Author Contributions

W.-C.F., H.-Y.C., S.-C.C., I.-W.W., C.-Y.S., and H.-C.P. contributed to data conception, design, and interpretation. W.-C.F., H.-Y.C., P.-H.W., H.-J.H., C.-Y.C., V.-C.W., Y.-C.C. and H.-C.P. contributed to collecting data and manuscript drafting. C.-C.L., I.-W.W., C.-Y.S., H.-J.H., and H.-C.P. provided patient information, participated in the design and coordination and helped draft the manuscript. W.-C.F., H.-Y.C., S.-C.C., P.-H.W., C.-C.L., I.-W.W., C.-Y.S., V.-C.W., and H.-C.P. provided intellectual content of the work and were involved in editing and revising the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the Chang Gung Memorial Hospital (CMRPG-2G0361, CMRPG-2H0161, CMRPG-2J0261, CMRPG-2K0091, CLRPG2L0051, CMRPG1M0041, CORPG1L0021) and Ministry of Science and Technology (MOST) of the Republic of China (Taiwan) (MOST 106–2314-B-182A-064, MOST 107-2314-B-182A-138, MOST 108-2314-B-182A-027, MOST 111-2314-B-182A-074-MY3, MOST 111-2320-B-182-035-MY3).

Figure 1. Flow diagram of this study. First case: 20130810, last case 20150124. Abbreviations: ELISA, enzyme-linked immunosorbent assay; NTCMRC, Northeastern Taiwan Community Medicine Research Cohort; RKFD, rapid kidney function decline.

Figure 1. Flow diagram of this study. First case: 20130810, last case 20150124. Abbreviations: ELISA, enzyme-linked immunosorbent assay; NTCMRC, Northeastern Taiwan Community Medicine Research Cohort; RKFD, rapid kidney function decline.

Figure 2. Correlations among FGF-23, UACR, eGFRcr-cys, vitamin D, calcium, inorganic phosphorus, and intact PTH. (* p-value < 0.05; ** p-value < 0.01; *** p-value < 0.001).

Figure 2. Correlations among FGF-23, UACR, eGFRcr-cys, vitamin D, calcium, inorganic phosphorus, and intact PTH. (* p-value < 0.05; ** p-value < 0.01; *** p-value < 0.001).

Figure 3. The areas under the receiver operating characteristic (AUROC) curve for biomarkers to predict the occurrence of 5-year RKFD.

Figure 3. The areas under the receiver operating characteristic (AUROC) curve for biomarkers to predict the occurrence of 5-year RKFD.

Figure 4. Generalized additive model plot for the FGF-23 (cut-off value: 32 pg/mL) against the probability of RKFD (adjusted with eGFRcr-cys, UACR, age, gender, metabolic syndrome, total cholesterol, LDL).

Figure 4. Generalized additive model plot for the FGF-23 (cut-off value: 32 pg/mL) against the probability of RKFD (adjusted with eGFRcr-cys, UACR, age, gender, metabolic syndrome, total cholesterol, LDL).

Figure 5. Kaplan–Meier estimation of the probability of the occurrence of RKFD stratified by FGF-23.

Figure 5. Kaplan–Meier estimation of the probability of the occurrence of RKFD stratified by FGF-23.

Table 1. Baseline characteristics of the study population.

Table 1. Baseline characteristics of the study population.

Total
(n = 220)RKFD
(n = 110)No RKFD
(n = 110)p-ValueDemographics Age, years58.8 (10.8)59.3 (10.8)58.3 (10.9)0.52Male gender, n46 (20.9%)22 (20.0%)24 (21.8%)0.74Hypertension, n56 (25.5%)34 (30.9%)22 (20.0%)0.063DM, n25 (11.4%)17 (15.5%)8 (7.3%)0.056CKD, n6 (2.7%)4 (3.6%)2 (1.8%)0.41Cardiovascular disease, n17 (7.7%)10 (9.1%)7 (6.4%)0.45CVA, n3 (1.4%)3 (2.7%)0 (0.0%)0.081HBV, n28 (12.7%)14 (12.7%)14 (12.7%)1.00HCV, n5 (2.3%)2 (1.8%)3 (2.7%)0.65Gout, n7 (3.2%)5 (4.5%)2 (1.8%)0.25Autoimmune disease, n2 (0.9%)2 (1.8%)0 (0.0%)0.16Kidney stone4 (1.8%)1 (0.9%)3 (2.7%)0.31Mental disorder3 (1.4%)2 (1.8%)1 (0.9%)0.56Endocrine disorder2 (0.9%)0 (0.0%)2 (1.8%)0.16Metabolic syndrome63 (28.6%)43 (39.1%)20 (18.2%)<0.001Biochemical and physiological profiles SBP, mmHg129.50 (118.00–141.00)129.50 (118.00–143.00)129.50 (119.00–137.00)0.89BMI, kg/m223.95 (22.22–26.47)24.23 (22.22–26.25)23.72 (22.21–26.67)0.71BMI > 24, n108 (49.1%)61 (55.5%)47 (42.7%)0.059Central obesity, n95 (43.2%)56 (50.9%)39 (35.5%)0.021Hgb, g/dL13.70 (12.80–14.60)13.70 (12.60–14.60)13.60 (13.00–14.60)0.93Total cholesterol, mg/dL207.50 (189.50–230.00)199.50 (187.00–223.00)213.50 (195.00–235.00)0.011LDL cholesterol, mg/dL121.40 (105.05–144.70)117.80 (100.40–138.10)129.90 (109.90–150.60)0.016HDL cholesterol, mg/dL56.55 (47.75–66.95)54.70 (46.60–64.70)57.50 (48.90–71.80)0.084Triglyceride, mg/dL92.00 (69.00–132.00)96.00 (69.00–155.00)90.00 (69.00–127.00)0.33BUN, mg/dL12.00 (10.00–15.00)12.00 (10.00–16.00)12.00 (10.00–15.00)0.97Creatinine, mg/dL0.63 (0.55–0.77)0.61 (0.54–0.75)0.67 (0.55–0.78)0.049Alk-P, mg/dL64.5 (55.00–79.00)65.0 (54.00–80.00)64.0 (56.00–76.00)0.82eGFRcr-cys, mL/min/1.73 m2101.89 (82.68–114.96)108.13 (90.75–121.69)99.32 (80.85–110.07)<0.001Uric acid, mg/dL5.10 (4.30–6.10)5.10 (4.20–6.10)5.10 (4.40–6.10)0.93Albumin, g/dL4.69 (0.26)4.69 (0.27)4.69 (0.25)0.84GPT, U/L21.00 (17.00–30.00)22.00 (17.00–31.00)21.00 (17.00–28.00)0.27UACR, mg/g5.90 (3.85–9.50)6.50 (4.10–11.20)5.30 (3.70–8.00)0.020Fasting glucose, mg/dL 96.00 (91.50–104.00)97.00 (93.00–108.00)95.00 (91.00–102.00)0.038HbA1C, %5.60 (5.40–5.95)5.60 (5.40–6.10)5.60 (5.40–5.90)0.29Insulin, μIU/mL5.85 (4.21–9.20)6.16 (4.68–9.92)5.25 (3.89–8.58)0.048HOMA-IR1.45 (0.95–2.38)1.54 (1.18–2.58)1.31 (0.91–2.02)0.013FGF-23, pg/mL29.69 (27.10–32.43)30.73 (30.42–34.34)27.15 (23.63–29.04)<0.001Total Vitamin D, ng/mL24.54 (19.44–31.70)25.30 (20.16–32.81)23.98 (19.10–30.77)0.31iPTH, mg/dL44.10 (34.20–58.60)43.85 (31.60–53.40)44.60 (35.60–62.30)0.12P, mg/dL3.88 (0.53)3.90 (0.48)3.87 (0.58)0.62Ca, mg/dL9.30 (9.15–9.50)9.30 (9.20–9.60)9.30 (9.10–9.50)0.39Medication use OHA, n 24 (11.1%)17 (15.9%)7 (6.4%)0.027Anti-hypertensives, n51 (23.5%)31 (29.0%)20 (18.2%)0.061Pain killer, n30 (14.4%)20 (19.6%)10 (9.4%)0.037

Table 2. The prognostic significance of our variables for RKFD.

Table 2. The prognostic significance of our variables for RKFD.

VariablesBeta CoefficientStandard ErrorOdds Ratios (95% CI)p-ValueUnivariable analysisAge, per 10 years0.080.131.08 (0.85, 1.39)0.517Male−0.110.330.90 (0.47, 1.72)0.740Hypertension0.580.321.79 (0.96, 3.32)0.065DM0.850.452.33 (0.96, 5.65)0.061CKD0.710.882.04 (0.37, 11.36)0.417Cardiovascular disease0.390.511.47 (0.54, 4.02)0.451Gout0.940.852.57 (0.49, 13.55)0.265Metabolic syndrome1.060.322.89 (1.56, 5.36)0.001BMI, per 1 kg/m20.510.271.67 (0.98, 2.84)0.060Central obesity0.640.281.89 (1.10, 3.24)0.021Hgb, per 1 g/dL−0.020.100.98 (0.81, 1.19)0.830Total cholesterol, per 10 mg/dL−0.090.040.92 (0.85, 0.99)0.029LDL cholesterol, per 10 mg/dL−0.090.050.91 (0.83, 1.00)0.043HDL cholesterol, per 10 mg/dL−0.170.090.85 (0.71, 1.02)0.074Triglyceride, per 10 mg/dL0.030.021.03 (0.99, 1.07)0.175BUN, per 1 mg/dL−0.000.031.00 (0.93, 1.07)0.890Creatinine, per 1 mg/dL−1.590.900.20 (0.04, 1.19)0.077eGFRcr-cys, per 10 mL/min/1.73 m20.240.071.27 (1.11, 1.45)<0.001Uric acid, per 1 mg/dL0.030.111.03 (0.83, 1.28)0.804Albumin, per 1 g/dL0.110.521.11 (0.40, 3.06)0.836GPT, per 10 U/L0.030.061.03 (0.92, 1.16)0.613UACR, per 1 mg/g0.070.031.07 (1.02, 1.14)0.012Fasting glucose, per 10 mg/dL0.170.081.19 (1.02, 1.39)0.025HbA1C, per 1 %0.450.211.56 (1.04, 2.35)0.030Insulin, per 10 μIU/mL0.480.271.62 (0.95, 2.75)0.077HOMA-IR0.190.101.21 (0.99, 1.46)0.056FGF-23, per 10 pg/mL0.800.222.23 (1.43, 3.45)<0.001Total Vitamin D, per 1 ng/mL0.020.021.02 (0.98, 1.05) 0.338iPTH, per 1 mg/dL−0.000.011.00 (0.99, 1.01) 0.634P, per 1 mg/dL0.130.261.14 (0.69, 1.87) 0.619Ca, per 1 mg/dL0.290.391.34 (0.62, 2.89) 0.460OHA use1.010.472.75 (1.09, 6.94)0.032Anti-hypertensives0.610.331.84 (0.97, 3.48)0.063Pain killer use0.850.422.34 (1.04, 5.29)0.041Vegetarian0.020.361.02 (0.51, 2.06)0.950Multivariable analysis *Central obesity1.630.765.09 (1.15, 22.60)0.032eGFRcr-cys, per 10 mL/min/1.73 m20.920.252.50 (1.54, 4.05)<0.001UACR, per 1 mg/g0.150.061.16 (1.03, 1.32)0.017FGF-23, per 10 pg/mL1.060.342.87 (1.47, 5.62)0.002

Table 3. Demographic characteristics of enrolled subjects stratified by cut-off values of FGF-23 and 32 pg/mL.

Table 3. Demographic characteristics of enrolled subjects stratified by cut-off values of FGF-23 and 32 pg/mL.

High FGF-23
≥32 pg/mL
(n = 57)Low FGF-23
<32 pg/mL
(n = 163)p-ValueRKFD40 (70.2%)70 (42.9%)<0.001Demographics Age, years55.9 (11.0)59.8 (10.6)0.020Male gender, n15 (26.3%)31 (19.0%)0.24Hypertension, n11 (19.3%)45 (27.6%)0.22DM, n7 (12.3%)18 (11.0%)0.80CKD, n3 (5.3%)3 (1.8%)0.17Cardiovascular disease, n6 (10.5%)11 (6.7%)0.36CVA, n1 (1.8%)2 (1.2%)0.77HBV, n9 (15.8%)19 (11.7%)0.42HCV, n0 (0.0%)5 (3.1%)0.18Gout, n4 (7.0%)3 (1.8%)0.055Autoimmune disease, n1 (1.8%)1 (0.6%)0.43Metabolic syndrome14 (24.6%)49 (30.1%)0.43SBP, mmHg126.00 (116.00–136.00)131.00 (119.00–143.00)0.041BMI, kg/m223.12 (21.75–25.44)24.16 (22.28–26.94)0.039BMI > 24, n25 (43.9%)83 (50.9%)0.36Central obesity, n18 (31.6%)77 (47.2%)0.040Hgb, g/dL13.80 (13.10–14.60)13.60 (12.70–14.60)0.41Total cholesterol, mg/dL206.00 (187.00–235.00)208.00 (191.00–230.00)0.50LDL cholesterol, mg/dL117.20 (93.70–144.80)123.70 (108.40–144.60)0.15HDL cholesterol, mg/dL56.40 (46.70–69.40)57.00 (48.60–66.90)0.82Triglyceride, mg/dL86.00 (61.00–138.00)97.00 (71.00–132.00)0.24BUN, mg/dL12.00 (10.00–15.00)12.00 (10.00–15.00)0.77Creatinine, mg/dL0.61 (0.54–0.73)0.64 (0.55–0.77)0.31eGFR-cys, mL/min/1.73 m2109.81 (95.51–121.47)100.96 (80.85–113.33)0.009Uric acid, mg/dL5.00 (4.30–6.00)5.10 (4.40–6.20)0.31Albumin, g/dL4.66 (0.28)4.70 (0.26)0.39GPT, U/L22.00 (17.00–31.00)21.00 (17.00–29.00)0.95UACR, mg/g5.40 (3.50–8.20)6.40 (4.10–9.90)0.074Fasting glucose, mg/dL 95.00 (90.00–101.00)97.00 (92.00–104.00)0.064HbA1C, %5.60 (5.30–5.80)5.70 (5.40–6.00)0.13Insulin, μIU/mL5.82 (3.16–8.43)5.86 (4.48–9.56)0.12HOMA-IR1.45 (0.76–2.10)1.45 (1.05–2.39)0.11FGF-23, pg/mL39.70 (34.34–54.48)27.57 (24.52–30.54)<0.001Total Vitamin D, ng/mL24.80 (19.28–30.98)24.29 (19.46–31.70)0.66iPTH, mg/dL40.10 (32.70–51.30)45.20 (34.80–60.10)0.16P, mg/dL3.88 (0.55)3.89 (0.53)0.89Ca, mg/dL9.30 (9.10–9.50)9.30 (9.20–9.60)0.74Medication use OHA, n 7 (13.0%)17 (10.5%)0.62Anti-hypertensives, n9 (16.4%)42 (25.9%)0.15Pain killer, n9 (16.7%)21 (13.6%)0.59