Mechanisms of Diabetic Kidney Disease in American Indians

The purpose of this protocol is to examine the long-term impact of treatment with the angiotensin receptor blocker losartan on progression of diabetic kidney disease in American Indians with type 2 diabetes. Data from this protocol will also be used to guide the search for candidate biomarkers of diabetic end-organ damage in serum and urine and to identify mechanisms of diabetic kidney disease that may be amenable to new treatment strategies. All participants previously enrolled in a 6-year randomized clinical trial under Protocol OH95-DK-N037 and their first-degree relatives who have type 2 diabetes will be invited to participate. Participants in this protocol will undergo annual renal clearance studies to measure glomerular filtration rate and renal plasma flow, unless they have developed kidney failure. At each visit, we will also conduct tests of the peripheral and autonomic nervous system to determine the frequency, severity, and rate of progression of diabetic neuropathy in this cohort and identify linkages between diabetic kidney disease and diabetic neuropathy. We will also perform a kidney biopsy at the initial visit. In those who had a previous research kidney biopsy during the clinical trial, we will examine the extent of structural changes that occurred since their last kidney biopsy done at the end of the clinical trial. First-degree relatives and those who were enrolled in the clinical trial, but did not undergo a research kidney biopsy as part of that trial, will be invited to undergo a second kidney biopsy after 5-years of follow-up. Tissue from these biopsies will undergo morphometric examination and compartment-specific gene expression and epigenetic profiling. A small punch skin biopsy may be obtained at various times in some participants for assessment of intraepidermal nerve fiber density or for fibroblast culture. The skin biopsy for fibroblast culture will be done only once unless the culture fails, in which case the participant may be invited to undergo another biopsy. We may invite participants to undergo skin biopsy on several occasions for assessment of changes in nerve fiber density. We may also perform magnetic resonance imaging of the kidneys or the brain in some participants. Imaging of the kidneys will be done as near to the time of the kidney biopsy as possible. We many invite participants to undergo the brain imaging on 2 occasions about 3-5 years apart. Participants will be followed annually until death or development of end-stage renal disease.