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The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status.

ABSTRACT: Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study.We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses.Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], -3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001).Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects.

SUBMITTER: Estrella MM

PROVIDER: S-EPMC4318914 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status.

Estrella Michelle M MM Li Man M Tin Adrienne A Abraham Alison G AG Shlipak Michael G MG Penugonda Sudhir S Hussain Shehnaz K SK Palella Frank J FJ Wolinsky Steven M SM Martinson Jeremy J JJ Parekh Rulan S RS Kao W H Linda WH

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20141003 4

<h4>Background</h4>Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study.<h4>Methods</h4>We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects ...[more]

PMID: 25281610

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Project description:BackgroundAPOL1 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 designObservational study.Setting & participants431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS).PredictorAPOL1 genotype.OutcomesAlbumin-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.MeasurementsParticipants 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.ResultsAt 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.LimitationsResults may not be generalizable to men.ConclusionsAmong HIV-infected African American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules.

Project description:Background and objectivesTrajectories of eGFR in patients with CKD are highly variable. Only a subset of patients with CKD experiences a steady decline in eGFR. The objective of our study was to investigate whether eGFR trajectory patterns differ by APOL1 risk status.Design, setting, participants, & measurementsOur study was a longitudinal observational study of 622 participants in the African American Study of Kidney Disease and Hypertension with APOL1 genotyping and sufficient follow-up for estimating GFR trajectories. The predictor was APOL1 high-risk status (having two copies of the G1 or G2 risk alleles) versus low-risk status (zero or one copy of the risk alleles), and the outcome was four eGFR trajectory patterns on the basis of the joint probabilities of linearity and progression: steady decline, unsteady decline, steady stable, and unsteady stable.ResultsOver a median follow-up of 9 years, 24.0% of participants experienced steady eGFR decline, 25.9% had an unsteady decline, 25.6% were steady and stable, and 24.6% were unsteady but stable. Those experiencing steady decline had lower eGFR and higher urine protein-to-creatinine ratio at baseline than participants with the other eGFR trajectory patterns. The APOL1 high-risk group was associated with a greater odds for the steady decline pattern than the APOL1 low-risk group (unadjusted odds ratio, 2.45; 95% confidence interval, 1.62 to 3.69). This association remained significant after adjusting for demographic factors, baseline eGFR, urine protein-to-creatinine ratio, treatment assignment, and follow-up time (adjusted odds ratio, 1.59; 95% confidence interval, 1.00 to 2.52).ConclusionsAmong patients with CKD attributed to hypertension, those with the APOL1 high-risk genotype were more likely to experience a steady decline trajectory in eGFR than those without the APOL1 high-risk genotype. These findings suggest a persistent underlying pathophysiologic process in those patients with the APOL1 high-risk genotype.

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The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status.

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The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status.

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