Calcitriol Production Research Articles

Placental CYP27B1 and CYP24A1 Expression in Human Placental Tissue and Their Association With Maternal and Neonatal Calcitropic Hormones

Placental CYP27B1 may contribute to circulating maternal calcitriol concentrations across gestation, but determinants of CYP27B1 and CYP24A1 expression in term human placental tissue are not well established. We hypothesized that higher CYP27B1 protein expression would be associated with increased maternal calcitriol during gestation and that CYP27B1 expression would be impacted by substrate availability. This was a prospective, longitudinal study. The study was completed in an urban, prenatal clinic located in Rochester, New York. The study was undertaken in a cohort of 70 pregnant adolescents (≤18 y of age) and their term neonates. There was no intervention. Protein and mRNA expressions of CYP27B1, CYP24A1, and vitamin D receptor were measured in term placental tissue and related to 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, PTH, serum total calcium, IL-6, leptin, and osteoprotegerin measured in maternal serum at midgestation and delivery and in umbilical cord serum at birth. Placental CYP27B1 protein expression was significantly positively associated with maternal 25(OH)D at both midgestation (n = 68, P = .009) and delivery (n=67, P = .006). Maternal serum 1,25-dihydroxyvitamin D concentrations at midgestation were positively correlated with term placental CYP27B1 mRNA expression (n = 49, P = .002). Significant positive associations were evident between placental CYP27B1 and CYP24A1 protein expression (P = .001, n = 70). Maternal PTH concentrations at midgestation or delivery did not significantly impact placental protein or transcript level of either enzyme. Variability in placental CYP27B1 protein expression was best captured by a model that included maternal midgestation 25(OH)D concentration, placental vitamin D receptor protein expression, and maternal midgestation IL-6 concentrations (P = .002, n = 60, R(2) = 0.22). Higher maternal 25(OH)D during pregnancy was associated with significantly higher placental protein expression of CYP27B1 at term supportive of a link between substrate availability and placental production of calcitriol.

Ektope Calcitriol-Produktion durch ein Non-Hodgkin-Lymphom als Ursache einer hyperkalzämischen Krise

A 92-year-old woman was admitted because her general condition had deteriorated during the last two weeks and acute kidney injury had developed. Moreover, she suffered from periods of disorientation and confusion while heretofore she was autonomous. INVESTIGATION, TREATMENT AND COURSE: Clinical and biochemical evaluation revealed a hypercalcemic crisis with markedly increased serum levels of calcium (3.77 mmol/l; reference values 2.2-2.65), an acute kidney injury and neuropsychiatric disturbances. Ultrasound scan and magnetic resonance imaging of a palpable mass in the right abdomen showed a tumor in the retroperitoneal space. Histological evaluation specified the tumor as non-Hodgkin lymphoma. Further investigation revealed no other reason for the hypercalcemia but enhanced levels of calcitriol. Since serum levels of calcidiol were increased while levels of calcidiol were normal, we assumed ectopic production of calcitriol by non-Hodgkin lymphoma as the cause of hypercalcemic crises. This could been proven by the decrease of calcium and calcitriol levels during the course of lymphoma treatment. Hypercalcemia of malignancy is the most common cause of hypercalcemia in the inpatient setting. The evaluation of these cases should consider ectopic production of calcitriol a cause of hypercalcemia.

Letter to the Editor Hypercalcemia and acute renal failure associated with calcium carbonate consumption in a patient with hypoparathyroidism

Letter to the Editor Hypercalcemia and acute renal failure associated with calcium carbonate consumption in a patient with hypoparathyroidism

Regulation of CYP27B1 and CYP24A1 gene expression by recombinant pro-inflammatory cytokines in cultured human trophoblasts

Placenta is an important source of endocrine and immunological factors. During pregnancy, calcitriol, the active metabolite of vitamin D, is also metabolized by decidua and placental tissue by means of CYP27B1 and CYP24A1 for synthesis and inactivation of calcitriol respectively. Calcitriol production is regulated by several factors in a tissue-specific manner. However, the association of pro-inflammatory cytokines on calcitriol metabolism has not been studied in human placenta. The aim of the present study was to investigate the effects of TNF-α, INF-γ, IL-6 and IL-1β upon CYP27B1 and CYP24A1 gene expression in primary cultures of human placental cells. Placentas were obtained immediately after delivery by cesarean section from normotensive women. Cytokine effects upon mRNA of CYPs in enriched trophoblastic cell preparations were evaluated by using qPCR. The results showed that incubation of trophoblasts in the presence of each cytokine resulted in a significant increase of both CYPs expression. Interestingly, TNF-α increased significantly the ratio of CYP24A1/CYP27B1 gene expression, while IFN-γ preferentially induced CYP27B1, whereas IL-1β and IL-6 stimulated gene expression of both CYPs in the same proportion. The results suggest that cytokines among other factors regulate calcitriol metabolism in human placenta; specifically, INF-γ may contribute to calcitriol production while TNF-α favors its catabolism.

Hypercalcemia Due to Giant Cell Myocarditis: A Case Report

Granulomatous diseases are a rare cause of hypercalcemia. The pathogenesis is presumed to be from endogenous production of 1,25-dihydroxyvitamin D by activated macrophages in granulomatous lesions, which harbor the 1α-hydroxylase enzyme. Herein the first case of hypercalcemia associated with giant cell myocarditis, an unusual type of granulomatous process, is reported. In this case, a patient with giant cell myocarditis had development of progressive heart failure and cardiorenal syndrome that required biventricular support. One year later, hypercalcemia associated with a relatively high 1,25-vitamin D level and a concomitantly suppressed parathyroid hormone level developed in the presence of stage 4 chronic kidney disease. Her other workup of hypercalcemia was unrevealing for vitamin D intoxication and multiple myeloma. Computed tomography of her chest showed no signs of hilar lymphadenopathy. Her calcium levels returned to normal with low-dose steroid therapy and have remained normal following a successful heart transplant. This case illustrates an unusual cause of hypercalcemia thought to be due to extrarenal calcitriol production associated with giant cell myocarditis.

Growth hormone and Klotho

Acromegaly is characterized by excessively high GH and IGF1 levels. Recent data suggest that soluble Klotho (sKlotho) is also elevated in patients with active acromegaly. sKlotho decreases towards normal following removal of the GH-producing pituitary adenoma. The Klotho gene was identified in mice following its accidental disruption by ectopic DNA. It is an ageing suppressor gene of restricted expression (mainly in kidneys, brain, and parathyroid and pituitary glands) encoding a transmembrane protein, mKlotho. mKlotho serves as a co-receptor in fibroblast growth factor 23 (FGF23) signalling. FGF23 promotes urinary phosphate excretion and inhibits the synthesis of calcitriol. The ectodomain of mKlotho is enzymatically released to result in a humoral factor, sKlotho, which exerts systemic effects (on ion channels and signalling pathways), possibly by working as an enzyme that modifies glycans of cell surface glycoproteins. GH enhances renal phosphate reabsorption and calcitriol production, i.e. exerts effects in the proximal tubule opposing those attributed to mKlotho, and attenuates calciuria in the distal tubule similar to sKlotho. sKlotho can be measured in extracellular fluids (serum, urine and cerebrospinal fluid (CSF)) by an ELISA. In line with predominant expression of Klotho in kidneys and choroid plexus, concentrations of sKlotho are particularly high in urine and CSF. Determination of sKlotho in serum and urine (both presumably reflecting GH action on the kidneys) could be used as a supplementary tool in the diagnosis and follow-up of patients with acromegaly. The question arises whether GH exerts selected actions via modifying activities of Klotho.

FGF23 and Phosphate Wasting Disorders.

A decade ago, only two hormones, parathyroid hormone and 1,25(OH)2D, were widely recognized to directly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 (FGF23) in 2000 (1), our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteoblasts in the skeleton (2,3), it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimental to humans. In this review, we will discuss the pathophysiology of FGF23 and hyper-FGF23 related renal phosphate wasting disorders (4).

Attivazione dei recettori della Vitamina D nell'insufficienza renale cronica

I pazienti affetti da IRC presentano fin dai primi stadi della malattia una ridotta attivazione del recettore per la Vitamina D (VDR), determinata da ridotti livelli sia di 1.25-idrossivitamina D (1.25(OH)2D3) che di 25-idrossivitamina D (25(OH)D3), con il conseguente sviluppo di anomalie del metabolismo osseo e minerale. La Vitamina D e i suoi metaboliti di sintesi, oltre a controllare l'iperparatiroidismo secondario (IPTS), esercitano numerosi effetti pleiotropici in diversi sistemi cellulari e, in particolare, sembrano giocare un ruolo fondamentale nella salute del sistema cardiovascolare e nella riduzione della mortalità, come suggerito da studi osservazionali. È stato di recente dimostrato che il paracalcitolo orale nell'IRC non solo riduce il paratormo-ne, ma è anche associato a un effetto antiproteinurico significativo, e ciò appare di particolare interesse in quanto la proteinuria è un fattore di rischio renale e cardiovascolare. I dati attuali non sono, tuttavia, sufficienti per raccomandare l'uso degli agenti attivatori dei VDR (VDRa) oltre al trattamento delle alterazioni del metabolismo minerale legate all'iperparatiroidismo secondario.

Correction of hypocalcemia allows optimal recruitment of FGF-23-dependent phosphaturic mechanisms in acute hyperphosphatemia post-phosphate enema

Both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are phosphaturic hormones. These hormones should increase in response to phosphate excess. However, they also regulate serum calcium; PTH increases serum calcium concentration and FGF23 suppresses renal production of calcitriol, favoring hypocalcemia. We report the case of an 83-year-old woman with hyperphosphatemia and hypocalcemia resulting from phosphate-containing enemas. PTH and calcitriol increased in response to hypocalcemia, and FGF23 increased in response to hyperphosphatemia. Unexpectedly, peak FGF23 did not coincide with peak serum phosphate. Rather, peak FG23 was observed only after severe hypocalcemia was partially corrected with exogenous calcium administration, even though serum phosphate had been already decreasing for 32h. Correction of severe hypocalcemia was thus associated with peak FGF23 values and with a precipitous decrease in PTH. Peak FGF23 was followed by an accelerated decrease in serum phosphate and significant phosphaturia. This clinical report is consistent with experimental data in rats showing a blunted FGF23 response to high phosphate in the presence of severe hypocalcemia. Thus, complementary experimental and clinical data suggest that partial correction of severe hypocalcemia is required for optimal FGF23-mediated phosphaturia, which takes place despite correction of PTH levels. We believe this the first human report suggesting blunting of the FGF23 response to high phosphate by severe hypocalcemia.

Calcium Absorption Response to Cholecalciferol Supplementation in Hemodialysis

Recent understanding of extrarenal production of calcitriol has led to the use of more vitamin D supplementation in CKD populations. This paper reports the effect of cholecalciferol supplementation on calcium absorption. Paired calcium absorption tests were done before and after 12-13 weeks of 20,000 IU weekly cholecalciferol supplementation in 30 participants with stage 5 CKD on hemodialysis. The study was conducted from April to December of 2011. Calcium absorption was tested with a standardized meal containing 300 mg calcium carbonate intrinsically labeled with (45)Ca; 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured. 25-Hydroxyvitamin D rose from 14.2 ng/ml (11.5-18.5) at baseline to 49.3 ng/ml (42.3-58.1) at the end of the study (P<0.001). 1,25-Dihydroxyvitamin D rose from 15.1 (10.5-18.8) pg/ml at baseline to 20.5 (17.0-24.7) pg/ml at the end of the study (P<0.001). The median baseline calcium absorption was 12% (7%-17%) and 12% (7%-16%) at the end of study. Patients with stage 5 CKD on hemodialysis had very low calcium absorption values at baseline, and cholecalciferol supplementation that raised 25(OH)D levels to 50 ng/ml had no effect on calcium absorption.

VDR activation in CKD

Disturbances of mineral metabolism occurs in virtually all patients during the progression of chronic kidney disease (CKD), because the decreasing functional renal mass and the reduction in renal 1a-hydroxylase activity lead to defective renal production of calcitriol at very early CKD stages. Beyond the effect of parathyroid hormone suppression, an increasing body of experimental data suggests that vitamin D exerts pleiotropic effects, which have been associated with an improvement of cardiovascular disease and mortality rate in observational studies. Recent data from randomized controlled studies showed that paracalcitol treatment in CKD patients also results in a significant reduction of albuminuria, which is a major risk factor for cardiorenai syndrome outcome. However, the current K/DOQI and KDIGO recommendations limit the administration of VDR activation agents for the sole treatment of hyperparathyroidism. The role of different vitamin D metabolites and their analogues, administered in CKD patients, will be discussed in this review.

Pathophysiology of chronic kidney disease-mineral and bone disorder

Chronic kidney disease (CKD) alters the metabolism of several minerals, thereby inducing bone lesions and vessel-wall calcifications that can cause functional impairments and excess mortality. The histological bone abnormalities seen in CKD, known as renal osteodystrophy, consist of alterations in the bone turnover rate, which may be increased (osteitis fibrosa [OF]) or severely decreased (adynamic bone disease [AD]); abnormal mineralization (osteomalacia [OM]), and bone loss. Secondary hyperparathyroidism is related to early phosphate accumulation (responsible for FGF23 overproduction by bone tissue), decreased calcitriol production by the kidneys, and hypocalcemia. Secondary hyperparathyroidism is associated with OF. Other factors that affect bone include acidosis, chronic inflammation, nutritional deficiencies, and iatrogenic complications.

Treatment of immobilization-related hypercalcaemia with denosumab.

Hypercalcaemia has been reported to occur in ∼1–4% of the general adult population, and in 0.5–3% of hospitalized adult patients [1]. Hypercalcaemia results when the entry of calcium (Ca) into the extracellular fluid exceeds excretion in the urine or deposition in bone. This occurs when there is accelerated bone resorption, excessive gastrointestinal absorption or decreased renal excretion of Ca. Under most pathologic conditions, hypercalcaemia results from increased skeletal resorption or intestinal absorption with normal or decreased renal excretion. In some disorders more than one mechanism may be involved. As an example, in primary hyperparathyroidism, elevated parathyroid hormone (PTH) levels increase bone resorption, tubular Ca reabsorption and, indirectly, intestinal Ca absorption (by increasing renal synthesis of calcitriol). Among all causes of hypercalcaemia, primary hyperparathyroidism and malignancy are the most common, accounting for >90% of cases [2]. The differential diagnosis of hypercalcaemia may be broadly divided into PTH-mediated and non-PTH-mediated hypercalcaemia [3] (Table 1). PTH-mediated hypercalcaemia is associated most frequently with primary hyperparathyroidism. The most common cause of non-PTH-mediated hypercalcaemia is that of malignancy. Hypercalcaemia in patients with cancer is primarily due to increased bone resorption and the release of Ca from bone. There are three major mechanisms by which this can occur: osteolytic metastases with local release of cytokines which stimulates the differentiation of osteoclast precursors into mature osteoclasts and activates bone resorption (mainly breast cancer, myeloma and lymphomas), tumour secretion of PTH-related protein (PTHrP) (mainly solid tumours, such as squamous cell carcinomas and renal carcinomas) and tumour production of calcitriol (mainly lymphomas). In the latter condition, hypercalcaemia results from the increase of either bone resorption or intestinal absorption. Ectopic PTH secretion has been documented in single cases of small cell and squamous cell lung cancer, ovarian carcinoma, papillary thyroid carcinoma, hepatocellular carcinoma and undifferentiated neuroendocrine neoplasia. Non-PTH-mediated hypercalcaemia may be caused also by different endocrine disorders such as thyrotoxicosis and adrenal insufficiency. In hyperthyroidism, hypercalcaemia mainly results from increased bone resorption. Hypercalcaemia is a rare complication of pheochromocytoma. It can be due to concurrent hyperparathyroidism (in MEN, Type II) or to the pheochromocytoma itself due to tumoural production of PTHrp. Granulomatous diseases (such as sarcoidosis, and focal or disseminated tuberculosis) can cause hypercalcaemia by overproduction of 1,25-dihydroxyvitamin D. Immobilization is a rare cause of hypercalcaemia. For the diagnosis of immobilization-related hypercalcaemia, all the other causes of PTH- and vitamin D-dependent hypercalcaemia should be carefully excluded (Table 1). In this issue of CKJ, de Beus and Boer [4] report the case of a patient with chronic renal failure and immobilization-related hypercalcaemia successfully treated with denosumab, a monoclonal antibody with affinity for the receptor activator of nuclear factor-kB (RANK) ligand (RANKL). Prolonged immobilization uncouples bone remodelling because of the lack of mechanical stress. The greater deceleration in bone formation than in bone resorption results in a net efflux of Ca from bone that induces hypercalciuria and suppression of the parathyroid-1,25-vitamin D axis [5]. Hypercalcaemia develops when the efflux of Ca from bone exceeds the capacity of the kidney to excrete Ca. Immobilized patients with pre-existing states of high bone turnover (e.g. adolescents and patients with Paget's disease, thyrotoxycosis or primary hyperparathyroidism), and/or reduced renal function are at particular risk of developing severe hypercalcaemia [6–8] Table 1. Causes of hypercalcaemia

25-Hydroxyvitamin D response to cholecalciferol supplementation in hemodialysis.

Recent understanding of extrarenal production of calcitriol has led to the exploration of native vitamin D treatment in dialysis patients. This paper reports the pharmacokinetics of 25-hydroxyvitamin D response to 10,333 IU cholecalciferol given weekly in subjects on chronic dialysis. This randomized, double-blind, placebo-controlled trial of 15 weeks of oral cholecalciferol in subjects with stage 5 CKD requiring maintenance hemodialysis was conducted from November of 2007 to March of 2010. The time course of serum 25-hydroxyvitamin D was measured over the course of treatment. Additionally, blood was drawn at baseline and last visit for calcium, phosphorus, calcitriol, and parathyroid hormone levels. The median (interquartile range) baseline 25-hydroxyvitamin D level was 13.3 (11.1-16.2) ng/ml for the treatment group and 15.2 (10.7-19.9) ng/ml for the placebo group. 25-hydroxyvitamin D steady state levels rose by 23.6 (19.2-29.9) ng/ml in the treatment group, and there was no change in the placebo group. Calcitriol levels also increased significantly in the treatment group. There were no significant changes in levels of calcium, albumin, phosphorus, and parathyroid hormone in either group. Cholecalciferol (10,333 IU) given weekly in patients on chronic hemodialysis produces a steady state in 25-hydroxyvitamin D of approximately 24 ng/ml.

Calcium Deficiency Reduces Circulating Levels of FGF23

Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia.

The inflammatory response of keratinocytes and its modulation by vitamin D: The role of MAPK signaling pathways

The hormonal form of vitamin D, calcitriol, and its analogs are known for their beneficial effect in the treatment of inflammatory skin disorders. Keratinocytes play a role in epidermal inflammatory responses invoked by breeching of the epidermal barrier, by infectious agents and by infiltrating immune cells. We studied the role of calcitriol in the initiation of keratinocyte inflammatory response by the viral and injury mimic polyinosinic-polycytidylic acid (poly(I:C)) and in its maintenance by tumor-necrosis-factor α (TNFα) and investigated the role of the mitogen-activated protein kinase cascades in these processes and their regulation by calcitriol. The inflammatory response of human HaCaT keratinocytes to poly(I:C) or TNFα was assessed by measuring mRNA levels of 13 inflammation-related molecules by real-time PCR microarray and by in-depth investigation of the regulation of interleukin 8, intercellular-adhesion-molecule 1, and TNFα expression. We found that while calcitriol had only a minor effect on the keratinocyte response to poly(I:C) and a modest effect on the early response (2 h) to TNFα, it markedly attenuated the later response (16-24 h) to TNFα. The expression of CYP27B1, the enzyme responsible for calcitriol production, was marginally increased by poly(I:C) and markedly by TNFα treatment. This pattern suggests that while allowing the initial keratinocyte inflammatory response to proceed, calcitriol contributes to its timely resolution. Using pharmacological inhibitors we found that while the p38 MAPK and the extracellular signal-regulated kinase have only a minor role, c-Jun N-terminal kinase plays a pivotal role in the induction of the pro-inflammatory genes and its modulation by calcitriol.

Vitamin D: An innate antiviral agent suppressing hepatitis C virus in human hepatocytes

Vitamin D supplementation was reported to improve the probability of achieving a sustained virological response when combined with antiviral treatment against hepatitis C virus (HCV). Our aim was to determine the in vitro potential of vitamin D to inhibit HCV infectious virus production and explore the mechanism(s) of inhibition. Here we show that vitamin D(3) remarkably inhibits HCV production in Huh7.5 hepatoma cells. These cells express CYP27B1, the gene encoding for the enzyme responsible for the synthesis of the vitamin D hormonally active metabolite, calcitriol. Treatment with vitamin D(3) resulted in calcitriol production and induction of calcitriol target gene CYP24A1, indicating that these cells contain the full machinery for vitamin D metabolism and activity. Notably, treatment with calcitriol resulted in HCV inhibition. Collectively, these findings suggest that vitamin D(3) has an antiviral activity which is mediated by its active metabolite. This antiviral activity involves the induction of the interferon signaling pathway, resulting in expression of interferon-β and the interferon-stimulated gene, MxA. Intriguingly, HCV infection increased calcitriol production by inhibiting CYP24A1 induction, the enzyme responsible for the first step in calcitriol catabolism. Importantly, the combination of vitamin D(3) or calcitriol and interferon-α synergistically inhibited viral production. This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system. It proposes an interplay between the hepatic vitamin D endocrine system and HCV, suggesting that vitamin D has a role as a natural antiviral mediator. Importantly, our study implies that vitamin D might have an interferon-sparing effect, thus improving antiviral treatment of HCV-infected patients.

Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes

Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndromes (CRS) has been identified wherein a vicious cycle is established as an acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. Progressive loss of kidney function observed in patients with CRS (mostly types 2 and 4) leads to reduced production of calcitriol (active vitamin D) and an imbalance in calcium and phosphorus levels, which are correlated with increased rates of cardiovascular events and mortality. In addition, hypocalcemia can lead to prolonged and excessive secretion of parathyroid hormone (PTH), eventually leading to development of secondary hyperparathyroidism. Therefore, based on this important mechanism of organ damage, one of the major goals of therapy for patients with CRS is to restore regulatory control of PTH. Although administration of calcitriol increases serum calcium levels and reduces PTH levels, it is also associated with elevated serum levels of calcium-phosphorus product. Therefore, compounds that selectively activate vitamin D receptors, potentially reducing calcium×phosphate toxicity, are likely to enhance cardiorenal protection and provide significant clinical benefit.

Équilibre phosphocalcique : régulation et explorations

Calcium and phosphate play a key role in bone mineralization but have also many other physiological functions. The control of serum phosphate concentration is mandatory to avoid the occurrence of severe metabolic disorders, but is less tightly regulated than serum ionized calcium concentration, which is maintained in a very limited range thanks to parathyroid hormone (PTH) and the active vitamin D metabolite calcitriol. Any change in serum ionized calcium concentration is detected by the calcium sensing receptor (CaSR), a membranous protein located principally in the parathyroid glands and the kidney. A decrease in ionized calcium level inactivates the CaSR, thus stimulating PTH secretion. PTH in turn stimulates the release of calcium and phosphate from bone, renal calcium reabsorption and calcium and phosphate intestinal absorption by inducing renal calcitriol production. Moreover, PTH inhibits phosphate reabsorption in proximal tubular cells, thus contributing towards phosphate homeostasis. Fibroblast growth factor 23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate by inhibiting renal phosphate reabsorption and calcitriol production and may have a great physiological role in phosphate homeostasis. Recently, vitamin D actions independent of calcium and phosphate homeostasis were discovered. Basal exploration of phosphocalcic metabolism abnormalities consists in measurement of serum calcium (ionized calcium if possible), phosphate, 25-hydroxy vitamine D and PTH and of 24 hours urinary calcium excretion as well as renal function. Hence, the understanding of physiopathological mechanisms has been improved by newly identified genetic disorders responsible for phophocalcic homeostasis disturbances.

Clinical practice

Until a decade ago, two main hormones were recognized as directly affecting phosphate homeostasis and, with that, bone metabolism: parathyroid hormone and 1,25(OH)(2) vitamin D (calcitriol). It was only a decade ago that the third major player hormone was found, linking gut, bone, and kidney. The physiologic role of fibrinogen growth factor (FGF)23 is to maintain serum phosphate concentration within a narrow range. Secreted from osteocytes, it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23-manifested by hypophosphatemia, low serum calcitriol, and rickets/osteomalacia-or hypo-FGF23, expressed by hyperphosphatemia, high serum calcitriol, and extra-skeletal calcifications. In patients with chronic renal failure, FGF23 levels increase as kidney functions deteriorate and are under investigation to learn if the hormone actually participates in the pathophysiology of the deranged bone and mineral metabolism typical for these patients and, if so, whether it might serve as a therapeutic target. This review addresses the physiology and pathophysiology of FGF23 and its clinical applications.