Physiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting.

Phosphate is a cornerstone of several physiological pathways including skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis with three hormones having important functions in renal phosphate handling or intestinal absorption: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1-25-dihydroxyvitamin D (1,25(OH)2D). FGF23 is mainly synthesized by osteocytes; it is a direct phosphaturic factor that also inhibits 1,25(OH)2D and PTH. In addition to crucial effects on phosphate and calcium metabolism, FGF23 also has 'off-target' effects notably on the cardiovascular, immune and central nervous systems. Genetic diseases may affect the FGF23 pathway, resulting in either increased FGF23 levels leading to hypophosphatemia (such as in X-linked hypophosphatemia) or defective secretion/action of intact FGF23 inducing hyperphosphatemia (such as in familial tumoral calcinosis). The aim of this review is to provide an overview of FGF23 physiology and pathophysiology in X-linked hypophosphatemia, with a focus on FGF23-associated genetic diseases.

Clinical and genetic analysis of two Chinese infants with Mabry syndrome.

OBJECTIVE: Hyperphosphatasia mental retardation syndrome (Mabry syndrome) is an autosomal recessive disorder. We aim to analyze two Chinese patients diagnosed as Mabry syndrome. METHODS: The clinical manifestations, diagnosis and treatment were observed in two patients. Genetic analysis including PIGV and PIGO was examined. RESULTS: Two patients were diagnosed as Mabry syndrome clinically and genetically. Developmental delay, hyperphosphatasia and seizures were presented in both of them. Typical facial dysmorphism and hypoplastic terminal phalanges were only found in one. Some novel presentations including congenital laryngeal cartilage softening, inguinal hernia, broken palmprint, optic atrophy and skeleton dysplasia such as carpal age delay and metaphysis anomalies were observed in two patients. Molecular genetic analysis revealed compound heterozygous mutations of PIGV or PIGO in our patients, including c.615C>G (p.Asn205Lys) and c.854A>G (p.Tyr285Cys) of PIGV in patient 1, and c.458T>C (p.Phe153Ser) and c.1355_1356del (p.Ala452Glyfs*52) of PIGO in patient 2. Additionally, a heterozygous c.2926G>A (Asp976Asn) of PCDH19 was identified in patient with PIGV mutations, the causative gene of Epilepsy and mental retardation limited to females (EFMR). CONCLUSION: To our best knowledge, this is the first time to report Chinese patients diagnosed as Mabry syndrome. For the PCDH19 mutation in our patient carrying PIGV mutations, due to lacking characteristics of EFMR and the ambiguity results in pathogenicity analysis, we were not sure how much pathogenic role PCDH19 mutation shared with PIGV mutations in this disease. The novel mutations of PIGV and PIGO, and novel clinical manifestations reported here might expand the genotype and phenotype spectrum of Mabry syndrome.

Clinical assessment of phosphorus status, balance and renal handling in normal individuals and in patients with chronic kidney disease.

PURPOSE OF REVIEW: The concepts of steady state, external balance, total body status and internal distribution are not always appreciated or even considered in clinical practice. The current tests available for clinical assessment of phosphorus physiology and pathophysiology are valid in some aspects, but also have many limitations. The purpose of this review is to clarify the above concepts and discuss the utility of the currently available tests to assess phosphorus disorders. RECENT FINDINGS: Both epidemiologic and preclinical data have shown that disturbances in mineral metabolism contribute significantly to the morbidity and mortality in chronic kidney disease. There are also emerging data supporting the notion that phosphotoxicity may exist even in individuals with normal renal function. In chronic kidney disease (CKD), hyperphosphatemia is a relative late event and is a suboptimal indicator of phosphorus balance and status. The judicious use of plasma and urine chemistry and hormonal biomarkers such as fibroblast growth factor 23 should be considered. SUMMARY: There is a dire need to increase awareness of what physiologic parameters should be monitored in terms of phosphorus pathophysiology. Although the current available tests in the clinical armamentarium are not ideal, understanding their implications and limitations will improve patient care and motivate practitioners and investigators to develop better tests.

Associations of dietary phosphorus intake, urinary phosphate excretion, and fibroblast growth factor 23 with vascular stiffness in chronic kidney disease.

OBJECTIVE: Elevated serum phosphate concentrations are established risk factors for cardiovascular disease and mortality in chronic kidney disease (CKD). Independent associations of other indices of phosphorus metabolism, such as phosphorus intake, urinary phosphate excretion, or hormones that regulate these systems, like fibroblast growth factor 23 (FGF23), with markers of cardiovascular disease in CKD, have been studied in less detail. DESIGN: Cross-sectional study. PARTICIPANTS: Seventy-four adult CKD patients with mean creatinine clearance of 51 ± 19 mL/minute. OUTCOME: Augmentation index (AI)--a surrogate marker of arterial stiffness. RESULTS: Although serum phosphate varied little across quartiles of creatinine clearance, average daily phosphorus intake and 24-hour urinary phosphate excretion decreased from highest to lowest quartile (by 31% and 60%, respectively, P for trend <.05). FGF23 was associated with serum phosphate (r = 0.24, P = .03) and creatinine clearance (r = -0.4, P = .001), but not with dietary phosphorus or 24-hour urinary phosphate excretion (P > .05 for both). Older age, higher systolic blood pressure, female gender, and black race were independently associated with increased AI. In contrast, there were no associations of serum phosphate, dietary phosphorus intake, urinary phosphate excretion, or FGF23 with AI in multivariate-adjusted models. CONCLUSIONS: In this sample of patients with CKD, established risk factors for arterial stiffness, but not mediators of phosphorus metabolism, were associated with increased AI. In addition, there were no significant associations between FGF23 and dietary phosphorus or urinary phosphate excretion. Future studies are needed to determine the main factors associated with elevations in FGF23 in CKD and to further assess the association of disordered phosphorus metabolism with subclinical markers of vascular disease.

Disorders of phosphorus homeostasis.

PURPOSE OF REVIEW: The study of phosphorus physiology and investigations into clinical disorders of phosphorus metabolism has blossomed over the past decade. Recent work has confirmed and further extended our knowledge of basic mechanisms of phosphorus metabolism. RECENT FINDINGS: This review will focus on FGF-23 and Klotho, and on the recent further dissection of their roles in phosphorus and skeletal metabolism. Additionally, this review will detail recent studies that implicate a role for these phosphaturic and vitamin D regulating factors in extraskeletal calcification, including that occurring in soft tissue and vascular beds. SUMMARY: These findings in total provide fertile ground for investigations into the cause and treatment of abnormal skeletal and extraskeletal calcification in patients with inherited hypophosphatemic disorders. More importantly, and certainly with wider potential clinical application, these studies likewise imply a role for these factors in the pathogenesis of accelerated cardiovascular disease that occurs in patients with the most common hyperphosphatemic disorder, chronic kidney disease. Future studies are needed to confirm a harmful or possibly even beneficial role for FGF-23 and other factors in these disease states, and to determine whether therapeutic manipulation of these factors does truly affect clinical outcomes in patients with hypophosphatemia and hyperphosphatemia.

Novel regulators of phosphate homeostasis and bone metabolism.

The regulation of phosphate homeostasis remains incompletely understood. Most insights into the underlying mechanisms were established by defining the molecular basis of different inherited disorders that are characterized by an abnormal regulation of phosphate homeostasis. Using this approach, three novel regulators were previously identified, namely PHEX (a phosphate-regulating gene with homologies to endopeptidases on the X chromosome), fibroblast growth factor (FGF)-23 and UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). Other studies had revealed heterozygous mutations in the sodium phosphate co-transporter NaPi-IIa as the cause of hypophosphatemia associated with hypercalciuria and osteoporosis, and homozygous or compound heterozygous mutations in NaPi-IIc were shown to cause hereditary hypophosphatemic rickets with hypercalciuria. Recently, positional cloning approaches furthermore led to the identification of homozygous inactivating mutations in dentin matrix protein 1 (DMP1) as the cause of an autosomal recessive form of hypophosphatemia. Using different immunometric assays, intact and C-terminal FGF-23 levels were found to be elevated in patients with oncogenic osteomalacia, and the tumors responsible for this disease showed increased expression of FGF-23 mRNA. Intact and C-terminal FGF-23 levels are furthermore elevated in patients with X-linked hypophosphatemia. This disorder is caused by inactivating PHEX mutations suggesting that this endopeptidase is somehow, most likely indirectly, involved in the metabolism of intact FGF-23. FGF-23 levels were also found to be elevated in some patients with ARHP indicating that the lack of DMP1 up-regulates expression of this phosphaturic hormone. The concentration of C-terminal FGF-23, but not of intact FGF-23, is significantly elevated in two forms of tumoral calcinosis (TC). One form of TC is caused by homozygous inactivating GALNT3 mutations implying that the encoded enzyme, which is involved in the initiation of O-glycosylation, is important for preventing cleavage of FGF-23 into biologically inactive fragments. The second form of tumoral calcinosis is caused by different homozygous FGF-23 mutations that affect conserved serine residues that may undergo O-glycosylation by GALNT3; the lack of this post-translational modification leads to an abnormal processing of FGF-23 and increased secretion of C-terminal fragments. It remains unknown whether and how the different phosphate-regulating proteins interact with each other and it appears very likely that additional proteins are involved in this process. It also remains unclear whether the dramatically elevated FGF-23 levels in patients with different stages of chronic kidney disease affect bone metabolism, particularly the mineralization of newly formed osteoid.

Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake.

Elevated serum phosphorus has been identified as a cardiovascular risk factor in chronic kidney disease (CKD) patients and a clear understanding of phosphorus homeostasis is very important for practicing nephrologists. At any particular point, serum phosphorus levels reflect the balance between movements of this mineral from and into the intestine, bone, intracellular space, and kidneys. We briefly review here all these exchanges with a particular emphasis on dietary phosphorus intake. Despite all the oral phosphorus binders currently available in the market, dietary restriction of this mineral remains a cornerstone for the prevention and treatment of hyperphosphatemia. An effective restriction of dietary intake of phosphorus requires prescription of a moderate protein intake (0.9-1.0 g/kg/day) and restricted consumption of highly processed fast and convenience foods. Phosphorus added during food processing is an important source of this mineral because of its magnitude and high bioavailabilty. Moreover, as food manufacturers are not required to label the amount of phosphorus added during food processing, a significant amount of the current daily phosphorus intake remains unaccounted when estimating phosphorus intake in CKD patients. The recent development of low phosphorus-containing food products represents a very useful addition for CKD patients.

Renal osteodystrophy, phosphate homeostasis, and vascular calcification.

New advances in the pathogenesis of renal osteodystrophy (ROD) change the perspective from which many of its features and treatment are viewed. Calcium, phosphate, parathyroid hormone (PTH), and vitamin D have been shown to be important determinants of survival associated with kidney diseases. Now ROD dependent and independent of these factors is linked to survival more than just skeletal frailty. This review focuses on recent discoveries that renal injury impairs skeletal anabolism decreasing the osteoblast compartment of the skeleton and consequent bone formation. This discovery and the discovery that PTH regulates the hematopoietic stem cell niche alters our view of secondary hyperparathyroidism in chronic kidney disease (CKD) from that of a disease to that of a necessary adaptation to renal injury that goes awry. Furthermore, ROD is shown to be an underappreciated factor in the level of the serum phosphorus in CKD. The discovery and the elucidation of the mechanism of hyperphosphatemia as a cardiovascular risk in CKD change the view of ROD. It is now recognized as more than a skeletal disorder, it is an important component of the mortality of CKD that can be treated.

Role of fibroblast growth factor 23 in phosphate homeostasis and pathogenesis of disordered mineral metabolism in chronic kidney disease.

The discovery of fibroblast growth factor 23 (FGF23), a novel bone-derived hormone that inhibits phosphate reabsorption and calcitriol production by the kidney, has uncovered primary regulatory pathways and new systems biology governing bone mineralization, vitamin D metabolism, parathyroid gland function and renal phosphate handling. This phosphaturic hormone, which is made predominately by osteocytes in bone, appears to have a physiologic role as a counter-regulatory hormone for vitamin D. Evidence has also emerged to support the existence of a bone-kidney axis to coordinate the mineralization of bone with renal handling of phosphate. Pathologically, high circulating levels of FGF23 result in hypophosphatemia, decreased production of 1,25(OH)(2)D, elevated parathyroid hormone and rickets/osteomalacia in patients with functioning kidneys, whereas low levels are associated with tumoral calcinosis, hyperphosphatemia and elevated 1,25(OH)(2)D. In addition, patients with chronic kidney disease (CKD) exhibit marked elevations of circulating FGF23. While the significance of increased FGF23 levels in CKD remains to be defined, it might contribute to phosphate excretion and suppression of 1,25(OH)(2)D levels in CKD stages 3 and 4, as well as potentially contribute to secondary hyperparathyroidism through direct actions on the parathyroid gland in more advanced renal failure. As our knowledge expands regarding the regulation and functions of FGF23, the assessment of FGF23 will become an important diagnostic marker as well as a therapeutic target for management of disordered mineral metabolism in a variety of acquired and hereditary disorders.

The safety of phosphate binders.

Disturbances of mineral metabolism occur during the early stages of chronic kidney disease. As renal function worsens, excess dietary phosphorus accumulates and blood levels increase, that can be clearly seen when the glomerular filtration rate has fallen below 30 ml/min/1.73 m2. In patients with end stage renal disease, standard dialysis (three times/week) falls far short of removing adequate amounts of absorbed phosphorus; therefore, hyperphosphataemia is found in the majority of these patients. Hyperphosphataemia has long been associated with progression of secondary hyperparathyroidism and renal osteodystrophy, it can also lead to soft-tissue and vascular calcification. Recent observational data have associated hyperphosphataemia with increased cardiovascular mortality among dialysis patients. Adequate control of serum phosphorus remains a cornerstone in the clinical management and, despite the growing amount of available therapeutic options, achievement of NFK/KDOQI targets for mineral metabolism remain poor. Several reasons may explain the failure to adequately treat hyperphosphataemia: poor compliance with diet and phosphate binder prescriptions are common causes. Also, factors related with cost, tolerance, palatability, safety and efficacy are important. In this article, the authors review the advantages and drawbacks of conventional and emerging therapies in phosphorous binding.

Phosphate diabetes, tubular phosphate reabsorption and phosphatonins.

Phosphate diabetes is defined as inadequate tubular reabsorption. Hypophosphatemia is responsible for most of the clinical manifestations, which vary with the age of the patient and the severity of the phosphate wasting. Vitamin D-resistant rickets in children or osteomalacia in adults, osteoporosis, bone pain including spinal pain, and pain in the joints and periarticular areas are the main manifestations. Several factors are known to affect tubular phosphate reabsorption via the sodium/phosphate cotransporters located on the tubular cell membranes. Factors that decrease phosphate reabsorption include a high intake of dietary phosphate, acidosis, parathyroid hormone (PTH), PTH-related peptide (PTHrp), glucocorticoid therapy, calcitonin, and vitamin D. On the other hand, a low-phosphate diet, alkalosis, growth hormone, insulin, IGF-1, and thyroid hormones increase tubular phosphate reabsorption. Physiological concepts about tubular phosphate reabsorption have been radically changed by the recent identification of phosphaturic factors called phosphatonins. The most extensively studied phosphatonin to date is fibroblast growth factor 23 (FGF23), which was first identified in patients with tumor-induced osteomalacia and shown to be secreted by the neoplastic cells. The FGF23 has also been implicated in autosomal dominant hypophosphatemic rickets, in which a gene mutation results in production of abnormal FGF23 that resists hydrolysis. In healthy individuals, FGF23 contributes to regulate phosphate reabsorption via Na/Pi cotransporters. Other phosphatonins may exist, such as matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein 4 (SFRP4), whose role remains to be defined. The part played by these proteins in idiopathic renal phosphate wasting in adults needs to be investigated.

Health and economic consequences of sevelamer use for hyperphosphatemia in patients on hemodialysis.

OBJECTIVES: The safety and efficacy of sevelamer hydrochloride in binding phosphate in patients with end-stage renal disease and its ability to attenuate the progression of cardiac calcification have been well documented but not the longer-term health and economic implications. Thus, a model of the predicted long-term consequences of sevelamer compared with calcium-based binders (acetate and carbonate) was developed. METHODS: Long-term cardiovascular implications of 1 year of treatment with phosphate binders in patients on hemodialysis are estimated based on the patient's demographics, comorbidities, and physiologic and renal parameters. The initial calcification score and expected changes over 1 year are derived using regression equations developed from the Treat-to-Goal study and translated to cardiovascular disease risk based on equations developed from a long-term cohort study. In this article, the implications of cardiovascular disease for life expectancy and medical costs are accounted for from a US payer perspective. RESULTS: The cardioprotective effect of sevelamer over 1 year is estimated to result in a 12% reduction in cardiovascular events compared with calcium acetate. In a population of 100 patients, the savings of 205,600 dollars accrued due to avoiding nine cardiovascular events with sevelamer, largely offset the increased binder costs, leading to a favorable cost-effectiveness ratio of about 2200 dollars per (discounted) life-year gained. CONCLUSIONS: Although both binders provide equivalent phosphate binding capacity, the results indicate that the advantage of 1 year of treatment with sevelamer in attenuating the progression of calcification has important clinical and economic consequences, suggesting that this provides good value for money.

Calcium and phosphorus metabolism in patients who have chronic kidney disease.

Disturbances in calcium and phosphorus metabolism are almost invariable consequences of chronic kidney disease (CKD). Because the capacity to regulate calcium and phosphorus metabolism becomes compromised progressively as kidney function declines, calcium and phosphorus homeostasis is disrupted and serum calcium or phosphorus levels are perturbed in many patients with CKD. The level of interest in, and concerns about, abnormalities in calcium and phosphorus metabolism among patients with CKD has increased substantially in recent years. Strategies for clinical management are being revised, and recent recommendations differ substantially from those used previously with a renewed emphasis on safety.

Avaliação da histologia óssea e cardiovascular em ratos urêmicos paratireoidectomizados submetidos à dieta rica e pobre em fósforo associado à infusão de paratôrmonio / Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function and bone in rats with renal failure

A hiperfosfatemia (HP) contribui para a patogênese da doença cardiovascular e da osteodistrofia renal. Avaliamos o efeito da HP na histologia cardiovascular, na função renal e no tecido ósseo em uremia experimental. Ratos Wistar foram submetidos a PTx e Nx com reposição contínua de paratormônio ou eram sham operados. Apenas o conteúdo de fósforo era diferente nas dietas. O peso do coração corrigido para o peso do animal e a creatinina foram maior no grupo PTx+Nx+HP que nos demais grupos. A histologia não evidenciou calcificação vascular ou fibrose. / Hyperphosphatemia (HP) contributes to cardiovascular disease and renal osteodystrophy. We evaluated the effect of HP on cardiovascular system, renal function and bone in experimental uremia. Wistar rats were submitted to PTx and Nx with rat parathormone replacement, or were sham-operated. Only phosphorus content differentiated diets. Heart weight normalized to body weight and creatinine levels were higher in PTx+Nx+HP rats than in any other group. We detected no cardiovascular calcification or fibrosis...

Hyperphosphatemia aggravates cardiac fibrosis and microvascular disease in experimental uremia.

BACKGROUND: Hyperphosphatemia is a known predictor of cardiovascular death and specifically of cardiac death in hemodialysis patients. The pathomechanisms involved have not been completely clarified. While a number of observations suggest an important role of hyperphosphatemia and positive calcium balance on atherosclerosis and calcification of the coronary conduit arteries, independent effects on postcoronary microvessels and on cardiac fibrosis have not been excluded. METHODS: Male Sprague-Dawley rats were sham operated (N = 14) or subtotally nephrectomized (SNX, N = 17) and subsequently placed on low phosphorus (0.08% w/w) and high phosphorus (1.2% w/w) diet under pair-feeding conditions. After 8 weeks, serum chemistry and inhibitory parathyroid hormone (iPTH) were measured, and the hearts were harvested using perfusion fixation. Arteriolar thickness and volume density of the interstitium (excluding vessels) were quantitated using stereologic techniques. RESULTS: In SNX animals with moderate renal failure serum phosphorus concentrations were higher than in sham-operated controls on low phosphorus diet (1.7 +/- 0.37 mmol/L) and were significantly higher in SNX + high phosphorus diet (2.33 +/- 0.23 mmol/L) compared to SNX + low phosphorus diet (1.95 +/- 0.32 mmol/L; P < 0.05). In sham-operated controls, dietary phosphorus content had no effect on cardiac morphologic indices. In contrast, in SNX + high phosphorus diet the index of interstitial cardiac fibrosis was significantly higher (3.22 +/- 0.44%) than in SNX + low phosphorus (2.75 +/- 0.46%) or in sham-operated controls (2.5 +/- 0.05% on high phosphorus and 2.4 +/- 0.89 on low phosphorus, respectively). In SNX + high phosphorus (14.0 +/- 9.0 microm), but not in SNX + low phosphorus (9.2 +/- 4.5 microm), arterial wall thickness was significantly higher compared to sham-operated controls (10.2 +/- 5.1 on high phosphorus and 9.8 +/- 5.0 micro;m on low phosphorus, respectively). The data were confirmed in an independent repeat experiment. CONCLUSION: High dietary phosphorus and hyperphosphatemia have significant effects on cardiac fibrosis and arterial wall thickening. Such abnormalities of cardiac architecture may be relevant for the increased cardiac risk in hyperphosphatemic uremic patients.

Consequences of hyperphosphatemia and elevated levels of the calcium-phosphorus product in dialysis patients.

Control of serum phosphorus levels is a central goal in the management of patients with chronic renal failure. Inadequate control of serum phosphorus leads to elevated levels of the calcium-phosphorus product. This plays a pivotal role in vascular calcification, cardiovascular disease, calciphylaxis, and death. Elevated phosphorus and elevated levels of the calcium-phosphorus product are both significant predictors of cardiovascular mortality, at phosphorus and calcium-phosphorus product levels that were considered safe until recently. A lowering of levels such that phosphorus is maintained between 2.2 and 5.5 mg/dl, calcium-phosphorus product is below 55 mg(2)/dl(2), and serum calcium is at 9.2-9.6 mg/dl, respectively, might well be the goal of therapeutic management strategies.

Magnesium and phosphorus.

A summary of new findings regarding alterations of magnesium (Mg2+) and phosphorus (P) metabolism are reviewed for the clinician caring for patients in general wards. Alterations in serum concentrations of Mg2+ and P are frequently observed in acute or very ill patients in emergency rooms or intensive-care areas. A significant proportion of these alterations are iatrogenic. Most of the symptoms related are non-specific, and usually they are associated with changes in concentration of other ions. The need to measure Mg2+ and P routinely and to define better the real abnormal values is stressed. Correction of the abnormalities must be early in the course of the alterations.