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Profibrotic circulating proteins and risk of early progressive renal decline in Type 2 Diabetes patients with and without albuminuria

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posted on 04.09.2020 by Katsuhito Ihara, Jan Skupien, Hiroki Kobayashi, Zaipul I. Md Dom, Jonathan M. Wilson, Kristina O’Neil, Hannah S. Badger, Lenden M. Bowsman, Eiichiro Satake, Matthew D. Breyer, Kevin L. Duffin, Andrzej S. Krolewski
OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and MMP-7 (Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline.

RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with eGFR ≥60 ml/min/1.73m2 were followed for 6-12 years to ascertain fast early progressive renal decline defined as eGFR loss ≥5 ml/min/1.73m2/year.

RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and ACR at baseline were 97 ml/min/1.73m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups risk of renal decline increased with increasing baseline levels of WFDC2 (p <0.0001) and MMP-7 (p <0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the Fibrosis Index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (OR 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria.

CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in development of early renal decline.

Funding

This study was supported by the JDRF grant “Biomarkers of Diabetic Nephropathy Collaborative Research Initiative (DN-BIO)” No.3-SRA-2015-106-Q-R to ASK; by the NIH grant DK-041526 to ASK; by the Uehara Memorial Foundation (Postdoctoral Fellowship) and the Japan Society for the Promotion of Science (Overseas Research Fellowship) to HK; by the Sunstar Foundation, Japan (Hiroo Kaneda Scholarship) and the Foundation for Growth Science from Japan to ES; by grant from the Lilly Inc. to ASK to study biomarkers of early renal decline in T2D; by the NIH Diabetes Research Center (DRC) grant P30 DK036836.

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