Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

doi:10.21203/rs.2.12237/v2

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Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

https://doi.org/10.21203/rs.2.12237/v2

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published 11 May, 2020

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Background:phosphate homeostasis is mediated through complex counter regulatory feed-back balance between parathyroid hormone, FGF-23 and 1,25(OH)2D. Both parathyroid hormone and FGF-23 regulate proximal tubular phosphate excretion through signaling on sodium- phosphate cotransporters II a and II c . However, the interaction between these hormones on phosphate excretion is not clearly understood. We performed the present study to evaluate whether the existence of sufficient parathyroid hormone is necessary for full phosphaturic function of FGF-23 or not. Methods:In this case-control study, 19 patients with hypoparathyroidism and their age- and gender-matched normal population were enrolled. Serum calcium, phosphate, alkaline phosphatase,parathyroid hormone, FGF-23, 25(OH)D, 1,25(OH)2D and Fractional excretion of phosphorous were assessed and compared between the two groups, using SPSS software. Results:The mean serum calcium and parathyroid hormone level was significantly lower in hypoparathyroid patients in comparison with the control group(P<0.001 and P<0.001, respectively). We found high serum level of phosphate and FGF-23 in hypoparathyroid patients compared to the control group (P<0.001 and P<0.001,respectively). However, there was no significant difference in Fractional excretion of phosphorous or 1,25OH2D level between the two groups. There was a positive correlation between serum FGF-23 and Fractional excretion of phosphorous just in the normal individuals (P <0.001, r = 0.79). Conclusions:Although the FGF-23 is a main regulator of urinary phosphate excretion but the existence of sufficient parathyroid hormone is necessary for the full phosphaturic effect of FGF-23.

Urology & Nephrology

FGF-23

FE PO4

Hypoparathyroidism

PO4

Phosphorus (PO₄) has several biologic role in human, and is an essential ion in bone mineral component, cell membrane structure, and energy exchange. Also, it is a second messenger in controlling cellular biochemical activities through phosphorylation or dephosphorylation [1-3] . Kidney plays an important role in PO₄ homeostasis. About 80% of the ﬁltered PO₄ is reabsorbed through speciﬁc sodium- phosphate cotransporters (NaPi II_a and II_c) located in the proximal tubule [4-8].

PO₄ serum concentration is kept within the normal range by a complex regulation between intestinal absorption, renal filtration- reabsorption, and bone resorption of PO₄mediated by regulatory hormones [9-11]. The most important hormones that regulate tubular PO₄ handling, are parathyroid hormone (PTH) secreted by the parathyroid gland, and ﬁbroblast growth factor 23 (FGF-23), which is an osteocytes derived hormone. FGF-23 decreases serum PO₄ by inhibiting renal PO₄ reabsorption through FGF-23-Klotho (coreceptor) signaling on NaPi II_a and II_c at proximal tubule of the kidney. FGF-23 also suppresses 1,25-dihydroxyvitamin D (1,25(OH)2 D) production by decreasing 1α-hydroxylase expression [12-14]. PTH promotes PO₄ excretion by suppressing NaPi-II in the kidney [15]. PTH also enhances calcium absorption through the direct effect on bones and kidneys, and indirectly increases intestinal calcium and PO₄ absorption via the stimulation of 1α -hydroxylase activity and increase 1,25(OH)2 D production [16-18]. The same site of action of FGF-23 and PTH in NaPi II_a and II_cat proximal tubule of kidney might raise the question that whether there is an overlapping effect between these hormones or not?

Hypoparathyroidism is a rare endocrine disorder characterized by inappropriately low or absent levels of PTH associated with hypocalcemia and hyperphosphatemia [17, 19]. Hypoparathyroidism might occur as a primary congenital defect or might be due to a secondary cause. The most common cause of secondary hypoparathyroidism is the incidental destruction of parathyroid glands during anterior neck surgeries. Other causes are autoimmune disorders, radiation to the neck and inﬁltrative disorders of the parathyroid glands [20-22].

In the present study, we aim to evaluate the role of FGF-23 on PO₄ hemostasis in state of low or insufficient PTH in human. Hence, we conducted this case – control study to evaluate whether the renal excretion of PO₄ by serum FGF-23 in patients with hypoparathyroidism was different from normal population or not.

Patients and Method

A total of 38 participants including 19 patients with hypoparathyroidism and their healthy controls were enrolled in this study. The study was performed at Shiraz University of Medical Sciences affiliated endocrine clinics in Fars province, southern Iran, from October 2017 till March 2018. Both groups were matched for age and gender. Hypoparathyroidism was diagnosed on the basis of hypocalcemia (serum calcium less than 8.5 mg/dl) accompanied with documented PTH levels below the lower limit of the normal range.

All hypoparathyroid patients were follow up by an expert endocrinologist. Patients received proper doses of calcium carbonate (500mg tablet, manufactured Toliddaru pharmaceutical, Tehran, Iran), and calcitriol (0.25µg capsule, manufactured Zahravi pharmaceutical, Tehran, Iran) to maintain albumin-corrected serum calcium in the low-normal range ( 8–9 mg/dl) [23]. The exclusion criteria in both groups were renal failure (Glomerular filtration rate less than 60 ml/min), liver failure, other metabolic bone disease (e.g., rickets), hyperthyroidism, and diabetes mellitus. None of the patients received phosphate binder resins during the study.

Laboratory tests

All the samples were taken after 8 hours overnight fasting. Blood samples were centrifuged for 15 min at 3,000 rpm and the plasma was collected and stored at –70°C till further analysis. All the biochemical studies were performed at the endocrinology and metabolism research center laboratory of Shiraz University of Medical Sciences. Colorimetric assays were used to measure calcium (mg/dL), phosphorus (mg/dL), albumin (g/dL) and alkaline phosphatase (ALP) (IU/L) levels, by using Biosystem SA auto-analyzer, made in Spain. Serum PTH (pg/ml) and 25(OH)D (ng/ml) levels were assessed by Electrochemiluminescence methods produced by Roche company in Germany with Sensitivity, intra- and inter-assay CVs 3.3 and 5.1%, respectively. ELISA method was used to determine the serum intact FGF-23 (pg/ ml) and 1,25(OH)2D (pmol/l) using Bioassay technology laboratory kit. Intra- and inter-assay CVs for 1,25(OH)2D and FGF-23 were <8 and <10%, respectively. Normal references for serum calcium, phosphorus, ALP, PTH, 25(OH)D and 1,25(OH)2D were 8.5–10.5 mg/ dL, 3.5–5.5 mg/ dL, 44–147 IU/L, 10–65(pg/ml), 20–100 ng/ml, and 20 to 45 pg/ml, respectively. Initial morning urine collection was done to determine renal PO₄ clearance. Urinary PO₄ and creatinine concentrations were determined by digital flame spectrophotometer. Fractional excretion of phosphorous (FE PO₄) was done using the following formula: FE PO₄ = [PO₄ (Urine) ×Creatinine (Serum)] / [PO₄ (Serum) × Creatinine (Urine)] × 100

Ethical statement: An informed written consent form was obtained from the participants after explaining the aim, method and goal of the study. Shiraz University of Medical Sciences local Ethics Committee and Vice-Chancellor of research at SUMS approved this study with number 1396-01-01-15805.

Statistics

SPSS statistical software (version 22, IBM ) were used to perform Statistical analysis. Data are mentioned as mean ± SD. Shapiro-Wilk was used to evaluate the normality of data distribution. Normally distributed data were compared using Student’s t-test, and the Mann–Whitney test was used to compare non-normally distributed ones. Pearson’s test and Spearman’s ranking test were used to evaluate the correlations between normally distributed parameters and non-normal distributed ones, respectively. P value less than 0.05 was considered to be statically significant.

A total of 38 participants were enrolled in this study, 19 with hypoparathyroidism as case group and 19 volunteers with normal parathyroid function as the control group. Mean age in the case and control groups was 43.6±17 years and 46.7±15.9 years, which was not statistically significant (P=0.57). Both case and control groups included 5 male and 14 female. Also, there were no significant differences in weight and BMI between case and control groups.

In the case group, 9 patients had hypoparathyroidism due to previous neck thyroidectomy and 10 patients were case of primary hypoparathyroidism. General characteristic of patients and controls are summarized in Table1.

The mean serum calcium and PTH level was significantly lower in the case group in comparison with the control group (P<0.001 and P<0.001, respectively). In patients with hypoparathyroidism serum PO₄ was significantly higher than the control group (P<0.001). Serum FGF-23 was higher in patients with hypoparathyroidism in comparison with the control group (P=0.001). However, there was no significant difference between the case and control groups with respect to the mean serum level of 1,25(OH)2D, 25(OH)D, ALP, and FE PO₄(P= 0.25, P=0.11, P=0.23 and P=0.08, respectively).

As shown in Table 2 there was a strong positive correlation between FGF-23 and FE PO₄in the control; however, this correlation was not observed amongst hypoparathyroid patients. There was no correlation between FE PO₄, serum PO₄, PTH and 1, 25(OH)2 D in both case and control groups. Fig. 1 shows the correlation between values of FE PO₄ and serum FGF-23 in both control and case groups (Spearman rho =0.79, P < 0.001). In addition, we have done an analysis in our hypoparathyroid patients evaluating the association of FGF23 and serum calcium in 2 separate group of low calcium and normal calcium level. It showed that there was no correlation between calcium and FGF23 in low calcium and normal calcium level groups (P= 0.598 and P= 0.054, respectively).

Maintaining serum PO₄ homeostasis necessitates a complex counter regulatory feed-back balance between PTH, FGF-23 and 1,25(OH)2 D [24-26]. FGF-23 and PTH are probably the most important phosphaturic hormones in human [1]. FGF-23 is mainly produced by osteoblasts and osteocytes. Local expression of FGF-23 coreceptor (Klotho) is necessary for its function at the renal proximal tubules [27]. It inhibits renal Phos reabsorption through inhibitory effects on NaPi II_a and II _cat proximal renal tubules [28]. However, there are still controversies about the action site of FGF-23 in the kidney [29]. previous studies had showed that klotho is essentially expressed in distal renal tubules, and alteration in the extracellular signal-regulated kinase (ERK) phosphorylation in distal tubules occurs soon after FGF-23 injection [30, 31]. Therefore, it still remain unclear as how FGF-23 could affect proximal tubules to suppress phosphate reabsorption. Data suggest that FGF-23 might require other factors such as PTH for signal transduction pathway at the proximal tubules [32].

PTH also increases renal PO₄ excretion at proximal tubule of the kidney by reducing apical membrane NaPi II_a and II_c [33, 34, 14]. Moreover, PTH increases FGF-23 gene expression [35]. In addition to kidneys, parathyroid gland also express considerable amount of klotho and FGF-23 receptor [36]. On the other hand, FGF-Klotho complex could activate the MAPK pathway leading to decreased PTH mRNA and PTH secretion [37-39]. Olena et al. showed that the phosphaturic actions of PTH, are blunted by FGF-23 or Klotho deficiency. Hence, FGF-23 might be an important modulator of PTH signaling in the kidney [40].

Although the regulatory counterbalance between FGF-23 and PTH secretion was investigated, there is still insufficient information about the role of PTH on phosphaturic function of FGF-23 in human. Study of phosphaturic effect of FGF-23 in normal human physiology might be confounded by the fact that PTH and FGF-23 have some overlapping effects on PO₄excretion. Hence, the present study on hypoparathyroid patients and normal population provides an opportunity to observe whether the phosphaturic effect of FGF-23 is independent of PTH or not.

In the present study, we detected high serum level of PO₄ and FGF-23 in hypoparathyroid patients compared to the control group; however, we found no significant difference in FE PO₄ or 1,25(OH)2 D level between the two groups. Also, we found a strong positive correlation between serum FGF-23 and FE PO₄ in the control population, but this correlation was absent in hypoparathyroid patients. These findings could suggest that although the FGF-23 is one of the main regulator of urinary PO₄ excretion, the existence of intact PTH is necessary for the full phosphaturic effect of FGF-23. However, further relevant human studies are warranted.

In the presence of normal parathyroid and kidney function inappropriate high serum FGF-23 could result in urinary PO₄ loss and hypophosphatemia such as X-linked dominant hypophosphatemic rickets (XLH), [41-44],autosomal dominant hypophosphatemic rickets [45, 46], Autosomal recessive hypophosphatemic rickets (ARHR) [47, 48] or Fibrous dysplasia (FD)/McCune–Albright syndrome [49]. As well as some acquired disorders such as Tumor-induced osteomalacia (TIO) [50-52].

Previous studies showed that mean serum PO₄ levels in hypoparathyroid patients remained above the normal range, even in the presence of high serum FGF-23 level [53].Yamashita et al showed that in transient hypoparathyroidism high serum level of FGF23 and hyperphosphatemia will be normalized only after parathyroid recovery[54]. Animal studies also showed that PTH-null mice experienced high PO₄ in spite of high circulating FGF-23, resembling participants with hypoparathyroidism in the present study [55]. In another study on hypoparathyroid patients, treatment with rhPTH could reduce serum PO₄ level from the upper normal range to the normal values parallel with increased urinary PO₄ excretion [56-58]. These findings also support our hypothesis about the importance of PTH in phosphaturic action of FGF-23. Another explanation by Gracia-Iguacel et al was that PTH may have effect on phosphaturic function of FGF-23 through the serum calcium level [59]. Also, some studies showed that FGF23 have positive correlation with serum calcium [60,61]. In our study, we found no correlation between calcium and FGF23 in low calcium and normal calcium level hypoparathyroid patients. However, the number of hypoparathyroid patients in low Ca group was just 7, which could affect the results. Another important issue in this regards was that normal renal function is necessary for this association. In some patients with chronic kidney disease, high serum phosphate was observed in spite of high serum PTH and FGF23 level [62]. Also, it was shown that in chronic kidney disease patients treated with hemodialysis, FGF23 could predict the progression of secondary hyperparathyroidism. Interestingly, in these patients total parathyroidectomy could decrease high serum FGF-23 level to normal values [63, 64].

In spite of many strengths of this study that evaluated FGF23 function in hypoparathyroid patients, we had some limitations. This study was a case-control cross sectional study, which could be better if we design an interventional clinical trial to evaluate the effect of PTH in hypoparathyroid patients in the future.

The present study could suggest that although the FGF-23 is one of the main regulator of urinary PO₄ excretion, the existence of sufficient parathyroid hormone is necessary for the full phosphaturic effect of FGF-23. We hypothesized that PTH might play a role in PO₄ excretory signal pathway of FGF-23. However, further in vivo and in vitro studies are necessary to determine the mechanism of action of parathyroid hormone on PO₄ excretory function of FGF-23.

1,25-dihydroxyvitamin D (1,25(OH)2 D)

25-hydroxy vitamin D (25OHD)

Alkaline phosphatase (ALP)

Calcium (Ca)

Chronic kidney diseases(CKD)

Dual-energy X-ray absorptiometry (DXA)

Fractional excretion of phosphorous (FE PO₄)

Fibroblast growth factor 23 (FGF-23),

Parathyroid hormone(PTH)

Phosphorus (PO₄)

Shiraz University of Medical Sciences (SUMS)

Sodium- phosphate cotransporters (NaPi II_a and II_c)

Ethics approval and consent to participate: Shiraz University of Medical Sciences local ethic committee and vice-chancellor of research at SUMS approved this study with number 1396-01-01-15805. All the patients signed a written informed consent form after a session explaining the aim, method and goal of the study for each participant.

Consent to publish: All the patients signed a written informed consent form to publish their data in manuscript after a session explaining the aim, method and goal of the study.

Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request

Competing Interests: Gholamhossein Ranjbar Omrani, Azita Salehifar, Seyed Reza Kassaee and Forough Saki declare that they have no conflict of interest.

Funding: There is no financial support.

Authors contribution:

FS: design, data gathering, Analysis, preparing the manuscript
AS: design, data gathering, preparing the manuscript
SRK: design, data gathering, preparing the manuscript
GHRO: design, data gathering, preparing the manuscript and the correspondence

All authors have read and approved the manuscript

Acknowledgment:The authors wish to thank Mr. H. Argasi at the Research Consultation Center (RCC) of Shiraz University of Medical Sciences for his invaluable assistance in editing this manuscript.

Jüppner H. Phosphate and FGF-23. Kidney International. 2011;79:S24-S7.
Miyamoto K-I, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M et al. Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. Journal of pharmaceutical sciences. 2011;100(9):3719-30.
Berndt T, Kumar R. Novel mechanisms in the regulation of phosphorus homeostasis. Physiology. 2009;24(1):17-25.
Kuro-o M. Endocrine FGFs and Klothos: emerging concepts. Trends in Endocrinology & Metabolism. 2008;19(7):239-45.
Berndt TJ, Schiavi S, Kumar R. “Phosphatonins” and the regulation of phosphorus homeostasis. American Journal of Physiology-Renal Physiology. 2005;289(6):F1170-F82.
Murer H, Hernando N, Forster I, Biber Jr. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiological reviews. 2000;80(4):1373-409.
Tenenhouse HS, Murer H. Disorders of renal tubular phosphate transport. Journal of the American Society of Nephrology. 2003;14(1):240-7.
Fujii T, Shiozaki Y, Segawa H, Nishiguchi S, Hanazaki A, Noguchi M et al. Analysis of opossum kidney NaPi-IIc sodium-dependent phosphate transporter to understand Pi handling in human kidney. Clinical and experimental nephrology. 2019;23(3):313-24.
Farrow EG, White KE. Recent advances in renal phosphate handling. Nature Reviews Nephrology. 2010;6(4):207.
Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. American Journal of Physiology-Renal Physiology. 2010;299(2):F285-F96.
Kaneko I, Tatsumi S, Segawa H, Miyamoto K-i. Control of phosphate balance by the kidney and intestine. Clinical and experimental nephrology. 2017;21(1):21-6.
Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y et al. FGF‐23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. Journal of Bone and Mineral Research. 2004;19(3):429-35.
Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. The Journal of clinical investigation. 2004;113(4):561-8.
Fujii T, Segawa H, Hanazaki A, Nishiguchi S, Minoshima S, Ohi A et al. Role of the putative PKC phosphorylation sites of the type IIc sodium-dependent phosphate transporter in parathyroid hormone regulation. Clinical and experimental nephrology. 2019:1-10.
Weinman EJ, Biswas RS, Peng Q, Shen L, Turner CL, Xiaofei E et al. Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor–1. The Journal of clinical investigation. 2007;117(11):3412-20.
Shoback D. Hypoparathyroidism. New England Journal of Medicine. 2008;359(4):391-403.
Bilezikian JP, Khan A, Potts JT, Brandi ML, Clarke BL, Shoback D et al. Hypoparathyroidism in the adult: Epidemiology, diagnosis, pathophysiology, target‐organ involvement, treatment, and challenges for future research. Journal of Bone and Mineral Research. 2011;26(10):2317-37.
Pajevic PD, Wein MN, Kronenberg HM. Parathyroid hormone actions on bone and kidney. Hypoparathyroidism. Springer; 2015. p. 99-109.
Hadker N, Egan J, Sanders J, Lagast H, Clarke B. Understanding the burden of illness associated with hypoparathyroidism reported among patients in the paradox study. Endocrine Practice. 2014;20(7):671-9.
Marx SJ. Hyperparathyroid and hypoparathyroid disorders. New England Journal of Medicine. 2000;343(25):1863-75.
Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow‐up study. Journal of Bone and Mineral Research. 2013;28(11):2277-85.
Powers J, Joy K, Ruscio A, Lagast H. Prevalence and incidence of hypoparathyroidism in the United States using a large claims database. Journal of Bone and Mineral Research. 2013;28(12):2570-6.
Abate EG, Clarke BL. Review of hypoparathyroidism. Frontiers in endocrinology. 2017;7:172.
Berndt T, Kumar R. Phosphatonins and the regulation of phosphate homeostasis. Annu Rev Physiol. 2007;69:341-59.
Imel EA, Econs MJ. Fibroblast growth factor 23: roles in health and disease. Journal of the American Society of Nephrology. 2005;16(9):2565-75.
Quarles LD. Endocrine functions of bone in mineral metabolism regulation. The Journal of clinical investigation. 2008;118(12):3820-8.
Tan SJ, Smith ER, Hewitson TD, Holt SG, Toussaint ND. The importance of klotho in phosphate metabolism and kidney disease. Nephrology. 2014;19(8):439-49.
Strom TM, Jüppner H. Phex, FGF23, DMP1 and beyond. Current opinion in nephrology and hypertension. 2008;17(4):357-62.
Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2–SGK1 signaling pathway. Bone. 2012;51(3):621-8.
Farrow EG, Davis SI, Summers LJ, White KE. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. Journal of the American Society of Nephrology. 2009;20(5):955-60.
Kuro-o M. The FGF23 and Klotho system beyond mineral metabolism. Clinical and experimental nephrology. 2017;21(1):64-9.
Chang Q, Hoefs S, Van Der Kemp A, Topala C, Bindels R, Hoenderop J. The ß-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science. 2005;310(5747):490-3.
Cole JA. Parathyroid hormone activates mitogen-activated protein kinase in opossum kidney cells. Endocrinology. 1999;140(12):5771-9.
de Groot T, Lee K, Langeslag M, Xi Q, Jalink K, Bindels RJ et al. Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation. Journal of the American Society of Nephrology. 2009;20(8):1693-704.
Lavi-Moshayoff V, Wasserman G, Meir T, Silver J, Naveh-Many T. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. American Journal of Physiology-Renal Physiology. 2010;299(4):F882-F9.
Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A et al. α-Klotho as a regulator of calcium homeostasis. Science. 2007;316(5831):1615-8.
Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goetz R, Kuro-o M, Mohammadi M et al. The parathyroid is a target organ for FGF23 in rats. The Journal of clinical investigation. 2007;117(12):4003-8.
Krajisnik T, Björklund P, Marsell R, Ljunggren O, Akerström G, Jonsson KB et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol. 2007;195(1):125-31.
Canalejo R, Canalejo A, Martinez-Moreno JM, Rodriguez-Ortiz ME, Estepa JC, Mendoza FJ et al. FGF23 fails to inhibit uremic parathyroid glands. Journal of the American Society of Nephrology. 2010;21(7):1125-35.
Andrukhova O, Streicher C, Zeitz U, Erben RG. Fgf23 and parathyroid hormone signaling interact in kidney and bone. Molecular and cellular endocrinology. 2016;436:224-39.
Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T, Imanishi Y et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. New England Journal of Medicine. 2003;348(17):1656-63.
Yamazaki Y, Okazaki R, Shibata M, Hasegawa Y, Satoh K, Tajima T et al. Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. The Journal of Clinical Endocrinology & Metabolism. 2002;87(11):4957-60.
Miyamoto K-i, Taketani Y, Morita K, Segawa H, Nii T, Fujioka A et al. Molecular and cellular regulation of renal phosphate transporters in X-linked hypophosphatemia. Clinical and Experimental Nephrology. 1998;2(3):178-82.
Nii T, Taketani Y, Tani Y, Ohkido I, Segawa H, Yamamoto H et al. Direct demonstration of humorally mediated inhibition of the transcription of phosphate transporter in XLH patients. Clinical and Experimental Nephrology. 2001;5(3):144-52.
Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K et al. Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology. 2002;143(8):3179-82.
Imel EA, Hui SL, Ecibs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. Journal of Bone and Mineral Research. 2007;22(4):520-6.
Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. The American Journal of Human Genetics. 2010;86(2):273-8.
Lorenz-Depiereux B, Schnabel D, Tiosano D, Häusler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. The American Journal of Human Genetics. 2010;86(2):267-72.
Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. The Journal of clinical investigation. 2003;112(5):683-92.
Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proceedings of the National Academy of Sciences. 2001;98(11):6500-5.
Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY et al. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. The American journal of surgical pathology. 2004;28(1):1-30.
Rowe PS. X-linked rickets and tumor-acquired osteomalacia: PHEX and the missing link. Clinical and Experimental Nephrology. 1998;2(3):183-93.
Gupta A, Winer K, Econs M, Marx S, Collins M. FGF-23 is elevated by chronic hyperphosphatemia. The Journal of Clinical Endocrinology & Metabolism. 2004;89(9):4489-92.
Yamashita H, Yamazaki Y, Hasegawa H, Yamashita T, Fukumoto S, Shigematsu T, et al. Fibroblast growth factor-23 (FGF23) in patients with transient hypoparathyroidism: its important role in serum phosphate regulation. 2007;54(3):465-70.
Bai X, Miao D, Goltzman D, Karaplis AC. Early lethality in Hyp mice with targeted deletion of Pth gene. Endocrinology. 2007;148(10):4974-83.
Clarke BL, Vokes TJ, Bilezikian JP, Shoback DM, Lagast H, Mannstadt M. Effects of parathyroid hormone rhPTH (1–84) on phosphate homeostasis and vitamin D metabolism in hypoparathyroidism: REPLACE phase 3 study. Endocrine. 2017;55(1):273-82.
Clarke BL, Berg JK, Fox J, Cyran JA, Lagast H. Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1–84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study. Clinical therapeutics. 2014;36(5):722-36.
Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L, Group HS. The effect of adding PTH (1–84) to conventional treatment of hypoparathyroidism: a randomized, placebo‐controlled study. Journal of Bone and Mineral Research. 2011;26(10):2358-70.
Gracia-Iguacel C, Gonzalez-Parra E, Rodriguez-Osorio L, Sanz AB, Almaden Y, de la Piedra C, et al. Correction of hypocalcemia allows optimal recruitment of FGF-23-dependent phosphaturic mechanisms in acute hyperphosphatemia post-phosphate enema. 2013;31(6):703-7.
Rodriguez-Ortiz ME, Lopez I, Muñoz-Castañeda JR, Martinez-Moreno JM, Ramírez AP, Pineda C, et al. Calcium deficiency reduces circulating levels of FGF23. 2012;23(7):1190-7.
Yamashita H, Yamashita T, Miyamoto M, Shigematsu T, Kazama JJ, Shimada T, et al. Fibroblast growth factor (FGF)-23 in patients with primary hyperparathyroidism. 2004;151(1):55-60.
Ramon I, Kleynen P, Body J-J, Karmali RJEjoe. Fibroblast growth factor 23 and its role in phosphate homeostasis. 2010;162(1):1-10.
Nakanishi S, Kazama JJ, Nii-Kono T, Omori K, Yamashita T, Fukumoto S, et al. Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. 2005;67(3):1171-8.
Sato T, Tominaga Y, Ueki T, Goto N, Matsuoka S, Katayama A, et al. Total parathyroidectomy reduces elevated circulating fibroblast growth factor 23 in advanced secondary hyperparathyroidism. 2004;44(3):481-7.

Table 1 General characteristics and biochemical studies in both case and control groups and the related comparisons

Variable	control	case	P value
Age (y)	46.72 ± 15.89	43.68 ± 17.01	0.57
Weight (Kg)	70.89 ± 14.33	75.06 ± 22.11	0.51
Height (cm)	159.83 ± 10.4	163.47 ± 9.92	0.29
BMI (Kg/m²)	27.82 ± 3.53	27.75 ± 7.83	0.97
PTH (pg/ml)	57.97 ± 18.06	8.92 ± 4.38	<0.001
Ca (mg/dl)	9.20 ± 0.46	7.98 ± 0.86	<0.001
PO₄ (mg/dl)	3.82 ± 0.46	5.26 ± 0.93	<0.001
ALP(IU/L)	148.22 ± 37.9	132.58 ± 40.69	0.23
1,25(OH)2D (pg/ml)	23.73 ± 17.90	30.57 ± 17.77	0.25
25 (OH)D (ng/ml)	33.56 ± 32.35	53.11 ± 40.71	0.11
FGF23 (pg/ml)	24.66 ± 17.73	47.88 ± 22.14	<0.001
FE PO₄ (%)	15.77 ± 6.64	16.96 ± 11.40	0.70

BMI : Body mass index ,FGF-23: Fibroblast Growth Factor 23 , ALP: Alkaline phosphatase , PO₄: phosphorus, Ca: Calcium, PTH: Parathyroid Hormone, FE PO₄:Fraction excretion of phosphorus

Table 2 Correlation between fractional excretion of PO₄and serum biochemical parameters in the case and control groups, separately

FGF-23

PO₄

PTH

FE PO₄

Control group

P <0.001

cc = 0.79

P = 0.94

cc = 0.016

P = 0.97

cc = 0.01

Case group

P = 0.38

cc = -0.21

P = 0.82

cc = -0.053

P = 0.98

cc = 0.005

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published 11 May, 2020

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Editorial decision: Accept
22 Apr, 2020
Review #2 received at journal
15 Apr, 2020
Review #1 received at journal
12 Apr, 2020
Reviewers invited by journal
25 Mar, 2020
Reviewer #1 agreed at journal
25 Mar, 2020
Reviewer #2 agreed at journal
25 Mar, 2020
Editor assigned by journal
16 Dec, 2019
Submission checks completed at journal
15 Dec, 2019
Editor invited by journal
15 Dec, 2019

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Interaction between serum FGF-23 and PTH in renal phosphate excretion, a case-control study in hypoparathyroid patients

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