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Diabetic Nephropathy

Diabetic Nephropathy. Dinkar Kaw, M.D., Division of Nephrology. Objectives. Prevalence of diabetic kidney disease Pathogenesis of diabetic nephropathy Clinical course of diabetic nephropathy Slowing the progression of nephropathy Screening for early nephropathy.

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Diabetic Nephropathy

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  1. Diabetic Nephropathy Dinkar Kaw, M.D., Division of Nephrology

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

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

  4. Diabetic Nephropathy • The most common cause of ESRD in USA. • Accounts for nearly 40% of ESRD in USA. This proportion of ESRD due to DN is less in Europe than in USA. • Incidence is increasing, accounted for 10% in 1973 but now around 40% of USRD populations. • However one needs to keep in mind all diabetic patients with ESRD do not have DN as underlying cause of ESRD.

  5. Diabetic Nephropathy • Mortality of ESRD patients with Diabetes Mellitus is higher than in ESRD patients without Diabetes. • This higher mortality is due to increase in Cardiovascular, cerebro-vascular, peripheral vascular and infection related morbidity. • In USA the health care cost for diabetic ESRD patients has approached to $ 2 billion per year.

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

  7. Diabetic Nephropathy • 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). • More frequent in Native Americans, Hispanics and possibly Asian Indians. • Definition or Criteria for diagnosis of DN • Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.

  8. D.N.- Pathogenesis • Familial - Genetic • Only 35-40% patients with IDDM develop DN. • There is an increased risk of DN in a patient with family member having DN. • Increased predisposition of Native Americans, Hispanic to DN.

  9. D.N.- Pathogenesis • Glycemic Control-in both expt & human • DN does not occur in euglycemic patients. • In early 80s some controversy but DCCT confirmed role of hyperglycemia in pathogenesis of DN. • Renal transplant with early DN showed structural recovery in euglycemic receipient. (Abouna)

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

  11. D.N.- Pathogenesis • Glomerular Hyperfiltration • Glomerular Hypertension • Glomerular Hypertrophy • GBM thickening • Mesangial Expansion

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

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

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

  15. Diffuse and Nodular Glomerulosclerosis in Diabetic Nephropathy From UpToDate v 6.2 Courtesy H. Rennke, M.D.

  16. Diabetic Nephropathy

  17. Advanced Diabetic Glomerulosclerosis From: UpToDate v 6.2 Courtesy H. Rennke, M.D.

  18. Diabetic Nephropathy

  19. Diabetic NephropathyGlomerular Basement Membrane Thickening From: UpToDate v 6.2 Courtesy H. Rennke, M.D.

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

  21. Natural History of IDDM Clinical type 1 diabetes Functional changes* Structural changes† Microalbuminuria Proteinuria Rising blood pressure Proteinuria Rising serum creatinine levels End-stage renal disease CV events 2 5 10 20 30 Onset of diabetes Years * Kidney size ­, GFR ­. † GBM thickening ­, mesangial expansion ­

  22. Natural History of NIDDM Clinical type 2 diabetes Functional changes* Structural changes† Rising blood pressure Microalbuminuria Proteinuria Rising serum creatinine levels End-stage renal disease Cardiovascular death Onset of diabetes 2 5 10 20 30 Years * Kidney size ­, GFR ­. † GBM thickening ­, mesangial expansion ­

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

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

  25. ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes 100 75 50 25 0 Baseline creatinine >1.5 mg/dL % with doubling of baseline creatinine Placebo n=202 P<.001 Captopril n=207 0 1 2 3 4 Years of follow-up Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.

  26. RENAAL Primary Composite End Point: Doubling of Serum Creatinine, ESRD or Death (Kaplan – Meier Curve) Brenner BM et al.N Engl J Med 345:861-869, 2001

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

  28. Irbesartan in patients with type 2 diabetes & microalbuminuria study • 590 NIDDM patients with HTN and microalbuminuria with nearly normal GFR. • Randomly assigned to placebo, 150 mg or 300 mg of irbesartan for 2 years. • Primary outcome was time to the onset of diabetic nephropathy (urinary albumin excretion rate >200 mcg/min and at least 30% greater albuminuria) • 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)

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

  30. Lewis et al NEJM 2001

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

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

  33. DN: ADA Position Statement Screening: Perform an annual test for the presence of microalbuminuria in • type 1 diabetic patients who have had diabetes > 5 years and • 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

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

  35. 5 1 p<0.0001 17% decrease per 10 mmHg decrement in BP 0 . 5 1 1 0 1 2 0 1 3 0 1 4 0 1 5 0 1 6 0 1 7 0 UKPDS: Relationship Between BP Control And Diabetes-Related Deaths Hazard ratio Mean systolic blood pressure (mmHg) Adler AI, et al. BMJ. 2000;321:412-419. Reprinted by permission, BMJ Publishing Group.

  36. Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS DM Deaths Microvascular Complications Stroke Any Diabetic Endpoint 0 5% 10% -10 12% -20 24% % Reduction In Relative Risk * 32% 32% -30 * 37% *P <0.05 compared to tight glucose control * -40 44% Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL) Tight BP Control (Average 144/82 mmHg) * -50 Bakris GL, et al. Am J Kidney Dis.2000;36(3):646-661. Reprinted by permission, Harcourt Inc.

  37. National Kidney Foundation Recommendations on Treatment of HTN and Diabetes • Blood pressure goal: 130/80 mmHg • Target blood pressure: 125/75 for patients with >1 gram/day proteinuria • Blood pressure lowering medications should reduce both blood pressure + proteinuria • 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 • Randomized single-blinded study • 34 NIDDM patients • Lovastatin or Placebo • Followed for 2 years GFR ml/min Months Lam, etal. Diabetologia (1995) 38:604-609

  39. Management of ESRD due to DN • Early planning of Vascular Access • Both HD & PD could be appropriate modalities. • Early initiation of Dialysis at GFR 18-20 mls/min. • Renal Transplantation • CHD very common even in absence of symptoms. • Coronary Angiogram in diabetics under 40 years age. • Combined Renal & Pancreatic Transplantation for IDDM.

  40. Comparison of Patient Survival on Hemodialysis and CAPD by Cause of Renal Failure From UpToDate v 6.2; Data from Nelson, et al JASN(1992)3:1147.

  41. Simultaneous Pancreas-Kidney Transplantation Patient and Graft Survival From: UpToDate v 6.2

  42. Screening for microalbuminuria in diabetes

  43. Hypertension BP < 130/80 mmHg Hypercholesterolemia LDL < 100 mg/dL Hyperglycemia Hgb A1C < 7.0 % Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients American Diabetes Association Clinical Practice Recommendations. Diabetes Care. 2001;24(suppl1):S1-S133.

  44. Management of HTN and Chronic Renal Disease (CRD) in Diabetics • Reduce BP to <130/80 mmHg • Use multiple antihypertensive drugs (ACEI, ARB, diuretic, CCB, beta-blocker) • Maximal reduction of proteinuria • Treat hyperlipidemia (LDL <100 mg/dL) • Control Hgb A1C to <7% • Low salt diet (<2 gm NaCl/day) • Stop cigarette smoking

  45. Thanks for your attention

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