HIV Infection, Tenofovir, and Urine α1-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study

Vasantha Jotwani; Rebecca Scherzer; Michelle Estrella; Lisa P. Jacobson; Mallory D. Witt; Frank J. Palella; Bernard Macatangay; Michael Bennett; Chirag R. Parikh; Joachim H. Ix; Michael G. Shlipak

doi:10.1053/j.ajkd.2016.03.430

HIV Infection, Tenofovir, and Urine α₁-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study

Vasantha Jotwani, Rebecca Scherzer, Michelle Estrella, Lisa P. Jacobson, Mallory D. Witt, Frank J. Palella, Bernard Macatangay, Michael Bennett, Chirag R. Parikh, Joachim H. Ix, Michael G. Shlipak

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	571-581
Number of pages	11
Journal	American Journal of Kidney Diseases
Volume	68
Issue number	4
DOIs	https://doi.org/10.1053/j.ajkd.2016.03.430
State	Published - Oct 1 2016

Keywords

HIV infection
Multicenter AIDS Cohort Study (MACS)
Tenofovir disoproxil fumarate (TDF)
antiretroviral (ARV) medication
biomarker
kidney damage
nephrotoxicity
proximal tubular dysfunction
tubular toxicity
urine α-microglobulin (A1M)

ASJC Scopus subject areas

Nephrology

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10.1053/j.ajkd.2016.03.430

Cite this

Jotwani, V., Scherzer, R., Estrella, M., Jacobson, L. P., Witt, M. D., Palella, F. J., Macatangay, B., Bennett, M., Parikh, C. R., Ix, J. H., & Shlipak, M. G. (2016). HIV Infection, Tenofovir, and Urine α₁-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study. American Journal of Kidney Diseases, 68(4), 571-581. https://doi.org/10.1053/j.ajkd.2016.03.430

Jotwani, V, Scherzer, R, Estrella, M, Jacobson, LP, Witt, MD, Palella, FJ, Macatangay, B, Bennett, M, Parikh, CR, Ix, JH & Shlipak, MG 2016, 'HIV Infection, Tenofovir, and Urine α₁-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study', American Journal of Kidney Diseases, vol. 68, no. 4, pp. 571-581. https://doi.org/10.1053/j.ajkd.2016.03.430

@article{97939b4fc153492cb628bb1ec5f8f8a3,

title = "HIV Infection, Tenofovir, and Urine α1-Microglobulin: A Cross-sectional Analysis in the Multicenter AIDS Cohort Study",

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.",

keywords = "HIV infection, Multicenter AIDS Cohort Study (MACS), Tenofovir disoproxil fumarate (TDF), antiretroviral (ARV) medication, biomarker, kidney damage, nephrotoxicity, proximal tubular dysfunction, tubular toxicity, urine α-microglobulin (A1M)",

author = "Vasantha Jotwani and Rebecca Scherzer and Michelle Estrella and Jacobson, {Lisa P.} and Witt, {Mallory D.} and Palella, {Frank J.} and Bernard Macatangay and Michael Bennett and Parikh, {Chirag R.} and Ix, {Joachim H.} and Shlipak, {Michael G.}",

note = "Funding Information: Support: MACS Kidney Study is funded by grant R01-AG034853-01A2 (Principal Investigator [PI], Dr Shlipak), which was administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, CA. Data in this manuscript were collected by the MACS with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Barbara Crain, Adrian Dobs, Richard Elion, Michelle Estrella, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven M. Wolinsky (PI), John P. Phair, Sheila Badri, Dana Gabuzda, Frank J. Palella Jr, Sudhir Penugonda, Susheel Reddy, Matthew Stephens, Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Mart{\'i}nez-Maza (Co-PI), Aaron Aronow, Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D{\textquoteright}Souza (Co-PI), Alison Abraham, Keri Althoff, Jennifer Deal, Priya Duggal, Sabina Haberlen, Alvaro Muoz, Derek Ng, Janet Schollenberger, Eric C. Seaberg, Sol Su, Pamela Surkan. Institute of Allergy and Infectious Diseases : Robin E. Huebner; National Cancer Institute: Geraldina Dominguez. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional co-funding from the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute of Mental Health. Targeted supplemental funding for specific projects was also provided by the National Heart, Lung and Blood Institute, and the National Institute on Deafness and Communication Disorders. MACS data collection is also supported by UL1-TR001079 (Johns Hopkins University Institute for Clinical and Translational Research) from the National Center for Advancing Translational Sciences a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH, Johns Hopkins Institute for Clinical and Translational Research, or the National Center for Advancing Translational Sciences. The funders of this study had no role in study design; collection, analysis or interpretation of data; manuscript preparation; or the decision to submit the report for publication. The MACS website is located at https://statepi.jhsph.edu/macs/macs.html Publisher Copyright: {\textcopyright} 2016 National Kidney Foundation, Inc.",

year = "2016",

month = oct,

day = "1",

doi = "10.1053/j.ajkd.2016.03.430",

language = "English (US)",

volume = "68",

pages = "571--581",

journal = "American Journal of Kidney Diseases",

issn = "0272-6386",

publisher = "W.B. Saunders Ltd",

number = "4",

}

TY - JOUR

T1 - HIV Infection, Tenofovir, and Urine α1-Microglobulin

T2 - A Cross-sectional Analysis in the Multicenter AIDS Cohort Study

AU - Jotwani, Vasantha

AU - Scherzer, Rebecca

AU - Estrella, Michelle

AU - Jacobson, Lisa P.

AU - Witt, Mallory D.

AU - Palella, Frank J.

AU - Macatangay, Bernard

AU - Bennett, Michael

AU - Parikh, Chirag R.

AU - Ix, Joachim H.

AU - Shlipak, Michael G.

N1 - Funding Information: Support: MACS Kidney Study is funded by grant R01-AG034853-01A2 (Principal Investigator [PI], Dr Shlipak), which was administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, CA. Data in this manuscript were collected by the MACS with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Barbara Crain, Adrian Dobs, Richard Elion, Michelle Estrella, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven M. Wolinsky (PI), John P. Phair, Sheila Badri, Dana Gabuzda, Frank J. Palella Jr, Sudhir Penugonda, Susheel Reddy, Matthew Stephens, Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Martínez-Maza (Co-PI), Aaron Aronow, Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, Eric N. Miller, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), Lawrence A. Kingsley (Co-PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D’Souza (Co-PI), Alison Abraham, Keri Althoff, Jennifer Deal, Priya Duggal, Sabina Haberlen, Alvaro Muoz, Derek Ng, Janet Schollenberger, Eric C. Seaberg, Sol Su, Pamela Surkan. Institute of Allergy and Infectious Diseases : Robin E. Huebner; National Cancer Institute: Geraldina Dominguez. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases, with additional co-funding from the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute of Mental Health. Targeted supplemental funding for specific projects was also provided by the National Heart, Lung and Blood Institute, and the National Institute on Deafness and Communication Disorders. MACS data collection is also supported by UL1-TR001079 (Johns Hopkins University Institute for Clinical and Translational Research) from the National Center for Advancing Translational Sciences a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the NIH, Johns Hopkins Institute for Clinical and Translational Research, or the National Center for Advancing Translational Sciences. The funders of this study had no role in study design; collection, analysis or interpretation of data; manuscript preparation; or the decision to submit the report for publication. The MACS website is located at https://statepi.jhsph.edu/macs/macs.html Publisher Copyright: © 2016 National Kidney Foundation, Inc.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - 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.

AB - 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.

KW - HIV infection

KW - Multicenter AIDS Cohort Study (MACS)

KW - Tenofovir disoproxil fumarate (TDF)

KW - antiretroviral (ARV) medication

KW - biomarker

KW - kidney damage

KW - nephrotoxicity

KW - proximal tubular dysfunction

KW - tubular toxicity

KW - urine α-microglobulin (A1M)

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