Renal Phosphate Loss Research Articles

Genetic Causes of Rickets.

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.

Phosphaturic Mesenchymal Tumors: Clinicopathologic, Immunohistochemical and Molecular Analysis of 22 Cases Expanding their Morphologic and Immunophenotypic Spectrum.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm of uncertain histogenesis that has been linked to tumor-induced osteomalacia (TIO) since 1959. The neoplastic cells produce increased amount of FGF23 which results in TIO via uncontrolled renal loss of phosphate (phosphaturia), and consequently diminished bone mineralization. To date, ∼300 cases have been reported. Although there is increasing evidence that PMT can be diagnosed by reproducible histopathologic features, firm diagnosis has been often restricted to cases associated with TIO and, hence, diagnosis of "nonphosphaturic variants" remained challenging. Recently, FGFR1/FN1 gene fusions were detected in roughly half of cases. We herein reviewed the clinicopathologic features of 22 PMTs (15 cases not published before), stained them with an extended immunohistochemical marker panel and examined them by fluorescence in situ hybridization for FGFR1 gene fusions. Patients were 12 males and 9 females (one of unknown sex) aged 33 to 83 years (median: 52 y). Lesions affected the soft tissues (n=11), bones (n=6), sinonasal tract (n=4), and unspecified site (n=1). Most lesions originated in the extremities (9 in the lower and 4 in the upper extremities). Acral sites were involved in 10 patients (6 foot/heel, 3 fingers/hands, and 1 in unspecified digit). Phosphaturia and TIO were recorded in 10/11 and 9/14 patients with detailed clinical data, respectively. Limited follow-up (5 mo to 14 y; median: 16 mo) was available for 14 patients. Local recurrence was noted in one patient and metastasis in another patient. Histologically, 11 tumors were purely of conventional mixed connective tissue type, 3 were chondromyxoid fibroma-like, 2 were hemangio-/glomangiopericytoma-like with giant cells, and 1 case each angiomyolipoma-like and reparative giant cell granuloma-like. Four tumors contained admixture of patterns (predominantly cellular with variable conventional component). Immunohistochemistry showed consistent expression of CD56 (11/11; 100%), ERG (19/21; 90%), SATB2 (19/21; 90%), and somatostatin receptor 2A (15/19; 79%), while other markers tested negative: DOG1 (0/17), beta-catenin (0/14), S100 protein (0/14), and STAT6 (0/7). FGFR1 fluorescence in situ hybridization was positive in 8/17 (47%) evaluable cases. These results add to the phenotypic delineation of PMT reporting for the first time consistent expression of SATB2 and excluding any phenotypic overlap with solitary fibrous tumor or sinonasal glomangiopericytoma. The unifying immunophenotype of the neoplastic cells irrespective of the histologic pattern suggests a specific disease entity with diverse morphotypes/variants rather than different neoplasms unified by TIO.

Hypophosphatemia in Critically Ill Children: Risk Factors, Outcome and Mechanism.

To determine the prevalence of hypophosphatemia in critically ill children and its association with clinical outcomes; to determine risk factors and mechanism of hypophosphatemia. Levels of serum phosphate, phosphate intake, renal phosphate handling indices and blood gases were measured on days 1, 3, 7 and 10 of pediatric intensive care unit (PICU) stay. Hypophosphatemia was defined as any serum phosphorus <3.8mg/dl for children younger than 2y and <3.5mg/dl for children 2y or older. Renal phosphate loss was assessed using the ratio of tubular maximum reabsorption of phosphate (TmP) to glomerular filtration rate (GFR) [TmP/GFR]. Prevalence of hypophosphatemia was 71.6% (95% CI: 64.6-78.6). On adjusted analysis, hypophosphatemia was associated with prolonged PICU length of stay (PICU LOS>6d) (adjusted OR: 3.0 [95% CI: 1.4-6.7; p=0.005]) but not associated with increased mortality. Renal phosphate threshold was significantly lower on all the days in hypophosphatemic group compared to that of non-hypophosphatemic group. No statistically significant difference in the amount of phosphate intake was seen in both the groups. Hypophosphatemia is highly prevalent in critically ill children and is associated with prolonged PICU LOS. Increased phosphate loss in urine is one of the mechanism responsible for hypophosphatemia in critically ill children.

Phosphaturic mesenchymal tumors. Survey of 8 cases from a single Mexican medical institution

Phosphaturic mesenchymal tumor (PMT) is a morphologically heterogeneous soft tissue and bone neoplasm, producing a paraneoplastic syndrome due to phosphate wasting. These tumors produce fibroblast growth factor 23, which is implicated in renal tubule phosphate loss. Medical records of patients seen from 1999 to 2013 with osteomalacia associated or not with a tumor were reviewed. Clinical and laboratory data, radiographic studies, and follow-up of 8 patients were tabulated. Histologic features and the immunoprofile of the tumors were analyzed. There were 208 patients with osteomalacia, but only 8 (3.84%) had osteomalacia associated with a tumor. The median age of the patients was 40 years. The tumor size ranged from 1.5 to 4 cm. Five were located in soft tissues and skin; and 3, in bones. Osteomalacia symptoms lasted from 2 to 14 years with a median of 6 years. Laboratory data showed hypophosphatemia and phosphaturia in all patients. All tumors were histologically benign. Histologically, the salient features were a hemangiopericytoid pattern, chronic hemorrhage, and microcystic areas. All neoplasms were diffusely positive for vimentin and focally positive for epithelial membrane antigen, CD34, and S-100 protein. Ki-67 was positive in approximately 10% of neoplastic cells in 2 cases and less than 1% in the remainder. We report 8 cases of PMTs producing osteomalacia, from a single third-level Mexican medical institution. These tumors occurred in soft tissues, skin, and bones. All tumors were benign, small, not easily detected by physical examination and diagnosed due to the metabolic abnormalities.

Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets

ContextHypophosphatemic rickets (HR) is a rare disease that includes a group of hereditary and sporadic conditions characterized by renal phosphate loss associated with normal to low vitamin D serum concentration. The most common form is the X-linked hypophosphatemic rickets, with an incidence of 1:20,000. Several mutations have recently been identified in the PHEX, FGF23, DMP1 and ENPP1 genes in patients with HR. Moreover, in vitro and in vivo studies suggested an involvement of MEPE for defective mineralization in HR. ObjectiveThe present case series describes the clinical features and the analysis of genes implicated in HR in a cohort of 26 Italian HR patients. Setting and designAll patients were analyzed for the PHEX and FGF23 genes by direct sequencing. When no mutations were detected, Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed. The negative patients were screened for the DMP1, MEPE and ENPP1 genes by direct sequencing. ResultsTwenty-two patients (84%) harbored mutations in the PHEX gene. In particular, we detected 19 different mutations, 15 of which were novel. One patient presented a novel splice variation in the ENPP1 gene while no alterations were identified in the FGF23, DMP1 and MEPE genes. The genetic study of the families showed that 11 patients (55%) had de novo mutations. Clinical presentation and disease severity did not show an evident correlation between the mutation types. ConclusionsThis report represents the first large familial study performed on Italian patients. It confirms that mutations in PHEX are the most frequent cause of HR. Furthermore, the variety of clinical manifestations identified in our HR patients underlines the extreme clinical and genetic heterogeneity of this disease.

Mineral and bone disorder after kidney transplantation.

After successful kidney transplantation, accumulated waste products and electrolytes are excreted and regulatory hormones return to normal levels. Despite the improvement in mineral metabolites and mineral regulating hormones after kidney transplantation, abnormal bone and mineral metabolism continues to present in most patients. During the first 3 mo, fibroblast growth factor-23 (FGF-23) and parathyroid hormone levels decrease rapidly in association with an increase in 1,25-dihydroxyvitamin D production. Renal phosphate excretion resumes and serum calcium, if elevated before, returns toward normal levels. FGF-23 excess during the first 3-12 mo results in exaggerated renal phosphate loss and hypophosphatemia occurs in some patients. After 1 year, FGF-23 and serum phosphate return to normal levels but persistent hyperparathyroidism remains in some patients. The progression of vascular calcification also attenuates. High dose corticosteroid and persistent hyperparathyroidism are the most important factors influencing abnormal bone and mineral metabolism in long-term kidney transplant (KT) recipients. Bone loss occurs at a highest rate during the first 6-12 mo after transplantation. Measurement of bone mineral density is recommended in patients with estimated glomerular filtration rate > 30 mL/min. The use of active vitamin D with or without bisphosphonate is effective in preventing early post-transplant bone loss. Steroid withdrawal regimen is also beneficial in preservation of bone mass in long-term. Calcimimetic is an alternative therapy to parathyroidectomy in KT recipients with persistent hyperparathyroidism. If parathyroidectomy is required, subtotal to near total parathyroidectomy is recommended. Performing parathyroidectomy during the waiting period prior to transplantation is also preferred in patients with severe hyperparathyroidism associated with hypercalcemia.

Genetic diseases of renal phosphate handling.

Renal control of systemic phosphate homeostasis is critical as evident from inborn and acquired diseases causing renal phosphate wasting. At least three transport proteins are responsible for renal phosphate reabsorption: NAPI-IIa (SLC34A1), NAPI-IIc (SLC34A3) and PIT-2 (SLC20A2). These transporters are highly regulated by various cellular mechanisms and factors including acid-base status, electrolyte balance and hormones such as dopamine, glucocorticoids, growth factors, vitamin D3, parathyroid hormone and fibroblast growth factor 23 (FGF23). Whether renal phosphate wasting is caused by inactivating mutations in the NAPI-IIa transporter is controversial. Mutations in the NAPI-IIc transporter cause hereditary hypophosphatemic rickets with hypercalciuria. Besides the primary inherited defects, there are also inherited defects in major regulators of phosphate homeostasis that lead to alterations in phosphate handling. Autosomal dominant hypophosphatemic rickets is due to FGF23 mutations leading to resistance against its own degradation. Similarly, inactivating mutations in the PHEX gene, which causes FGF23 inactivation, cause X-linked hypophosphatemia due to renal phosphate losses. In contrast, mutations in galactosamine:polypeptide N-acetyl-galactosaminyltransferase, responsible for O-glycosylation of FGF23, or in klotho, a cofactor for FGF23 signalling result in hyperphosphatemia. Acquired syndromes of renal phosphate wasting, hypophosphatemia and osteomalacia (tumour-associated osteomalacia) can be due to the excessive synthesis or release of phosphaturic factors (FGF23, FGF-7, MEPE and sFRP4) from mesenchymal tumours. bone, FGF23, kidney, phosphate, PTH.

Osteomalacia Induced by Adefovir in Patient With Hepatitis B

Osteomalacia is defined as a defect in mineralization of the bone matrix. We describe the case of a patient with chronic hepatitis B infection in whom treatment with adefovir induced renal phosphate loss with intense and sustained hypophosphatemia which derived in symptomatic osteomalacia.

Incidence and aetiology of renal phosphate loss in patients with hypophosphatemia in the intensive care unit

Hypophosphatemia is a common finding in patients in the intensive care unit (ICU). Its cause is often poorly understood. The aim of this study was to understand the incidence of renal phosphate loss in ICU-related hypophosphatemia, and to examine the role of phosphaturic hormones in its etiology. Plasma phosphate levels were measured on day 1, 3, 5 and 7 in 290 consecutive patients admitted to the ICU. Renal phosphate handling and phosphaturic hormones were studied in a subset of patients with phosphate levels <0.6 mmol/L. Renal phosphate loss was defined as a TmP/gfr < 0.6 mmol/L. Hypophosphatemia developed in 24% of all patients. This mainly occurred within the first 3 days of stay and in patients with serum creatinine levels <150 μmol/L. Renal phosphate loss was present in 80% of patients who developed hypophosphatemia, and was not related to serum levels of parathyroid hormone (PTH), PTH-related protein (PTH-rp), fibroblast growth factor 23 (FGF-23), or calcitonin. Hypophosphatemia in the ICU is commonly associated with renal phosphate loss. It mainly occurs within the first 3 days of admission, in particular in patients with preserved renal function. Renal phosphate loss is not explained by elevated PTH, PTH-rp, FGF-23 or calcitonin levels.

Osteomalacia inducida por adefovir en paciente con hepatitis B

Osteomalacia is defined as a defect in mineralization of the bone matrix. We describe the case of a patient with chronic hepatitis B infection in whom treatment with adefovir induced renal phosphate loss with intense and sustained hypophosphatemia which derived in symptomatic osteomalacia.

Hypophosphatemia on the intensive care unit: Individualized phosphate replacement based on serum levels and distribution volume

BackgroundHypophosphatemia occurs in about 25% of patients admitted to the intensive care unit. To date, a safe and validated phosphate replacement protocol is not available. ObjectiveTo evaluate an individualized phosphate replacement regimen. DesignFifty consecutive intensive care unit patients with a serum phosphate level <0.6 mmol/L were treated with sodium-potassium-phosphate intravenously at a rate of 10 mmol/h. The dose was calculated according to the following equation: Phosphate dose in mmol = 0.5 × Body Weight × (1.25 – [serum Phosphate]). Phosphate levels were measured immediately upon completion of the infusion, as well as the next morning at 8 am. ResultsPost-infusion phosphate levels were >0.6 mmol/L in 98% of the patients. Hyperphosphatemia, hyperkalemia or a decrease in serum calcium were not observed. In about a third of patients serum phosphate decreased to <0.6 mmol/L within the next 24 hours after infusion. The phosphate distribution volume calculated from the results of infusion and corrected for renal phosphate loss during the infusion period was 0.51 L/kg (95% CI 0.42–0.61 L/kg). ConclusionThis study shows that phosphate replacement with dose calculation based on serum phosphate levels and a Vd of 0.5 L/kg is effective and safe.

Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice

X-linked hypophosphatemic rickets (XLH) is a genetic disorder caused by mutational inactivation of the PHEX gene, encoding a transmembrane endopeptidase expressed in osteoblasts. Since several experiments involving Phex-deficient Hyp mice have demonstrated that an increased expression of Fgf23 in osteoblasts is causative for the renal phosphate loss characteristic of XLH, we performed genome-wide expression analysis to compare differentiated osteoblasts from wildtype and Hyp mice. Here we did not only observe the expected increase of Fgf23 expression in the latter ones, but also a differential expression of genes that are either induced by or involved in retinoic acid signaling, which led us to analyze whether dietary retinol deprivation would influence the phenotype of Hyp mice. Unexpectedly, feeding a retinol-free diet resulted in a partial rescue of the growth plate and bone mineralization defects in 6weeks old Hyp mice. When we fed the same diet for 24weeks the amount of non-mineralized bone matrix (osteoid) was reduced by more than 70%, although phosphate homeostasis was unaffected. In contrast, a dietary normalization of serum phosphate levels in Hyp mice reduced the osteoid amount by less than 30%, thereby demonstrating a previously unknown impact of retinol on the cell-autonomous mineralization defect of Phex-deficient osteoblasts.

Treatment of Calcium and Vitamin D Deficiency in HIV-Positive Men on Tenofovir-Containing Antiretrovial Therapy

Background: Hypophosphatemia and bone disease are common in HIV-positive (HIV+) patients on tenofovir disoproxil fumarate–containing antiretroviral therapy (TDF-containing ART). The underlying etiology is not completely understood. Objective: To examine the effects of treatment of calcium and vitamin D deficiency on phosphate metabolism and bone disease in HIV+ patients on tenofovir. Methods: This was an open-label, pilot study of calcium and phosphate metabolism, bone turnover, and bone density in 24 HIV+ patients on TDF, who were receiving a 1-year treatment for vitamin D and/or calcium deficiency according to a predefined protocol. Eight patients without calcium or vitamin D deficiency served as controls. Results: One-year treatment improved vitamin D levels, decreased serum parathyroid hormone (PTH), and improved calcium balance and bone mineral density. It did not affect the serum levels of PTH-related peptide (PTH-rp) or fibroblast growth factor 23 (FGF-23) nor did it raise serum phosphate levels or decrease renal phosphate loss. Conclusion: Treatment of calcium or vitamin D deficiency in HIV+ patients on ART including TDF has favorable effects on bone density, but it does not improve serum phosphate levels. Renal phosphate wasting in these patients is not caused by excess PTH, PTH-rp, or FGF-23 nor by vitamin D or calcium deficiency.

Oncogenic osteomalacia and its symptoms: hypophosphatemia, bone pain and pathological fractures

Oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome induced by tumor produced phosphaturic factors, i.e. phosphatonins. The disorder is characterized by renal tubular phosphate loss, secondary to this process hypophosphatemia and defective production of active form of vitamin D. The clinical course of oncogenic osteomalacia is characterized by bone pain, pathological fractures, muscle weakness and general fatigue. Osteomalacia-associated tumors are usually located in the upper and lower limbs, with half of the lesions primarily situated in the bones. Most of them are small, slow-growing tumors. Their insignificant size and various location coupled with rare occurrence of the disease and non-specificity of clinical symptoms lead to difficulties in reaching a diagnosis, which is often time-consuming and requires a number of additional tests. The average time between the appearance of the first symptoms and the establishment of an accurate diagnosis and the beginning of treatment is over 2.5 years. The aim of this study is to discuss the pathophysiology of disease symptoms, pathomorphology of tumors, diagnostic methods and treatment of oncogenic osteomalacia.

A New Human NHERF1 Mutation Decreases Renal Phosphate Transporter NPT2a Expression by a PTH-Independent Mechanism

BackgroundThe sodium-hydrogen exchanger regulatory factor 1 (NHERF1) binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule.MethodsWe compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production.ResultsWe identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A) located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a.ConclusionsOur results indicate that the PDZ1 domain is critical for NHERF1- NPT2a interaction in humans and for the control of NPT2a expression at the plasma membrane. Thus we have identified a new mechanism of renal phosphate loss and shown that different mutations in NHERF1 can alter renal phosphate reabsorption via distinct mechanisms.

Rickets-vitamin D deficiency and dependency.

Rickets is an important problem even in countries with adequate sun exposure. The causes of rickets/osteomalacia are varied and include nutritional deficiency, especially poor dietary intake of vitamin D and calcium. Non-nutritional causes include hypophosphatemic rickets primarily due to renal phosphate losses and rickets due to renal tubular acidosis. In addition, some varieties are due to inherited defects in vitamin D metabolism and are called vitamin D dependent rickets. This chapter highlights rickets/osteomalacia related to vitamin D deficiency or to inherited defects in vitamin D metabolism. Hypophosphatemic rickets and rickets due to renal tubular acidosis are discussed in other sections of the journal.

Renal Phosphate Loss in Long-Term Kidney Transplantation

Renal phosphate wasting occurs early postkidney transplantation as a result of an accumulation of parathyroid hormone and fibroblast growth factor 23 from the CKD period. Serum phosphate, parathyroid hormone, and fibroblast growth factor 23 return to baseline 1 year postkidney transplantation. What happens beyond this period is unknown. Mineral parameters were obtained from 229 kidney transplant recipients at least 1 year posttransplantation; 46 normal subjects and 202 CKD patients with similar GFR served as controls. Factors associated with phosphate metabolism were analyzed. Despite the reduced graft function, most kidney transplant recipients had lower serum phosphate than normal subjects accompanied by renal phosphate loss. Fibroblast growth factor 23 was mostly lower or comparable with normal subjects, whereas parathyroid hormone was elevated in most patients. Hyperparathyroidism is also more common among kidney transplant recipients compared with CKD patients. Both parathyroid hormone and fibroblast growth factor 23 showed relationships with renal phosphate excretion, but only parathyroid hormone displayed an independent association. Parathyroid hormone showed the highest area under the curve in predicting renal phosphate leak. When patients were categorized according to parathyroid hormone and fibroblast growth factor 23 levels, only subset of patients with high parathyroid hormone had an increased renal phosphate excretion. Relatively low serum phosphate from renal phosphate leak continued to present in long-term kidney transplantation. Both parathyroid hormone and fibroblast growth factor 23 participated in renal tubular phosphate handling, but persistent hyperparathyroidism seemed to have a greater influence in this setting.

PKB/SGK-Resistant GSK3 Enhances Phosphaturia and Calciuria

Insulin and IGF1-dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase (PKB/SGK), which together phosphorylate and inactivate glycogen synthase kinase GSK3. Because insulin and IGF1 increase renal tubular calcium and phosphorus reabsorption, we examined GSK3 regulation of phosphate transporter activity and determined whether PKB/SGK inactivates GSK3 to enhance renal phosphate and calcium transport. Overexpression of GSK3 and the phosphate transporter NaPi-IIa in Xenopus oocytes decreased electrogenic phosphate transport compared with NaPi-IIa-expressing oocytes. PKB/SGK serine phosphorylation sites in GSK3 were mutated to alanine to create gsk3(KI) mice resistant to PKB/SGK inactivation. Compared with wildtype animals, gsk3(KI) animals exhibited greater urinary phosphate and calcium clearances with higher excretion rates and lower plasma concentrations. Isolated brush border membranes from gsk3(KI) mice showed less sodium-dependent phosphate transport and Na-phosphate co-transporter expression. Parathyroid hormone, 1,25-OH vitamin D levels, and bone mineral density were decreased in gsk3(KI) mice, suggesting a global dysregulation of bone mineral metabolism. Taken together, PKB/SGK phosphorylation of GSK3 increases phosphate transporter activity and reduces renal calcium and phosphate loss.

Phosphaturic mesenchymal tumor of spinal nerve in a patient with osteomalacia and multiple fractures

Osteomalacia associated with a neoplasm (oncogenic osteomalacia, OO) is a rare and unusual paraneoplastic syndrome that subsides after complete tumor resection. It results from hypophosphatemia due to renal phosphate loss [6]. OO was originally reported by McCance in 1947 in a patient with a femoral tumor, while Prader et al. described its direct correlation with giant cell reparative granuloma of the rib [3]. The term phosphaturic mesenchymal tumor (PMT) was proposed by Weidner and Santa Cruz [7] in 1987 and the largest series was reported by Folpe et al. [3] in 2004. OO depends on tumor secretion of phosphatonins. Fibroblast growth factor-23 (FGF23), which is expressed in almost 90% of PMTs, plays a significant role in the pathogenesis of OO [3]. We report a 56-year-old female with osteomalacia and multiple fractures associated with PMT developing within the Th5 nerve. Laboratory examination disclosed hypophosphatemia (1.9 mg/dl), elevated serum alkaline phosphatase activity (217 U/l), and normal serum calcium level (9.07 mg/dl). Parathyroid and thyroid gland dysfunction and multiple myeloma were excluded as a potential cause of the osteolysis. CT and MRI scans revealed an extradural spindle lesion measuring 30 9 22 mm within the confines of the Th5 nerve. It compressed the meninges and the spinal cord (Fig. 1). The tumor was resected with the surgical diagnosis of neurofibroma. After surgery, blood concentrations of calcium and phosphate gradually returned to normal levels. In the following 6 months the bone lesions receded. Morphologically, the tumor was delivered in pieces measuring up to 1 cm in the largest diameter. Microscopically, cellular areas of the tumor were intermingled with hypocellular ones (Fig. 2a). The tumor cells were monomorphous with bland nuclei (Fig. 2b). Small spindle cells were arranged in a storiform pattern. Small conglomerates of tumor cells were surrounded by a network of capillaries, but larger angulated vessels were also present. The hypocellular areas were rich in eosinophilic matrix with

Mechanisms of Renal Phosphate Loss in Liver Resection-Associated Hypophosphatemia

To determine precisely the role of parathyroid hormone (PTH) and of phosphatonins in the genesis of posthepatectomy hypophosphatemia. Posthepatectomy hypophosphatemia has recently been related to increased renal fractional excretion of phosphate (FE P). To address the cause of hypophosphatemia, we measured serum concentrations of PTH, various phosphatonins, and the number of removed hepatic segment in patients with this disorder. Serum phosphate (PO4), ionized calcium (Ca++), HCO3-, pH and FE P, intact PTH (I-PTH), carboxyl-terminal fibroblast growth factor 23 (C-FGF-23) and intact fibroblast growth factor 23 (I-FGF-23), FGF-7, and secreted frizzled related-protein-4 (sFRP-4) were measured before and on postoperative (po) days 1, 2, 3, 5, and 7, in 18 patients undergoing liver resection. The number of removed hepatic segments was also assessed. Serum PO4 concentrations decreased within 24 hours, were lowest (0.66 +/- 0.03 mmol/L; P < 0.001) at 48 hours, and returned to normal within 5 days of the procedure. FE P peaked at 25.07% +/- 2.26% on po day 1 (P < 0.05). Decreased ionized calcium concentrations (1.10 +/- 0.01 mmol/L; P < 0.01) were observed on po day 1 and were negatively correlated with increased I-PTH concentrations (8.8 +/- 0.9 pmol/L; P < 0.01; correlation: r = -0.062, P = 0.016). FE P was positively related to I-PTH levels on po day 1 (r = 0.52, P = 0.047) and negatively related to PO4 concentrations (r = -0.56, P = 0.024). Severe hypophosphatemia and increased urinary phosphate excretion persisted for 72 hours even when I-PTH concentrations had returned to normal. I-FGF-23 decreased to its nadir of 7.8 +/- 6.9 pg/mL (P < 0.001) on po day 3 and was correlated with PO4 levels on po days 0, 3, 5, and 7 (P < 0.001). C-FGF-23, FGF-7 and sFRP-4 levels could not be related to either PO4 concentrations or FE P. Posthepatectomy hypophosphatemia is associated with increased FE P unrelated to I-FGF-23 or C-FGF-23, FGF-7, or sFRP-4. I-PTH contributes to excessive FE P partially on po day 1 but not thereafter. Other yet defined factors should explain post hepatectomy hypophosphatemia.