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Diabetic Nephropathy

Diabetic Nephropathy. Sunil Agrawal, MD. Disclosures. Amgen. Outline. INTRODUCTION EPIDEMOLOGY PATHOGENSIS AND MECHANISM PATHOLOGY DIAGNOSIS TREATMENT. Introduction. Why do we care? Most common disorder leading to kidney disease in adults

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Diabetic Nephropathy

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  1. Diabetic Nephropathy Sunil Agrawal, MD

  2. Disclosures • Amgen

  3. Outline • INTRODUCTION • EPIDEMOLOGY • PATHOGENSIS AND MECHANISM • PATHOLOGY • DIAGNOSIS • TREATMENT

  4. Introduction Why do we care? Most common disorder leading to kidney disease in adults 44% of all new incidents of ESRD secondary to diabetes Annual cost to health care more than $9 billion

  5. Introduction Prevalence of CKD (secondary to DM) by ethnic background: Severity 3 to 6 fold more in African Americans v. Caucasians Adjusted for Socioeconomics/HTN African Americans are 4.8 X greater to get DM Nephropathy Pima Indians have large Glomeruli than Caucasians

  6. Epiemiology 0.5 % of US and Central Europe have Type I DM 25 to 35% will develop DM nephropathy in 20 years Type II DM  9 x more prevalent Risk in Type II: glycemic control, BP, and Genetic Factors

  7. Diabetes and ESRD 5 year adjusted survival (2004): 31%! 5 year adjusted survival (1980s) 20%!

  8. Pathogenesis and Mechanism

  9. Pathogenesis and Mechanism • Clinical manifestations of diabetic nephropathy: • Albuminuria • Hematuria • Typically Bland • Rare finding • Progressive chronic kidney disease

  10. Pathogenesis and Mechanism(Hyperfiltration) • Typical early change • Type I DM > Type II DM • Increase in GFR “supranormal” • Renal Hypertrophy > 12 cm • Amyloid/HIV/MM/PCKD • Hyperfiltration associated with: • FSGS • Obesity • OSA • Solitary Kidney

  11. Pathogenesis and Mechanism(Hyperfiltration) • Unclear what the mechanism is for Hypertrophy: • Hyperglycemia • IGF-1 • TGF –b • Stimulates fibrosis • Increase growth of proximal tubular cells • Vascular endothelial growth factor (VEGF) • Released by podocyte • Ornithinedecarboxylase (OCD) • Increase secretion or prolonged ½ life • Stimulated by IGF-1? • Increase kidney growth • Protein Kinase C • AMP activated protein kinase

  12. Pathogenesis and MechanismRole of Hyperglycemia: • Like directly causes injury to the kidney: • Mesangial expansion • Increased matrix production • Mesangial cell apoptosis • Microvascular/Macrovascular injury • Secondary to advanced glycation end products (AGEs) • AGE increase in renal insufficiency • Working on medications to inhibit effects • Cytokines • VEGF  causes endothelial injury in DM • TGF-b

  13. Pathogenesis and Mechanism • Genetics: • Family History of proteinuria/DM Nephropathy may be a clue • DD polymorphism has been associated with an increased risk for the development of diabetic nephropathy • Variation in the ACE gene? • Angiotensin-II type 2 receptor gene (AT2) on the X-chromosome

  14. Pathogenesis and Mechanism • Genetic Linkage to Diabetes Nephropathy: • European-Americans: Chromosome 6p and 22q • American-Indians: Chromosome 7p • African Americans: Chromosomes 3p and 16q • Mexican Americans: Chromosome 22q

  15. Pathogenesis and Mechanism “Sleeping Sickness” Interesting Overlap • Chromosome overlap of 22q with APOL1 • APOL1 may contribute to increase risk of DN • May be involved in: HTN/HIV/FSGS • Favored gene in African Americans: resistance to trypanosomiasis

  16. Pathology

  17. Pathology • The common structural changes include seen in Diabetic Nephropathy: • Mesangial expansion • Glomerular basement membrane thickening • Glomerular sclerosis

  18. Pathology Renal Pathology Society Calcification • Class I: Isolated glomerular basement membrane thickening. • Basement membranes are greater than 430 nm in males older than age 9 and 395 nm in females. • There is no evidence of mesangial expansion, increased mesangial matrix, or global glomerulosclerosis involving >50 percent of glomeruli. • Class II: Mild (class IIa) or severe (class IIb) mesangial expansion • considered severe if areas of expansion larger than the mean area of a capillary lumen are present in >25 percent of the total mesangium. • Class III: At least one Kimmelstiel-Wilson lesion (nodular intercapillaryglomerulosclerosis) is observed on biopsy and there is <50 percent global glomerulosclerosis. • Class IV: Advanced diabetic sclerosis. There is >50 percent global glomerulosclerosis that attributable to diabetic nephropathy.

  19. Diagnosis

  20. Diabetic Nephropathy • How do we make the diagnosis? • Gold Standard: Kidney Biopsy • History • Retinopathy • Neuropathy • Family • Screening for proteinuria • Microablumin First Morning Void • Best sensitivity and specificity • 5 years after diagnosis

  21. Diabetic Nephropathy • Exclusion Criteria • Rapid rise in creatinine or decrease of GFR • Rapid increase in proteinuria • Active urinary sediment • Refractory HTN

  22. Management of Diabetic Nephropathy

  23. Glycemic Control

  24. Glycemic Control in DM Nephropathy • Goal Therapy  A1C 7% • Diabetes Control and Complication Trial (DCCT) • 1441 participants • Showed tight glycemic control <8% (A1C) • Prevented development of albuminuria/proteinuria • Reduced relative risk of loss of renal function

  25. Glycemic Control in DM Nephropathy • Early glycemic control in Type I DM: • Reduction of retinopathy • Reduction of Neuropathy • Reduction of Cardiovascular endpoints • Early glycemic control in Type II DM: • Reduced microaluminuria • No clear reduction of macroalbuminuria • No clear reduction of worsening of renal function (once decline has occurred) • Studies: The Kumamoto Study/VA Cooperative Study

  26. Glycemic Control in DM Nephropathy • Important new concepts about A1C in type II: • A1C 6.5% did show 21% reduction in renal outcomes than A1C of 7.3% • Between the groups of Type II DM: NO MAJOR REDUCTION IN CARDIOVASCULAR EVENTS • Intensive glycemic control in type I DM did show some cardiovascular benefit

  27. Glycemic Control in DM Nephropathy • How good is A1C in ESRD/CKD patients? • Reduced RBC lifespan • Get transfusions • Hemolysis • Fructosamine (glycated albumin) • May be better for ESRD/CKD • Mixed results

  28. Glycemic Control in DM Nephropathy • General recommendations of choice of therapy in DM: • 1/3 of the degradation of Insulin is conducted by the kidney! • First Generation sulfonyureas should be avoid in CKD Stage III – ESRD • Second Generation: Glipizde is recommended • Cleared by the Liver • Thiazolidinediones/pioglitazone/rosiglitazone • Watch for fluid retention  via ENAC • Increase bone fractures

  29. Glycemic Control in DM Nephropathy • Metformin • FDA recommendation: • Contraindicated in creatinine >1.5 in men, >1.4 women • Contraindicated in GFR < 60 ml/min • Decreased clearance and life threatening Lactic Acidosis • Sitagliptin/saxagliptin/linagliptin • Dipeptidylpeptidase inhibitor • May effect the kidney directly • SGLT2 inhibitors • Block Na-Glucose Transporter of the proximal tubule • Under review by the FDA • Will  lower glucose level/reduce weight/lower insulin requirements

  30. Blood Pressure Control

  31. Blood Pressure Control in CKD/DM • Target >130/80 (JNC-7/NKF/ADA) • Strong correlation with reduction in progression with good SBP in DM/CKD • Question: “The lower the blood pressure the better?” • Common question form patients! • What is the answer? LETS SEE WHAT THE TRIALS SAY!

  32. Blood Pressure Control in CKD/DM • Action to Control Cardiovascular Risk in Diabetes (ACCCORD) • 4733 participants  Type II DM • Two arms randomly assigned: • Intensive arm (SBP <120) • Standard arm (SBP < 140) • Follow-up after about 5 years • NOT a significant reduction in primary outcomes • Nonfatal MI/CVA/death from CV causes • Slight increase in annual rates of death and adverse events in intensive arms

  33. Blood Pressure Control in CKD/DM • Irbesartan in Diabetic Nephropathy Trial (IDNT) • 1715 participants with CKD/DM • Randomly assigned to irbesartan/amlodipine/placebo • Showed reduction in decline of renal function with every 10 mm Hg reduction in SBP • Increase in all-cause mortality in patients with SBP <120

  34. Blood Pressure Control in CKD/DM

  35. Blood Pressure Control in CKD/DM • What does this mean? • Patients with CKD and DM: • Good control of SBP important! • Goal: reasonable to treat <130/80 • If they have CKD  SBP 120 to 130 • If the don’t have CKD  SBP 120 to140

  36. Blood Pressure Control in CKD/DM • What to use for blood pressure control? • The Standard is: the use of medications that block RAS (Renin-Angiotensin-System) • Ace inhibitors (First Line therapy) • Angiotensin Receptor Blockers • Projecting with the use of these mediations: • Reducing incidence of ESRD • Reducing cost per patient by $24,000

  37. Quick review about how Acei/ARBs work. They effect the efferent arteriole. Vasodilitation leading to decrease in hydraulic pressure thus reduction in GFR.

  38. Quick Physiology

  39. Blood Pressure Control in CKD/DM • More Trials: • ACEi Efficacy • DETAIL • RENAAL • ONTARGET • AVOID • ALTITUDE DON’T WORRY  WE WILL GO FAST!

  40. Blood Pressure Control in CKD/DM • DETAIL • Randomized participants to enalapril and telmisartan • Participants had proteinuria (macro/micro) and CKD Stage I • Followed for 5 years • Both groups showed similar reductions : • GFR/Change in Serum creatinine • Blood pressure • Urinary albumin excretion • ESRD • Cardiovascular events • Mortality.

  41. Blood Pressure Control in CKD/DM • ACE Inhibitors vs. ARBs • Very few studies available • Similar rates of protection • ACE inhibitors first line • ARBs usually for intolerance of Acei ACE Inhibitor ARB

  42. Blood Pressure Control in CKD/DM • RENAAL • 1513 participants  with type 2 diabetes and nephropathy • Randomly assigned to: • Losartan or Placebo • In addition to conventional therapy (Not Acei) • Results: • Losartan reduced the incidence of a doubling of the creatinine by 25 % • Reduced ESRD by 28 %

  43. Blood Pressure Control in CKD/DM • Other Conclusions form RENAAL: • Every 10 mmHg increase in the baseline systolic • Enhanced risk of ESRD or death of 6.7 % • Reduction of albuminuria within the first 6 months • decreased subsequent cardiovascular risk • Baseline retinopathy was associated with: • Poor renal outcome • Increased proteinuria • Decreased GFR • Development of ESRD • Higher risk of death

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