William R Zhang1, Rebecca Scherzer1, Michelle M Estrella1, Simon B Ascher1,2, Anthony Muiru1, Vasantha Jotwani1, Carl Grunfeld1, Chirag R Parikh3, Deborah Gustafson4, Seble Kassaye5, Anjali Sharma6, Mardge Cohen7, Phyllis C Tien8, Derek K Ng9, Frank J Palella10, Mallory D Witt11, Ken Ho12, Michael G Shlipak1. 1. Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Healthcare System. 2. Department of Medicine, University of California, Los Angeles, California. 3. Division of Nephrology, Johns Hopkins School of Medicine, Baltimore, Maryland. 4. Department of Medicine, SUNY Downstate Medical Center, Brooklyn, New York. 5. Georgetown University Medical Center, Washington, District of Columbia. 6. Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. 7. Department of Medicine, Stroger Hospital and Rush University, Chicago, Illinois. 8. Department of Medicine, Division of Infectious Disease, University of California, San Francisco and Department of Veterans Affairs Healthcare System, San Francisco, California. 9. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 10. Department of Medicine, Division of Infectious Disease, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 11. Division of HIV Medicine, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California. 12. Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Abstract
OBJECTIVES: Urinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity. DESIGN: This observational study included 198 HIV-infected participants from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, who initiated TDF between 2009 and 2015 and had urine samples collected at baseline before and after TDF initiation. METHODS: We used linear mixed-effects models controlling for urine creatinine and time on TDF to evaluate the effects of TDF initiation on changes in 14 urinary biomarkers. RESULTS: Within 1 year after TDF initiation, concentrations of trefoil factor 3 [+78%; 95% confidence interval (CI) +38%, +129%), alpha-1 microglobulin (α1m) (+32%; 95% CI +13%, +55%), clusterin (+21%; 95% CI +6%, +38%), uromodulin (+19%; 95% CI +4%, +36%), and kidney injury molecule-1 (KIM-1) (+13%; 95% CI +1%, +26%) significantly increased, whereas interleukin-18 (IL-18) significantly decreased (-13%, 95% CI -7%, -25%). Subsequent to the first year of TDF use, biomarker concentrations stabilized, and these changes were not statistically significant. When stratifying by baseline viremia (HIV-1 RNA < vs. ≥80 copies/ml), concentration changes for most biomarkers during the first year of TDF use were greater among aviremic vs. viremic participants, with significant differences in α1m (+80 vs. +22%), KIM-1 (+43 vs. +10%), beta-2 microglobulin (+83 vs. -10%), YKL-40 (+33 vs. -5%), and IL-18 (+20 vs. -27%). CONCLUSIONS: TDF initiation was associated with substantial changes in urinary biomarkers of kidney injury within the first year of use, particularly among aviremic participants. A urinary biomarker panel may be a clinically useful tool to detect and monitor the heterogeneous effects of TDF on the kidney.
OBJECTIVES: Urinary biomarkers of kidney injury may have potential to identify subclinical injury attributable to tenofovir disoproxil fumarate (TDF) toxicity. DESIGN: This observational study included 198 HIV-infected participants from the Multicenter AIDS Cohort Study and the Women's Interagency HIV Study, who initiated TDF between 2009 and 2015 and had urine samples collected at baseline before and after TDF initiation. METHODS: We used linear mixed-effects models controlling for urine creatinine and time on TDF to evaluate the effects of TDF initiation on changes in 14 urinary biomarkers. RESULTS: Within 1 year after TDF initiation, concentrations of trefoil factor 3 [+78%; 95% confidence interval (CI) +38%, +129%), alpha-1 microglobulin (α1m) (+32%; 95% CI +13%, +55%), clusterin (+21%; 95% CI +6%, +38%), uromodulin (+19%; 95% CI +4%, +36%), and kidney injury molecule-1 (KIM-1) (+13%; 95% CI +1%, +26%) significantly increased, whereas interleukin-18 (IL-18) significantly decreased (-13%, 95% CI -7%, -25%). Subsequent to the first year of TDF use, biomarker concentrations stabilized, and these changes were not statistically significant. When stratifying by baseline viremia (HIV-1 RNA < vs. ≥80 copies/ml), concentration changes for most biomarkers during the first year of TDF use were greater among aviremic vs. viremic participants, with significant differences in α1m (+80 vs. +22%), KIM-1 (+43 vs. +10%), beta-2 microglobulin (+83 vs. -10%), YKL-40 (+33 vs. -5%), and IL-18 (+20 vs. -27%). CONCLUSIONS:TDF initiation was associated with substantial changes in urinary biomarkers of kidney injury within the first year of use, particularly among aviremic participants. A urinary biomarker panel may be a clinically useful tool to detect and monitor the heterogeneous effects of TDF on the kidney.
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