Diabetic nephropathy (DN), causing 46% of all chronic kidney disease (CKD), develops slowly and there may be severe structural damage before DN is clinically apparent. 85% of DN occurs in type 2 (T2DM) diabetes. DN risk is extraordinarily high among T2DM American Indians. In Caucasian T2DM, more complex patterns of renal injury affect clinical outcomes and confuse clinical categorizations. Together, this consortium [Universities of Minnesota (U of MN) and Padova, Italy, and the Phoenix Epidemiology and Clinical Research Branch of NIDDK] have performed most of the research kidney biopsies in T1DM and T2DM in the world. The large Pima Indian T2DM cohort, followed longitudinally for decades, has stored samples through the entire natural history of DN. A major advantage is our ability to study biomarkers of early DN structural changes prior to detectability of functional abnormalities. Also, since microalbuminuria (MA) is associated with only a 35-45% risk of progression to proteinuria (P), we will search for predictors of this progression. Finally, in the non-biopsy Pima cohort, we can examine predictors of progression rates from MA to P to ESRD.
Our aims are to: (1) develop a DN risk index (DNRI) from albumin excretion rate and other variables (e.g., duration, glycemia, blood pressure, lipid levels, etc.) for Tl DM and T2DM patients (pts), (2) determine whether urine proteomic and/or metabolomic patterns predict the underlying renal structure or changes in structure or clinical progression, (3) determine the changes in urinary proteomic and/or metabolomic patterns as DN progresses from early DN to advanced CKD. Cohorts include>500 NA T1DM pts, with baseline and 5-yr biopsies and baseline and interval clinical and renal functional measures. T2DM biopsy populations include >200 Pima and >130 Northern Italian pts. In addition there are >2000 Pima pts without renal biopsies. We will initially use non-targeted proteomic and metabolomic methods on urine samples of selected pt subsets to derive more targeted assays for broader surveys of these cohorts. Studies will be done in world class mass spectroscopy facilities at the U of MN. Data analysis involves repeated measures (Wake Forest U) and Bioinformatics (Dartmouth) statistical expertise. Although focused on biomarker discovery, capabilities for negotiating validation regulatory processes are available at the U/MN.
Diabetic nephropathy (DN) is the leading cause of kidney failure. Early identification of patients at risk could allow for patient selection for more aggressive diabetes intervention and better design of primary prevention studies. Since DN, like coronary artery disease, may be far advanced before becoming clinically detectable, we will focus heavily on research populations we have studied using kidney biopsies in order to develop urinary tests for early DN using sophisticated molecular detection methods.
|Foster, Meredith C; Coresh, Josef; Hsu, Chi-Yuan et al. (2016) Serum Î²-Trace Protein and Î²2-Microglobulin as Predictors of ESRD, Mortality, and Cardiovascular Disease in Adults With CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis 68:68-76|
|Waikar, Sushrut S; Sabbisetti, Venkata; Ã„rnlÃ¶v, Johan et al. (2016) Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies. Nephrol Dial Transplant 31:1460-70|
|Foster, Meredith C; Inker, Lesley A; Hsu, Chi-Yuan et al. (2015) Filtration markers as predictors of ESRD and mortality in Southwestern American Indians with type 2 diabetes. Am J Kidney Dis 66:75-83|
|Rebholz, Casey M; Grams, Morgan E; Coresh, Josef et al. (2015) Serum fibroblast growth factor-23 is associated with incident kidney disease. J Am Soc Nephrol 26:192-200|
|Fufaa, Gudeta D; Weil, E Jennifer; Nelson, Robert G et al. (2015) Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus. Nephrol Dial Transplant 30:599-606|
|Fufaa, Gudeta D; Weil, E Jennifer; Nelson, Robert G et al. (2015) Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Diabetologia 58:188-98|
|Hsu, Chi-Yuan; Ballard, Shawn; Batlle, Daniel et al. (2015) Cross-Disciplinary Biomarkers Research: Lessons Learned by the CKD Biomarkers Consortium. Clin J Am Soc Nephrol 10:894-902|
|Mauer, Michael; Caramori, Maria Luiza; Fioretto, Paola et al. (2015) Glomerular structural-functional relationship models of diabetic nephropathy are robust in type 1 diabetic patients. Nephrol Dial Transplant 30:918-23|
|Foster, Meredith C; Coresh, Josef; Bonventre, Joseph V et al. (2015) Urinary Biomarkers and Risk of ESRD in the Atherosclerosis Risk in Communities Study. Clin J Am Soc Nephrol 10:1956-63|