Bartter's syndrome in Arabic children: review of 13 cases

BACKGROUND: Bartter's syndrome (BS) is an inherited disease of renal potassium wasting characterized by hypokalemic alkalosis, normal blood pressure, vascular insensitivity to pressor agents and elevated plasma concentrations of renin and aldosterone. It is caused by generalized hyperplasia of the juxtaglomerular apparatus at the site of renin production caused by mutations in the Na-K-2Cl cotransporter gene, NKCC2. The objective of our study is to establish the prevalence and incidence of BS in Kuwait and to assess treatment modalities for it. METHODS AND RESULTS: Bartter's syndrome was diagnosed in 13 Kuwaiti children over a 14 year period (1981-1995) with the estimated incidence of 1.7/100,000 live births. The mean age at diagnosis was 9.3 months (range 2-32 months). There were five males and eight females (ratio 1:1.6). The mean duration of follow up was 5.6 years (1-14 years). Both consanguinity and familial history among our patients were high (69 and 54%, respectively). All patients had hypokalemia, hypochloremia with metabolic alkalosis, hyperreninemia and were normotensive. Clinical presentation was essentially similar to that in other series. Eleven patients (85%) had growth failure, two had nephrocalcinosis (15%) and one had renal failure. All patients were treated with supplemental potassium, an aldosterone antagonist (spironolactone) and a prostaglandin synthetase inhibitor (indomethacin or aspirin) sequentially. Significant catch-up of growth (four patients) and increases in serum potassium (eight patients) were recorded after administration of indomethacin therapy. One patient died of severe pneumonia with respiratory failure from hypokalemic myopathy. Clinical presentation, inheritance, complications and therapy of BS are briefly discussed. CONCLUSION: Bartter's syndrome is a rare disease, but should be considered in the differential diagnosis of other disorders with growth failure and/or hypokalemia. Early diagnosis, close follow up and compliance with treatment may lead to appropriate growth and development.     

Long-term use of propranolol, ibuprofen, and spironolactone in the management of Bartter's syndrome.

This report concerns two patients with Bartter's syndrome who were treated with propranolol, spironolactone, and potassium supplements. When ibuprofen was added to this regimen, potassium supplements were no longer required. In both patients, plasma renin activity decreased, plasma volumes increased, and a "catch-up" in linear growth ensued. This report confirms others that indicate prostaglandin synthetase inhibitors are a useful adjunct in the therapy of Bartter's syndrome.     

Treatment of Bartter's syndrome with indomethacin

Two patients with Bartter's syndrome were treated with indomethacin (2 mg/kg/day). The administration of the drug resulted in weight gain; a decrease in the rate of urinary excretion of sodium and inorganic phosphate suggesting an increase in proximal tubular reabsorption; an increase in serum potassium concentration, with a transient decrease in the rate of urinary potassium excretion in one patient; and a decrease in plasma renin activity and in the rate of urinary aldosterone excretion. Since indomethacin has been shown to inhibit prostaglandin synthetase, these observations support the hypothesis that prostaglandin excess is a basic pathogenic mechanism in Bartter's syndrome.     

The role of prostaglandins in Bartter's syndrome

In two children with Bartter's syndrome, treatment with indomethacin halved the urinary excretion of prostaglandins E and F within 24 hours and subsequently maintained it within the normal range during follow-up for more than 5 years. Growth rate was improved and plasma renin and aldosterone and the urinary excretions of sodium and calcium fell to normal. Both children continued to lose excessive quantities of potassium in the urine. The results provide further evidence that over-production of prostaglandins is not the primary cause of Bartter's syndrome.     

Bartter's syndrome. Differentiation into two clinical groups.

We were able to separate Bartter's syndrome patients into two groups: Group 1 patients are seen at a young age, with hyponatremia and episodes of extracellular volume contraction. Group 2 patients are older and most have tetany; plasma sodium values and renal sodium balances are normal. Plasma potassium values are lower and plasma renin activity and plasma magnesium levels are higher in group 1 than in group 2. It may be that all patients with Bartter's syndrome manifest the features of both groups, group 1 patients with time developing into group 2 patients. These observations have important implications in the treatment of patients with Bartter's syndrome.     

Effect of indomethacin in a patient with Bartter's syndrome: evidence against a primary role of prostaglandin in this disorder

It has been claimed that in patients with Bartter's syndrome, enhanced prostaglandin synthesis causes the blunted vasopressor response to angiotensin II. The present study was undertaken to test this hypothesis by administering indomethacin to a patient with Bartter's syndrome. In domethacin corrected the subnormal pressor response to angiotensin II and lowered plasma renin activity from 115 to 15 ng/ml/hr. This effect was associated with renal sodium retention and a 7% increase in body weight. In contrast, when indomethacin was given but the sodium retention prevented by concomitant administration of furosemide, the blunted vasopressor response to angiotensin II and the hyperreninemia were not corrected. It is concluded that the effectiveness of indomethacin to correct the hyperreninemia and the blunted vasopressor to angiotensin II in the preset patient was due in large part to the ability of the drug to correct sodium balance rather than by inhibition of prostaglandin synthesis.     

Erythrocyte Sodium Transport in Bartter's Syndrome

ABSTRACT. Erythrocyte sodium transport was evaluated by measurement of intracellular Na concentration (ICNa), ²²Na efflux rate constant (NaERC) and 3H-ouabain binding (BMax) (reflecting the number of Na/K ATPase pump sites) in 9 children with Bartter's syndrome compared to controls (children and adults) and children with various forms of salt wasting disease. There were no differences between control children and adults. In untreated Bartter's syndrome ICNa was significantly increased with NaERC and BMax significantly decreased compared to findings in controls and patients with other salt wasting disease. On prostaglandin synthetase inhibitor (Indomethacin) therapy, ICNa decreased but remained higher than in controls, NaERC increased to normal values but BMax remained low. These data support the view that there is a widespread defect in membrane electrolyte transport in Bartter's syndrome but suggest that the benefit of indomethacin therapy is not manifest via an effect on Na/K ATPase.     

Erythrocyte sodium transport in Bartter's syndrome

Erythrocyte sodium transport was evaluated by measurement of intracellular Na concentration (ICNa), 22Na efflux rate constant (NaERC) and 3H-ouabain binding (BMax) (reflecting the number of Na/K ATPase pump sites) in 9 children with Bartter's syndrome compared to controls (children and adults) and children with various forms of salt wasting disease. There were no differences between control children and adults. In untreated Bartter's syndrome ICNa was significantly increased with NaERC and BMax significantly decreased compared to findings in controls and patients with other salt wasting disease. On prostaglandin synthetase inhibitor (Indomethacin) therapy, ICNa decreased but remained higher than in controls, NaERC increased to normal values but BMax remained low. These data support the view that there is a widespread defect in membrane electrolyte transport in Bartter's syndrome but suggest that the benefit of indomethacin therapy is not manifest via an effect on Na/K ATPase.     

Neonatal variant of Bartter syndrome]

A male preterm infant of 32 weeks of gestation with history of severe polyhydramnios during pregnancy presented soon after birth with polyuria with initial sodium chloride loss subsequently followed by increasing potassium loss. After manifestation of hypokalaemia, hypochloraemia, alkalosis and high urinary prostaglandin concentrations, the diagnosis of the neonatal variant of Bartter's syndrome was made. The treatment consisted of administered of large amounts of fluid with sodium chloride and potassium supplementation and indomethacin (1.5 to 2 mg/kg per day).     

Association of Bartter's syndrome and empty sella

Bartter's syndrome is characterized by hypochloremia, hypokalemia, metabolic alkalosis associated with renal potassium leakage, and normal blood pressure despite increased plasma renin activity. Although association of empty sella with Gitelman syndrome has been reported, no association has been reported with Bartter's syndrome. Here we report a patient with Bartter's syndrome and empty sella. A 12 month-old male patient presented with a history of nausea, vomiting, abdominal distension, constipation, and edema in the lower extremities that had begun in the early postnatal period. The patient was born at 32 weeks gestation by operative delivery for polyhydramnios. Blood pressure was normal. Serum sodium, potassium, calcium, phosphate, chloride, albumin and alkaline phosphatase levels were 129 mEq/l, 2.5 mEq/l, 9 mg/dl, 3.8 mg/dl, 72 mg/dl, 4.2 g/dl and 1285 IU/l, respectively. Serum magnesium level was normal. Arterial blood gas levels revealed pH 7.55 (normal, 7.35-7.45), PCO2 33.6 mm/Hg (36-46), base excess +7.1 (+/- 2.3), and total CO2 33.6 mmol/l (23-27). Renin and aldosterone levels were elevated. Urine had pH 8.0 and specific gravity 1.010. Urinary calcium excretion was 22.8 kg/day (urine calcium/creatinine ratio 0.46). Urinary potassium and chloride levels were elevated. MRI of the brain was normal except for partially empty sella. We present the first pediatric patient with the association of Bartter's syndrome and empty sella.     

A Variant of Bartter's Syndrome

ABSTRACT. A case of early onset Bartter's syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis is reported. A literature review of Bartter's syndrome supports the hypothesis that the findings in this infant constitute a specific variant of Bartter's syndrome inherited in an autosomal recessive mode. Fetal polyuria in Bartter's syndrome leads to hydramnios, and the excess fluid causes premature birth. This variant of Bartter's syndrome should be included in the differential diagnosis of hydramnios, especially if the woman has had previous hydramnios resulting in a perinatal death. The disorder responds to treatment with indomethacin.     

Bartter's syndrome: two case reports in childhood

OBJECTIVE: To report a syndrome that is uncommon in childhood and call pediatrician?attention to the tubular diseases - just like Bartters syndrome - in differential diagnosis of failure to thrive and other diseases that can be usually found in children.METHODS: Two patients are presented. The first, a 3 years and 2 months old boy who was submitted for investigation of a failure to thrive detected when he was 9 months old. The second patient, a 3 months old girl, was admitted to the Intensive Care Unit due to severe electrolyte disturbances. She was supposed to have a pyloric hypertrophic stenosis.RESULTS: Both patients had failure to thrive, hypocloremic alkalosis, hypokalemia, and hypercalciuria. The first had a positive obstetric history for polihydramnios that is frequently found in the neonatal form of this syndrome. Treatment was done by blood potassium correction, together with indometacin and spironolactone administration. These drugs where well tolerated by the patients who have improved their growth rhythm only a short time after electrolytic disturbances had been corrected.CONCLUSIONS: The Bartter's syndrome is a tubular disease that is unusual in childhood. It must be considered as a possible cause of failure to thrive. The neonatal form is rare and can produce severe hydro-electrolytic disturbances, increasing the difficulties for diagnosis. The treatment is well tolerated, even by small children, and must begin early to reduce the troubles to thrive.     

Treatment of Bartter syndrome. Unsolved issue

ObjectiveTo describe the results of a long-term follow-up of Bartter syndrome patients treated with different drugs.MethodPatients were diagnosed according to clinical and laboratory data. Treatment protocol was potassium supplementation, sodium, spironolactone, and non-steroidal anti-inflammatory drug. Patients who developed proteinuria were converted to angiotensin conversion enzyme inhibitor. The variables evaluated for each drug were Z-score for weight and stature, proteinuria, creatinine clearance, gastrointestinal complaints, amount of potassium supplementation, serum potassium and bicarbonate levels, and findings of upper digestive endoscopy.Results20 patients were included. Follow-up was 10.1 ± 5.2 years. 17 patients received indomethacin for 5.9 ± 5.3 years; 19 received celecoxib, median of 35 months; and five received enalapril, median of 23 months. During indomethacin, a statistically significant increase was observed in the Z-score for stature and weight, without a change in the creatinine clearance. Seven of 17 patients had gastrointestinal symptoms, and upper digestive endoscopy evidenced gastritis in three patients and gastric ulcer in four patients. During celecoxib use, a significant increase was detected in the Z-score for stature and weight and a reduction of hyperfiltration; seven patients presented gastrointestinal symptoms, and upper digestive endoscopy evidenced mild gastritis in three. During enalapril use, no significant changes were observed in the Z-score for stature, weight and creatinine clearance. The conversion to enalapril resulted in a significant reduction in proteinuria.ConclusionThe authors suggest starting the treatment with celecoxib, and replacing by ACEi if necessary, monitoring the renal function. The safety and efficacy of celecoxib need to be assessed in larger controlled studies.     

A circulating inhibitor of platelet aggregation in Bartter's syndrome.

Aggregation studies were performed on platelets from five patients with Bartter's syndrome. Epinephrine failed to induce aggregation in all five patients. Adenosine 5'-diphosphate (ADP) produced a single reversible phase of aggregation, and there was depressed sensitivity to collagen. Response to ristocetin was normal. There was a dose-related inhibition of ADP-induced platelet aggregation when plasma from the patients was addeded to normal platelet-rich plasma. This inhibition was diminished or absent when patients were receiving aspirin. Washed platelets from two patients who were no longer undergoing aspirin therapy, showed a normal response to epinephrine in normal platelet-poor plasma. Bleeding time was reduced from 23 minutes to 12 minutes in one patient while on aspirin therapy. These studies suggest that a circulating inhibitor of platelet aggregation, probably of prostaglandin origin, is present in the plasma of patients with Bartter's syndrome.     

原发肾小管性低钾碱中毒的临床特点

目的 探讨原发肾小管性低钾碱中毒的临床特点.方法 收集在天津市儿童医院住院治疗的原发肾小管性低钾碱中毒患儿8例,其中Bartter综合征(BS)、Gitelman综合征(GS)各4例.回顾性分析其临床表现、实验室检查、治疗方法及转归情况.结果 4例BS均婴幼儿期起病,临床表现为间断呕吐、腹泻、脱水、生长发育迟缓.4例GS发病年龄为10～15岁,临床表现为肢体无力、四肢麻木及间断手足搐搦.8例患儿血压均正常.实验室检查均表现为低血钾、代谢性碱中毒、尿钾、尿氯排出增加;4例BS息儿血浆肾素、血管紧张素、醛固酮明显升高;4例GS患儿血管紧张素均升高,血浆肾素升高3例、醛固酮明显升高2例;BS患儿尿钙肌酐比>0.2,GS患儿伴低血镁、尿钙肌酐比<0.2.2例BS患儿B超示双肾回声均匀增强,其中1例左肾盂扩张.单纯补钾或联合补镁、吲哚美辛、螺内酯和卡托普利后症状缓解.结论 原发肾小管性低钾碱中毒主要表现为低血钾、代谢性碱中毒、血压正常.检查其血镁、尿钾、尿氯、尿钙肌酐比和血浆肾素、血管紧张素、醛固酮水平可帮助诊断.BS和GS的发病机制、临床表现、治疗及预后均有不同.     

Genotype/phenotype observations in African Americans with Bartter syndrome.

BACKGROUND: Two Bartter syndrome phenotypes have been described, and molecular analyses demonstrate mutations in 1 of 3 genes encoding ascending limb of Henle transporters. We report phenotypic observations in 5 African American children with Bartter syndrome in the context of a distinct genotype. METHODS: Mutation analyses were performed in 5 unrelated African American children with Bartter syndrome. These results were correlated to clinical and laboratory data. Calcium metabolism was evaluated with a bone disk bioassay. RESULTS: Mutation analyses demonstrated homozygous deletion of the ClC-Kb gene in all children. Two children had polyhydramnios and premature birth; the others were born at term and presented with failure to thrive or dehydration. All receive indomethacin, spironolactone, and potassium chloride with improved but borderline hypokalemia. Growth has improved with therapy, but height SD scores range from -3.9- to -1.4. Urinary calcium excretion is normal, and bone disk bioassay shows no abnormal calciotropic activity. No patient had nephrocalcinosis, but renal sonograms show loss of corticomedullary differentiation. CONCLUSIONS: African Americans with Bartter syndrome genotyped to date have homozygous deletion of ClC-Kb Clinical observations in our patients include partial correction of hypokalemia and suboptimal growth despite therapy. Abnormal calciotropic activity and nephrocalcinosis are not seen, but renal ultrasounds are abnormal.     

Bartter syndrome in two siblings--antenatal and neonatal observations

Bartter syndrome was diagnosed in two siblings born to healthy unrelated parents. Each pregnancy was complicated by severe polyhydramnios. The first child was treated with indomethacin from the age of then weeks on. At the age of six years he is doing very well: height is 109.9 cm (P3) and weight 17.8 (P3). Studies of the amniotic fluid during the mother's second pregnancy showed high chloride concentrations (112, 117, and 119 mEq/l), normal levels of sodium, potassium, calcium and creatinine and low prostaglandin E2 (5.0-22.3 pg/ml) and F2 alpha (36-71.7 pg/ml) concentrations. Severe chloride and sodium wasting after birth resulted in hypochloremia, hyponatremia and dehydration. Concomitantly an immediate and striking increase in urinary PGE2 excretion from 45 to 1022 pg/ml was observed. Indomethacin therapy had to be stopped after one week when necrotising enterocolitis developed.     

Effect of prolonged indomethacin therapy on renal function and selected vasoactive hormones in very-low-birth-weight infants with symptomatic patent ductus arteriosus

Renal function and changes in the activity of selected vasoactive hormones during prolonged indomethacin therapy (1 week) were studied in 11 very-low-birth-weight infants with symptomatic patent ductus arteriosus. The initiation of indomethacin therapy was associated with a reduction in diuresis, a transient decrease in creatinine clearance, and an increase in body weight (P less than 0.01). Furthermore, there was a transient trend toward hyponatremia and hyperkalemia. This acute renal dysfunction was compatible with a complex picture of renal hypoperfusion associated with a fall of plasma renin activity from high levels prior to indomethacin treatment, with a transient rise in the plasma level of arginine vasopressin and with suppressed renal and systemic prostaglandin synthesis. During treatment, an effective circulatory volume was restored by closing the ductus. In parallel, PRA and AVP plasma concentrations returned to nearly normal values. Subsequently, kidney function was not further impaired despite continued indomethacin therapy. These observations suggest that prolonged indomethacin therapy for prevention of sPDA relapse probably constitutes no further risk to kidney function after successful pharmacologically induced ductal constriction.     

Third-generation Aromatase Inhibitor Improved Adult Height in a Japanese Boy with Testotoxicosis

In this study, we report a Japanese boy with testotoxicosis due to a heterozygous mutation [p. A572V] in the LH/CGR gene, who was the first boy treated with a third-generation aromatase inhibitor (AI) and reached his adult height in Japan. He showed accelerated growth and rapid penile growth from 3 yr of age and was diagnosed as having testotoxicosis. Combined treatment with anastrozole and spironolactone was started when he was 7 yr old and 145.8 cm (+4.45 SD) tall, at which point his bone age (BA) was 13.5 yr. His predicted adult height (PAH) was estimated to be 158.3 cm. The combined treatment was continued until he was 13 yr old and 166.5 cm tall, with his BA being 15.5 yr. He reached his adult height of 166.9 cm at 15 yr of age. Combined treatment with anastrozole and spironolactone successfully decelerated BA advancement, prolonged pubertal period and improved adult height.     

Transient gall bladder dilatation associated with hypokalaemia in a patient with Bartter syndrome

A 5.5-month-old male infant with hypokalaemia and gall bladder dilatations is reported. The child was shown to have Bartter syndrome. After oral treatment with potassium and indomethacin, serum potassium levels became low normal and the gall bladder enlargement resolved. This entity should be included in the clinical spectrum of neuromuscular disturbances resulting from hypokalaemia and should be considered in a hypokalaemic infant with a right-sided abdominal mass.