Search

Phosphate is an integral part of human cellular structure and function. Though most recognised disorders of phosphaturia are genetic in origin, phosphate loss due to acquired conditions is commonly encountered in clinical practice. Acquired hypophosphatemia is most commonly due to renal phosphate wasting and can produce significant morbidity. It also heralds future kidney damage, and continued exposure can lead to progressive kidney injury and potentially renal failure. These conditions are a diverse group of disorders with common shared mechanisms causing loss of phosphate in the urine. Renal phosphate loss can occur as an isolated entity or as a part of generalised proximal tubular dysfunction, i.e., Fanconi's syndrome. An insight into the pathophysiological mechanisms of acquired phosphaturia can help clinicians monitor their patients better and avoid potential harms., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Hypophosphatemia is a common and dangerous complication of acute liver failure (ALF) of various etiologies. While various mechanisms for ALF-associated hypophosphatemia have been proposed including high phosphate uptake into regenerating hepatocytes, acetaminophen (APAP)-associated hypophosphatemia was linked to renal phosphate wasting, and APAP-induced renal tubular injury was proposed as underlying mechanism. We studied 30 normophosphatemic and 46 hypophosphatemic (serum phosphate < 2.5 mg/dL) patients from the Acute Liver Failure Study Group registry with APAP- or non-APAP-induced ALF. Since kidney injury affects phosphate excretion, patients with elevated serum creatinine (>1.2 mg/dL) were excluded. Maximal amount of renal tubular phosphate reabsorption per filtered volume (TmP/GFR) was calculated from simultaneous serum and urine phosphate and creatinine levels to assess renal phosphate handling. Instead of enhanced renal phosphate reabsorption as would be expected during hypophosphatemia of non-renal causes, serum phosphate was positively correlated with TmP/GFR in both APAP- and non-APAP-induced ALF patients (R 2  = 0.66 and 0.46, respectively; both P < 0.0001), indicating renal phosphate wasting. Surprisingly, there was no evidence of kidney damage based on urinary markers including neutrophil gelatinase-associated lipocalin and cystatin C even in the APAP group. Additionally, there was no evidence that the known serum phosphatonins parathyroid hormone, fibroblast growth factor 23, and α-Klotho contribute to the observed hypophosphatemia. We conclude that the observed hypophosphatemia with renal phosphate wasting in both APAP- and non-APAP-mediated ALF is likely the result of renal tubular phosphate leak from yet-to-be identified factor(s) with no evidence for proximal tubular damage or contribution of known phosphatonins., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The kidneys play an important role in phosphate homeostasis. Patients with CKD develop hyperphosphatemia in the later stages of the disease. Currently, treatment options are limited to dietary phosphate restriction and oral phosphate binders. The sodium-phosphate cotransporter Npt2a, which mediates a large proportion of phosphate reabsorption in the kidney, might be a good therapeutic target for new medications for hyperphosphatemia., Methods: The authors assessed the effects of the first orally bioavailable Npt2a inhibitor (Npt2a-I) PF-06869206 in normal mice and mice that had undergone subtotal nephrectomy (5/6 Nx), a mouse model of CKD. Dose-response relationships of sodium, chloride, potassium, phosphate, and calcium excretion were assessed in response to the Npt2a inhibitor in both groups of mice. Expression and localization of Npt2a/c and levels of plasma phosphate, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) were studied up to 24-hours after Npt2a-I treatment., Results: In normal mice, Npt2a inhibition caused a dose-dependent increase in urinary phosphate (ED 50 approximately 21 mg/kg), calcium, sodium and chloride excretion. In contrast, urinary potassium excretion, flow rate and urinary pH were not affected dose dependently. Plasma phosphate and PTH significantly decreased after 3 hours, with both returning to near baseline levels after 24 hours. Similar effects were observed in the mouse model of CKD but were reduced in magnitude., Conclusions: Npt2a inhibition causes a dose-dependent increase in phosphate, sodium and chloride excretion associated with reductions in plasma phosphate and PTH levels in normal mice and in a CKD mouse model., (Copyright © 2019 by the American Society of Nephrology.)

Introduction: Phosphaturic mesenchymal tumor mixed connective tissue type (PMT/MCT) is the most common type (up to 90%) of phosphaturic mesenchymal tumor (PMT), a rare clinicopathologic entity. Besides overproduction of fibroblast growth factor 23 (FGF23), there is a big variation of immunohistochemical characteristic across types of PMT, which makes it difficult to obtain an early diagnosis of PMT/MCT. As a benign tumor, PMT/MCT usually happens in subcutaneous tissues and leads to nonhealing of wound. A complete excision of PMT/MCT facilitates wound healing., Conclusions: Review of the existing evidence indicates that early diagnosis of PMT/MCT is critically important when treating PMT/MCT wound. Hence standardization of early diagnosis for PMT/MCT is mandated.

Phosphaturic mesenchymal tumor (PMT) is a rare mesenchymal neoplasm associated with tumor-induced osteomalacia (TIO) and elevated serum FGF-23. Common in extremities, PMT rarely occurs in sinonasal region. We report a series of sinonasal PMT diagnosed at our institute over a 6-year period. Six cases of sinonasal PMT were identified during this period, of which five presented with features of TIO. Median age of patients was 45.5 years. All six tumors were composed of stellate to spindled cells, with prominent staghorn vasculature in four cases. Typical smudgy matrix was seen in all cases, but only focally; grungy calcification was absent. Accurate diagnosis of PMTs is imperative, as complete excision leads to dramatic resolution of TIO symptoms. Lack of knowledge of this entity prevents clinicians from ordering relevant investigations. Absence of specific morphological features, like grungy calcification, and presentation at atypical locations makes the diagnosis challenging. Awareness of this entity is essential in order to suspect PMT in patients presenting with a soft tissue mass and features of TIO, however unusual the location may be., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rationale: Tumor-induced osteomalacia (TIO) is a rare and often misdiagnosed syndrome. Surgical resection is currently the first line treatment for TIO., Patient Concerns: Here we report the case of a 49-year-old woman presented with intermittent pain in the right chest and bilateral hip that had persisted for over two years., Diagnoses: She was diagnosed of TIO caused by a phosphaturic mesenchymal tumor based on the following examinations. Laboratory tests revealed high serum alkaline phosphatase, high urinary phosphorus, hypophosphatemia and normal serum calcium levels. 18-FDG PET/CT indicated a systemic multi-site symmetrical pseudo fracture and a tumor in the 7th right rib., Interventions: Curettage of the tumor was performed, and pathological analysis also confirmed our diagnoses as a phosphaturic mesenchymal tumor., Outcomes: At seven months post-surgery, the symptoms were relieved, proximal muscle strength was improved and serum levels of phosphorus and alkaline phosphatase normalized. The bilateral femoral neck and bilateral pubic bone fractures were blurred in the pelvic plain X-ray, suggesting that the fracture was healing., Lessons: This case report strengthened the importance of recognition of this rare disease to avoid delay of diagnosis and surgical removal of the causative tumor is recommended., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: After kidney transplantation, fibroblast growth factor-23 (FGF-23) normally returns to baseline within 1 year whereas hyperparathyroidism persists in most kidney transplant (KT) recipients. As a result, serum phosphate remains relatively low in association with increased serum calcium and urinary phosphate excretion when compared to chronic kidney disease patients. The relationship between mineral metabolism and outcomes in long-term KT recipients has not been extensively studied. This study investigated whether the alteration in mineral metabolism influenced graft survival in long-term KT recipients., Methods: This study included 273 KT recipients after 1 year of transplantation. Mineral parameters were obtained at the time of enrolment and patients were followed prospectively for an average of 71 months., Results: Graft loss (death-censored) occurred in 41 (15%) patients. In univariate analysis, deceased donor transplantation, decreased serum albumin and estimated glomerular filtration rate, increased serum phosphate, parathyroid hormone (PTH), FGF-23 and fractional excretion of phosphate (FePi) predicted future allograft loss. After adjustments for cardiovascular disease risk factors, donor type, dialysis vintage, serum albumin and allograft function, only increased PTH and FePi remained associated with the outcome. Relationships between increased serum phosphate and FGF-23 with graft survival were lost after adjustments. Adjusted survival curves revealed the association between PTH > 90 pg/mL and FePi > 20% with worse graft survival., Conclusions: Hyperparathyroidism and increased FePi predicted allograft loss in long-term KT recipients.

Introduction: Osteomalacia is associated with diffuse pain and multiple fractures and therefore, diagnosis and treatment of this condition are necessary. Clinicians should be aware of an uncommon mechanism of osteomalacia where hypophosphataemia is secondary to renal phosphaturia because of the production by a mesenchymal phosphaturic tumor of FGF-23. This tumor should be localized and removed to cure this tumor-induced osteomalacia., Observation: A 70-year-old female patient was admitted to explore diffuse pain caused by multiple fractures secondary to osteomalacia. Despite vitamin D supplementation, she remained profoundly hypophosphoremic with major renal phosphaturia. A tumor-induced mechanism was suspected because of high level of FGF-23. It took more than three years of investigation to spot the causal phosphaturic mesenchymal tumor despite annual repetition of indium-labelled scintigraphy and PET-scan. The resection of the tumor, located between two phalanges of the right foot, cured the patient with sustained normal rate of serum level of phosphorus after two years., Conclusion: Tumor-induced osteomalacia is a diagnostic challenge because the localization of the tumor may be a long process. Patients should be monitored clinically and imaging studies repeated until a diagnosis is made and the causal tumor removed., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Phosphate (Pi) homeostasis is regulated by renal, intestinal, and endocrine mechanisms through which Pi intake stimulates parathyroid hormone (PTH) and fibroblast growth factor-23 secretion, increasing phosphaturia. Mechanisms underlying the early adaptive phase and the role of the intestine, however, remain ill defined. We investigated mineral, endocrine, and renal responses during the first 4 hours after intravenous and intragastric Pi loading in rats. Intravenous Pi loading (0.5 mmol) caused a transient rise in plasma Pi levels and creatinine clearance and an increase in phosphaturia within 10 minutes. Plasma calcium levels fell and PTH levels increased within 10 minutes and remained low or high, respectively. Fibroblast growth factor-23, 1,25-(OH) 2 -vitamin D 3 , and insulin concentrations did not respond, but plasma dopamine levels increased by 4 hours. In comparison, gastric Pi loading elicited similar but delayed phosphaturia and endocrine responses but did not affect plasma mineral levels. Either intravenous or gastric loading led to decreased expression and activity of renal Pi transporters after 4 hours. In parathyroidectomized rats, however, only intravenous Pi loading caused phosphaturia, which was blunted and transient compared with that in intact rats. Intravenous but not gastric Pi loading in parathyroidectomized rats also led to higher creatinine clearance and lower plasma calcium levels but did not reduce the expression or activity of Pi transporters. This evidence suggests that an intravenous or intestinal Pi bolus causes rapid phosphaturia through mechanisms requiring PTH and downregulation of renal Pi transporters but does not support a role of the intestine in stimulating renal clearance of Pi., (Copyright © 2017 by the American Society of Nephrology.)

Introduction: Residual renal function (RRF) and phosphaturia had not stimulated particular interest in studies regarding patients on hemodialysis. In the current year the Authors have selected a series of patients with RRF undergoing infrequent hemodialysis treatments., Purpose: The Authors have carried out a study of the phosphate balance in patients on infrequent hemodialysis with the hypothesis that the phosphaturia was always neglected in hemodialysis patients, but it could represent a positive impact element on the cardiovascular events and mortality in hemodialysis., Methods: During 6 months, the Authors have conducted forty urine collections in 10 patients on twice a week hemodialysis (TWH) (age: 69,3 years, dialysis vintage: 42,7 months and 40.9 months on TWH) and eighty urine collections in 8 patients on once a week hemodialysis and low-protein diet (CDDP) (age: 69.6 years, dialysis vintage: 24.7 months and 24 months in CDDP) to determine RRF and phosphaturia. We compared the balance of phosphate compared with a thrice-weekly hemodialysis considering on phosphate removal: dialysis efficiency, phosphate-binders power on the protein- phosphates intake and the extent of phosphaturia., Results: The patients on infrequent hemodialysis have demonstrated a significant share of urinary phosphate output leading to a weekly phosphoric balance equal to zero or even negative., Conclusions: The phosphoric balance in infrequent hemodialysis patients is a decisive way to remove the phosphates, confirming that this factor could be decisive on the improved survival and reduced cardiovascular mortality compared to patients receiving thrice-weekly hemodialysis. The Authors stress again the need to keep as long as possible the FRR.

Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and phosphate in the proximal tubule via processes that are mediated by PGE-2.

Phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMT-MCT) are tumors that may cause tumor-induced osteomalacia and rarely appear intracranially. The authors describe the case of an 8-year-old girl who was found to have PMT-MCT with involvement of the cerebellar hemisphere and a small tumor pedicle breaching the dura mater and involving the skull. This was removed surgically in gross-total fashion without further complication. Histologically the tumor was confirmed to be a PMT-MCT. There was no evidence of tumor-induced osteomalacia. At the 42-month follow-up, the patient is doing well, has no abnormalities, and is free of recurrence. PMT-MCTs are rare tumors that may involve the brain parenchyma. A gross-total resection may be effective to cure these lesions.

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour-induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1-FGFR1 fusion gene in three out of four PMTs by next-generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT-PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1-FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia-inducing FGFR1 fusion genes, which are ligand-independent, the FN1-FGFR1 chimeric protein was predicted to preserve its ligand-binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)