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. 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 –  Stimulates fibrosis Increase growth of proximal tubular cells Vascular endothelial growth factor (VEGF) Released by podocyte Ornithine decarboxylase (OCD) Increase secretion or prolonged ½ life Stimulated by IGF-1? Increase kidney growth Protein Kinase C AMP activated protein kinase

12. Pathogenesis and Mechanism Role 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- 

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 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 “Sleeping Sickness”

16. Pathology

17. 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 intercapillary glomerulosclerosis) 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.

24. Diagnosis

25. 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

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

27. Management of Diabetic Nephropathy

28. Glycemic Control

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. Blood Pressure Control

36. 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!

37. 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

38. 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

39. Blood Pressure Control in CKD/DM

40. 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

41. 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

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

43. Quick Physiology

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

47. 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.

48. 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

49. 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 %

50. 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

51. Blood Pressure Control in CKD/DM Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) 25,000 participants with  DM and vascular disease Most did not have CKD, HTN, or Proteinuria Why use combination therapy with ACEi/ARB: Proteinuria Better BP control Greater incidence of: AKI Hypotension Hyperkalemia Limited Benefit in comparison of monotherapy Increase in Mortality

52. Blood Pressure Control in CKD/DM Recommendations for dual therapy: Would Avoid use of both Must have compelling reason Refractory proteinuria?

53. Blood Pressure Control in CKD/DM AVOID trial: Aliskiren (Tekturna) + Losartan Irreversible inhibitor of Renin Decrease of proeinturia by 20% compared to monotherapy with losartan Unknown CKD protection

54. Blood Pressure Control in CKD/DM Aliskiren Trial in Type II Diabetes Using Cardio- Renal endpoints (ALTITUDE) 8606 participants with  high risk DM type II Randomized Double-blind Two groups: Aliskiren + ACEi/ARB or Placebo + ACEi/ARB Trial stopped early due to: Hypotension/hyperkalemia AKI Nonfatal CVA

55. Blood Pressure Control in CKD/DM General recommendations: Goal < 130/80 Avoid aggressive control (SBP 120s is okay!) First Line: ACEi then ARB ~ 30% increase in Creatinine is acceptable CKD is not a contraindication for ACEi/ARB Not great idea in AKI or recovering AKI Watch for hyperkalemia Never in Bilateral Renal Artery Stenosis

56. Proteinuria in Diabetes

57. Microalbuminuria Independent Risk Factor For: (non-diabetic) Cardiovascular Disease Left Ventricular Hypertrophy Microalbuminuria: 30-300 mg/day Typically seen in Type I DM  5-15 Years Stronger association with Nephropathy Typically seen in Type II DM  10 years Natural course doesn’t always proceed to overt proteinuria Best Biomarker at this time Sometimes it may revert before therapy

58. Microalbuminuria Result of low grade Inflammation? Inverse relationship with circulating adipokines: adiponectin Associated with BMI >25 and visceral fat deposition Knockout mice shown to have podocyte dysfunction and albuminuria

59. Overt Proteinuria Natural course doesn’t always proceed to overt proteinuria Definition : > 300 mg/day (abluminuria) Nephrotic Range Proteinuria: >3.5 gm/24hrs <2 gm likely tubulointerstitial Type I DM associated increase risk: Mortality ESRD

60. Proteinuria in Diabetes More Trials! Post Analysis of RENAAL and IDNT: Risk for renal failure doubled with each doubling of baseline protein excretion (IDNT) reduction in proteinuria was significantly associated with decreased blood pressure (IDNT)

61. Proteinuria and Diabetes Albuminuria reduction by one-half in the first 6 months was associated with: 36 % decreased risk for the renal end points 45 % lower risk for the development of ESRD at follow-up (RENAAL)

62. Proteinuria and Diabetes Initial Therapy: Like for HTN  ACEi/ARB Aldosterone Antagonist: Eplerenone and Spironolactone Expense v. Side effects Reduce both Blood Pressure and Proteinuria Has additive effect with ACEi and ARB May reduce loss of GFR WATCH POATSSIUM CLOSELY  especially in advanced CKD Avoid NSAIDs in conjunction

63. Proteinuria and Diabetes Calcium Channel Blockers Shown to reduce proteinuria in conjunction with ACEi/ARB Only the non-dihydropyridine calcium channel blockers: Verapmil Diltiazem Reduce intraglomerular pressure

64. Proteinuria and Diabetes Other Non-pharmacological interventions: Reduction in salt intake Weight reduction Novel Drugs? Pentoxifylline Fenofibrate

65. Final Thoughts Early Diagnosis is important Good Glycemic Control Good Blood Pressure Control CKD Stage III-V likely need referral Don’t guess about proteinuria

66. Acknowledgments ASN Board Review Course NephSAP Up-to-Date Primer on Kidney Disease (NKF) Chronic Kidney Disease, Dialysis, and Transplantation

67. THE END NEPHROLOGY SPECIALIST OF OKLAHOMA PHONE NUMBER 918-592-0296 EMAIL: AGRAWAL@NSOK.ORG