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 (TNF?, 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

Krolewski, Andrzej S. The narrative: 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. PHS 398/2590 (Rev. 05/01) Page ___42____ Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041526-23
Application #
8457120
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
2013-04-01
Budget End
2014-03-31
Support Year
23
Fiscal Year
2013
Total Cost
$479,875
Indirect Cost
$182,739
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Pavkov, Meda E; Nelson, Robert G; Knowler, William C et al. (2015) Elevation of circulating TNF receptors 1 and 2 increases the risk of end-stage renal disease in American Indians with type 2 diabetes. Kidney Int 87:812-9
Krolewski, Andrzej S; Niewczas, Monika A; Skupien, Jan et al. (2014) Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care 37:226-34
Fiorina, Paolo; Vergani, Andrea; Bassi, Roberto et al. (2014) Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol 25:1415-29
Sabbisetti, Venkata S; Waikar, Sushrut S; Antoine, Daniel J et al. (2014) Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes. J Am Soc Nephrol 25:2177-86
Niewczas, Monika A; Sirich, Tammy L; Mathew, Anna V et al. (2014) Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study. Kidney Int 85:1214-24
Skupien, Jan; Warram, James H; Niewczas, Monika A et al. (2014) Synergism between circulating tumor necrosis factor receptor 2 and HbA(1c) in determining renal decline during 5-18 years of follow-up in patients with type 1 diabetes and proteinuria. Diabetes Care 37:2601-8
Lee, Jung Eun; Gohda, Tomohito; Walker, William H et al. (2013) Risk of ESRD and all cause mortality in type 2 diabetes according to circulating levels of FGF-23 and TNFR1. PLoS One 8:e58007
Wanic, Krzysztof; Krolewski, Bozena; Ju, Wenjun et al. (2013) Transcriptome analysis of proximal tubular cells (HK-2) exposed to urines of type 1 diabetes patients at risk of early progressive renal function decline. PLoS One 8:e57751
Skupien, Jan; Warram, James H; Groop, Per-Henrik et al. (2013) Cystatin-based estimated GFR versus creatinine-based and creatinine- and cystatin-based estimated GFR for ESRD and mortality risk in diabetes. Am J Kidney Dis 62:184-6
Merchant, Michael L; Niewczas, Monika A; Ficociello, Linda H et al. (2013) Plasma kininogen and kininogen fragments are biomarkers of progressive renal decline in type 1 diabetes. Kidney Int 83:1177-84

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