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

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Presentation on theme: "Diabetic Nephropathy Dinkar Kaw, M.D., Division of Nephrology."— Presentation transcript:

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

2 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

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

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

5 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. n 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 n DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in % of patients with type II diabetes (NIDDM). n More frequent in Native Americans, Hispanics and possibly Asian Indians. 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.

8 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. u Increased predisposition of Native Americans, Hispanic to DN.

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

10 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.

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

12 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 - Contributes to interstitium expansion - Contributes to interstitium expansion

13 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

14 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

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

20 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

21 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 Years * Kidney size , GFR  † GBM thickening , mesangial expansion  Microalbuminuria 30 CV events

22 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 Years * Kidney size , GFR  † GBM thickening , mesangial expansion 

23 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.

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

26 ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes % with doubling of baseline creatinine 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): Years of follow- up

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

28 RENAAL Brenner BM et al. N Engl J Med 345: , 2001 Losartan could delay ESRD by years.

29 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)

30 ARBs in NIDDM,HTN & microalbuminuria-Parving 2001

31 Lewis et al NEJM 2001

32 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: Reprinted by permission, Blackwell Science, Inc. -33% -27% -62% *p <0.001 combination vs either monotherapy Percent reduction n=12n=11n=14

33 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

34 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

35 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:

36 17% decrease per 10 mmHg decrement in BP p< UKPDS: Relationship Between BP Control And Diabetes- Related Deaths Mean systolic blood pressure (mmHg) Hazard ratio Adler AI, et al. BMJ. 2000;321: Reprinted by permission, BMJ Publishing Group.

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

38 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):

39 Cholesterol Lowering Therapy and Diabetic Nephropathy n Randomized single- blinded study n 34 NIDDM patients n Lovastatin or Placebo n Followed for 2 years GFR ml/mi n Months Lam, etal. Diabetologia (1995) 38:

40 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 mls/min. n Renal Transplantation u CHD very common even in absence of symptoms. u Coronary Angiogram in diabetics under 40 years age. n Combined Renal & Pancreatic Transplantation for IDDM.

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

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

43 Screening for microalbuminuria in diabetes

44 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.

45 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

46 Thanks for your attention


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