The correlation between fibroblast growth factor-23 and ESRD patients with hearing impairment

Background End-stage renal disease (ESRD) patients often experience hearing impairment, resulting in a high rate of disability and a decline in their quality of life. Fibroblast growth factor-23 (FGF23) is a diagnostic biomarker for chronic kidney disease (CKD) and a pathogenic contributor to CKD progression. However, the correlation between FGF23 level and CKD patients with hearing impairment remains elusive. This study aimed to investigate the relationship between the FGF23 and ESRD accompanied with hearing impairment. Methods A total of 144 ESRD patients, who were admitted to the First Affiliated Hospital of Kunming Medical University from November to December 2020, were enrolled in this study. Firstly, 144 ESRD patients underwent pure-tone audiometry (PTA). Secondly, it was attempted to randomly select 20 ESRD patients with normal hearing, and 20 ESRD patients with hearing impairment (match ratio, 1:1). Age- and gender-matched healthy people (n = 20) were also recruited as controls group. The expression levels of FGF23 was detected by enzyme-linked immunosorbent assay (ELISA). Results The results of pure-tone audiometry showed that the prevalence of hearing impairment in ESRD patients was 80.5%. Male ESRD patients were more likely to develop hearing impairment compared to female patients. The incidence rate of hearing impairment at a high frequency was significantly higher than that at a low frequency (P < 0.01). The serum levels of FGF23, phosphorus, and parathyroid hormone (PTH) in ESRD patients with hearing impairment significantly increased compared with those with normal hearing and healthy controls. Conclusion ESRD patients had a higher risk of hearing loss, especially high-frequency hearing impairment. As FGF23 level increased, the risk of hearing loss was also elevated. The hearing impairment in ESRD patients was associated with the degree of kidney injury, and serum FGF23 level.

Severe Hypophosphatemia and Elevated FGF23 Level Following Zoledronic Acid Infusion

Background: Severe hypophosphatemia may be seen following zoledronic acid infusion, however FGF23 elevation has not been previously reported. Clinical Case: A 67-year-old man with Crohn’s disease status post remote ileocolonic resection, malnutrition (BMI 16.7), anemia, history of hypovitaminosis D, secondary hyperparathyroidism, and severe osteoporosis, was advised to present to the emergency room for hypocalcemia and hypophosphatemia after routine lab draw. His initial ionized calcium was 0.89 mmol/L (1.09–1.29 mmol/L) and phosphorus was 0.9 mg/dL (2.3–4.4 mg/dL), with a 25-hydroxyvitamin D level of 62 ng/mL (20–50 ng/mL), PTH of 132 pg/mL (11–51 pg/mL), and normal renal function. Hemoglobin was stable between 8–9 g/dL (13.5–17.1 g/dL). He endorsed ongoing fatigue, oral ulcers, and perioral numbness, which had been attributed to Humira infusion 2 months prior. He denied other paresthesias, carpopedal spasms, seizures, bone pain, or confusion. He reported receiving his second annual infusion of zoledronic acid 10 days prior in Turkey. He was started on high-dose oral calcium, calcitriol, and phosphate, which were continued on discharge 5 days later. Several days into his hospitalization, the patient spoke with his wife in Turkey who confirmed that his calcium and phosphorus were both within normal limits immediately prior to his infusion. A 1,25-hydroxyvitamin D level obtained during his workup was normal at 42.5 pg/mL (19.9–79.3 pg/mL), however an FGF23 level, which returned 2 weeks later, was elevated at 287 RU/mL (&lt;=180 RU/mL). Dotatate PET to rule out oncogenic osteomalacia was negative. One month later, after normalization of calcium and phosphorus levels, repeat PTH and FGF23 levels were both within normal limits. Conclusion: This case demonstrates that a transient increase in FGF23 levels may accompany and exacerbate hypophosphatemia following zoledronic acid infusion. The mechanism for this elevation is unclear, though we speculate that in the setting of acute hypocalcemia and hypophosphatemia due to zoledronic acid infusion, secondary hyperparathyroidism may upregulate FGF23 production, which further decreases phosphorus levels. If this scenario is accurate, the transient FGF23 elevation seen is not pathologic, but physiologic. Indeed, in the patient above, calcium and phosphorus repletion lead to normalization of both PTH and FGF23.

Favorable Effects of Burosumab on Fibroblast Growth Factor 23-Related Osteomalacia: A Case Report

Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl &lt; n &lt; 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml &lt; n &lt; 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml &lt; n &lt; 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.

Serum intact fibroblast growth factor 23 in healthy paediatric population

Introduction It is believed that fibroblast growth factor 23 (FGF23) can become an early biomarker of chronic kidney disease progression. Data on FGF23 age dependency are inconsistent. We present the results of the cross-sectional study concerning FGF23 levels in healthy Polish children. Material and methods This study was conducted in 121 children aged 0–18 years. Kidney function and intact FGF23 levels in serum were assessed. Differences between age groups and according to gender were analysed. Results The difference in FGF23 between age groups and according to gender was statistically insignificant. In the youngest and the oldest group, a trend to higher FGF23 levels was observed. FGF23 level in girls tended to be higher than boys, apart from the age group between 1 and 4 years. There was a negative correlation between eGFR and FGF23 (r = −0.26, p < 0.05) – strong in girls (r = −0.38, p < 0.05), but not in boys. In each age group, we found no significant correlation between eGFR and FGF23. Conclusions Our study supports the evidence that the FGF23 level in paediatric population is not age or sex dependent. The results can serve as a reference point under clinical conditions and for other studies on the topic.

P0892PROFILE OF FIBROBLAST GROWTH FACTOR 23 IN CHRONIC KIDNEY DISEASE IN INDIAN POPULATION

Background Chronic kidney disease (CKD) is a complex disease. Recent discovery that fibroblast growth factor 23 (FGF23) play a major role in development of CKD related bone mineral disorder (BMD) indicated a paradigm shift in our understanding of CKD–BMD. Recent research indicates that higher levels of FGF23 are associated with rapid progression of CKD and higher mortality in CKD patients. It is found that FGF23 level in blood is elevated significantly early in the course of CKD, even before a rise in parathyroid hormone (PTH) level which could contribute directly to tissue injury in heart, blood vessels and kidneys, apart from just being a marker of adverse outcome, and this needs further research. The dietary habits, especially phosphate intake is likely to be different in Indian CKD population compared to western CKD population. Aims and objectives Method This is an observational study on 75 consecutive patients visiting Apollo hospital nephrology OPD in Chennai, India from June 2015 to Nov 2015. FGF23 level were determined simultaneously with serum creatinine, albumin, Vitamin D level, serum calcium, phosphate and serum PTH level done on enrolment. Serum samples when not immediately processed, were stored at -20oC. Results The age of the patient population varied from 19 to 80 years, mean 53.33 yrs with a SD of 15.49. 57(76%) were males and 18(24%) females. In our study, 46.7%patients belonged to CKD stage 4 while CKD stage 3 and 5 had 25.3% and 28% among the study population respectively. The mean FGF23 level in study population was 154.82pg/ml (Normal range 11-48.6 pg/ml). Though the FGF23 values in stage 5 CKD were higher than those in stage 3 and 4 CKD, the difference was not statistically significant (p=0.74). In our study, 63 patients (84%) had high FGF23 level and 56(74.7%) patients were already on phosphate binding drugs and PTH suppressing drugs like vit D or cinacalcet for at least 2 months. 48(85.7%) patients of those on medications and 15 (79%) of those not on medications had high FGF23 level (P value -0.48, Yates P value-0.739). In our study, PTH had an inverse correlation with eGFR and the association was statistically significant (P value 0.001). Serum Phosphorus level had an inverse correlation with eGFR and the association was statistically significant (P value 0.0001). Correlation of FGF23 values with eGFR was negative which was expected as the FGF23 levels increased with decreasing eGFR, but the association was not statistically significant. Similar results were obtained when FGF23 values were studied for association with serum calcium levels where the P value was 0.359 which was not statistically significant. Similarly, vit D levels had a negative association with P value of 0.077 and PTH levels had a positive association with P value of 0.987 (No statistical significance). Similarly, FGF23 levels and phosphate levels had a positive association without statistical significance(p= 0.224). Conclusion In conclusion, our data indicate that the rise of serum FGF23 levels in progressive Indian CKD patients is a common finding in CKD stage 3 and beyond.

Fibroblast growth factor 23 and new-onset chronic kidney disease in the general population: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

Background Fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone that increases early in the course of chronic kidney disease (CKD), is associated with disease progression in patients with established CKD. Here we aimed to investigate the association between plasma FGF23 and new-onset CKD in the general population. Methods We included 5253 individuals without CKD who participated in the Prevention of Renal and Vascular Endstage Disease study, a prospective, population-based cohort. Multi-variable Cox regression was used to study the association of plasma C-terminal FGF23 with new-onset CKD, defined as a combined endpoint of estimated glomerular filtration rate (eGFR) &lt;60 mL/min/ 1.73 m2, urinary 24-h albumin excretion (UAE) &gt;30 mg/24 h or both, or with all-cause mortality. Results The median baseline FGF23 was 68 [interquartile range (IQR) 56–85] RU/mL, eGFR was 95 ± 13 mL/min/1.73 m2 and UAE was 7.8 (IQR 5.8–11.5) mg/24 h. After follow-up of 7.5 (IQR 7.2–8.0) years, 586 participants developed CKD and 214 participants died. A higher FGF23 level was associated with new-onset CKD, independent of risk factors for kidney disease and parameters of bone and mineral homoeostasis {fully adjusted hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.10–1.44] per doubling of FGF23; P = 0.001}. In secondary analyses, FGF23 was independently associated with new-onset eGFR &lt;60 mL/min/1.73 m2 [adjusted HR 1.28 (95% CI 1.00–1.62); P = 0.048] or with UAE &gt;30 mg/24 h [adjusted HR 1.24 (95% CI 1.06–1.45); P = 0.01] individually. A higher FGF23 level was also associated with an increased risk of all-cause mortality [fully adjusted HR 1.30 (95% CI 1.03–1.63); P = 0.03]. Conclusions High FGF23 levels are associated with an increased risk of new-onset CKD and all-cause mortality in this prospective population-based cohort, independent of established CKD risk factors.

Short-Term Effects of Very-Low-Phosphate and Low-Phosphate Diets on Fibroblast Growth Factor 23 in Hemodialysis Patients

Background and objectivesThe short-term effects of low-phosphate diets on fibroblast growth factor 23 (FGF23) level and the optimal amount of dietary phosphate restriction in patients undergoing hemodialysis remain unknown.Design setting, participants, & measurementsThis was a randomized, active-controlled trial with a crossover design that included 35 adults with ESKD undergoing thrice-weekly hemodialysis and with a serum phosphate level >5.5 mg/dl or between 3.5 and 5.5 mg/dl with regular phosphate binder use at a hemodialysis unit of tertiary teaching hospital in Taiwan. Subjects were randomized 1:1 to receive a very-low-phosphate diet, with a phosphate-to-protein ratio of 8 mg/g, or a low-phosphate diet, with a phosphate-to-protein ratio of 10 mg/g for 2 days, each with a 5-day washout during which subjects adhered to their usual diet. The primary outcome measure was mean difference in change-from-baseline intact FGF23 level between intervention groups. Secondary outcomes included difference in change-from-baseline serum phosphate, intact parathyroid hormone (PTH), and C-terminal FGF23 level between intervention groups.ResultsThere was no significant difference in the mean change-from-baseline in intact FGF23 levels between the two study diets. The very-low-phosphate diet significantly lowered serum phosphate (mean difference, 0.6 mg/dl; 95% confidence interval [95% CI], 0.2 to 1.0; P=0.002). There were no significant differences in change-from-baseline intact PTH and C-terminal FGF23 levels between the two study diets.ConclusionsOver the 2-day period, the FGF23-lowering effect of the very-low-phosphate diet is similar to that of the low-phosphate diet. The very-low-phosphate diet has an additional phosphate-lowering effect compared with the low-phosphate diet.