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Diabetic Nephropathy

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    • 1. Diabetic Nephropathy Joel Michels Topf, MD Clinical Nephrologist
    • 2.  
    • 3.  
    • 4.
      • Year Capacity
      • 1926 84,401
      • 85,753
      • 97,239
      • 101,001
      • 1991 102,501
      • 107,501
      • 111,238
      • 2006 111,238
    • 5.
      • Year Capacity
      • 1926 84,401
      • 85,753
      • 97,239
      • 101,001
      • 1991 102,501
      • 107,501
      • 111,238
      • 2006 111,238
      Incident ESRD 0 0 0 0 56,137 87,089 91,523 104,364
    • 6.  
    • 7. Diabetes has gone from being one of 3 major causes of ESRD to the single most important cause
    • 8.  
    • 9.
      • Diabetics on Dialysis: 172,938
      USRDS Atlas 2005 http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7 Total no of Diabetics: 20,000,000 0.86%
    • 10.
      • Diabetics on Dialysis: 172,938
      USRDS Atlas 2005 http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7 Total no of Diabetics: 20,000,000 0.86% Though diabetes is the most important cause of ESRD very few diabetics are on dialysis
    • 11. ESRD CV Mortality
    • 12. Finne, P. JAMA 2005; 294:1782-87.
    • 13. Finne, P. JAMA 2005; 294:1782-87.
    • 14. Finne, P. JAMA 2005; 294:1782-87. The risk of ESRD is dwarfed by the risk of death
    • 15. Diabetic nephropathy
      • Progressive renal damage as a result of diabetes mellitus type I or II
      • Initially patients present with increased GFR (2x normal)
      • Followed by proteinuria
      • Patients then have progressively deteriorating GFR
    • 16. 5-10 years 15-20 years 20 years
    • 17. Diabetic nephropathy is relatively rare before 10 years, peaks at 15-20 years and if the patient has not been affected by 20 years, is unlikely to get the disease 5-10 years 15-20 years 20 years
    • 18. Ritz E, et al. N Engl J Med 1999;341 :1127-33.
    • 19. 220 g 240 g Size Matters Normal kidney weight is 150 g
      • Diseases with large kidneys:
      • Multiple Myeloma • Hydronephrosis
      • Amyloidosis • Renal Cell Cancer
      • ADPKD/ARPKD • Not HIVAN
    • 20. nodular glomerulosclerosis Kimmelstiel-Wilson lesions
    • 21.
      • The Kimmelstiel-Wilson (K-W) lesions are ovoid or spherical, often laminated, hyaline masses situated in the periphery of the glomerulus.
      • The nodules are composed of lipids and fibrin.
      • The K-W nodules enlarge until they compress and obliterate the glomerular tuft.
      • Because of these glomerular and arteriolar lesions, the blood flow to the kidney is compromised and the kidney becomes ischemic. This results in tubular atrophy and interstitial fibrosis and leads to a roughened renal cortical surface.
    • 22.
      • One in five diabetic patients on dialysis do not have this “classic” pathology.
      • They have ischemic nephropathy, with non-specific vascular and interstitial lesions
      Ritz E, Orth SR. N Eng J Med 1999; 341:1127-33.
    • 23. Type I Diabetes Type II Diabetes No difference in glycemic control between people who get nephropathy and those who don’t Ritz E, et al. N Engl J Med 1999;341 :1127-33. Incidence of proteinuria at 25 years after diagnosis
    • 24. Genetics
      • Familial clustering
        • Diabetic family members of patients with diabetic nephropathy have an OR of 4.0
      • Race
        • ESRD is 5 times more likely in African Americans with family members on dialysis from DN
        • Pima indians have very high rates of diabetic nephropathy
    • 25. Transforming Growth Factor Beta Angiotensin II Hyperglycemia Extracellular matrix Fibrosis Scientific studies on TGFß and renal disease Huang Y, Et al. Kidney International 2006; 69: 1713-4. TGFß
    • 26. Hyperfiltration
      • Early finding
      • Renal vasodilation
        • Causes early increases in GFR
      • Later
        • Nephron loss results in compensatory hyperfiltration
        • No increase in GFR
    • 27. Pathology
    • 28. Pathology Two biopsies from the same patient, the patient had unilateral RAS on the left. The RAS prevented hyper-filtration on the left and protected that kidney.
    • 29. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Diabetes Microalbuminuria Dipstick negative Macroalbuminuria Dipstick positive 30 300 mg/d 0  MI, CVA, CV Death  All-cause mortality  CHF hospitalization Gerstein, H. C. et al. JAMA 2001;286:421-426. Albuminuria (mg/d)
    • 30. Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
      • Associated with a reduction in microalbuminuria
      • Cholesterol
      • Glycemic control
      • Blood pressure
      Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I
    • 31. Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
      • Associated with a reduction in microalbuminuria
      • Cholesterol
      • Glycemic control
      • Blood pressure
      Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I
    • 32. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type II
    • 33. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type II Diagnosis
    • 34. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type II Diagnosis Diagnosis
    • 35. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type II Diagnosis Diagnosis Diagnosis
    • 36. U/A at Diagnosis (Type 2 patients) Random spot collection Albumin:creatinine Repeat 3x in 3-6 months 2 of 3 ≥ 30mg/g creatinine Microalbuminuria, begin treatment Nephropathy Quantify µalb:Cr Consider referral Modified from the American Diabetes Association. Diabetes Care. 2002; 25 Suppl 1: S85-S89. No microalbuminuria Re-screen yearly Negative Positive No Yes
      • Differential of microalbuminuria
      • Early diabetic nephropathy
      • Obesity
      • Hypertension
      • Endothelial dysfunction
      • Metabolic syndrome
      • Atherosclerosis
    • 37. When is proteinuria not diabetic nephropathy? When does a diabetic need a biopsy?
    • 38. Suspicious for non-diabetic nephropathy
      • Onset within 5 years of dx of diabetes
      • Acute onset
      • Active sediment
      • Unusual review of systems
      • Serologies
        • ANA, Hep B, Hep C
      • Absence of retinopathy or neuropathy
    • 39. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 40. Randomized prospective trial of treatment strategies in type two diabetes Protocol written in 1976 Recruitment from 1977 - 1991 End of study 1997 Type 2 diabetic patients 5,102 Person years follow-up 53,000 ukpds
    • 41. Primary Endpoint: Any Diabetes Related Endpoint
      • 1401 of 3867 patients (36%)
      • First occurrence of any one of:
        • diabetes related death
        • non fatal myocardial infarction, heart failure or angina
        • non fatal stroke
        • amputation
        • renal failure
        • retinal photocoagulation or vitreous haemorrhage
        • cataract extraction or blind in one eye
    • 42. Microvascular Endpoints Any Diabetes Related Endpoint Favors conventional 0.5 1 2 0.88 0.90 0.94 0.84 1.11 0.75 0.029 0.34 0.44 0.052 0.52 0.0099 Any diabetes related endpoint Diabetes related deaths All cause mortality Myocardial infarction Stroke Microvascular RR p Favors intensive Relative Risk
    • 43. Microvascular Endpoints Any Diabetes Related Endpoint 0 10 20 30 40 50 0 3 6 9 12 15 Proportion of patients (%) Years from randomization Hypoglycemia: any episode 0 1 2 3 4 5 0 3 6 9 12 15 Hypoglycemia: major episodes Proportion of patients (%)
    • 44. Blood pressure: Tight vs less tight control 60 80 100 140 160 180 0 2 4 6 8 mmHg Years from randomisation 144 154 87 82
    • 45. Blood pressure: Tight vs less tight control 60 80 100 140 160 180 0 2 4 6 8 mmHg Years from randomisation 144 154 87 82 Blood pressure: Bad vs worse control
    • 46. Any diabetes-related endpoints 0% 10% 20% 30% 40% 50% 0 3 6 9 % of patients with events Tight blood pressure control (758) Less tight blood pressure control (390) risk reduction 24% p=0.0046 Years from randomisation risk reduction 32% p=0.019 Diabetes-related deaths Stroke 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 44% p=0.013 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 37% p=0.0092 Microvascular endpoints
    • 47. Any diabetes-related endpoints 0% 10% 20% 30% 40% 50% 0 3 6 9 % of patients with events Tight blood pressure control (758) Less tight blood pressure control (390) risk reduction 24% p=0.0046 Years from randomisation risk reduction 32% p=0.019 Diabetes-related deaths Stroke 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 44% p=0.013 0% 5% 10% 15% 20% 0 3 6 9 % patients with event Years from randomisation risk reduction 37% p=0.0092 Microvascular endpoints
    • 48. UK Prospective Diabetes Study
      • An intensive glucose control policy HbA 1c 7.0 % vs 7.9 %
      • reduces risk of
        • any diabetes-related endpoints 12% p=0.030
        • microvascular endpoints 25% p=0.010
        • myocardial infarction 16% p=0.052
      • A tight blood pressure control policy 144/82 vs 154/87
      • mmHg reduces risk of
        • any diabetes-related endpoint 24% p=0.005
        • microvascular endpoint 37% p=0.009
        • stroke 44% p=0.013
    • 49. UK Prospective Diabetes Study
      • An intensive glucose control policy HbA 1c 7.0 % vs 7.9 %
      • reduces risk of
        • any diabetes-related endpoints 12% p=0.030
        • microvascular endpoints 25% p=0.010
        • myocardial infarction 16% p=0.052
      • A tight blood pressure control policy 144/82 vs 154/87
      • mmHg reduces risk of
        • any diabetes-related endpoint 24% p=0.005
        • microvascular endpoint 37% p=0.009
        • stroke 44% p=0.013
      The benefit from tight glycemic control is less than the benefit from lousy blood pressure control
    • 50.
      • Hypertension Optimal Treatment trial (HOT Trial) randomized 18,790 patients to one of three diastolic blood pressure goals
      • 8% of the original cohort was diabetic
      • The first line agent was felodipine
      Harrison L, Et al. Lancet 1998; 351: 1755-1762. HOT Diabetics
    • 51.  
    • 52. Don’t worry about the glucometer get the BP under control
    • 53. Microalbumin is the Hemoglobin A1c of blood pressure management. Dr Whitey routinely checks A1c to make sure my diabetes is on track.
    • 54. Microalbumin is the Hemoglobin A1c of blood pressure management. Dr Whitey routinely checks Hgb A1c to make sure my diabetes is on track. Dr Whitey routinely checks µAlb to verify my blood pressure is on track.
    • 55. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 56. Lewis, E. J. et al. N Engl J Med 1993;329:1456-1462 Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups
    • 57. RENAAL Trial 1513 type II DM with nephropathy Cr 1.9 Randomized to placebo or losartan Primary outcome: composite of doubling serum Cr, ESRD, or death Brenner BM, Et al. NEJM 2001; 343: 861-9.
    • 58. ACEi are good ARB are good What about both together?
    • 59. CALM Study
      • N= 200
      • Type II DM with microalbuminuria
      • Randomized to:
        • Lisinopril 20 mg qd
        • Candesartan 16 mg qd
        • Combination of lisinopril 20 mg and candesartan 16 mg
      Mogensen CE, Et al. BMJ 2000; 321: 1440-4.
    • 60. CALM Study
      • N= 200
      • Type II DM with microalbuminuria
      • Randomized to:
        • Lisinopril 20 mg qd
        • Candesartan 16 mg qd
        • Combination of lisinopril 20 mg and candesartan 16 mg
      Mogensen CE, Et al. BMJ 2000; 321: 1440-4.
    • 61. Cooperate Trial: ACEi+ARB in non-diabetics 263 patients with non-diabetic renal disease Average GFR 37.5 mL/min Average protein excretion 2.5 g/day Randomized to losartan 100mg, trandolapril 3mg, or both Nakao N, Et al. Lancet 2003; 361: 117-24. Endpoint: doubling of serum creatinine or dialysis
    • 62. Potassium Potassium
    • 63.
      • RESOLVD
        • 768 patients with heart failure (NYHA II to IV)
        • Potassium rose 0.11 mmol/L (p<0.05 vs Candesartan alone and enalepril alone)
      • ValHeFT
        • 5010 patients with heart failure (NYHA II to IV and EF<40%)
        • Potassium rose 0.12 mmol/L (p<0.001)
      • CHARM-Added trial
        • 2548 patients with heart failure (NYHA II to IV and EF<40%)
        • No significant change in potassium
      McKelvie RS, Et al. Circulation 1999; 100: 1056-64. Cohn JN, Et al. N Eng J Med 2001; 345: 1667-75. McMurray JJ, Et al. Lancet 2003; 362: 767-71.
    • 64.
      • Any addition of an:
        • ACEi
        • ARB
        • Aldosterone antagonist
        • Diuretic
      • Must check electrolytes one week later
      • High potassium
        • Stop the drug
        • Low potassium diet
        • Loop diuretic
        • Thiazide diuretic
        • Liberalize sodium restriction
    • 65. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 66. Theory: reduce proteinuria, reduce cardiovascular events High  High | High  Low | Low  High | Low  Low Ibsen H, Et al. Hypertension 2005; 45: 198-202. Pre-specified subanalysis of the LIFE trial 8206 men and women ages 55-80 with hypertension and LVH 13% were diabetics Primary analysis was Atenolol vs Losartan Composite endpoint (CEP) was CV death, non-fatal stroke, or non-fatal MI
    • 67. Theory: reduce proteinuria, reduce cardiovascular events High  High | High  Low | Low  High | Low  Low Ibsen H, Et al. Hypertension 2005; 45: 198-202. Pre-specified subanalysis of the LIFE trial 8206 men and women ages 55-80 with hypertension and LVH 13% were diabetics Primary analysis was Atenolol vs Losartan Composite endpoint (CEP) was CV death, non-fatal stroke, or non-fatal MI … Reduction in albuminuria during treatment translates to a reduction in cardiovascular events…
    • 68. Theory: reduce proteinuria, reduce cardiovascular events and renal end-points Reanalysis of the RENAAL trial. Instead of the intension to treat analysis, patients were analyzed by baseline proteinuria or reduction in proteinuria. The reduction in albuminuria at 6 months predicted outcomes at 42 months De Zeeuw D, Et al. Circulation 2004; 110: 921-927.
    • 69. Theory: reduce proteinuria, reduce cardiovascular events and renal end-points Reanalysis of the RENAAL trial. Instead of the intension to treat analysis, patients were analyzed by baseline proteinuria or reduction in proteinuria. The reduction in albuminuria at 6 months predicted outcomes at 42 months … Interestingly, suppression of albuminuria was the strongest predictor of long-term protection from cardiovascular events… De Zeeuw D, Et al. Circulation 2004; 110: 921-927.
    • 70. Conclusion: reduction in proteinuria reduces CV complications and renal complications Implications: reduction in proteinuria can be used as an intermediate end-point, i.e. interventions which reduce proteinuria are good.
    • 71. Calcium channel blockers
      • Verapamil does not delay development of microalbuminuria
      • Verapamil does reduce proteinuria in diabetics independent of changes in blood pressure
      Ruggenenti P, Et al. N Eng J Med 2004; 351: 1941-51. % Change in Proteinuria Blood pressure Bakris GL, Et al. Kidney Int 1998; 58: 1283-9.
    • 72. Calcium channel blockers
      • Verapamil does not delay development of microalbuminuria
      • Verapamil does reduce proteinuria in diabetics independent of changes in blood pressure
      Aldosterone antagonists
      • Spironolactone reduces proteinuria in diabetics
        • Change in proteinuria is independent of blood pressure
      • All patients were treated with an ACEi or ARB
      • 24-Hr ambulatory BP fell 6/2
      Schjoedt KJ, Et al. Kidney International 2006; 70: 536 -5 42.
    • 73. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 74. Run-in ACEi or ARB ACEi + ARB Atorvastatin Group A Placebo Group B Randomization Bianchi S, Et al. Am J Kidney Dis 2003; 41:565-570. A Controlled, Prospective Study of the Effects of Atorvastatin on Proteinuria and Progression of Kidney Disease 56 men and women with non-diabetic GN CrCl 53 mL/min and proteinuria = 2.5 g/d
    • 75. GREACE Study 1541Greek men and women Age < 75, LDL > 100 and hx CHD 20% DM 3 year follow-up CHD events: Study:12% vs control: 24.5% Athyros VG, Et al. J Clin Pathol 2004; 57: 728 - 34.
    • 76. Conclusions
      • Diabetic nephropathy is the most common cause of ESRD in the world
      • ESRD is a rare out-come among diabetics
      • Just over half of diabetics will develop nephropathy
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 reduction
      • Proteinuria reduction
        • ACEi + ARB
        • Statins
        • Aldosterone antagonists
        • Dihydropyridine calcium channel blockers
        • Carvedilol
    • 77. Incidence of ESRD due to diabetic nephropathy IDNT RENALL
    • 78. fin

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