Diabetic kidney disease (DKD) is the major health problem in patients with Insulin- Dependent Diabetes Mellitus (IDDM). Recent clinical trials have shown that the natural history of DKD can be modified by intervening at an early stage, so called microalbuminuria. The goal of this competitive renewal is to study prospectively the natural history of microalbuminuria in IDDM.
The specific aims of this project are as follow: A. From the investigators' currently funded research, it appears that about 20% of patients with IDDM develop microalbuminuria early in the course of diabetes, and twice as many develop it later. Those with early onset microalbuminuria probably constitute the majority of IDDM patients who develop renal failure. Therefore, they should be identified early and should be targeted for preventive programs. The goal of the proposed 6 year follow-up study is to discover the determinants of early and late onset microalbuminuria. For this purpose, the investigators propose to examine the incidence density of microalbuminuria according to duration of IDDM and level of HgbA1 in 1100 normoalbuminuric IDDM patients. In a random subset (n=479) of these patients, the baseline and follow-up examination included measurements of lipid abnormalities, hypertension and predisposition to hypertension, dietary protein intake, and DNA markers of susceptibility to DKD. B. From their case-control study, it appears that progression from low to high levels of microalbuminuria and, perhaps, to overt proteinuria is influenced less by level of hyperglycemia and more by other factors. The goal of the proposed 6 year follow-up study in 230 IDDM patients with microalbuminuria is to test the role of putative risk factors such as hypercholesterolemia, hypertension as well as predisposition to hypertension, autonomic neuropathy, smoking and DNA markers of susceptibility to DKD. C. They have developed molecular genetics protocols and identified specific DNA sequence differences in three candidate genes - angiotensinogen, angiotensin converting enzyme, and insulin receptor - which they found to be associated with susceptibility to DKD. The goal is to study further these associations to understand the pathogenetic mechanisms of DKD and, perhaps, use DNA markers to identify patients at risk. Using DNA samples from their large case-control study and the cases found during follow-up, they will examine associations between these DNA sequence differences and the development/progression of microalbuminuria. The investigators state that the proposed research has a high probability of success. They further state that the results of this study will advance understanding of the etiology of the early stages of DKD and provide dose-specific information on putative exposures and the risk of developing microalbuminuria. They conclude that this dose-response information will be crucial for designing accurate disease models which will be used to develop and evaluate preventive or therapeutic programs against DKD.
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