Plasma biomarkers are associated with renal outcomes in individuals with APOL1 risk variants

Girish N. Nadkarni, Kinsuk Chauhan, Divya A. Verghese, Chirag Parikh, Ron Do, Carol R. Horowitz, Erwin P. Bottinger, Steven G. Coca

Research output: Contribution to journalArticle

Abstract

G1/G2 variants in the Apolipoprotein L1 (APOL1) gene are associated with end-stage renal disease (ESRD) in people with African ancestry. Plasma biomarkers may have utility for risk stratification in APOL1 high-risk individuals of African ancestry. To evaluate this, we measured tumor necrosis factor receptor 1/2 (TNFR1/2) and kidney injury molecule-1 (KIM1) in baseline plasma specimens from individuals of African ancestry with high-risk APOL1 genotype. Biomarker association with a composite renal outcome of ESRD or 40% sustained decline in estimated glomerular filtration rate (eGFR) was then determined and then assessed as improvement in area under curve. Among the 498 participants, the median age was 56 years, 67.7% were female, and the baseline eGFR was 83.3 ml/min/1.73 m2 with 80 reaching outcome over 5.9 years. TNFR1, TNFR2, and KIM1 at enrollment were independently associated with renal outcome continuously (adjusted hazard ratio 2.0 [95% confidence interval 1.3-3.1]; 1.5 [1.2-1.9]; and 1.6 [1.3-1.9] per doubling in levels, respectively) or by tertiles. The area under the curve significantly improved from 0.75 with the clinical model to 0.79 with the biomarker-enhanced model. The event rate was 40% with all 3 biomarkers elevated (adjusted odds ratio of 5.3 (2.3-12.0) vs. 17% (adjusted odds ratio 1.8 [0.9-3.6] with 1 or 2 elevated and 7% with no biomarkers elevated. Thus, plasma concentrations of TNFR1, TNFR2, and KIM1 are independently associated with renal outcome and improve discrimination or reclassification of African ancestry individuals with a high-risk APOL1 genotype and preserve renal function. Elevation of all markers had higher risk of outcome and can assist with better clinical prediction and improved clinical trial efficiency by enriching event rates.

Original languageEnglish (US)
Pages (from-to)1409-1416
Number of pages8
JournalKidney International
Volume93
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Apolipoproteins
Biomarkers
Kidney
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Glomerular Filtration Rate
Chronic Kidney Failure
Area Under Curve
Wounds and Injuries
Odds Ratio
Genotype
Clinical Trials
Confidence Intervals
Genes

Keywords

  • APOL1
  • biomarkers
  • chronic kidney disease
  • inflammation

ASJC Scopus subject areas

  • Nephrology

Cite this

Nadkarni, G. N., Chauhan, K., Verghese, D. A., Parikh, C., Do, R., Horowitz, C. R., ... Coca, S. G. (2018). Plasma biomarkers are associated with renal outcomes in individuals with APOL1 risk variants. Kidney International, 93(6), 1409-1416. https://doi.org/10.1016/j.kint.2018.01.026

Plasma biomarkers are associated with renal outcomes in individuals with APOL1 risk variants. / Nadkarni, Girish N.; Chauhan, Kinsuk; Verghese, Divya A.; Parikh, Chirag; Do, Ron; Horowitz, Carol R.; Bottinger, Erwin P.; Coca, Steven G.

In: Kidney International, Vol. 93, No. 6, 01.06.2018, p. 1409-1416.

Research output: Contribution to journalArticle

Nadkarni, GN, Chauhan, K, Verghese, DA, Parikh, C, Do, R, Horowitz, CR, Bottinger, EP & Coca, SG 2018, 'Plasma biomarkers are associated with renal outcomes in individuals with APOL1 risk variants', Kidney International, vol. 93, no. 6, pp. 1409-1416. https://doi.org/10.1016/j.kint.2018.01.026
Nadkarni, Girish N. ; Chauhan, Kinsuk ; Verghese, Divya A. ; Parikh, Chirag ; Do, Ron ; Horowitz, Carol R. ; Bottinger, Erwin P. ; Coca, Steven G. / Plasma biomarkers are associated with renal outcomes in individuals with APOL1 risk variants. In: Kidney International. 2018 ; Vol. 93, No. 6. pp. 1409-1416.
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abstract = "G1/G2 variants in the Apolipoprotein L1 (APOL1) gene are associated with end-stage renal disease (ESRD) in people with African ancestry. Plasma biomarkers may have utility for risk stratification in APOL1 high-risk individuals of African ancestry. To evaluate this, we measured tumor necrosis factor receptor 1/2 (TNFR1/2) and kidney injury molecule-1 (KIM1) in baseline plasma specimens from individuals of African ancestry with high-risk APOL1 genotype. Biomarker association with a composite renal outcome of ESRD or 40{\%} sustained decline in estimated glomerular filtration rate (eGFR) was then determined and then assessed as improvement in area under curve. Among the 498 participants, the median age was 56 years, 67.7{\%} were female, and the baseline eGFR was 83.3 ml/min/1.73 m2 with 80 reaching outcome over 5.9 years. TNFR1, TNFR2, and KIM1 at enrollment were independently associated with renal outcome continuously (adjusted hazard ratio 2.0 [95{\%} confidence interval 1.3-3.1]; 1.5 [1.2-1.9]; and 1.6 [1.3-1.9] per doubling in levels, respectively) or by tertiles. The area under the curve significantly improved from 0.75 with the clinical model to 0.79 with the biomarker-enhanced model. The event rate was 40{\%} with all 3 biomarkers elevated (adjusted odds ratio of 5.3 (2.3-12.0) vs. 17{\%} (adjusted odds ratio 1.8 [0.9-3.6] with 1 or 2 elevated and 7{\%} with no biomarkers elevated. Thus, plasma concentrations of TNFR1, TNFR2, and KIM1 are independently associated with renal outcome and improve discrimination or reclassification of African ancestry individuals with a high-risk APOL1 genotype and preserve renal function. Elevation of all markers had higher risk of outcome and can assist with better clinical prediction and improved clinical trial efficiency by enriching event rates.",
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