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Association of Fibroblast Growth Factor-23 (FGF-23) With Incident Frailty in HIV-Infected and HIV-Uninfected Individuals

Wang, Ruibin, MHS*; Shlipak, Michael G., MD, MPH; Ix, Joachim H., MD, MS‡,§; Brown, Todd T., MD, PhD*,║; Jacobson, Lisa P., ScD*; Palella, Frank J. Jr, MD; Lake, Jordan E., MD#; Koletar, Susan L., MD**; Semba, Richard D., MD, MA, MPH††; Estrella, Michelle M., MD, MHS

JAIDS Journal of Acquired Immune Deficiency Syndromes: January 1, 2019 - Volume 80 - Issue 1 - p 118–125
doi: 10.1097/QAI.0000000000001868
Translational Research
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Background: In the Multicenter AIDS Cohort Study, we examined whether fibroblast growth factor-23 (FGF-23), a bone-derived phosphaturic hormone involved in bone metabolism, is associated with incident frailty. Furthermore, we examined whether this association differs by HIV serostatus and race.

Methods: Of 715 men assessed for frailty and selected for FGF-23 measurements using stored blood samples (2007–2011), 512 men were nonfrail at/before the baseline visit. Frailty was defined by the presence of ≥3 of the following on 2 consecutive 6-month visits within 1 year: unintentional weight loss ≥10 pounds, weakness, slowness, low energy, and low physical activity. We determined the association of FGF-23 levels with incident frailty using proportional hazards models adjusting for sociodemographics, comorbidities, and kidney function.

Results: Sixty-five percent were HIV-infected; 29% were black. Median baseline FGF-23 levels were lower in HIV-infected vs. HIV-uninfected men (33.7 vs. 39.9 rU/mL, P = 0.006) but similar by race. During a median follow-up of 6.6 years, 32 men developed frailty; they had higher baseline FGF-23 levels vs. men who remained nonfrail (45 vs. 36 rU/mL, P = 0.02). FGF-23 (per doubling) was associated with a 1.63-fold risk of frailty [95% confidence interval (CI): 1.19 to 2.23]; results did not differ by HIV serostatus. Conversely, FGF-23 was associated with a 2.72-fold risk of frailty among blacks (95% CI: 1.51 to 4.91) but had minimal association among nonblacks (hazard ratio = 1.26, 95% CI: 0.77 to 2.05; p-interaction = 0.024).

Conclusions: Among men with or at-risk of HIV infection, higher FGF-23 was associated with greater risk of frailty, particularly in blacks. The mechanisms by which FGF-23 may contribute to frailty warrant further study.

*Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD;

Department of Medicine, Kidney Health Research Collaborative, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA;

Department of Medicine, University of California San Diego;

§Nephrology Section, Department of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, CA;

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;

Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL;

#Department of Medicine, University of Texas Health Science Center at Houston, Houston, TX;

**Department of Internal Medicine, Ohio State University Wexner Medical Center, Columbus, OH; and

††Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD.

Correspondence to: Michelle M. Estrella, MD, MHS, 4150 Clement Street, Building 2, Room 145, San Francisco, CA 94121 (e-mail: michelle.estrella@ucsf.edu).

Supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R03DK096975 to M.M.E. J.E.L. was supported by the National Institute of Allergy and Infectious Diseases (NIAID) grant K23 AI110532, and RDS was supported by the National Institute of Aging (NIA) grant R01AG027012. Data in this article were collected by the Multicenter AIDS Cohort Study (MACS) with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Adrian Dobs, Michelle Estrella, W. David Hardy, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, and Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven M. Wolinsky (PI), Sheila Badri, Dana Gabuzda, Frank J. Palella, Jr., Sudhir Penugonda, John P. Phair, Susheel Reddy, Matthew Stephens, and Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Martínez-Maza (PI), Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, and Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Lawrence A. Kingsley, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, and Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D'Souza (PI), Alison Abraham, Keri Althoff, Michael Collaco, Priya Duggal, Sabina Haberlen, Eithne Keelaghan, Heather McKay, Alvaro Muñoz, Derek Ng, Anne Rostich, Eric C. Seaberg, Sol Su, Pamela Surkan, and Nicholas Wada. 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 (NIAID), with additional cofunding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). The MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS) 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 National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at http://aidscohortstudy.org/.

M.G.S. and M.M.E. report receiving honoraria from Gilead Sciences. F.J.P. consults for Gilead Sciences, Janssen Pharmaceuticals, Merck and Co., and ViiV. J.E.L. reports consulting for Gilead Sciences and Merck and research funding from Gilead. The remaining authors have no funding or conflicts of interest to disclose.

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Received June 07, 2018

Accepted August 31, 2018

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