Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032617 (polyuria)
 3,056 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is now evident that the term Bartter syndrome does not represent a unique entity but encompasses a variety of disorders of renal electrolyte transport. Application of molecular biology techniques has permitted a better understanding of these "Bartter-like syndromes," which at present can be divided into three different genetic and clinical entities. Neonatal Bartter syndrome is observed in newborn infants and characterized by polyhydramnios, premature delivery, life-threatening episodes of fever and dehydration during the early weeks of life, growth retardation, hypercalciuria, and early-onset nephrocalcinosis. Two molecular defects have been identified: either at the gene encoding the renal bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) or the gene encoding an ATP-sensitive inwardly rectifying K channel (ROMK). "Classic" Bartter syndrome is mostly observed during infancy and childhood and is characterized clinically by polyuria and growth retardation. Nephrocalcinosis is not present. Very recently, either deletions or mutations at the gene encoding a renal chloride channel (ClC-Kb) have been identified. Gitelman syndrome is observed in older children and adults presenting with intermittent episodes of muscle weakness and tetany, hypokalemia, and hypomagnesemia. Mutations at the gene encoding the thiazide-sensitive Na-Cl cotransporter have been identified in the majority of patients studied. Obviously the validity of this classification must be confirmed in the near future when all mutations have been described and genotypic-phenotypic correlations are better defined.
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PMID:Bartter and related syndromes: the puzzle is almost solved. 965 65

The CLC-K1 chloride channel is a kidney-specific CLC chloride channel expressed in the thin ascending limb of Henle's loop (tAL). Recently, we determined that Clcnk1-/- mice show nephrogenic diabetes insipidus (NDI). To investigate the pathogenesis of impaired urinary concentrating ability, we analyzed renal functions of Clcnk1-/- mice in more detail. The osmolar clearance-to-creatinine clearance ratio was not significantly different between Clcnk1+/- and Clcnk1+/+ mice. Fractional excretion of sodium, chloride, and urea was also not significantly affected in Clcnk1-/- mice. These results indicate that the polyuria observed in Clcnk1-/- mice was water diuresis and not osmotic diuresis. The papillary osmolarity in Clcnk1-/- mice was significantly lower than that in Clcnk1+/+ mice under a hydrated condition, and it did not increase even after water deprivation. Sodium and chloride contents in the inner medulla in Clcnk1-/- mice were at about one-half the levels observed in Clcnk1+/+ mice. Furthermore, the accumulation of urea was also impaired in Clcnk1-/- mice, suggesting that the overall countercurrent system was impaired by a defect of its single component, chloride transport in the tAL. The aldose reductase mRNA abundance in Clcnk1-/- mice was decreased, further evincing that inner medullary tonicity is decreased in Clcnk1-/- mice. We concluded that NDI in Clcnk1-/- mice resulted from an impairment in the generation of inner medullary hypertonicity by a dysfunction of the countercurrent systems.
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PMID:Impaired solute accumulation in inner medulla of Clcnk1-/- mice kidney. 1113 17

We report on two cases of Bartter's syndrome, together with the review of current literature on the aetiology, development and treatment of Bartter's syndrome. Bartter's syndrome belongs to a group of hypokalaemic renal channelopathies, which are caused by a molecular hereditary disorder of ion channels in renal tubules. These channels are located in the lipid layer of cell membranes where they exist as water channels through which ion transport is performed. Based on the type of genetic disorder and clinical presentation, Bartter's syndrome is classified as neonatal, classical and Gitelman's syndrome. Neonatal form is found in newborns and is characterized by foetal polyuria, premature birth, postnatal episodes of severe dehydration, growth retardation, hypercalciuria and early nephrocalcinosis. It is the result of mutation of a gene responsible for renal tubular Na-K-2Cl cotransport or another gene which controls the ATP-dependant potassium channel (ROMK). Classic form is found in young children with polyuria, hypokalaemia and growth retardation. This type is caused by a defect of a gene for chloride channel (CIC-Kb) in the distal tubule. Gitelman's syndrome is found in late childhood or adolescence. It is caused by mutation in the gene for Na-Cl co-transport in the distal tubule. Children with Gitelman's syndrome occasionally have muscle weakness or tetany, hypokalaemia and hypomagnesaemia. Even though there have been advances in understanding the aetiology and pathogenesis of Bartter's syndrome in the recent years, the possibilities and strategies for its management remained almost the same. Treatment is based on prostaglandin inhibitors, potassium sparing diuretics and substitution therapy.
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PMID:[Bartter's syndrome: new classification, old therapy]. 1179 62

Bartter syndrome, which presents clinically with polyuria, urinary potassium loss, hypokalemia, hypercalciuria, and alkalosis, is an autosomal recessive disorder with mutations in genes encoding the Na-K-2Cl cotransporter, the chloride channel CLC-NKB, and the potassium channel ROMK. Prenatal diagnosis of Bartter syndrome is now possible; however, there are no reports of the placental pathology associated with fetal Bartter syndrome. We present the placental pathologic findings in two siblings with fetal Bartter syndrome. Both pregnancies were complicated by polyhydramnios and preterm delivery. The first pregnancy delivered at 30 weeks, and Bartter syndrome was diagnosed in the perinatal period. The subsequent pregnancy required periodic therapeutic amniocentesis secondary to massive polyhydramnios and delivered at 32 weeks gestation. The suspicion of fetal Bartter syndrome was very high in this second pregnancy, and the infant was confirmed to have Bartter syndrome subsequently. Both placentas were large for gestational age, weighing greater than the 95th percentile. Microscopic examination showed extensive subtrophoblastic basement membrane mineralization (special stains positive for iron and calcium) in the chorionic villi. This striking finding was present in both placentas. Subtrophoblastic mineralization has been described in the literature in placentas of fetuses with abnormalities including anencephaly, trisomy 21, and other congenital abnormalities; however, it has also been described in normal pregnancies. Mechanisms of calcification in the placenta are not well understood, but these striking cases suggest that defects in fetal renal excretion of ions can lead to dystrophic calcification within the placenta, particularly in a subtrophoblastic pattern.
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PMID:Placental pathology in fetal bartter syndrome. 1181 71

Antenatal Bartter Syndrome (ABS) is a rare autosomic recessive tubulopathy characterized by idiopathic hydramnios, fetal polyuria and elevated levels of amniotic chloride. It is related to mutations affecting several transporters in the loop of Henle e.g. the Na-K-2Cl cotransporter, the chloride channel CLC-NKB and the potassium channel ROMK. We report two cases of ABS in siblings born to consanguineous parents (first cousins). The first pregnancy showed hydramnios of unknown etiology at week 23. Two amnio drains were performed at weeks 26 and 27. The baby was born in week 29 and developed polyuria with hyponatremia, hypokalemia and hyperaldosteronism. After eliminating diabetes insipidus and adrenal insufficiency, ABS was diagnosed. The baby was treated with 0.5 mg/kg/d indomethacine, which controlled the polyuria and the hydroelectrolytic disorder. The second pregnancy showed idiopathic hydramnios at week 24. The elevated amniotic chloride level (above 112 mmole/l) led to the antenatal diagnosis of ABS. The mother was treated with 1 mg/kg/d indomethacine until week 31 in order to stabilize the hydramnios. Two amnio drains at weeks 31 and 33 allowed the pregnancy to be prolonged until week 34. A genetic study of the family showed homozygosity of the NKCC2 gene marker suggesting its implication in the disease.
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PMID:[Prenatal Bartter's syndrome. Report of two cases]. 1506 2

Dent's disease is an X-linked renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis or nephrolithiasis. The disease is caused by mutations in a renal chloride channel gene, CLCN5. We report on three boys, of Indian origin, with Dent's disease that presented at an early age (1-4 years), with polyuria, polydipsia, salt craving, recurrent vitamin A-responsive night blindness, hypophosphataemic rickets, hypercalciuria and low molecular weight proteinuria. All these patients were found to have novel mutations in the CLCN5 gene.
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PMID:Vitamin A responsive night blindness in Dent's disease. 1944 83

ClC-K chloride channels are crucial for auditory transduction and urine concentration. Mutations in CLCNKB, the gene encoding the renal chloride channel hClC-Kb, cause Bartter syndrome type III, a human genetic condition characterized by polyuria, hypokalemia, and alkalosis. In recent years, several Bartter syndrome-associated mutations have been described that result in truncations of the intracellular carboxyl terminus of hClC-Kb. We here used a combination of whole-cell patch clamp, confocal imaging, co-immunoprecipitation, and surface biotinylation to study the functional consequences of a frequent CLCNKB mutation that creates a premature stop codon at Trp-610. We found that W610X leaves the association of hClC-Kb and the accessory subunit barttin unaffected, but impairs its regulation by barttin. W610X attenuates hClC-Kb surface membrane insertion. Moreover, W610X results in hClC-Kb channel opening in the absence of barttin and prevents further barttin-mediated activation. To describe how the carboxyl terminus modifies the regulation by barttin we used V166E rClC-K1. V166E rClC-K1 is active without barttin and exhibits prominent, barttin-regulated voltage-dependent gating. Electrophysiological characterization of truncated V166E rClC-K1 demonstrated that the distal carboxyl terminus is necessary for slow cooperative gating. Since barttin modifies this particular gating process, channels lacking the distal carboxyl-terminal domain are no longer regulated by the accessory subunit. Our results demonstrate that the carboxyl terminus of hClC-Kb is not part of the binding site for barttin, but functionally modifies the interplay with barttin. The loss-of-activation of truncated hClC-Kb channels in heterologous expression systems fully explains the reduced basolateral chloride conductance in affected kidneys and the clinical symptoms of Bartter syndrome patients.
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PMID:Carboxyl-terminal Truncations of ClC-Kb Abolish Channel Activation by Barttin Via Modified Common Gating and Trafficking. 2645 2

Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.
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PMID:Clinical and Genetic Spectrum of Bartter Syndrome Type 3. 2838 50

Bartter syndromes (BS) types 1-5 are rare salt-losing tubulopathies presenting with overlapping clinical phenotypes including marked salt wasting and hypokalemia leading to polyuria, polydipsia, volume contraction, muscle weakness and growth retardation. These diseases are due to an impairment of sodium, potassium, chloride reabsorption caused by mutations in genes encoding for ion channel or transporters expressed in specific nephron tubule segments. Particularly, BS type 3 is a clinically heterogeneous form caused by mutations in CLCNKB gene which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. Specific therapy for BS is lacking and the only pharmacotherapy up today available is purely symptomatic and characterized by limiting side effects. The improvement of our understanding of the phenotype/genotype correlation and of the precise pathogenic mechanisms associated with BS type 3 as well as the pharmacological characterization of ClC-K chloride channels are fundamental to design therapies tailored upon patients' mutation. This mini review focused on recent studies representing relevant forward steps in the field as well as noteworthy examples of how basic and clinical research can cooperate to gain insight into the pathophysiology of this renal channelopathy, paving the way for a personalized therapy.
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PMID:[Bartter syndrome, severe rare orphan kidney disease: a step towards therapy through pharmacogenetic and epidemiological studies]. 2978 80