In our long-term studies on Natural History of Microalbuminuria (MA) in type 1 diabetes we found that in the majority of patients MA regresses to normo-albuminuria, however, in a third of patients with MA significant renal function decline occurs;this decline is progressive and appears to be launched at the onset of MA. Because renal function at the onset of MA is in the normal or elevated range, we call this phenomenon early renal function decline (ERFD). Once initiated, ERFD progresses until significant renal function impairment is reached with subsequent development of ESRD. In this renewal we aim to study etiology of ERFD and find diagnostic tools for it. This proposal has the following specific aims: 1) To continue the follow-up of the cohort of 935 patients recruited into the """"""""2nd Joslin Study on the Natural History of MA in T1DM"""""""". Extended follow-up measurements of cystatin C will provide critical precision to determinations of the rate of renal function loss in these patients and at the same time the prospective measurements of biomarkers in serum and urine will provide data for the examination of hypotheses about the mechanisms underlying initiation and promotion of ERFD;2) To examine in the extended study the associations of serum uric acid and serum biomarkers of inflammation (TNF1, sTNFR-1, sTNFR-2, sFas, IP-10 and ICAM) with the risk of ERFD;3) To examine in the extended study the associations of various biomarkers excreted in urine with the risk of ERFD. The following urinary biomarkers will be studied: a) Albumin, IgG2 and IgA - biomarkers of glomerular filtration barrier damage, b) NAG and Kim-1 - biomarkers of proximal tubule damage and c) MCP-1, IL-8, IP- 10, VCAM, sTNFR-1, and sTNFR-2 - biomarkers of inflammation in the kidney. 4) To determine whether the 21 genomic regions and genes identified by the leading SNPs associated with ERFD in the whole genome association study (WGAS) performed in the """"""""1st Joslin Study"""""""" are replicated in the """"""""2nd Joslin Study"""""""" samples. 5) To design a diagnostic protocol (analogous to the Framingham score for the assessment of risk of CAD) that combines clinical predictors with serum, urinary, and genetic biomarkers for ERFD, so that ERFD can be diagnosed early in the course of disease (within 1-2 years of observation instead of 4-8 years). The Joslin Clinic is a unique and ideal setting that makes this proposal feasible. The success of the proposal is further assured because we have already recruited and examined 935 patients with T1DM and MA, implemented the protocols required for this research, demonstrated our ability to continuously follow these patients and analyzed preliminary data and developed several new exiting hypothesis about etiology of ERFD.

Public Health Relevance

In our long-term studies on Natural History of Microalbuminuria (MA) in type 1 diabetes we found that significant renal function decline leading to ESRD occurs in a third of patients with MA. This decline is progressive and appears to be launched at the onset of MA. Because renal function at the onset of MA is in the normal or elevated range, we call this phenomenon early renal function decline (ERFD). This renewal has two overarching goals. The first is to increase our knowledge of the etiology of ERFD to provide foundations for new interventions to prevent ESRD that could then be tested in clinical trials. The second is to develop diagnostic tools to identify those patients at risk of ESRD 5-10 year earlier than current methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041526-21
Application #
8063189
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
1990-02-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
21
Fiscal Year
2011
Total Cost
$561,756
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

Showing the most recent 10 out of 96 publications