1. DIABETIC NEPHROPAHTY BY Syed Rizwan, MD

3. 19841986198819901992199419961998200020022004200620082010 0 100 200 300 400 500 600 700 Incidence R 2 = 99.8% Point prevalence R 2 = 99.7% Projection Number of Patients 95% Confidence Interval 326,217 372,407 661,330 86,825 98,953 172,667

5. Adjusted for age, gender, race 350 300 250 200 150 100 50 0 AII Diabetes Hypertension Cystic Kidney 19921994199619982000

9. Chronic Kidney Disease Increase in incidence due to, – age of population – increase in diabetes –Decrease in Cardiovascular Mortality

11. Diabetic Nephropathy will increase with more Diabetics all over world. Higher morbididty and mortality compared to non-Diabetics. Higher cost of health care

12. Diabetic Nephropathy What to do? – prevent or slow progression of disease – decrease morbidity/ mortality – Prepare for RRT(renal replacement Therapy

13. prevent or slow progression of Diabetic Nephropahty –diet,exercise, life style modifications –Glycemic control –HTN control –ACEI/ARBs –Protein restriction –Hyperlipidemia management

14. Glycemic control in DN Stage- earlier the better Degree- tighter the better Renal disease in Type1 Diabetic may be decreasing.

16. Glycemic control in DN Is game over once Proteinuric? Pancreatic Transplantation can reverse proteinuria and establised Glomerular pathology.

17. HTN control in DN Most important Most practical

19. For Individuals With:BP Goal: Hypertension (no diabetes or renal disease) Diabetes Mellitus Renal Disease with proteinuria >1 gram/24 hours or diabetic kidney disease <140/90 mmHg (JNC 7) <130/80 mmHg (ADA, JNC 7) <135/85 mmHg <125/75 mmHg (NKF) Target Blood Pressure Chobanian AV et al. JAMA. 2003;289:2560–2571. American Diabetes Association. Diabetes Care. 2002;25:134–147. National Kidney Foundatrion. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.

20. ACEI/ARBs in DN RAS activated in Diabetic Kidney. Strict Glycemic contron in overt Nephropathy- not as helpful in DN. Glomerular Hyperfiltration injures kidney. Lowering intraglomerular pressure is beneficial

25. ACEI/ARBs in DN Is ACEI effective in slowing DN in Type 2 Diabetics? No clear evidence that ACEIs are renoprotective in Type 2 Diabetics Drug companies would not research on generic medicine.

27. ACEI/ARBs in DN ACE escape phenomenon. Biological action of Ang11 are not completley prevented by ACEI. Biological actions of Ang11 are mediated by AT-1 receptor.

28. AcronymDiagnosisRandomization Primary Endpoint Duration IDNT 1 N = 1,715 Type 2 DM with nephropathy Irbesartan/ amlodipine/ placebo + AHT* ESRD 2x creatinine mortality 2.6 yrs *AHT = other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs). † AHT = other antihypertensive therapy (excluding ACEIs and ARBs). RENAALType 2 DM with nephropathy Losartan/ placebo + AHT † ESRD 2x creatinine mortality 3.4 yrs N = 1,513 Effect of ARBs on Diabetic Nephropathy

29. Multicenter (210 sites), prospective, randomized, double-blind trial in 1,715 hypertensive patients with nephropathy due to type 2 diabetes Composite of doubling of serum creatinine, onset of ESRD, or death from any cause Usual AHT* + placebo Usual AHT* + irbesartan 300 mg/day Usual AHT* + amlodipine 10 mg/day 2.6 yrs  135/85 mmHg *Antihypertensive therapy (excluding ACEIs, ARBs, CCBs). Design: Duration: Primary Endpoint: Randomization: Target BP: IDNT: Study Design

31. Doubling of Serum Creatinine, ESRD, and/or Death 32.6% 41.1% 39.0% 20 25 30 35 40 45 IrbesartanAmlodipinePlacebo * *P = 0.02 vs placebo; P = 0.006 vs amlodipine. 20%  - irb vs pbo 23%  - irb vs aml Patients, % IDNT: Primary Composite Endpoint

32. Multicenter, randomized, double-blind, placebo- controlled trial in 1,513 patients with type 2 diabetes and nephropathy Composite of doubling of serum creatinine, onset of ESRD, or death from any cause Usual AHT* + placebo Usual AHT* + losartan 50–100 mg/day 3.4 yrs SBP <140 mmHg DBP <90 mmHg Brenner BM et al. N Engl J Med. 2001;345:861–869. *Antihypertensive therapy (excluding ACEIs or other ARBs). Design: Duration: Primary Endpoint: Target BP: RENAAL: Study Design

33. Doubling of Serum Creatinine, ESRD, and/or Death 43.5% 47.1% 30 34 38 42 46 50 LosartanPlacebo (16%  ) P = 0.02. Patients, % RENAAL: Primary Composite Endpoint Brenner BM et al. N Engl J Med. 2001;345:861–869

35. ACEI/ARBs in DN Stronger evidence to use ARBs than ACEI in type2 Diabetic Nephropahty. ACEI use is warranted because of cost, BP control and beneficial effects on CVS.

36. Effect of ARBs on Type 2 Diabetic Nephropathy: Conclusions Losartan/irbesartan significantly slow deterioration of renal function in nephropathy ARBs significantly reduce the risk of doubling serum creatinine or progressing to ESRD In type 2 diabetics with nephropathy, ARBs provide renal benefits independent of their BP-lowering effect Lewis EJ et al. N Engl J Med. 2001;345:851–860. Brenner BM et al. N Engl J Med. 2001;345:861–869.

37. Mogensen CE et al. BMJ. 2000;321:1440– 1444. CALM: Study Design Primary Outcome Measures: Multicenter, randomized, double-blind, placebo-controlled trial in 199 patients with type 2 diabetes, hypertension, and microalbuminuria BP and urinary albumin:creatinine ratio Group 1:candesartan 16 mg for 24 weeks (n = 66) Group 2:lisinopril 20 mg for 24 weeks (n = 64) Group 3:C16 for 12 weeks with add-on L20 for 2 weeks (n = 34) Group 4:L20 for 12 weeks with add-on C16 for 12 weeks (n = 35) Design: Randomization:

38. Change in Urinary Albumin: Creatinine Ratio, % Candesartan 16 mg Lisinopril 20 mg Both *P = 0.05 from baseline. † P < 0.001 from baseline. –60 –50 –40 –30 –20 –10 0 * † † Mogensen CE et al. BMJ. 2000;321:1440–1444. CALM: Reductions From Baseline in Urinary Albumin:Creatinine Ratio (Week 24)

39. *P = 0.05 from baseline. † P < 0.001 from baseline. Mogensen CE et al. BMJ. 2000;321:1440–1444. Change in BP, mmHg Candesartan 16 mg Lisinopril 20 mg Both –30 –25 –20 –15 –10 –5 0 † SBP DBP † * † † † CALM: Reductions From Baseline in BP

40. Design: Randomized, double-blind trial in 263 patients with nondiabetic renal disease Primary Composite of time to doubling of serum Endpoint: creatinine concentration or ESRD Randomization:Losartan 100 mg/day + AHT* as needed Trandolapril 3 mg/day + AHT* as needed Duration:3 yrs Target BP: SBP <130 mmHg DBP <80 mmHg Nakao N et al. Lancet. 2003;361:117–124. *Antihypertensive therapy (excluding other ACEIs or other ARBs). COOPERATE: Study Design

41. Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124. Doubling of Serum Creatinine or Progression to ESRD 0 5 10 15 05121824303636 20 25 30 Proportion Reaching Endpoint, % Months After Randomization 737683868788 Combination 637275838586 Trandolapril 59 6579848889 Losartan Number at Risk Trandolapril Losartan Combination P = 0.02 COOPERATE: Primary Endpoint

42. 0 1 2 3 0515203035 Trandolapril Losartan Combination Months After Randomization Median Urinary Protein Excretion, g/day Baseline 102540 COOPERATE: UAER

44. Management of Hyperkalemia in Patients Treated With ACEIs or ARBs Discontinue other meds that interfere in K excretion Low K diet (70 mEq/d) Effective diuretic therapy: loop diuretics when creatinine >1.8 mg/dl NaHCO3 tablets (650-mg tablet, 8 mEq) Decrease dose of ACEI Consider change to ARB Palmer BF. N Engl J Med. 2002;347:1256–1261.

45. ACEI and ARB combination No good study in Diabetic Nephropathy. Overall use is safer and seems beneficial Hyperkalemia is a major concern. Benefit proven in Non-Diabetic CKD Pts.

46. Protein restriction in DN Unproven. Uncertain. Problems with compliance. Risk of Malnutrition. Avoid High Protein diet. About 1gm/kg/day.

47. Hyperlipidemia and DN Common in Diabetics. Can cause Glomerular injury. Lowering lipid can slow renal disease

54. Proteinuria in DN Proteinuria in Diabetes means more than Glomerular damage. Proteinuria in DM points to widespread endothelial and epithelial cell injury. High association with, –Retinopathy –Neuropathy –Coronary Artery disease

56. ANEMIA AND DIABETIC NEPHROPATHY

60. Anemia Independent risk factor for ESRD. Associated with higher mortality & moebidity. Correcting anemia could delay progression of DM. Do not ignore ANEMIA in your Diabetic Patients.

61. Cardiovascular Disease and Diabetic Nephropathy

65. Renal Osteodystrophy Almost all Patient with advanced CKD have Renal Bone disease. Vitamin D3 deficiency Hypocalcemia Hyperphosphatemia Hyperparathyroidism Phosphate Binders used for years are Calcium(PhosLo=Ca acetate)

67. Diabetic Nephropathy What to do? – prevent or slow progression of disease – decrease morbidity/ mortality – Prepare for RRT(renal replacement Therapy

68. Vascular Access Placement As early as possible and indicated

73. CKD and Diabetes Outcome(Morbididty and Mortality) is better if Patient wirh DN started on dilalysis earlier. Indication for Dialysis, Diabetics- Cr. Cl < 15 cc/min. Non- Diabetics- Cr.Cl < 10cc/min

74. Transplantation Renal Transplant- graft survival> 90%- 1yr. Simultaneous Kid./Pancrease(SKP) 92% Pancease after Kid. TX(PAK) 93% Pancrease Transplant alone(PTA) 97% Islet Transplant- results encouraging