Proteomic risk score for early prediction of kidney disease progression in individuals with APOL1 high-risk genotypes
). Using elastic net Cox regression adjusted for age, sex, eGFR and albuminuria, we derived a nine-protein APOL1 Proteomic Risk Score (APRS) that predicts a composite outcome of ≥40% eGFR decline, kidney failure or death. APRS achieved a time-dependent area under the receiver operating characteristic curve (tAUC) of 86.5%, outperforming the Kidney Failure Risk Equation (66.1%) and polygenic risk scores, with 10-year event rates of 62.5% versus 3.3% across risk quintiles. External validation in Atherosclerosis Risk in Communities and UK Biobank cohorts confirmed robust accuracy (tAUC 82-85%) and consistent performance across demographic and clinical subgroups. Plasma levels of APRS component proteins correlated with kidney tissue fibrosis and tubular injury pathways, indicating strong biological plausibility. By enabling early and accurate prediction of disease progression in APOL1 high-risk individuals, APRS bridges the gap between genetic susceptibility and clinical translation. This scalable and biologically informed approach provides a precision medicine framework for early intervention and may accelerate development of APOL1-targeted therapies to reduce kidney disease disparities.
Authors
- Vesna Barros (ORCID: https://orcid.org/0000-0002-3057-8140)
- Lori L. Jennings (ORCID: https://orcid.org/0000-0001-5130-8417)
- Anurag Verma (ORCID: https://orcid.org/0000-0002-5063-9107)
- Joseph Loureiro (ORCID: https://orcid.org/0000-0001-7222-9160)
- Morgan E. Grams (ORCID: https://orcid.org/0000-0002-4430-6023)
- Rebecca Pitts (ORCID: https://orcid.org/0000-0003-4733-414X)
- Josef Coresh (ORCID: https://orcid.org/0000-0002-4598-0669)
- Amin Abedini (ORCID: https://orcid.org/0000-0002-8875-0070)
- Katalin Suszták (ORCID: https://orcid.org/0000-0002-1005-3726)
- Ghazal Z. Quinn (ORCID: https://orcid.org/0000-0002-0907-8459)
- Daniel James Rader (ORCID: https://orcid.org/0000-0002-9245-9876)
- Samer Mohandes
- Marylyn DeRiggi Ritchie (ORCID: https://orcid.org/0000-0002-1208-1720)
- Nancy Finkel (ORCID: https://orcid.org/0000-0002-8937-4150)
- Anil Karihaloo
- Chenyu Li (ORCID: https://orcid.org/0000-0002-5402-584X)
- William F. Dietrich
- Shola M. Richards
- Aditya Surapaneni
- Xiazi Qiu
- Minyan Zhu
- Taehwan Shin
- Penn Medicine BioBank
- Tanya Verma
Institutions
- Novartis (Switzerland) (CH)
- Medical University of South Carolina (US)
- Novo Nordisk (Denmark) (DK)
- Novartis (United States) (US)
- Penn Center for AIDS Research (US)
- Institute for Medical Informatics and Biostatistics (CH)
- New York University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Medicine
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1038/s41591-026-04337-2
- Primary Topic
- Renal Diseases and Glomerulopathies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute of Diabetes and Digestive and Kidney Diseases