Complement Proteins Identify Rapidly Progressive Diabetic Kidney Disease

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Introduction: Mechanisms underlying diabetic kidney disease (DKD) progression remain incompletely understood. This study used untargeted and targeted mass spectrometry-based proteomics in 2 independent cohorts to capture rapidly progressive DKD. Methods: = 282), respectively. Urine proteins associated with kidney disease progression (doubling of serum creatinine, ≥ 50% decrease in estimated glomerular filtration rates [eGFRs], or progression to end-stage kidney disease[ESKD]) were identified after adjusting for eGFR, proteinuria, and other clinical variables. Results: In the SNUH-DN patients, urine proteins clustered into 2 groups, with cluster 1 exhibiting a 4.6-fold higher hazard of disease progression (95% confidence interval [CI]: 1.9-11.5) than cluster 0. Proteins in cluster 1 mapped to 10 pathways, 4 of the top 5 being complement-related. A high complement score, derived from urine complement protein abundance, correlated with histopathologic features of DKD and conferred a 2.4-fold greater hazard of disease progression (95% CI: 1.0-5.4) than a low complement score. In CRIC-T2D, targeted mass spectrometry similarly confirmed that complement score stratified patients into rapid and slow DKD progression groups. In both cohorts, complement score exhibited a linear association with disease progression. Conclusion: The strong association between complement activation and rapid DKD progression highlights the need to explore complement inhibition as a potential therapeutic strategy for DKD.

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