X-linked hypophosphatemia: Management and treatment prospects.

X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life. Treatment options include active vitamin D analogs and phosphate supplementation to correct the 1.25(OH)2 vitamin D deficiency and to compensate for the renal phosphate wasting, respectively. The recently introduced FGF23 antagonist burosumab is designed to restore renal phosphate reabsorption by the proximal tubule and to stimulate endogenous calcitriol production. In Europe, burosumab is licensed for use in pediatric patients older than 1 year who have XLH. This review discusses the diagnosis and treatment of XLH and describes the indications of the various available treatments.

Increased Phosphaturia Accelerates The Decline in Renal Function: A Search for Mechanisms.

In chronic kidney disease (CKD), high serum phosphate concentration is associated with cardiovascular disease and deterioration in renal function. In early CKD, the serum phosphate concentration is normal due to increased fractional excretion of phosphate. Our premise was that high phosphate intake even in patients with early CKD would result in an excessive load of phosphate causing tubular injury and accelerating renal function deterioration. In CKD 2-3 patients, we evaluated whether increased phosphaturia accelerates CKD progression. To have a uniform group of patients with early CKD, 95 patients with metabolic syndrome without overt proteinuria were followed for 2.7 ± 1.6 years. The median decline in eGFR was 0.50 ml/min/1.73 m2/year. Patients with a more rapid decrease in eGFR had greater phosphaturia. Moreover, the rate of decrease in eGFR inversely correlated with the degree of phosphaturia. Additionally, phosphaturia independently predicted renal function deterioration. In heminephrectomized rats, a high phosphate diet increased phosphaturia resulting in renal tubular damage associated with inflammation, oxidative stress and low klotho expression. Moreover, in rats with hyperphosphatemia and metabolic syndrome antioxidant treatment resulted in attenuation of renal lesions. In HEK-293 cells, high phosphate promoted oxidative stress while melatonin administration reduced ROS generation. Our findings suggest that phosphate loading in early CKD, results in renal damage and a more rapid decrease in renal function due to renal tubular injury.

Bone mineral density reductions after tenofovir disoproxil fumarate initiation and changes in phosphaturia: a secondary analysis of ACTG A5224s.

Background: It is unknown if the greater reductions in bone mineral density (BMD) associated with initiation of tenofovir disoproxil fumarate compared with abacavir in previously untreated HIV-infected participants in the ACTG A5224s clinical trial were associated with potentially worsening tenofovir-related phosphaturia. Methods: We correlated changes in BMD at the hip and spine with changes in phosphaturia [transtubular reabsorption of phosphorus (TRP) and tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR)] from entry through week 96 in those initiating tenofovir ( n = 134) versus abacavir ( n = 135) with efavirenz or atazanavir/ritonavir in A5224s. We also correlated changes in BMD with tenofovir AUC measured between weeks 4 and 24. Results: Changes in TRP and TmP/GFR through week 96 between the tenofovir and abacavir arms were not significantly different (both P ≥ 0.70) and did not differ with use of efavirenz versus atazanavir/ritonavir. There were no significant correlations between changes in either TRP or TmP/GFR and with either hip or spine BMD in the tenofovir arms. Tenofovir AUC was significantly correlated with changes in hip BMD, but not spine BMD, at week 24 ( r = -0.22, P = 0.028) and week 48 ( r = -0.26, P = 0.010), but not at week 96 ( r = -0.14, P = 0.18). Conclusions: Changes in phosphaturia were not different between the tenofovir and abacavir arms in A5224s. Changes in hip and spine BMD with tenofovir were not related to changes in phosphaturia. However, tenofovir exposure was weakly associated with changes in hip BMD through week 48.

Hyperparathyroidism and increased fractional excretion of phosphate predict allograft loss in long-term kidney transplant recipients.

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.

Renalase, hypertension, and kidney - the discussion continues.

Hypertension and cardiovascular complications are very common in chronic kidney disease (CKD). Overactivation of sympathetic nervous system is also widely recognized in CKD. Renalase may play an important role in the control of blood pressure (BP) by its regulatory function of catecholamine metabolism. Renalase could be synthesized not only by the kidney but also by cardiomyocytes, liver, and adipose tissue. It probably exerts a hypotensive action, at least in animal models. Whether it metabolizes catecholamines remains to be proved. Another issue that remains to be resolved is the relationship between renalase and renal natriuresis and phosphaturia. In this review, the updated experimental and clinical data on renalase are presented and possible interactions with the endothelium are discussed. Renalase is "a new postulated therapeutic target." Proof of concept studies are needed to define the pathophysiological link between the kidney, sympathetic tone, BP, and cardiovascular complications.

Osteopetrosis, osteopetrorickets and hypophosphatemic rickets differentially affect dentin and enamel mineralization.

Osteopetrosis (OP) is an inherited disorder of defective bone resorption, which can be accompanied by impaired skeletal mineralization, a phenotype termed osteopetrorickets (OPR). Since individuals with dysfunctional osteoclasts often develop osteomyelitis of the jaw, we have analyzed, if dentin and enamel mineralization are differentially affected in OP and OPR. Therefore, we have applied non-decalcified histology and quantitative backscattered electron imaging (qBEI) to compare the dental phenotypes of Src(-/-), oc/oc and Hyp(-/0) mice, which serve as models for OP, OPR and hypophosphatemic rickets, respectively. While both, Src(-/-) and oc/oc mice, were characterized by defects of molar root formation, only oc/oc mice displayed a severe defect of dentin mineralization, similar to Hyp(-/0) mice. Most importantly, while enamel thickness was not affected in either mouse model, the calcium content within the enamel phase was significantly reduced in oc/oc, but not in Src(-/-) or Hyp(-/0) mice. Taken together, these data demonstrate that dentin and enamel mineralization are differentially affected in Src(-/-) and oc/oc mice. Moreover, since defects of dental mineralization may trigger premature tooth decay and thereby osteomyelitis of the jaw, they further underscore the importance of discriminating between OP and OPR in the respective individuals.

Hereditary disorders of renal phosphate wasting.

Inherited diseases of renal phosphate handling lead to urinary phosphate wasting and depletion of total body phosphorus stores. Clinical sequelae of inherited disorders that are associated with increased urinary phosphate excretion are deleterious and can lead to abnormal skeletal growth and deformities. This Review describes hereditary disorders of renal phosphate wasting taking into account developments in our understanding of renal phosphate handling from the last decade. The cloning of genes involved in these disorders and further studies on their pathophysiological mechanisms have given important insights in to how phosphatonins, such as FGF-23, regulate renal phosphate reabsorption in health and disease. X-linked dominant hypophosphatemic rickets results from mutation of a metalloprotease (PHEX) that has an unidentified role in FGF-23 degradation. Mutation of an RXXR proteolytic cleavage site in FGF-23 prevents degradation and increases circulating levels of FGF-23 in autosomal dominant hypophosphatemic rickets. FGF-23 acts to remove sodium phosphate co-transporters from the luminal membrane of proximal tubular cells with resultant renal phosphate wasting. Loss of function mutations in genes encoding the transporters NaPi-IIc and NaPi-IIa also result in renal phosphate wasting and rickets.

Can we generate new hypotheses about Dent's disease from gene analysis of a mouse model?

In humans, Dent's disease, an X-linked renal tubular disorder, is characterized by low molecular weight proteinuria, aminoaciduria, glycosuria, hyperphosphaturia, hypercalciuria, nephrolithiasis, progressive renal failure and sometimes rickets or osteomalacia. The aetiology of X-linked Dent's disease is established to be caused by mutations of the CLCN5 gene. The protein product of this gene is the voltage-gated chloride-proton exchanger CLC-5. Previous studies by the Johns Hopkins group (Guggino) and the Hamburg group (Jentsch) have established that the Clcn5 knockout mouse recapitulates the renal attributes of Dent's disease. In order to understand the changes in kidney function that accompany the knockout of the Clcn5 gene, we examined gene expression profiles from dissected proximal segment 1 (S1) and segment 2 (S2) tubules of mouse kidneys. Overall, 725 genes are expressed differentially in the proximal tubules of the Dent Clcn5 knockout mouse model compared with those of control wild-type mice. A major finding is the change in the cholesterol synthesis pathway. Some interesting changes also occur in genes encoding transport proteins. One of these transport proteins, the sodium bile cotransporter gene, Slc10a2, has transcripts increased by 17-fold in the Clcn5 knockout mouse. The Clc-3 protein encoded by Clcn3, a chloride-proton exchanger related to Clc-5, has a 1.9-fold increase in transcripts. The Npt2c protein, a proximal tubule sodium phosphate cotransporter encoded by Slc34a3, has a 0.6-fold decrease in the number of transcripts. The sodium-proton exchanger-like protein, Nhe10/sperm, encoded by Slc9a10, has a 0.5-fold decrease in transcript number. These genes are discussed with regard to the possible physiological outcomes of their transcript or protein changes.

Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction.

BACKGROUND AND OBJECTIVES: Lowe syndrome is defined by congenital cataracts, mental retardation, and proximal tubulopathy and is due to mutations in OCRL. Recently, mutations in OCRL were found to underlie some patients with Dent disease, characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. This phenotypic heterogeneity is poorly understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The renal phenotype of 16 patients with Lowe syndrome (10.9 +/- 7.0 yr) under care of the authors was characterized to define overlap of symptoms with Dent disease and infer clues about OCRL function. Medical charts of patients were reviewed for data regarding glomerular filtration rate and markers of proximal tubular function. RESULTS: All patients had low molecular weight proteinuria and albuminuria. Lysosomal enzymuria was elevated in all 11 patients assessed. Fifteen patients had hypercalciuria, and 14 aminoaciduria. Seven patients required bicarbonate and three required phosphate replacement; all others maintained normal serum values without supplementation. None of the patients had detectable glycosuria, and none had clinically overt rickets. GFR was mildly to moderately impaired and highly variable, with a trend of deterioration with age. CONCLUSIONS: Patients with Lowe syndrome do not have renal Fanconi syndrome but a selective proximal tubulopathy, variable in extent and dominated by low molecular weight proteinuria and hypercalciuria, the classical features of Dent disease. These findings suggest that OCRL and ClC-5, the chloride channel mutated in Dent disease, are involved in similar reabsorption pathways in the proximal tubule.

Growth in X-linked hypophosphatemic rickets.

Growth failure appears frequently in children with X-linked hypophosphatemic rickets (XLHR) due to hypophosphatemia, disease severity, body disproportion, and primary bone abnormality. Recombinant human growth hormone (rhGH) increases phosphate tubular reabsorption and phosphate level in blood and, thus, constitutes an attractive but controversial therapy in short children with XLHR, those efficacy was demonstrated in small uncontrolled series. Our aim was to report our experience regarding growth in XLHR. Twenty-seven children with XLHR--20 girls, seven boys--diagnosed at a median (md) of 1.46 years of age, (range 0.39-8.5 years), were studied at 10.12 years of age (1.58-18.56), md (range). All received oral treatment with phosphate and calcitriol. At the first visit, grouped Z-height was -1; (-4.58; 0.54) md (range). After 5 years' follow-up (0.92-15.6), Z-height was -0.91 (- 4.56; 0.17), not different from that at baseline (P = 0.465). In 16 children entirely controlled in our program upon presentation, a "catch up" phenomenon after the rickets had healed (P = 0.823) or throughout the long-term was not observed (P = 0.995). Eight patients had a Z-height 2 years at diagnosis, male gender and non-adherence to treatment. Four children, all boys, received rhGH, and in two cases with sufficient follow up stature normalized. No rhGH side effects were observed, and phosphate and calcitriol doses remained stable. Linear growth failure appeared in a third of XLHR children. Efforts need to be made to reduce the age of diagnosis and to improve adherence to treatment. Treatment with rhGH should be considered early, after the rickets has been controlled, in those patients with impaired growth or delayed diagnosis.

Material matters: a mechanostat-based perspective on bone development in osteogenesis imperfecta and hypophosphatemic rickets.

This perspective paper presents a hypothesis that links abnormalities of bone material with densitometric findings in two congenital metabolic bone disorders, osteogenesis imperfecta type I (OI) and X-linked hypophosphatemic rickets (XLH). Analyses of iliac bone samples from OI patients have shown that material bone density is elevated and that the bone material is abnormally stiff in this disorder. Therefore, a given mechanical load on an OI bone will generate a smaller than normal deformation. This in turn should lead osteocytes, the putative mechanosensing cells, to systematically underestimate the prevailing mechanical forces. According to the mechanostat model, bone strength should then be adapted to the underestimated mechanical loads, which means that bone architecture and mass remain below requirements. Available densitometric studies are in accordance with this hypothesis. In XLH, a mild mineralization defect persists despite treatment. This mineralization defect should lead to soft bone material. In analogy to the above model for OI, mechanical loads should be overestimated, resulting in increased densitometric parameters of bone strength. Indeed, lumbar spine areal bone mineral density is usually elevated in such patients.

[Hereditary hypophosphatemia in adults]. / Hypophosphatémies génétiquement déterminées chez l'adulte.

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).

"Phosphatonins" and the regulation of phosphorus homeostasis.

Phosphate ions are critical for normal bone mineralization, and phosphate plays a vital role in a number of other biological processes such as signal transduction, nucleotide metabolism, and enzyme regulation. The study of rare disorders associated with renal phosphate wasting has resulted in the discovery of a number of proteins [fibroblast growth factor 23 (FGF-23), secreted frizzled related protein 4 (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF 7 (FGF-7)] that decrease renal sodium-dependent phosphate transport in vivo and in vitro. The "phosphatonins," FGF-23 and sFRP-4, also inhibit the synthesis of 1alpha,25-dihydroxyvitamin D, leading to decreased intestinal phosphate absorption and further reduction in phosphate retention by the organism. In this review, we discuss the biological properties of these proteins, alterations in their concentrations in various clinical disorders, and their possible physiological role.

Evaluation of stature development during childhood and adolescence in individuals with familial hypophosphatemic rickets.

This review was conducted to study the diagnosis, treatment, and growth progression in infants and adolescents with familial hypophosphatemic rickets. The bibliographic search was carried out utilizing the electronic databases MEDLINE, OVID, and LILACS and by direct research within the last 15 years using the keywords rickets, familial hypophosphatemia, vitamin D deficiency, stature growth, childhood, and adolescence. Article selection was done by comparing the evaluation of the growth in patients with familial hypophosphatemic rickets, including the variables that might affect them, for possible future therapeutic proposals. It is concluded that the most significant fact in the treatment of familial hypophosphatemic rickets in infancy was the magnitude of the final stature. The use of growth hormone can be helpful in these patients. However, research reporting treatments with the use of the growth hormone for rickets are controversial. The majority of the authors agree that treatment using vitamin D and phosphate enables some statural growth in cases of early diagnosis, reflecting a better prognosis.

Co-existence of X-linked hypophosphatemic rickets (XLH) and primary hyperparathyroidism: case report and review of the literature.

X-linked hypophosphatemic rickets (XLH) is a dominant disorder characterized by hypophosphatemia due to impaired renal tubular reabsorption of inorganic phosphate. Cardinal manifestations include defective calcification of cartilage and bone, growth retardation and resistance to phosphorus and vitamin D therapy. Although secondary hyperparathyroidism (HPT) is a common complication of treatment, autonomous HPT is rare, especially in the absence of previous phosphate therapy. We report a case of an adult untreated male XLH patient with primary HPT and give a brief review of the literature regarding the prevalence and pathophysiology of this complication.