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Diabetic Nephropathy 2009

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best ever lecture on diabetic nephropathy

best ever lecture on diabetic nephropathy


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  • Start with big superman symbol Talk about three important points on the S Where the flattening ends Where the peak incidence is Where the fades away
  • 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.
  • Two biopsies from the same patient, the patient had unilateral RAS on the left. The RAS prevented the hyperfiltration on the left and protected the patient.
  • 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 renal failure or death, vitreous haemorrhage or photocoagulation
  • Hypertension optimal treatment rqandomized 18,790 patients to one ot 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.
  • Picture of blood pressure cuff and glucometer State why does every diabetic patient get a glucometer and none get home bp monitor? Rhetoric question: The reason is bp therapy can safely be administered without home monitoring while tight glycemic control requires glycemic monitoring
  • Figure 1. Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups. Panel A shows the cumulative percentage of patients with the primary end point: a doubling of the base-line serum creatinine concentration to at least 2.0 mg per deciliter. Panel B shows the cumulative percentage of patients who died or required dialysis or renal transplantation. The numbers at the bottom of each panel are the numbers of patients in each group at risk for the event at base line and after each six-month period.
  • Transcript

    • 1. Diabetic Nephropathy
      • Joel Michels Topf, MD Clinical Nephrologist
    • 2.
      • Year Capacity
      • 1926 84,401
      • 85,753
      • 97,239
      • 101,001
      • 1991 102,501
      • 107,501
      • 107,501
      • 2006 107,501
      • 2009 106,201
      Incident ESRD 0 0 0 0 56,103 87,179 91,275 110,854 117,632
    • 3.  
    • 4.  
    • 5. Etiologies of ESRD
    • 6.  
    • 7.  
    • 8. Diabetes, diabetic nephropathy and the epidemic raging in the U.S.
    • 9.
      • Diabetics on Dialysis: 183,706
      USRDS Atlas 2005 http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7 Total no of Diabetics: 23,600,000 0.78%
    • 10. ESRD CV Mortality
    • 11. Finne, P. JAMA 2005; 294:1782-87.
    • 12. Diabetic nephropathy
      • Progressive renal damage as a result of diabetis mellitus type I or II
      • Initially, patients have increased GFR (2x normal)
      • Followed by proteinuria
      • Followed by progressively deteriorating GFR
    • 13. Diabetic nephropathy
      • Progressive renal damage as a result of diabetis mellitus type I or II
      • Initially, patients have increased GFR (2x normal)
      • Followed by proteinuria
      • Followed by progressively deteriorating GFR
    • 14. 5-10 years 15-20 years 20 years
    • 15. Ritz E, et al. N Engl J Med 1999;341 :1127-33.
    • 16. 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
    • 17. nodular glomerulosclerosis Kimmelstiel-Wilson lesions
    • 18.
      • 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.
    • 19. 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
    • 20. 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
    • 21. 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
    • 22. Hyperfiltration
      • Early finding
      • Renal vasodilation
        • Causes early increases in GFR
      • Later
        • Nephron loss results in compensatory hyperfiltration
        • No increase in GFR
    • 23. Pathology
    • 24.  
    • 25. A B C 0 years 5 years 10 years
    • 26.
      • What is microalbuminuria?
      • Any albumin in the urine
      • Trace protein on dipstick in a first morning specimen
      • 20-200 µg/min on a timed specimen
      • 30-300 mg albumin/g creatinine
      • 30-300 mg/L
      • What is macroalbuminuria?
      • 1+ protein on a dipstick in a first morning specimen
      • 1+ protein on a dipstick at any time
      • >250 mg in 24 hours
      • >3.5 g per 24 hours
      Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Diabetes
    • 27. 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)
    • 28. Perkins BA, Et al. N Engl J Med 2003;348:2285-93. Cholesterol < 198 Triglycerides < 145 Glycemic control (hgb a1c <8) Blood pressure (sbp<115) ACEi Diagnosis Hyperfiltration Microalbuminuria Macroalbuminuria Renal failure Type I
    • 29. 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
    • 30. 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
    • 31. When is proteinuria not diabetic nephropathy? When does a diabetic need a biopsy?
    • 32. 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, HIV
      • Absence of retinopathy or neuropathy
    • 33. TREATMENT
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 34. Intensive therapy
      • Low fat (<30%) diet
      • 30 minutes exercise 3-5 days/week
      • Smoking cessation
      • ACEi regardless of blood pressure
      • Vitamin
      • Aspirin
      • A1c <6.5
      • Blood pressure control
      • Cholesterol control
      Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.
    • 35. Primary end point
      • CV Death
      • Non fatal MI
      • CABG/PCI
      • Nonfatal stroke
      • Amputation
      • Peripheral revascularization
      Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.
    • 36. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 37. 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
    • 38. 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
    • 39. 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 0 10 20 30 40 50 0 3 6 9 12 15 Proportion of patients (%) Years from randomisation Hypoglycemia: any episode 0 1 2 3 4 5 0 3 6 9 12 15 Hypoglycemia: major episodes Proportion of patients (%)
    • 40. 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
    • 41. 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
    • 42. 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
    • 43.  
    • 44.  
    • 45.  
    • 46.
      • 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
    • 47.  
    • 48. Home blood pressure is the hemoglobin A1c of blood pressure management. Dr Whitey routinely checks Hgb A1c to make sure my diabetes is on track. Dr Whitey asks me check my home BP to verify my BP is on track.
    • 49. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 50. 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
    • 51. 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.
    • 52. Picture of world with/without electricity
    • 53. ACEi are good, ARB are good… in patients with albuminuria. What about in normotensive patients without albuminuria?
    • 54. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
    • 55.
      • Multicenter, randomized, double blind controlled trial
      • 285 normotensive patients with type I dm and albuminuria < 20 µg/min
      • Randomized to placebo, enalepril 10/20 mg or losartan 50/100 mg
      • Primary endpoint was change in mesangial volume on renal biopsy
      Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
    • 56. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
    • 57. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
    • 58. Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51. Progression of diabetic retinopathy (2 steps) Odds ratio vs placebo Placebo 38% 1 Enalepril 25% 0.35 (65% reduction) Losartan 21% 0.30 (70% reduction)
    • 59. ACEi are good ARB are good What about both together?
    • 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. Combination ACEi & ARB: the Meta analysis
      • 10 studies of patients with diabetic nephropathy
      • 315 patients randomized to ACEi or ACEi and ARB
      Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007
    • 62. Problem: Too short Wrong target
    • 63.
      • Studies use change in proteinuria as the primary endpoint
      • Most were 8-12 weeks in duration
        • Significant reduction in proteinuria compared to ACEi (p=0.01)
        • Reduced GFR (3.9 ml/min, p=0.03)
        • Increase in potassium (0.2 mmol/L, p<0.01)
        • Reduction in BP (5.2/5.3, p<0.01)
      Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007
    • 64. STUDIES OF ACEI + ARB IN NON-DIABETICS
      • What about the data of dual therapy in non-diabetics
    • 65. On Target
      • Telmisartan + ramipril vs ramipril vs telmisartan
      • Outcome: CV death, MI, CVA, hospitalization for CHF
      • 25,620 patients were randomized
      • Study population: age >55, coronary, peripheral or cerebrovascular disease or diabetes with end-organ damage
      ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
    • 66.
      • 37% had diabetes
      • 13% had microalbuminuria
      • 50% had prior MI
      • 22%had prior CABG
      • 68% had history of hypertension
      • 56 months of follow-up
      ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
    • 67. Primary outcome ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
    • 68. Renal outcomes
      • Renal impairment:
        • 13.5% with combo tx
        • 10.2% ramipril
        • 10.6% telmisartan
        • RR 1.33 for combination tx (p=<0.001)
      • Initiation of dialysis
        • 0.8% with combination therapy
        • 0.6% with monotherapy
        • RR 1.37 (p=0.1)
      ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
    • 69. Renal outcomes
      • Second publication with data focused on renal outcomes
        • Primary outcome for this publication was dialysis, death or doubling of serum creatinine
      Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008
    • 70. Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008 0.037 0.038 0.020
    • 71. Increased renal outcomes despite better proteinuria
    • 72. 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
    • 73. Potassium Potassium
    • 74.
      • 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.
    • 75.
      • Any addition of
        • 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
    • 76. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 77. 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…
    • 78. 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.
    • 79. 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.
    • 80. 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
      Carvedilol
      • RCT of metoprolol vs. carvedilol, improved A1c and albuminuria
      Bakris GL, Et al. JAMA 2004; 292: 2227-36. 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. Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.
    • 81. Aliskiren in addition to losartan in DM2 and nephropathy
      • RCT double blind, multicenter
      • N=599
      • Placebo vs 150 mg aliskiren for 3 months
      • Followed by doubling of the dose of the placebo and aliskiren (300 mg)
      • Study duration 6 months
    • 82.
      • Use of aliskiren 150 mg for 3 months and 300 mg for 3 months lowered albuminuria 20% compared to placebo
      150 mg 300 mg
    • 83. Treatment
      • Blood pressure control
      • Glycemic control
      • Angiotensin 2 control
      • Proteinuria control
      • Cholesterol control
    • 84. 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
    • 85. 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.
    • 86. Endothelin antagonists
      • Avosentan is an endothelin A antagonist
      • Endothelin A receptors stimulate matrix production in animal models of diabetic nephropathy
      • Avosentan proof of concept
        • 286 diabetics with 1.0-1.5 g proteinuria on ACEi/ARB
        • reduced the urinary albumin excretion rate by about 50%
        • No change in BP, HR, CrCl
        • Slight decrease in Hct
    • 87. Ascend trial, Phase III trial of Avosentan
      • International multi-center, double-blind, placebo-controlled trial.
      • Randomization is 1:1:1
        • 25 mg avosentan
        • 50 mg avosentan
        • Placebo
      • End-point is doubling of serum creatinine, ESRD or death
      • Enrollment criteria
        • Type II diabetics age 21-80
        • Diabetes at least 3 yrs ago
        • Albuminuria > 300 mg/day
        • Cr 1.0-1.4 for men
        • Cr 1.0-1.3 for women
        • All patients must be on ACEi/ARB or intolerant
    • 88. 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
        • Endothelin antagonists
    • 89. Incidence of ESRD due to diabetic nephropathy IDNT RENALL
    • 90. fin

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