Inherited renal tubular defects with hypokalemia.

Bartter's and Gitelman's syndrome are two ends of a spectrum of inherited renal tubular disorders that present with hypokalemic metabolic alkalosis of varying severity. Clinical features and associated calcium and magnesium ion abnormalities are used to diagnose these cases after excluding other commoner causes. We report on two cases, the first being a young boy, born of pregnancy complicated by polyhydramnios, who had classical dysmorphic features, polyuria, hypokalemia and hypercalciuria and was diagnosed as having Bartter's syndrome. The second patient is a lady who had recurrent tetany as the only manifestation of Gitelman's syndrome, which is an unusual presentation. Potassium replacement with supplementation of other deficient ions led to satisfactory clinical and biochemical response.

Antenatal Bartter's syndrome: why is this not a lethal condition?

There are four themes in this teaching exercise for Professor McCance. The first challenge was to explain how a premature infant with Bartter's syndrome could survive despite having such a severe degree of renal salt wasting. Second, the medical team wanted to know why there was such a dramatic decrease in the natriuresis in response to therapy, despite the presence of a permanent molecular defect that affected the loop of Henle. Third, Professor McCance was asked why this patient seemed to have a second rare disease, AQP2 deficiency type of nephrogenic diabetes insipidus. The fourth challenge was to develop a diagnostic test to help the parents of this baby titrate the dose of indomethacin to ensure an effective dose while minimizing the likelihood of developing nephrotoxicity. The missing links in this interesting story emerge during a discussion between the medical team and its mentor.

Prenatal diagnosis of Bartter syndrome with biochemical examination of amniotic fluid: case report.

Antenatal Bartter syndrome typically presents with marked fetal polyuria that leads to polyhydramnios and premature delivery. In our case, polyhydramnios was detected at 26 weeks of gestation and amniotic fluid chloride level was high. Serial amnion-drains were performed. During indomethacine treatment, fetal bradycardia developed. The mother was given daily oral potassium to maintain normal serum level and prevent fetal arrhythmias. After birth, hypokalaemic alkalosis, low chloride, hyper-reninemia and hyperaldosteronemia were detected.

Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome.

OBJECTIVE: 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. RESULTS: 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. CONCLUSIONS: 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.

pH gating of ROMK (K(ir)1.1) channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome.

Inward-rectifier K(+) channels of the ROMK (K(ir)1.1) subtype are responsible for K(+) secretion and control of NaCl absorption in the kidney. A hallmark of these channels is their gating by intracellular pH in the neutral range. Here we show that a lysine residue close to TM1, identified previously as a structural element required for pH-induced gating, is protonated at neutral pH and that this protonation drives pH gating in ROMK and other K(ir) channels. Such anomalous titration of this lysine residue (Lys-80 in K(ir)1.1) is accomplished by the tertiary structure of the K(ir) protein: two arginines in the distant N and C termini of the same subunit (Arg-41 and Arg-311 in K(ir)1.1) are located in close spatial proximity to the lysine allowing for electrostatic interactions that shift its pK(a) into the neutral pH range. Structural disturbance of this triad as a result from a number of point mutations found in patients with antenatal Bartter syndrome shifts the pK(a) of the lysine residue off the neutral pH range and results in channels permanently inactivated under physiological conditions. Thus, the results provide molecular understanding for normal pH gating of K(ir) channels as well as for the channel defects found in patients with antenatal Bartter syndrome.

Conjunctive effects of fibroblast growth factor and glycosaminoglycan on bone metabolism in neonatal bartter syndrome.

The calciotropic activity of urine from a subject with neonatal Bartter syndrome (NBS) has been partially purified using ion-exchange and gel chromatographic techniques. A bioassay using bone disks from rat calvaria was used to estimate calciotropic activity, which in the urine of the subject with NBS appears to be due to basic fibroblast growth factor (bFGF) bound to a glycosaminoglycan susceptible to heparitinase digestion. The calciotropic activity is eluted from DEAE-Sephacel and Sepharose CL-6B in a narrow band in association with metachromatic material and is destroyed by heparitinase and blocked by an antibody to bFGF. After treatment of purified preparations with heparitinase, a component that is inactive alone but develops calciotropic activity in association with heparin can be isolated by affinity chromatography on heparin-Sepharose columns. This component is recovered from the column at NaCl concentrations expected to elute bFGF and is inactivated by antibodies to bFGF. No calciotropic activity can be shown in glycosaminoglycan-containing fractions from urine from a normal boy or a normal man, but such fractions exhibit calciotropic activity if bFGF is added to the assay system. When bFGF is added to urine from either normal subject followed by ion-exchange chromatography on DEAE-Sephacel, calciotropic activity is eluted at NaCl concentrations closely similar to those found to elute calciotropic activity from the urine of the NBS subject. It appears that the abnormal findings in NBS urine are due to excess bFGF, although they could be due to some abnormality of the glycosaminoglycan component.

Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder.

The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting either coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS.

Alcalosis metabólica hipokalémica

Se expone un caso de síndrome de Bartter en un lactante menor de dos meses de edad con antecedente prenatal de polihidramnios y parto pretérmino. Con historia de vómito, diarrea y estreñimiento ocasional, asociado con retardo pondoestatural. Este paciente presentó cuadro de bronconeumonía viral la cual evolucionó en forma tórpida con aumento del síndrome de dificultad respiratoria (SDR) y deterioro del estado general por lo cual hubo necesidad de trasladarlo a la unidad de cuidado intensivo de pediatría. Allí se corroboró la presencia de alcalosis metabólica hipokalémica e hipoclorémica con aumento de la excreción urinaria de K, Na y Cl y defecto en la habilidad de concentrar la orina. Aunado a esto se detectó hiperreninemia, poliuria y aldosterona elevada. La tensión arterial fue normal con un percentil menor de cinco para el peso y de 10 para la talla. Con base en todo lo anterior se pudo confirmar el diagnóstico de síndrome de Bartter

Growth from birth to adulthood in a patient with the neonatal form of Bartter syndrome.

Growth from birth to the age of 19 years was studied in a patient with the neonatal form of Bartter syndrome. The initial modes of therapy (extra fluid, potassium supplements and triamterene) resulted in satisfactory but not optimal growth. Treatment with spironolactone together with potassium led to impressive catch-up growth. When the patient reached the age of 9 years, indomethacin therapy was started, which resulted in a second growth acceleration and was also accompanied by a significant reduction of both polyuria and hypercalciuria. Puberty developed normally, menarche occurred at 12 years 4 months and a normal adult height of 162 cm was reached at the age of 14 years. Treatment with prostaglandin synthetase inhibitors seems to be the best therapy for children with the neonatal form of Bartter syndrome.

Fetal polyuria and hydramnios associated with Bartter's syndrome.

The case of a woman with recurrent hydramnios in three pregnancies, from which the only surviving infant was later found to have Bartter's syndrome, is described. Analysis of electrolytes, renin activity, and aldosterone levels in amniotic fluid from this pregnancy are presented. The finding of maternal hydramnios in the present and 12 other reported cases of Bartter's syndrome suggests that increased fetal voiding is the most likely causative factor in the development of increased amniotic fluid volume. Early onset hydramnios might signify Bartter's syndrome in the offspring in families with an index case. In cases of hydramnios of unknown etiology, appropriate investigations might lead to early diagnosis and treatment of Bartter's syndrome.