[Cystic fibrosis primarily presenting with pseudo-Bartter syndrome: a report of three cases and literature review]. / 以假性Bartter综合征为主要表现的囊性纤维化患儿3ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

OBJECTIVES: 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.

Polymyxin B-induced Bartter syndrome.

Bartter syndrome is a genetic disorder characterised by chloride-unresponsive metabolic alkalosis, hypokalaemia, hypomagnesaemia and hypercalciuria. While it commonly presents antenatally or in early infancy, sometimes, drugs can induce a state similar to Bartter syndrome in any age group, called acquired Bartter syndrome. Polymyxins and aminoglycosides are the most commonly implicated drugs. Polymyxin B and polymyxin E (popularly known as colistin) are the two chemically similar polymyxins that are commonly used clinically. While colistin is frequently associated with nephrotoxicity, polymyxin B is generally considered less nephrotoxic. This difference is due to the way these two drugs are handled by the kidneys. In this case report, we discuss a middle-aged male who developed Bartter syndrome due to polymyxin B, which resolved on discontinuation of the drug, and re-appeared after its re-introduction later. This case exemplifies the nephrotoxicity caused by polymyxin B and the need for vigilance when using this drug.

Adult classic Bartter syndrome: a case report with 5-year follow-up and literature review.

Bartter syndrome (BS) is a rare, inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism, hypokalemia, hypochloremia, metabolic alkalosis, and low-to-normal blood pressure. Classic BS, or BS Type 3, the most common subtype in the Asian population, is caused by a molecular defect in ClC-Kb, a voltage-gated chloride channel in renal tubules, due to CLCNKB gene mutation. Because the onset of BS is more common in children than in adults, the diagnosis, treatment outcomes, genotype/phenotype association, and follow-up of adult-onset BS Type 3 are limited. This case report describes the findings in a 20-year-old man who was admitted with hypokalemic paralysis, with clinical manifestations were similar to those of Gitelman syndrome (GS); however, the patient was later diagnosed to have BS Type 3 through genetic testing (NM_000085.4 (CLCNKB): c.1052G>T). A literature review showed that no homozygous mutations have been reported to date. After 5 years of treatment and follow-up, we found that this genotype requires high levels of potassium and is prone to urinary protein and metabolic syndrome. Distinguishing adult-onset BS from GS is challenging in clinical practice. However, genetic diagnosis can help solve this problem effectively, and genotypes play a guiding role in treatment planning.

Bartter syndrome-like phenotype in a patient with type 2 diabetes mellitus.

Bartter syndrome (BS) is a rare genetic tubulopathy affecting the loop of Henle leading to salt wasting. It is commonly seen in utero or in the early neonatal period. Rare cases of acquired BS are reported in association with infections like tuberculosis, granulomatous conditions like sarcoidosis, autoimmune diseases and drugs. The mainstay of management includes potassium, calcium and magnesium supplementation. We report the case of a woman in her 50s with a history of type 2 diabetes mellitus for the last 10 years, who presented with diabetic foot ulcers and generalised weakness with ECG changes suggestive of hypokalaemia. She had severe hypokalaemia with high urine potassium excretion and hypochloraemic metabolic alkalosis. She poorly responded to intravenously administered potassium supplements and had persistent hypokalaemia. On further evaluation of the persistent hypokalaemia, a diagnosis of idiopathic Bartter-like phenotype was made. She responded well to tablet indomethacin and is presently asymptomatic and is being maintained on tablet indomethacin after 6 months of follow-up.

Pseudo-Bartter syndrome as the initial presentation of cystic fibrosis in children: an important diagnosis not to be missed.

Pseudo-Bartter syndrome (PBS) is characterised by hyponatraemic, hypochloraemic metabolic alkalosis that mimics Bartter syndrome, without renal tubular disease. We present a case of an infant with a positive cystic fibrosis (CF) newborn screening, hospitalised during the summer with dehydration, oliguria and apathy. Blood analysis revealed hypochloraemic metabolic alkalosis, hypokalaemia and hyponatraemia. Urine analysis showed leucocyturia with reduced sodium and chloride excretion fraction, and urinary culture was positive for Citrobacter koseri After antibiotherapy and intravenous rehydration with additional supplementation of sodium and chloride, the patient recovered completely. PBS is one of CF complications that is especially prevalent in infants and young children with increased sweating and/or other causes of additional loss of sodium and chloride. Clinical awareness of this syndrome and its strong clinical suspicion are extremely important for an early diagnosis and treatment of CF, particularly in countries where the universal screening of CF is not routinely performed.

Recurrent transient severe hypocalcaemia in two siblings with type 1 Bartter syndrome.

Type 1 Bartter syndrome causes hypokalaemia and metabolic alkalosis owing to mutation in the SLC12A1 gene. Meanwhile, hypocalcaemia is rare in Bartter syndrome, except in type 5 Bartter syndrome. Herein, we describe two siblings with type 1 Bartter syndrome with recurrent transient severe hypocalcaemia. They each visited our hospital several times with chief complaints of numbness in the limbs, shortness of breath and tetany after stresses such as exercise or fever. Severe hypocalcaemia was also observed with a serum calcium level of approximately 6.0 mg/dL at each visit. The clinical symptoms and abnormalities in laboratory findings quickly improved with rest and intravenous treatment. In a steady state, no severe hypocalcaemia was evident, but serum intact parathyroid hormone (PTH) levels were high. In recent years, a large-scale study has revealed that type 1 and type 2 Bartter syndrome have high PTH values. In addition, there are reports that these patients develop hypocalcaemia due to PTH resistance. Therefore, our patient was also in a PTH-resistant state, and hypocalcaemia was thought to be exacerbated by physical stress. It is not well known that Bartter syndrome patients other than those with type 5 suffer from hypocalcaemia. And hypocalcaemia was not detected in normal examinations under steady-state conditions. Therefore, in patients with type 1 and type 2 Bartter syndrome, severe hypocalcaemia may occur, but may go unnoticed. When following up these patients, the attending physician must keep in mind that such patients are in a PTH-resistant state and that physical stress can cause severe hypocalcaemia.

Successful antenatal treatment of MAGED2-related Bartter syndrome and review of treatment options and efficacy.

A new form of transient antenatal Bartter syndrome (aBS) was recently identified that is associated with the X-linked MAGED2 variant. Case reports demonstrate that this variant leads to severe polyhydramnios that may result in preterm birth or pregnancy loss. There is limited but promising evidence that amnioreductions may improve fetal outcomes in this rare condition. We report a woman with two affected pregnancies. In the first pregnancy, the patient was diagnosed with mild-to-moderate polyhydramnios in the second trimester that ultimately resulted in preterm labor and delivery at 25 weeks with fetal demise. Whole exome sequencing of the amniotic fluid sample resulted after the pregnancy loss and revealed a c.1337G>A MAGED2 variant that was considered diagnostically. The subsequent pregnancy was confirmed by chorionic villi sampling to also be affected by this variant. The pregnancy was managed with frequent ultrasounds and three amnioreductions that resulted in spontaneous vaginal delivery at 37 weeks and 6 days of a viable newborn with no evidence of overt electrolyte abnormalities suggesting complete resolution. A detailed review of the published cases of MAGED2-related transient aBS is provided. Our review focuses on individuals who received antenatal treatment. A total of 31 unique cases of MAGED2-related transient aBS were compiled. Amnioreduction was performed in 23 cases and in 18 cases no amnioreduction was performed. The average gestational age at delivery was significantly lower in cases without serial amnioreduction (28.7 vs. 30.71 weeks, p = 0.03). Neonatal mortality was seen in 5/18 cases without serial amnioreduction, and no mortality was observed in the cases with serial amnioreduction. In cases of second trimester severe polyhydramnios without identifiable cause, whole exome sequencing should be considered. Intensive ultrasound surveillance and serial amnioreduction is recommended for the management of MAGED2-related transient aBS.

Bartter Syndrome: A Systematic Review of Case Reports and Case Series.

Background and Objectives: Bartter syndrome (BS) is a rare group of autosomal-recessive disorders that usually presents with hypokalemic metabolic alkalosis, occasionally with hyponatremia and hypochloremia. The clinical presentation of BS is heterogeneous, with a wide variety of genetic variants. The aim of this systematic review was to examine the available literature and provide an overview of the case reports and case series on BS. Materials and Methods: Case reports/series published from April 2012 to April 2022 were searched through Pubmed, JSTOR, Cochrane, ScienceDirect, and DOAJ. Subsequently, the information was extracted in order to characterize the clinical presentation, laboratory results, treatment options, and follow-up of the patients with BS. Results: Overall, 118 patients, 48 case reports, and 9 case series (n = 70) were identified. Out of these, the majority of patients were male (n = 68). A total of 21 patients were born from consanguineous marriages. Most cases were reported from Asia (73.72%) and Europe (15.25%). In total, 100 BS patients displayed the genetic variants, with most of these being reported as Type III (n = 59), followed by Type II (n = 19), Type I (n = 14), Type IV (n = 7), and only 1 as Type V. The most common symptoms included polyuria, polydipsia, vomiting, and dehydration. Some of the commonly used treatments were indomethacin, potassium chloride supplements, and spironolactone. The length of the follow-up time varied from 1 month to 14 years. Conclusions: Our systematic review was able to summarize the clinical characteristics, presentation, and treatment plans of BS patients. The findings from this review can be effectively applied in the diagnosis and patient management of individuals with BS, rendering it a valuable resource for nephrologists in their routine clinical practice.

Pattern of hereditary renal tubular disorders in Egyptian children.

BACKGROUND: Hereditary renal tubular disorders (HRTD) represent a group of genetic diseases characterized by disturbances in fluid, electrolyte, and acid-base homeostasis. There is a paucity of studies on pediatric HRTD in Egypt. In this study, we aimed to study the pattern, characteristics, and growth outcome of HRTD at an Egyptian medical center. METHODS: This study included children from one month to < 18-years of age with HRTD who were diagnosed and followed up at the Pediatric Nephrology Unit of Sohag University Hospital from January 2015 to December 2021. Data on patients` demographics, clinical features, growth profiles, and laboratory characteristics were collected. RESULTS: Fifty-eight children (57% males; 72% parental consanguinity; 60% positive family history) were diagnosed with seven HRTD types. The most commonly encountered disorders were distal renal tubular acidosis (distal renal tubular acidosis [RTA] 27 cases, 46.6%) and Bartter syndrome (16 cases 27.6%). Other identified disorders were Fanconi syndrome (6 cases with cystinosis), isolated proximal RTA (4 cases), nephrogenic diabetes insipidus (3 cases), and one case for each RTA type IV and Gitelman syndrome. The median age at diagnosis was 17 months with a variable diagnostic delay. The most common presenting features were failure to thrive (91.4%), developmental delay (79.3%), and dehydration episodes (72.4%). Most children showed marked improvement in growth parameters in response to appropriate management, except for cases with Fanconi syndrome. Last, only one case (with cystinosis) developed end-stage kidney disease. CONCLUSIONS: HRTD (most commonly distal RTA and Bartter syndrome) could be relatively common among Egyptian children, and the diagnosis seems challenging and often delayed.

Genotypic variability in patients with clinical diagnosis of Bartter syndrome type 3.

Bartter syndrome (BS) is a salt-losing hereditary tubulopathy characterized by hypokalemic metabolic alkalosis with secondary hyperaldosteronism. Confirmatory molecular diagnosis may be difficult due to genetic heterogeneity and overlapping of clinical symptoms. The aim of our study was to describe the different molecular findings in patients with a clinical diagnosis of classic BS. We included 27 patients (26 families) with no identified pathogenic variants in CLCNKB. We used a customized Ion AmpliSeq Next-Generation Sequencing panel including 44 genes related to renal tubulopathies. We detected pathogenic or likely pathogenic variants in 12 patients (44%), reaching a conclusive genetic diagnosis. Variants in SLC12A3 were found in 6 (Gitelman syndrome). Median age at diagnosis was 14.6 years (range 0.1-31), with no history of prematurity or polyhydramnios. Serum magnesium level was low in 2 patients (33%) but urinary calcium excretion was normal or low in all, with no nephrocalcinosis. Variants in SLC12A1 were found in 3 (BS type 1); and in KCNJ1 in 1 (BS type 2). These patients had a history of polyhydramnios in 3 (75%), and the mean gestational age was 34.2 weeks (SD 1.7). The median age at diagnosis was 1.8 years (range 0.1-6). Chronic kidney disease and nephrocalcinosis were present in 1 (25%) and 3 (75%) patients, respectively. A variant in CLCN5 was found in one patient (Dent disease), and in NR3C2 in another patient (Geller syndrome). Genetic diagnosis of BS is heterogeneous as different tubulopathies can present with a similar clinical picture. The use of gene panels in these diseases becomes more efficient than the study gene by gene with Sanger sequencing.

HNF1B variant without hyperglycaemia as a cause of isolated profound hypomagnesaemia.

A young man presented unconscious with severe hyponatraemia, hypokalaemia, hypomagnesaemia and metabolic alkalosis. After 4 months of treatment in hospital, the hypomagnesaemia persisted. The patient had no signs of diabetes mellitus, and radiology showed no abnormalities of the kidneys, pancreas or genitourinary tract. A parenteral magnesium load demonstrated renal wasting with increased fractional urinary excretion of magnesium. Genetic tests for Gitelman as well as Bartter syndromes were negative. However, a wider genetic panel revealed that the patient was heterozygous for a deletion on chromosome band 17q12, encompassing the whole HNF1B gene.This case highlights the importance of considering pathogenic HNF1B variants in isolated profound hypomagnesaemia caused by renal wasting. Pathogenic HNF1B variants may partly mimic hypomagnesaemia found in Gitelman and Bartter syndromes and may be present without other features linked to HNF1B variants, including diabetes mellitus.

Pathophysiologic approach in genetic hypokalemia: An update.

The pathophysiology of genetic hypokalemia is close to that of non-genetic hypokalemia. New molecular pathways physiologically involved in renal and extrarenal potassium homeostasis have been highlighted. A physiological approach to diagnosis is illustrated here, with 6 cases. Mechanisms generating and sustaining of hypokalemia are discussed. After excluding acute shift of extracellular potassium to the intracellular compartment, related to hypokalemic periodic paralysis, inappropriate kaliuresis (>40mmol/24h) concomitant to hypokalemia indicates renal potassium wasting. Clinical analysis distinguishes hypertension-associated hypokalemia, due to hypermineralocorticism or related disorders. Genetic hypertensive hypokalemia is rare. It includes familial hyperaldosteronism, Liddle syndrome, apparent mineralocorticoid excess,11beta hydroxylase deficiency and Geller syndrome. In case of normo- or hypo-tensive hypokalemia, two etiologies are to be considered: chloride depletion or salt-wasting tubulopathy. Diarrhea chlorea is a rare disease responsible for intestinal chloride depletion. Due to the severity of hypokalemic metabolic alkalosis, this disease can be misdiagnosed as pseudo-Bartter syndrome. Gitelman syndrome is the most frequent cause of genetic hypokalemia. It typically associates renal sodium and potassium wasting, hypomagnesemia, conserved chloride excretion (>40mmol/24h), and low-range calcium excretion (urinary Ca/creatinine ratio<0.20mmol/mmol). Systematic analysis of hydroelectrolytic disorder and dynamic hormonal investigation optimizes indications for and orientation of genotyping of hereditary salt-losing tubulopathy.

Acquired autoimmune Bartter syndrome in a patient with primary hypothyroidism.

We describe an unusual clinical presentation of autoimmune Bartter syndrome in a patient with primary hypothyroidism. A 65-year-old female patient was admitted with neuromuscular weakness associated with hypokalemia and metabolic alkalosis. She had a suboptimal response to potassium supplementation and potassium-sparing diuretic resulting in re-hospitalization with the same symptoms. A detailed serum and urinary biochemistry analysis in the absence of other causes of potassium wasting helped diagnose Bartter syndrome, a rare entity in adults. An autoimmune profile showed anti-Scl-70 antibody to be positive, although she did not develop other systemic features of the disease. Our patient responded to a steroid-based regimen potassium supplement, Indomethacin, and aldosterone antagonist with remarkable resolution of symptoms and correction of electrolyte derangement. We reviewed the literature to search for similar cases and included twenty-seven full-length publications on acquired and autoimmune causes of Bartter syndrome. Our case highlights the fact that hypokalemia with metabolic alkalosis in an adult patient should prompt clinicians to evaluate for common and uncommon conditions. While assessing for abnormal conditions, acquired Bartter syndrome should be considered if a patient has an underlying autoimmune, endocrine, or connective tissue disease.

Bartter-like Syndrome Induced By Tacrolimus in a Renal Transplanted Boy: A Case Report.

BACKGROUND: Losing-salt tubulopathies, such as Bartter syndrome, are rare and usually inherited due to mutations of tubular reabsorption channels of the nephrons. Despite its scarcity, some cases of acquired losing-salt tubulopathies have been described. In this case report, we discuss the main aspects of Bartter syndrome and present a rare pediatric case of probable tacrolimusinduced Bartter-like syndrome in a renal transplanted boy. CASE PRESENTATION: A ten-year-old male patient with end-stage renal disease due to endo and extra capillary glomerulonephritis was submitted to renal transplantation from a deceased donor. The post-operatory evolution was satisfactory with normalization of serum creatinine levels, mild hypertension, and the absence of metabolic disorders. The immunosuppression protocol included tacrolimus (0.3 mg/kg/day), mycophenolate (455 mg/m2/day) and prednisone (0.5 mg/kg/day). Two months later, the patient was hospitalized due to vomiting, dehydration, intense hypokalemia (1.3 mEq/L), hyponatremia (125 mEq/L), and hypochloremia (84 mmol/L). During hospitalization, he evolved with polydipsia (3000 mL/day) and polyuria (120-160 mL/m2/h) associated with major elevation of urinary potassium excretion, hypercalciuria, mild metabolic alkalosis, hyperfiltration, and proteinuria. The tacrolimus dose was reduced under the suspicion of tubular dysfunction, leading to a better metabolic profile. However, the patient developed a Banff IIb graft rejection, which required pulse therapy and elevation of tacrolimus and mycophenolate doses. Recovery of renal function parameters occurred, but the metabolic disorders worsened following tacrolimus dose elevation. The patient required chronic potassium, chloride, and sodium replacement. CONCLUSION: After administering immunosuppressive medications, physicians should be aware of the possibility of Bartter-like or other losing-salt tubulopathies syndromes that can affect metabolic homeostasis. The suspicion must always be considered in the case of a transplanted patient who presents dehydration and hydroelectrolytic disorders right after the commencement of nephrotoxic immunosuppressive drugs, including tacrolimus and cyclosporine.

Acute Kidney Injury with Severe Metabolic Alkalosis Caused by Habitual Vomiting in an Alcohol Abuser with Pyloric Stenosis.

A 47-year-old man was complaining of consciousness disorder. He had acute kidney injury, hypokalemia, and severe metabolic alkalosis. Initial treatment using intravenous infusion of 0.9% saline and potassium chloride improved his consciousness. It was clarified that he was a severe alcohol abuser who habitually self-vomited. We diagnosed him with volume depletion and pseudo-Bartter's syndrome due to loss of chloride by habitual vomiting. Gastrointestinal endoscopy demonstrated pyloric stenosis, which was ameliorated by Helicobacter pylori eradication therapy. We should consider volume depletion and pseudo-Bartter's syndrome as differential diagnoses when we encounter patients with acute kidney injury and severe metabolic alkalosis.

Genetic diagnosis and treatment of hereditary renal tubular disease with hypokalemia and alkalosis.

Renal tubules play an important role in maintaining water, electrolyte, and acid-base balance. Renal tubule dysfunction can cause electrolyte disorders and acid-base imbalance. Clinically, hypokalemic renal tubular disease is the most common tubule disorder. With the development of molecular genetics and gene sequencing technology, hereditary renal tubular diseases have attracted attention, and an increasing number of pathogenic genes related to renal tubular diseases have been discovered and reported. Inherited renal tubular diseases mainly occur due to mutations in genes encoding various specific transporters or ion channels expressed on the tubular epithelial membrane, leading to dysfunctional renal tubular reabsorption, secretion, and excretion. An in-depth understanding of the molecular genetic basis of hereditary renal tubular disease will help to understand the physiological function of renal tubules, the mechanism by which the kidney maintains water, electrolyte, and acid-base balance, and the relationship between the kidney and other systems in the body. Meanwhile, understanding these diseases also improves our understanding of the pathogenesis of hypokalemia, alkalosis and other related diseases and ultimately promotes accurate diagnostics and effective disease treatment. The present review summarizes the most common hereditary renal tubular diseases (Bartter syndrome, Gitelman syndrome, EAST syndrome and Liddle syndrome) characterized by hypokalemia and alkalosis. Further detailed explanations are provided for pathogenic genes and functional proteins, clinical manifestations, intrinsic relationship between genotype and clinical phenotype, diagnostic clues, differential diagnosis, and treatment strategies for these diseases.