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• W3123290933 abstract "Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care. Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care. The term Bartter syndrome (BS) encompasses different inherited salt-losing tubulopathies characterized by polyuria, hypokalemia, hypochloremic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. Five different forms (BS1–5), based on molecular genetics, have been identified to date (Table 1).1Kleta R. Bockenhauer D. Salt-losing tubulopathies in children: what’s new, what’s controversial?.J Am Soc Nephrol. 2018; 29: 727-739Crossref PubMed Scopus (31) Google ScholarTable 1Molecular genetics of Bartter syndromeCharacteristicType 1Type 2Type 3Type 4aType 4bType 5OMIM601678241200607364602522613090300971GeneSLC12A1KCNJ1CLCNKBBSNDCLCNKA + CLCNKBMAGED2ProteinNKCC2KCNJ1 (ROMK or Kir1.1)ClC-KbBarttinClC-Ka + ClC-KbMAGE-D2InheritanceARARARARARXLRAR, autosomal recessive; OMIM, Online Mendelian Inheritance in Man; XLR, X-linked recessive. Open table in a new tab AR, autosomal recessive; OMIM, Online Mendelian Inheritance in Man; XLR, X-linked recessive. Clinical characteristics include polyuria, dehydration, failure to thrive, growth retardation, and a medical history of polyhydramnios with premature birth. Hypercalciuria and nephrocalcinosis are typical for some forms. BS is a potentially life-threatening condition necessitating rapid diagnosis and therapy. The primary molecular defect in all types of BS leads to impaired salt reabsorption in the thick ascending limb of the loop of Henle.2Gill Jr., J.R. Bartter F.C. Evidence for a prostaglandin-independent defect in chloride reabsorption in the loop of Henle as a proximal cause of Bartter’s syncrome.Am J Med. 1978; 65: 766-772Abstract Full Text PDF PubMed Scopus (184) Google Scholar Regardless of the underlying molecular defect, mutations result in renal tubular salt wasting with activation of the renin-angiotensin system and consequent hypokalemic and hypochloremic metabolic alkalosis. In addition, the tubuloglomerular feedback is altered at the level of the macula densa, which, under physiologic conditions, senses low tubular chloride concentrations in conditions of volume contraction. This activates cyclooxygenases (primarily COX-2) to produce high amounts of prostaglandins (primarily prostaglandin E2), which in turn stimulate renin secretion and aldosterone production, in the attempt to reestablish normal intravascular volume and glomerular perfusion.3Schnermann J. Homer W. Smith Award lectureThe juxtaglomerular apparatus: from anatomical peculiarity to physiological relevance.J Am Soc Nephrol. 2003; 14: 1681-1694Crossref PubMed Scopus (59) Google Scholar In BS, the tubuloglomerular feedback is uncoupled because chloride is not reabsorbed in the macula densa owing to the underlying molecular defects. Therefore, cells produce high amounts of prostaglandin E2 regardless of volume status, causing excessive synthesis of renin and aldosterone. This constitutes the rationale for treating BS patients with prostaglandin synthesis inhibitors, which often results in noticeable clinical improvement.4Bartter F.C. Gill Jr., J.R. Frolich J.C. et al.Prostaglandins are overproduced by the kidneys and mediate hyperreninemia in Bartter’s syndrome.Trans Assoc Am Physicians. 1976; 89: 77-91PubMed Google Scholar, 5Seyberth H.W. Rascher W. Schweer H. et al.Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome.J Pediatr. 1985; 107: 694-701Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 6Reinalter S.C. Jeck N. Brochhausen C. et al.Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome.Kidney Int. 2002; 62: 253-260Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar Impaired salt reabsorption in the thick ascending limb has 2 additional consequences that are important in BS, namely (i) a reduction of calcium reabsorption with hypercalciuria and progressive medullary nephrocalcinosis,7Fanconi A. Schachenmann G. Nussli R. Prader A. Chronic hypokalaemia with growth retardation, normotensive hyperrenin-hyperaldosteronism (“Bartter’s syndrome”), and hypercalciuria. Report of two cases with emphasis on natural history and on catch-up growth during treatment.Helv Paediatr Acta. 1971; 26: 144-163PubMed Google Scholar,8Ohlsson A. Sieck U. Cumming W. et al.A variant of Bartter’s syndrome. Bartter’s syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis.Acta Paediatr Scand. 1984; 73: 868-874Crossref PubMed Scopus (62) Google Scholar and (ii) a reduction or complete blunting of the osmotic gradient in the renal medulla, causing isosthenuria, i.e., an impaired ability to dilute or concentrate the urine.9Stein J.H. The pathogenetic spectrum of Bartter’s syndrome.Kidney Int. 1985; 28: 85-93Abstract Full Text PDF PubMed Scopus (108) Google Scholar An exception is seen in most patients with BS3, who have a milder defect without hypercalciuria and partial capacity to concentrate the urine. To date, 5 different causative genes have been identified (Table 1; Figure 1), encoding proteins directly involved in salt reabsorption in the thick ascending limb (BS1–4) or regulating their expression (BS5). The mode of inheritance is autosomal recessive in BS1–410Simon D.B. Karet F.E. Hamdan J.M. et al.Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.Nat Genet. 1996; 13: 183-188Crossref PubMed Scopus (745) Google Scholar, 11Simon D.B. Karet F.E. Rodriguez-Soriano J. et al.Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K+ channel, ROMK.Nat Genet. 1996; 14: 152-156Crossref PubMed Scopus (677) Google Scholar, 12Simon D.B. Bindra R.S. Mansfield T.A. et al.Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III.Nat Genet. 1997; 17: 171-178Crossref PubMed Scopus (712) Google Scholar, 13Birkenhager R. Otto E. Schurmann M.J. et al.Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.Nat Genet. 2001; 29: 310-314Crossref PubMed Scopus (391) Google Scholar, 14Schlingmann K.P. Konrad M. Jeck N. et al.Salt wasting and deafness resulting from mutations in two chloride channels.N Engl J Med. 2004; 350: 1314-1319Crossref PubMed Scopus (191) Google Scholar and X-linked recessive in BS5.15Laghmani K. Beck B.B. Yang S.S. et al.Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations.N Engl J Med. 2016; 374: 1853-1863Crossref PubMed Scopus (76) Google Scholar Clinical characteristics, such as severity of biochemical abnormalities, presence of polyhydramnios and preterm delivery, degree of calciuria with or without medullary nephrocalcinosis, and presence of sensorineural deafness show typical gene-specific patterns. Several patients with BS3 have clinical features that are virtually indistinguishable from Gitelman syndrome (GS), another salt-losing tubulopathy.1Kleta R. Bockenhauer D. Salt-losing tubulopathies in children: what’s new, what’s controversial?.J Am Soc Nephrol. 2018; 29: 727-739Crossref PubMed Scopus (31) Google Scholar Most patients with BS receive supplementation with sodium chloride, potassium chloride and fluids that are adjusted individually based on symptoms, tolerability, severity of the tubulopathy, age of the patient and glomerular filtration rate. In addition, nonsteroidal antiinflammatory drugs (NSAIDs) are for most patients a mainstay of treatment,16Jeck N. Schlingmann K.P. Reinalter S.C. et al.Salt handling in the distal nephron: lessons learned from inherited human disorders.Am J Physiol Regul Integr Comp Physiol. 2005; 288: R782-R795Crossref PubMed Scopus (93) Google Scholar at least during the first years of life (except in transient BS5). The use of other therapies, such as potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, have been reported in the literature, but evidence supporting their efficacy, tolerability, and safety is limited. Despite significant gain in knowledge since the genetic elucidation of these diseases, information on long-term outcome of BS is almost completely lacking. In particular, the risk of chronic renal failure and its potential relationship to prolonged use of NSAIDs, chronic hypokalemia, and chronic hypovolemia is not well documented. Likewise, little information exists on the incidence of secondary hypertension and cardiac arrhythmias. Other open questions include optimal diagnostic approaches, particularly in the neonatal period, and the best therapeutic strategies based on outcome data. Also, the best management of BS during pregnancy has not been established. Therefore, an interdisciplinary group of experts was assembled under the umbrella of the European Rare Kidney Disease Reference Network to develop recommendations for the diagnosis and management of patients with BS (for full version, see Konrad et al.17Konrad M. Nijenhuis T. Ariceta G. et al.Diagnosis and management of Bartter syndrome: consensus and recommendations from the ERKNet working group for tubular disorders. 2020.http://bartter-consensus-paper.erknet.orgGoogle Scholar). The recommendations are listed in Box 1, Box 2, Box 3. It is beyond the scope of this executive summary to discuss each recommendation in detail. Instead, we highlight the significant underlying concepts. The recommendations are endorsed by the European Society for Paediatric Nephrology and the Working Group on Inherited Kidney Disorders of the European Renal Association–European Dialysis and Transplantation Association. The consensus process was initiated by European Rare Kidney Disease Reference Network. Two groups were assembled: a consensus core group and a voting panel. The core group comprised specialists for pediatric and adult nephrology, genetics, and obstetrics and a patient representative. The voting group included 36 members with special expertise in Bartter syndrome. The core group performed a systematic literature review via the PubMed and Cochrane databases through October 15, 2018. The following key MeSH terms were used: Bartter syndrome, inherited hypokalemic alkalosis, SLC12A1, KCNJ1, CLCNKA, CLCNKB, BSND, and MAGED2. The search retrieved 2218 results, and 135 articles were referenced in the full version.17Konrad M. Nijenhuis T. Ariceta G. et al.Diagnosis and management of Bartter syndrome: consensus and recommendations from the ERKNet working group for tubular disorders. 2020.http://bartter-consensus-paper.erknet.orgGoogle Scholar Initial recommendations were developed during a first meeting by discussion in thematic workgroups and plenary sessions. Evidence and recommendations were graded (whenever possible) according to the method used in the current American Academy of Pediatrics guidelines.18American Academy of Pediatrics Steering Committee on Quality Improvement and ManagementClassifying recommendations for clinical practice guidelines.Pediatrics. 2004; 114: 874-877Crossref PubMed Scopus (221) Google Scholar,19Flynn J.T. Kaelber D.C. Baker-Smith C.M. et al.Clinical practice guideline for screening and management of high blood pressure in children and adolescents.Pediatrics. 2017; 140: e20171904Crossref PubMed Scopus (1013) Google Scholar A first written draft was compiled and reviewed by the consensus core group. Remaining gaps were identified by a second meeting. Consequently, 2 rounds of anonymous voting were performed using the Delphi method until at least 70% support was reached for each individual recommendation. See Box 1. For details, see Konrad et al.17Konrad M. Nijenhuis T. Ariceta G. et al.Diagnosis and management of Bartter syndrome: consensus and recommendations from the ERKNet working group for tubular disorders. 2020.http://bartter-consensus-paper.erknet.orgGoogle ScholarBox 1Recommendations for diagnosis of Bartter syndromePrenatal period•During pregnancy, a diagnosis of (antenatal) BS should be considered in the presence of a polyhydramnios of fetal origin (grade C, weak recommendation).•We do not recommend the assessment of electrolytes and/or aldosterone from amniotic fluid for prenatal diagnosis of BS (grade C, moderate recommendation).•Molecular genetic testing can be applied for prenatal diagnosis; however, recommendations should be adapted to country-specific ethical and legal standards and communicated with appropriate genetic counseling (grade D, weak recommendation).•Whenever genetic testing is unavailable, the assessment of the “Bartter index” (AFP × total protein) in the amniotic fluid might be considered for prenatal diagnosis of BS (grade C, weak recommendation).Postnatal period•Postnatally, a diagnosis of BS should be considered in the presence of renal salt wasting, polyuria, rapid weight loss, and signs of dehydration. Failure to thrive, recurrent vomiting, repeated fever, hypochloremic and hypokalemic metabolic alkalosis, and nephrocalcinosis should raise the suspicion of BS beyond the neonatal period (grade C, moderate recommendation),•For initial diagnostic work-up, we recommend the following (grade C, moderate recommendation):•Evaluation of medical history including polyhydramnios, premature birth, growth failure, and family history.•Biochemical parameters: serum electrolytes (sodium, chloride, potassium, calcium, magnesium), acid-base status, renin, aldosterone, creatinine, fractional excretion of chloride, and urinary calcium-creatinine ratio.•Renal ultrasound to detect medullary nephrocalcinosis and/or kidney stones.•We recommend confirming the clinical diagnosis of BS by means of genetic analysis whenever possible (grade B, moderate recommendation).•We suggest offering genetic counseling for families with probands with confirmed clinical and/or genetic diagnosis of BS (grade D, weak recommendation).•We do not recommend tubular function tests with furosemide or thiazides for patients with suspected BS if genetic testing is accessible (grade D, moderate recommendation).AFP, alpha fetoprotein; BS, Bartter syndrome. Prenatal period•During pregnancy, a diagnosis of (antenatal) BS should be considered in the presence of a polyhydramnios of fetal origin (grade C, weak recommendation).•We do not recommend the assessment of electrolytes and/or aldosterone from amniotic fluid for prenatal diagnosis of BS (grade C, moderate recommendation).•Molecular genetic testing can be applied for prenatal diagnosis; however, recommendations should be adapted to country-specific ethical and legal standards and communicated with appropriate genetic counseling (grade D, weak recommendation).•Whenever genetic testing is unavailable, the assessment of the “Bartter index” (AFP × total protein) in the amniotic fluid might be considered for prenatal diagnosis of BS (grade C, weak recommendation). Postnatal period•Postnatally, a diagnosis of BS should be considered in the presence of renal salt wasting, polyuria, rapid weight loss, and signs of dehydration. Failure to thrive, recurrent vomiting, repeated fever, hypochloremic and hypokalemic metabolic alkalosis, and nephrocalcinosis should raise the suspicion of BS beyond the neonatal period (grade C, moderate recommendation),•For initial diagnostic work-up, we recommend the following (grade C, moderate recommendation):•Evaluation of medical history including polyhydramnios, premature birth, growth failure, and family history.•Biochemical parameters: serum electrolytes (sodium, chloride, potassium, calcium, magnesium), acid-base status, renin, aldosterone, creatinine, fractional excretion of chloride, and urinary calcium-creatinine ratio.•Renal ultrasound to detect medullary nephrocalcinosis and/or kidney stones.•We recommend confirming the clinical diagnosis of BS by means of genetic analysis whenever possible (grade B, moderate recommendation).•We suggest offering genetic counseling for families with probands with confirmed clinical and/or genetic diagnosis of BS (grade D, weak recommendation).•We do not recommend tubular function tests with furosemide or thiazides for patients with suspected BS if genetic testing is accessible (grade D, moderate recommendation). AFP, alpha fetoprotein; BS, Bartter syndrome. The diagnosis of BS is primarily based on clinical, biochemical and sonographic findings (Box 1). Even if the different subtypes of BS can usually be characterized clinically (Table 220Komhoff M. Laghmani K. Pathophysiology of antenatal Bartter’s syndrome.Curr Opin Nephrol Hypertens. 2017; 26: 419-425Crossref Scopus (10) Google Scholar,21Legrand A. Treard C. Roncelin I. et al.Prevalence of novel MAGED2 mutations in antenatal bartter syndrome.Clin J Am Soc Nephrol. 2018; 13: 242-250Crossref PubMed Scopus (18) Google Scholar), we recommend genetic analysis for confirmation.Table 2Main clinical and biochemical characteristics of different types of Bartter syndromeCharacteristicType 1Type 2Type 3Type 4aType 4bType 5Age at onsetPrenatallyPrenatally0–5 yearsPrenatallyPrenatallyPolyhydramniosSevereSevereAbsent or mildSevereVery severeGestational age at birth, wks, median (IQR)32 (29–34)33 (31–35)37 (36–41)31 (28–35)29 (21–37)Leading symptomsPolyuria, hypochloremia,alkalosis,hypokalemiaPolyuria, hypochloremia,alkalosis,transient neonatal hyperkalemiaHypokalemia, hypochloremia,alkalosis,failure to thrivePolyuria, hypochloremia,alkalosis,hypokalemiaPolyuria, hypochloremia,alkalosis,hypokalemiaCalcium excretionHighHighVariableVariableHighNephrocalcinosisVery frequentVery frequentRare, mildRare, mildRare, mildPlasma Cl/Na ratioNormalNormalDecreasedDecreasedIncreasedOther findingsMild hypomagnesemiaDeafness, risk for CKD, ESRDLarge for gestational age, transient diseaseCKD, chronic kidney disease; ESRD end-stage renal disease; IQR, interquartile range.Data from Komhoff and Laghmani20Komhoff M. Laghmani K. Pathophysiology of antenatal Bartter’s syndrome.Curr Opin Nephrol Hypertens. 2017; 26: 419-425Crossref Scopus (10) Google Scholar and Legrand et al.21Legrand A. Treard C. Roncelin I. et al.Prevalence of novel MAGED2 mutations in antenatal bartter syndrome.Clin J Am Soc Nephrol. 2018; 13: 242-250Crossref PubMed Scopus (18) Google Scholar Open table in a new tab CKD, chronic kidney disease; ESRD end-stage renal disease; IQR, interquartile range. Data from Komhoff and Laghmani20Komhoff M. Laghmani K. Pathophysiology of antenatal Bartter’s syndrome.Curr Opin Nephrol Hypertens. 2017; 26: 419-425Crossref Scopus (10) Google Scholar and Legrand et al.21Legrand A. Treard C. Roncelin I. et al.Prevalence of novel MAGED2 mutations in antenatal bartter syndrome.Clin J Am Soc Nephrol. 2018; 13: 242-250Crossref PubMed Scopus (18) Google Scholar Early polyhydramnios of fetal origin should raise the clinical suspicion of BS. In principle, there are 2 possible options to confirm the diagnosis: (i) prenatal genetic testing and (ii) biochemical analysis of amniotic fluid. Both measures are invasive and carry the risk of procedure-related complications. However, whenever prenatal diagnosis is indicated, we consider genetic testing to be the most reliable method. In situations, where prenatal genetic testing is not available or diagnostic, the assessment of the “Bartter index” (total protein × alfa-fetoprotein) may be considered.22Allaf B. Dreux S. Schmitz T. et al.Amniotic fluid biochemistry in isolated polyhydramnios: a series of 464 cases.Prenat Diagn. 2015; 35: 1331-1335Crossref Scopus (12) Google Scholar In larger studies, other parameters, such as high chloride or aldosterone levels, failed to distinguish between amniotic fluid from polyhydramnios related to other causes and control pregnancies.23Massa G. Proesmans W. Devlieger H. et al.Electrolyte composition of the amniotic fluid in Bartter syndrome.Eur J Obstet Gynecol Reprod Biol. 1987; 24: 335-340Abstract Full Text PDF Scopus (23) Google Scholar,24Shalev H. Ohaly M. Meizner I. Carmi R. Prenatal diagnosis of Bartter syndrome.Prenat Diagn. 1994; 14: 996-998Crossref PubMed Scopus (19) Google Scholar The diagnostic work-up for BS after birth should include a detailed clinical evaluation asking for a family history of pregnancy complicated by polyhydramnios with or without premature birth, and a medical history of polyuria, episodes of dehydration, unexplained fever, failure to thrive, and recurrent vomiting. In children, growth charts are very helpful to assess the development of height and weight. Additional clinical signs may include salt craving, muscle weakness, low blood pressure, and pubertal delay. Laboratory analysis for suspected BS should include the parameters listed in Box 1. The assessment of urinary prostaglandin excretion (prostaglandin E2) may be helpful, although this procedure is not feasible in a routine clinical setting. For definitive diagnosis, we recommend genetic testing. Key clinical and biochemical findings in patients with BS are detailed below and in Table 2, with a special focus on gene-specific differences between the known subtypes of BS. For differential diagnosis, see the Differential Diagnosis section below. •BS causes polyhydramnios, leading to premature birth in the majority of patients.•Polyhydramnios typically develops between the 20th and 30th weeks of gestation. Timing and severity vary according to the underlying genetic defect. In BS4 and BS5, polyhydramnios is typically observed earlier than in BS1 and BS2.15Laghmani K. Beck B.B. Yang S.S. et al.Polyhydramnios, transient antenatal Bartter’s syndrome, and MAGED2 mutations.N Engl J Med. 2016; 374: 1853-1863Crossref PubMed Scopus (76) Google Scholar,20Komhoff M. Laghmani K. Pathophysiology of antenatal Bartter’s syndrome.Curr Opin Nephrol Hypertens. 2017; 26: 419-425Crossref Scopus (10) Google Scholar,21Legrand A. Treard C. Roncelin I. et al.Prevalence of novel MAGED2 mutations in antenatal bartter syndrome.Clin J Am Soc Nephrol. 2018; 13: 242-250Crossref PubMed Scopus (18) Google Scholar,25Brochard K. Boyer O. Blanchard A. et al.Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome.Nephrol Dial Transplant. 2009; 24: 1455-1464Crossref PubMed Scopus (89) Google Scholar•BS5 always presents antenatally, but symptoms spontaneously resolve typically around the estimated date of delivery.•BS3 usually manifests later in life. Nevertheless, a prenatal presentation does not exclude BS3. The vast majority of patients with BS3 are diagnosed after the age of 1 year.26Konrad M. Vollmer M. Lemmink H.H. et al.Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.J Am Soc Nephrol. 2000; 11: 1449-1459Crossref PubMed Google Scholar, 27Peters M. Jeck N. Reinalter S. et al.Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies.Am J Med. 2002; 112: 183-190Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 28Bettinelli A. Borsa N. Bellantuono R. et al.Patients with biallelic mutations in the chloride channel gene CLCNKB: long-term management and outcome.Am J Kidney Dis. 2007; 49: 91-98Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 29Lee B.H. Cho H.Y. Lee H. et al.Genetic basis of Bartter syndrome in Korea.Nephrol Dial Transplant. 2012; 27: 1516-1521Crossref PubMed Scopus (29) Google Scholar, 30Seys E. Andrini O. Keck M. et al.Clinical and genetic spectrum of Bartter syndrome type 3.J Am Soc Nephrol. 2017; 28: 2540-2552Crossref PubMed Scopus (40) Google Scholar, 31Garcia Castano A. Perez de Nanclares G. Madariaga L. et al.Poor phenotype-genotype association in a large series of patients with type III Bartter syndrome.PLoS One. 2017; 12e0173581Crossref Scopus (14) Google Scholar, 32Walsh P.R. Tse Y. Ashton E. et al.Clinical and diagnostic features of Bartter and Gitelman syndromes.Clin Kidney J. 2018; 11: 302-309Crossref Scopus (21) Google Scholar Patients typically present with failure to thrive, poor weight gain, or polyuria with polydipsia. Less frequent symptoms are related to dehydration. Most patients exhibit salt craving, although this is rarely a presenting symptom.•In a minority of cases, the diagnosis of BS is incidental after noticing abnormal laboratory results, discovery of nephrocalcinosis, or family screening. •After birth, the first symptom is often hypovolemia from renal salt loss.•Hypochloremic and hypokalemic metabolic alkalosis may not be present during the first days of life.•Infants with BS2 often have transient neonatal acidosis and hyperkalemia and, on average, hypokalemia and alkalosis are less pronounced during follow-up.•In contrast, patients with BS3 and BS4 tend to have the lowest plasma potassium levels and the most pronounced hypochloremic alkalosis.•In some patients with BS3, hypomagnesemia may be present. •Hypercalciuria with subsequent nephrocalcinosis occurring after 1–2 months of life is a typical feature of BS1 and BS2. Although computerized tomography provides more accurate assessment of renal calcifications than renal ultrasound, it is associated with radiation burden and thus should be reserved for clinical situations where there is a direct therapeutic consequence, e.g., localization of stones in obstructive uropathy which may occur in rare cases in BS.•In contrast, patients with BS3 and BS4 usually have normocalciuria, although hypercalciuria may occur.•Interestingly, hypocalciuria has also been reported in patients with BS3, and these patients mimic the phenotype of GS.•In transient BS5, hypercalciuria may be observed, but nephrocalcinosis is a rare finding. •We recommend offering genetic testing with the use of a gene panel to all patients with a clinical suspicion of BS. Recommendations for genes to be included in the panel are detailed in Table 3.Table 3Genes recommended to be included in genetic testing for Bartter syndromeGeneAssociated disorder (MIM)SLC12A1aGenes in rows 2–8 should be included in a minimal diagnostic panel, i.e., the genes underlying BS, as well as Gitelman syndrome, which can be difficult to distinguish clinically from BS3. The remaining list also includes genes, which can have phenotypic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the neonatal period. The listed hypertensive disorders can biochemically mimic BS.BS1 (601678)KCNJ1aGenes in rows 2–8 should be included in a minimal diagnostic panel, i.e., the genes underlying BS, as well as Gitelman syndrome, which can be difficult to distinguish clinically from BS3. The remaining list also includes genes, which can have phenotypic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the neonatal period. The listed hypertensive disorders can biochemically mimic BS.BS2 (241200)CLCNKBaGenes in rows 2–8 should be included in a minimal diagnostic panel, i.e., the genes underlying BS, as well as Gitelman syndrome, which can be difficult to distinguish clinically from BS3. The remaining list also includes genes, which can have phenotypic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the neonatal period. The listed hypertensive disorders can biochemically mimic BS.BS3 (607364)BS4b (613090)CLCNKAaGenes in rows 2–8 should be included in a minimal diagnostic panel, i.e., the genes underlying BS, as well as Gitelman syndrome, which can be difficult to distinguish clinically from BS3. The remaining list also includes genes, which can have phenotypic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the neonatal period. The listed hypertensive disorders can biochemically mimic BS.BS4b (613090)BSNDaGenes in rows 2–8 should be included in a minimal diagnostic panel, i.e., the genes underlying BS, as well as Gitelman syndrome, which can be difficult to distinguish clinically from BS3. The remaining list also includes genes, which can have phenotypic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the neonatal period. The listed hypertensive disorders can bio" @default.
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• W3123290933 title "Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders" @default.
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