Distinct phenotype of kidney stone formers with renal phosphate leak.

Background: Hypercalciuria is the most frequent metabolic disorder encountered in kidney stone formers (SF). Reduced renal phosphate reabsorption (i.e. renal phosphate leak) was proposed to be a driver of hypercalciuria in calcium SF. However, the phenotype of SF with renal phosphate leak remains poorly defined and the association of renal phosphate leak with stone history, stone composition and bone mineral density (BMD) has not been studied. Methods: To fill these knowledge gaps, we conducted a cross-sectional analysis in a cohort of 555 idiopathic calcareous SF. The ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was used to evaluate renal phosphate transport. Results: Multivariable regression analyses revealed a negative association of parathyroid hormone (PTH), a positive association of 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) but no association of fibroblast growth factor 23 (FGF23) with TmP/GFR. SF with low TmP/GFR had their first stone event at a younger age and were more likely to have a positive family history of kidney stones. In addition, urinary calcium excretion and prevalence of brushite stones were significantly higher in SF with low TmP/GFR. However, BMD, measured by dual-energy X-ray absorptiometry, was not associated with TmP/GFR in SF. Conclusions: Renal phosphate handling has a strong heritable component in SF and correlates with PTH, 25(OH)D and 1,25(OH)2D, but not with FGF23 levels. Furthermore, a low TmP/GFR (i.e. a renal phosphate leak) is associated with higher urinary calcium excretion and an increased prevalence of brushite stones.

Women have enhanced bone loss associated with phosphaturia and CD4+ cell restoration during initial antiretroviral therapy.

OBJECTIVE: We compared bone mineral density (BMD) changes and their correlates, between men and women participating in two randomized trials of initial [antiretroviral therapy (ART)] regimens, with or without tenofovir disoproxil fumarate (TDF). METHODS: Covariates in linear regression models of 48-week hip and spine %BMD changes, by dual energy X-ray absorptiometry, included baseline and 48-week changes in plasma viral load, CD4 cells, plasma C-terminal telopeptide, procollagen 1 N-terminal propeptide and glomerular filtration rates, and the 48-week area under the curve of fractional excretion of phosphate. RESULTS: Despite overall hip and spine BMD declines of 2.8 and 2.9%, respectively, plasma viral load suppression to less than 50 vs. at least 50 copies/ml was associated 1.0% (P = 0.02) and 0.8% (P = 0.01) less BMD decline. Women had lower baseline spine (P = 0.04; n = 59 women, 418 men) and hip BMD (P = 0.01) in adjusted models, with 1.7% more hip decline on ART than men (P = 0.001). Serum phosphate was positively associated with baseline spine BMD in women (P = 0.03) but not men, and area under the curve of fractional excretion of phosphate was negatively associated with spine BMD changes, particularly in women randomized to TDF regimens (P = 0.03 and 0.054 for interactions by sex, and randomization to TDF vs. non-TDF regimens, respectively; n = 44 women, 326 men). Women also had 0.6% (P = 0.004) more hip BMD decline than men associated with each 100 CD4 cells/µl increase on ART (P = 0.02; n = 49 women, 379 men). CONCLUSION: Women randomized to TDF-containing ART had accentuated spine loss associated with phosphaturia, and accentuated hip loss associated with CD4 restoration, regardless of TDF exposure. Viral load suppression reduced bone loss.

Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications.

OBJECTIVE: Hereditary hypophosphatemias (HH) are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response, and complications of treatment in the Norwegian population of children with HH. DESIGN: Retrospective national cohort study. METHODS: Sanger sequencing and multiplex ligand-dependent probe amplification analysis of PHEX and Sanger sequencing of FGF23, DMP1, ENPP1KL, and FAM20C were performed to assess genotype in patients with HH with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family, exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype. RESULTS: Twety-eight patients with HH (18 females and ten males) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by 1st January 2010 was 1,109,156, giving an XLHR prevalence of ∼1 in 60,000 Norwegian children. FAM20C mutations were found in two brothers and SLC34A3 mutations in one patient. In XLHR, growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis tended to be slightly more common in patients starting treatment before 1 year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance. CONCLUSIONS: We present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.

Thoracic phosphaturic mesenchymal tumors causing oncogenic osteomalacia.

Oncogenic osteomalacia is a rare paraneoplastic syndrome induced by mesenchymal tumors. Just over 100 cases have been reported for this rare disorder, and only seven instances were caused by phosphaturic mesenchymal tumors of the spine. The authors present an illustrative case of a 61-year-old woman with oncogenic osteomalacia induced by a tumor of the spine, and review the literature describing the clinical presentation, surgical treatment, and follow-up of this syndrome.

Fractional excretion of phosphorus modifies the association between fibroblast growth factor-23 and outcomes.

Fibroblast growth factor-23 (FGF23) induces phosphaturia through its effects on renal tubules. Higher levels of FGF23 associate with cardiovascular disease (CVD) events and all-cause mortality, but it is unknown whether these associations differ by the degree of phosphaturia. Here, we measured serum FGF23 and 24-hour urine fractional excretion of phosphorus (FePi) in 872 outpatients with stable CVD and a mean estimated GFR of 71 ml/min per 1.73 m(2). During an average 7.5 years of follow-up, there were 337 deaths and 199 CVD events. Urinary FePi significantly modified the association of FGF23 with each outcome (P interaction<0.001 for all-cause mortality and P interaction<0.05 for CVD events). In models adjusted for CVD risk factors, kidney function, and PTH, those patients who had FGF23 above the median (≥ 42.3 relative units [RU]/ml) but FePi below the median (<15.7%) had the highest risks of both all-cause mortality (HR=1.98, 95% CI=1.42-2.77) and CVD events (HR=1.92, 95% CI=1.25-2.94) compared with those patients who had low concentrations of FGF23 and low FePi. In summary, associations of FGF23 with mortality and CVD events are stronger in persons with lower FePi independent of PTH and kidney function. In such individuals, the renal tubular response to FGF23 may be suboptimal.

Demography and biochemistry of 2800 patients from a renal stones clinic.

BACKGROUND: Because the causes of stones are uncertain, interventions to prevent recurrence have an insecure foundation. Progress depends on careful evaluation of stone formers. METHODS: A descriptive retrospective database study of 1983 men and 816 women from the Southampton stones clinic from 1990 to March 2007. Anonymized data from the first attendance were analysed using non-parametric statistical tests. RESULTS: Sex ratio (2.43:1), age (median 49 y, 2.5th-97.5th percentiles, 23-77 y men, 20-79 y women), recurrent stone formers (30%) and type of stone were similar to other centres. Women more often had a positive family history (24% versus 19% men), previous urinary infection (31% versus 5%) and structural urinary tract abnormality (14% versus 7%); more men had gout (5% versus 1%) and bladder outlet obstruction (3% versus <1%). Calcium, oxalate and uric acid excretion were increased in 43%, 17% and 22% respectively of men and 31%, 7% and 10% of women. Urinary calcium, oxalate and uric acid correlated significantly, r ranging from 0.149 to 0.311 for 24 h excretion and 0.510 to 0.695 for concentrations per litre. Twenty-two percent of men and 8% of women with normal parathyroid hormone had phosphaturia (excretion of phosphate corrected for glomerular filtration rate (TmPO4/GFR) < 0.70 mmol/L); 6% men and 1.6% women also had low plasma phosphate. Many variables correlated significantly but often weakly with age. Creatinine clearance, pH and (men) TmPO4/GFR decreased from 50 y, urine creatinine, calcium and citrate from 60 y. CONCLUSIONS: Risk factors for stones differ between men and women, change with ageing and in some may have a genetic basis. The role of phosphaturia merits further exploration.

Diagnosis of phosphaturic mesenchymal tumor (mixed connective tissue type) by cytopathology.

Oncogenic osteomalacia (OO) is a rare paraneoplastic condition in which a bone or soft tissue tumor induces biochemical and clinical signs and symptoms of osteomalacia (or rickets) most often by the production of the phosphaturic protein, fibroblast growth factor-23. Phosphaturic mesenchymal tumor, mixed connective tissue type (PMTMCT) is a rare, histologically distinct tumor that represents the most common cause of OO. As the clinical diagnosis of OO is typically suspected on the basis of clinical and biochemical features and the presence of a bone or soft tissue tumor, cytologic examination might potentially provide the necessary pathologic confirmation of OO. In this case of a 46-year-old female with clinical stigmata of OO and a right distal humeral mass, we report that the fine-needle aspiration findings of short, cytologically bland spindled cells embedded in a fine, fibrillary stromal-rich matrix and the presence of osteoclast-type giant cells associated with the stromal matrix provide strong pathological evidence for PMTMCT and assist in pathologically confirming the clinical impression of OO, thus alleviating the need for a more invasive diagnostic surgical procedure.

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies.

Refractory rickets in the tropics.

Rickets is an important problem in children. The majority of rickets in children is due to deficiency of calcium, phosphorus or vitamin D. However, rickets may also be a feature of renal diseases, e.g. renal tubular acidosis, hypophosphatemic rickets or rickets associated with renal insufficiency. The treatment varies with etiology and hence complete workup is essential before initiating therapy.

[Oncogenic osteomalacia due to phosphaturic mesenchymal tumour in infratemporal fossa]. / Osteomalacia oncogénica por tumor mesenquimal fosfatúrico en fosa infratemporal.

Oncogenic osteomalacia is an uncommon syndrome characterized by phosphaturic tumours that produce mineral metabolism abnormalities. Head and neck is the second most frequent location of these tumours. We describe a case of a phosphaturic mesenchymal tumour in the infratemporal fossa that caused oncogenic osteomalacia, resolved by means of surgical excision.

Clinical manifestations and etiology of renal stones in children less than 14 years age.

Urolithiasis is one of the commonest problems in pediatric nephrology. Prevalence of urolithiasis in pediatric patients is increasing. The purpose was to properly diagnose and treat with the special attention to the risk factors. This study is case-series and was performed on 100 pediatric patients for evaluation of clinical manifestation and etiology of renal stone in Qom. Hundred Children, fewer than 14 years old with mean age of 3.32 years, were included (54% male). Etiology of urolithiasis in 5% was unclear. Metabolic disorders found in patients were mainly: Hypocitraturia in 54, hyperoxaluria in 14, hyperuricosuria in 25, cystinuria in 6, hypercalciuria in 28 and phosphaturia in 8 patients. The main clinical presentation was fever, pain, irritability, dysuria and hematuria. Family history of urolithiasis was found in 23% of patients and 54% presented with urinary tract infection (UTI). We conclude that majority of patients were symptomatic and hypocitraturia was the commenest risk factor among others.

Identification of a novel dentin matrix protein-1 (DMP-1) mutation and dental anomalies in a kindred with autosomal recessive hypophosphatemia.

An autosomal recessive form of hypophosphatemia (ARHP) was recently shown to be caused by homozygous mutations in DMP1, the gene encoding dentin matrix protein-1 (DMP-1), a non-collagenous bone matrix protein with an important role in the development and mineralization of bone and teeth. Here, we describe a previously not reported consanguineous ARHP kindred in which the three affected individuals carry a novel homozygous DMP-1 mutation. The index case presented at the age of 3 years with bowing of his legs and showed hypophosphatemia due to insufficient renal phosphate retention. Serum alkaline phosphatase activity was elevated, with initially normal PTH. FGF23 was inappropriately normal at an older age while being treated with oral phosphate and 1,25(OH)(2)D. Similar clinical and biochemical findings, except for elevated FGF23 levels, were present in his 16-month-old brother and his 12.5-year-old female cousin; the parents of the three affected children are first-degree cousins. Nucleotide sequence analysis was performed on PCR-amplified exons encoding DMP-1 and flanking intronic regions. A novel homozygous frame-shift mutation (c.485Tdel; p.Glu163ArgfsX53) in exon 6 resulting in a premature stop codon was identified in all effected individuals. The parents and available unaffected siblings were heterozygous for c.485Tdel. Tooth growth and shape were normal for the index case, his affected brother and cousin, but their permanent and deciduous teeth displayed enlarged pulp chambers. The identified genetic mutation underscores the importance of DMP-1 mutations in the pathogenesis of ARHP. Furthermore, DMP-1 mutations appear to contribute, through yet unknown mechanisms, to tooth development.

Defective O-glycosylation due to a novel homozygous S129P mutation is associated with lack of fibroblast growth factor 23 secretion and tumoral calcinosis.

BACKGROUND: Homozygous mutations in fibroblast growth factor (FGF23) have recently been described as the genetic cause of one form of hyperphosphatemic tumoral calcinosis (HFTC). However, it remained unclear to date how these mutations lead to loss of biologically active FGF23 in the circulation. METHODS: We here report a novel homozygous mutation, c.385T>C in FGF23 exon 2, which changes codon 129 from serine to proline (S129P) in a previously described individual affected by HFTC. The S129P mutation as well as two known FGF23 mutations, S71G and S129F, were introduced into an expression vector encoding wild-type (wt) human (h) FGF23 to yield [P129]hFGF23, [F129]hFGF23, and [G71]hFGF23; whole lysates, glycoprotein fractions, and conditioned media from HEK293 and COS-7 cells expressing these constructs were subjected to Western blot analysis using affinity-purified goat anti-hFGF23(51-69) and anti-hFGF23(206-222) antibodies. RESULTS: We detected 25- and 32-kDa protein species in total lysates of HEK293 cells expressing wt-hFGF23. The 32-kDa band, representing O-glycosylated hFGF23, was not detectable in the glycoprotein fraction of lysates from HEK293 cells expressing [P129]hFGF23, and in comparison with wt-FGF23 only small amounts of [P129]hFGF23 were secreted into the medium. Similar results were obtained for cells expressing [G71]hFGF23 and [F129]hFGF23. CONCLUSION: Our data for the first time directly show that FGF23 mutations associated with HFTC impair O-glycosylation in vitro resulting in poor secretion of the mutant hormone thereby explaining the characteristic hyperphosphatemic phenotype of homozygous carriers in vivo.