Parathyroid Hormone Suppression Research Articles

Does it Matter How Parathyroid Hormone Levels are Suppressed in Secondary Hyperparathyroidism?

Because secondary hyperparathyroidism is associated with morbidity and mortality in patients with chronic kidney disease, suppression of parathyroid hormone (PTH) and minimization of associated derangements in mineral metabolism are cardinal therapeutic goals. There is an ongoing debate regarding the proper treatment strategy for PTH suppression in this population. While some practitioners believe that calcitriol analogues should be the primary therapy in this setting, others contend that calcimimetics offer unique treatment benefits. Recent advancements in the understanding of the pathophysiology of secondary hyperparathyroidism and the secondary effects of these agents may help clarify this debate. Here, we review the classical actions of calcitriol analogues and calcimimetics on mineral metabolism. We also examine the potential nonclassical effects of these therapies on the renin-angiotensin-aldosterone system, proteinuria, vascular calcification, fibroblast growth factor-23, inflammation, and overall survival.

Effect of Intravenous Saccharated Ferric Oxide on Serum FGF23 and Mineral Metabolism in Hemodialysis Patients

Background/Aims: Fibroblast growth factor-23 (FGF23) plays a central role in the development of hypophosphatemia and inappropriately low 1,25-dihydroxyvitamin D induced by iron therapy for iron-deficiency anemia. The aim of this study was to examine the effect of intravenous saccharated ferric oxide on serum FGF23 levels and mineral metabolism in hemodialysis patients. Methods: This prospective study enrolled 27 hemodialysis patients who had iron-deficiency anemia defined by a hemoglobin concentration <10.5 g/dl and serum ferritin <100 ng/ml. Intravenous saccharated ferric oxide at a dose of 40 mg was administered three times weekly over 3 weeks. The dose of active vitamin D and phosphate binders was kept unchanged. Serum FGF23, intact parathyroid hormone (PTH) and other parameters were prospectively monitored for 5 weeks. Results: Serum FGF23 levels were markedly elevated [3,453 (338–6,383) pg/ml] at baseline. After 3 weeks of intravenous saccharated ferric oxide treatment, serum FGF23 further increased to 4,701 (1,251–14,396) pg/ml, and returned to the baseline values after 2 weeks of observation. There was also a significant decrease in intact PTH but no changes in serum calcium and phosphorus. Conclusions: Intravenous saccharated ferric oxide induces further increase in elevated FGF23 levels in hemodialysis patients. This increase does not induce hypophosphatemia and inappropriately low 1,25-dihydroxyvitamin D in the absence of functioning kidney, but may result in transient PTH suppression – possibly by directly acting on the parathyroid.

Defective renal maintenance of the vitamin D endocrine system impairs vitamin D renoprotection: a downward spiral in kidney disease

In kidney disease, the progressive loss of renal capacity to produce calcitriol, the vitamin D hormone, is a key contributor to elevations in parathyroid hormone (PTH) and mineral and skeletal disorders predisposing to renal and cardiovascular damage, ectopic calcifications, and high mortality rates. Thus, the safe correction of calcitriol deficiency to suppress PTH has been the treatment of choice for decades. However, recent epidemiological and experimental data suggest that calcitriol replacement may improve outcomes through renal and cardioprotective actions unrelated to PTH suppression. Furthermore, a striking incidence of vitamin D deficiency occurs in kidney disease and associates more strongly than calcitriol deficiency with a higher risk for kidney disease progression and death. Despite the translational relevance of these findings, no prospective trials are currently available in support of the efficacy of vitamin D supplementation and/or calcitriol replacement to safely halt/moderate renal disease progression. This review updates the pathophysiology behind the vicious cycle by which kidney injury impairs the maintenance of normal vitamin D and calcitriol levels, which in turn impedes vitamin D/calcitriol renoprotective actions, a requirement for the design of prospective trials to improve current recommendations for vitamin D interventions at all stages of kidney disease.

Effect of Alfacalcidol on Anemia in Renal Failure Patients

Background: Anemia is a major feature of chronic kidney disease (CKD). Additionally, secondary hyperparathyroidism (SHPT) has been associated with anemia in uremic patients. Administration of active vitamin D metabolites like alfacalcidol is established for PTH suppression and may also play a role in hematopoiesis. Aim:To investigate the effect of alfacalcidol on anemia and SHPT with end stage renal failure patients underwent hemodialysis. Subjects and Methods: In the present study 17 anemic patients over 15years, with serum level of PTH greater than 500pg/ml. The study was carried out by means of data collection and analysis of serum parathyroid hormone (PTH) and hemoglobin (Hb) levels in these patients. Results: Low serum PTH levels were detected in uremic patients treated with alfacalcidol. Also, in these patients, Hb levels increased. Serum PTH and Hb levels were inversely correlated. Conclusions: High-dose alfacalcidol can decrease serum PTH levels and elevate Hb level in uremic patients showing considerable resistance to Epoetin.

Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism

We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized to 8 months of therapy with either oral calcitriol or doxercalciferol, combined with either calcium carbonate or sevelamer. Bone formation rates decreased during therapy and final values were within the normal range in 72% of patients. A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol. On initial bone biopsy, a mineralization defect was identified in the majority of patients which did not normalize with therapy. Serum phosphate concentrations were controlled equally well by both binders, but serum calcium levels increased during treatment with calcium carbonate, and serum parathyroid hormone levels were decreased by 35% in all groups. Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol, irrespective of phosphate binder. Thus, doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate. Sevelamer allows the use of higher doses of vitamin D. Implications of these changes on bone and cardiovascular biology remain to be established.

Switch from calcitriol to paricalcitol in secondary hyperparathyroidism of hemodialysis patients: Responsiveness is related to parathyroid gland size

Paricalcitol is more effective than calcitriol in hemodialysis patients (HD) with secondary hyperparathyroidism (SHPT), but it is not effective in some of them. We have investigated the relationship between paricalcitol responsiveness and parathyroid gland (PTG) size. Thirty HD with SHPT treated previously with calcitriol for at least 6 months were switched to paricalcitol (1:4 conversion ratio). Parathyroid gland number and size (maximum longitudinal diameter [MLD] of largest PTG) was measured by ultrasonography. Patients were divided into 2 groups: group A (MLD ≤9.0 mm [17 HD]); and group B (MLD >9.0 mm [13 HD]). They were defined responder if both the last 2 monthly determinations of inhibit parathyroid hormone (iPTH) were within the target (<300 pg/mL) according to National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommendations. Twenty-six and 20 HD completed 6-month and 12-month paricalcitol therapy, respectively. After 6 months of paricalcitol treatment, 23.5% HD of group A and 7.7% of group B were responders. At 12 months, 41.2 % of group A and 7.7% of group B were responders. Throughout paricalcitol therapy, serum calcium and phosphorus concentrations slightly increased in all HD but more significantly in group B. The baseline iPTH and MLD of the largest PTG were significantly correlated with final iPTH levels. Paricalcitol is more effective than calcitriol in SHPT, but the responsiveness to paricalcitol and hypercalcemia are related to PTG size. The measurement of MLD by ultrasonography may be useful for predicting responsiveness to paricalcitol, avoiding an unnecessary and expensive therapy.

Recent insights into vitamin D and its receptor

The widely differing functions of vitamin D are based both on a wide diffusion of its specific receptor (VDR) and on the ability of many cells, in addition to renal tubular cells, to synthesize calcitriol for autocrine and paracrine functions. In the last few years, many published studies have added new insights into some important points on this topic. Recent data suggest that the control of calcitriol synthesis at tissue levels other than kidneys might differ greatly from the control system working at the renal level. Furthermore, the mechanisms by which the VDR might mediate either the genomic and nongenomic (rapid) vitamin D-mediated effects became much clearer. However, new evidence accumulated suggests that some additional receptor(s), responsive to vitamin D and different from the VDR, could play a role in the rapid response to vitamin D, probably interfering also with the genomic pathway. In this context, there are new possible interpretations of the mechanisms by which different vitamin D metabolites might express variable activities at different levels. In addition, some recent data have challenged the role of the VDR in direct parathyroid hormone (PTH) control, at least in physiological conditions, suggesting that vitamin D-mediated PTH inhibition is mainly secondary to the intestinal effect on calcium absorption. Finally, there is a renewed interest in the field of polymorphic variants in the VDR gene in relation to some clinical conditions, though the mechanisms underlining these associations are far from being clear. The present review briefly addresses all of the above points.

A naturally occurring isoform inhibits parathyroid hormone receptor trafficking and signaling

Parathyroid hormone (PTH) regulates calcium homeostasis and bone remodeling through its cognitive receptor (PTHR). We describe here a PTHR isoform harboring an in-frame 42-bp deletion of exon 14 (Δe14-PTHR) that encodes transmembrane domain 7. Δe14-PTHR was detected in human kidney and buccal epithelial cells. We characterized its topology, cellular localization, and signaling, as well as its interactions with PTHR. The C-terminus of the Δe14-PTHR is extracellular, and cell surface expression is strikingly reduced compared with the PTHR. Δe14-PTHR displayed impaired trafficking and accumulated in endoplasmic reticulum. Signaling and activation of cAMP and ERK by Δe14-PTHR was decreased significantly compared with PTHR. Δe14-PTHR acts as a functional dominant-negative by suppressing the action of PTHR. Cells cotransfected with both receptors exhibit markedly reduced PTHR cell membrane expression, colocalization with Δe14-PTHR in endoplasmic reticulum, and diminished cAMP activation and ERK phosphorylation in response to challenge with PTH. Δe14-PTHR forms heterodimers with PTHR, which may account for cytoplasmic retention of PTHR in the presence of Δe14-PTHR. Analysis of the PTHR heteronuclear RNA suggests that base-pair complementarity in introns surrounding exon 14 causes exon skipping and accounts for generation of the Δe14-PTHR isoform. Thus Δe14-PTHR is a poorly functional receptor that acts as a dominant-negative of PTHR trafficking and signaling and may contribute to PTH resistance. © 2011 American Society for Bone and Mineral Research.

Klotho, FGF23, and FGF receptors in chronic kidney disease: a yin–yang situation?

Secondary hyperparathyroidism in chronic kidney disease (CKD) develops in response to disturbances in calcium and phosphate metabolism associated with CKD, including FGF23 and klotho. FGF23 activates its receptor FGFR1, splice variant IIIC, in the parathyroid gland via a klotho-dependent mechanism and suppresses parathyroid hormone (PTH) secretion. Klotho also may regulate PTH secretion in an FGF23-independent mode, by modulating parathyroid Na+/K+-ATPase activity. The persistence of hyperparathyroidism with progressing CKD despite high serum FGF23 is indicative of FGF23 resistance.

An Inflection Point of Serum 25-Hydroxyvitamin D for Maximal Suppression of Parathyroid Hormone Is Not Evident from Multi-Site Pooled Data in Children and Adolescents ,

In adults, maximal suppression of serum parathyroid hormone (PTH) has commonly been used to determine the sufficiency of serum 25-hydroxyvitamin D [25(OH)D]. In children and adolescents, the relationship between serum 25(OH)D and PTH is less clear and most studies reporting a relationship are derived from relatively small samples and homogeneous cohorts. Our objective was to determine the relationship between serum 25(OH)D and PTH in children and adolescents from a large and diverse U.S. cohort and to identify a point of inflection of serum 25(OH)D for maximal suppression of serum PTH. Data from 735 participants, ages 7–18 y, were pooled from 3 study sites located in Indiana, Texas, and Massachusetts. A two-phase linear spline was used to model the relationship between serum 25(OH)D and PTH. The value of serum 25(OH)D for maximal suppression of serum PTH was identified as the inflection point of the spline. Before adjustment for site, the inflection point of serum 25(OH)D for maximal suppression of serum PTH was 92.4 nmol/L (95% CI: 62.2, 130.7). After adjusting for site, the point of inflection was poorly defined and the relationship between serum 25(OH)D and PTH appeared to be linear. The lack of an inflection point of serum 25(OH)D for maximal suppression of PTH brings into question the value of using maximal suppression of serum PTH as a basis for determining optimal serum 25(OH)D for healthy children and adolescents.

Progressive escape from parathyroid suppression: a common phenomenon in primary hyperparathyroidism (a calcium clamp study).

Induced aggravation of hypercalcaemia in vivo and in vitro causes partial suppression of parathyroid hormone (PTH) secretion in primary hyperparathyroidism (PHP). Furthermore, one in-vitro study also demonstrates progressive escape from such action. The aim of the present in-vivo study was to examine whether escape from suppression is a common feature of PHP. A rapid increment in blood ionized calcium (B-Ca2+) to 0.25-0.30 mmol/l above individual baselines was achieved by intravenous calcium infusions. This induced or aggravated hypercalcaemia was kept constant for 2 hours (controls) or 4 hours (patients). The study of PHP comprised 19 patients (18 females and one male) aged 39-85 years (geometric mean 66). For comparison we included the results obtained in a control group of 24 healthy subjects (11 women and 13 men) aged 20-68 years (geometric mean 32). The individual levels of B-Ca2+ were controlled by frequent bedside measurements of B-Ca2+. The changes in serum intact parathyroid hormone (S-PTH(1-84)) were registered. After 30 minutes of calcium infusion average concentrations of S-PTH(1-84) had decreased from 7.9 (6.7-9.4) pmol/l in PHP and 2.5 (2.1-2.9) pmol/l in controls to their respective nadir values of 2.9 (2.1-4.1) pmol/l and 0.6 (0.5-0.8) pmol/l. While S-PTH(1-84) remained suppressed at a stable level for 120 minutes in controls, in PHP it started to escape progressively after 30 minutes to a level of 4.2 (3.0-5.8) pmol/l (P < 0.001). Linear regression analysis of the individual S-PTH(1-84) observations in PHP, from 30 to 240 minutes of study, revealed that five patients did not escape (group A) while the remainder 14 patients escaped progressively (group B). Within group B, seven patients escaped significantly after 120 minutes, 10 after 180 minutes and 14 after 240 minutes. Although comparable respecting B-Ca2+ before and during calcium infusion, group A and B presented different S-PTH(1-84) curves. Thus, at times zero, 30, 120 and 240 minutes their respective average concentrations of S-PTH(1-84) measured 9.9 (9.1-10.9) vs 7.3 (5.9-9.0) (P < 0.02), 4.6 (3.7-5.7) vs 2.5 (1.6-3.9) (P < 0.01), 5.0 (3.9-6.5) vs 3.0 (1.9-4.8) (P < 0.05) and 5.2 (3.6-7.4) vs 3.9 (2.6-6.0) (NS) pmol/l. We hypothesize that two different mechanisms are involved in the parathyroid response to the calcium clamp, an initial and fast inhibition of PTH release, while the subsequent course depends on the balance between the intra-glandular secretion rate of PTH and the intra-glandular capacity for PTH degradation. The escape from parathyroid suppression during a sustained stable increment in B-Ca2+ suggests that the basal secretion over-rides degradation in a majority of the patients with PHP.

Discovery of a class of calcium sensing receptor positive allosteric modulators; 1-(benzothiazol-2-yl)-1-phenylethanols

1-(Benzothiazol-2-yl)-1-(4-chlorophenyl)ethanol ( 1) was identified as a positive allosteric modulator (PAM) of the CaSR in a functional cell-based assay. This compound belongs to a class of compounds that is structurally distinct from other known positive allosteric modulators, for example, the phenylalkylamines cinacalcet, a modified analog ( 13) potently suppressed parathyroid hormone (PTH) release in rats, consistent with its profile as a PAM of CaSRs.

A Case of Lithium-Induced Symptomatic Hypercalcemia

To the Editor: Hypercalcemia has been associated with long-term lithium carbonate treatment, yet is often unrecognized.1 Symptoms of hypercalcemia can progress insidiously and can mimic psychiatric disturbances, eg, delirium and symptoms resembling mood disturbances.2,3 We report on a unique case of a lithium-treated patient presenting with depression-like symptoms secondary to hypercalcemia requiring lithium discontinuation. Case report. Ms A, a 53-year-old woman, presented to the hospital in 2009 complaining of abdominal pain, nausea, constipation, and weakness of 1 week's duration. Prescribed lithium carbonate 300 mg tid daily for 10 years for DSM-IV-TR bipolar disorder, she complained of fatigue, decreased concentration, decreased appetite, and muscle weakness for several weeks, prompting concerns of an exacerbation of depression. Admission laboratory studies revealed a marginally elevated serum lithium level at 1.27 mEq/L and hypercalcemia (13.5 mg/dL; normal range, 8.4–10.2 mg/dL). Serum phosphate was 3.2 mg/dL (normal range, 2.7–4.5 mg/dL), and magnesium was 1.35 mg/dL (normal range, 1.69–2.73 mg/dL). Hypercalcemia workup revealed a parathyroid hormone (PTH) level of 24.4 pg/mL (normal range, 15–65 pg/mL) and a 25-hydroxy vitamin D level of 36.8 ng/mL (normal 32–100 ng/mL), both within normal limits. Blood urea nitrogen and creatinine levels were 9 mg/100 mL (normal range, 6–20 mg/100 mL) and 0.5 mg/dL (normal range, 0.5–0.1 mg/dL), respectively. A skeletal series and chest x-ray failed to identify malignancy or sarcoid as potential etiologies. Intravenous fluids and furosemide were initiated to decrease serum calcium; Ms A was asymptomatic once levels reached 11.3 mg/dL. Lithium was discontinued and substituted with lamotrigine. Serum calcium levels normalized within 4 weeks following lithium discontinuation. Rates of lithium-induced hypercalcemia are estimated to be 5%–40%.3 Symptoms can consist of anorexia, nausea, constipation, mood disturbances, and, in severe cases, delirium, stupor, and coma. In the present case, the gastrointestinal symptoms and weakness prompted evaluation of medical etiologies, unearthing an underlying hypercalcemia ascribable to long-term lithium use. Other potential causes, eg, primary or secondary hyperparathyroidism, malignancy, sarcoid, and vitamin D toxicity, were eliminated by history and laboratory investigations. Lithium may induce increased calcium reabsorbtion within the loop of Henle. Concurrently, lithium can alter feedback mechanisms within the parathyroid gland, impeding the suppression of PTH normally produced by hypercalcemia.1 Evidence of asymptomatic hypercalcemia can be monitored with continued lithium use. Traditionally, symptomatic cases may be managed with discontinuation of lithium along with use of diuretics and hydration, resulting in prompt symptom resolution. Recently, use of calciuric agents, eg, cinacalcet, has been advocated, allowing resolution of hypercalcemia without necessitating lithium discontinuation.4 Refractory cases, unresponsive to the above measures, may warrant parathyroidectomy. Although the interval has not been established, clinicians should periodically monitor lithium-treated patients for hypercalcemia. Exacerbation of mood symptoms may be the initial sign of emerging hypercalcemia.

Discrepant influence of vitamin D status on parathyroid hormone and bone mass after two years of calcium supplementation

To investigate the influence of vitamin D status on parathyroid hormone and bone mass after a 2-year supplementation of calcium alone. Randomized, double-blind, placebo-controlled clinical trial, in healthy postmenopausal women without osteoporosis: three hundred and thirty-six subjects aged 60-97 years were studied and randomized to receive elemental calcium 500 mg/day (n = 175) or placebo (n = 161) for 2 years. Changes in parathyroid hormone (PTH) and bone mineral density (BMD) from baseline and vitamin D status. Values are presented as means +/- SD. After 2 years, subjects with calcium supplementation had significant decrease in plasma PTH level (4.4 +/- 1.7 vs 4.7 +/- 1.9 pmol/l, P < 0.01), improved lumbar BMD (1.031 +/- 0.12 vs 1.004 +/- 0.12 g/cm(2), P < 0.001) and total hip BMD (0.890 +/- 0.10 vs 0.883 +/- 0.10 g/cm(2), P < 0.001) without change in femoral neck BMD. In the placebo group, PTH level significantly increased (4.8 +/- 1.6 vs 4.5 +/- 1.5 pmol/l, P < 0.001), lumbar BMD slightly increased (1.027 +/- 0.14 vs 1.018 +/- 0.14 g/cm(2), P < 0.001), total hip and femoral neck BMD decreased (0.876 +/- 0.11 vs 0.887 +/- 0.11 g/cm(2), P < 0.001 and 0.783 +/- 0.10 vs 0.798 +/- 0.10 g/cm(2), P < 0.001, respectively). When subjects were classified according to baseline 25-hydroxyvitamin D [25(OH)D] levels into those with 25(OH)D in the lower tertile (lowVitD) and those in the middle and upper tertiles combined (normVitD). The degree of PTH suppression after calcium supplementation was significantly higher in the normVitD compared to the lowVitD groups (-5.6 +/- 26.7%vs 1.3 +/- 27.2%, P < 0.05). No effect of vitamin D status on the change in lumbar BMD after calcium supplementation was demonstrated. Despite the higher suppression of PTH, there was a slight decrease in femoral neck BMD after calcium supplementation in the normVitD group while femoral neck BMD was more or less maintained in the lowVitD group (-0.6 +/- 3.2%vs 0.5 +/- 2.9%, P < 0.05). Calcium supplementation appears to affect femoral bone mass less in Thai postmenopausal women with adequate vitamin D status, despite higher suppression of PTH.

Acute activation of the calcium-sensing receptor inhibits plasma renin activity in vivo.

In vitro, the renin-secreting juxtaglomerular cells express the calcium-sensing receptor, and its activation with the calcimimetic cinacalcet inhibits renin release. To test whether the activation of calcium-sensing receptor similarly inhibits plasma renin activity (PRA) in vivo, we hypothesized that the calcium-sensing receptor is expressed in juxtaglomerular cells in vivo, and acutely administered cinacalcet would inhibit renin activity in anesthetized rats. Since cinacalcet inhibits parathyroid hormone, which may stimulate renin activity, we sought to determine whether cinacalcet inhibits renin activity by decreasing parathyroid hormone. Lastly, we hypothesized that chronically administered cinacalcet would inhibit basal and stimulated renin in conscious rats. Calcium-sensing receptors and renin were localized in the same juxtaglomerular cells using immunofluorescence in rat cortical slices fixed in vivo. Cinacalcet was administered acutely via intravenous bolus in anesthetized rats and chronically in conscious rats by oral gavage. Acute administration of cinacalcet decreased basal renin activity from 13.6 ± 2.4 to 6.1 ± 1.1 ng ANG I·ml(-1)·h(-1) (P < 0.001). Likewise, cinacalcet decreased furosemide-stimulated renin from 30.6 ± 2.3 to 21.3 ± 2.3 ng ANG I·ml(-1)·h(-1) (P < 0.001). In parathyroidectomized rats, cinacalcet decreased renin activity from 9.3 ± 1.3 to 5.2 ± 0.5 ng ANG I·ml(-1)·h(-1) (P < 0.05) similar to sham-operated controls (13.5 ± 2.2 to 6.6 ± 0.8 ng ANG I·ml(-1)·h(-1), P < 0.05). Chronic administration of cinacalcet over 7 days had no significant effect on PRA under basal or stimulated conditions. In conclusion, calcium-sensing receptors are expressed in juxtaglomerular cells in vivo, and acute activation of these receptors with cinacalcet inhibits PRA in anesthetized rats, independent of parathyroid hormone.

Use of vitamin D in chronic kidney disease patients

Chronic kidney disease (CKD) has been recognized as a significant public health problem, with 20 million Americans, or 11% of the adult population, currently living with CKD. Life expectancy in patients with CKD is limited by the development of disturbances of mineral metabolism, which occurs in virtually all patients during the progression of their disease, and is associated with bone loss and fractures, cardiovascular disease, immune suppression, and increased mortality. As kidney disease develops, there is decreased functional renal mass and a reduction in renal 1alpha-hydroxylase activity and thus in renal production of calcitriol at very early CKD stages. Recently, a potentially important role of vitamin D receptor activation (VDRa) in the survival of patients undergoing dialysis has been suggested. Beyond the effect on parathyroid hormone suppression, the pleiotropic effect of vitamin D has been associated with improvement of cardiovascular risk factors, including increased renin activity, hypertension, inflammation, insulin resistance, diabetes, and albuminuria. However, the current K/DOQI and KDIGO recommendations limit the administration of VDRa agents for treatment of hyperparathyroidism only. The role of vitamin D administration in the different CKD stages will be discussed in this review.

Hypercalcemia secondary to persistent hyperparathyroidism in kidney transplant patients: analysis after a year with cinacalcet

The most common cause of hypercalcemia in patients with transplanted kidneys is persistent hyperparathyroidism, which presents in 10%-30% of patients with functioning renal grafts. In these patients, the treatment of vitamin D-resistant hyperparathyroidism traditionally required parathyroidectomy. Calcimimetic agents represent a new therapeutic alternative; they inhibit parathyroid hormone (PTH) secretion, increasing the sensitivity of the calcium-sensitive receptor in the parathyroid gland. The objective of this study is to evaluate the efficacy of cinacalcet in renal transplant patients with persistent hyperparathyroidism. Cinacalcet 30 mg/day was prescribed to 17 renal transplant patients (6 women, 11 men) with a mean age of 49 years and hypercalcemia secondary to persistent hyperparathyroidism. The treatment started 58.17 ± 35.16 months posttransplant, with 1 year of follow-up. Calcium in serum fell from 10.5 ± 0.74 to 9.4 ± 0.84 mg/dL (p<0.001), whereas phosphorous levels were not significantly altered. The fall in PTH was from 204.79 ± 78 to 148.55 ± 56 pg/mL (p<0.011). Kidney function remained stable, and immunosuppressant drug levels remained unchanged. The dose of cinacalcet was increased to 60 mg in 2 patients. No significant adverse effects were described, and none of the patients had to suspend the treatment. Calcimimetic agents represent a therapeutic alternative in transplant patients with persistent hyperparathyroidism, as they correct hypercalcemia and reduce PTH levels with no adverse effects on kidney function. Prospective, controlled studies should be designed to evaluate the long-term effects and evolution after suspension of the treatment.

The Fibroblast Growth Factor 23: A New Player in the Field of Cardiovascular, Bone and Renal Disease

Recently, a new view into the molecular mechanisms of phosphate homeostasis and secondary hyperparathyroidism pathogenesis has been proposed, with Fibroblast Growth Factor 23 (FGF-23) as a novel player in the field. Enhanced serum FGF-23 levels cause a reduction in serum phosphate, together with calcitriol suppression and consequent hyperparathyroidism. In contrast, reduced serum FGF-23 levels are associated with hyperphosphatemia, higher calcitriol levels and parathyroid hormone (PTH) suppression. In addition, there are different FGF-23 actions that need investigation. In clinical practice, increased knowledge of mineral metabolism disorders alterations in chronic kidney disease (CKD) may be used to improve diagnostics and select future treatments. The discovery of FGF23 represents a novel factor in the pathogenesis of phosphate handling and secondary hyperparathyroidism in cardiovascular, bone and renal disease.

Eldecalcitol is less effective in suppressing parathyroid hormone compared to calcitriol in vivo

Eldecalcitol is a vitamin D 3 analog under clinical development for the treatment of osteoporosis. Previous studies have shown that the binding activities of eldecalcitol to the serum vitamin D binding protein (DBP) and the vitamin D receptor (VDR) are 421.9% and 44.6% of those of calcitriol, respectively, and also, suppressed parathyroid hormone (PTH) production by only 3.5% of calcitriol in vitro using bovine parathyroid cell primary culture. Here, we compared in vivo activities of eldecalcitol on serum calcium, BMD and PTH with those of calcitriol. Six-week old male rats were given either vehicle (medium chain triglyceride; n = 6), eldecalcitol (0.025, 0.05, 0.1, 0.25, 0.5 μg/kg; n = 6) or calcitriol (0.25, 0.5, 1.0, 2.5, 5 μg/kg; n = 6) daily for 14 days by oral gavages. Eldecalcitol was approximately five-times more potent than calcitriol in increasing serum calcium. Eldecalcitol significantly increased lumbar spine BMD, however, calcitriol had no effect on BMD at any given doses. On the contrary, eldecalcitol did not affect PTH mRNA synthesis at the normocalcemic doses, despite the BMD was higher than normal. These observations indicate that, as previous in vitro study suggested, eldecalcitol is less effective in suppressing PTH compared to calcitriol.

The relationship of serum 25‐hydroxyvitamin D and parathyroid hormone from pooled data in children and adolescents

Serum 25-hydroxyvitamin D (25(OH)D) is the primary indicator of vitamin D status. In adults, maximal suppression of serum parathyroid hormone (PTH) has been used to determine sufficiency for serum 25(OH)D. In children and adolescents, however, the relationship between serum 25(OH)D and PTH is less clear and the normal range for PTH is not well established. We pooled data from 735 children and adolescents (7–18 y, 30% male) studied at 3 different geographical sites to investigate the relationship between serum 25(OH)D and PTH. Using a spline approach, the point of inflection for PTH suppression is 25(OH)D = 39.4, 95% CI 25.99, 53.0 ng/mL. The average 25(OH)D is 26.6±10.3 ng/mL. When high PTH (>100 pg/mL) values are excluded, no point of inflection for PTH suppression is evident. As serum 25(OH)D has not been associated with improved Ca absorption or retention in children and adolescents and PTH has been positively associated with Ca absorption in adolescents, we infer that the inflection point for suppression of PTH around the average serum 25(OH)D indicates this is inappropriate as a basis for determining optimal 25(OH)D for this age group. Grant Funding Source: NIH 1R01HD061908-01A2