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DIABETIC NEPHROPAHTY

DIABETIC NEPHROPAHTY. BY Syed Rizwan, MD. 700. 661,330. Number of Patients. Projection. 600. 95% Confidence Interval. 500. Point prevalence. 400. R 2 = 99.7%. 372,407. 300. 172,667. 326,217. 200. 98,953. 86,825. Incidence. 100. R 2 = 99.8%. 0. 1984. 1986. 1988. 1990.

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DIABETIC NEPHROPAHTY

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  1. DIABETIC NEPHROPAHTY BY Syed Rizwan, MD

  2. 700 661,330 Number of Patients Projection 600 95% Confidence Interval 500 Point prevalence 400 R2 = 99.7% 372,407 300 172,667 326,217 200 98,953 86,825 Incidence 100 R2 = 99.8% 0 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010

  3. Adjusted for age, gender, race 350 AII 300 250 200 150 Diabetes 100 Hypertension 50 Cystic Kidney 0 1992 1994 1996 1998 2000

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

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

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

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

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

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

  10. HTN control in DN • Most important • Most practical

  11. Target Blood Pressure For Individuals With: BP Goal: Hypertension(no diabetes or renal disease) <140/90 mmHg (JNC 7) <130/80 mmHg (ADA, JNC 7) Diabetes Mellitus Renal Disease with proteinuria >1 gram/24 hours or diabetic kidney disease <135/85 mmHg<125/75 mmHg (NKF) 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.

  12. 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

  13. 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.

  14. 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.

  15. Effect of ARBs on Diabetic Nephropathy Acronym Diagnosis Randomization Primary Endpoint Duration IDNT1 •ESRD •2x creatinine •mortality Irbesartan/amlodipine/placebo + AHT* 2.6 yrs Type 2 DM with nephropathy N = 1,715 •ESRD •2x creatinine •mortality RENAAL Type 2 DM with nephropathy Losartan/placebo + AHT† 3.4 yrs N = 1,513 *AHT = other antihypertensive therapy (excluding ACEIs, ARBs, and CCBs). †AHT = other antihypertensive therapy (excluding ACEIs and ARBs).

  16. IDNT: Study Design Design: 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 Primary Endpoint: Randomization: Duration: Target BP: *Antihypertensive therapy (excluding ACEIs, ARBs, CCBs).

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

  18. RENAAL: Study Design Design: 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 Primary Endpoint: Duration: Target BP: *Antihypertensive therapy (excluding ACEIs or other ARBs). Brenner BM et al. N Engl J Med. 2001;345:861–869.

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

  20. 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.

  21. 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.

  22. CALM: Study Design Design: 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) Primary Outcome Measures: Randomization: Mogensen CE et al. BMJ. 2000;321:1440–1444.

  23. CALM: Reductions From Baseline in Urinary Albumin:Creatinine Ratio (Week 24) 0 –10 –20 Change in Urinary Albumin: Creatinine Ratio, % * –30 –40 † –50 † –60 Candesartan16 mg Lisinopril 20 mg Both *P = 0.05 from baseline. †P < 0.001 from baseline. Mogensen CE et al. BMJ. 2000;321:1440–1444.

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

  25. COOPERATE: Study Design 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 *Antihypertensive therapy (excluding other ACEIs or other ARBs). Nakao N et al. Lancet. 2003;361:117–124.

  26. COOPERATE: Primary Endpoint Doubling of Serum Creatinine or Progression to ESRD Trandolapril Losartan Combination 30 25 20 15 Proportion Reaching Endpoint, % 10 5 P = 0.02 0 0 5 12 18 24 30 36 Months After Randomization Number at Risk 59 89 88 84 79 65 Losartan 86 85 83 75 72 63 Trandolapril 88 87 86 83 76 73 Combination Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124.

  27. COOPERATE: UAER Trandolapril Losartan Combination 3 2 Median Urinary Protein Excretion, g/day 1 0 0 5 10 15 20 25 30 35 40 Months After Randomization Baseline

  28. 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.

  29. 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.

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

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

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