Diabetic Nephropathy. Diabetic Nephropathy A clinical syndrome DM + Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure

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  • Slide 1
  • Diabetic Nephropathy
  • Slide 2
  • Diabetic Nephropathy A clinical syndrome DM + Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure Persistent albuminuria, Worsening proteinuria, Hypertension & progressive renal failure
  • Slide 3
  • Diabetic nephropathy (DN) is a major cause of ESRD, and the incidence of diabetes mellitus is rising rapidly.
  • Slide 4
  • Objectives n Prevalence of diabetic kidney disease n Pathogenesis of diabetic nephropathy n Clinical course of diabetic nephropathy n Slowing the progression of nephropathy n Screening for early nephropathy
  • Slide 5
  • Causes of End Stage Renal Disease USRDS 1993 Annual Data Report
  • Slide 6
  • Diabetic Nephropathy n The most common cause of ESRD in USA. n However one needs to keep in mind all diabetic patients with ESRD do not have DN as underlying cause of ESRD.
  • Slide 7
  • Diabetic Nephropathy n Mortality of ESRD patients with Diabetes Mellitus is higher than in ESRD patients without Diabetes. n This higher mortality is due to increase in Cardiovascular, cerebro-vascular, peripheral vascular and infection related morbidity.
  • Slide 8
  • Patient Survival on Dialysis by Cause of Renal Failure From UpToDate v 6.2; Data from USRDS 1995 Annual Report
  • Slide 9
  • Diabetic Nephropathy n DN occurs in 35-40% of patients with type I diabetes (IDDM) whereas it occurs only in 15- 20% of patients with type II diabetes (NIDDM). n Definition or Criteria for diagnosis of DN u Presence of persistent proteinuria in sterile urine of diabetic patients with concomitant diabetic retinopathy and hypertension.
  • Slide 10
  • D.N.- Pathogenesis n Familial - Genetic u Only 35-40% patients with IDDM develop DN. u There is an increased risk of DN in a patient with family member having DN.
  • Slide 11
  • D.N.- Pathogenesis n Glycemic Control-in both expt & human F DN does not occur in euglycemic patients. F Confirmed role of hyperglycemia in pathogenesis of DN. F Renal transplant with early DN showed structural recovery in euglycemic receipient. (Abouna)
  • Slide 12
  • Strict Glycemic Control Prevents Microalbuminuria in Type 1 Diabetes mellitus From UpToDate v 6.2; Data from the DCCT Research Group, NEJM(1993) 329:977.
  • Slide 13
  • D.N.- Pathogenesis n Glomerular Hyperfiltration n Glomerular Hypertension n Glomerular Hypertrophy n GBM thickening n Mesangial Expansion
  • Slide 14
  • D.N.- Pathogenesis n Renal lesions mainly related to extracellular matrix accumulation - Occurs in glomerular & tubular basement - Occurs in glomerular & tubular basement membrane membrane - Principal cause of mesangial expansion - Principal cause of mesangial expansion
  • Slide 15
  • D.N.- Pathogenesis n Extracellular matrix accumulation - Imbalance between synthesis & degradation of - Imbalance between synthesis & degradation of ECM components ECM components - Linkage between glucose concentration & ECM - Linkage between glucose concentration & ECM accumulation accumulation - Transforming growth factor-Beta associated with - Transforming growth factor-Beta associated with increased production of ECM molecules increased production of ECM molecules
  • Slide 16
  • D.N.- Pathogenesis n Extracellular matrix accumulation - TGF-B can down regulate synthesis of ECM - TGF-B can down regulate synthesis of ECM degrading enzymes & upregulate inhibitors of degrading enzymes & upregulate inhibitors of these enzymes these enzymes - Angiotensin II can stimulate ECM synthesis - Angiotensin II can stimulate ECM synthesis through TGF-B activity through TGF-B activity - Hyperglycemia activates protein kinase C, - Hyperglycemia activates protein kinase C, stimulating ECM production through cyclic AMP stimulating ECM production through cyclic AMP Pathway Pathway
  • Slide 17
  • Diffuse and Nodular Glomerulosclerosis in Diabetic Nephropathy
  • Slide 18
  • Diabetic Nephropathy
  • Slide 19
  • Advanced Diabetic Glomerulosclerosis
  • Slide 20
  • Diabetic Nephropathy
  • Slide 21
  • Diabetic Nephropathy Glomerular Basement Membrane Thickening From: UpToDate v 6.2 Courtesy H. Rennke, M.D.
  • Slide 22
  • Natural Course of D.N. n Stage 1: Renal hypertrophy - hyperfunction n Stage 2 : Presence of detectable glomerular lesion with normal albumin excretion rate & normal blood pressure n Stage 3 : Microalbuminuria n Stage 4 : Dipstick positive proteinuria n Stage 5 : End stage renal disease
  • Slide 23
  • Functional changes* Natural History of IDDM Proteinuria End-stage renal disease Clinical type 1 diabetes Structural changes Proteinuria Rising serum creatinine levels Rising blood pressure Onset of diabetes 251020 Years * Kidney size , GFR GBM thickening , mesangial expansion Microalbuminuria 30 CV events
  • Slide 24
  • Functional changes* Natural History of NIDDM Proteinuria End-stage renal disease Clinical type 2 diabetes Structural changes Rising blood pressure Rising serum creatinine levels Cardiovascular death Microalbuminuria Onset of diabetes 2510203030 Years * Kidney size , GFR GBM thickening , mesangial expansion
  • Slide 25
  • D.N.- Pathogenesis n Hypertension - in both expt & human F Hypertension follows 8-10 years of hyperglycemia in IDDM patients but it is frequently present at the diagnosis of NIDDM. F Many experimental & human studies have shown HTN accelerating progressive renal injury in DN.
  • Slide 26
  • Slide 27
  • Effect of Angiotensin Blockade Afferent arteriole Efferent arteriole Glomerular pressure ( GFR) Glomerulus Bowmans Capsule Angiotensin II Proteinuria A II blockade:
  • Slide 28
  • ACE-I Is More Renoprotective Than Conventional Therapy in Type 1 Diabetes % with doubling of baseline creatinine 100 75 50 25 0 01234 Baseline creatinine >1.5 mg/dL Captopril n=207 Placebo n=202 P
  • Irbesartan in patients with type 2 diabetes & microalbuminuria study n 590 NIDDM patients with HTN and microalbuminuria with nearly normal GFR. n Randomly assigned to placebo, 150 mg or 300 mg of irbesartan for 2 years. n Primary outcome was time to the onset of diabetic nephropathy (urinary albumin excretion rate >200 mcg/min and at least 30% greater albuminuria) n 14.9% patients on placebo group, 9.7% of irbesartan 150mg group and 5.2% of irbesartan 300 mg group reached the primary point. (Parving et al, NEJM, 2001)
  • Slide 31
  • ARBs in NIDDM,HTN & microalbuminuria-Parving 2001
  • Slide 32
  • Lewis et al NEJM 2001
  • Slide 33
  • ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 Year Trandolapril (5.5 mg/d) Verapamil (315 mg/d) Trandolapril (2.9 mg/d) + Verapamil (219 mg/d) * Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc. -33% -27% -62% *p
  • DN: ADA Position Statement Screening: Perform an annual test for the presence of microalbuminuria in 1) 1)type 1 diabetic patients who have had diabetes > 5 years and 2) 2)all type 2 diabetics patients starting at diagnosis. Treatment: In the treatment of albuminuria/nephropathy both ACE inhibitors and ARBs can be used: In hypertensive and nonhypertensive type 1 diabetic patients with microalbuminuria or clinical albuminuria, ACE inhibitors are the initial agents of choice In hypertensive type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARBs are the initial agents of choice. If one class is not tolerated, the other should be substituted American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002
  • Slide 36
  • UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions Better blood pressure control reduces n Strokes by > one third n Serious deterioration of vision by > one third n Death related to diabetes by one third Better glucose control reduces n Early kidney damage by one third n Major diabetic eye disease by one fourth Turner RC, et al. BMJ. 1998;317:703- 713.
  • Slide 37
  • National Kidney Foundation Recommendations on Treatment of HTN and Diabetes n Blood pressure goal: 130/80 mmHg n Target blood pressure: 125/75 for patients with >1 gram/day proteinuria n Blood pressure lowering medications should reduce both blood pressure + proteinuria n Therapies that reduce both blood pressure and proteinuria have been known to reduce renal disease progression and incidence of ischemic heart disease Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.
  • Slide 38
  • Cholesterol Lowering Therapy and Diabetic Nephropathy
  • Slide 39
  • Management of ESRD due to DN n Early planning of Vascular Access n Both HD & PD could be appropriate modalities. n Early initiation of Dialysis at GFR 18-20 mls/min. n Renal Transplantation n Combined Renal & Pancreatic Transplantation for IDDM.
  • Slide 40
  • Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients n Hypertension u BP < 130/80 mmHg n Hypercholesterolemia u LDL < 100 mg/dL n Hyperglycemia u H