APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV.
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.


METHODS
Observational study.


METHODS
431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS).


METHODS
APOL1 genotype.


RESULTS
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.


METHODS
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.


CONCLUSIONS
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.
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.
Vasantha
V
Jotwani
Department of Medicine, San Francisco VA Medical Center, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
Michael G
MG
Shlipak
Department of Medicine, San Francisco VA Medical Center, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.
Rebecca
R
Scherzer
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.
Rulan S
RS
Parekh
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
W H Linda
WH
Kao
Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Michael
M
Bennett
Department of Medicine, Stroger Hospital, Rush University, Chicago, IL; Department of Medicine, Rush University, Chicago, IL.
Mardge H
MH
Cohen
Department of Medicine, University of Southern California, Los Angeles, CA.
Marek
M
Nowicki
Division of Infectious Diseases, Department of Medicine, SUNY Downstate Medical Center, Brooklyn, NY.
Anjali
A
Sharma
Division of Infectious Diseases and Travel Medicine, Department of Medicine, Georgetown University Medical Center, Washington, DC.
Mary
M
Young
Department of Medicine, San Francisco VA Medical Center, San Francisco, CA.
Phyllis C
PC
Tien
Section of Nephrology, Department of Medicine, Yale University, New Haven, CT; Program of Applied Translational Research, Yale University, New Haven, CT.
Chirag R
CR
Parikh
Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD.
Michelle M
MM
Estrella
D000209:Acute-Phase Proteins / Q000378:metabolism; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000419:Albuminuria / Q000378:metabolism; D000510:Alpha-Globulins / Q000378:metabolism; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D016022:Case-Control Studies; D003404:Creatinine / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015658:HIV Infections / Q000150:complications*; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D012709:Serum Albumin
C108666:APOL1 protein, human; D000209:Acute-Phase Proteins; D000510:Alpha-Globulins; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D020382:Interleukin-18; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D011991:Receptors, Virus; D012709:Serum Albumin; D003404:Creatinine
APOL1 genotype; African American; G1 allele; G2 allele; Women’s Interagency HIV Study (WIHS); albumin-creatinine ratio (ACR); apolipoprotein L1; glomerular injury; kidney disease; proteinuria; renal function; risk allele; risk variant; single-nucleotide polymorphism (SNP); tubular injury biomarker