Urinary Complement proteome strongly linked to diabetic kidney disease progression.

Journal: Nature communications
Published Date: Aug 7, 2025

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.

Authors

  • Zaipul I Md Dom
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Salina Moon
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Eiichiro Satake
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Daigoro Hirohama
    Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
  • Nicholette D Palmer
    Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
  • Heather Lampert
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Linda H Ficociello
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Amin Abedini
    ICMR-UMR CNRS 7312, Groupe Isolement et Structure, Campus Sciences, Bât. 18, BP 1039, 51687 Reims, France; EA 4691, Biomatériaux et inflammation en site osseux, Laboratoire de microbiologie, UFR de pharmacie, 1, Rue du Maréchal-Juin, 51096 Reims, France.
  • Karen Fernandez
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Xiujie Liang
    Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
  • Sara Pickett
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Jonathan Levinsohn
    Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
  • Kristina O'Neil
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Simon T Dillon
    Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Michael Mauer
    Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
  • Andrzej T Galecki
    Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Barry I Freedman
    Department of Internal Medicine-Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
  • Katalin Susztak
    Departments of Medicine and Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • Alessandro Doria
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Andrzej S Krolewski
    Research Division, Joslin Diabetes Center, Boston, MA, USA.
  • Monika A Niewczas
    Research Division, Joslin Diabetes Center, Boston, MA, USA. monika.niewczas@joslin.harvard.edu.

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