Urinary Complement proteome strongly linked to diabetic kidney disease progression

Zaipul I. Md Dom, Salina Moon, Eiichiro Satake, Daigoro Hirohama, Nicholette D. Palmer, Heather Lampert, Linda H. Ficociello, Amin Abedini, Karen Fernandez, Xiujie Liang, Sara Pickett, Jonathan Levinsohn, Kristina O’Neil, Simon T. Dillon, Michael Mauer, Andrzej T. Galecki, Barry I. Freedman, Katalin Susztak, Alessandro Doria, Andrzej S. Krolewski and Monika A. Niewczas ()
Additional contact information
Zaipul I. Md Dom: Joslin Diabetes Center
Salina Moon: Joslin Diabetes Center
Eiichiro Satake: Joslin Diabetes Center
Daigoro Hirohama: Perelman School of Medicine
Nicholette D. Palmer: Wake Forest University School of Medicine
Heather Lampert: Joslin Diabetes Center
Linda H. Ficociello: Joslin Diabetes Center
Amin Abedini: Perelman School of Medicine
Karen Fernandez: Joslin Diabetes Center
Xiujie Liang: Perelman School of Medicine
Sara Pickett: Joslin Diabetes Center
Jonathan Levinsohn: Perelman School of Medicine
Kristina O’Neil: Joslin Diabetes Center
Simon T. Dillon: Harvard Medical School
Michael Mauer: University of Minnesota
Andrzej T. Galecki: University of Michigan
Barry I. Freedman: Wake Forest University School of Medicine
Katalin Susztak: Perelman School of Medicine
Alessandro Doria: Joslin Diabetes Center
Andrzej S. Krolewski: Joslin Diabetes Center
Monika A. Niewczas: Joslin Diabetes Center

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Diabetic kidney disease (DKD) progression is not well understood. Using high-throughput proteomics, biostatistical, pathway and machine learning tools, we examine the urinary Complement proteome in two prospective cohorts with type 1 or 2 diabetes and advanced DKD followed for 1,804 person-years. The top 5% urinary proteins representing multiple components of the Complement system (C2, C5a, CL-K1, C6, CFH and C7) are robustly associated with 10-year kidney failure risk, independent of clinical covariates. We confirm the top proteins in three early-to-moderate DKD cohorts (2,982 person-years). Associations are especially pronounced in advanced kidney disease stages, similar between the two diabetes types and far stronger for urinary than circulating proteins. We also observe increased Complement protein and single cell/spatial RNA expressions in diabetic kidney tissue. Here, our study shows Complement engagement in DKD progression and lays the groundwork for developing biomarker-guided treatments.

Date: 2025
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DOI: 10.1038/s41467-025-62101-5

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