Diabetic nephropathy is the major health problem in patients with IDDM. Recent clinical trials have shown that the natural history of diabetic nephropathy in IDDM can be modified by intervening at an early stage, microalbuminuria. Previous research supported by this grant provided strong evidence that the onset of microalbuminuria is determined by a different set of factors than its progression to overt proteinuria. This proposal explores this hypothesis and has the following goals: (1) To identify determinants of the onset of microalbuminuria: We will obtain frequent measurements of relevant exposures and of urinary albumin excretion (ACR) in our cohort of 787 IDDM patients with normoalbuminuria during an additional 5 years of followup. We will examine the relationship between the development of microalbuminuria and novel measures of hyperglycemia exposure, urinary levels of interleukin 6, and cigarette smoking. (2) To identify determinants of progression of microalbuminuria: We will obtain frequent measurements of ACR and will repeat biennial clinical and laboratory measurements in our cohort of 713 IDDM with microalbuminuria during the next 5 years of followup. We will use these new data to examine the relationship between progression of microalbuminuria and novel indices of lipid abnormalities, hyperfibrinogenemia, elevated blood pressure, and treatment with ACE inhibitors. (3) To identify genetic markers associated with the onset of microalbuminuria and its progression: We will collect DNA samples from available parents and IDDM individuals with (a) normoalbuminuria (n=400), (b) new onset microalbuminuria (n=200), (c) microalbuminuria and non-progression (n=400), and (d) microalbuminuria and progression to proteinuria (n=200). These DNA samples will be used to study eNOS, ACE, and ApoE, genes for which we have found linkage association and linkage with advanced nephropathy. We will test the hypothesis that polymorphisms in eNOS and ACE genes contribute to the onset of microalbuminuria and polymorphism in ApoE contributes to progression of microalbuminuria to overt proteinuria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK041526-10
Application #
2910958
Study Section
Special Emphasis Panel (ZRG1-HPD (01))
Program Officer
Meyers, Catherine M
Project Start
1990-02-01
Project End
2003-06-30
Budget Start
1999-08-23
Budget End
2000-06-30
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Skupien, Jan; Smiles, Adam M; Valo, Erkka et al. (2018) Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy. Diabetes Care :
Nowak, Natalia; Skupien, Jan; Smiles, Adam M et al. (2018) Markers of early progressive renal decline in type 2 diabetes suggest different implications for etiological studies and prognostic tests development. Kidney Int 93:1198-1206
Yamanouchi, Masayuki; Skupien, Jan; Niewczas, Monika A et al. (2017) Improved clinical trial enrollment criterion to identify patients with diabetes at risk of end-stage renal disease. Kidney Int 92:258-266
Niewczas, Monika A; Mathew, Anna V; Croall, Stephanie et al. (2017) Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care 40:383-390
Krolewski, Andrzej S; Skupien, Jan; Rossing, Peter et al. (2017) Fast renal decline to end-stage renal disease: an unrecognized feature of nephropathy in diabetes. Kidney Int 91:1300-1311
Niewczas, Monika A; Krolewski, Andrzej S (2017) Response to Comment on Niewczas et al. Circulating Modified Metabolites and a Risk of ESRD in Patients With Type 1 Diabetes and Chronic Kidney Disease. Diabetes Care 2017;40:383-390. Diabetes Care 40:e109-e110
Skupien, Jan; Warram, James H; Smiles, Adam M et al. (2016) Patterns of Estimated Glomerular Filtration Rate Decline Leading to End-Stage Renal Disease in Type 1 Diabetes. Diabetes Care 39:2262-2269
Nowak, Natalia; Skupien, Jan; Niewczas, Monika A et al. (2016) Increased plasma kidney injury molecule-1 suggests early progressive renal decline in non-proteinuric patients with type 1 diabetes. Kidney Int 89:459-67
Pavkov, Meda E; Weil, E Jennifer; Fufaa, Gudeta D et al. (2016) Tumor necrosis factor receptors 1 and 2 are associated with early glomerular lesions in type 2 diabetes. Kidney Int 89:226-34
Orlov, Steven; Cherney, David Z I; Pop-Busui, Rodica et al. (2015) Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes. Clin J Am Soc Nephrol 10:1136-44

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