One clinical trial is presently underway as part of this project. The clinical trial is a single-center randomized, double-blinded, placebo-controlled study involving 170 diabetic Pima Indian adults with normal urinary albumin excretion or microalbuminuria. It was designed to determine whether blockade of the angiotensin II receptor with losartan will prevent or further attenuate the development and progression of early diabetic nephropathy in subjects with type 2 diabetes mellitus who are receiving standard diabetes care that now includes treatment with the angiotensin converting enzyme inhibitor lisinopril. Subjects in each albumin excretion group were randomized to treatment with either losartan, or placebo. Measurements of glomerular filtration rate, renal plasma flow and fractional clearances of albumin and IgG were made using standard urinary clearance methods as outlined in Project Number Z01 DK069063-12. These tests were performed initially, at one month, and at 12-month intervals from baseline thereafter. The primary outcome measure is a decline in GFR to less than 60 ml/min or to half the baseline value in subjects that enter the study with a GFR of <120 ml/min. A kidney biopsy was performed after 5.5 years in 122 of these subjects. Morphometric analysis of kidney biopsies, as reported in Project Number Z01 DK069100-01, will be used to determine differences in the prevalence of global sclerosis, the number of visceral epithelial cells per glomerulus, and the breadth of epithelial foot processes between treatment groups. Differences in a severity index computed from the joint distribution of these morphometric variables will be used to assess the renoprotective efficacy of losartan at the tissue level. Following the kidney biopsy and after the 72-month renal clearance study, treatment with all ACEi and ARBs will be stopped for six weeks. At the end of the six-week washout period a second clearance study will be performed. Randomized study treatment will end at that time, but quarterly follow-up visits and annual renal clearance studies will continue to the onset of kidney failure. This project, in part, represents extensions of work previously reported as Project Number Z01 DK69037. We completed the randomized treatment portion of the losartan clinical trial four years ago and we completed the laboratory assays of glomerular filtration rate and renal plasma flow last year. We are performing morphometric analyses on the kidney biopsies as described in Project Number Z01 DK069100-01 and about two thirds of the biopsies are now complete. In addition, portions of the kidney tissue from each patient underwent laser microdissection to separate the tubular and glomerular components, and gene expression and methylation studies are being conducted on these tissues. Results of these expression studies will be correlated with the appearance of various urinary biomarkers. This project is expected to yield new insights into the management of kidney disease in type 2 diabetes.

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Wheelock, Kevin M; Saulnier, Pierre-Jean; Tanamas, Stephanie K et al. (2018) White blood cell fractions correlate with lesions of diabetic kidney disease and predict loss of kidney function in Type 2 diabetes. Nephrol Dial Transplant 33:1001-1009
Koye, Digsu N; Magliano, Dianna J; Nelson, Robert G et al. (2018) The Global Epidemiology of Diabetes and Kidney Disease. Adv Chronic Kidney Dis 25:121-132
Looker, Helen C; Mauer, Michael; Nelson, Robert G (2018) Role of Kidney Biopsies for Biomarker Discovery in Diabetic Kidney Disease. Adv Chronic Kidney Dis 25:192-201
Nair, Viji; Komorowsky, Claudiu V; Weil, E Jennifer et al. (2018) A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome. Kidney Int 93:439-449
Weil, E Jennifer; Fufaa, Gudeta; Jones, Lois I et al. (2018) Erratum. Effect of Losartan on Prevention and Progression of Early Diabetic Nephropathy in American Indians With Type 2 Diabetes. Diabetes 2013;62:3224-3231. Diabetes 67:532
Qiu, Chengxiang; Hanson, Robert L; Fufaa, Gudeta et al. (2018) Cytosine methylation predicts renal function decline in American Indians. Kidney Int 93:1417-1431
Wheelock, Kevin M; Cai, Jian; Looker, Helen C et al. (2017) Plasma bradykinin and early diabetic nephropathy lesions in type 1 diabetes mellitus. PLoS One 12:e0180964
Saulnier, Pierre-Jean; Nelson, Robert G (2017) Burden of Proof-When Is Kidney Disease Attributable to Diabetes? Clin J Am Soc Nephrol 12:1917-1918
Looker, Helen C; Nelson, Robert G (2017) Reading the tree leaves-how to enrich clinical trials of diabetic kidney disease. Kidney Int 92:23-25
Parsa, Afshin; Kanetsky, Peter A; Xiao, Rui et al. (2017) Genome-Wide Association of CKD Progression: The Chronic Renal Insufficiency Cohort Study. J Am Soc Nephrol 28:923-934

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