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1 Author(s): Frank Brosius, M.D, 2011 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution Noncommercial Share Alike 3.0 License: We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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3 Kidney Systemic Disease Diabetes Frank Brosius, M.D. Fall 2010
4 Diabetic Nephropathy--Objectives Understand pathology and pathogenesis Identify early clinical predictors or indicators Describe most important therapeutic interventions to prevent progression
5 Diabetic Nephropathy: You can't cure it so you have to endure it King, et al. Qual Health Res. 2002;12: American Diabetes Association
6 Diabetes is the dominant cause of ESRD in USA Incident ESRD patients; Medical Evidence form data; rates adjusted for age, gender, & race. U.S. Renal Data System, 2009 USRDS 2009
7 Incidence rates of ESRD (per million population): 1997 Incident ESRD patients, by HSA; rates adjusted for age, gender, & race. Excludes patients residing in Puerto Rico & the Territories. U.S. Renal Data System, 2009 USRDS 2009
8 Incidence rates of ESRD (per million population): 2007 Incident ESRD patients, by HSA; rates adjusted for age, gender, & race. Excludes patients residing in Puerto Rico & the Territories. U.S. Renal Data System, 2009 USRDS 2009
9 Obesity, metabolic syndrome and type 2 diabetes mellitus CalorieLab CalorieLab based on the Behavioral Risk Factor Surveillance System database maintained by the CDC. Rankings use a three-year average for smoothing.
10 Adjusted five-year survival, by modality & primary diagnosis: : still lousy Incident dialysis patients & patients receiving a first transplant in the calendar year. All probabilities are adjusted for age, gender, & race; overall probabilities are also adjusted for primary diagnosis. All ESRD patients, 1996, used as reference cohort. Modality determined on first ESRD service date; excludes patients transplanted or dying during the first 90 days (fiveyear survival probabilities noted in parentheses). U.S. Renal Data System, 2009 USRDS 2009
11 Adjusted five-year survival, by modality & primary diagnosis: : still lousy ESRD Non small-cell lung cancer AJCC stage: IIIA or IIIB U.S. Renal Data System, 2009 Diabetic nephropathy = Cancer Int J Radiat Oncol Biol Phys Jul 15 USRDS 2009
12 American Diabetes Association 15-20%
13 Risk factors for renal disease in Type II DM Genetic factors (familial clustering) Hyperglycemia Hypertension Glomerular hyperfiltration/hypertension Smoking Male gender Advanced age Race UpToDate, 2010
14 Genetic factors ELMO1, NOS3, etc Family Investigation of Nephropathy of Diabetes (FIND) Consortium American Diabetes Association
15 Hyperglycemia American Diabetes Association
16 Race: Diabetes is the dominant cause of ESRD in USA more so in AAs December 31 point prevalent ESRD patients; rates adjusted for age & gender. U.S. Renal Data System, 2009 USRDS 2009
17 Screening American Diabetes Association
18 Screening for diabetic nephropathy: 1) Microalbuminuria from Standards of Medical Care in Diabetes 2010 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010
19 Evaluation of microalbuminuria Test type 1 patients after 5 years and every year thereafter Test type 2 patients every year If positive, rule out transient causes of microalbuminuria (e.g., CHF, exercise (within 24 hr), infection, fever, severe HTN) Repeat 2 times in 3-6 months Microalbuminuria = 2/3 tests positive.
20 Screening for diabetic nephropathy: 2) Estimate GFR Measure serum creatinine at least annually in all adults with diabetes regardless of the degree of urine albumin excretion. The serum creatinine should be used to estimate GFR and stage the level of chronic kidney disease (CKD), if present. from Standards of Medical Care in Diabetes-2010 DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2010
21 Pathology American Diabetes Association
22 Source Undetermined
23 Pathology of DM nephropathy Normal Glomerulus Early Diabetic Glomerulus Podocyte damage & loss Capillary lumen Basement membrane Thickened BM Mesangial cell Mesangium Expanded mesangium Source Undetermined Afferent and efferent hyaline arteriolosclerosis Interstitial fibrosis and tubular atrophy
24 Pathology of DM nephropathy Normal glomerulus Diffuse mesangial sclerosis Nodular mesangial sclerosis Source Undetermined
25 Pathology of DM nephropathy Normal Glomerulus Early Diabetic Glomerulus Podocyte damage & loss Capillary lumen Basement membrane Thickened BM Mesangial cell Mesangium Expanded mesangium Source Undetermined Afferent and efferent hyaline arteriolosclerosis Interstitial fibrosis and tubular atrophy
26 Podocyte loss predicts progression of nephropathy Albuminuria 4 yrs later Incr. in albuminuria in 4 yrs Podocyte number Podocyte number Meyer, et al. Diabetologia. 1999;42:1341
27 Pathogenesis American Diabetes Association
28 Source Undetermined?
29 Simpleminded model of pathogenesis of DM nephropathy Renal preglomerular vasodilation Systemic hypertension from T. Hostetter Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors Δ metabolism of glom. cells
30 Source Undetermined
31 Simpleminded model of pathogenesis of DM nephropathy Renal preglomerular vasodilation Systemic hypertension from T. Hostetter Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors Δ metabolism of glom. cells
32 Potential mechanisms for increased matrix production in hyperglycemia glucose stretch AII TGF-β GLUT1 AGEs ROS glucose sorbitol fructose DAG NADH/NAD PKCβ ERKs TGF-β fibronectin collagen IV Mesangial cell Source Undetermined
33 Unified field theorem for diabetic complications: oxidative stress rules Brownlee, Nature, 414:813, 2001 Brownlee, Nature, 414:813, 2001
34 or maybe it s all inflammation? Scmid et al., Modular activation of nuclear factor-kappab transcriptional programs in human diabetic nephropathy. Diabetes, 2006; 200;55:2993
35 Treatment American Diabetes Association
36 Treatment of DM nephropathy: Glucose control Renal preglomerular vasodilation Systemic hypertension from T. Hostetter Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors Δ metabolism of glom. cells
37 The Diabetes Control And Complications Trial (DCCT) INDIVIDUALS WITH IDDM CONVENTIONAL INSULIN THERAPY INTENSIVE INSULIN THERAPY CONTROL OF Sx s. NORMALIZE BLOOD SUGAR Does long-term normalization of blood glucose levels in type 1 diabetes reduce the risk of development or progression of microvascular complications?
38 The Benefits of Tight Control : The DCCT DCCT RESULTS: The Good News Rate/100 pt-yrs Rate/100 pt-yrs. RETINOPATHY CONVENTIONAL NEPHROPATHY NEUROPATHY INTENSIVE Intensive metabolic control dramatically reduced the risk of developing or worsening microvascular complications in type 1 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS), demonstrated very similar results in individuals with type 2 diabetes.
39 Intensive insulin Rx prevents diabetic nephropathy for years after (EDIC) HbA1c levels after end of DCCT Cumulative incidence of nephropathy Arch Int Med; 2009;169(14):1307 Arch Int Med; 2009;169(14):1307
40 American Diabetes Association
41 Treatment of DM nephropathy: Hypertension control Renal preglomerular vasodilation Systemic hypertension from T. Hostetter Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors Δ metabolism of glom. cells
42 Effect of antihypertensives on progression of DM nephropathy Rate of decline In GFR (ml/min/mo.) MAP post Rx (mmhg) Source Undetermined
43 Treatment of DM nephropathy: Effect of ACEIs and ARBs Renal preglomerular vasodilation Systemic hypertension from T. Hostetter Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors Δ metabolism of glom. cells
44 Source Undetermined ACEI or ARB DM
45 Delaying nephropathy with ACE inhibitors Lewis et al., NEJM 329:1456, 1993 Lewis et al., NEJM 329:1456, 1993
46 Delay of diabetic nephropathy in type 2 patients with ARBs RENAAL Reduction of endpoints in non-insulindependent diabetes mellitus with the angiotensin II receptor antagonist losartan IDNT IRMA-II Irbesartan diabetic nephropathy trial irbesartan in patients with type II diabetes and microalbuminuria NEJM, 2001 ARB = angiotensin receptor blocker
47 Delay of diabetic nephropathy in type 2 patients with ARBs RENAAL and IDNT-- pts with established overt nephropathy Age = 60 (IDNT) virtually all pts hypertensive; groups had similar BPs endpoints = 2x serum creatinine, ESRD, death 20-33% reduction in endpoints in ARB treated pts vs control or amlodipine-treated pts IRMA-II reduction in proteinuria and rate of progression to overt nephropathy in type 2 pts with microalbuminuria
48 Treatment of DM nephropathy: Effect of dietary protein restriction Renal preglomerular vasodilation Systemic hypertension from T. Hostetter Glomerular hypertension Glomerular sclerosis Hyperglycemia Genetic factors Δ metabolism of glom. cells
49 Effect of dietary protein restriction on progression of DM nephropathy GFR (ml/min) Source Undetermined
50 Treatment of DM nephropathy: Effect of statins Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia ROS Genetic factors Δ metabolism of glom. cells from T. Hostetter
51 Effects of lipid lowering on progression of diabetic nephropathy Fried, et al., Kidney Int, 2001; 59:260 Fried, et al., Kidney Int, 2001; 59:260
52 Treatment of DM nephropathy: All together! Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Glomerular sclerosis Hyperglycemia ROS Genetic factors Δ metabolism of glom. cells from T. Hostetter
53 Remission of microalbuminuria Likelihood of regression NEJM 348: 2265, 2003 NEJM 348: 2265, 2003
54 American Diabetes Association?
55 Remittive effect of pancreas Tx on DM nephropathy GBM TBM time after Tx 0 yr 5 yr 10 yr Mesangial fx. vol Matrix fx. vol Fioretto, et al. N Engl J Med. 1998, 339:69 Fioretto, et al. N Engl J Med. 1998, 339:69
56 Remittive effect of long term ACEI on chronic nephropathies Ruggenenti, JASN10:997, 99
57 Remission of microalbuminuria results in fewer cardiovascular and kidney events N=123 N=93 Araki, et al., Diabetes Jun;56:1727 Araki, et al., Diabetes Jun;56:1727
58 Clinical course M.W. (34 yo female with type 1 DM for 33.5 yrs) 3 BP = 133/83 4 Pregnancy Estimated GFR (ml/min) U Pro/creat BP = 100/ Stopped ACEI Source Undetermined Last egfr = 47 ml/min Source Undetermined
59 Diabetic Nephropathy: You can't cure it so you have to endure it With current treatment, we can keep patients stable or in remission for years.. But can we do better? Estimated GFR (ml/min) U Pro/creat American Diabetes Association Source Undetermined
60 Management of Diabetic Nephropathy-Dx Screen for microalbuminuria and egfr (1x/yr). Identify high risk patients. Monitor BP, blood glucose closely at home. Monitor for macrovascular disease.
61 Management of Diabetic Nephropathy-Rx Normalize BP. Target <130/80. Treat with ACE inhibitors or ARBs. Treat hyperlipidemia and hyperglycemia aggressively. Moderate protein restriction ( gm/kg/day). Treat cardiovascular disease aggressively. Refer to nephrologist early in course of azotemia.
62 Slide 5: American Diabetes Association Slide 6: U.S. Renal Data System, 2009, Slide 7: U.S. Renal Data System, 2009, Slide 8: U.S. Renal Data System, 2009, Slide 9: CalorieLab, Slide 10: U.S. Renal Data System, 2009, Slide 11: U.S. Renal Data System, 2009, Slide 12: American Diabetes Association Slide 14: American Diabetes Association Slide 15: American Diabetes Association Slide 16: U.S. Renal Data System, 2009, Slide 17: American Diabetes Association Additional Source Information for more information see: Slide 18: Standards of Medical Care in Diabetes 2010 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010 Slide 20: Diabetes Care, 23:S69, 2000 Slide 21: American Diabetes Association Slide 22: Source Undetermined Slide 23: Source Undetermined Slide 24: Source Undetermined Slide 25: Source Undetermined Slide 26: Meyer, et al. Diabetologia. 1999;42:1341 Slide 27: American Diabetes Association Slide 28: Source Undetermined Slide 30: Source Undetermined Slide 32: Source Undetermined Slide 33: Brownlee, Nature, 414:813, 2001 Slide 34: Scmid et al., Modular activation of nuclear factor-kappab transcriptional programs in human diabetic nephropathy. Diabetes, 2006; 200;55:2993 Slide 35: American Diabetes Association Slide 39: Arch Int Med; 2009;169(14):1307 Slide 40: American Diabetes Association Slide 42: Source Undetermined Slide 44: Source Undetermined Slide 45: Lewis et al., NEJM 329:1456, 1993 Slide 49: Source Undetermined Slide 51: Fried, et al., Kidney Int, 2001; 59:260 Slide 53: NEJM 348: 2265, 2003 Slide 54: American Diabetes Association Slide 55: Fioretto, et al. N Engl J Med. 1998, 339:69 Slide 56: Ruggenenti, JASN10:997, 99 Slide 57: Araki, et al., Diabetes Jun;56:1727 Slide 58: Source Undetermined Slide 59: American Diabetes Association; Source Undetermined
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