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Fibroblast growth factor (FGF) 23 inhibits renal phosphate reabsorption by activating FGF receptor (FGFR) 1c in a Klotho-dependent fashion. The phosphaturic activity of FGF23 is abrogated by proteolytic cleavage at the RXXR motif that lies at the boundary between the FGF core homology domain and the 72-residue-long C-terminal tail of FGF23. Here, we show that the soluble ectodomains of FGFR1c and Klotho are sufficient to form a ternary complex with FGF23 in vitro. The C-terminal tail of FGF23 mediates binding of FGF23 to a de novo site generated at the composite FGFR1c-Klotho interface. Consistent with this finding, the isolated 72-residue-long C-terminal tail of FGF23 impairs FGF23 signaling by competing with full-length ligand for binding to the binary FGFR-Klotho complex. Injection of the FGF23 C-terminal tail peptide into healthy rats inhibits renal phosphate excretion and induces hyperphosphatemia. In a mouse model of renal phosphate wasting attributable to high FGF23, the FGF23 C-terminal peptide reduces phosphate excretion, leading to an increase in serum phosphate concentration. Our data indicate that proteolytic cleavage at the RXXR motif abrogates FGF23 activity by a dual mechanism: by removing the binding site for the binary FGFR-Klotho complex that resides in the C-terminal region of FGF23, and by generating an endogenous inhibitor of FGF23. We propose that peptides derived from the C-terminal tail of FGF23 or peptidomimetics and small-molecule organomimetics of the C-terminal tail can be used as therapeutics to treat renal phosphate wasting.

[alpha]-Klotho was first identified as an aging gene and was later shown to be a regulator of phosphate metabolism. Fibroblast growth factor 23 (FGF23) is the key regulator of phosphate metabolism. Serum levels of soluble [alpha]-Klotho in chronic kidney disease (CKD) patients have not previously been determined, especially in relation with FGF23 and creatinine levels. This study was designed to investigate whether serum soluble [alpha]-Klotho levels are modulated by renal function, age, and FGF23 level in CKD patients. This study is the first report on the utility of measuring soluble [alpha]-Klotho levels in human CKD. A total of 292 CKD patients were enrolled. Serum samples were collected, and FGF23 and soluble [alpha]-Klotho levels were measured using enzyme-linked immunosorbent assay kits. In addition, serum creatinine, hemoglobin, albumin, calcium, and phosphate levels were measured. Serum soluble [alpha]-Klotho levels were associated positively with estimated glomerular filtration rate (eGFR) (P < 0.0001) and inversely with serum creatinine level (P < 0.01). Interestingly, [alpha]-Klotho levels were significantly decreased in stage 2 CKD compared with stage 1 (P = 0.0001). Serum FGF23 levels were associated positively with serum creatinine and negatively with eGFR. FGF23 levels were significantly increased in stage 5 compared with stage 1 CKD. Soluble [alpha]-Klotho was associated inversely with log-transformed FGF23 level (P < 0.01). Our data indicate that soluble [alpha]-Klotho levels are significantly decreased in stage 2 CKD compared to stage 1, and not only in the advanced stages of the disease. Soluble [alpha]-Klotho may thus represent a new biomarker for the diagnosis of CKD, especially in the early stage.[PUBLICATION ABSTRACT]

Background. To describe the case of a patient with polymyalgia rheumatica (PMR) and suboptimal response to steroid therapy with the incidental finding of hyperphosphaturic hypophosphatemia, suspected for tumor-induced osteomalacia (TIO), to highlight the importance of a multidisciplinary approach and targeted diagnostic laboratory and instrumental workup.   Materials and Methods. Male patient, 76 years old, with a functionally single kidney following nephrectomy of an ectopic kidney at age 33, medical history of arterial hypertension, dyslipidemia, OSAS, subcritical stenosis of the supraaortic trunks, and polyglobulia (JAK2 mutation negative, endogenous EPO within normal limits); on chronic therapy with NSAIDs as needed, antihypertensives, ASA 100 mg/day, statins, and benzodiazepines for anxiety-depressive syndrome. Symptom onset approximately 3 months prior with arthralgias of the shoulder and pelvic girdles, prolonged morning stiffness >2 h, functional limitation, and elevation of inflammatory markers. Underwent initial treatment with prednisone 37.5 mg/day with tapering as indicated by the general practitioner. Subsequent relapse upon discontinuation and therefore referred for urgent rheumatology evaluation with reintroduction of PDN 18.75 mg/day and slow tapering and initiation of antiresorptive therapy with risedronate, calcium, and vitamin D supplementation.   Results. At 3-month rheumatology follow-up visit, reported recurrence of arthralgias and morning stiffness upon reduction of prednisone below 7.5 mg/day. Laboratory tests revealed CRP 2.1 mg/dL; serum calcium 9.9 mg/dL; serum phosphorus 2.0 mg/dL (normal range 2.7-5.1); serum magnesium 2.1 mg/dL; spot urine phosphorus 49.9 mg/dL; plasma creatinine 1.01 mg/dL; TmPO4/GFR 1.42 mg/dL (normal range >2.7). Given suspicion of TIO, intact and C-terminal FGF23 assays were requested, with values resulting inappropriately normal in relation to serum phosphorus levels. Systematic monitoring of serum phosphorus was concurrently initiated, with IV supplementation of fructose-1,6-diphosphate and oral potassium phosphate as needed, and introduction of calcitriol up to 0.5 µg/day. Gallium-DOTAPEPTIDE PET/CT extended to the appendicular skeleton was also requested, with results not yet available at the time of publication.   Conclusions. Tumor-induced osteomalacia represents a rare cause of renal hyperphosphaturia and severe hypophosphatemia, frequently masked by nonspecific musculoskeletal symptoms in elderly patients; this case highlights the need to integrate clinical suspicion of PMR with complete biochemical investigations, including serum phosphate and TmPO4/GFR calculation, and to employ advanced imaging techniques for localization of FGF23-secreting neoplasms, in order to promptly direct the patient toward specific surgical or medical therapy and improve functional and metabolic outcome. Currently, burosumab, a recombinant human monoclonal antibody (IgG1) directed against FGF23, is approved in both children and adults for the treatment of FGF23-related hypophosphatemia secondary to phosphaturic mesenchymal tumors that cannot be curatively resected or localized.

This research was funded by Instituto de Salud Carlos III (ISCIII; PI17/00384, PI17/00715, PI19/00532, PI20/00633, PI20/00753), the ISCIII Retic REDinREN (RD06/0016/1013, RD12/0021/0023, RD16/0009/0017 and RD16/0009/0001), Fondo Europeo de Desarrollo Regional (FEDER), Plan Estatal de I+D+I 2013-2016, Plan de Ciencia, Tecnología e Innovación 2013-2017 y 2018-2022 del Principado de Asturias (GRUPIN14-028, IDI-2018-000152), Fundación Renal Iñigo Álvarez de Toledo (FRIAT), and University of Oviedo. The APC was funded by PI19/00532.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumoral production of fibroblast growth factor 23 (FGF23). The hallmark biochemical features include hypophosphatemia due to renal phosphate wasting, inappropriately normal or frankly low 1,25-dihydroxy-vitamin D, and inappropriately normal or elevated FGF23. TIO is caused by typically small, slow growing, benign phosphaturic mesenchymal tumors (PMTs) that are located almost anywhere in the body from the skull to the feet, in soft tissue or bone. The recent identification of fusion genes in a significant subset of PMTs has provided important insights into PMT tumorigenesis. Although management of this disease may seem straightforward, considering that complete resection of the tumor leads to its cure, locating these often-tiny tumors is frequently a challenge. For this purpose, a stepwise, systematic approach is required. It starts with thorough medical history and physical examination, followed by functional imaging, and confirmation of identified lesions by anatomical imaging. If the tumor resection is not possible, medical therapy with phosphate and active vitamin D is indicated. Novel therapeutic approaches include image-guided tumor ablation and medical treatment with the anti-FGF23 antibody burosumab or the pan-FGFR tyrosine kinase inhibitor, BGJ398/infigratinib. Great progress has been made in the diagnosis and treatment of TIO, and more is likely to come, turning this challenging, debilitating disease into a gratifying cure for patients and their providers.

Since calcium and phosphorus play vital roles in a multitude of physiologic systems, disorders of calcium and phosphorus metabolism always lead to severe consequences such as skeletal-related and cardiovascular morbidity, or even life-threatening. Physiologically, the maintenance of calcium and phosphorus homeostasis is achieved via a variety of concerted actions of hormones such as parathyroid hormone (PTH), vitamin D, and fibroblast growth factor (FGF23), which could be regulated mainly at three organs, the intestine, kidney, and bone. Disruption of any organ or factor might lead to disorders of calcium and phosphorus metabolism. Currently, lacking of accurate diagnostic approaches and unknown molecular basis of pathophysiology will result in patients being unable to receive a precise diagnosis and personalized treatment timely. Therefore, it is urgent to identify early diagnostic biomarkers and develop therapeutic strategies. Fortunately, proteomics and metabolomics offer promising tools to discover novel indicators and further understanding of pathological mechanisms. Therefore, in this review, we will give a systematic introduction on PTH-1,25(OH)2D-FGF23 axis in the disorders of calcium and phosphorus metabolism, diagnostic biomarkers identified, and potential altered metabolic pathways involved.

In an open label, randomized, controlled, phase 3 trial in 61 children 1 to 12 years old with X-linked hypophosphatemia (XLH), burosumab improved rickets versus continuing conventional therapy with active vitamin D and phosphate. Here, we conducted an analysis to determine whether skeletal responses differed when switching to burosumab versus continuing higher or lower doses of conventional therapy. Conventional therapy dose groups were defined as: higher dose phosphate >40 mg/kg [HPi], lower dose phosphate ≤40 mg/kg [LPi], higher dose alfacalcidol >60 ng/kg or calcitriol >30 ng/kg [HD], and lower dose alfacalcidol ≤60 ng/kg or calcitriol ≤30 ng/kg [LD]. At Week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomized to burosumab versus conventional therapy for all pre-baseline dose groups: HPi (+1.72 versus +0.67), LPi (+2.14 versus +1.08), HD (+1.90 versus +0.94), LD (+2.11 versus +1.06). At Week 64, the RGI-C for rickets was also higher in children randomized to burosumab (+2.06) versus conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase also decreased in the burosumab treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses. Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum alkaline phosphatase more than continuing either higher or lower doses of phosphate or active vitamin D.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months–90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ − 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Changes in the expression of klotho, a β-glucuronidase, contribute to the development of features that resemble those of premature aging, as well as chronic renal failure. Klotho knockout mice have increased expression of the sodium/phosphate cotransporter (NaPi2a) and 1α-hydroxylase in their kidneys, along with increased serum levels of phosphate and 1,25-dihydroxyvitamin D. These changes are associated with widespread soft-tissue calcifications, generalized tissue atrophy, and a shorter lifespan in the knockout mice. To determine the role of the increased vitamin D activities in klotho knockout animals, we generated klotho and 1α-hydroxylase double-knockout mice. These double mutants regained body weight and developed hypophosphatemia with a complete elimination of the soft-tissue and vascular calcifications that were routinely found in klotho knockout mice. The markedly increased serum fibroblast growth factor 23 and the abnormally low serum parathyroid hormone levels, typical of klotho knockout mice, were significantly reversed in the double-knockout animals. These in vivo studies suggest that vitamin D has a pathologic role in regulating abnormal mineral ion metabolism and soft-tissue anomalies of klotho-deficient mice.