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
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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
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
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31. When is proteinuria not diabetic nephropathy? When does a diabetic need a biopsy?
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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
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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.
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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.
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.
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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?
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
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.
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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.
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.