Influence of Calcium-Sensing Receptor Gene on Urinary Calcium Excretion in Stone-Forming Patients

Vezzoli, Giuseppe; Tanini, Annalisa; Ferrucci, Luigi; Soldati, Laura; Bianchin, Cristiana; Franceschelli, Francesco; Malentacchi, Cecilia; Porfirio, Berardino; Adamo, Donatella; Terranegra, Annalisa; Falchetti, Alberto; Cusi, Daniele; Bianchi, Giuseppe; Brandi, Maria Luisa

doi:10.1097/01.asn.0000030077.72157.d2

Cited by 137 publications

(111 citation statements)

References 31 publications

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“…In a study from Italy, the relative risk of hypercalciuria was increased in individuals carrying this haplotype, both among stone formers [52] and non-stone formers [51], but it explained only 4.1% of the total variance in urinary calcium excretion, and was not felt to be a major gene determining IH.…”

Section: Genetic Associations Of Ih and Hypercalciuriamentioning

confidence: 95%

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

Worcester

Coe

2008

Seminars in Nephrology

146

125

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Idiopathic hypercalciuria (IH) is the commonest metabolic abnormality in patients with calcium kidney stones. It is characterized by normocalcemia, absence of diseases that cause increased urine calcium, and calcium excretion that is above 250 mg/day in women and 300 mg/day in men. Subjects with IH have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, negative calcium balance is commonly seen in balance studies, especially on a low calcium diet. The mediator of decreased renal calcium reabsorption is not clear; it is not associated with either an increase in filtered load of calcium or altered PTH levels. There is an increased incidence of hypercalciuria in first-degree relatives of those with IH, but IH appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion. Increased tissue vitamin D response may be responsible for the manifestations of IH in at least some patients. Definition of HypercalciuriaCalcium, the most abundant cation in human beings, is an important participant in many physiologic processes, including hormonal secretion, cardiac contraction, blood clotting, and neurotransmission. In addition, growth and repair of our skeleton demands an adequate supply of calcium, and careful maintenance of extracellular calcium concentrations. For this reason, prevailing levels of intracellular and extracellular calcium are tightly regulated, by a complex system of control mechanisms. These mechanisms control calcium absorption by gut and renal tubular epithelia, as well as fluxes of calcium on and off bone, during varying dietary calcium intakes. In healthy, non-pregnant adults, whose skeleton is no longer growing, net intestinal calcium absorption is matched by renal excretion, and provides sufficient calcium for skeletal maintenance; however, under pathologic conditions, some urine calcium may derive from bone loss.Abnormalities of calcium homeostasis could result in a number of undesired consequences, including abnormally high or low serum calcium levels, or inadequate maintenance of bone mineral. Hypercalciuria might be defined as any level of urine calcium that exceeds net intestinal absorption, leading to net loss of calcium. However, in practice net intestinal absorption is seldom measured, and under the assumption that urine calcium is primarily derived from intestinal absorption, the working definition of hypercalciuria is urine calcium excretion that exceeds that found in the majority of healthy adults eating their usual diets. In practice, this is usually defined as a daily calcium excretion over 250 mg/day in women or 300Mailing address: Elaine Worcester, M.D., Nephrology Section, Suite 511 / MC 5100, University of Chicago, 5841 S. Maryland Avenue, Chicago, Illinois 60637, Phone: 773-702-7459, Fax: 773-702-5818. Publisher's Disclaimer: This is a PDF file ...

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Section: Genetic Associations Of Ih and Hypercalciuriamentioning

confidence: 95%

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

Worcester

Coe

2008

Seminars in Nephrology

146

125

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“…Moreover, activating or silencing mutations in TRPV5 and TRPV6 can hypothetically lead to primary renal as well as absorptive IH. Single nucleotide polymorphisms (SNPs) in the Ca 2+ -sensing receptor (CaSR) have been shown to significantly increase the relative risk of hypercalciuria (Vezzoli et al 2002). The same may be applicable to SNPs in the genes encoding the epithelial Ca 2+ channels or genes involved in the regulation of TRPV5 and TRPV6 activity and, therefore, may be involved in the complex genetic background of IH.…”

Section: Idiopathic Hypercalciuria and Renal Stone Diseasementioning

confidence: 99%

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Abel

Hoenderop

Bindels

2005

Naunyn-Schmiedeberg's Arch Pharmacol

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The epithelial Ca 2+ channels TRPV5 and TRPV6 represent a new family of Ca 2+ channels that belongs to the superfamily of transient receptor potential channels. TRPV5 and TRPV6 constitute the apical Ca 2+ entry mechanism in active Ca 2+ transport in kidney and intestine. The central role of TRPV5 and TRPV6 in active Ca 2+ (re)absorption makes it a prime target for regulation to maintain Ca 2+ balance. This review covers the hormonal regulation, interaction with accessory proteins and (patho)physiological implications of these epithelial Ca 2+ channels.

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“…One of the few SNPs for which causal effects have been demonstrated on the protein level is rs1042636. This SNP has been associated with primary hypercalciuria, 8 lower circulating calcium in healthy individuals 9 and with lower plasma PTH in patients with primary or sHPT. 10,11 Patients with the glycine allele show a more pronounced suppression of PTH after administration of cinacalcet, as compared with homozygous arginine carriers.…”

Section: Introductionmentioning

confidence: 99%

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

et al. 2011

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Calcium-sensing receptor polymorphism rs1042636 (Arg990Gly) affects the response to the calcimimetic cinacalcet, used to treat hypercalcemia in secondary hyperparathyroidism (sHPT) or parathyroid carcinoma. Carriers of the Arg allelle, show less parathyroid hormone secretion suppression in response to the drug. This effect was reproducible in transfected cultured human embryonic kidney cells, supporting a causal relationship on the protein level. We previously established that cinacalcet has an antilipolytic effect in isolated human adipocytes; however, there were a number of samples that did not respond to the treatment. The present work aimed to investigate whether the variable antilipolytic response to cinacalcet in adipocytes was consistent with the effect reported for the rs1042636 polymorphism. Lipolysis was assessed by measuring glycerol release after exposure to cinacalcet (10 lM) or vehicle in adipocytes isolated from 38 donors. Responsiveness was defined as lipolysis suppression (cinacalcet vs vehicle control) greater than 20%. Genotype analysis showed that 23 adipocyte donors were homozygous for Arg at position 990, 14 heterozygous and 1 homozygous Gly-Gly. Among the Arg homozygotes, one was responsive to cinacalcet, whereas five Gly carriers responded to the calcimimetic. In all, 83% of adipocytes showing response to cinacalcet carried the glycine allele, whereas in 96% of Arg-Arg individuals adipocytes did not respond to the calcimimetic (P¼0.027, Fisher's exact test). Confirming sHPT observations, adipocytes from rs1042636 Gly-allele carriers show higher sensitivity to the antilipolytic action of cinacalcet. The potential benefit of cinacalcet as a suppressor of basal lipolysis and free fatty acid release in uremic patients needs to consider the rs1042636 single-nucleotide polymorphism.

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Influence of Calcium-Sensing Receptor Gene on Urinary Calcium Excretion in Stone-Forming Patients

Cited by 137 publications

References 31 publications

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

New Insights Into the Pathogenesis of Idiopathic Hypercalciuria

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

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