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Beyond Genotype: Multidomain Biomarker-Integrated Risk Scores Reveal Prognostic phenotypes Among Individuals with

George Vasquez-Rios1, Kinsuk Chauhan2, Nidhi Naik3

  • 1Glomerular and Genetic Diseases Center, Renal Medicine Associates, NM, USA.

Medrxiv : the Preprint Server for Health Sciences
|June 12, 2026
PubMed

Insights

Plasma biomarkers can predict kidney disease progression in individuals with high-risk APOL1 variants. This helps identify those at greater risk beyond genetic factors alone.

Area of Science:

  • Nephrology
  • Genetics
  • Biomarker Discovery

Background:

  • APOL1 high-risk variants increase kidney disease susceptibility in individuals of African ancestry.
  • A subset of carriers develops clinically significant kidney disease, indicating a gap between genetic risk and clinical outcomes.
  • Current prognostic tools inadequately reflect biological processes driving APOL1-associated kidney injury.

Purpose of the Study:

  • To investigate if plasma biomarkers of inflammation and tubular injury can identify biologically active disease states.
  • To improve prognostic stratification in individuals with high-risk APOL1 genotypes.
  • To explore novel biomarkers for APOL1-associated kidney disease.

Main Methods:

  • Followed 498 participants with two APOL1 high-risk alleles for a median of 6 years.
  • Measured baseline plasma biomarkers of inflammation and tubular injury (TNFR1, TNFR2, KIM-1, MCP-1, YKL-40, IL-18, suPAR).
  • Developed a weighted biomarker risk score and assessed associations with composite kidney outcomes (sustained eGFR decline or ESKD).

Main Results:

  • 16.1% of participants reached the composite outcome.
  • Higher concentrations of TNFR1, TNFR2, suPAR, KIM-1, and IL-18 were independently associated with kidney events.
  • Biomarker risk score categorized participants into low (7%), moderate (16%), and high (36%) risk groups for kidney events.

Conclusions:

  • Plasma biomarkers reveal heterogeneity in kidney outcomes among individuals with high-risk APOL1 genotypes.
  • A biology-weighted biomarker score identifies distinct prognostic phenotypes beyond genotype and traditional measures.
  • Supports multidomain biomarker frameworks for risk stratification and potential trial enrichment in APOL1-associated kidney disease.
Abstract

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