1. Updates in Diabetic Nephropathy Rodica Pop-Busui, M.D., Ph.D Division of Metabolism, Endocrinology and Diabetes Michigan Comprehensive Diabetes Center University of Michigan

2. Diabetes is the dominant cause of ESRD in USA USRDS 2013 Incident ESRD patients; rates adjusted for age, gender, & race.

5. RASS Group 5 Number of new cases USRDS 2008 Incidence of ESRD Among Patients with Type 1 Diabetes -100 -250 +1600 Overall a greater than 35% increase in ESRD in T1D in the USA in the last 25 years Rosolowsky, Krolewski, et al, JASN 22:545, 2011

6. Pathology of diabetic nephropathy Normal Glomerulus Early Diabetic Glomerulus Capillary lumen Mesangial cell Thickened BM Expanded mesangium Mesangium Podocyte damage & loss Basement membrane – Afferent and efferent hyaline arteriolosclerosis – Interstitial fibrosis and tubular atrophy

7. Progression of diabetic nephropathy from T. Hostetter Renal preglomerular vasodilation Systemic hypertension Glomerular hypertension Hyperglycemia Genetic factors Ox stress Inflammation Glomerular sclerosis and tubulointerstitial fibrosis

11. Current strategies to prevent kidney function loss on in diabetes Intensive glycemic control DCCT, NEJM 1993 N Engl J Med. 2011 Dec 22;365(25):2366 DCCT Nephropathy Incidence during EDIC = Metabolic memory

14. Current strategies to prevent kidney function loss on in diabetes RAAS Inhibition Lewis et al, NEJM 1993

15. Limits of RAAS inhibitors in preventing kidney function loss in diabetes From Lewis et al, NEJM 1993 GFR ≤50-60 ml/min GFR >50-60 ml/min

16. Prevention of nephropathy ACEIs vs. ARBs??? “Early blockade of the renin-angiotensin system in patients with type 1 diabetes did not slow nephropathy progression but slowed the progression of retinopathy.” RASS Study N Engl J Med. 2009 Jul 2;361(1):40-51.

17. Treatment of diabetic nephropathy: Effect of ACEIs PLUS ARBs Now we know for sure

18. Perkins, et al. J Am Soc Nephrol 2007; 18:1353–1361. DN progression, decline in GFR, without development of albuminuria in T1 and T2 DN

19. Kidney International (2012) 82, 1010–1017 DN pathology precedes clinical disease

20. Serum uric acid predicts CKD risk in the general population Adapted from Domrongkitchaiporn et al, JASN 2005 Adjusted Odds Ratio of CKD ≤3 Q1 (1.50-4.49) Q2 (4.50-5.39) Q3 (5.40-6.29) Q4 (6.30-14.50) (Ref.) Baseline Serum Uric Acid (mg/dl) n=3,499 12-year follow-up

21. Steno Diabetes Center T1D inception cohort n=270 18-yr follow-up Outcome: Macroalbuminuria Hovind et al. Diabetes 2009 Serum uric acid predicts albuminuria in the type 1 diabetic population

22. Serum uric acid predicts GFR loss in the type 1 diabetic population Joslin Kidney Study (n=355) T1D Natural History cohort Baseline GFR >60 ml/min/1.73m 2 6-yr follow-up Outcome: GFR loss (>3.3%/yr) Ficociello et al. Diabetes Care 2010

23. Serum uric acid predicts CKD in the type 2 diabetic population Verona Diabetes Study (n=1,449) T2D, no proteinuria, GFR ≥60 ml/min/1.73 m 2 5-yr follow-up Outcome: CKD (GFR <60 ml/min/1.73 m 2 or proteinuria), n=194 Zoppini et al. Diabetes Care 2012