Renal Tubular Reabsorption Of Calcium Research Articles

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics

Introduction: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. Methods: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. Results: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 mM vs. 1.1 ± 0.23 mM, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. Conclusion: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

Abstract 14073: Hypercalcemia Induced Reversible LBBB

Background: Parathyroid hormone (PTH) and calcitriol are the two hormones responsible for calcium and phosphate homeostasis. PTH exerts its effect on the renal tubular calcium reabsorption and bone resorption. PTH secretion is modulated by calcium acting on the sensitive calcium-sensing receptor on the parathyroid cells. Primary hyperparathyroidism has been linked to hypertension and valvular calcification. Structural changes are also seen including elevated left ventricular mass, diastolic dysfunction and myocardial calcification. Case presentation: A 61-year old female with hyperlipidemia and osteoporosis presented with polyarticular joint pain and diffuse myalgia noted to have elevated PTH of 90 pg/ml and elevated Ca of 10.1 mg/dl. Her calcium levels has ranged from 10.1 to 11.2 mg/dl and her PTH ranged from 90 to 113 pg/ml. She had a negative sestamibi scan, and thyroid ultrasound showed fusiform&amp;nbsp;lesion measuring&amp;nbsp;0.82 x 0.36 in the right posterior neck&amp;nbsp;suspicious for a parathyroid adenoma with the plan made for resection. The diagnosis at this time was primary hyperparathyroidism induced hypercalcemia. She developed exertional dizziness and was found to have a new LBBB and reduced ejection fraction of 40-45% with a small fixed defect in the septal area which was attributed to the LBBB. She was initiated on metoprolol succinate 25 mg, irbesartan 75 mg, atorvastatin 40 mg and aspirin 81 mg because of the reduced systolic function. SPECT was negative for ischemia with a fixed decreased uptake of the septum. She underwent right lower parathyroid excision on 11/2021 with normalization of calcium to 9.4 mg/dl and PTH to 9 pg/ml with resolution of the LBBB and systolic function in 2/2021 improving to 48%. Discussion: Calcium plays a key role in cardiac excitation, depolarization, repolarization, and also coupling of these signals to mechanical contraction via calcium induced calcium release and myofibril cross linking. In this case, calcium was only mildly elevated to cause a partial conduction defect. Literature is lacking on whether there is a threshold level for calcium that predisposes to varying degrees of conduction disease. This case also highlights the temporal nature of symptom resolution following parathyroid surgery with resolution of the LBBB.

Nefrolitiaziste Tıbbi Beslenme Tedavisi

Dünya çapında nefrolitiazisin prevalansı ve insidansının giderek arttığı bildirilmektedir. Son yıllarda nefrolitiazis alanında önemli ilerlemeler kaydedilmiştir. Taş oluşum nedenleri ve spesifik moleküler defektler daha kapsamlı olarak ortaya konulmaktadır. İdrar yoğunluğunun yanında idrarda çözünen kristallerin miktarı da böbrek taşı oluşumunda etkilidir. İdrar hacminin azalmasıyla birlikte idrardaki çözünen maddelerin saturasyanu değişir ve taş oluşum riski artar. İdrarda okzalat ve fosfor gibi bazı maddelerin yüksek düzeyi ile böbrek taşları oluşabilmektedir. Genler, metabolik ve çevresel etmenler idrar bileşimini etkileyebilmekte ve taş oluşum riskini arttırabilmektedir. Diyet de böbrek taş oluşumuna neden olabilen ya da taş oluşumunu önleyebilen bir etmendir. Diyet uygulamasındaki değişiklikler ise böbrek taşlarının tedavisinde ve önlenmesinde anahtar bir rol oynayabilmektedir. Böbrek taşlarının ortaya çıkışının ya da yenilenmesinin önlenmesinde idrar süper saturasyonunun azaltılması önemlidir. Bu yüzden idrar hacmi 2-2.5 litre olana kadar sıvı alımının arttırılması hedeflenmelidir. Diyetteki okzalat miktarı arttığında veya kalsiyum düşük olduğunda ortaya çıkabilen hiperoksalüri, kalsiyum okzalat taşı oluşumu için risk etmenidir. Gereksiz diyetsel kalsiyum kısıtlamalarından kaçınmak ve okzalattan zengin besinleri diyette kontrol altına almak böbrek taşının önlenmesi için önemlidir. Artmış diyet sodyum alımı, kalsiyum renal tübüler geri emilimini azaltarak böbrek taşı için risk etmeni olan hiperkalsiüriyi tetikleyebileceği için, diyetle sodyum alımının düzenlemesine gidilebilmektedir. Bu yüzden böbrek taşı oluşumunu ve tekrarlamasını önleyebilmek adına çevresel etmenlerden özellikle beslenmenin de kontrol altına alınması gerekebilmektedir.

SINGLE-NUCLEOTIDE POLYMORPHISMS OF CALCIUM-SENSING RECEPTOR ENCODING GENE ASSOCIATED WITH CALCIUM KIDNEY STONE DISEASE IN BABYLON PROVINCE

Objective: The calcium-sensing receptor (CASR) is a G-protein-coupled receptor that is mainly expressed in the parathyroid and the kidneys where it regulates parathyroid hormone secretion and renal tubular calcium reabsorption. Inactivating and activating CASR gene due to mutations severally caused hypercalcemia or hypocalcemia disorders. The aim of the study was to investigate the risk factor of CASR rs1801725 (Ala986Ser) patients with renal disease.Method: The blood samples were collected from 100 patients and divided into two groups, each one containing 50 samples; chronic kidney disease and end-stage renal disease, who admitted Merjan Teaching Hospital in Babylon Province, Iraq, from February to July 2016. In addition, healthy persons as a control group (50 samples). Genotyping of CASR single-nucleotide polymorphisms (SNP) was performed using a polymerase chain reaction technique, followed by single-strand conformation polymorphism. Accordingly, these DNA polymorphisms were confirmed using DNA sequencing.Results: The conformational haplotypes of CASR, exon7 NCBI Primer3plus reference were obtained in three patterns, including two, three, and four bands, due to the presence SNPs within the studied region. These SNPs leads to change three amino acid residues of CASR, including amino acid substitutions were Ala 128→ Ser 128, Leu 155→Tye 155, and Leu 156→ Ser 156 that may affect or modified the tertiary structure of the receptor, subsequently the function like the affinity to calcium ion may be effected.Conclusion: These results suggest that the variants of CASR SNP, namely, rs1801725 might be involved in susceptibility to kidney stone disease.

Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Pleiotropic Actions of FGF23.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium–phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems.

Update on recent progress in vitamin D research. Vitamin D treatment for hypoparathyroidism.

The patients with hypoparathyroidism have been treated with active vitamin D(ie, alfacalcidol and calcitriol). Parathyroid hormone(PTH)increases extracellular calcium concentration partly through the activation of vitamin D, and active vitamin D corrects hypocalcemia mainly by increasing intestinal calcium abosorption. PTH coordinately increases blood calcium level with vitamin D in bone and kidney, however, renal tubular reabsorption of calcium is regulated by PTH-dependent mechanism. Hypercalciuria is an complication of long-term vitamin D treatment for PTH-deficient hypoparathyroidism.

Is the renal kallikrein-kinin system a factor that modulates hypercalciuria?

Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics.

Tetany Secondary to the Use of a Proton-Pump Inhibitor

Introduction: Chronic PPI use has been reported to cause hypocalcemia, bone density loss and osteoporoticrelated fractures but an acute drop in serum calcium level with PPI use is rare. We present a rare case of symptomatic hypocalcemia with 2 weeks use of PPI. Case Report: 61-year-old female with past medical history of hypothyroidism and hypoparathyroidism secondary to thyroidectomy and parathyroidectomy came to the emergency department(ED) with complaints of spasm and twitching of her upper extremities associated with lethargy and difficulty ambulation. 2 weeks prior to this presentation patient had upper endoscopy done for dyspepsia which showed antral erythema and stomach biopsies came back positive for Helicobacter Pylori gastritis. Patient started taking omeprazole after the endoscopy and later she was given antibiotics treatment for Helicobacter Pylori which she started taking three days prior to the ED presentation. Prior to initiate the omeprazole patient's serum calcium was 8.1 mg/DL. The patient has been taking magnesium citrate 200 mg two times a day and calcium carbonate 1200 mg daily with meals since surgery. No recent change in the dosage of these medications. In ED, EKG done showed QT prolongation, serum calcium was 5.7 mg/DL, magnesium was 1.7 mg/DL and albumin was 3.3 g/DL Thyroid function was within normal limit and parathyroid hormone(PTH) was Discussion Gastric acidic PH is required for absorption of the calcium. Calcium carbonate is a widely use form of calcium supplement which become soluble in the gastric acidic PH and then get absorb in the small intestine. PPI increase the gastric PH so decrease the absorption of calcium which later can cause hypocalcemia. This effect is more seen in the patient with low PTH as it plays a key role in maintaining the serum calcium level within normal limit by stimulating bone resorption, renal tubular calcium reabsorption, and by enhancing gastrointestinal absorption of calcium. The patients with hypoparathyroidism when take PPI their serum calcium needs to be closely monitored to avoid the life threatening complication of hypocalcemia and should be advised to take calcium citrate as a calcium supplement which does not require gastric acidic PH.

¿Es el sistema calicreína/quinina renal un factor modulador de la calciuria?

Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics.

Hypercalcemia of Malignancy: A New Twist on an Old Problem.

Hypercalcemia associated with malignancy is an old clinical problem, first described by Fuller Albright more than 50 years ago. It can cause significantmorbidity in patients with cancer and is associated with a poor prognosis in most patients. Thus, it is important to understand the pathophysiology to properly diagnosis and treat this important clinical syndrome. The accompanying article by Goldner presents a comprehensive review of this topic, which includes the latest addition to our therapeutic armamentarium to lower pathologic increases in serum calcium concentration: the receptor activator of nuclear factor k B–ligand antibody denosumab. Goldnermakes several important points in this review. First, the clinician must determine if the hypercalcemia is indeed a result of malignancy, rather than just associated with a nonmalignant cause of hypercalcemia such as primary hyperparathyroidism. After this has been established, treatment is directed against the cancer as well as thehypercalcemia. Tumor-produced systemic factors, such as parathyroid hormone–related peptide (PTHrP) or 1,25dihydroxyvitaminD, or locally active factors in bone, such as interleukin-6 or tumor necrosis factor-a, disrupt normal calcium homeostasis by excessive stimulation of osteoclastic bone resorption, in addition to lesser effects, to increase renal tubular reabsorption of calcium to result in hypercalcemia. As such, the mainstay of supportive care is to block pathologic osteoclast activity and maintain adequate hydration. For many years, this therapy consisted of bisphosphonates and fluid hydration, and for the most part was effective, particularly with the advent of the potent bisphosphonate zoledronic acid. As therapy evolved to include the most potent bisphosphonates, our understanding of the pathophysiology also evolved. The discovery thatmost tumor osteolytic factors, either humoral or local, stimulated bone resorption via receptor activator of nuclear factor k B–ligand led to more potent therapy to block osteoclastic bone resorption with the monoclonal antibody denosumab directed against this powerful stimulator of osteoclast formation and resorption. Indeed, recent reports indicate that denosumab is effective to reduce serum calcium concentration in the setting of bisphosphonate resistance and is more effective than zoledronic acid to prevent hypercalcemia associated with bone metastases. One downside to this new and more potent treatment is the increased risk of hypocalcemia. Thus, calcium should be closely monitored with the use of denosumab. Furthermore, because the studies describing denosumab use are small or retrospective analyses, further clinical studies using denosumab in the setting of hypercalcemia of malignancy are indicated. A future molecular target for the treatment of hypercalcemiaofmalignancy involvesPTHrPrelated antibodies. In an animal model, PTHrP antibodies corrected hypercalcemia and also suppressed the release of cytokines associated with malignancy. Taken together, insight into the pathogenesis of hypercalcemia ofmalignancy has resulted in new and better therapy for an old but difficult clinical problem.

Thiazide-Associated Hypercalcemia: A Population-Based Study

Thiazide diuretics can increase renal tubular reabsorption of calcium, resulting in hypercalcemia. However, thiazide-associated hypercalcemia also can

Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences.

Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous condition resembling primary hyperparathyroidism (PHPT) but not curable by surgery; FHH types 1, 2, and 3 are due to loss-of-function mutations of the CASR, GNA11, or AP2S1 genes, respectively. This study aimed to compare the phenotypes of patients with genetically proven FHH types 1 or 3 or PHPT. This was a mutation analysis in a large cohort, a cross-sectional comparison of 52 patients with FHH type 1, 22 patients with FHH type 3, 60 with PHPT, and 24 normal adults. There were no interventions. Abnormalities of the CASR, GNA11, and AP2S1 genes, blood calcium, phosphate, and PTH concentrations, urinary calcium excretion were measured. In 133 families, we detected 101 mutations in the CASR gene, 68 of which were previously unknown, and in 19 families, the three recurrent AP2S1 mutations. No mutation was detected in the GNA11 gene. Patients with FHH type 3 had higher plasma calcium concentrations than patients with FHH type 1, despite having similar PTH concentrations and urinary calcium excretion. Renal tubular calcium reabsorption levels were higher in patients with FHH type 3 than in those with FHH type 1. Plasma calcium concentration was higher whereas PTH concentration and urinary calcium excretion were lower in FHH patients than in PHPT patients. In patients with FHH or PHPT, all data groups partially overlapped. In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.

Successful management of repetitive urinary obstruction and anuria caused by double j stent calculi formation after renal transplantation.

This report firstly describes an extremely rare case of repetitive double J stent calculi formation after renal transplantation caused by the antihyperparathyroidism (HPT) drug calcitriol. In 2012, a woman initially presented to our hospital for anuria with lower abdominal pain. She was diagnosed with allograft hydronephrosis and double J stents obstruction by calculi formation after transplantation and treated with triplicate stents replacements in another hospital without clinical manifestations improvements. Through detailed exploration of medical history, we conclude that the abnormal calculi formation is due to the calcitriol (1,25-dihydroxyvitamin D3) administration, a drug which can increase renal tubular reabsorption of calcium for treating posttransplant HPT bone disease. After discontinuing calcitriol, the patient was stone-free and had a good recovery without severe complications during the 9-month follow-up. Our novel findings may provide an important clue and approach to managing formidable repetitive double J stent calculi formation in the clinical trial.

Albright’s hereditary osteodystrophy

A 22-year-old man was referred to our endocrine clinic for evaluation of asymptomatic hypocalcemia. His past medical history included hypothyroidism on oral thyroxine replacement. On physical examination, he was obese and had a short stature with a round face. Both of his fourth and fifth fingers were shortened (Fig. 1a) with absence of the fourth and fifth knuckles on clenched fists, showing the characteristic ‘‘knuckle, knuckle, dimple, dimple’’ appearance (Fig. 1b). The patient reported that his mother also had shortened ring fingers (Fig. 1c) and dimpling over the fourth knuckles of clenched fists (Fig. 1d). Significant laboratory investigations showed a low calcium level of 7.8 mg/dL (normal 8.4–10.2 mg/dL), a high phosphate level of 5 mg/dL (normal 2.5–4.5 mg/dL), and markedly elevated parathyroid hormone (PTH) level of 496 pg/dL (normal 12–65 pg/dL). His 25-hydroxy vitamin D level was within normal range. In contrast, his mother had normal calcium, phosphate, vitamin D and PTH levels. The patient’s clinical features, including short stature, obesity, round face, and shortening of the fourth and fifth metacarpal bones, are compatible with those of Albright’s hereditary osteodystrophy (AHO). Given his family history, hypothyroidism, biochemical abnormalities, and characteristic physical findings of AHO, the patient was diagnosed as pseudohypoparathyroidism type Ia (PHP-Ia). The patient’s mother, on the other hand, was diagnosed as pseudo-pseudohypoparathyroidism (PPHP) due to lack of disturbances of calcium homeostasis. The patient was treated with oral vitamin D and calcium supplements. After 3 months of therapy, his serum calcium, phosphate and PTH levels were normalized. One of the skeletal abnormalities of AHO—‘‘knuckle, knuckle, dimple, dimple’’ appearance of the hand resulting from premature closure of the epiphyses—is known as knuckle-dimple sign or Archibald’s sign (Fig. 1b, d) [1, 2]. Clinical manifestations of AHO can be present in both PHP-Ia and PPHP. There are different forms of PHP, namely, type I (subdivided into type Ia and Ib) and type II. Their working classifications, biochemical and clinical findings are described as in Table 1 [3]. The PHP-I is the most common and is due to mutations in the GNAS gene. This gene codes for the stimulatory alpha-subunit of the trimeric Gs protein that connects G-protein coupled receptors of various hormones (particularly thyroid-stimulating hormone, TSH) with their intracellular signaling cascades [3, 4]. The primary response to PTH by the kidneys is to increase renal tubular calcium reabsorption and phosphate excretion. Mutations in GNAS gene lead to hormonal resistance of renal tissues to PTH, which causes hypocalcemia and hyperphosphatemia; and a decreased response to TSH results in primary hypothyroidism. The patient’s mother has a phenotype of AHO with preserved calcium metabolism, consistent with PPHP (Table 1). PPHP characteristically displays an inheritance pattern known as tissue-specific paternal gene imprinting— only females can transmit the full disease with Z. Min (&) Department of Medicine, Division of Infectious Diseases, Allegheny General Hospital, 420 East North Avenue, East Wing, Suite 407, Pittsburgh, PA 15212, USA e-mail: zmin@wpahs.org

1,25(OH)2D3-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet

The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.

Cinacalcet attenuates hypercalcemia observed in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors

Excessive secretion of parathyroid hormone-related protein (PTHrP) by tumors stimulates bone resorption and increases renal tubular reabsorption of calcium, resulting in hypercalcemia of malignancy. We investigated the ability of cinacalcet, an allosteric modulator of the calcium-sensing receptor, to attenuate hypercalcemia by assessing its effects on blood ionized calcium, serum PTHrP, and calcium-sensing receptor mRNA in mice bearing either Rice H-500 Leydig cell or C26-DCT colon tumors. Cinacalcet effectively decreased hypercalcemia in a dose- and enantiomer-dependent manner; furthermore, cinacalcet normalized phosphorus levels, but did not affect serum PTHrP. Ribonuclease protection assay results demonstrated presence of PTHrP receptor, but not calcium-sensing receptor mRNA in C26-DCT tumors. The mechanism by which cinacalcet lowered serum calcium was investigated in parathyroidectomized rats (i.e., without PTH) made hypercalcemic by PTHrP. Cinacalcet attenuated PTHrP-mediated elevations in blood ionized calcium, which were accompanied by increased plasma calcitonin. Taken together these results suggest that the cinacalcet-mediated decrease in serum calcium is not the result of a direct effect on tumor cells, but rather is the result of increased calcitonin release. In summary, cinacalcet effectively reduced tumor-mediated hypercalcemia and corrected hypophosphatemia in mice. Further investigation of cinacalcet for treatment of hypercalcemia of malignancy is warranted.

Calcium-sensing receptor: Role in health and disease

The calcium-sensing receptor (CaSR) is a 1,078 amino acid G protein-coupled receptor (GPCR), which is predominantly expressed in the parathyroids and kidney. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium re-absorption in response to alterations in extracellular calcium concentrations. Loss-of-function CaSR mutations have been reported in the hypercalcemic disorders of familial benign (hypocalciuric) hypercalcemia (FBH or FHH), neonatal severe primary hyperparathyroidism (NSHPT), and adult primary hyperparathyroidism. However, some individuals with loss-of-function CaSR mutations remain normocalcemic. Gain-of-function CaSR mutations have been shown to result in autosomal-dominant hypocalcemia with hypercalciuria (ADHH) and Bartter's syndrome type V. CaSR auto-antibodies have been found in FHH patients who did not have loss-of-function CaSR mutations and in patients with an acquired form (i.e. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with 4 hypercalcemic and 3 hypocalcemic disorders.

A TYPICAL PRESENTATION WITH AN ATYPICAL DIAGNOSIS

To the Editor: A 74-year-old man presented to the emergency department with sudden-onset sharp pleuritic central chest discomfort radiating to his left shoulder that resolved spontaneously on admission to hospital. He had complained of similar intermittent chest discomfort occurring at rest over 6 weeks with associated breathlessness and poor exercise tolerance. Initial investigations revealed high white cell count (13 × 109/L; normal 4–11 × 109/L), high C-reactive protein (188 mg/L; normal 0–6 mg/L), moderately high corrected calcium (2.77 mmol/L; normal 2.1–2.5 mmol/L), high troponin-I (0.75 μg/L; normal 0–0.1 μg/L) and a normal electrocardiogram. There was also left lower lobe opacification on chest radiograph. He was treated for acute coronary syndrome in view of his history and high cardiac enzymes. Past medical history included total penectomy, perineal urethrostomy, and bilateral groin dissection for penile squamous cell carcinoma (SCC) 18 months before this admission. His annual follow-up computed tomography (CT) did not reveal any metastases. A CT pulmonary angiography (CTPA) was performed on admission because the possibility of the presence of pulmonary emboli was raised. The CTPA (Figure 1) and subsequent abdominal CT showed a solitary splenic tumor invading the left hemidiaphragm and the pericardial sac. A splenic biopsy and immunohistochemistry confirmed it to be metastatic SCC. Subsequent other relevant investigations included a bone scan, which excluded bony metastases, and a low parathyroid hormone (PTH) level (0.64 pmol/L; normal 1.48–7.63 pmol/L). It was not possible to measure PTH-related peptide (PTHrP) levels. Computed tomography images (anterior-posterior lateral views) show a sizable mass invading the left hemidiaphragm and pericardial sac, with a small pleural effusion. Moderate hypercalcemia was treated aggressively with intravenous fluids to marginal effect and required intravenous pamidronate. The case was discussed extensively with surgical and oncology colleagues, but their general consensus in view of his premorbid performance status was to manage the aggressive splenic metastasis conservatively. The patient was discharged to the care of community palliative care colleagues. The authors have not found any previous published cases of metastatic penile SCC presenting as a solitary splenic metastasis invading through the left hemidiaphragm and the pericardial sac. This case highlights the importance of careful evaluation of older adults presenting with a typical history of angina-like chest discomfort but a resultant unusual diagnosis. Physiological changes of aging and multiple comorbid diseases often complicate and obscure the presentation of older adults to the hospital.1 Penile cancers are rare in developed countries but can account for up to 10% of male cancers in developing regions. In the United Kingdom, the reported incidence is 0.6 cases per 100,000 per year.2 The prevalence increases with age after the age of 60 and reaches a peak incidence at the age of 70, with rates probably differing as a result of religious practices and socioeconomic status.3 Risk factors include poor penile hygiene, penile inflammation, phimosis, and number of sexual partners; almost half of patients have had previous exposure to the human papilloma virus.4 Splenic metastasis is a rare complication, arising in fewer than 1% of all metastases, and is associated with a poor prognosis.5,6 SCC accounts for 95% of all penile carcinomas and is a malignant tumor of keratinocytes. Keratinocytes secrete PTHrP, inducing bone osteoclastic resorption, and PTHrP is associated with hypercalcemia as a paraneoplastic complication.7 Hypercalcemia and leukocytosis have reported associations with penile SCC and, in one case report, both resolved after surgery.8 Although the current patient had leukocytosis, the association cannot be definitively determined because there was significant necrotic tissue in the splenic metastasis that could have contributed to leukocytosis. Hypercalcemia in older adults must always prompt urgent evaluation because age-related renal changes lead to fluid loss and may be a manifestation of malignancy as bony metastases or humoral hypercalcemia of malignancy.9 It may present in up to 30% of people with penile cancer with lymphadenopathy.10 The moderately high hypercalcemia was probably a result of the presence of PTHrP because it shares the same N-terminal binding to the type 1 PTH receptor in the body as PTH, increasing bone osteoclastic activity and renal distal tubular calcium reabsorption. Bisphosphonates have been the main treatment for PTHrP-induced hypercalcemia because they inhibit osteoclast formation and their function. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Melvin P.W. Chua and Joel Chin were responsible for the conception of the letter and jointly wrote the first draft. Chinga Chileshe and Surabhi Singh contributed significantly to subsequent critical revisions of the article. All authors were involved in the final approval of version submitted for publication. Sponsor's Role: The authors report no financial conflicts of interest with this article.

Fgf-23 stimulates renal tubular calcium reabsorption by regulating membrane trafficking of glycosylated TRPV5 through SGK1 and WNK4

Fgf-23 stimulates renal tubular calcium reabsorption by regulating membrane trafficking of glycosylated TRPV5 through SGK1 and WNK4