Bartter's Syndrome Research Articles

NKCC1: Newly Found as a Human Disease-Causing Ion Transporter.

Among the electroneutral Na+-dependent chloride transporters, NKCC1 had until now evaded identification as a protein causing human diseases. The closely related SLC12A transporters, NKCC2 and NCC have been identified some 25 years ago as responsible for Bartter and Gitelman syndromes: two renal-dependent salt wasting disorders. Absence of disease was most surprising since the NKCC1 knockout mouse was shown in 1999 to be viable, albeit with a wide range of deleterious phenotypes. Here we summarize the work of the past 5 years that introduced us to clinical cases involving NKCC1. The most striking cases are of 3 children with inherited mutations, who have complete absence of NKCC1 expression. These cases establish that lack of NKCC1 causes deafness; CFTR-like secretory defects with mucus accumulation in lung and intestine; severe xerostomia, hypotonia, dysmorphic facial features, and severe neurodevelopmental disorder. Another intriguing case is of a patient with a dominant deleterious SLC12A2 allele. This de novo mutation introduced a premature stop codon leading to a truncated protein. This mutant transporter seems to exert dominant-negative effect on wild-type transporter only in epithelial cells. The patient who suffers from lung, bladder, intestine, pancreas, and multiple endocrine abnormalities has, however, normal hearing and cognition. Finally, new reports substantiate the haploinsufficiency prediction of the SLC12A2 gene. Cases with single allele mutations in SLC12A2 have been linked to hearing loss and neurodevelopmental disorders.

Differential diagnosis of perinatal Bartter, Bartter and Gitelman syndromes.

The common finding of hypokalemic alkalosis in several unrelated disorders may confound the early diagnosis of salt-losing tubulopathy (SLT). Antenatal Bartter syndrome (BS) must be considered in idiopathic early-onset polyhydramnios. Fetal megabladder in BS may allow its distinction from third-trimester polyhydramnios that occurs in congenital chloride diarrhea (CCD). Fetal megacolon occurs in CCD while fecal chloride >90 mEq/L in infants is diagnostic. Failure-to-thrive, polydipsia and polyuria in early childhood are the hallmarks of classic BS. Unlike BS, there is low urinary chloride in hypokalemic alkalosis of intractable emesis and cystic fibrosis. Rarely, renal salt wasting may result from cystinosis, Dent disease, disorders of paracellular claudin-10b and Kir4.1 potassium-channel deficiency. Acquired BS may result from calcimimetic up-regulation of a calcium-sensing receptor or autoantibody inactivation of sodium chloride co-transporters in Sjögren syndrome. A relatively common event of heterozygous gene mutations for Gitelman syndrome increases the likelihood of its random occurrence in certain diseases of adult onset. Finally, diuretic abuse is the most common differential diagnosis of SLT. Unlike the persistent elevation in BS, urinary chloride concentration losses waxes and wanes on day-to-day assessment in patients with diuretic misuse.

Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2

PurposeBartter syndrome type 2 (BS2) is an autosomal recessive renal tubular disorder, which is caused by the mutations in KCNJ1. This study was designed to analyze and describe the genotype and clinical features of five Chinese probands with BS2. MethodsIdentify KCNJ1 gene variants by the next generation sequencing and evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. ResultsTen variants including eight novel ones of KCNJ1 gene were found, the most common type was missense variant. The common symptoms and signs from high to low incidence were: polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Two patients presented with hypochloremic metabolic alkalosis and hypokalemia; whereas the acid-base disturbance was absent in the others. One patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal PTH levels. All patients had nephrocalcinosis and/or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin has significant therapeutic effect on the growth retardation, polydipsia and polyuria and treatment was associated with a decrease in urine calcium excretion, normalization of electrolyte disturbance and PTH parameters. ConclusionsTen variants of KCNJ1 gene were identified in five Chinese probands. These patients had atypical BS phenotype lacking evident metabolic alkalosis and/or manifesting with PTH overaction/resistance, which reminds clinicians to carefully differentiate BS2 with other parathyroid disorders. This is the first report of BS2 from Chinese populations.

Bartter Syndrome in Children; A Cause of Severe Hypokalemic Metabolic Alkalosis: Clinical Case Report and Literature Review

Bartter syndrome is an inherited renal tubular disorder caused by a defective salt reabsorption in the thick ascending limb of loop of Henle. It characterized by urinary loss of sodium, potassium, and chloride; hypokalemic metabolic alkalosis; normal blood pressure, high plasma levels of renin and aldosterone. There is phenotypical and genetic variability of Bartter syndrome since were identified five genes responsible for five different forms of Bartter syndrome. The objective of this work is to report a clinical case to study the pathophysiological, clinical, biological and therapeutic features of this syndrome.
 Materials and Methods: We reported a case of 04-month-old male infant admitted for acute dehydration secondary to polyuro-polydipsia syndrome and vomiting. In clinical presentation the patient had a dysmorphic syndrome with triangular face, protruding ears and flattened nasal root. Laboratory tests revealed hypokalemia, hyponatremia, metabolic alkalosis and hypercalciuria. Treatment with indomethacin was started at 1 mg/kg per day with favorable outcome.

Adult Bartter syndrome with hypertension: a case report

Bartter综合征主要临床特征为低血钾、高尿钾、代谢性碱中毒、高肾素和高醛固酮，血压正常或降低，合并高血压的Bartter综合征极为罕见。本例患者低血钾、碱中毒、高肾素、高醛固酮合并高血压，除外继发性醛固酮增多症的病因后，诊断为合并高血压的Bartter综合征。给予非甾体类抗炎药吲哚美辛，血钾恢复正常，证实了Bartter综合征的临床诊断。基因检测结果为SLC12A3杂合突变，目前尚未报道该杂合突变意义。.

VP32.08: Clinical case of pregnancy and follow‐up of Bartter syndrome (type 2) with a novel mutation

VP32.08: Clinical case of pregnancy and follow‐up of Bartter syndrome (type 2) with a novel mutation

Bartter Syndrome Masquerading as Acute Kidney Injury in a Neonate

Bartter Syndrome Masquerading as Acute Kidney Injury in a Neonate

Medical Perioperative Management In Patient with Acute Kidney Disease

Bartter syndrome is inherited tubulopathy caused by mutations in several genes causing hypokalemia, hypomagnesemia, hypocalcemia with hypercalciuria, and metabolic alkalosis. Beside from inherited disorder, Bartter syndrome can be caused by the use of aminoglycosides, so it is called Bartter-like syndrome. Hypokalemia has been reported as a side effect of aminoglycosides in many studies, but Bartter-like syndrome due to aminoglycosides has only been reported in a few case reports. We report a 43 years old female patient who developed muscle weakness due to hypokalemia. We found the patient’s laboratory results was consistent with Bartter syndrome. The patient had MDR-TB and received combination therapy with capreomycin for two months. We diagnosed a patient with Bartter-like syndrome due to capreomycin. Following diagnosis, we discontinued capreomycin and started potassium, magnesium and calcium therapy. After electrolyte imbalances improved, capreomycin was given three times per week and the patient was no longer experiencing the same condition.

Bartter-like Syndrome In a Patient Receiving Capreomycin For The Treatment Of Multidrug-Resistant Tuberculosis

Bartter syndrome is inherited tubulopathy caused by mutations in several genes causing hypokalemia, hypomagnesemia, hypocalcemia with hypercalciuria, and metabolic alkalosis. Beside from inherited disorder, Bartter syndrome can be caused by the use of aminoglycosides, so it is called Bartter-like syndrome. Hypokalemia has been reported as a side effect of aminoglycosides in many studies, but Bartter-like syndrome due to aminoglycosides has only been reported in a few case reports. We report a 43 years old female patient who developed muscle weakness due to hypokalemia. We found the patient’s laboratory results was consistent with Bartter syndrome. The patient had MDR-TB and received combination therapy with capreomycin for two months. We diagnosed a patient with Bartter-like syndrome due to capreomycin. Following diagnosis, we discontinued capreomycin and started potassium, magnesium and calcium therapy. After electrolyte imbalances improved, capreomycin was given three times per week and the patient was no longer experiencing the same condition.

Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses

Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown.

Long – term effect of nephrocalcinosis on renal function and body growth index in children

Aims: To evaluate effect of NC on growth index, kidney function and its etiology of children at National Children’s Hospital. Methods: A case series prospective study,34 patients from 1/07/2013 to 30/06/2019. Results: 58,8% cases were males. The most common symptoms were failure to develop heightand weight for 64,7% and 73,5%, respectively. Ultrasound examinations reveal a higher degree, stage 2b and 3 were the most frequent according to Hoyer’s grading. Mean GFR was 101,2 ± 27,5 ml/min/1,73 m2 in presentation.There were 35,3% patients with hypercalciuria and 38,2% cases had sterile pyuria. During a median follow – up of 30 months in 24 patients, growth index improved more than -2SD in 60%,mean GFR 105,2 ± 22 ml/min/1,73 m2 in follow - up. The most common leading cause to NC was renal tubular acidosis in 50% followed by primary hypercalciuria and the cause of NC remained unknown (14,7%). Other causes included vitamin D excess, bartter syndrome, nephrocalcinosis - hypercalciuria -hypomagiemia, hypophosphomia ricket. Conclusions:nephrocalcinosis is a rare disease, and clinical signs are atypical.Growth retardation was the most common clinical manifestation andthe most popular cause of this condition in our study is renal tubular acidosis. There was significant increase in height and weight from the first to last observation. GFR remained stable within a long - term.

Pseudo-Bartter syndrome in Chinese children with cystic fibrosis: Clinical features and genotypic findings.

To characterize the clinical and genotypic features of cystic fibrosis-associated pseudo-Bartter syndrome (CF-PBS) in Chinese children. We recruited and characterized the clinical manifestations of 12 Chinese children with CF-PBS. Sweat test, blood and urinary analysis, sputum culture, chest and sinus computed tomography, and abdominal ultrasonography were obtained. Whole-exome sequencing, bioinformatics analysis, and Sanger sequencing validation were performed to define the genotypes. CF-PBS was accompanied by recurrent and/or persistent pneumonia (91.7%), pancreatitis (83.3%), vomiting and/or diarrhea (66.7%), failure to thrive and liver disease (58.3% respectively), among our patients. The predominant organisms found in the airways were Pseudomonas aeruginosa (83.3%) and Staphylococcus aureus (75.0%). The mean concentrations of blood gas and electrolytes were pH 7.58, bicarbonate 40.8 mmol/L, sodium 125.9 mmol/L, chloride 77.5 mmol/L, and potassium 2.6 mmol/L. A high recurrence rate (50.0%) of CF-PBS was observed despite continued electrolyte supplementation during follow-up. In all, 19 different variants of CFTR gene were identified, and 10 of these were found to be novel observations (c.262_266delTTATA[p.L88FfsX21], c.579+2insACAT, c.1210-3C>G, c.1733T>C[p.L578P], c.2236_2246delGAGGCGATACTinsAAAAATC[p.E746KfsX8], c.3068T>G [p.I1023R], c.3635delT[p.V1212AfsX16], c.3859delG[p.G1287EfsX2], c.3964-7A>G and ΔE23 [c.3718-?_3873+?del]). The c.2909G>A[p.G970D] was the most common variant, with an allele frequency of 16.6%. A homozygous genotype of c.1521_1523delCTT[p.F508del] was discovered for the first time in patients of Chinese origin. In China, CF-PBS usually presents early and recurs frequently in infancy, accompanied by multiple comorbidities. Recurrence of CF-PBS in school-going patients does occur but is rare. The p.G970D is the most frequent variant, with a significant ethnic tendency of Chinese origin.

Are the Clinical Presentations (Phenotypes) of Gitelman's and Bartter's Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their "pH" Enotype?

Gitelman’s syndrome (GS) and Bartter’s syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature’s experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine’s ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.

Early onset children\u2019s Gitelman syndrome with severe hypokalaemia: a case report

BackgroundHypokalaemia is a common condition among paediatric patients, but severe hypokalaemia is rare and can be life-threatening if not treated properly. The causes of hypokalaemia are complex. Finding the root cause is the key.Case presentationThis article reports on a 2-year-old boy with severe hypokalaemia who was diagnosed with pneumonia. The child’s lab findings were low blood potassium minimum level of 1.7 mmol/L, hypomagnesemia, and metabolic alkalosis. However, he was without the common features of hypokalaemia, such as respiratory paralysis, severe arrhythmia, weakness and decreased blood pressure. After recovering from pneumonia, his potassium levels did not return to normal. This outcome was suspected to be due to chronic renal loss of potassium. After undergoing second-generation gene sequencing tests, it was discovered he carried the SLC12A3 gene mutation with an Asp486Asn mutation site, which he had inherited from his mother. The final diagnosis was made, confirming the child suffered from Gitelman syndrome.ConclusionsGenetic predisposition is an important cause of hypokalaemia in children. Children with unexplained persistent hypokalaemia should be examined for the possibility of Gitelman syndrome, which should be distinguished from Bartter syndrome. Genetic testing is the gold standard.

Identification of compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome exhibiting Bartter syndrome-liked phenotypes

BackgroundGitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity.MethodsIn this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome.ResultsThe proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C > T (p.Arg145Cys), c.1077C > G (p.Asn359Lys), and c.1666C > T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges.ConclusionsIn this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.

ACE2 and prognosis of COVID‐19: Insights from Bartter's and Gitelman's syndromes patients

The relationship between Renin-Angiotensin system (RAS) and COVID-19 pandemic and, in particular, RAS as part of the CoV-2 infection process via Angiotensin Converting Enzyme 2 (ACE2), the entry point of SARS-CoV-2, has resulted in conflicting suggestions regarding how RAS and its role(s) should inform treating COVID-19. ACE inhibitors or angiotensin II (Ang)-type 1 receptor blockers (ARBs), in fact, have been suggested to be avoided as they potentially upregulate ACE2 1 and, conversely, there are suggestions that ARBs might be beneficial 2 as SARS-CoV-2 causing ACE2 downregulation slows the Ang II conversion to the vasodilatory, anti-inflammatory, antioxidant and antiatherosclerotic Ang 1-7 3-5 , and the use of ARBs by blocking the excessive Ang II type-1 receptors activation, would be beneficial upregulating ACE2 activity and increasing Ang 1-7 levels. This article is protected by copyright. All rights reserved.

Calcium-Sensing Receptor and Regulation of WNK Kinases in the Kidney.

The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca2+ levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca2+ transport systems, CaSR signaling affects relevant distal Na+-(K+)-2Cl− cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure.

Syndromes de Bartter–Gitelman

Bartter–Gitelman syndromes are rare inherited autosomal recessive salt-losing tubulopathies characterized by severe and chronic hypokalemia associated with metabolic alkalosis and secondary hyperaldosteronism. Bartter syndrome results from a furosemide-like defect in sodium reabsorption in the Henle's loop leading to hypercalciuria and defect in urinary concentration capacity. The antenatal Bartter syndrome is defined by polyhydramnios and an infantile polyuria with severe dehydration whereas classic Bartter syndrome appears during childhood or adulthood. Gitelman syndrome is a thiazide-like salt-losing tubulopathy. It is associated with hypomagnesemia, hypocalciuria without defect in urinary concentration capacity. The diagnosis is most often made in adolescents or adults. Clinical symptoms include tetany, delay in the height-weight growth curves, chronic tiredness, muscle weakness, myalgia and vertigo. Nephrocalcinosis in Bartter syndrome could lead to chronic kidney disease. Antenatal Bartter syndrome requires hospitalization in intensive care unit to manage the severe newborn dehydration. Chondrocalcinosis is the major complication in the Gitelman syndrome. The corner stones of treatment is the fluid and electrolyte management Bartter and Gitelman syndromes need lifelong oral supplementations of potassium, salt (Bartter) and magnesium (Gitelman). Indomethacin is efficient to reduce water and electrolyte loss in Bartter. In Gitelman, potassium-sparing diuretics may be helping for severe hypokaliemia but they will reinforce hypovolemia.

Angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers and risk of COVID 19: information from Bartter's and Gitelman's syndromes patients.

Angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers and risk of COVID 19: information from Bartter's and Gitelman's syndromes patients.

Transient hyponatremia of prematurity caused by mild Bartter syndrome type II: a case report

BackgroundBartter syndrome subtypes are a group of rare renal tubular diseases characterized by impaired salt reabsorption in the tubule, specifically the thick ascending limb of Henle’s loop. Clinically, they are characterized by the association of hypokalemic metabolic alkalosis, hypercalciuria, nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II. Bartter syndrome type II is caused by mutations in the renal outer medullary potassium channel (ROMK) gene (KCNJ1), can present in the newborn period and typically requires lifelong therapy.Case presentationWe describe a case of a prematurely born female infant presenting with antenatal polyhydramnios, and postnatal dehydration and hyponatremia. After 7 weeks of sodium supplementation, the patient demonstrated complete resolution of her hyponatremia and developed only transient metabolic alkalosis at 2 months of age but continues to be polyuric and exhibits hypercalciuria, without development of nephrocalcinosis. She was found to have two pathogenic variants in the KCNJ1 gene: a frameshift deletion, p.Glu334Glyfs*35 and a missense variant, p. Pro110Leu. While many features of classic ROMK mutations have resolved, the child does have Bartter syndrome type II and needs prolonged pediatric nephrology follow-up.ConclusionTransient neonatal hyponatremia warrants a multi-system workup and genetic variants of KCNJ1 should be considered.