BACKGROUND: Type III Bartter syndrome (BS) is an autosomal recessive renal tubular disease caused by the mutation of the chloride voltage-gated channel Kb (CLCNKB) gene. This condition is characterized by renal sodium loss, hypokalemia, metabolic alkaliosis, high renin, and high aldosterone levels.
METHODS: We report a case of adult type III BS caused by a novel complex heterozygous mutation of the CLCNKB gene. The peripheral blood was extracted for whole genome DNA extraction, and the genome exon region of BS- related genes, was predicted by high-throughput sequencing and protein function prediction software. The selected mutation sites were verified by sequencing with Sanger method.
RESULTS: The new complex heterozygous mutations of CLCNKB include heterozygous deletion of exon 2 - 20 of CLCNKB and nonsense mutation of exon 19, c.2010G>A (p.W670X). This complex heterozygous mutation has not been reported in humans.
CONCLUSIONS: For patients with high clinical suspicion of BS, a clear diagnosis should be made through genetic test-ing to improve patients\' quality of life and provide genetic guidance.

The clinical presentation, treatment, and follow-up of two boys with type 1 Dent disease who exhibited a Bartter-like phenotype were retropectively analysed. The related literature of pediatric patients with type 1 Dent disease who had hypokalemia and metabolic alkalosis was screened through databases such as PubMed, CNKI, and Wanfang until February 1, 2024, and common features among these patients were summarized through literature review. A total of 7 literatures were included, and 9 children were included in the analysis. All patients were male, presenting with significant low molecular weight proteinuria and hypercalciuria. Other prominent characteristic phenotypes included short stature (7/8), hypophosphatemia (8/9), and rickets (6/8). Seven previously reported patients had missense or nonsense mutations, while 2 patients in this study carried possible pathogenic mutations in the CLCN5 gene, c.315+2T>A (p.?) and c.584dupT (p.I196Yfs*6), respectively. Five patients were able to maintain blood potassium levels around 3 mmol/L with oral potassium chloride solution combined with non-steroidal anti-inflammatory drugs (ibuprofen or indomethacin). The follow-up showed that 2 patients developed chronic kidney disease stage 4 and stage 3 at the age of 13 and 21 years, respectively. The phenotypic overlap between Dent disease and Batter syndrome is considerable,with the distinguishing feature being the presence of significant low molecular weight proteinuria. Patients with type 1 Dent disease presenting with the Bartter-like phenotype have a high prevalence of short stature, hypophosphatemia, and rickets. Non-steroidal anti-inflammatory drugs can be used to correct hypokalemia in patients under periodic renal function assessment.
回顾性分析2例以巴特样表型起病的登特病1型男性患儿的临床表现、治疗及随访。检索PubMed、知网、万方等数据库，从建库至2024年2月1日，筛选低钾血症合并代谢性碱中毒的登特病1型患儿相关文献，通过文献复习总结此病患儿的临床特征。纳入7篇文献，9例患儿纳入分析。患者均为男性，均有大量低分子蛋白尿和高钙尿症，其他突出的特征性表型包括身材矮小（7/8）、低磷血症（8/9）及佝偻病（6/8）。已报道的7例患者为CLCN5基因错义或无义突变，本研究报道的2例患者分别携带CLCN5基因可能致病性突变：c.315+2T>A（p.？）及c.584dupT（p.I196Yfs*6）。5例患者经氯化钾口服液联合非甾体类抗炎药（布洛芬或吲哚美辛）能维持血钾水平在3 mmol/L左右。随访显示有2例患者分别在13和21岁时出现慢性肾脏病4期和3期。登特病与巴特综合征表型重合度高，鉴别点在于是否存在大量低分子蛋白尿。以巴特样表型起病的登特病1型患者身材矮小、低磷血症及佝偻病的发生率高。在定期检测肾功能的情况下，非甾体抗炎药可用于纠正患者的低钾血症。.

UNASSIGNED: To investigate the characteristics of 4 Chinese patients with Bartter syndrome type 3 (BS Type 3).
UNASSIGNED: The clinical data, genetic analysis, and outcome of four cases with Bartter syndrome type 3 were retrospectively summarised.
UNASSIGNED: Gene sequencing analysis showed that all children carried a compound heterozygous mutation in the CLCNKB gene and were diagnosed with BS type 3. All types of mutations were detected, including two missense mutations, one nonsense mutation, one small fragment deletion mutation, two large deletion mutations and one splice-site mutation. The splice-site mutation c.100 + 1 (IVS2) C > T was novel. Two cases carried large deletion mutations. The patients presented as classic BS with modest manifestations. The most common sign was growth retardation. There was no polyhydramnios or preterm delivery. All cases were treated with potassium chloride supplementation and indomethacin. During long-term follow-up, clinical symptoms and growth retardation improved significantly. Nephrocalcinosis or renal dysfunction was not observed.
UNASSIGNED: The clinical manifestations of BS type 3 are mostly presented as cBS. Growth retardation is a common sign. BS type 3 had a good long-term prognosis. There were various types of mutations in the CLCNKB gene. Large deletions were the most common.

Potassium-wasting syndromes, including Gitelman or Bartter syndrome, require close medical and biochemical review during pregnancy to reduce potentially severe complications, morbidity and mortality. We report a case of severe potassium-wasting syndrome managed successfully in pregnancy with extremely high oral potassium intake.

Type 1 Bartter\'s syndrome and Gitelman\'s syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter\'s syndrome and Gitelman\'s syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter\'s syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman\'s syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca2+ excretion in type 1 Bartter\'s syndrome and Gitelman\'s syndrome are well understood, Mg2+ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca2+ and Mg2+ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg2+ preservation over Ca2+ in Bartter\'s syndrome and Ca2+ preservation over Mg2+ in Gitelman\'s syndrome and are stronger in females than in males.

Cystic fibrosis is a multisystem disease with extremely variable onset, symptoms and course. One of the onset modality but also a complication of the disease is the pseudo-Bartter syndrome, characterized by hyponatremia, hypochloremic dehydration and metabolic alkalosis in absence of any renal disease. This syndrome occurs more frequently in the first year of life and has a peak in the summer. In this article, we describe two cases of cystic fibrosis associated with pseudo-Bartter syndrome in childhood. Excluding every possible cause of metabolic alkalosis associated with hyponatremia was crucial for our diagnostic pathway, and the experience gained with the first case helped a lot with the second one.

OBJECTIVE: Postnatal renal tubule development is critical to adult kidney function. Several postnatal changes regulate the differentiation and proliferation of renal tubular cells. Here, we review the literature and our efforts on thick ascending limb (TAL) development in Bartter syndrome (BS).
RESULTS: Glomerular filtrate quickly increases after birth, imposing fluid shear stress and circumferential stretch on immature renal tubules. Recent studies showed that kidney organoids under flow (superfusion) have better development of tubular structures and the expression of cilia and solute transporters. These effects are likely mediated by mechanosensors, such as cilia and the piezo1 channel. Improved renal oxygenation and sodium pump-dependent active transport can stimulate mitochondrial respiration and biogenesis. The functional coupling between transport and mitochondria ensures ATP supply for energy-demanding reactions in tubular cells, including cell cycle progression and proliferation. We recently discovered that postnatal renal medulla maturation and TAL elongation are impaired in Clc-k2-deficient BS mice. Primary cultured Clc-k2-deficient TAL cells have G1-S transition and proliferation delay. These developmental defects could be part of the early pathogenesis of BS and worsen the phenotype.
CONCLUSIONS: Understanding how tubular flow and transepithelial ion fluxes regulate renal tubule development may improve the treatment of congenital renal tubulopathies.

BACKGROUND Bartter syndrome is a rare, inherited salt-wasting tubulopathy caused by mutations in 1 of 6 genes that express ion transport channels in the thick ascending limb of nephrons. Excessive prostaglandin E2 and associated hyperreninemic hyperaldosteronism occurs, causing polyhydramnios, polyuria, prematurity, failure to thrive, and characteristic physical features. Hypokalemia, hypochloremic metabolic alkalosis, and, depending on the affected gene, hypercalciuria and nephrocalcinosis are hallmarks of Bartter syndrome. CASE REPORT A 9-month-old male infant, born prematurely due to polyhydramnios, presented in the Emergency Department with dehydration due to incoercible vomiting and significant polyuria. A 6-year-old male infant with a previous history of prematurity due to polyhydramnios was referred to the Pediatric Endocrinology Department due to short stature and notable polydipsia and polyuria. Considering these marked symptoms, both cases triggered suspicion and started workup for arginine-vasopressin insufficiency/resistance. However, during the investigations, a broader clinical revision revealed that both had dysmorphic physical features (triangularly shaped face, prominent forehead, protruding ears, drooping mouth), poor growth, impaired weight gain, and typical biochemical findings (hypokalemic metabolic alkalosis, hypercalciuria, secondary hyperaldosteronism) of Bartter syndrome. Genetic testing confirmed the diagnosis of Bartter syndrome types 1 and type 2, respectively, and this diagnosis allowed proper treatment and significant clinical improvements, personalized follow-up, and genetic counseling for parents desiring further healthy pregnancies. CONCLUSIONS Here, we present clinical and follow-up findings of 2 patients with Bartter syndrome types 1 and 2 discovered upon a broader clinical revision of suspected arginine-vasopressin insufficiency/resistance. We also review pertinent data on diagnosis and management of this challenging syndrome.

OBJECTIVE: To summarize the clinical characteristics and genetic variations in children with cystic fibrosis (CF) primarily presenting with pseudo-Bartter syndrome (CF-PBS), with the aim to enhance understanding of this disorder.
METHODS: A retrospective analysis was performed on the clinical data of three children who were diagnosed with CF-PBS in Hunan Children\'s Hospital from January 2018 to August 2023, and a literature review was performed.
RESULTS: All three children had the onset of the disease in infancy. Tests after admission showed hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, and genetic testing showed the presence of compound heterozygous mutation in the CFTR gene. All three children were diagnosed with CF. Literature review obtained 33 Chinese children with CF-PBS, with an age of onset of 1-36 months and an age of diagnosis of 3-144 months. Among these children, there were 29 children with recurrent respiratory infection or persistent pneumonia (88%), 26 with malnutrition (79%), 23 with developmental retardation (70%), and 18 with pancreatitis or extrapancreatic insufficiency (55%). Genetic testing showed that c.2909G>A was the most common mutation site of the CFTR gene, with a frequency of allelic variation of 23% (15/66).
CONCLUSIONS: CF may have no typical respiratory symptoms in the early stage. The possibility of CF-PBS should be considered for infants with recurrent hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis, especially those with malnutrition and developmental retardation. CFTR genetic testing should be performed as soon as possible to help with the diagnosis of CF.
目的: 总结以假性Bartter综合征（pseudo-Bartter syndrome, PBS）为主要表现的囊性纤维化（cystic fibrosis, CF）（CF-PBS）患儿的临床特征和基因变异，以提高对CF-PBS的认识。方法: 回顾性分析2018年1月—2023年8月在湖南省儿童医院确诊的3例CF-PBS患儿的临床资料并文献复习。结果: 3例患儿均在婴儿期起病，入院后检验示低钠、低钾、低氯血症和代谢性碱中毒，基因检测示CFTR基因存在复合杂合变异，均诊断为CF。文献检索33例CF-PBS中国患儿，起病年龄和诊断年龄分别为1~36月龄、3~144月龄，伴有反复呼吸道感染或持续肺炎29例（88%）、营养不良26例（79%）、发育落后23例（70%）、胰腺炎或可疑胰腺外分泌功能不全18例（55%）；c.2909G>A是CFTR基因最常见的变异位点，等位基因变异频率为23%（15/66）。结论: CF早期无典型的呼吸道症状，对于反复出现的低钠、低钾、低氯血症和代谢性碱中毒的婴儿，特别是同时存在营养不良、发育落后，需警惕CF-PBS可能，应尽早进行CFTR基因检测协助诊断CF。.

Mutations in NKCC2 generate antenatal Bartter syndrome type 1 (type 1 BS), a life-threatening salt-losing nephropathy characterized by arterial hypotension, as well as electrolyte abnormalities. In contrast to the genetic inactivation of NKCC2, inappropriate increased NKCC2 activity has been associated with salt-sensitive hypertension. Given the importance of NKCC2 in salt-sensitive hypertension and the pathophysiology of prenatal BS, studying the molecular regulation of this Na-K-2Cl cotransporter has attracted great interest. Therefore, several studies have addressed various aspects of NKCC2 regulation, such as phosphorylation and post-Golgi trafficking. However, the regulation of this cotransporter at the pre-Golgi level remained unknown for years. Similar to several transmembrane proteins, export from the ER appears to be the rate-limiting step in the cotransporter\'s maturation and trafficking to the plasma membrane. The most compelling evidence comes from patients with type 5 BS, the most severe form of prenatal BS, in whom NKCC2 is not detectable in the apical membrane of thick ascending limb (TAL) cells due to ER retention and ER-associated degradation (ERAD) mechanisms. In addition, type 1 BS is one of the diseases linked to ERAD pathways. In recent years, several molecular determinants of NKCC2 export from the ER and protein quality control have been identified. The aim of this review is therefore to summarize recent data regarding the protein quality control of NKCC2 and to discuss their potential implications in BS and blood pressure regulation.