Summary
Background and objectives
Elevated circulating fibroblast growth factor 23 (FGF23) predicts progression of CKD, but it is unknown whether circulating FGF23 independently predicts incident CKD. This study aimed to determine whether circulating FGF23 predicts incident CKD in community-dwelling women.
Design, setting, participants, & measurements
This study examined the relationship of intact serum FGF23, 1,25-dihydroxyvitamin D3 (1,25[OH]2D), 25-hydroxyvitamin D (25[OH]D), parathyroid hormone, calcium, and phosphate with prevalent and incident CKD in 701 disabled women, ≥65 years of age, from the Women’s Health and Aging Study I in Baltimore, Maryland, from 1993 to 1997. Incident CKD was defined as a low estimated GFR (eGFR) <60 ml/min per 1.73 m2 only, low eGFR <60 ml/min per 1.73 m2 and a ≥25% decline in eGFR from baseline, and an increase in serum creatinine (≥0.4 mg/dl) at follow-up.
Results
At baseline, 381 women (54.3%) had stage 3 CKD. Of 307 women without CKD at baseline, 63 (20.5%) developed stage 3 CKD over 24 months of follow-up. After excluding prevalent cases of CKD, FGF23 (per 1 SD increase) was associated with incident stage 3 CKD (hazard ratio [HR], 1.51; 95% confidence interval [95% CI], 1.06, 2.16; P=0.02), low and declining eGFR (HR, 3.69; 95% CI, 1.68, 8.11; P=0.001), and increase in serum creatinine (HR, 5.35; 95% CI, 1.27, 22.54; P=0.02) in respective multivariable Cox proportional hazards models adjusting for baseline eGFR, age, race, phosphate, 1,25-dihydroxyvitamin D3, parathyroid hormone, and other potential confounders.
Conclusions
Elevated FGF23 is an independent risk factor for incident CKD in older, disabled, community-dwelling women.
Introduction
CKD affects more than 15 million people in the United States (1) and is associated with higher morbidity and mortality (2). Risk factors for CKD include age, baseline GFR, body mass index, smoking, HDL cholesterol, diabetes, and hypertension (3). Inflammation is also implicated in the progression of kidney disease (4). The management of CKD is mostly limited to slowing the progression of kidney disease and cardiovascular risk in those with established CKD. The early identification of those at risk of developing CKD in the general population may facilitate early intervention to lower the risk of kidney disease.
Fibroblast growth factor 23 (FGF23) is a recently discovered hormone that regulates calcium and phosphate metabolism (5) and is secreted into the circulation primarily by osteocytes (6). Circulating FGF23 interacts with the klotho-FGF23 receptor complex in the proximal tubules and induces phosphaturia by decreasing phosphate reabsorption; in addition, FGF23 reduces circulating 1,25 dihydroxyvitamin D3 (1,25[OH]2D) concentrations by inhibiting renal 1-α hydroxylase and stimulating 24-hydroxylase (7). Serum 1,25(OH)2D stimulates intestinal calcium and phosphate absorption. Thus, FGF23 lowers serum phosphate by inhibiting both the reabsorption of phosphate in the proximal tubule and the absorption of phosphate in the intestine. In addition, FGF23 inhibits secretion of parathyroid hormone (PTH) (8). Recently, elevated plasma FGF23 concentrations were shown to predict progression of CKD in nondiabetic patients (9) and kidney transplant loss and mortality among adults with CKD (10). In the Chronic Renal Insufficiency Cohort, elevated plasma FGF23 increased the risk of ESRD or death (11). Although FGF23 has been implicated as playing a key role in disordered mineral metabolism in CKD, there are still many basic unanswered questions regarding FGF23 (12). For example, one question concerns whether elevated serum FGF23 can identify individuals who are at risk for developing CKD in the general population.
We postulated that elevated serum FGF23 was an independent predictor of incident CKD. To address this hypothesis, we characterized the relationship of serum FGF23, PTH, 1,25(OH)2D, 25-hydroxyvitamin D (25[OH]D), calcium, and phosphate in patients with prevalent CKD and identified to what extent disturbances in these measures predict the onset of CKD in a prospective study of older women living in the community.
Materials and Methods
Study Population
Participants in this study were women, ≥65 years of age, who participated in the Women’s Health and Aging Study I, a population-based study of physical disability in older community-dwelling women. Details of sampling, procedures, and disease adjudication are provided in detail elsewhere (13). Of the 1409 women who met study eligibility criteria, 1002 were enrolled. The study period was from May 1993 to March 1997. There were no major differences in sociodemographic or reported health characteristics between eligible participants and those who declined to participate. Of the 1002 women enrolled in the study, 753 participated in the blood drawing and 701 had a previously unthawed serum aliquot available in the study repository for FGF23 analyses. Women who did and did not participate in the blood drawing differed by age (77.4 versus 80.7 years; P<0.0001) but not by race or body mass index.
Data Collection
Standardized questionnaires were administered by trained interviewers. Data were collected on medication use, including use of vitamin D supplements. The Mini–Mental State Examination was administered at enrollment and a score <23 was defined as cognitive impairment (14). Women were seen every 6 months for a follow-up visit. During the 24 months of follow-up, vital status was determined through follow-up interviews with proxies, obituaries, and matching with the National Death Index. Median time of follow-up was 18.0 months. Causes of death were classified using the International Classification of Diseases, version 9 (ICD-9) (15). Deaths from cardiovascular disease, cancer, and respiratory disease were based upon ICD-9 codes 390–459, 140–239, 460–519, and 580–589, respectively. Deaths from chronic renal disease were based upon ICD-9 codes 250.4, 403, 404, 581–583, 585–589, 591, 593, 593.7, and 753 (16). The Johns Hopkins University Institutional Review Board approved the study protocol, and written informed consent was obtained from all participants.
Laboratory Studies
Nonfasting blood samples were obtained by venipuncture between 9:00 am and 2:00 pm. Serum creatinine was measured at baseline, 12, and 24 months at Quest Diagnostics Laboratories using the Jaffe method. Estimated GFR (eGFR) was calculated using the four-variable Modification of Diet in Renal Disease (MDRD) study equation (17). An alternative analysis was conducted in which eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (18). Serum 25-hydroxyvitamin D (25[OH]D) was measured using a radioreceptor assay (19), with intra- and inter-assay coefficients of variation (CVs) of 7.5% and 9.6%, respectively. Serum 1,25-dihydroxyvitamin D3 (1,25[OH]2D) was measured with the use of chromatography and radioreceptor assay (20), with intra- and inter-assay CVs of 7.5% and 10.9%, respectively. Intact serum PTH was measured using chemiluminescence (21) with intra- and inter-assay CVs of 5.7% and 6.7%, respectively. Serum ionized calcium was measured with ion selective electrodes (Nova 8; Nova Biomedical, Waltham, MA) with a SD of 0.05 mmol/L for standards. Serum phosphate was measured using a colorimetric assay with intra- and inter-assay CVs of 5.7% and 6.5%, respectively. Total cholesterol and HDL cholesterol were measured by enzymatic methods with intra- and inter-assay CVs of 1.4% and 1.6%, respectively, for total cholesterol and 3.2% and 5.0%, respectively, for HDL cholesterol. Serum was stored at −80°C until the time of analyses of intact serum FGF23. Active full-length FGF23 was measured in baseline sera using ELISA (Kainos Laboratories Inc, Tokyo, Japan) (22). The intra- and interassay CVs were 2.8% and 4.9%, respectively. IL-6 was measured using ELISA (Quantikine Human IL-6; R&D Systems, Minneapolis, MN) with inter- and intra-assay CVs of 4.1% and 5.9%, respectively.
Statistical Analyses
Continuous variables were compared using rank-sum tests. Categorical variables were compared using chi-squared tests. Appropriate variable transformations were made for highly skewed variables [i.e., FGF23, PTH, 25(OH)D, and IL-6]. The primary exposure was serum FGF23 measured at baseline. Women were categorized into ordinal tertiles of FGF23 in descriptive analyses. Three definitions of incident CKD were used in the longitudinal analyses: low eGFR <60 ml/min per 1.73 m2 only, low eGFR <60 ml/min per 1.73 m2 and declining (≥25% decrease) eGFR, and increase in serum creatinine (≥0.4 mg/dl) at follow-up visits, per Bash et al. (16). In time to event analyses, the censoring indicators were loss to follow-up, death, or no development of CKD. Variables that were significantly associated with prevalent CKD in univariate analyses or were significantly different across tertiles of serum FGF23 were included in the multivariable models. Multivariable Cox proportional hazards models were used to examine the relationship of FGF23 and other factors with incident CKD. Because reduced kidney function is a risk factor for the development of CKD, we adjusted for eGFR at baseline. Assumptions of the Cox models were tested by generating time-dependent covariates of the interactions of the predictors and the log of survival time and including them in the models. The main independent variables were examined for collinearity, and there was none except for a significant relationship between FGF23 and PTH. The variable inflation factor of the interaction term FGF23×PTH was >70; thus, the interaction term was not introduced into the multivariable models. Given the potential problem of overadjustment in the multivariable models, additional parsimonious models were fitted with six covariates that reached a significance level of P<0.001 in univariate analyses. SAS software (SAS Institute, Cary, NC) was used. The level of significance used in this study was P<0.05.
Results
Overall, median (25th, 75th percentile) serum FGF23 concentration was 39.9 (29.3, 51.2) pg/ml. At baseline, mean (SD) serum creatinine was 1.1 (0.3) mg/dl, and eGFR was 60.1 (16.2) ml/min per 1.73 m2. The demographic and health characteristics of 701 women by tertile of serum FGF23 are shown in Table 1. Women with higher serum FGF23 had a significantly lower education level, higher serum creatinine, lower eGFR, lower HDL cholesterol, higher PTH, lower 1,25(OH)2D, higher 25(OH)D, higher calcium, higher phosphate; higher prevalence of hypertension, coronary artery disease, congestive heart failure, and CKD; and lower prevalence of chronic obstructive pulmonary disease.
Table 1.
Characteristics of 701 women, ≥65 years of age, in the Women’s Health and Aging Study I by tertiles of serum FGF23 at baseline
| Characteristic | Tertile of Serum FGF23 (pg/ml) | Pa | ||
|---|---|---|---|---|
| <32.9 (n=233) | 32.9–45.4 (n=234) | >45.4 (n=234) | ||
| Age (yr) | 77.0 (70.0, 85.0) | 77.0 (72.0, 86.0) | 76.0 (71.0, 85.0) | 0.53 |
| Race, white | 70.4 | 70.9 | 75.6 | 0.38 |
| Education <12 yr | 70.1 | 66.2 | 56.9 | 0.009 |
| Uses alcohol | 17.6 | 15.0 | 17.9 | 0.64 |
| Current smoker | 12.0 | 10.7 | 11.5 | 0.90 |
| Use of vitamin D supplements | 7.4 | 10.2 | 12.3 | 0.20 |
| Taking calcium-based medications | 1.7 | 1.8 | 2.6 | 0.74 |
| Body mass index (kg/m2) | 27.4 (22.6, 32.2) | 27.6 (24.5, 32.3) | 27.9 (25.0, 31.7) | 0.30 |
| Mini–Mental State Examination score <24 | 19.3 | 19.7 | 12.4 | 0.06 |
| Systolic BP (mmHg) | 135 (123, 154) | 138 (123, 155) | 140 (124, 160) | 0.31 |
| Diastolic BP (mmHg) | 67 (60, 75) | 67 (60, 74) | 68 (59, 77) | 0.94 |
| Serum creatinine (mg/dl) | 1.00 (0.90, 1.10) | 1.00 (0.90, 1.20) | 1.20 (0.90, 1.40) | <0.0001 |
| eGFR (ml/min per 1.73 m2) | 63.1 (55.2, 72.9) | 60.1 (49.8, 70.5) | 50.8 (42.3, 64.0) | <0.0001 |
| eGFR (ml/min per 1.73 m2) | ||||
| ≥90 | 5.3 | 1.3 | 1.3 | 0.009 |
| 60–89 | 48.7 | 48.9 | 28.4 | <0.0001 |
| <60 | 46.0 | 49.8 | 70.3 | <0.0001 |
| Hemoglobin A1c | 7.70 (7.10, 8.40) | 7.70 (7.20, 8.40) | 7.80 (7.10, 8.60) | 0.37 |
| HDL cholesterol (mg/dl) | 53 (44, 64) | 53 (42, 64) | 49 (41, 59) | 0.006 |
| Albumin (g/dl) | 4.10 (3.90, 4.20) | 4.10 (3.80, 4.20) | 4.10 (3.80, 4.20) | 0.83 |
| IL-6 (pg/ml) | 2.14 (1.45, 3.49) | 2.36 (1.55, 3.56) | 2.46 (1.57, 4.01) | 0.06 |
| Calcium (mg/dl) | 9.20 (9.00, 9.50) | 9.30 (9.10 , 9.50) | 9.30 (9.10, 9.60) | 0.02 |
| Phosphate (mg/dl) | 3.50 (3.20, 3.80) | 3.60 (3.30, 3.90) | 3.80 (3.40, 4.10) | <0.0001 |
| 1,25-Dihydroxyvitamin D3 (ng/ml) | 39.4 (31.8, 50.7) | 34.9 (29.5, 46.5) | 29.8 (21.5, 39.6) | <0.0001 |
| 25-Hydroxyvitamin D (ng/ml) | 17.8 (12.3, 25.0) | 20.5 (14.4, 25.5) | 21.9 (16.4, 3.36) | 0.0001 |
| Parathyroid hormone (pg/ml) | 66.7 (49.4, 92.7) | 72.2 (51.9, 100.5) | 90.0 (66.0, 141.2) | <0.0001 |
| Hypertension | 49.1 | 58.4 | 68.4 | 0.0001 |
| Coronary artery disease | 22.3 | 18.0 | 30.3 | 0.006 |
| Congestive heart failure | 12.0 | 6.4 | 14.5 | 0.02 |
| Peripheral artery disease | 17.6 | 24.4 | 23.9 | 0.14 |
| Stroke | 4.7 | 4.7 | 8.1 | 0.19 |
| Diabetes mellitus | 18.4 | 12.8 | 19.2 | 0.13 |
| Chronic obstructive pulmonary disease | 32.2 | 27.3 | 22.2 | 0.05 |
| Depression | 16.3 | 16.2 | 17.9 | 0.86 |
| Cancer | 9.4 | 13.2 | 13.2 | 0.34 |
Data are presented in percentages for categorical variables, and as median (25th, 75th percentile) for continuous variables. FGF23, fibroblast growth factor 23; eGFR, estimated GFR.
Chi-squared tests were used for categorical variables, and Kruskal–Wallis tests were used for continuous variables.
Of the 701 women, 381 (54.3%) had CKD (eGFR <60 ml/min per 1.73 m2) at baseline. The demographic and health characteristics of the 701 women by presence or absence of CKD at baseline are shown in Table 2. Women with CKD had significantly higher age, were more likely to be white, were less likely to use alcohol, and had significantly higher serum creatinine, FGF23, PTH, phosphate, and IL-6, and significantly lower eGFR, HDL cholesterol, 1,25(OH)2D, and higher 25(OH)D, compared with women without CKD. The prevalence of hypertension, coronary heart disease, and peripheral artery disease was higher and the prevalence of chronic obstructive pulmonary disease was lower among women with CKD compared with women without CKD.
Table 2.
Demographic and health characteristics of women, ≥65 years of age, in the Women’s Health and Aging Study I with and without an eGFR <60 ml/min per 1.73 m2 at baseline
| Characteristica | eGFR <60 ml/min per 1.73 m2 (n=381) | eGFR ≥60 ml/min per 1.73 m2 (n=307) | Pb |
|---|---|---|---|
| Age (yr) | 79.0 (72.0, 86.0) | 74.0 (70.0, 81.0) | <0.0001 |
| Race, white | 77.7 | 65.1 | 0.0003 |
| Education <12 yr | 63.7 | 66.5 | 0.45 |
| Uses alcohol | 13.7 | 20.5 | 0.02 |
| Current smoker | 10.5 | 12.7 | 0.38 |
| Use of vitamin D supplements | 8.5 | 11.2 | 0.24 |
| Taking calcium-based medications | 2.1 | 1.7 | 0.69 |
| Body mass index (kg/m2) | 27.6 (24.5, 31.8) | 27.7 (24.1, 32.4) | 0.91 |
| Mini–Mental State Examination score <24 | 17.3 | 17.3 | 0.98 |
| Systolic BP (mmHg) | 139 (123, 158) | 136 (123, 155) | 0.32 |
| Diastolic BP (mmHg) | 66 (59, 74) | 68 (60, 76) | 0.12 |
| Serum creatinine (mg/dl) | 1.20 (1.00, 1.40) | 0.90 (0.80, 0.90) | <0.0001 |
| eGFR (ml/min per 1.73 m2) | 49.7 (41.9, 55.7) | 70.3 (64.8, 76.3) | <0.0001 |
| Hemoglobin A1c | 7.80 (7.20, 8.50) | 7.70 (7.10, 8.40) | 0.45 |
| HDL cholesterol (mg/dl) | 50 (41, 61) | 52 (44, 64) | 0.03 |
| Albumin (g/dl) | 4.00 (3.80, 4.20) | 4.10 (3.90, 4.20) | 0.20 |
| IL-6 (pg/ml) | 2.43 (1.68, 3.74) | 2.25 (1.40, 3.59) | 0.04 |
| Calcium (mg/dl) | 9.30 (9.00, 9.50) | 9.30 (9.10, 9.60) | 0.18 |
| Phosphate (mg/dl) | 3.60 (3.40, 4.00) | 3.50 (3.20, 3.90) | 0.0002 |
| Fibroblast growth factor 23 (pg/ml) | 42.9 (31.8, 56.8) | 35.1 (27.7, 45.1) | <0.0001 |
| 1,25-Dihydroxyvitamin D3 (ng/ml) | 32.8 (25.2, 42.0) | 38.6 (30.4, 48.7) | <0.0001 |
| 25-Hydroxyvitamin D (ng/ml) | 20.7 (15.0, 27.7) | 19.5 (14.0, 25.2) | 0.03 |
| Parathyroid hormone (pg/ml) | 89.1 (60.9, 134.2) | 64.0 (43.8, 87.3) | <0.0001 |
| Hypertension | 63.2 | 53.3 | 0.009 |
| Coronary artery disease | 27.8 | 18.6 | 0.005 |
| Congestive heart failure | 11.8 | 9.8 | 0.39 |
| Peripheral artery disease | 25.7 | 17.6 | 0.01 |
| Stroke | 5.8 | 5.5 | 0.89 |
| Diabetes mellitus | 18.1 | 15.3 | 0.33 |
| Chronic obstructive pulmonary disease | 24.2 | 31.3 | 0.04 |
| Depression | 17.8 | 16.3 | 0.59 |
| Cancer | 11.3 | 13.4 | 0.41 |
Data are presented in percentages for categorical variables and as median (25th, 75th percentiles) for continuous variables. eGFR, estimated GFR.
Creatinine not measured in 13 women.
Chi-squared tests were used for categorical variables, and Wilcoxon rank-sum tests were used for continuous variables.
Of the 381 women with prevalent CKD at baseline, 293 and 195 had eGFR measured again at the 12- and 24-month visits, respectively. The proportion of the women with prevalent CKD who had eGFR <60 ml/min per 1.73 m2 at the 12- and 24-month visits was 80.0% and 83.6%, respectively.
Of the 307 women who did not have CKD at baseline, 63 (20.5%) developed CKD (eGFR <60 ml/min per 1.73 m2) over 24 months of follow-up. Serum FGF23 was significantly associated with incident CKD in multivariable Cox proportional hazards models (Table 3), adjusting for baseline eGFR, age, race, education, alcohol use, HDL cholesterol, IL-6, and calcium (model 1); additionally for phosphate, 1,25(OH)2D, 25(OH)D, and PTH (model 2); and finally, with addition of chronic diseases to all the previous covariates (model 3). Serum FGF23, baseline eGFR, and age were the only variables that were significantly associated with incident CKD in the three Cox proportional hazards models. In a parsimonious multivariable model that adjusted for six covariates (age, race, baseline eGFR, 1,25(OH)2D, phosphate, and PTH), log serum FGF23 (per 1 SD increase) was associated with incident CKD (hazard ratio [HR], 1.50; 95% confidence interval [95% CI], 1.13, 2.00; P = 0.005).
Table 3.
Separate multivariable Cox proportional hazards models of the relationship of serum FGF23 with incident CKD (eGFR <60 ml/min per 1.73 m2) in 307 women, ≥65 years of age, in the Women’s Health and Aging Study I
| Variable | Model 1 | Model 2 | Model 3 | ||||||
|---|---|---|---|---|---|---|---|---|---|
| HR | 95% CI | P | HR | 95% CI | P | HR | 95% CI | P | |
| Log FGF23 (pg/ml)a | 1.44 | 1.10, 1.90 | 0.008 | 1.45 | 1.03, 2.03 | 0.03 | 1.51 | 1.06, 2.16 | 0.02 |
| Baseline eGFR | 0.91 | 0.88, 0.95 | <0.0001 | 0.91 | 0.87, 0.95 | <0.0001 | 0.91 | 0.87, 0.95 | <0.0001 |
| Age (yr) | 1.03 | 0.99, 1.07 | 0.08 | 1.04 | 1.00, 1.08 | 0.04 | 1.04 | 1.00, 1.08 | 0.04 |
| Race, white | 0.67 | 0.99, 1.07 | 0.14 | 0.85 | 0.45, 1.60 | 0.61 | 0.85 | 0.44, 1.64 | 0.63 |
| Education <12 yr | 0.73 | 0.41, 1.30 | 0.28 | 0.75 | 0.40, 1.43 | 0.39 | 0.77 | 0.41, 1.47 | 0.43 |
| Alcohol use | 0.66 | 0.33, 1.29 | 0.22 | 0.77 | 0.37, 1.61 | 0.49 | 0.74 | 0.35, 1.56 | 0.43 |
| HDL cholesterol | 1.01 | 0.99, 1.03 | 0.33 | 1.00 | 0.98, 1.02 | 0.91 | 1.00 | 0.98, 1.03 | 0.85 |
| IL-6 (pg/ml) | 0.84 | 0.55, 1.29 | 0.43 | 0.73 | 0.45, 1.18 | 0.19 | 0.68 | 0.41, 1.13 | 0.13 |
| Calcium (mg/dl) | 0.94 | 0.55, 1.60 | 0.83 | 1.06 | 0.60, 1.90 | 0.83 | 1.07 | 0.58, 1.99 | 0.83 |
| Phosphate (mg/dl)a | 1.13 | 0.84, 1.53 | 0.40 | 1.12 | 0.83, 1.52 | 0.46 | |||
| 1,25(OH)2D (ng/ml)a | 0.89 | 0.66, 1.23 | 0.48 | 0.87 | 0.62, 1.21 | 0.40 | |||
| Log25(OH)D (ng/ml)a | 0.81 | 0.59, 1.11 | 0.19 | 0.82 | 0.59, 1.12 | 0.13 | |||
| Log PTH (pg/ml)a | 1.03 | 0.80, 1.32 | 0.84 | 0.98 | 0.75, 1.31 | 0.93 | |||
| Hypertension | 0.82 | 0.44, 1.51 | 0.51 | ||||||
| Coronary heart disease | 1.31 | 0.64, 2.67 | 0.46 | ||||||
| Congestive heart failure | 1.53 | 0.57, 4.09 | 0.40 | ||||||
| Peripheral artery disease | 1.19 | 0.58, 2.43 | 0.63 | ||||||
| Chronic obstructive pulmonary disease | 1.53 | 0.81, 2.89 | 0.19 | ||||||
eGFR, estimated GFR; HR, hazard ratio; 95% CI, 95% confidence interval; FGF23, fibroblast growth factor 23; 1,25(OH)2D, 1,25-dihydroxyvitamin D3; 25(OH)D, 25-hydroxyvitamin D; PTH, parathyroid hormone.
HRs expressed per 1 SD increase: log FGF23 (0.45 pg/ml), phosphate (0.47 mg/dl), 1,25(OH)2D (14.3 ng/ml), log 25(OH)D (0.55 ng/ml), log PTH (0.51 pg/ml).
Of the 307 women without CKD (eGFR <60 ml/min per 1.73 m2) at baseline, 25 (8.1%) developed eGFR <60 ml/min per 1.73 m2 and a ≥25% decline in eGFR during follow-up. Serum FGF23 was associated with incident CKD, using the definition of low and declining eGFR, in multivariable Cox proportional hazards models (Supplemental Material). Of the 307 women without CKD (eGFR <60 ml/min per 1.73 m2) at baseline, 14 (4.6%) had an increase of serum creatinine >0.4 mg/dl during follow-up. Serum FGF23 was associated with incident CKD, using the definition of a rise in creatinine, in multivariable Cox proportional hazards models (Supplemental Material). The relationship between FGF23 and the three respective definitions of CKD remained unchanged when current smoking was added to all covariates in model 3 (data not shown). FGF23 was not significantly associated with all-cause or cause-specific mortality (Supplemental Material).
Alternatively, if the CKD-EPI equation is used to define eGFR, of the 701 women, 438 (62.5%) had CKD (eGFR <60 ml/min per 1.73 m2). Of 263 women without CKD at baseline, 69 (26.2%) developed CKD during follow-up. Log serum FGF23 (per 1 SD) was associated with incident CKD (HR, 1.74; 95% CI, 1.26, 2.38; P=0.0006) in a multivariable Cox proportional hazards model, adjusting for baseline eGFR, age, race, 1,25(OH)2D, phosphate, and PTH.
Discussion
This study shows that elevated serum FGF23 is an independent risk factor for the development of CKD among older, disabled, community-dwelling women. To our knowledge, this is the first study to show that elevated serum FGF23 independently predicts incident CKD in individuals without CKD. Among the interrelated, circulating hormones related to calcium-phosphate metabolism (i.e., 1,25(OH)2D, PTH, and 25(OHD), only FGF23 was a significant predictor of incident CKD. The findings of this study are consistent with observations from cohorts of patients with CKD in which elevated circulating FGF23 was an independent predictor of progression of CKD, development of ESRD, and mortality (9–11). Although previous studies have reported that high serum phosphate is predictive of incident CKD (23) and progression of CKD to kidney failure (24), this study did not show that elevated phosphate was a predictor of CKD. Previous studies did not include FGF23, PTH, or 1,25(OH)2D, three hormones that regulate phosphate metabolism. In this study, the hazard ratios for FGF23 and CKD seem relatively large. A 1 SD increase in FGF23 should be considered in the interpretation of the hazard ratios because the magnitude of the association depends upon the unit of change.
Whether elevated circulating FGF23 is an early marker for compromised kidney function or plays a direct role in the pathogenesis of CKD is unknown. High dietary phosphorus intake seems to be the primary stimulant of FGF23 secretion (22). FGF23 concentrations increase with declining renal function among patients with CKD (25). Elevated serum FGF23 concentrations in individuals without CKD presumably occur to maintain normal phosphate balance but could possibly indicate early disruption of the feedback loops involving serum phosphate, 1,25(OH)2D, and/or PTH. In patients with CKD, a cross-sectional study suggested that elevations in FGF23 occur earlier than increases in PTH and phosphate (11). The precise mechanisms that underlie increased serum FGF23 levels are not well understood.
The strengths of this study include the population-based sampling, a racially diverse cohort, the careful adjudication of chronic diseases in the female participants, and the duration of follow-up that was accompanied by incident CKD in approximately 20% of the participants. Prospective analyses of incident CKD were adjusted for baseline eGFR. As with any epidemiologic study, it is not possible to measure all possible confounders. There may have been unmeasured confounders that could influence the relationship of circulating FGF23 with prevalent and incident CKD. A limitation of the study is that it included moderately to severely disabled older women, and whether the results could be extrapolated to nondisabled women or to older men is not known. This study utilized the MDRD study equation, which has not yet been validated in adults aged >70 years. When the recently devised CKD-EPI equation was used to calculate eGFR, the hazard ratio was higher and the P value was smaller compared with the multivariable model and same covariates in which eGFR was calculated using the MDRD equation.
A limitation is that the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative created guidelines for clinical diagnosis of CKD based upon two eGFR measurements of <60 ml/min per 1.73 m2 separated by 3 months (26). These clinical practice guidelines are difficult to apply to prospective epidemiologic studies such as this one, because most natural history studies do not involve frequent repeated measurements of eGFR (27). Thus, alternative methods for defining incident CKD in the research setting (16) have been applied in this study. One other limitation of the study is that albuminuria was not measured.
If FGF23 is a more accurate measure of kidney function than baseline eGFR, then the use of baseline eGFR as a covariate in the models predicting incident CKD could result in significant residual confounding. It is also possible that FGF23 is a biomarker of kidney function rather than a pathogenic factor in CKD. Thus, adults with higher FGF23 may be at greater risk of CKD in follow-up. The situation could be similar to a “horse-racing effect,” in which those with higher BP at baseline are at higher risk of developing hypertension (28). A single measurement of FGF23 does not reveal any data about long-term differences in FGF23 over time, because adults with higher FGF23 might have levels that have been rising faster than average and thus be at greater risk for the disease.
There are currently two types of assays to measure circulating FGF23: one that measures intact (full-length) FGF23 and another that measures both the intact peptide and the C-terminal fragment. Although several studies show that there is high correlation between the two assays, it is still not known which might be the more ideal assay for studies of CKD, because both assays seem reliable (12).
This study raises the possibility that circulating FGF23 could be used to identify older adults who are at higher risk of developing CKD. Further investigations in large, population-based cohorts may establish whether elevated circulating FGF23 is an independent predictor of CKD in adults with normal renal function. Future studies in animal models may also help distinguish FGF23 as a marker for kidney function versus an actual factor in the pathogenesis of CKD.
Disclosures
None.
Supplementary Material
Acknowledgments
This study was supported by Grants R01AG027012, R01AG029148, and R37AG019905 from the National Institutes of Health, as well as the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.08070811/-/DCSupplemental.
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