The correlation between serum fibroblast growth factor-23 with urinary fractional excretion of phosphate in predialysis chronic kidney disease

1Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, Universitas Udayana/ Sanglah General Hospital, Denpasar, Bali, Indonesia 2Department of Internal Medicine, Faculty of Medicine, Universitas Udayana/Sanglah General Hospital, Denpasar, Bali, Indonesia 3Department of Clinical Pathology, Faculty of Medicine, Universitas Udayana/Sanglah General Hospital, Denpasar, Bali, Indonesia


INTRODUCTION
Mineral and metabolism disorder as one of the chronic kidney disease (CKD) complications consisted of disorder of calcium, phosphate, and parathyroid homeostases. 1 Disorder of phosphate metabolism has been detected earlier in CKD. 2 Renal phosphate handling, or the excretion of phosphate filtrated by kidney, is expressed as fractional excretion of phosphate (FEPi). Recent clinical studies demonstrated a high FEPi value despite the presence of normophosphatemia in early CKD. 3 Fibroblast growth factor-23 (FGF-23) is known to stimulate phosphaturia as a response to phosphate overload. It exerts its action at renal tubules by increasing urinary phosphate excretion and decreasing serum calcitriol level, thus maintaining the normal level of phosphate in serum. 3-5 FGF-23 serum level rises progressively as estimated glomerular filtration rate (eGFR) declines in the beginning in CKD stage 2, and significantly elevated level of FGF-23 can be detected in most stage 3 and 4 of CKD. 3, 6 Early detection and intervention play an important role in decreasing mortality in CKD. 1 Currently, there is no evidence of the correlation between FGF-23 serum level and FEPi urine in the Indonesian population. This study aimed to investigate the correlation between FGF-23 serum level and urinary FEPi in predialysis CKD.

METHODS
The analytical cross-sectional study recruited out and inpatient in Sanglah General Hospital from October 2014 through March 2015. Participants were deemed eligible if they aged 18-65 years old with eGFR of 15-89 ml/minute or clinically stable patients with CKD stage 2-4. The exclusion was done with any evidence of the following: current treatment with activated vitamin D analogs, oral phosphate binders or supplements, treatment with calcimimetic, and history or laboratory evidence of malabsorption syndrome and malignancy.
Baseline data were retrieved from the medical record registry. Blood and 24-hour urine samples were taken from eligible participants to measure baseline characteristics. The samples were immediately sent to an independent out-ofhospital laboratory and processed using standard commercial assays. FGF-23 concentration was measured using Immunotopics enzyme-linked immunosorbent assay (ELISA). The value of FEPi General Hospital, and all subjects provided written and informed consent.
Statistical analyses were performed using Statistics Program for Social Science version 15.0. (SPSS Inc, USA). The results were expressed in suitable central tendency and dispersion based on the normality test. Spearman's correlation test was used to analyze the correlation between FGF-23 and FEPi. A P-value of less than 0.05 was considered statistically significant.

RESULTS
The subject characteristics were listed in Table 1. Study subjects were mostly male (72%) with CKD stage 3 (57.3%). The mean age and body mass index were 50±10.8 and 23.51±3.3, respectively. Hypertension (49.3%) and diabetes (40%) comorbidities were found in less than half of the subjects. The result in Figure 1 showed moderate positive correlation between FGF-23 and FEPi urine (r = 0.44; p<0.001).

DISCUSSON
Fibroblast growth factor-23 is released by multiple organs including bone, spleen, and brain, and additionally from kidney under pathophysiological circumstance. Pathophysiological circumstances closely related to CKD are well-known as FGF-23 production determinants. Together with its coreceptor, Klotho, FGF-23 plays an important role in regulating calcium and phosphate metabolism. 8 Predialysis CKD cases may exhibit normal level of serum phosphate, while the increase in FGF-23 and urinary FEPi have occurred. The secondary excess of serum FGF-23 has been proposed as a compensatory mechanism for phosphate retention due to impaired renal excretion or reduced renal expression of Klotho that induces FGF-23 resistance. FGF-23 promotes renal phosphate wasting by internalizing the sodium phosphate cotransporter IIa and IIc at the proximal tubular apical membrane. 9- 12 FEPi levels below 20% are considered normal in subjects with preserved renal function. In this study, the median FEPi value (24.3%) exceeded the upper limit, with the maximum value reaching 65.9%. Although the normal range and clinical significance of FEPi are not well-established, an incremental risk of progression into end-stage renal disease (ESRD) with increasing FEPi value was observed. FEPi level greater than 55% corresponded with 12.3 fold increase in the risk of dialysis initiation. 13 The upper limit of serum FGF-23 level normal value in previous studies was determined either by median or adverse outcomes risk. FGF-23 level There were some limitations in the current study. Current study design did not allow for causality assessment as no analysis on CKD progression was intended. Despite multiorgan clinical effects the FGF-23 inflicted, we only focus on one particular function of the kidney. Other biochemical parameters not addressed here may also represent potential confounders.

CONCLUSION
FGF-23 serum level had a positive correlation with urinary FEPi in predialysis CKD. Future efforts are required to validate their role in predialysis CKD management.