Urinary IgG4 and Smad1 are specific biomarkers for renal structural and functional changes in early stages of diabetic nephropathy

Toshio Doi, Tatsumi Moriya, Yui Fujita, Naoto Minagawa, Masaru Usami, Tomoko Sasaki, Hideharu Abe, Seiji Kishi, Taichi Murakami, Motoshi Ouchi, Go Ichien, Keiichi Yamamoto, Hiroki Ikeda, Yasuhiko Koezuka, Norimichi Takamatsu, Kenji Shima, Michael Mauer, Kojiro Nagai, Tatsuya Tominaga

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Diabetic nephropathy (DN) is the major cause of end-stage kidney disease, but early biomarkers of DN risk are limited. Herein we examine urinary IgG4 and Smad1 as additional early DN biomarkers. We recruited 815 patients with type 2 diabetes; 554 patients fulfilled the criteria of an estimated glomerular filtration rate (EGFR) >60 mL/min and no macroalbuminuria at baseline, with follow-up for 5 years. Patients without macroalbuminuria were also recruited for renal biopsies. Urinary IgG4 and Smad1 were determined by enzyme-linked immunoassays using specific antibodies. The specificity, sensitivity, and reproducibility were confirmed for each assay. Increased urinary IgG4 was significantly associated with lower EGFR. The level of urinary IgG4 also significantly correlated with surface density of peripheral glomerular basement membrane (Sv PGBM/Glom), whereas Smad1 was associated with the degree of mesangial expansion-both classic pathological findings in DN. Baseline EGFR did not differ between any groups; however, increases in both urinary IgG4 and Smad1 levels at baseline significantly predicted later development of EGFR decline in patients without macroalbuminuria. These data suggest that urinary IgG4 and Smad1 at relatively early stages of DN reflect underlying DN lesions and are relevant to later clinical outcomes.

Original languageEnglish (US)
Pages (from-to)986-993
Number of pages8
Issue number5
StatePublished - May 1 2018

Bibliographical note

Funding Information:
Funding. This study was supported by Grants-in-Aid from the Japan Science and Technology Agency (AS2115050G). Duality of Interest. M.M. is involved in investigator-initiated research funded by Boehringer Ingelheim. No other potential conflicts of interest relevant to this article were reported. Author Contributions. T.D. conceived and designed this study and wrote the manuscript. T.Mo., and M.M. conceived and designed the study. T.Mo. and M.O. analyzed renal biopsies. N.M. and G.I. performed statistical analyses. T.D., Y.F., T.S., H.A., S.K., T.Mu., K.N., and T.T. performed immunological and urinary analyses. N.M., M.U., G.I., H.I., Y.K., N.T., and K.S. enrolled patients and acquired clinical data. K.Y. estimated the costs of the study. M.M. wrote and edited the manuscript. All authors contributed to the critical review and comments and approved the final draft. T.D. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Publisher Copyright:
© 2018 by the American Diabetes Association.


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