Risk factors for mortality in patients with kidney failure on hemodialysis identified by proteomic analysis of CRIC and PACE studies

More than 50% of patients with kidney failure undergoing maintenance hemodialysis die within 5 years, a fate unexplained by traditional risk factors. To identify biological risk factors, we analyze 6287 circulating proteins and mortality in 893 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort (CRIC) and Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) studies. Proteins are measured shortly after (incident period) and one year after (prevalent period) dialysis initiation. In CRIC prevalent period, Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), R-spondin 4, tetranectin and 24 other proteins attain Bonferroni significance (p < 7 × 10<sup>-6</sup>). At false discovery rate<0.05, 184 proteins are significant in CRIC; 123/184 remain significant after adjustment for covariates including those linked to inflammation. Pathways related to insulin-like growth factor are prominent. In the pooled CRIC + PACE cohort, prevalent time period, AUC(95%CI) for a 3-protein model of 5-year mortality is 0.826 (0.742, 0.896), compared to 0.629 (0.528, 0.722) for a Cohort Clinical model (p < 0.001). Adding the 3 proteins (SVEP1, R-spondin 4 and tetranectin) to the Cohort Clinical model significantly improves the AUC (p < 0.001). These biomarkers should be validated in future studies and their roles as potential disease mediators elucidated.

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Publication Details

Journal
Nature Communications
Published
2025-11-27
DOI
https://doi.org/10.1038/s41467-025-66763-z
Primary Topic
Dialysis and Renal Disease Management
Type
article
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0.00

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article

Risk factors for mortality in patients with kidney failure on hemodialysis identified by proteomic analysis of CRIC and PACE studies

Ruth F. Dubin, Zeenat Bhat, Mark R. Segal, Stephen M. Sozio et al.
Nature Communications
Dialysis and Renal Disease Management
article

Risk factors for mortality in patients with kidney failure on hemodialysis identified by proteomic analysis of CRIC and PACE studies

Ruth F. Dubin, Zeenat Bhat, Mark R. Segal, Stephen M. Sozio, Glenn M. Chertow, Michelle M. Estrella, Jing Chen, Mark L. Unruh, Debbie L. Cohen, Laura M. Dember, Tariq Shafi, Rulan S. Parekh, Vallabh O. Shah, Michela Traglia, Alexander R. Pico, Peter Ganz, Bernard G. Jaar, Wei Chen, Hernan Rincon-Choles, Hongzhe Li, Min‐Gyoung Shin, Panduranga S. Rao, Sylvia E. Rosas, Amanda H. Anderson, Jiang He, Alan S. Go, Yue Ren, Mahboob U. Rahman, James P. Lash, Lawrence J. Appel
article en

Abstract

More than 50% of patients with kidney failure undergoing maintenance hemodialysis die within 5 years, a fate unexplained by traditional risk factors. To identify biological risk factors, we analyze 6287 circulating proteins and mortality in 893 participants undergoing hemodialysis in the Chronic Renal Insufficiency Cohort (CRIC) and Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) studies. Proteins are measured shortly after (incident period) and one year after (prevalent period) dialysis initiation. In CRIC prevalent period, Sushi von Willebrand factor type A EGF and pentraxin domain-containing protein 1(SVEP1), R-spondin 4, tetranectin and 24 other proteins attain Bonferroni significance (p < 7 × 10<sup>-6</sup>). At false discovery rate<0.05, 184 proteins are significant in CRIC; 123/184 remain significant after adjustment for covariates including those linked to inflammation. Pathways related to insulin-like growth factor are prominent. In the pooled CRIC + PACE cohort, prevalent time period, AUC(95%CI) for a 3-protein model of 5-year mortality is 0.826 (0.742, 0.896), compared to 0.629 (0.528, 0.722) for a Cohort Clinical model (p < 0.001). Adding the 3 proteins (SVEP1, R-spondin 4 and tetranectin) to the Cohort Clinical model significantly improves the AUC (p < 0.001). These biomarkers should be validated in future studies and their roles as potential disease mediators elucidated.

Nature CommunicationsVol. 16(1)
Joslin Diabetes Center (US), Albert Einstein College of Medicine (US), Beth Israel Deaconess Medical Center (US), Cleveland Clinic (US), Gladstone Institutes (US), Kaiser Permanente (US), Harvard University (US), Johns Hopkins University (US), Illinois College (US), University of New Mexico (US), University of California, San Francisco (US), University of Michigan (US), Women's College Hospital (CA), University of Alabama at Birmingham (US), University of Illinois Chicago (US), Southwestern Medical Center (US), Baylor Scott & White Medical Center - Temple (US), San Francisco VA Health Care System (US), Case Western Reserve University (US), University of Pennsylvania (US), The University of Texas Southwestern Medical Center (US), Stanford University (US)
Kaiser Permanente, University of Pennsylvania, Johns Hopkins University, Deutsches Krebsforschungszentrum, Georgia Clinical and Translational Science Alliance, National Institutes of Health, University of Illinois at Urbana-Champaign, Perelman School of Medicine, University of Pennsylvania, University of California, San Francisco, Michigan Institute for Clinical and Health Research, Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Openalex Percentile: Top 56%
Dialysis and Renal Disease Management
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