Vasantha Jotwani1, Rebecca Scherzer2, Michelle M Estrella3, Lisa P Jacobson4, Mallory D Witt5, Frank J Palella6, Bernard Macatangay7, Michael Bennett8, Chirag R Parikh9, Joachim H Ix10, Michael G Shlipak11. 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. Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD. 4. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. 5. Division of HIV Medicine, Department of Medicine, Harbor-UCLA Medical Center and the Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA. 6. Division of Infectious Diseases, Department of Medicine, Northwestern University, Chicago, IL. 7. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA. 8. Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 9. Section of Nephrology, Department of Medicine, Yale University, New Haven, CT; Program of Applied Translational Research, Yale University, New Haven, CT. 10. Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA. 11. Department of Medicine, San Francisco VA Medical Center, San Francisco, CA; Kidney Health Research Collaborative, San Francisco VA Medical Center and University of California, San Francisco, CA.
Abstract
BACKGROUND: Tenofovir disoproxil fumarate (TDF) can cause proximal tubular damage and chronic kidney disease in human immunodeficiency virus (HIV)-infected individuals. Urine α1-microglobulin (A1M), a low-molecular-weight protein indicative of proximal tubular dysfunction, may enable earlier detection of TDF-associated tubular toxicity. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 883 HIV-infected and 350 -uninfected men enrolled in the Multicenter AIDS Cohort Study. PREDICTORS: HIV infection and TDF exposure. OUTCOME: Urine A1M level. RESULTS: Urine A1M was detectable in 737 (83%) HIV-infected and 202 (58%) -uninfected men (P<0.001). Among HIV-infected participants, 573 (65%) were current TDF users and 112 (13%) were past TDF users. After multivariable adjustment including demographics, traditional kidney disease risk factors, and estimated glomerular filtration rate, HIV infection was associated with 136% (95% CI, 104%-173%) higher urine A1M levels and 1.5-fold (95% CI, 1.3- to 1.6-fold) prevalence of detectable A1M. When participants were stratified by TDF exposure, HIV infection was associated with higher adjusted A1M levels, by 164% (95% CI, 127%-208%) among current users, 124% (95% CI, 78%-183%) among past users, and 76% (95% CI, 45%-115%) among never users. Among HIV-infected participants, each year of cumulative TDF exposure was associated with 7.6% (95% CI, 5.4%-9.9%) higher A1M levels in fully adjusted models, a 4-fold effect size relative to advancing age (1.8% [95% CI, 0.9%-2.7%] per year). Each year since TDF treatment discontinuation was associated with 4.9% (95% CI, -9.4%--0.2%) lower A1M levels among past users. LIMITATIONS: Results may not be generalizable to women. CONCLUSIONS: HIV-infected men had higher urine A1M levels compared with HIV-uninfected men. Among HIV-infected men, cumulative TDF exposure was associated with incrementally higher A1M levels, whereas time since TDF treatment discontinuation was associated with progressively lower A1M levels. Urine A1M appears to be a promising biomarker for detecting and monitoring TDF-associated tubular toxicity.
BACKGROUND:Tenofovir disoproxil fumarate (TDF) can cause proximal tubular damage and chronic kidney disease in human immunodeficiency virus (HIV)-infected individuals. Urine α1-microglobulin (A1M), a low-molecular-weight protein indicative of proximal tubular dysfunction, may enable earlier detection of TDF-associated tubular toxicity. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 883 HIV-infected and 350 -uninfected men enrolled in the Multicenter AIDS Cohort Study. PREDICTORS: HIV infection and TDF exposure. OUTCOME: Urine A1M level. RESULTS: Urine A1M was detectable in 737 (83%) HIV-infected and 202 (58%) -uninfected men (P<0.001). Among HIV-infectedparticipants, 573 (65%) were current TDF users and 112 (13%) were past TDF users. After multivariable adjustment including demographics, traditional kidney disease risk factors, and estimated glomerular filtration rate, HIV infection was associated with 136% (95% CI, 104%-173%) higher urine A1M levels and 1.5-fold (95% CI, 1.3- to 1.6-fold) prevalence of detectable A1M. When participants were stratified by TDF exposure, HIV infection was associated with higher adjusted A1M levels, by 164% (95% CI, 127%-208%) among current users, 124% (95% CI, 78%-183%) among past users, and 76% (95% CI, 45%-115%) among never users. Among HIV-infectedparticipants, each year of cumulative TDF exposure was associated with 7.6% (95% CI, 5.4%-9.9%) higher A1M levels in fully adjusted models, a 4-fold effect size relative to advancing age (1.8% [95% CI, 0.9%-2.7%] per year). Each year since TDF treatment discontinuation was associated with 4.9% (95% CI, -9.4%--0.2%) lower A1M levels among past users. LIMITATIONS: Results may not be generalizable to women. CONCLUSIONS:HIV-infectedmen had higher urine A1M levels compared with HIV-uninfectedmen. Among HIV-infectedmen, cumulative TDF exposure was associated with incrementally higher A1M levels, whereas time since TDF treatment discontinuation was associated with progressively lower A1M levels. Urine A1M appears to be a promising biomarker for detecting and monitoring TDF-associated tubular toxicity.
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