In an era in which combination antiretroviral therapy has resulted in durable virologic suppression, the life expectancy of treated HIV-infected individuals nearly approximates those of HIV-uninfected individuals.1,2 However, this progress has been tempered by the early onset of multiple chronic age-related diseases, the prevalence of which in 1 report was similar in the HIV-infected population to HIV-uninfected persons who were 15 years older.3 Moreover, individuals aged 50 or older now comprise nearly half of persons living with HIV and nearly 20% of those newly diagnosed with HIV in the United States.4
With the aging of the HIV-infected population, management focus has pivoted toward chronic age-related, noninfectious conditions, such as frailty. Treated HIV-infected individuals seem to be more likely to develop frailty than HIV-uninfected persons.5,6 Regardless of HIV serostatus, frailty, a condition characterized by accelerated physiological decline and maladaptive responses to stressors,7 is independently associated with substantial risks of adverse health outcomes, including chronic disease, infection-related hospitalizations, and death.8,9
The mechanisms by which frailty develops in the context of HIV infection remain to be fully elucidated. The cumulative effects of multimorbidity, persistent immune activation, and heightened systemic inflammation likely play a major role in frailty pathogenesis.7,10 One potential contributor to frailty pathogenesis that has not been well-studied among HIV-infected persons is disturbances to the bone–endocrine axis that arise either through comorbid conditions such as chronic kidney disease (CKD) or through systemic inflammation. A growing body of evidence links CKD to frailty.11,12 Furthermore, CKD, like HIV infection, is accompanied by persistent systemic inflammation, which in turn may further impact hormones important for maintaining bone health.
One such hormone is fibroblast growth factor-23 (FGF-23) that is involved in the regulation of bone mineral metabolism. Primarily secreted by osteocytes, FGF-23 lowers serum phosphate levels by augmenting phosphate excretion within the renal proximal tubules13 and by inhibiting parathyroid hormone (PTH) secretion.14 It also lowers levels of active vitamin D13 and enhances calcium reabsorption in the renal distal tubules.15 A growing body of work suggests a bidirectional association between systemic inflammation and FGF-23 expression.16,17 In addition, experimental and epidemiological studies indicate that FGF-23 may affect cardiac smooth muscle cells and promote the development of left ventricular hypertrophy.18 Among patients with CKD, higher serum FGF-23 levels have been associated with a significant risk of progressive kidney disease, cardiovascular morbidity, and mortality.18–22 FGF-23's effects, however, may occur before overt CKD develops23 and may extend beyond the kidney and heart because FGF-23 is expressed in other organs.24
Despite the importance of FGF-23 in bone mineral metabolism, its potential relationship with inflammation, and its observed association with age-related co-morbidities, only one study among elderly HIV-uninfected adults examined FGF-23's association with frailty.25 In this previous study, higher serum FGF-23 levels were associated with significantly higher odds of frailty. To the best of our knowledge, no study has investigated this association in HIV-infected populations. To explore the potential role of FGF-23 in frailty development among individuals with or at-risk of HIV infection, we examined whether concentrations of FGF-23 were associated with incident frailty in the Multicenter AIDS Cohort Study (MACS). Because HIV infection involves persistent inflammation and abnormalities in bone mineral metabolism and because racial/ethnic differences exist in markers of bone mineral metabolism and in susceptibility to frailty,26 we also evaluated whether FGF-23's association with frailty differed by HIV serostatus and race.
Study Design and Population
The MACS is an ongoing, prospective cohort study of the natural and treated history of HIV infection among men who have sex with men. As of July 1, 2017, it included a total of 3912 HIV-infected and 3443 HIV-uninfected participants recruited in 4 waves (4954 in 1984–1985; 866 in 1987; 1350 in 2001–2003; and 383 in 2010+) from 4 sites located in the United States (Baltimore, MD/Washington, DC; Chicago, IL; Los Angeles, CA; and Pittsburgh, PA/Columbus, OH). Details on study design and methods have been described elsewhere.27–29 Briefly, MACS collects data regarding participants' demographics, medical history, HIV treatment, and behaviors at semiannual study visits using standardized questionnaires. Blood and urine specimens are collected during regular study visits. Unused specimens are stored in a central repository for future testing. All participants have provided written informed consent to study protocols. Study protocols were approved by local institutional review boards. The current investigation was also approved by the University of California, San Francisco, and San Francisco VA Medical Center Institutional Review Boards.
From October 2007 onward, frailty assessments have been conducted at all MACS sites semiannually. To assess the association between FGF-23 levels and frailty, we selected 715 HIV-infected and HIV-uninfected men enrolled in MACS cardiovascular ancillary study30 who had fasting plasma or serum specimens available between 2007 and 2011 (with oversampling of HIV-infected men by design). We measured FGF-23 levels at the earliest MACS study visit on or after October 2007. The visit at which specimens were chosen was designated as the baseline visit. During the sampling process, we excluded HIV-infected men who were naive to highly active antiretroviral therapy (HAART) at baseline. From those with FGF-23 measurements, we excluded men who were missing frailty data at the baseline visit (n = 47) or were frail at or before the baseline visit (n = 147). The final study population comprised 521 participants.
Measurement of Plasma FGF-23 Concentrations
Fasting (≥8 hours) plasma or serum specimens were stored at −70°C in a central repository and just thawed before the testing. A 2-site enzyme-linked immunosorbent assay (Kainos Laboratories, Inc, Tokyo, Japan) kit was used to measure the intact form of FGF-23 at Dr. Richard Semba's laboratory at the Johns Hopkins School of Medicine. The intra-assay and inter-assay coefficients of variation at this laboratory were both <5%.
Assessment of Frailty
The Fried Criteria for frailty were operationalized in 2007 to identify MACS participants with frailty phenotype.31 The frailty phenotype was defined by the presence of 3 of 5 conditions: (1) unintentional weight loss (self-reported unintentional weight loss of ≥10 pounds during the previous 6 months); (2) weakness (scored lower than the 20th percentile of HIV-uninfected men in grip strength test measured with a Jamar hydraulic handheld dynamometer); (3) low energy (self-reported difficulty in performing activities in past 4 weeks due to health); (4) slowness (walked slower than the 20th percentile of HIV-uninfected men over a course of 4 m); and (5) low physical activity level (self-reported limitation in vigorous activities due to health). Measures of these components were standardized across study sites and have been assessed consistently at semiannual visits beginning from October 1, 2007. For the current analysis, the presence of frailty was confirmed at consecutive visits within 1 year. An individual was considered nonfrail if he never fulfilled the frailty phenotype definition during the study follow-up, or only met the frailty phenotype definition at a single study visit that was not confirmed on a consecutive visit within 1 year.
Demographic characteristics were collected at the MACS enrollment visit. Variables that were assessed at the baseline visit (or at the closest visit within 2 years before the baseline visit) included body mass index (BMI), blood pressure, serum creatinine, fasting blood glucose and fasting lipid levels, spot urine protein-to-creatinine ratios (UPCRs) and self-reported cigarette smoking, alcohol use, and injection drug use. The CKD Epidemiology Collaboration equation was used to estimate glomerular filtration rate (eGFR, mL/min/1.73 m2) from serum creatinine.32 Proteinuria was defined as a spot UPCR ≥200 mg/g.33 Hepatitis C virus (HCV) serostatus was determined by the presence of HCV RNA or antibody in serum. Diabetes mellitus was defined as a fasting blood glucose ≥126 mg/dL or a self-reported diagnosis with the use of glucose-lowering medications. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, a diastolic blood pressure ≥90 mm Hg, or a self-reported diagnosis with the use of antihypertensive medications. Dyslipidemia was defined as a total cholesterol ≥200 mg/dL, low-density lipoprotein ≥130 mg/dL, high-density lipoprotein <40 mg/dL, triglyceride ≥150 mg/dL, or a self-reported diagnosis with the use of lipid-lowering medications. HIV serostatus was assessed using an enzyme-linked immunosorbent assay test and confirmed with a Western blot. CD4+ T-cell counts were determined using standardized flow cytometry; plasma HIV-1 RNA levels were measured using Amplicor HIV-1 monitor ultrasensitive test (Roche Diagnostics, 50 copies/mL lower limit of detection) or TaqMan HIV-1 test (Roche Diagnostics, 20 copies/mL lower limit of detection). We considered other HIV-specific factors including history of clinically defined AIDS diagnosis, current and cumulative exposure to HAART, nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), protease inhibitors (PIs), and tenofovir disoproxil fumarate (TDF). HAART was defined according to the Department of Health and Human Services/Henry J. Kaiser Family Foundation Panel guidelines.34
FGF-23 levels were categorized into tertiles for the comparison of demographic, behavioral, and clinical characteristics at the baseline visit. Continuous variables were compared using 1-way analysis of variance or the Kruskal–Wallis test, as appropriate. Fisher's exact test was used for categorical variables.
To assess the association of FGF-23 levels with incident frailty, we first constructed Kaplan–Meier plots to graphically explore the proportion of men who were frailty-free by FGF-23 tertiles. We then used multivariable Cox-proportional hazards models to evaluate the independent association between FGF-23 levels (per doubling on linear scale) and the risk of developing frailty. Three separate models were constructed with staged adjustment for potential confounders. The first model adjusted for age and race. The second model additionally adjusted for HIV serostatus and markers of kidney function and injury–eGFR and proteinuria. The fully adjusted model included additional adjustment for the enrollment cohort (ie, pre-2001 and 2001+) and other frailty-associated factors including BMI, HCV serostatus, hypertension, diabetes mellitus, dyslipidemia and smoking. All covariates were assessed before or at the baseline visit. The proportional hazard assumption was graphically explored using log–log plots and evaluated using Schoenfeld residuals. Potential effect modification of the associations between FGF-23 levels and frailty by HIV serostatus and by race were assessed in stratified analyses and with the inclusion of interaction terms. The likelihood ratio test was used to test the statistical significance of potential effect modification. We also explored whether FGF-23 levels were associated with presentation of individual components of frailty (including weakness, slowness, unintentional weight loss, low energy, and low physical activity). We repeated the multivariable Cox regression analyses evaluating each individual frailty component at the time of incident frailty as the outcomes. As a sensitivity analysis, we compared men with incident frailty to those who never met the definition of the frailty phenotype.
Among 521 participants included in this study, 39 (7.5%) were missing data on one or more covariates at the baseline visit. To address the potential bias because of missing covariates, we conducted multiple imputations using the Markov Chain Monte Carlo methods as a sensitivity analysis. In all analyses, P values less than 0.05 were considered statistically significant.
Baseline Participant Characteristics
In total, 521 nonfrail men were included in the study with a mean age of 49.8 years (SD: 7.1 years); 147 (28%) were black, and 335 (64%) were HIV-infected. The median eGFR and UPCR levels were 92.8 mL/min/1.73 m2 [interquartile range (IQR): 81.0–104.1] and 80 mg/g (IQR: 59–114). The overall median baseline FGF-23 level was 36.2 rU/mL (IQR: 23.7–53.8). When compared by HIV serostatus, the median FGF-23 levels were lower among HIV-infected men (33.7 vs. 39.9 rU/mL, P = 0.006). Black men also had slightly lower FGF-23 levels compared with nonblack men (median 34.2 vs. 37.1 rU/mL, P = 0.037).
Table 1 displays participant characteristics at the baseline visit across FGF-23 tertiles. Compared with individuals in the lowest FGF-23 tertile, those with higher levels were more likely to be diabetic and have lower UPCR levels, and less likely to be HIV-infected. Among HIV-infected men, 88% were on HAART, and 79% were virologically suppressed; the median CD4+ count was 575 (IQR: 430–755) cells/mm3.
Of note, 63% of HIV-infected men were receiving TDF-containing HAART, for which cumulative use up to the time of the baseline visit was inversely associated with FGF-23 levels [0.94% lower per year; 95% confidence interval (CI): 0.91 to 0.95%].
Incidence of Frailty and Distribution of Frailty Components
The median follow-up was 6.6 years (IQR: 5.8–7.0). Over a course of 3148 person-years (PYs), 32 men developed frailty, of whom 19 were HIV-infected. The overall incidence rate of frailty was 1.02 per 100-PYs and was similar among HIV-infected and HIV-uninfected men (0.95 vs. 1.13 per 100 PYs, respectively, P = 0.63). When compared by race, the incidence rate of frailty was higher among blacks compared with nonblacks (1.64 vs. 0.78 per 100 PYs, respectively, P = 0.03). Median FGF-23 levels at the baseline visit were higher in men who later developed frailty compared with those who did not (45.1 vs. 35.7 rU/mL, P = 0.02).
Among the 32 individuals who developed frailty, slowness (93%) and low physical activity (88%) were the 2 most common conditions at the incident frailty visit. In addition, low energy, weakness, and unintentional weight loss were present in 75%, 59%, and 4%, respectively, at the incident frailty visit.
Association of FGF-23 Levels With Incident Frailty
Figure 1 shows the Kaplan–Meier curves of frailty by FGF-23 tertiles in the overall study population. Compared with individuals in the lowest FGF-23 tertile, the proportion of individuals who survived frailty-free by the end of study follow-up was lower in those with higher FGF-23 levels. Results from the multivariable Cox model (Table 2) showed that each 2-fold higher concentration of FGF-23 at baseline was associated with 1.63-fold (95% CI: 1.19 to 2.23) risk of frailty in the minimally adjusted model. This association remained statistically significant after further adjustment for HIV serostatus, kidney function, enrollment cohort, and frailty-related comorbidities and in the fully adjusted model with multiple imputations for missing covariates.
Although the magnitude of association between FGF-23 and frailty seemed greater in HIV-infected than HIV-uninfected men, this difference was not statistically significant (p-interaction = 0.33) (Table 2). By contrast, race significantly modified the association between FGF-23 and frailty (p-interaction = 0.024) (Table 2). FGF-23 levels (per doubling) were independently associated with 2.72-fold (95% CI: 1.51 to 4.91) increased risk of frailty among blacks but not among nonblacks [hazard ratio (HR) = 1.26, 95% CI: 0.77 to 2.05].
Sensitivity analyses yielded overall consistent results when FGF-23 values were modeled as tertiles (see Table 1, Supplemental Digital Content, https://links.lww.com/QAI/B222). We also observed similar results when men with incident frailty were compared with those who never fulfilled the definition of the frailty phenotype [adjusted HR = 1.67 (95% CI: 1.21 to 2.30) per doubling of FGF-23].
Association of FGF-23 Levels With Individual Clinical Presentations of Frailty
When fully adjusted analyses were repeated using individual frailty components as the outcomes, FGF-23 levels were independently associated with slowness (HR = 1.88, 95% CI: 1.32 to 2.67), low physical activity (HR = 1.49, 95% CI: 1.05 to 2.10), low energy (HR = 1.61, 95% CI: 1.10 to 2.36), and weakness (HR = 1.67, 95% CI: 1.00 to 2.78), but not with weight loss (HR = 1.32, 95% CI: 0.51 to 3.39).
Among middle-aged men with or at-risk of HIV infection, we found that higher FGF-23 levels were associated with increased risk of frailty. The magnitude of this association was only minimally attenuated with adjustment for sociodemographic factors, HIV serostatus, kidney function, and aging-related comorbid conditions and was comparable with the risk observed in association with 10 additional years of age in studies focused on populations of advanced age.35,36 In addition, FGF-23's association with frailty was more pronounced among blacks compared with nonblacks, but did not differ significantly by HIV serostatus. Examination of the associations of FGF-23 with individual clinical presentations of frailty revealed that higher FGF-23 levels were significantly associated with measured slowness and marginally with weakness as well as self-reported low physical activity and energy. By contrast, the FGF-23 levels were not significantly associated with weight loss in the preceding 6 months, although the number of men who experienced weight loss was small (n = 4). In total, our findings suggest that FGF-23 may either play a direct role or reflect pathways involved in the pathogenesis of frailty.
Our results are consistent with those of the only previous epidemiological study evaluating the link between FGF-23 and frailty.25 In that community-based study of older adults (aged ∼77 years), each doubling of FGF-23 levels was associated with 1.38-fold higher odds of frailty.25 With regards to the associations of FGF-23 with individual clinical presentations of frailty observed in our study, some, but not all, are consistent with those reported in the study by Beben et al.25 These differential observations across the 2 studies may arise from heterogeneity in study population composition, including age and comorbidities.
Although the exact mechanisms underlying the association between FGF-23 and frailty remain unclear, we speculate that they likely encompass a complex interplay of vitamin D, klotho, and inflammation. First, experimental models have shown that FGF-23 inhibits 1α-hydroxylase and stimulates 24-hydroxylase activity, resulting in lower levels of 1,25-OH2 vitamin D.13,37 In turn, lower levels of active vitamin D may contribute to frailty by adversely impacting skeletal muscle integrity38 and function39,40 as well as by modulating inflammation.41–43 Although the association of vitamin D deficiency with frailty has not been well-studied in the HIV-infected population specifically, a recent meta-analysis of HIV-uninfected study populations demonstrated that 25-OH vitamin D deficiency is associated with 1.25–1.55 increased odds of frailty.44 Furthermore, among HIV-uninfected men aged 70 and older in the Concord Health and Ageing in Men Project, the lowest quartile of 1,25-OH2 vitamin D (<62 pmol/L) was cross-sectionally associated with higher odds of frailty, independent of sociodemographic factors, comorbid conditions as well as 25-OH vitamin D, and PTH levels.45
Second, the transmembrane form of klotho, a hormone that has been associated with longevity,46 physical function,47–49 and cognitive health,50 is a cofactor necessary for FGF-23's interaction with its receptor to regulate renal tubular phosphate excretion.51 A small study comparing HIV-infected with healthy HIV-uninfected individuals demonstrated that the adipocyte expression of transmembrane klotho is reduced among treated and untreated HIV-infected individuals;52 however, the clinical significance of this reduction needs further study. The circulating form of klotho has been associated inversely with mortality risk46 and positively with muscular strength47,48 in older HIV-uninfected populations. Whether these associations are independent of FGF-23 remains unclear because these previous studies did not assess circulating klotho concurrently with FGF-23 levels. Future studies are needed to elucidate the relative impact of klotho and FGF-23 on frailty and to investigate the potential influence of HIV infection and race on these hormones and their associations with age-related outcomes.
Finally, several studies support the potential role of chronic inflammation in the development of frailty in older and HIV-infected populations.53,54 Experimental studies implicate a positive feedback loop between inflammation and FGF-23, which seems independent of klotho. Specifically, cell studies have demonstrated that inflammation stimulates FGF-23 production by osteocytes16; in turn, FGF-23 induces the production of inflammatory cytokines by hepatocytes.17 Cross-sectional findings from the Chronic Renal Insufficiency Cohort Study, comprising HIV-uninfected individuals with CKD, corroborate a link between FGF-23 and inflammation and indicated that higher concentrations of FGF-23 were associated with inflammation.55 Prospectively, FGF-23 and inflammation are additively associated with increased risk of mortality in persons with CKD.56 Whether similar combined associations exist for the outcome of frailty, particularly among HIV-infected individuals needs further study. However, we observed that HIV-infected men had lower baseline levels of FGF-23 compared with HIV-uninfected men, despite the HIV-infected population being characterized by persistent systemic inflammation. The potential impact of inflammation on FGF-23 levels may be counterbalanced by TDF-mediated renal tubular phosphate wasting, thus leading to lower FGF-23 concentrations.
In our study, we also noted that the association of higher FGF-23 levels with incident frailty was more pronounced among blacks than nonblacks. Although disparities in comorbid conditions, such as kidney disease, may contribute to these observed racial differences, our findings remained significant after accounting for age, smoking, HIV serostatus, comorbidities, kidney function, proteinuria, and BMI. Studies of HIV-uninfected older adults and individuals with CKD have shown that blacks have lower FGF-2357,58 and 25-OH vitamin D levels but higher concentrations of 1,25-OH2 vitamin D and intact PTH.59 We observed similar differences in FGF-23 by race in this study. These racial differences extend to differences in bone integrity, with blacks having greater bone density60 but paradoxically higher prevalence of frailty compared with whites.61 Apart from this study, rigorous investigation of the clinical consequences of these racial differences in FGF-23 is lacking.
Our study has several strengths and limitations to consider. The study used prospectively collected longitudinal data from a well-characterized, diverse population of HIV-infected and HIV-uninfected men. This allowed for adjustment for important potential confounders. In addition, incident frailty was confirmed on 2 sequential visits. However, because our study population comprised only of men, our findings may not be generalizable to women. We were unable to more comprehensively examine the bone–endocrine axis and its association with frailty due to the lack of data on other biomarkers of bone mineral health.
In conclusion, we found that higher FGF-23 concentrations are independently associated with incident frailty among HIV-infected and HIV-uninfected men, particularly among blacks. This association is largely consistent across objective and self-reported components of the frailty phenotype. These results add to the growing evidence of a potential role played by the complex bone–endocrine axis in frailty pathogenesis. These findings also highlight the need to expand our understanding of FGF-23 and its impact on aging processes, beyond the context of CKD.
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