This project, in part, represents an extension of work previously reported as Project Number Z01 DK69037. Glomerular function was measured initially over a 4-year period in 194 Pima Indians selected to represent stages in the development and progression of diabetic renal disease. Eighty-six of these subjects had type 2 diabetes and micro- or macroalbuminuria. Subjects underwent serial determinations of albuminuria and glomerular filtration rate (GFR). Many of these subjects continue to be followed and we have accumulated over 20 years of data on glomerular hemodynamic function in these patients. We also followed a population-based cohort of Pima Indians who were invited every two years to participate in a research examinination until December 31, 2007. The methods for this longitudinal study are described in detail in Project Numbers Z01 DK069097 and Z01 DK069000. Urinary albumin-to-creatinine ratios (ACRs) and serum creatinine concentration are measured at each of these examinations, and participants who progress to kidney failure are identified. In the last year, we investigated predictive value of albuminuria and estimated glomerular filtration rate (eGFR) for end-stage renal disease (ESRD) in Pima Indians with type 2 diabetes. We found that albuminuria and eGFR were each significant predictors of ESRD and of mortality in type 2 diabetes, and the combination of albuminuria and eGFR were significantly better than either measure alone. This observation demonstrates that quantitative information about albuminuria significantly enhances prediction of ESRD in a population in which type 2 diabetes is, almost exclusively, the cause of ESRD. We also contributed these data to an international consortium that reported on the predictive value of low estimated glomerular filtration rate and elevated albuminuria for kidney outcomes in a meta-analysis that included many other cohorts. We developed a morphometric method to quantify podocyte detachment from the basement membrane in a study of glomerular structural characteristics in 40 Pima Indians with type 2 diabetes and albuminuria. Podocyte detachment was defined as a complete absence of foot processes along the interface of the glomerular basement membrane and the podocyte layer and was limited to the filtration surface. The majority of these denuded areas were free of any podocyte membrane or cytoplasm;Bowmans space was in direct contact with the denuded glomerular basement membrane (GBM). If podocyte cell membrane was observed along the GBM but the cytoplasm was electrolucent, that area was not considered denuded. Similarly, if only alternating foot processes from a single podocyte were missing, this was not considered denuded. The denuded length was divided by the total measured length of the GBM (along the filtration surface) to calculate the percentage of denuded GBM. The relationship between podocyte detachment and other structural and functional parameters in the kidney are presently being examined. We also demonstrated the importance of the mTOR pathway in podocytes by selectively modulating mTOR complex 1 and mTOR complex 2 activity in mice at various stages of diabetes and comparing these models with their expression in early human diabetic nephropathy. We demonstrated that too much or too little mTOR activity is deleterious to the podocyte and that mTOR activity is increased in humans with early kidney disease. This project continues to yield new insights into the pathogenesis, course, and management of kidney disease in type 2 diabetes. Characterization of hemodynamic function over prolonged periods, combined with detailed clinical information derived from ongoing epidemiologic evaluation have greatly enriched the value of this data resource for studying diabetic kidney disease.
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