Author(s): Frank Brosius, M.D, 2011License: Unless otherwise noted, this material is made available under the terms of the...
Citation Key                              for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share +...
Kidney Systemic Disease Diabetes                     Frank Brosius, M.D.Fall 2010
Diabetic Nephropathy--Objectives•  Understand pathology and pathogenesis•  Identify early clinical predictors or indicator...
Diabetic Nephropathy: You cant cure it so you have to endure it   King, et al. Qual Health Res. 2002;12:329-46            ...
Diabetes is the dominant                                cause of ESRD in USA                                Incident ESRD ...
Incidence rates of ESRD (per                        million population): 1997                                             ...
Incidence rates of ESRD (per                        million population): 2007                                             ...
Obesity, metabolic syndrome and type 2           diabetes mellitus                 CalorieLab      CalorieLab® based on th...
Adjusted five-year survival, by modality               & primary diagnosis: 1993-2002: still lousyIncident dialysispatient...
Adjusted five-year survival, by modality  & primary diagnosis: 1998-2002: still lousy                                     ...
15-20%American Diabetes Association
Risk factors for renal disease in               Type II DM                 •    Genetic factors (familial clustering)     ...
Geneticfactors                                          ELMO1, NOS3, etc                                                  ...
Hyper-glycemia           American Diabetes Association
Race: Diabetes is thedominant cause of  ESRD in USA …more so in AAs  December 31 point prevalent ESRD patients; rates     ...
Screening            American Diabetes Association
Screening for diabetic nephropathy:        1) Microalbuminuriafrom Standards of Medical Care in Diabetes—2010DIABETES CARE...
Evaluation of microalbuminuria•  Test type 1 patients after 5 years and every   year thereafter•  Test type 2 patients eve...
Screening for diabetic nephropathy:         2) Estimate GFR          Measure serum creatinine at least annually        in ...
Pathology            American Diabetes Association
Source Undetermined
Pathology of DM nephropathyNormal Glomerulus                                             Early Diabetic Glomerulus        ...
Pathology of DM nephropathyNormal glomerulus       Diffuse mesangial sclerosis   Nodular mesangial sclerosis  Source Undet...
Pathology of DM nephropathyNormal Glomerulus                                             Early Diabetic Glomerulus        ...
Albuminuria 4 yrs laterPodocyte loss   predictsprogression of                                                     Podocyte...
Pathogenesis               American Diabetes Association
?Source Undetermined
Simpleminded model of       pathogenesis of DM nephropathy                    Renal preglomerular vasodilation            ...
Source Undetermined
Simpleminded model of       pathogenesis of DM nephropathy                    Renal preglomerular vasodilation            ...
Potential mechanisms for increased            matrix production in hyperglycemia                                          ...
Unified field theorem for diabetic complications:               oxidative stress rules   Brownlee, Nature, 414:813, 2001  ...
…or maybe it s all inflammation?        Scmid et al., Modular activation of nuclear factor-kappaB transcriptional        p...
Treatment            American Diabetes Association
Treatment of DM nephropathy:                Glucose control                    Renal preglomerular vasodilation           ...
The Diabetes Control And Complications Trial               (DCCT) 1993                         1400 INDIVIDUALS WITH IDDM ...
The Benefits of Tight Control : The DCCT                                         DCCT RESULTS: The Good News              ...
Intensive insulin Rx prevents diabetic   nephropathy for years after (EDIC)HbA1c levels after end of DCCT     Cumulative i...
American Diabetes Association
Treatment of DM nephropathy:               Hypertension control                    Renal preglomerular vasodilation       ...
Effect of antihypertensives on         progression of DM nephropathyRate of declineIn GFR (ml/min/mo.)         MAP post Rx...
Treatment of DM nephropathy:            Effect of ACEIs and ARBs                    Renal preglomerular vasodilation      ...
ACEI or   DMSource Undetermined                       ARB
Delaying nephropathy with ACE inhibitors Lewis et al., NEJM 329:1456, 1993   Lewis et al., NEJM 329:1456, 1993
Delay of diabetic nephropathy in type        2 patients with ARBs   RENAAL    Reduction of endpoints in non-insulin-      ...
Delay of diabetic nephropathy in type 2          patients with ARBs   RENAAL and IDNT--     • pts with established overt n...
Treatment of DM nephropathy:      Effect of dietary protein restriction                    Renal preglomerular vasodilatio...
Effect of dietary protein restriction     on progression of DM nephropathy    GFR    (ml/min)Source Undetermined
Treatment of DM nephropathy:                          Effect of statins                        Renal preglomerular vasodil...
Effects of lipid lowering on progression          of diabetic nephropathyFried, et al., Kidney Int, 2001; 59:260   Fried, ...
Treatment of DM nephropathy:                            All together!                        Renal preglomerular vasodilat...
Remission of microalbuminuria                          Likelihood of regressionNEJM 348: 2265, 2003   NEJM 348: 2265, 2003
?American Diabetes Association
GBM                                       TBMRemittive effect ofpancreas Tx on DM   nephropathy                 time after...
Remittive effect of long termACEI on chronic nephropathies       Ruggenenti, JASN10:997, 99
Remission ofmicroalbuminuria                                                                                N=123 results ...
Clinical course — M.W. (34 yo female                                 with type 1 DM for 33.5 yrs)                     3   ...
Diabetic Nephropathy: You cant cure it soyou have to endure it                                            American Diabete...
Management of Diabetic    Nephropathy-Dx•  Screen for microalbuminuria and eGFR (1x/yr).•  Identify high risk patients.•  ...
Management of Diabetic          Nephropathy-Rx•  Normalize BP. Target <130/80.•  Treat with ACE inhibitors or ARBs.•  Trea...
Additional Source Information                                for more information see: http://open.umich.edu/wiki/Citation...
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09.22.10: Diabetic Nephropathy

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09.22.10: Diabetic Nephropathy

  1. 1. Author(s): Frank Brosius, M.D, 2011License: Unless otherwise noted, this material is made available under the terms of the CreativeCommons Attribution–Noncommercial–Share Alike 3.0 License:http://creativecommons.org/licenses/by-nc-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adaptit. 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 open.michigan@umich.edu with any questions, corrections, orclarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medicalevaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about yourmedical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. Kidney Systemic Disease Diabetes Frank Brosius, M.D.Fall 2010
  4. 4. Diabetic Nephropathy--Objectives•  Understand pathology and pathogenesis•  Identify early clinical predictors or indicators•  Describe most important therapeutic interventions to prevent progression
  5. 5. Diabetic Nephropathy: You cant cure it so you have to endure it King, et al. Qual Health Res. 2002;12:329-46 American Diabetes Association
  6. 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. 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. 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. 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. 10. Adjusted five-year survival, by modality & primary diagnosis: 1993-2002: still lousyIncident dialysispatients & patientsreceiving a firsttransplant in thecalendar year. Allprobabilities areadjusted for age,gender, & race;overallprobabilities arealso adjusted forprimary diagnosis.All ESRD patients,1996, used asreference cohort.Modalitydetermined onfirst ESRD servicedate; excludespatientstransplanted ordying during thefirst 90 days (five-year survivalprobabilities notedin parentheses). U.S. Renal Data System, 2009 USRDS 2009
  11. 11. Adjusted five-year survival, by modality & primary diagnosis: 1998-2002: still lousy Non–small-cell lung cancer ESRD AJCC stage: IIIA or IIIB Diabetic nephropathy = Cancer USRDS 2009U.S. Renal Data System, 2009 Int J Radiat Oncol Biol Phys. 2005 Jul 15
  12. 12. 15-20%American Diabetes Association
  13. 13. Risk factors for renal disease in Type II DM •  Genetic factors (familial clustering) •  Hyperglycemia •  Hypertension •  Glomerular hyperfiltration/hypertension •  Smoking •  Male gender •  Advanced age •  RaceUpToDate, 2010
  14. 14. Geneticfactors ELMO1, NOS3, etc Family Investigation of Nephropathy of Diabetes (FIND) Consortium American Diabetes Association
  15. 15. Hyper-glycemia American Diabetes Association
  16. 16. Race: Diabetes is thedominant cause of ESRD in USA …more so in AAs December 31 point prevalent ESRD patients; rates U.S. Renal Data System, 2009 adjusted for age & gender. USRDS 2009
  17. 17. Screening American Diabetes Association
  18. 18. Screening for diabetic nephropathy: 1) Microalbuminuriafrom Standards of Medical Care in Diabetes—2010DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010
  19. 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. 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-2010DIABETES CARE, VOLUME 32, SUPPLEMENT 1, JANUARY 2010
  21. 21. Pathology American Diabetes Association
  22. 22. Source Undetermined
  23. 23. Pathology of DM nephropathyNormal Glomerulus Early Diabetic Glomerulus Podocyte damage & loss Thickened BM BasementCapillary lumen membraneMesangial cell Mesangium Expanded mesangium – Afferent and efferent hyaline arteriolosclerosis – Interstitial fibrosis and tubular Source Undetermined atrophy
  24. 24. Pathology of DM nephropathyNormal glomerulus Diffuse mesangial sclerosis Nodular mesangial sclerosis Source Undetermined
  25. 25. Pathology of DM nephropathyNormal Glomerulus Early Diabetic Glomerulus Podocyte damage & loss Thickened BM BasementCapillary lumen membraneMesangial cell Mesangium Expanded mesangium – Afferent and efferent hyaline arteriolosclerosis – Interstitial fibrosis and tubular Source Undetermined atrophy
  26. 26. Albuminuria 4 yrs laterPodocyte loss predictsprogression of Podocyte number nephropathy Incr. in albuminuria in 4 yrs Podocyte number Meyer, et al. Diabetologia. 1999;42:1341
  27. 27. Pathogenesis American Diabetes Association
  28. 28. ?Source Undetermined
  29. 29. Simpleminded model of pathogenesis of DM nephropathy Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  30. 30. Source Undetermined
  31. 31. Simpleminded model of pathogenesis of DM nephropathy Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  32. 32. Potential mechanisms for increased matrix production in hyperglycemia AGEsglucose ROSstretch glucose sorbitol fructose AIITGF-β GLUT1 DAG NADH/NAD PKCβ ERKs TGF-β fibronectin collagen IV Mesangial cell Source Undetermined
  33. 33. Unified field theorem for diabetic complications: oxidative stress rules Brownlee, Nature, 414:813, 2001 Brownlee, Nature, 414:813, 2001
  34. 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. 35. Treatment American Diabetes Association
  36. 36. Treatment of DM nephropathy: Glucose control Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  37. 37. The Diabetes Control And Complications Trial (DCCT) 1993 1400 INDIVIDUALS WITH IDDM CONVENTIONAL INSULIN INTENSIVE INSULIN THERAPY 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. 38. The Benefits of Tight Control : The DCCT DCCT RESULTS: The Good News 100 100 90 90 80 80 70 70 60 60 50 50 40 Rate/100 pt-yrs. Rate/100 pt-yrs. 40 30 30 RETINOPATHY CONVENTIONAL NEPHROPATHY NEUROPATHY INTENSIVEIntensive 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. 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. 40. American Diabetes Association
  41. 41. Treatment of DM nephropathy: Hypertension control Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  42. 42. Effect of antihypertensives on progression of DM nephropathyRate of declineIn GFR (ml/min/mo.) MAP post Rx 111 99 114 (mmHg) Source Undetermined
  43. 43. Treatment of DM nephropathy: Effect of ACEIs and ARBs Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  44. 44. ACEI or DMSource Undetermined ARB
  45. 45. Delaying nephropathy with ACE inhibitors Lewis et al., NEJM 329:1456, 1993 Lewis et al., NEJM 329:1456, 1993
  46. 46. Delay of diabetic nephropathy in type 2 patients with ARBs RENAAL Reduction of endpoints in non-insulin- dependent diabetes mellitus with the angiotensin II receptor antagonist losartan IDNT Irbesartan diabetic nephropathy trial IRMA-II irbesartan in patients with type II diabetes and microalbuminuria ARB = angiotensin receptor blockerNEJM, 2001
  47. 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. 48. Treatment of DM nephropathy: Effect of dietary protein restriction Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  49. 49. Effect of dietary protein restriction on progression of DM nephropathy GFR (ml/min)Source Undetermined
  50. 50. Treatment of DM nephropathy: Effect of statins Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia ROS Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  51. 51. Effects of lipid lowering on progression of diabetic nephropathyFried, et al., Kidney Int, 2001; 59:260 Fried, et al., Kidney Int, 2001; 59:260
  52. 52. Treatment of DM nephropathy: All together! Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia ROS Genetic factors Δ metabolism of glom. cells Glomerular sclerosisfrom T. Hostetter
  53. 53. Remission of microalbuminuria Likelihood of regressionNEJM 348: 2265, 2003 NEJM 348: 2265, 2003
  54. 54. ?American Diabetes Association
  55. 55. GBM TBMRemittive effect ofpancreas Tx on DM nephropathy time after Tx0 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. 56. Remittive effect of long termACEI on chronic nephropathies Ruggenenti, JASN10:997, 99
  57. 57. Remission ofmicroalbuminuria N=123 results in fewercardiovascular and kidney events N=93 Araki, et al., Diabetes. 2007 Jun;56:1727 Araki, et al., Diabetes. 2007 Jun;56:1727
  58. 58. Clinical course — M.W. (34 yo female with type 1 DM for 33.5 yrs) 3 BP = 133/83 4 Pregnancy 2.5 3.5 Stopped U Pro/creat 2 3 ACEI 1.5 2.5 BP = 100/70 1 2 0.5 1.5 0 1 140 0.5Estimated GFR 120 0 100 07 08 09 (ml/min) 80 Source Undetermined 60 40 20 Last eGFR = 47 ml/min 0 97 98 99 00 01 02 03 04 05 Source Undetermined
  59. 59. Diabetic Nephropathy: You cant cure it soyou have to endure it American Diabetes Association 3With current treatment, 2.5 U Pro/creatwe can keep patients 2 1.5stable or in remission 1for years….. 0.5 0 140 Estimated GFR 120 (ml/min) 100 80 60But can we do better? 40 20 0 97 98 99 00 01 02 03 04 05 Source Undetermined
  60. 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. 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 (0.8- 1.0 gm/kg/day).•  Treat cardiovascular disease aggressively.•  Refer to nephrologist early in course of azotemia.
  62. 62. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 5: American Diabetes AssociationSlide 6: U.S. Renal Data System, 2009, http://www.usrds.org/Slide 7: U.S. Renal Data System, 2009, http://www.usrds.org/Slide 8: U.S. Renal Data System, 2009, http://www.usrds.org/Slide 9: CalorieLab, http://calorielab.com/index.htmlSlide 10: U.S. Renal Data System, 2009, http://www.usrds.org/Slide 11: U.S. Renal Data System, 2009, http://www.usrds.org/Slide 12: American Diabetes AssociationSlide 14: American Diabetes AssociationSlide 15: American Diabetes AssociationSlide 16: U.S. Renal Data System, 2009, http://www.usrds.org/Slide 17: American Diabetes AssociationSlide 18: Standards of Medical Care in Diabetes—2010 DIABETES CARE, VOLUME 33, SUPPLEMENT 1, JANUARY 2010Slide 20: Diabetes Care, 23:S69, 2000Slide 21: American Diabetes AssociationSlide 22: Source UndeterminedSlide 23: Source UndeterminedSlide 24: Source UndeterminedSlide 25: Source UndeterminedSlide 26: Meyer, et al. Diabetologia. 1999;42:1341Slide 27: American Diabetes AssociationSlide 28: Source UndeterminedSlide 30: Source UndeterminedSlide 32: Source UndeterminedSlide 33: Brownlee, Nature, 414:813, 2001Slide 34: Scmid et al., Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. Diabetes, 2006; 200;55:2993Slide 35: American Diabetes AssociationSlide 39: Arch Int Med; 2009;169(14):1307Slide 40: American Diabetes AssociationSlide 42: Source UndeterminedSlide 44: Source UndeterminedSlide 45: Lewis et al., NEJM 329:1456, 1993Slide 49: Source UndeterminedSlide 51: Fried, et al., Kidney Int, 2001; 59:260Slide 53: NEJM 348: 2265, 2003Slide 54: American Diabetes AssociationSlide 55: Fioretto, et al. N Engl J Med. 1998, 339:69Slide 56: Ruggenenti, JASN10:997, 99Slide 57: Araki, et al., Diabetes. 2007 Jun;56:1727Slide 58: Source UndeterminedSlide 59: American Diabetes Association; Source Undetermined
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