Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although acute nonoliguric renal failure is a well-known nephrotoxic effect of aminoglycoside antibiotics, less recognized is acquired Bartter-like syndrome. Herein, we describe four female patients who presented with marked paresthesia, muscle weakness, and tetany following gentamicin therapy with total dose ranging from 1.2 g to 2.6 g. All were normotensive. Biochemical abnormalities included hypokalemia (K+ 1.8-2.3 mmol/L), metabolic alkalosis (HCO(3-) 31.9-34.2 mmol/L), hypomagnesemia (Mg2+ 0.9-1.2 mg/dL), hypermagnesiuria (fractional excretion of Mg 3-6%), hypocalcemia (free Ca2+ 2.0-4.1 mg/dL), and hypercalciuria (molar ratio of Ca2+/creatinine 0.23-0.53), all consistent with Bartter-like syndrome. Serum immunoreactive parathyroid hormone concentration was low despite the hypocalcemia. The Bartter-like syndrome lasted for 2 to 6 weeks after cessation of gentamicin, coupled with supplementation of K+, Ca2+, and Mg2+. These biochemical abnormalities resembled those seen in patients with gain-of-function mutations in the calcium-sensing receptor. We hypothesize that gentamicin, a polyvalent cationic molecule, induces the action of calcium-sensing receptor on the thick ascending loop of Henle and distal convoluted tubule to cause renal wasting of Na+, K+, Cl-, Ca2+, and Mg2+.
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PMID:Acquired bartter-like syndrome associated with gentamicin administration. 1576 21

The calcium-sensing receptor has a key role in calcium homeostasis, it is involved in the regulation of the serum calcium level within minutes via the secretion and action of parathyroid and the excretion of calcium in the kidney in a negative feedback manner. Mutations of the calcium sensing receptor gene leads to inactivating and activating mutations resulting in diseases with hypercalcaemia and hypocalcaemia. The loss of function mutations are associated with familial benign hypocalciuric hypercalcaemia (FHH), an autosomal dominant disease characterised by lifelong mild hypercalcaemia, low urinary calcium excretion, and inappropriate high parathyroid hormone levels, sometimes difficult to distinguish from mild asymptomatic primary hyperparathyroidism. Patients with FHH did not profit from parathyroidectomy, a calcium lowering therapy is not necessary. The gain of function mutations of the calcium-sensing receptor are associated with autosomal dominant hypocalcaemia (ADH), a disease characterised by a generally asymptomatic hypocalcaemia, inappropriately high urinary calcium excretion and normal PTH levels. A therapy to raise the serum calcium concentration has to be done carefully and is only indicated in symptomatic patients, because of enhancement of hypercalciuria with the risk of nephrocalcinosis and nephrolithiasis. Molecular genetic analysis of the calcium sensing receptor gene facilitates the sometimes difficult diagnosis. The development of compounds modulating the calcium sensing receptor function and thereby the section of PTH may become an important role in treatment of diseases of calcium metabolism.
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PMID:The role of the extracellular calcium-sensing receptor in health and disease. 1703 19

An association between the R990G polymorphism of the CaSR gene, coding for calcium-sensing receptor, and primary hypercalciuria was found in kidney stone formers. To confirm this relationship, we investigated hypercalciuric women without stones and studied the effect of CaSR gene in human embryonic kidney cells (HEK-293). We genotyped for CaSR A986S, R990G, and Q1011E polymorphisms, 119 normocalciuric and 124 hypercalciuric women with negative history of kidney stones. Homozygous (n=2) or heterozygous (n=21) women for the 990G allele considered as one group had an increased risk to be hypercalciuric (odds ratio=5.2; P=0.001) and higher calcium excretion (P=0.005) in comparison with homozygous women for the 990R allele (n=220). HEK-293 cells were transfected with the variant allele at the three CaSR gene polymorphisms and with the most common allele with no variants. The transient increment of intracellular calcium caused by the stepwise increase of extracellular calcium was evaluated in stable transfected cells loaded with fura-2 AM. The extracellular calcium concentration producing the half-maximal intracellular calcium response was lower in HEK-293 cells transfected with the 990G allele than in those transfected with the wild-type allele (P=0.0001). Our findings indicate that R990G polymorphism results in a gain-of-function of the calcium-sensing receptor and increased susceptibility to primary hypercalciuria.
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PMID:R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. 1752 93

Mutations of the calcium-sensing receptor (CaR) gene give rise to disorders of renal calcium excretion. It is now demonstrated that even common variants of CaR can cause alteration in tissue sensitivity to extracellular calcium and are associated with primary hypercalciuria. Agents targeting these functional domains may well be an option for the management of hypercalciuria and renal stones.
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PMID:Genotype and phenotype correlation of calcium-sensing receptor variants. 1733 35

Serum level of parathyroid hormone (PTH) is strictly regulated by serum calcium concentration, which is sensed by the calcium-sensing receptor (CaSR) , a member of G-protein-coupled-receptor superfamily. Activating CaSR mutations result in the impaired PTH secretion and hypocalcemia, and the increased sensitivity of the receptor in kidney leads to relative hypercalciuria despite hypocalcemia. Recognizing the patients with activating mutations in CaSR is quite important, because these patients can exhibit unusual sensitivity to treatment of their hypocalcemia with calcium and vitamin D supplementation, with toxic effects including nephrocalcinosis, renal stones, and diminished renal function.
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PMID:[Calcium-sensing receptor and hypoparathyroidism]. 1766 Jun 14

Renal stone disease (nephrolithiasis) affects 5% of adults and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in more than 35% of patients, and may occur as a monogenic disorder, or as a polygenic trait involving 3 to 5 susceptibility loci in man and rat, respectively. Studies of monogenic forms of hypercalciuric nephrolithiasis in man, for example, Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels, and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal recessive disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) cotransporter, the renal outer-medullary potassium channel (ROMK), the voltage-gated chloride channel, CLC-Kb, or in its beta subunit, Barttin. Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis, is due to mutations of the chloride/proton antiporter, CLC-5; ADHH is associated with activating mutations of the calcium-sensing receptor, which is a G protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate cotransporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to kidney stones and bone disease.
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PMID:Genetics of hypercalciuric nephrolithiasis: renal stone disease. 1787 84

Renal stone disease (nephrolithiasis) affects 3-5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to hypercalciuria and nephrolithiasis.
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PMID:Genetic causes of hypercalciuric nephrolithiasis. 1844 82

The kidney plays a critical role in regulating water homeostasis through specific proteins highly expressed in the kidney, called aquaporins, allowing water permeation at a high rate. This brief review focuses on some nephropathies associated with impaired urinary concentrating ability and in particular analyzes the role of aquaporin 2 in hypercalciuria, the most common metabolic abnormality in patients with nephrolithiasis. Specifically, this review discusses the relationship between hypercalciuria and impaired aquaporin 2-mediated water handling in both acquired and inherited disorders characterized by hypercalciuria, including those affecting the sensor of extracellular calcium concentration, the calcium-sensing receptor, which represents the principal target for extracellular calcium regulation of several tissues including parathyroid glands and kidney. In the kidney, the calcium-sensing receptor regulates renal calcium excretion and influences the transepithelial movement of water and other electrolytes. Understanding the molecular basis of alteration of kidney concentrating ability found in hypercalciuria will help for devising strategies for reducing the risk of nephrocalcinosis, nephrolithiasis, and renal insufficiency.
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PMID:Aquaporin 2 and apical calcium-sensing receptor: new players in polyuric disorders associated with hypercalciuria. 1851 90

Autosomal dominant hypocalcemia (ADH) is an inherited form of hypoparathyroidism caused by activating mutations in the calcium-sensing receptor (CaR). Treatment with PTH(1-34) may be superior to conventional therapy but is contraindicated in children, and long-term effects on the skeleton are unknown. The patient is a 20-yr-old female with ADH treated with PTH continuously since 6 yr and 2 mo of age. A bone biopsy was obtained for histomorphometry and quantitative backscattered electron imaging (qBEI). Her data were compared with one age-, sex-, and length of hypoparathyroidism-matched control not on PTH and two sex-matched ADH controls before and after 1 yr of PTH. The patient's growth was normal. Hypercalciuria and hypermagnesuria persisted despite normal or subnormal serum calcium and magnesium levels. Nephrocalcinosis, without evidence of impaired renal function, developed by 19 yr of age. Cancellous bone volume was dramatically elevated in the patient and in ADH controls after 1 yr of PTH. BMD distribution (BMDD) by qBEI of the patient and ADH controls was strikingly shifted toward lower mineralization compared with the non-ADH control. Moreover, the ADH controls exhibited a further reduction in mineralization after 1 yr of PTH. These findings imply a role for CaR in bone matrix mineralization. There were no fractures or osteosarcoma. In conclusion, long-term PTH replacement in a child with ADH was not unsafe, increased bone mass without negatively impacting mineralization, and improved serum mineral control but did not prevent nephrocalcinosis. Additionally, this may be the first evidence of a role for CaR in human bone.
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PMID:PTH(1-34) replacement therapy in a child with hypoparathyroidism caused by a sporadic calcium receptor mutation. 1906 86

Claudin-16 (paracellin-1) is a tight junction protein localized mainly in the thick ascending limb of Henle's loop and also in the distal nephron. Its defect causes familial hypomagnesaemia with hypercalciuria and nephrocalcinosis. This had been taken as an indication that claudin-16 conveys paracellular Mg(2+) and Ca(2+) transport; however, evidence is still conflicting. We studied paracellular ion permeabilities as well as effects of claudin-16 on the driving forces for passive ion movement. MDCK-C7 cells were stably transfected with wild-type (wt) and mutant (R146T, T233R) claudin-16. Results indicated that paracellular permeability to Mg(2+) but not to Ca(2+) is increased in cells transfected with wt compared to mutant claudin-16 and control cells. Increased basolateral Mg(2+) concentration activated a transcellular Cl(-) current which was greatly enhanced in cells transfected with wt and T233R claudin-16, as compared to R146T claudin-16-transfected or control cells. This current was triggered by the basolateral calcium-sensing receptor causing Ca(2+) release from internal stores, thus activating apical Ca(2+)-sensitive Cl(-) channels and basolateral Ca(2+)-sensitive K(+) channels. Immunohistochemical data suggest that the Cl(-) channel involved is bestrophin. We conclude that claudin-16 itself possesses only moderate paracellular Mg(2+) permeability but governs transcellular Cl(-) currents by interaction with apical Ca(2+)-activated Cl(-) channels, presumably bestrophin. As the transepithelial voltage generated by such a current alters the driving force for all ions, this may be the major mechanism to regulate Mg(2+) and Ca(2+) absorption in the kidney.
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PMID:Claudin-16 affects transcellular Cl- secretion in MDCK cells. 1952 48


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