Vasantha Jotwani1, Michael G Shlipak2, Rebecca Scherzer2, Rulan S Parekh3, W H Linda Kao4, Michael Bennett5, Mardge H Cohen6, Marek Nowicki7, Anjali Sharma8, Mary Young9, Phyllis C Tien10, Chirag R Parikh11, Michelle M Estrella12. 1. Department of Medicine, San Francisco VA Medical Center, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA. Electronic address: vasantha.jotwani@ucsf.edu. 2. Department of Medicine, San Francisco VA Medical Center, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA. 3. Hospital for Sick Children, University Healthy Network and University of Toronto, Toronto, Canada; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. 4. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. 5. Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 6. Department of Medicine, Stroger Hospital, Rush University, Chicago, IL; Department of Medicine, Rush University, Chicago, IL. 7. Department of Medicine, University of Southern California, Los Angeles, CA. 8. Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY. 9. Division of Infectious Diseases and Travel Medicine, Department of Medicine, Georgetown University Medical Center, Washington, DC. 10. Department of Medicine, San Francisco VA Medical Center, San Francisco, CA. 11. Section of Nephrology, Department of Medicine, Yale University, New Haven, CT; Program of Applied Translational Research, Yale University, New Haven, CT. 12. Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
Abstract
BACKGROUND: APOL1 genotype is associated with advanced kidney disease in African Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury and kidney function decline were evaluated. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS). PREDICTOR: APOL1 genotype. OUTCOMES: Albumin-creatinine ratio (ACR), 4 tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [A1M]), and kidney function estimated using the CKD-EPI cystatin C equation. MEASUREMENTS: Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarkers were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-ups. RESULTS: At baseline, ACRs were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs 11mg/g; P<0.001). Compared with women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACRs (95% CI, 29-223mg/g) and 2-fold greater risk of ACR>30 (95% CI, 1.17-3.44) mg/g after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr ratio, KIM-1:Cr ratio, and NGAL:Cr ratio (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to -1%], and 10% [95% CI, -26% to 64%], respectively) or detectable urine A1M (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared with women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, 0.2 to 2.2) mL/min/1.73m(2) per year, and 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1 to 2.5) and 10% annual eGFR decline (95% CI, 1.7 to 6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarker levels. LIMITATIONS: Results may not be generalizable to men. CONCLUSIONS: Among HIV-infected African American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules. Published by Elsevier Inc.
BACKGROUND: APOL1 genotype is associated with advanced kidney disease in African Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury and kidney function decline were evaluated. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS). PREDICTOR: APOL1 genotype. OUTCOMES: Albumin-creatinine ratio (ACR), 4 tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [A1M]), and kidney function estimated using the CKD-EPI cystatin C equation. MEASUREMENTS: Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarkers were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-ups. RESULTS: At baseline, ACRs were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs 11mg/g; P<0.001). Compared with women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACRs (95% CI, 29-223mg/g) and 2-fold greater risk of ACR>30 (95% CI, 1.17-3.44) mg/g after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr ratio, KIM-1:Cr ratio, and NGAL:Cr ratio (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to -1%], and 10% [95% CI, -26% to 64%], respectively) or detectable urine A1M (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared with women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, 0.2 to 2.2) mL/min/1.73m(2) per year, and 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1 to 2.5) and 10% annual eGFR decline (95% CI, 1.7 to 6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarker levels. LIMITATIONS: Results may not be generalizable to men. CONCLUSIONS: Among HIV-infected African American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules. Published by Elsevier Inc.
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