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Recent advances in management of Diabetic Nephropathy

Recent advances in management of Diabetic Nephropathy. …Tiger by the tail. Normal Kidney. Diabetic Kidney. Diabetic nephropathy. Diabetic nephropathy is progressive kidney disease Most common cause of ESRD More likely to die than progress to ESRD Multi-risk factor intervention is critical

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Recent advances in management of Diabetic Nephropathy

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  1. Recent advances in management ofDiabetic Nephropathy

  2. …Tiger by the tail

  3. Normal Kidney Diabetic Kidney

  4. Diabetic nephropathy • Diabetic nephropathy is progressive kidney disease • Most common cause of ESRD • More likely to die than progress to ESRD • Multi-risk factor intervention is critical • Lowering blood pressure with RAAS blockade is critical • Combinations of ACEi + ARB or MRA sensible • No long term efficacy or safety data • Prevent cardiovascular morbidity and mortality

  5. Why is Diabetic Nephropathy Important?

  6. Other Glomerulonephritis 10% 13% No. of patients Diabetes Hypertension Projection 50.1% 27% 95% CI Diabetes: The Most Common Cause of ESRD Primary Diagnosis for Patients Who Start Dialysis 700 600 500 No. of dialysis patients (thousands) 400 520,240 300 281,355 200 243,524 100 r2=99.8% 0 1984 1988 1992 1996 2004 2000 2008 United States Renal Data System. Annual data report. 2000.

  7. ESRD Population Cardiovascular Death is Major Cause of Mortality in ESRD 100 GP Male 10 GP Female GP Black 1 GP White Annual Cardiovascular Mortality (%) Dialysis Male General Population 0.1 Dialysis Female Dialysis Black 0.01 Dialysis White 0.001 25-34 35-44 45-54 55-64 65-74 75-84 > 85 Age (years) Sarnak MJ and Levey AS. Am J Kidney Dis. 2000;35(4)(suppl1):S117-S131. Foley RN. Am J Kidney Dis. 1998;32(S3):S112-119.

  8. What is the Natural History of Diabetic Nephropathy?

  9. Definition of Diabetic Nephropathy • Clinical diagnosis based on Hx, Exam and urine albumin/creatinine ratio in most cases • Longstanding History of diabetes + retinopathy • Macroalbuminuria (a.k.a “overt nephropathy”) defined as random urine albumin/creatinine ratio > 300 mg/g • Hypertension (> 90%) • Renal Biopsy confirmation is rare

  10. Development of Macroalbuminuria Heralds Rapid Decline in Glomerular Filtration in Type II Diabetes Nelson RG. et al NEJM, 1996

  11. Diabetics with Nephropathy (DM/CKD) are More Likely to Die than to Progress to ESRD 5% Medicare sample , 1996-1997 cohort, 2 year follow-up N=1,045,263 188,596 33,586 19,335 100 Event Free ESRD 80 All Cause Death 65.12 73.18 60 Percent of Patients 85.04 90.53 5.85 40 2.25 0.31 20 0.07 29.04 24.57 14.65 9.40 0 NDM/Non-CKD DM/Non-CKD DM/CKD NDM/CKD Status in the entry period

  12. 1.4% No albuminruia 2.0% 3.0% Microalbuminruia 2.8% 4.6% Macroalbuminruia 2.3% 19% Elevated Serum Creatinine Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRD The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated C V D E A T H Adler et al. Kid Int, 2003

  13. Myocardial Infarction Heart Failure Stroke Sudden Death What are Diabetics with Nephropathy Dying From?

  14. Prevention of Cardiovascular Events Prevention of End-Stage Renal Disease Diabetic Nephropathy Improving Outcomes in Diabetic Nephropathy

  15. What is the Proper Therapy of Kidney Disease in patients with Diabetes?

  16. The Renal Injury Triad Angiotensin II Hypertension Proteinuria

  17. Definition of Abnormal Albuminuria in Diabetes Mellitus * Random (Spot) urine preferably A.M. recommended

  18. ADA Guidelines: Diabetic Nephropathy • A-Level Evidence (well done RCTs) • To reduce the risk and/or slow the progression of nephropathy, optimize glucose control. • To reduce the risk and/or slow the progression of nephropathy, optimize blood pressure control.

  19. ADA: Screening Guidelines • Perform an annual test for the presence of microalbuminuria in (1) type 1 diabetic patients who have had diabetes >5 years and (2) all type 2 diabetic patients starting at diagnosis. • Acceptable samples to test for increased urinary albumin excretion are timed (e.g., 12 or 24 h) collections for measurement of albumin concentration and timed or untimed samples for measurement of the albumin:creatinine ratio. For screening, an untimed sample for albumin measurement (without creatinine) may be considered if a concentration cutoff is used that allows high sensitivity for detection of an increased albumin excretion rate. Level of evidence: E • Expert Consensus

  20. ADA: Treatment Guidelines • In the treatment of albuminuria/nephropathy both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can be used: • In hypertensive and nonhypertensive type 1 diabetic patients with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (1a) • In hypertensive and non hypertensive type 2 diabetic patients with microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. (Cochrane 1a DOE) • In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dL), ARBs have been shown to delay the progression of nephropathy. • If one class is not tolerated, the other should be substituted. • A-Level Evidence (well done trials)

  21. ADA: Treatment • With the onset of overt nephropathy, initiate protein restriction to <0.8 g • kg-1 body weight • day-1 (approximately 10% of daily calories), the current adult recommended daily allowance for protein. Further restriction may be useful in slowing the decline of glomerular filtration rate in selected patients. • B-Level Evidence (well done cohort studies)

  22. ADA: Treatment • If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of hyperkalemia. • Consider referral to a physician experienced in the care of diabetic renal disease when the glomerular filtration rate has fallen to either <60 mL • min-1 • 173 m-2 or difficulties have occurred in the management of hypertension or hyperkalemia. • Consider the use of non-dihydropyridine calcium channel blockers or beta-blockers in patients unable to tolerate ACE inhibitors or ARBs. • Expert Consensus

  23. 0 Captopril % with Doubling of Baseline Creatinine Conventional therapy 25 50 75 Baseline creatinine > 1.5 mg/dl 100 0 1 2 3 4 • 2 – • 0 – • - 2 – • - 4 – • 6 – • 8 – • 40 – • - 20 – • 0 – • - 20 – • 40 – • 60 – P <.001 Decrease in Mean Blood Pressure (mm Hg) % Reduction in Proteinuria NS ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409) Lewis et al. N Engl J Med. 1993;329:1456-1462.

  24. ARB (losartan) Reduces Risk of ESRD in Diabetic Nephropathy BP 142 / 74 BP 140 / 74 Reduction in Endpoints in NIDDM with Angiotensin Antagonist Losartan (RENAAL) Trial:1513 type 2 Diabetics with Nephropathy Placebo ESRD 30 Losartan Risk Reduction: 28% p=0.002 20 % with event 10 • Avg: 3.5 BP drugs/pt • 90% in both groups • received a CCB 0 0 12 24 36 48 Months P (+ CT) 762 715 610 347 42 L (+ CT) 751 714 625 375 69 Brenner et al. New Engl J. Med Sept 20 2001

  25. Irbesartan Amlodipine Placebo BP 140/77 BP 141/77 BP 144/80 Irbesartan in Diabetic Nephropathy Trial: Time to Doubling of Serum Creatinine, ESRD, or Death 1,715 Type 2 Diabetics with Nephropathy 70 RRR 23%P=.006 60 RRR 20%P=.02 P=NS 50 40 Subjects (%) 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 Follow-up (mo) Lewis EJ, et al. N Engl J Med. 2001;345:851-860.

  26. Albuminuria at Baseline Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial (N=1513) 100 Baseline Albuminuria HR 80 ≥3.0 g/g 8.10 60 % with ESRD end point ≥1.5<3.0 g/g 3.23 40 20 <1.5 g/g 1.0 0 12 24 36 48 0 Month de Zeeuw et al. Kid. Int. June 2004

  27. Reduction in Proteinuria is Associated with Reduced Risk for End-Stage Renal Disease in Diabetic Nephropathy 4.0 3.5 3.0 2.5 Relative Risk for ESRD 2.0 1.5 1.0 0.5 0.0 <-40 ≥-40 ≥-10 ≥10 ≥60 ≥40 <40 <-10 <10 <60 Change in Albuminuria % de Zeeuw et al. Kid. Int. June 2004

  28. RENAAL; Proteinuria Reduction (<0% versus >30%) determines the cardiovascular outcome CV Endpoint Heart Failure <0% 40 40 >30% 30 30 % with CV endpoint % with heart failure 20 20 <0% 10 10 >30% 0 0 0 12 24 36 48 0 12 24 36 48 Month Month De Zeeuw et al; Circulation, in press

  29. Continuation of Losartan After Serum Creatinine Doubles Reduces Incidence of ESRD Risk Reduction: 30% 80 p=0.013 60 P L 40 % with ESRD event 20 0 0 6 12 18 24 Months P (+CT) 198 111 48 11 4 L (+CT) 162 104 43 19 3

  30. 20 15.4 17.1 15.7 13.2 15 Hazard Ratio 10 5.5 6.7 5 2.4 2.0 3.6 1.8 1.4 0 1.6 1.0 >2.5 >165 1.1 0.9 1.25 - 2..5 151 - 165 1.0 .5 – 1.2 140 - 151 <.5 <140 SBP Quartile at Baseline (mm Hg) Proteinuria Quartile at Baseline (g/g) RENAAL; Contribution of Baseline Systolic BP or Proteinuria to ESRD in diabetic nephropathy unpublished

  31. Combination Therapy for BP Control: Rule Rather Than Exception Trial/Systolic Blood Pressure Achieved (mm Hg) ALLHAT IDNT RENAAL UKPDS ABCD MDRD HOT AASK 138 138 141 144 132 132 138 128 Number of BP Medications Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646-661.

  32. How I do get My Patient’s BP to the Goal of <130 / < 80 mmHg? • ACE Inhibitor / AII Receptor Antagonist (maximum dose) • Low ( 2 gram ) Sodium Diet • Diuretic • eGFR > 50 ml/min, thiazide • eGFR < 50 ml/min, loop diuretic • Long-Acting CCB or b-blocker • Long-acting a-blocker vs clonidine • Minoxidil

  33. Proteinuria N=510 Systolic Blood Pressure N=1,338 5 2% 0 -5 -10 -15 -13% Change (%) -20 -18.5% -25 NS -30 -30% -35 P=0.01 Renal Effects of CCBs: Comparison NDHP-CCBs show greater reductions in proteinuria in hypertensive adults with proteinuria, with or without diabetes. DHP-CCB NDHP-CCB Bakris GL et al. Kidney Int. 2004. In press. Systematic Review of 28 Studies 17

  34. Combination ACEi and Non-Dihydropyridine CCB Reduces Proteinuria Further in Type 2 Diabetics With Nephropathy Trandolapril 5.5 mg/d Trandolapril (2.9 mg/d) + Verapamil SR (219 mg/d) Verapamil SR 314 mg/d 0 -20 -40 -60 Percent reduction from baseline Proteinuria Blood Pressure Bakris, et al. Kid Int. 1998;54:1283.

  35. NKF Kidney Disease Outcomes Quality Initiative: Pharmacologic Treatment KDOQI BP guidelines for CKD Am. J. Kid. Dis. Suppl. May 2004

  36. Steno-2: Multiple Risk Factor Intervention Improves Outcomes in Type 2 diabetics with Microalbuminuria • Randomized, open-label, target driven, long-term intensified intervention trial aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria • BP < 130/80, (all treated with an ACEi or ARB) • A1c < 6.5% • Total Cholesterol < 175 mg/dl • Total Triglyceride 150 mg/dl • Aspirin 81 mg daily • Exercise program • Smoking Cessation Gaede et al N.Engl.Med. 3448:383. 2003

  37. Intensive Multi-risk Factor Intervention Improves Outcomes in Type 2 Diabetes Composite outcome: CV death, MI, coronary or peripheral revascularization, CVA, amputation 60 P=0.007 50 Conventional therapy 40 Primary Composite End Point (%) 30 20 Intensive therapy 10 0 0 12 24 36 48 60 72 84 96 Months of Follow-up No. at Risk 80 72 70 63 59 50 44 41 13 Conventional therapy 80 78 74 71 66 63 61 59 19 Intensive therapy Gaede et al N.Engl.Med. 3448:383. 2003

  38. Risk of Death after AMI is Reduced across all Levels of Kidney Function with Recommended Interventions Shlipak et al., Ann Int Med 2002;137:555-62

  39. Diabetic Nephropathy: Important Message • Lower blood pressure < 130 / 80 mmHg • Reducing Proteinuria • Inhibition of Renin-Angiotensin System • Multiple risk factor intervention • Glycemia • Dyslipidemia • Physical activity • Aspirin • Smoking cessation

  40. Is Combination Therapy With An ACE Inhibitor And An ARB Safe And Effective For Patients With Diabetic Renal Disease?

  41. 50 RAAS blockade + Other? 40 ACEi or ARB DGFR = - 6 ml/min/yr Time to ESRD 6.6 yrs Glomerular Filtration Rate ml/min/1.73 m2 ACEi + ARB DGFR = - ? ml/min/yr Time to ESRD ? 30 20 No ACEi/ARB or BP control DGFR = - 10 ml/min/yr Time to ESRD 4 yrs 10 ESRD 2 4 6 8 10 Time (yrs) ACEi- or ARB-Based Regimens for Diabetic Nephropathy Do Not Go Far Enough!

  42. Combining an ACEi and an ARB is more Renoprotective than Either Agent alone in Non-Diabetic Nephropathy *Average number of medications 3.2 per pt, 90% in all groups on dihydropyridine CCB ** Hazard Ratio comparing combination with either agent alone Nakao et al. Lancet 361:117-124, 2003

  43. Summary of Studies combining ACEi and ARB in Diabetic nephropathy: Effects on Proteinuria and BP 1 Agarwal et al. Kid Int 59:2282, 2002; 2 Rossing et al. Diab Care. 25:95-100, 2002; 3 Jacobsen et al Neph. Dial. Transplant 17:1019-1024, 2002;4 Jacobsen et al. J. Am. Soc. Neph. 14:992-999, 2003;5 Rossing Et al. Kid Int 63:1874-80, 2003 ; 6 Rossing et al. Diab Care 26:2268-2274, 2003.

  44. Diabetic Nephropathy: Important Message • Small short-term studies suggest combinations of ACEi and ARB reduce proteinuria synergistically • Greater reductions in proteinuria with or without additional lowering in blood pressure • Hyperkalemia and Increased creatinine not well documented • Safety and Efficacy of combination ACEi and ARB in diabetic with nephropathy not well established

  45. Is There a Role for Spironolactone (or Eplerenone) in Combination with Other Drugs in Patients with Diabetic Nephropathy?

  46. Angiotensin II Non-Hemodynamic Hemodynamic Capillary wall injury Inflammation O2- , TGF-b1 / PAI-1 Aldosterone Proteinuria Injury to Glomerular Cells Sclerosis and Fibrosis Glomerular and Tubular Scarring Progressive Renal Failure Role of Aldosterone in the Pathogenesis of Diabetic Nephropathy Glomerular Hypertension

  47. Adverse Renal and Cardiovascular Effects of Aldosterone Aldosterone Glomerulosclerosis Interstitial Fibrosis Proteinuria Renal Failure Ventricular Hypertrophy Cardiac Fibrosis Contractile Dysfunction Heart Failure Endothelial dysfunction Inflammation Oxidative Stress

  48. Spironolactone improves survival in Chronic Heart Failure Eplerenone reduces sudden cardiac death Post myocardial infarction 1.00 10 P=0.03 RR=0.79 (95% Cl, 0.64-0.97) 0.95 9 Placebo P=0.001 RR=0.70 (95% Cl, 0.60-0.82 0.90 8 0.85 7 0.80 Eplerenone 6 Cumulative Incidence of (%) Probability of Survival 0.75 5 0.70 Spironolactone 4 0.65 3 0.60 2 0.55 1 Placebo 0.50 0 0 3 6 9 12 15 18 21 24 27 30 33 36 0.45 0.00 Months since Randomization 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Mineralocorticoid Receptor Blockade Improves Cardiac Outcomes: Placebo Controlled Trials

  49. ARB MRA Can Dual Blockade of the RAAS Improve Renal Outcomes in Diabetic Nephropathy? Ang I Non-ACE Pathways ACE Ang II ACEi + AT1 Receptor Aldosterone + Renal Injury and Proteinuria Progressive Diabetic Nephropathy

  50. Study Design and Objectives • Study Design: Randomized double-blind placebo controlled trial • Study Population: Diabetics with macroalbuminuria despite maximally dosed ACE inhibitor • Intervention: Lisinopril 80 mg/d + losartan 100 mg/d or + Aldactone 25 mg/d or + placebo • Primary Outcome: Change in albuminuria • Secondary Outcomes: Safety especially serum creatinine and hyperkalemia • Follow up: 52 weeks

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