Bartter syndrome

Since the initial description in the 1960s of patients with seemingly inherited disorders characterized by hypokalemia and metabolic alkalosis, the pathophysiologic processes underlying Bartter and Gitelman syndromes have generated tremendous study and speculation. Recently described mutations in genes encoding transport proteins important in sodium and chloride reabsorption in the thick ascending limb of Henle and distal convoluted tubule have confirmed these processes as the proximate defects in Bartter and Gitelman syndromes, respectively. Basic understanding of the role of these proteins in normal sodium and chloride homeostasis, and review of the secondary mediators stimulated by loss of their function provide insight into the clinical manifestations and response to treatment observed in these disorders.

Until recently, significant advances in our understanding of the mechanisms of blood pressure regulation arose from studies of monogenic forms of hypertension and hypotension, which identified rare variants that primarily alter renal salt handling. Genome-wide association and exome sequencing studies over the past 6 years have resulted in an unparalleled burst of discovery in the genetics of blood pressure regulation and hypertension. More importantly, genome-wide association studies, while expanding the list of common genetic variants associated with blood pressure and hypertension, are also uncovering novel pathways of blood pressure regulation that augur a new era of novel drug development, repurposing, and stratification in the management of hypertension. In this review, we describe the current state of the art of the genetic and molecular basis of blood pressure and hypertension.

Genetic kidney diseases (GKDs) are an important and well-known entity in pediatric nephrology. Advances in genetic and molecular approaches in the last 15 years have enabled elucidation of the underlying molecular defects in many of these disorders. Herein, the authors summarize the progress that has been made over this period in disclosing the molecular basis of several novel GKDs which were characterized in this area and include Bartter syndrome type IV, type II Bartter syndrome and transient neonatal hyperkalemia, cystinuria and mental retardation, familial hypomagnesemia with secondary hypocalcemia, infantile nephronophthisis and familial hemolytic uremic syndrome with factor H deficiency. Retrospective analysis of the authors' data reveals that GKDs are over-represented among the pediatric population in southern Israel. GKD are seen 4 times more often than end-stage renal disease (ESRD) and comprise 38% of all cases of ESRD in our area. This high rate of GKD is mainly due t...

Basal and bradykinin stimulated release of prostaglandins (6-oxo-PGF1 alpha, PGF2 alpha, PGE2) and of arachidonic acid (C20:4) from skin fibroblast cultures of two patients with Bartter's Syndrome were compared with age and sex matched controls. PG-formation from 14C-C20:4 was studied, and for PGE2 a radioimmunoassay was also employed. The data show that in basal release, Bartter's Syndrome fibroblasts produce significantly less PGE2 than controls. Stimulated release of 6-oxo-PGF1 alpha was higher, that of PGE2 lower and that of C2O:4 higher in Bartter's Syndrome than in controls, all differences being significant. Despite equal culturing conditions the estimated intracellular potassium was higher in the patients fibroblasts than in controls. In skin fibroblasts from patients with Bartter's Syndrome stimulated prostaglandin production from C2O:4 is mostly depressed, with the exeption of prostacyclin which is enhanced. The permeability of cell membranes for potassium ...

Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS. Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses. Polyuria, p...

Bartter syndrome (BS) is classified into 5 genotypes according to underlying mutant genes and BS III is caused by loss-of-function mutations in the CLCNKB gene encoding for basolateral ClC-Kb. BS III is the most common genotype in Korean patients with BS and W610X is the most common CLCNKB mutation in Korean BS III. In this study, we tested the hypothesis that the CLCNKB W610X mutation can be rescued in vitro using aminoglycoside antibiotics, which are known to induce translational read-through of a nonsense mutation. The CLCNKB cDNA was cloned into a eukaryotic expression vector and the W610X nonsense mutation was generated by site-directed mutagenesis. Cultured polarized MDCK cells were transfected with the vectors, and the read-through was induced using an aminoglycoside derivative, G418. Cellular expression of the target protein was monitored via immunohistochemistry. While cells transfected with the mutant CLCNKB failed to express ClC-Kb, G418 treatment of the cells induced the...

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto ...

Identification of neonatal hyperkalemia as a complication of Bartter syndrome (BS), a disorder usually characterized by hypokalemic metabolic alkalosis. Study design Case-series description of a group of 12 infants with mutations in the renal potassium channel ROMK, causing one of the antenatal variants of BS. Prematurity, postnatal polyuria, and dehydration were seen in all cases. Plasma potassium was as high as 9.0 +/- 1.2 mmol/L and sodium as low as 124 +/- 3.5 mmol/L, appearing usually at day 3 of life and normalizing by the end of the first postnatal week. No hyperkalemia was found in 12 neonates with the variant of BS and deafness. The mean plasma potassium level during the first week of life among a group of very low-birth-weight infants with similar relative azotemia was 4.9 +/- 1 mmol/L (P <.001). The postneonatal period in the ROMK-defective children with BS was characterized by failure to thrive, hypercalciuria, nephrocalcinosis, and minimal-to-no hypokalemia. Early postnatal hyperkalemia, sometimes severe, may complicate antenatal BS associated with ROMK mutations. Its association with hyponatremia and hyperreninemic hyperaldosteronism may erroneously suggest the diagnosis of pseudohypoaldosteronism type 1. The expression of ROMK in both the thick ascending limb and cortical collecting duct may explain this apparently tubular maturation phenomenon.

Bartter syndrome, a group of disorders that encompasses multiple genetic defects with similar clinical presentation, has been divided into six different genotypes, according to different genetic defects, and into three main clinical variants (or phenotypes). Classic ...

Bartter's syndrome is a rare autosomal recessive disorder characterized by hypokalemia, hyperaldosteronism, sodium wasting, normal blood pressure, hypochloremicalkalosis, and hyperplasia of the juxtaglomerular apparatus. We present a 28-year-old Indian nulliparous patient who was referred to our hospital at 16 weeks' gestation. Patient was known case of Hyperthyroidism diagnosed 18 months ago and was being treated with Propylthiouracil. She presented with Vomiting followed by ascending quadriparesis. She required increasing potassium supplementation. She developed hypomagnesemia which necessitated magnesium therapy. Patient suffered intrauterine death of her fetus. Bartter's syndrome, although extremely rare in pregnancy, requires prompt recognition and careful management, as it may have significant maternal and neonatal implications.

The bumetanide-sensitive Na+-K+-2Cl− cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene ( SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1I299F exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid ex...

Mutations in genes encoding ion channels have increasingly been identified to cause disease conditions collectively termed channelopathies. Recognizing the molecular basis of an ion channel disease has provided new opportunities for screening, early diagnosis, and therapy of such conditions. This synopsis provides an overview of progress in the identification of molecular defects in inwardly rectifying potassium (Kir) channels. Structurally and functionally distinct from other channel families, Kir channels are ubiquitously expressed and serve functions as diverse as regulation of resting membrane potential, maintenance of K(+) homeostasis, control of heart rate, and hormone secretion. In humans, persistent hyperinsulinemic hypoglycemia of infancy, a disorder affecting the function of pancreatic beta cells, and Bartter's syndrome, characterized by hypokalemic alkalosis, hypercalciuria, increased serum aldosterone, and plasma renin activity, are the two major diseases linked so f...

Idiopathic hypercalciuria associated with hyperreninemia and high urinary prostaglandin E. A patient with idiopathic hypercalciuria and some features suggestive of Bartter syndrome is reported. Excessive urinary prostaglandin E (PGE) excretion and renal calcium leak were ...

A 16-month-old boy was admitted to the clinic because of vomiting and growth failure. His weight and height measurements were under the fifth percentile. He had fair hair and skin, enlarged wrists and rachitic rosaries. The presence of metabolic alkalosis, hypokalemia, hypochloremia, and high renin and aldosterone levels were suggestive of Bartter syndrome. However, in view of the growth failure, fair hair and skin, proteinuria, polyuria and active rickets, cystinosis was considered. Bone marrow smear examination was normal, despite the existence of suspicious crystals in the cornea. Cystine crystals were seen in the conjunctiva biopsy and increased leukocyte cystine level was measured; therefore, definitive cystinosis diagnosis was made. Renal Fanconi syndrome with metabolic acidosis is prominent in cystinosis; however, in rare instances, if sodium-dependent trans-tubular transport defect is present, patients could have Bartter syndrome findings such as hypochloremic metabolic alka...

Antenatal Bartter syndrome (aBS) comprises a heterogeneous group of autosomal recessive salt-losing nephropathies. Identification of three genes that code for renal transporters and channels as responsible for aBS has resulted in new insights into renal salt handling, diuretic action and blood-pressure regulation. A gene locus of a fourth variant of aBS called BSND, which in contrast to the other forms is associated with sensorineural deafness (SND) and renal failure, has been mapped to chromosome 1p. We report here the identification by positional cloning, in a region not covered by the human genome sequencing projects, of a new gene, BSND, as the cause of BSND. We examined ten families with BSND and detected seven different mutations in BSND that probably result in loss of function. In accordance with the phenotype, BSND is expressed in the thin limb and the thick ascending limb of the loop of Henle in the kidney and in the dark cells of the inner ear. The gene encodes a hitherto ...