesis of DN. F Renal transplant with early DN showed structural recovery in euglycemic receipient. (Abouna)

12. Strict Glycemic Control Prevents Microalbuminuria in Type 1 Diabetes mellitus From UpToDate v 6.2; Data from the DCCT Research Group, NEJM(1993) 329:977.

13. D.N.- Pathogenesis n Glomerular Hyperfiltration n Glomerular Hypertension n Glomerular Hypertrophy n GBM thickening n Mesangial Expansion

14. D.N.- Pathogenesis n Renal lesions mainly related to extracellular matrix accumulation - Occurs in glomerular & tubular basement - Occurs in glomerular & tubular basement membrane membrane - Principal cause of mesangial expansion - Principal cause of mesangial expansion

15. D.N.- Pathogenesis n Extracellular matrix accumulation - Imbalance between synthesis & degradation of - Imbalance between synthesis & degradation of ECM components ECM components - Linkage between glucose concentration & ECM - Linkage between glucose concentration & ECM accumulation accumulation - Transforming growth factor-Beta associated with - Transforming growth factor-Beta associated with increased production of ECM molecules increased production of ECM molecules

16. D.N.- Pathogenesis n Extracellular matrix accumulation - TGF-B can down regulate synthesis of ECM - TGF-B can down regulate synthesis of ECM degrading enzymes & upregulate inhibitors of degrading enzymes & upregulate inhibitors of these enzymes these enzymes - Angiotensin II can stimulate ECM synthesis - Angiotensin II can stimulate ECM synthesis through TGF-B activity through TGF-B activity - Hyperglycemia activates protein kinase C, - Hyperglycemia activates protein kinase C, stimulating ECM production through cyclic AMP stimulating ECM production through cyclic AMP Pathway Pathway

17. Diffuse and Nodular Glomerulosclerosis in Diabetic Nephropathy

18. Diabetic Nephropathy

19. Advanced Diabetic Glomerulosclerosis

20. Diabetic Nephropathy

21. Diabetic Nephropathy Glomerular Basement Membrane Thickening From: UpToDate v 6.2 Courtesy H. Rennke, M.D.

22. Natural Course of D.N. n Stage 1: Renal hypertrophy - hyperfunction n Stage 2 : Presence of detectable glomerular lesion with normal albumin excretion rate & normal blood pressure n Stage 3 : Microalbuminuria n Stage 4 : Dipstick positive proteinuria n Stage 5 : End stage renal disease

23. Functional changes* Natural History of IDDM Proteinuria End-stage renal disease Clinical type 1 diabetes Structural changes † Proteinuria Rising serum creatinine levels Rising blood pressure Onset of diabetes 251020 Years * Kidney size , GFR  † GBM thickening , mesangial expansion  Microalbuminuria 30 CV events

24. Functional changes* Natural History of NIDDM Proteinuria End-stage renal disease Clinical type 2 diabetes Structural changes † Rising blood pressure Rising serum creatinine levels Cardiovascular death Microalbuminuria Onset of diabetes 2510203030 Years * Kidney size , GFR  † GBM thickening , mesangial expansion 

25. D.N.- Pathogenesis n Hypertension - in both expt & human F Hypertension follows 8-10 years of hyperglycemia in IDDM patients but it is frequently present at the diagnosis of NIDDM. F Many experimental & human studies have shown HTN accelerating progressive renal injury in DN.

27. Effect of Angiotensin Blockade Afferent arteriole Efferent arteriole  Glomerular pressure  (  GFR) Glomerulus Bowman’s Capsule Angiotensin II Proteinuria A II blockade:

28. ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes % with doubling of baseline creatinine 100 75 50 25 0 01234 Baseline creatinine >1.5 mg/dL Captopril n=207 Placebo n=202 P<.001 Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462. Years of follow- up

29. Brenner BM et al. N Engl J Med 345:861-869, 2001 Losartan could delay ESRD by 1.5-2 years.

30. Irbesartan in patients with type 2 diabetes & microalbuminuria study n 590 NIDDM patients with HTN and microalbuminuria with nearly normal GFR. n Randomly assigned to placebo, 150 mg or 300 mg of irbesartan for 2 years. n Primary outcome was time to the onset of diabetic nephropathy (urinary albumin excretion rate >200 mcg/min and at least 30% greater albuminuria) n 14.9% patients on placebo group, 9.7% of irbesartan 150mg group and 5.2% of irbesartan 300 mg group reached the primary point. –(Parving et al, NEJM, 2001)

31. ARBs in NIDDM,HTN & microalbuminuria-Parving 2001

32. Lewis et al NEJM 2001

33. ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 Year Trandolapril (5.5 mg/d) Verapamil (315 mg/d) Trandolapril (2.9 mg/d) + Verapamil (219 mg/d) * Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc. -33% -27% -62% *p <0.001 combination vs either monotherapy Percent reduction n=12n=11n=14

34. D.N.-Management n ACEI or AII RB- in both expt & human u Reduce glomerular hypertension u Reduce proteinuria independent of hemodynamic effects u Reduce glomerular hypertrophy u well tolerated apart from hyperkalemia & worsening of anemia in severe CRF u Cautious use in presence of severe renovascular disease

35. DN: ADA Position Statement Screening: Perform an annual test for the presence of microalbuminuria in 1) 1)type 1 diabetic patients who have had diabetes > 5 years and 2) 2)all type 2 diabetics patients starting at diagnosis. Treatment: In the treatment of albuminuria/nephropathy both ACE inhibitors and ARBs can be used: In hypertensive and nonhypertensive type 1 diabetic patients with microalbuminuria or clinical albuminuria, ACE inhibitors are the initial agents of choice In hypertensive type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARBs are the initial agents of choice. If one class is not tolerated, the other should be substituted American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002

36. UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions Better blood pressure control reduces… n Strokes by > one third n Serious deterioration of vision by > one third n Death related to diabetes by one third Better glucose control reduces… n Early kidney damage by one third n Major diabetic eye disease by one fourth Turner RC, et al. BMJ. 1998;317:703- 713.

37. National Kidney Foundation Recommendations on Treatment of HTN and Diabetes n Blood pressure goal: 130/80 mmHg n Target blood pressure: 125/75 for patients with >1 gram/day proteinuria n Blood pressure lowering medications should reduce both blood pressure + proteinuria n Therapies that reduce both blood pressure and proteinuria have been known to reduce renal disease progression and incidence of ischemic heart disease Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

38. Cholesterol Lowering Therapy and Diabetic Nephropathy

39. Management of ESRD due to DN n Early planning of Vascular Access n Both HD & PD could be appropriate modalities. n Early initiation of Dialysis at GFR 18-20 mls/min. n Renal Transplantation n Combined Renal & Pancreatic Transplantation for IDDM.

40. Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients n Hypertension u BP < 130/80 mmHg n Hypercholesterolemia u LDL < 100 mg/dL n Hyperglycemia u Hgb A 1C < 7.0 % American Diabetes Association Clinical Practice Recommendations. Diabetes Care. 2001;24(suppl1):S1- S133.

41. Management of HTN and Chronic Renal Disease (CRD) in Diabetics n Reduce BP to <130/80 mmHg n Use multiple antihypertensive drugs (ACEI, ARB, diuretic, CCB, beta-blocker) n Maximal reduction of proteinuria n Treat hyperlipidemia (LDL <100 mg/dL) n Control Hgb A 1C to <7% n Low salt diet (<2 gm NaCl/day) n Stop cigarette smoking

42. n Metformin

43. Hyperuricemia ?? Allopurinol ??