Expression of calcium-sensing receptor gene by avian parathyroid gland in vivo: relationship to plasma calcium

Calcium-sensing receptor (CaR) gene expression and parathyroid hormone (PTH) content were evaluated in situ in chicken parathyroid glands (PG) in relation to changes in plasma calcium. The CaR gene is expressed by the parathyroid chief cells, the same cells that store and secrete PTH. An increase in plasma calcium, achieved by repletion of vitamin D-deficient chicks with a normal diet, by PTH injection, or during eggshell formation, increased the expression of the CaR gene. Low plasma calcium concentration in vitamin D-deficient chicks or in layers, before or after eggshell formation, was associated with decrease in CaR gene expression in the PG. The level of CaR gene expression was inversely correlated with the PTH content of the PG. The results of this study demonstrate for the first time that, in contrast to mammals, the CaR gene expression in the PG of the chicken is inversely associated with changes in plasma calcium.     

Ca(2+) receptor from brain to gut: common stimulus, diverse actions.

An extracellular Ca(2+)-sensing receptor (CaR) plays central roles in Ca(2+) homeostasis by regulating parathyroid hormone (PTH)secretion and renal Ca(2+) handling. The CaR is also expressed in intestine and bone, where its functions in mineral metabolism are not yet well defined. The receptor is also present in various types of cells seemingly uninvolved in systemic mineral ion homeostasis (such as neuronal and glial cells in the brain and various epithelial cells), where its actions are poorly understood but might involve the regulation of local ionic homeostasis and/or diverse cellular processes, such as cellular differentiation and proliferation.     

Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93-99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.     

Parathyroid gland calcium receptor mRNA levels are unaffected by chronic renal insufficiency or low dietary calcium in rats

Extracellular ionized calcium (Ca(2+)) is the primary physiological regulator of parathyroid hormone (PTH) secretion and the G protein-coupled receptor (CaR) that mediates this response has been cloned from bovine and human parathyroid glands. The Ca(2+) set-point for the regulation of PTH secretion is right-shifted in primary hyperparathyroidism (1°HPT), but whether there is a similar shift in 2°HPT is unclear. Additionally, the molecular defects associated with such changes in the set-point remain uncharacterized. These experiments were designed to determine (1) if changes in set-point occur in rats with 2°HPT induced by chronic renal insufficiency (CRI) or dietary Ca deficiency, and (2) whether any changes in set-point are mirrored by changes in steady-state mRNA levels for the parathyroid CaR. CaR mRNA levels were quantified in pairs of glands from individual rats using a solution hybridization assay. Blood urea nitrogen and PTH levels were ～ 4-fold higher in rats with CRI induced by 5/6 nephrectomy 7 weeks earlier. Rats with CRI were also significantly hypocalcemic and hyperphosphatemic. The setpoint was unchanged in CRI rats and CaR mRNA levels were also unaffected. Normal rats fed a 0.02% Ca diet for 6 weeks were markedly hypocalcemic, and had 10- and 15-fold increases in plasma PTH and 1,25-dihydroxyvitamin D(3) levels, respectively. Technical problems prevented assessment of the set-point in these animals, but parathyroid gland CaR mRNA levels were identical in both dietary groups. Thus, neither alterations in mRNA levels for the CaR nor changes in the set-point play demonstrable roles in the pathogenesis of 2°HPT in these models.     

Calcium Receptor and Regulation of Parathyroid Hormone Secretion

The cloning of the CaR has made it possible to show definitively that the CaR is a critical mediator of the inhibitory effect of high Cao2+ on PTH secretion and parathyroid cellular proliferation. The receptor may also mediate the suppressive action of high Cao2+ on PTH gene expression, while its involvement in several other known actions of Cao2+ on parathyroid function remain to be examined. Alterations in CaR expression and/or function are clearly involved in hyper- and hypocalcemic disorders caused by inactivating or activating CaR mutations, respectively, and could contribute to the deranged Cao(2+)-sensing in primary and uremic secondary HPT. Finally, CaR activators offer promise as the first truly effective mode of medical therapy for these latter two conditions.     

Decreased expression of caveolin-1 and altered regulation of mitogen-activated protein kinase in cultured bovine parathyroid cells and human parathyroid adenomas

Caveolins are key components of caveolae membranes. The calcium-sensing receptor (CaR) resides within caveolin-rich membrane domains in bovine parathyroid (PT) cells. Recent studies reported reduced CaR expression, and abnormal calcium-sensing in PT tumors. To examine this altered CaR signaling, we investigated ERK activation after CaR stimulation in human and bovine PT cells. In freshly prepared bovine PT cells, high extracellular calcium (Ca(2+)(0)) stimulates ERK1/2 phosphorylation, and activated ERK1/2 colocalizes with caveolin-1 at the plasma membrane but fails to translocate to the nucleus, and cell proliferation is low. In cultured bovine PT cells, CaR and caveolin-1 levels are reduced; activated ERK1/2 localizes in the cell periphery at 10 min and in the perinuclear and nuclear regions at 60 min after exposure to high Ca(2+)(0), and cell proliferation is increased. In PT cells from adenomas, there are high levels of caveolin-2, variably reduced caveolin-1, and hyperactivation of ERK1/2, which colocalizes with caveolin-1 in some cells, but localizes in the cytosol and nucleus in others. Finally, caveolin-1 negative human PT cells exhibit reduced suppressibility of PTH secretion by high Ca(2+)(0). Thus, CaR and caveolin-1 colocalize in PT cells, and reduced levels of caveolin-1 could participate in the abnormal cellular function and proliferation of cultured bovine PT cells and PT adenomas.     

Parathyroid hormone (PTH) secretion, PTH mRNA and calcium-sensing receptor mRNA expression in equine parathyroid cells, and effects of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha on equine parathyroid cell function

Parathyroid hormone (PTH) is secreted by the chief cells of the parathyroid gland in response to changes in ionized calcium (Ca(2+)) concentrations. In this study, we measured PTH secretion, and PTH mRNA and calcium-sensing receptor (CaR) mRNA expression by equine parathyroid chief cells in vitro. We also evaluated the effects of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha on PTH secretion, and PTH and CaR mRNA expression. The relationship between PTH and Ca(2+) was inversely related. PTH secretion decreased from 100% (day 0) to 13% (day 30). PTH mRNA expression declined from 100% (day 0) to 25% (day 30). CaR mRNA decreased from 100% (day 0) to 16% (day 30). Chief cells exposed to high (2.0 mM) Ca(2+) concentrations had a lower PTH mRNA expression compared with low Ca(2+) concentrations. Ca(2+) concentrations had no effect on CaR mRNA expression. The inhibitory effect of high Ca(2+) concentrations on PTH secretion also declined over time. After day 10, there was no significant difference in PTH secretion between low and high Ca(2+ )concentrations. IL-1beta decreased both PTH secretion (75%) and PTH mRNA expression (73%), and resulted in a significant overexpression of CaR mRNA (up to 142%). The effects of IL-1beta were blocked by an IL-1 receptor antagonist. IL-1beta decreased the Ca(2+) set-point from 1.4 mM to 1.2 mM. IL-6 decreased PTH secretion (74%), but had no effect on PTH and CaR mRNA expression. TNF-alpha had no effect on PTH secretion, and PTH and CaR mRNA expression. In summary, the decreased responsiveness of parathyroid cells to Ca(2+) from 0 to 30 days can be explained, in part, by the reduced CaR expression. IL-1beta and IL-6 but not TNF-alpha affected parathyroid function in vitro and may be important in influencing PTH secretion in the septic horse.     

Physiology and pathophysiology of the extracellular calcium-sensing receptor

The system governing extracellular calcium (Ca2+o) homeostasis maintains near constancy of Ca2+o so as to ensure continual availability of calcium ions for their numerous intracellular and extracellular roles. In contrast to the intracellular ionized calcium concentration (Ca2+i), which varies substantially during intracellular signaling via this key second messenger, Ca2+o remains nearly invariant. Yet there must be a mechanism that senses small changes in Ca2+o so as to set into motion the homeostatic responses that return Ca2+o to its normal level. The recent identification and molecular cloning of the mechanism through which parathyroid cells and a number of other cell types sense Ca2+o, a G protein-coupled Ca2+o-sensing receptor (CaR), has proven unequivocally that extracellular calcium ions serve in an informational capacity. The CaR permits Ca2+o to function in a hormone-like role as an extracellular first messenger through which parathyroid, kidney, and other cells communicate with one another via the CaR. The identification of inherited human hypercalcemic and hypocalcemic disorders arising from inactivating and activating mutations of the CaR, respectively, has provided additional proof of the essential, nonredundant role of the CaR in mineral ion homeostasis. Moreover, CaR-active drugs are currently in clinical trials for the treatment of primary and uremic hyperparathyroidism, disorders in which there are acquired, tissue-specific reductions in CaR expression and, in turn, defective Ca2+o-sensing by pathological parathyroid cells. No doubt further studies of Ca2+o-sensing by the CaR will reveal additional functions of Ca2+o, not only as a systemic "hormone" but also in local, paracrine, and autocrine signaling through this novel Ca2+o-sensing receptor.     

Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism

A reduced expression of calcium-sensing receptor (CaR) messenger ribonucleic acid and protein accompanied by abnormalities in parathyroid cell proliferation and PTH secretion are present in primary hyperparathyroidism. We studied the expression of CaR protein by immunohistochemistry in 36 sporadic parathyroid adenomas and investigated the relationship between CaR expression and several preoperative clinical parameters, including the set-point of Ca(2+)-regulated PTH secretion (measured in vivo). The adenomas were classified in 4 categories according to the intensity of immunohistochemical staining: 5 (14%) showed a CaR staining intensity similar to that of normal parathyroid ( ), 10 (27%) showed moderate staining (++), 16 (45%) showed weak staining (+), and 5 (14%) were negative (-). The intensity of CaR staining was not related to preoperative serum Ca(2+), PTH levels or adenoma volume. Twenty-nine patients underwent preoperatively the calcium infusion test to evaluate the PTH-Ca(2+) set-point. Individual values of PTH-Ca(2+) set-point ranged from 1.38-1.93 mmol/L and were significantly correlated with basal Ca(2+) levels (r = 0.96; P: = 0. 0001) and adenoma volume (r = 0.5; P: = 0.01). The mean PTH-Ca(2+) set-point values were significantly different in the 4 groups of patients classified according to immunohistochemical staining intensity of their adenoma (P: = 0.025; F = 3.78); the mean PTH-Ca(2+) set-point was significantly higher in the groups classified as negative than in those classified as weak or moderate. No correlation was observed between the PTH-Ca(2+) set-point and basal PTH levels or between the percent maximal PTH inhibition and adenoma volume and basal PTH or Ca(2+) levels. In summary, our data suggest that there is a relationship between apparent CaR protein expression and PTH-Ca(2+) set-point abnormality, suggesting that a reduced receptor content might have an important role in the pathogenesis of primary hyperparathyroidism.     

Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism

Autoimmune hypoparathyroidism is thought to result from immune-mediated destruction of the parathyroid glands. We encountered two patients with hypoparathyroidism and other autoimmune conditions (Graves' disease and Addison's disease, respectively) in whom autoimmune destruction of the parathyroid glands had not taken place. In the first, a histologically normal parathyroid gland was observed at the time of subtotal thyroidectomy; and in the second, the hypoparathyroidism remitted spontaneously. Both patients had antibodies that reacted with the cell surface of bovine parathyroid cells and human embryonic kidney (HEK293) cells transfected with the extracellular calcium-sensing receptor (CaR) but not with nontransfected HEK293 cells. The antibodies also reacted with the same bands on Western analysis of extracts of bovine parathyroid tissue and CaR-transfected HEK293 cells that were identified by an authentic, polyclonal, anti-CaR antiserum and reacted with several peptides with sequences from the CaR's extracellular domain. These anti-CaR antibodies activated the receptor based on their ability to increase inositol phosphate accumulation, activate MAPK, and inhibit PTH secretion. These results, therefore, demonstrate that patients with the biochemical findings of primary hypoparathyroidism can harbor activating antibodies to the CaR, which, in the two cases studied here, did not produce irreversible destruction of the parathyroid glands.     

Parathyroid hormone release in vitro in hyperparathyroidism associated with multiple endocrine neoplasia type 1

Hyperparathyroidism (HPT) in the syndrome of multiple endocrine neoplasia type 1 (MEN-1) exhibits a different picture regarding its propensity for recurrence compared with sporadic primary HPT. In order to shed further light on the MEN-1 syndrome an investigation in vitro was made of parathyroid hormone (PTH) release of dispersed parathyroid cell from 11 patients with parathyroid hyperplasia associated with MEN-1, 10 patients with single parathyroid adenomas, and 10 preparations of normal bovine parathyroid glands. The two patient groups had the same average serum calcium value prior to surgery. Immunoreactive concentrations of PTH were measured after 2-h incubations at extracellular calcium concentrations of 0.5-3.0 mmol/l. Compared with the normal bovine parathyroid cells, the cells of the MEN-1 patients had a reduced calcium sensitivity of the PTH release and secreted smaller amounts of hormone at both low and high extracellular calcium concentrations. A similar abnormality of the PTH release was found for the cells of the hyperplastic and adenomatous parathyroid glands. Although individual parathyroid glands were investigated in only three MEN-1 patients, the results suggested the secretory regulation to be less defective in the small glands of each patient. It is concluded that in patient groups matched for serum calcium, the parathyroid tissue of MEN-1 patients has an abnormality of the PTH release similar to that of parathyroid adenomas.     

Abnormal regulation of parathyroid cell secretion and proliferation in primary cultures of bovine parathyroid cells

We developed a method for establishing primary monolayer cultures of bovine parathyroid cells, characterized the cells morphologically, and studied the effects of calcium on PTH secretion and cellular proliferation. Fresh bovine parathyroid glands were enzymatically and mechanically dispersed, as previously described, using sterile solutions and apparatus. The cells were then plated at a density of 2.5 X 10(5) cells/cm2 into cluster wells and incubated at 37 C in a medium containing Dulbecco's Modified Eagle's and Ham's F-12 medium, 15% newborn calf serum, Hepes, antibiotics, and insulin. In 3-4 days, a near-confluent monolayer of polygonal-shaped cells with less than 10% fibroblasts was achieved. Electron microscopy revealed a homogeneous cell population containing electron-dense secretory granules as well as abundant rough endoplasmic reticulum and mitochondria, with no evidence of organelle swelling. Two parameters of cellular proliferation increased significantly in culture; viable cell number increased from 289,000 +/- 63,000 to 530,000 +/- 60,000 per well (P less than 0.02), and cellular protein increased from 40.00 +/- 1.40 to 177.60 +/- 57.10 micrograms/well (P less than 0.035). On an hourly basis, cultured cells showed a greater secretory rate than that of acutely dispersed cells (9.3 vs. 5.0 ng/10(5) cells X h, respectively). Unlike normal bovine parathyroid cells, however, high calcium concentrations inhibited PTH secretion only slightly (21.2 +/- 4.7%) and had no effect on cellular proliferation. Addition of the divalent cation ionophore A23187, on the other hand, inhibited PTH release by 50% or more, suggesting that the secretory apparatus is responsive to increases in the cytosolic calcium concentration. The present study reveals that bovine parathyroid cells in primary culture proliferate and secrete PTH in vitro. These cells display, however, a generalized decrease in sensitivity to the suppressive effects of extracellular calcium on hormonal secretion and cellular proliferation comparable to that of pathological parathyroid tissue. Thus, this cell culture system may provide a useful model for investigating the relationship between secretion and proliferation in normal and abnormal tissue.     

Hyperparathyroidism is associated with reduced expression of a parathyroid calcium receptor mechanism defined by monoclonal antiparathyroid antibodies

Parathyroid tissue from patients with hyperparathyroidism (HPT) exhibited reduced immunohistochemical reactivity with monoclonal antiparathyroid antibodies, previously shown to stain intensely the surface of normal human parathyroid cells and to interfere with a receptor mechanism of these cells which is involved in the sensing and gating of Ca2+. Parathyroid hormone (PTH) release and cytoplasmic Ca2+ concentrations (Ca2+i) of dispersed cells from the pathological parathyroid glands had right-shifted dependencies on extracellular Ca2+, and exposure to the antibodies rendered both Ca2+i and PTH release almost completely insensitive to changes in ambient Ca2+. The results suggest that reduced expression of a parathyroid calcium receptor mechanism may be an important cause for the aberrant PTH release in HPT.     

Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor

Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.     

A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo

Circulating calcium (Ca(2+)) is a primary regulator of bone homeostasis through its action on PTH secretion. Extracellular Ca(2+) modulates PTH secretion through a cell surface G protein-coupled receptor, the calcium-sensing receptor (CaR). The expression of the CaR suggests a critical role in cellular regulation by calcium in various organs, including parathyroid gland, bone, and kidney. Despite an obvious pharmacological utility for CaR antagonists in the treatment of disease, only a limited number of such classes of compounds exist. We have identified a novel class of small molecules with specific activity at the CaR. This class of compounds is represented by compound 1. It possesses potent antagonist activity at the human CaR with IC(50) values of 64 nm and 230 nm in inhibiting intracellular Ca(2+) flux and inositol phosphate generation in vitro, respectively. When administered to male rats in vivo, compound 1 robustly increased serum PTH levels. The stimulation of PTH secretion was rapid and transient when administered either iv or orally. The pharmacokinetic profile of compound 1 after oral administration revealed that maximal plasma levels of compound were reached within 1 h and the half-life of the compound to be approximately 2 h in rats. These data describe a representative compound of a novel chemical class than previously described allosteric modulators that offer a new avenue for the development of improved treatments of osteoporosis.     

Familial hypocalciuric hypercalcemia and other disorders with resistance to extracellular calcium.

Cloning of the CaR has increased understanding of the normal control of mineral ion homeostasis and has clarified the pathophysiology of PTH-dependent hypercalcemia. Cloning of the CaR has enabled identification of FHH and NSHPT as inherited conditions with generalized resistance to Ca2+o, which is caused in many cases by inactivating mutations in the CaR gene. In most kindreds with FHH, there is resetting of Ca2+o to a mildly elevated level that does not require an increase in the circulating level of PTH above the normal range to maintain it. FHH is not accompanied by the usual symptoms, signs, and complications of hypercalcemia. The kidney participates in the genesis of the hypercalcemia in FHH by avidly reabsorbing Ca2+; consequently, there is no increased risk of forming urinary calculi in most cases. Generally, there is no compelling rationale for attempting to lower the level of Ca2+o in these patients to a nominal normal level. In contrast, in primary hyperparathyroidism, the Ca2+o resistance is limited to the pathologic parathyroid glands, and the rest of the body suffers the consequences of high circulating levels of calcium, PTH, or both. In this condition, removal of the offending parathyroid glands is often the treatment of choice. Parathyroidectomy may also be appropriate in disorders with generalized resistance to Ca2+o owing to inactivating CaR mutations in the following special circumstances: in selected families with FHH in which there is unusually severe hypercalcemia, frankly elevated PTH levels, or atypical features such as hypercalciuria; in cases of NSHPT with severe hypercalcemia and hyperparathyroidism; and in the occasional mild case of homozygous FHH owing to CaR mutations that confer mild-to-moderate resistance to Ca2+o that escapes clinical detection in the neonatal period. As discussed elsewhere in this issue, selective calcimimetic CaR activators are being tested in clinical trials, which potentiate the activation of the CaR by Ca2+o, thereby resetting the elevated set point for Ca2+o-regulated PTH release in primary and secondary hyperparathyroidism toward normal. It is hoped that these agents may become an effective medical therapy for the acquired Ca2+o resistance in primary and secondary hyperparathyroidism and perhaps for that present in the unusual cases of FHH and NSHPT, resetting the "calciostat" downward and thereby reducing Ca2+o and PTH toward normal.     

Calcium homeostasis and hyperparathyroidism: Nephrologic and endocrinologic points of view

Parathyroid hormone (PTH) is a hypercalcemic hormone acting on kidneys, bone and intestine. PTH promotes calcium release from the bone, renal calcium reabsorption and phosphate excretion, and conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D-3. Hyperparathyroidism consists in PTH elevation, which may be adapted (secondary hyperparathyroidism) or non-adapted to calcemia levels (primary hyperparathyroidism, familial hypercalcemia/hypocalciuria, tertiary hyperparathyroidism). Primary hyperparathyroidism (PHP) features hypercalcemia and elevated or inappropriate PTH elevation. PHP may be revealed by biological abnormalities such as hypercalcemia and can be accompanied by renal complications (hypercalciuria, nephrolithiasis, nephrocalcinosis) and/or osteoporosis. However, it can also be normocalcemic and calcium loading will be necessary to diagnosis it. The differential diagnosis of PHP is familial hypocalciuric hypercalcemia (FHH), a dominant autosomal disease implicating a calcium sensing receptor-inactivating mutation. It impairs parathyroid cell sensitivity to calcemia elevation and thus induces excessive PTH stimulation, leading to hypercalcemia. Secondary HP (SHP) consists in PTH elevation secondary to a stimulus that needs to be corrected. 25 OHvitD deficiency, kidney failure, renal hypercalciuria, malabsorption and some drugs can induce SHP. Tertiary HP (THP) consists in autonomous PTH secretion by the parathyroid glands after prolonged stimulation under SHP, of whatever cause. This parathyroid autonomy results from the polyclonal hyperplasia observed in SHP progressing toward monoclonal nodular proliferation, leading to nodular hyperplasia or parathyroid adenoma (or, exceptionally, carcinoma), with reduced expression of CaSR and vitamin D receptor. In patients under dialysis, the frontier between SHP and THP is a matter of debate. This review will focus on the pathophysiology of calcium, diagnosis, and management of hyperparathyroidism.