Bartter and Gitelman Syndromes

Hereditary salt-wasting tubulopathies with hypochloraemic metabolic alkalosis and hypokalaemia: Bartter syndrome types 1 to 5 (SLC12A1, KCNJ1, CLCNKB, BSND, CLCNKA with CLCNKB and MAGED2), due to a defect of the thick ascending limb of the loop of Henle, and Gitelman syndrome (SLC12A3), due to a defect of the distal convoluted tubule.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

The following table summarises the molecular entities of this article. OMIM numbers follow Table 1 of the 2021 European Rare Kidney Disease Reference Network (ERKNet) consensus, and Orphanet codes were accessed in Orphadata in October 2026; code ORPHA:358 belongs to Gitelman syndrome rather than Bartter type 3, whose code is ORPHA:93605 [1–3].

1. Introduction

1.1. Founding descriptions

In 1962, Frederic Bartter and colleagues published in the American Journal of Medicine the description of a ‘new syndrome’ characterised by juxtaglomerular apparatus hyperplasia, hyperaldosteronism and hypokalaemic alkalosis [30]. Four years later, Hillel Gitelman, John Graham and Louis Welt described in the Transactions of the Association of American Physicians a ‘new familial disorder characterised by hypokalaemia and hypomagnesaemia’ [31]. For three decades, the distinction between the two entities rested on clinical and biochemical criteria: Bartter presented early, with polyuria, growth retardation and normal or elevated urinary calcium, whereas Gitelman manifested later, with hypomagnesaemia and hypocalciuria, and was considered a Bartter variant [15, 19].

1.2. Milestones in molecular discovery

The genetic basis was elucidated between 1996 and 2016 by Richard Lifton's group and European groups. In January 1996, Simon and colleagues demonstrated that the Gitelman variant was caused by variants in the thiazide-sensitive Na-Cl cotransporter (SLC12A3, NCC) [19]. In June of the same year, the same group attributed Bartter with hypercalciuria to variants in the Na-K-2Cl cotransporter (SLC12A1, NKCC2) [32] and, in October, demonstrated genetic heterogeneity with variants in the ROMK potassium channel (KCNJ1) [33]. In 1997, the chloride channel CLCNKB was identified as the cause of Bartter type III [34]. In 2001, Birkenhäger and colleagues associated the BSND gene with Bartter with sensorineural deafness and kidney failure [35], and Estévez and colleagues showed that barttin is the β subunit of ClC-K chloride channels, required for renal chloride reabsorption and potassium secretion in the inner ear [36]. In 2004, Schlingmann and colleagues described the digenic form with salt wasting and deafness due to variants in two chloride channels, ClC-Ka and ClC-Kb [11]. In 2016, Laghmani and colleagues identified MAGED2 variants on the X chromosome as a cause of polyhydramnios with transient antenatal Bartter [13]; spontaneous resolution of neonatal Bartter had been reported in 1998, before the gene was known [37]. In 2002, two groups described activating calcium-sensing receptor (CASR) variants in patients with autosomal dominant hypocalcaemia and a Bartter-like phenotype [38, 39].

1.3. Nomenclature and reclassifications

The numbering of Bartter types has changed over time and is a frequent source of error. Before MAGED2 was identified, the designation ‘Bartter type 5’ was used for autosomal dominant hypocalcaemia with Bartter due to CASR gain of function (OMIM 601198), and still appears in gene databases and reviews [18, 40]. The current classification, adopted by the 2021 ERKNet consensus and Orphanet, reserves number 5 for MAGED2-related transient antenatal Bartter (OMIM 300971; ORPHA:570371) and treats CASR-related disease as a differential diagnosis within the spectrum of calcium homeostasis disorders [1, 14, 18]. Autosomal dominant hypocalcaemia type 1 with or without a Bartter phenotype corresponds to CASR gain of function; when reading literature predating this reclassification, ‘type 5’ should be interpreted as CASR. Type 4 is divided into 4a (BSND) and 4b (CLCNKA with CLCNKB), which share code ORPHA:89938 [1, 9]. Orphanet has made the terms ‘Antenatal Bartter syndrome’ (ORPHA:93604) and ‘Non-pore-loop channelopathy due to Cl- channel barttin anomaly’ (ORPHA:98120) obsolete [17]. Some reference sources still list SLC12A3 among neonatal Bartter genes, for example the Oxford Desk Reference on clinical genetics; this inclusion is imprecise, because biallelic SLC12A3 variants cause Gitelman syndrome [15, 41]. In curated databases, the Bartter type 3 entry may be incorrectly linked to the Orphanet code for Gitelman syndrome, with its prevalence; the correct BS3 code is ORPHA:93605, with prevalence recorded as unknown [2, 42].

Clinical terminology distinguishes three presentations. Antenatal (or neonatal) Bartter manifests in utero with polyhydramnios and corresponds mainly to types 1, 2, 4 and 5. Classic Bartter presents in early childhood with growth retardation and corresponds mainly to type 3. The Gitelman-like phenotype describes patients with hypomagnesaemia and hypocalciuria, usually with CLCNKB or SLC12A3 variants [1, 8]. These categories overlap: BS3 may present prenatally and Gitelman may present in childhood, so the definitive diagnosis is molecular [1, 15].

1.4. Definition of the entities within scope

The ERKNet consensus defines Bartter syndromes as hereditary salt-wasting tubulopathies characterised by polyuria, hypokalaemia, hypochloraemic metabolic alkalosis and normotensive hyperreninaemic hyperaldosteronism, with five molecular forms (BS1 to BS5); hypercalciuria and nephrocalcinosis are typical of some forms, and the disease is potentially fatal, requiring prompt diagnosis and treatment [1]. The primary defect lies in salt reabsorption in the thick ascending limb (TAL) of the loop of Henle [1]. Gitelman syndrome is an AR salt-wasting tubulopathy caused by biallelic inactivating SLC12A3 variants, encoding NCC in the distal convoluted tubule (DCT); it is defined biochemically by hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria, with elevated renin and normal or low blood pressure, and is probably the most frequent hereditary tubulopathy [3, 15]. Outside the central scope and treated as differential diagnoses are CASR-related autosomal dominant hypocalcaemia, HNF1B nephropathy, EAST/SeSAME syndrome (KCNJ10), HELIX syndrome (CLDN10), congenital chloride diarrhoea (SLC26A3) and Gitelman-like tubulopathy due to mitochondrial DNA variants (ORPHA:620371) [1, 21].

2. Molecular Genetics and Pathophysiology

2.1. Physiology of the thick ascending limb and distal convoluted tubule

The TAL reabsorbs 20 to 30 % of filtered sodium chloride, whereas the DCT reabsorbs 5 to 7 %; this quantitative difference largely explains why Bartter forms are more severe than Gitelman syndrome [25, 26]. In the TAL, NaCl enters the cell across the apical membrane through NKCC2; potassium is recycled into the lumen through the ROMK channel, maintaining K+ availability for the cotransporter and generating a lumen-positive transepithelial voltage that drives paracellular calcium and magnesium reabsorption; chloride leaves across the basolateral membrane through the ClC-Ka and ClC-Kb channels, both dependent on the accessory subunit barttin [1, 10, 43]. In the DCT, NaCl enters through NCC and chloride exits through the same basolateral ClC-K channels, explaining the phenotypic overlap between BS3 and Gitelman syndrome [1, 15].

The defect common to Bartter syndromes is renal salt wasting, which contracts extracellular volume and activates the renin–angiotensin–aldosterone system (RAAS); sodium reaching the collecting duct is reabsorbed in exchange for potassium and hydrogen ions, producing hypokalaemic hypochloraemic alkalosis [1, 5]. In the macula densa, failure of chloride reabsorption uncouples tubuloglomerular feedback: cyclooxygenase 2 (COX-2) is induced and prostaglandin E2 (PGE2) production increases independently of volume status, stimulating renin and aldosterone secretion; this mechanism underpins use of prostaglandin synthesis inhibitors [1]. The TAL defect has two additional consequences: reduced calcium reabsorption causes hypercalciuria and progressive medullary nephrocalcinosis, and the reduced or abolished medullary osmotic gradient causes isosthenuria [1]. Most BS3 patients have a milder defect, without hypercalciuria and with partial urinary concentrating ability [1]. The functional picture of Bartter type 1 is equivalent to chronic administration of a loop diuretic, since NKCC2 is the target of furosemide and bumetanide [5].

In Gitelman syndrome, loss of NCC function increases distal NaCl delivery, contracts extracellular volume and produces hyperreninaemia and secondary hyperaldosteronism, with renal potassium wasting and alkalosis; renal magnesium wasting causes hypomagnesaemia and upstream compensatory calcium reabsorption explains hypocalciuria [16]. Salt and water loss is less marked than in antenatal or classic Bartter because urinary concentrating ability remains largely intact [15]. Gordon syndrome (pseudohypoaldosteronism type II, due to WNK1, WNK4, KLHL3 or CUL3 variants) is the physiological mirror of Gitelman syndrome: excessive NCC activation through the WNK-SPAK pathway causes hypertension, hyperkalaemia and acidosis, corrected by thiazides; WNK4 deletion in animal models produces a Gitelman-like phenotype [44].

2.2. Genes and mechanisms, gene by gene

SLC12A1 (BS1). NKCC2 is the apical Na-K-2Cl cotransporter of the TAL and macula densa, responsible for most renal NaCl reabsorption and creation of the medullary gradient enabling urine concentration; it can transport ammonium instead of potassium [5]. Biallelic loss of function reproduces the action of a loop diuretic, with polyuria, hypercalciuria and PGE2 stimulation [5, 32].

KCNJ1 (BS2). ROMK (Kir1.1) is an apical ATP-activated inwardly rectifying potassium channel that recycles K+ into the TAL lumen and secretes K+ in the cortical collecting duct [43]. Loss of function prevents potassium recycling and collapses lumen-positive voltage, with salt wasting and hypercalciuria. More than 40 variants have been described, mainly missense or nonsense in exon 2, reducing or abolishing surface expression through misfolding and trafficking defects; some proteins remain trapped in a defective conformation and are degraded through the endoplasmic reticulum-associated degradation pathway [43]. Transient neonatal hyperkalaemia is attributed to loss of ROMK-mediated K+ secretion in the cortical collecting duct and immaturity of Na+/K+-ATPase [43].

CLCNKB (BS3). ClC-Kb is a basolateral chloride channel of the TAL, DCT and collecting duct that, with barttin, provides the chloride exit pathway required for transepithelial NaCl reabsorption; it is also expressed in the stria vascularis [42]. In a French study, 9 of 10 variants tested in Xenopus oocytes reduced or abolished chloride conductance [8]. In Clcnkb-/- mice, channel loss reduces DCT and connecting tubule volume and expression of DCT TRPM magnesium channels while preserving calcium transport, providing a probable explanation for BS3 hypomagnesaemia (preclinical study) [45].

CLCNKA and BSND (BS4). ClC-Ka is a basolateral chloride channel dependent on barttin for targeting and function; in the kidney it mediates chloride transport in the thin ascending limb and, in the inner ear, generates with ClC-Kb the stria vascularis chloride currents sustaining the endocochlear potential [46]. CLCNKA lies approximately 10 kb from CLCNKB and is highly homologous [46]. Barttin is the obligatory β subunit of both ClC-K channels: it accompanies the heteromeric channel to the basolateral membrane and keeps its common gating mechanism open [10, 36]. Loss of barttin (BS4a) or combined loss of ClC-Ka and ClC-Kb (BS4b) simultaneously suppresses basolateral renal chloride exit and stria vascularis chloride conductance, explaining the association of severe salt wasting with sensorineural deafness [10, 11].

MAGED2 (BS5). MAGE-D2 protects NKCC2 and NCC from intracellular degradation through interaction with heat shock protein HSP40, and promotes their targeting to the apical membrane through Gs-alpha protein [1, 13]. Cell studies show that MAGE-D2 depletion increases Gsα endocytosis and reduces cyclic AMP (cAMP), with NKCC2 retention in the endoplasmic reticulum and lysosomal NCC degradation; forskolin, which directly increases cAMP, rescues NCC in MAGED2-depleted cells [47]. MAGE-D2 may be essential only in hypoxia; transient disease is explained by renal oxygenation after birth, a hypothesis supported by cell studies, that is, preclinical studies [47].

SLC12A3 (Gitelman). NCC is the electroneutral thiazide-sensitive Na-Cl cotransporter of the DCT apical membrane, constituting the final regulated step in NaCl reabsorption; it determines extracellular volume, blood pressure and renal handling of potassium, magnesium and calcium [16]. WNK1 kinase activates SPAK, which phosphorylates and activates NCC [44]. A study of plasma proteomics and isogenic cells in a Chinese (Yi) population homozygous for the variant NM_001126108.2:c.1262G>T p.(Cys421Phe) (published designation p.C421F) suggested reduced oxidative phosphorylation and increased glycolysis; this is a mechanistic hypothesis without clinical application [48].

2.3. Genes, reference transcripts and identifiers

The table uses MANE Select transcripts (GRCh38) confirmed in VariantValidator in October 2026. For SLC12A3, the literature mainly uses historical transcripts NM_000339.2 and NM_000339.3; for KCNJ1, the MANE transcript is NM_153766.3 rather than NM_000220, and for MAGED2 it is NM_177433.3 [49].

Sources: phenotype OMIM numbers according to the ERKNet consensus; gene OMIM numbers and cytobands according to GeneGuidance and the French PNDS; transcripts according to VariantValidator [1, 5, 10, 16, 25, 40, 42, 43, 46, 47, 49].

2.4. Variant spectrum and genomic architecture

Gitelman. In 2017, more than 350 SLC12A3 variants had been described; most patients are compound heterozygotes and a substantial number have only one detected variant [15]. In the largest European series, which studied 448 unrelated patients with suspected Gitelman using direct genomic sequencing, 172 distinct variants (100 novel) were identified: two variants in 315 patients (70 %), one in 81 (18 %) and none in 52 (12 %) [50]. MLPA in 88 patients detected 9 deletions and 2 duplications in 24 of the 51 heterozygotes tested, and large rearrangements accounted for approximately 6 % of cases, generated through non-allelic homologous recombination between Alu sequences or non-homologous end joining; missense variants accounted for approximately 59 % of the total [50]. In the literature, 18 to 40 % of patients with suspected Gitelman have only one identified allele [50]. Splice variants outside canonical dinucleotides are relevant: NM_000339.3:c.1925+5G>T causes complete exon 15 skipping in a minigene assay [49, 51]. A variant published as ‘c.2531T>G p.(Leu844Arg)’ in NM_000339.3 failed VariantValidator validation (the reference base at that position is G), so it should not be reproduced without confirmation [49, 51].

CLCNKB and the CLCNKA-CLCNKB region. A large proportion of pathogenic CLCNKB alleles are complete or partial gene deletions and CLCNKA-CLCNKB hybrid alleles generated by rearrangement [42, 52]. Long-read sequencing in 32 patients with BS3 (29 families) and one patient with BS4b identified a common haplotype with transposition of approximately 3 kb of the CLCNKB 3' untranslated region to the CLCNKA locus, present in approximately 50 % of healthy control alleles and enriched in patients with deletion (45 of 51 alleles; p = 9.16 × 10⁻⁹); 8 different deletion alleles were found, representing independent recurrent events at a small number of hotspots, one complex rearrangement and two patients with hybrid genes with probable residual function [52]. MLPA reports these alleles only as ‘simple homozygous deletion’, a limitation of the method [52]. An apparently heterozygous CLCNKB point variant in a patient with a Bartter phenotype should prompt investigation for a deletion in the other allele [42]. The ERKNet consensus notes that large rearrangements are particularly frequent in CLCNKB and have also been described in KCNJ1, BSND and MAGED2, and recommends confirming rearrangements detected by next-generation sequencing (NGS) using a second method, for example MLPA [1].

BS4b. The digenic form was described in a consanguineous family with homozygous variants in both genes [11]. A non-consanguineous 2-year-old child had four loss-of-function alleles: a CLCNKA nonsense variant and a CLCNKB splice variant on one chromosome, and an approximately 12 kb deletion joining CLCNKA to CLCNKB on the other [12]. A family with non-syndromic sensorineural deafness, without hypokalaemic alkalosis or kidney disease, had a truncating CLCNKA variant in trans with a contiguous CLCNKA-CLCNKB deletion; this is a single report suggesting a possible predominantly auditory phenotype [53].

MAGED2. In the French cohort of Legrand and colleagues, 15 different variants were identified (1 complete deletion, 3 frameshift, 3 splice, 3 nonsense, 2 inframe deletions and 3 missense; 13 novel) [54]. A review of 53 published cases brought together 38 distinct variants, 65.8 % of which were null, and described two novel frameshift variants, NM_177433.3:c.1511del p.(Gly504Alafs*72) and NM_177433.3:c.338del p.(Pro113Argfs*4), and a deletion chrX:54,820,664–54,839,053 (GRCh37) [55]. The abstract does not state the transcript; both descriptions are valid and concordant on the MANE Select transcript NM_177433.3 [49]. Partial and exon deletions and deep intronic variants altering splicing are documented causes; after a negative exome with a convincing phenotype, copy number analysis and intronic assessment are justified [47, 55].

CASR. More than 70 gain-of-function variants have been catalogued (approximately 95 % missense), a subgroup of which with marked receptor activation causes, in addition to hypocalcaemia, renal salt wasting with hypokalaemic alkalosis [40].

2.5. Founder and recurrent variants

The GeneReviews definition of a founder variant is three or fewer variants accounting for more than 50 % of a gene's pathogenic variants within an ancestry [22]. Variants in the table were normalised in VariantValidator; for SLC12A3 variants, numbering in NM_000339.3 and the MANE transcript NM_001126108.2 is identical at these positions [49].

GeneReviews prints the Amish variant as ‘c.Arg642Gly’, a typographical error in protein notation [22]. The recurrent Japanese variants described by Tago and colleagues (T180K, A569V, L623P, R642C, L849H) and the Chinese variants of Hsu and colleagues (T60M, T163M, S283Y, R642C, W844X, R928C and a frameshift variant at R959) use historical one-letter protein nomenclature, without c. notation in the abstracts [61, 62]. Up to residue 642 the numbering is identical between the MANE Select transcript NM_001126108.2 and NM_000339.3, and T163M, S283Y and R642C correspond to NM_001126108.2:c.488C>T p.(Thr163Met), c.848C>A p.(Ser283Tyr) and c.1924C>T p.(Arg642Cys); in the distal region MANE has 9 fewer codons, so that, if the published numbering is that of NM_000339.3, R928C is equivalent to NM_001126108.2:c.2755C>T p.(Arg919Cys) and W844X to p.(Trp835Ter), and the designations W844X and R928C are kept as published designations [49].

2.6. Genotype–phenotype correlations, penetrance and modifiers

In BS3, severe variants (large deletions, frameshift, nonsense, canonical splice) and missense variants with low residual conductance are associated with earlier diagnosis, but the biochemical phenotype does not predict genotype [8, 42]. In Gitelman syndrome, phenotypic variability exists even among relatives with identical variants; proposed factors include genotype, sex, modifier genes, compensatory mechanisms, diet and environment [15]. In a Chinese series of 95 patients, compound heterozygotes had higher serum magnesium than homozygotes (0.65 versus 0.51 mmol/L) [63]. In two Chinese paediatric cohorts, the affected functional domain did not predict phenotype [60]. Women with Gitelman in the Chinese registry had less presentation before 18 years, less polyuria and higher potassium than men [64].

Penetrance of biallelic forms is high, but expressivity varies. In BS5, disease mainly affects hemizygous boys; in the French cohort, two girls had disease, one with findings consistent with selective X-inactivation [54]. SLC12A3 heterozygotes did not differ from non-carriers in blood pressure in Taiwanese and Japanese populations; in Taiwan they had slightly higher fasting glucose (91 ± 2.3 versus 88 ± 0.4 mg/dL), and in Japan higher urinary pH [61, 62].

2.7. Gene–disease validity

ClinGen classifies the KCNJ1–BS2 relationship (AR inheritance) and MAGED2–BS5 relationship (X-linked, curated 17 March 2022) as ‘Definitive’ [43, 47]. CLCNKA has no ClinGen validity curation; GenCC records BS4b as ‘Moderate’ (Ambry) and ‘Limited’ (G2P), and no curator asserts monogenic disease due to isolated CLCNKA; ClinGen assigns it a haploinsufficiency score of 30 (gene associated with an AR phenotype) [46].

2.8. Allelic disorders and related entities

Biallelic BSND variants also appear in the list of autosomal recessive deafness genes (DFNB73), and OMIM 602522 encompasses sensorineural deafness with mild renal dysfunction [10, 65]. Loss-of-function CASR variants cause familial hypocalciuric hypercalcaemia and gain-of-function variants cause autosomal dominant hypocalcaemia, sometimes with Bartter [40]. Gain-of-function variants in the WNK-NCC pathway cause Gordon syndrome, the mirror of Gitelman syndrome [44]. Mitochondrial DNA variants in MT-TI and MT-TF cause a maternally inherited Gitelman-like tubulopathy, described in approximately 14 cases or families [21].

3. Clinical Spectrum and Manifestations by System

3.1. Comparative features of Bartter types

Table 2 of the ERKNet consensus, constructed using data from Komhoff and Laghmani (2017) and Legrand's French cohort (2018), summarises differences between types [1]. In the electronic version consulted, the table has six headings (1, 2, 3, 4a, 4b, 5) and five values per row; judging by the other-findings row, the columns correspond to BS1, BS2, BS3, BS4 (4a and 4b together) and BS5.

3.2. Antenatal Bartter: BS1, BS2 and BS4

Polyhydramnios due to fetal polyuria typically develops between 20 and 30 weeks of gestation, earlier in BS4 and BS5 than in BS1 and BS2, and leads to preterm birth in most cases [1, 5]. After birth, the first sign is frequently hypovolaemia due to renal salt wasting, with massive polyuria, often exceeding 10 mL/kg/h, rapid weight loss and dehydration from the first day [1, 5]. Hypokalaemic hypochloraemic alkalosis may be absent in the first days, particularly with dehydration-induced acute kidney injury [1]. After the neonatal period, polyuria and polydipsia, salt craving, recurrent dehydration, unexplained fever, vomiting, constipation, muscle weakness, growth retardation and short stature predominate, with low or low-normal blood pressure [1, 5]. Hypercalciuria with medullary nephrocalcinosis from the first or second month is typical of types 1 and 2; nephrocalcinosis is never prenatal [1, 5]. Some patients with BS1 or BS2 develop secondary nephrogenic diabetes insipidus, altering salt and water management [1]. The infant's clinical appearance includes a large head, prominent forehead, triangular face with a downturned mouth, large external ears and large eyes [41, 43].

In the French cohort of Brochard and colleagues (42 children with antenatal or neonatal Bartter, median follow-up 8.3 years: KCNJ1 19, SLC12A1 13, CLCNKB 6, BSND 4), age at polyhydramnios onset, gestational age at birth, height and weight were similar between genetic groups; three CLCNKB patients had neither polyhydramnios nor prematurity [7]. Deafness was present at diagnosis in all BSND patients; transient neonatal hyperkalaemia occurred in two thirds of KCNJ1 patients; nephrocalcinosis was constant in the KCNJ1 and SLC12A1 groups and absent in the BSND and CLCNKB groups [7]. Supplementation and indometacin enabled catch-up growth in most [7].

BS2 (KCNJ1). Transient acidosis and hyperkalaemia occur in the first days of life; during follow-up, hypokalaemia and alkalosis are less marked than in other types [1]. Cases with polyhydramnios labelled pseudohypoaldosteronism type I proved to have KCNJ1 variants [1]. A late-onset form has been described, so the ‘antenatal’ label does not exclude later presentation; focal segmental glomerulosclerosis has been described during the course [43].

BS4a and BS4b. These are characterised by polyhydramnios, prematurity, severe salt wasting with polyuria and dehydration, congenital sensorineural deafness and a risk of deteriorating kidney function progressing to CKD [1, 10]. Urinary calcium excretion is variable and nephrocalcinosis is rare and mild; the Orphanet definition describes it as typically absent [1, 9]. BS3 and BS4 have lower plasma potassium and more marked hypochloraemic alkalosis than types 1 and 2 [1]. Deafness cannot be detected in utero [66].

3.3. Bartter type 3 (CLCNKB)

BS3 usually presents after the first year of life, with failure to thrive, poor weight gain, polyuria or polydipsia; dehydration is less frequent and salt craving, present in most, rarely prompts consultation [1]. Antenatal presentation does not exclude the diagnosis, and a minority are diagnosed incidentally through blood tests, nephrocalcinosis or family screening [1]. In the French series of Seys and colleagues (115 patients with CLCNKB variants, 60 variants, of which 27 novel), 29.5 % had antenatal or neonatal presentation (polyhydramnios or diagnosis in the first month), 44.5 % classic Bartter (childhood diagnosis with hypercalciuria and/or polyuria) and 26.0 % a Gitelman-like phenotype (incidentally discovered hypokalaemia, with hypomagnesaemia and/or hypocalciuria, in childhood or adulthood) [8]. Electrolyte supplements and indometacin were frequently used to induce catch-up growth, with few reported adverse effects [8]. Patients with CLCNKB variants at Great Ormond Street Hospital had lower serum potassium and magnesium and higher bicarbonate than the others [67]. Growth hormone (GH) deficiency has been described mainly in BS3 [1]. Deafness is not a feature of isolated BS3 [42]. Diagnosis of BS3 in a 66-year-old woman has been published (section 10) [28].

3.4. Bartter type 5 (MAGED2)

In the series of Laghmani and colleagues, three male pregnancies in one family had severe polyhydramnios and prematurity, with one fetal death and two newborns with transient massive salt wasting and polyuria; analysis of six additional families and women with idiopathic polyhydramnios of male fetuses identified MAGED2 variants in all 13 infants with transient antenatal Bartter and in two families with idiopathic polyhydramnios [13]. Of the 15 affected cases overall, 4 died perinatally and 11 survived; initial presentation was more severe than in other types, with earlier polyhydramnios and delivery, and all symptoms disappeared spontaneously in survivors [13]. The difference between the ‘13 infants’ and ‘15 cases’ therefore results from inclusion of the two idiopathic polyhydramnios families. Polyhydramnios begins at 19–20 weeks, mean gestational age at delivery was 28 weeks, and neonatal polyuria generally ends around 30–33 weeks of corrected age [66]. The ERKNet consensus states that symptoms resolve spontaneously around the expected date of delivery [1].

The French cohort of Legrand and colleagues showed that the phenotype is variable and, on average, less severe than in the original cases [54]. The French PNDS adds proportionate macrosomia and an increased plasma Cl/Na ratio [25]. In the review of 53 cases, polyhydramnios was the most consistent prenatal sign, followed by a fetus large for gestational age; in the three Chinese families described in the same work, all had polyhydramnios, two had large-for-gestational-age fetuses, with ventriculomegaly, scrotal enlargement and one fetal death at 26+1 weeks; no intellectual disability was reported in survivors [55]. Newborns may present with shock, dehydration and metabolic acidosis [47]. Residual morbidity depends on prematurity rather than kidney disease [47].

3.5. Gitelman syndrome

Gitelman syndrome presents mainly in adolescents and adults, but may occur in childhood and even in the neonatal period [15]. Blood pressure is typically low, particularly with severe hypokalaemia and hypomagnesaemia; hypertension has been described in middle-aged and older adults [15]. KDIGO organises manifestations by frequency in the following table; in the electronic version consulted, the table had lost column alignment and each item's allocation followed sequential order [15].

Cardiovascular system. Prolonged QT has been described in approximately 50 % of patients, because potassium and magnesium depletion prolongs the action potential; there are isolated reports of sustained ventricular tachycardia and sudden death [15]. The French PNDS reports long QT in 9 % of treated and 40 % of untreated patients [26].

Musculoskeletal system and eyes. Magnesium increases calcium pyrophosphate crystal solubility and activates tissue-nonspecific alkaline phosphatase, which hydrolyses pyrophosphate; hypomagnesaemia favours joint (chondrocalcinosis) and scleral deposits [15]. Increased renal calcium reabsorption is associated with higher bone mineral density and lower bone turnover [15]. In a prospective Chinese cohort of 110 patients (mean age 39.9 years, 52.7 % women), 41.8 % had arthralgia and 41.82 % (46/110) radiological calcium pyrophosphate deposition disease, associated with older age, lower serum magnesium and lower estimated glomerular filtration rate (eGFR); the most affected sites were knees, cervical spine and Achilles tendon [68].

Growth, metabolism and kidney. Growth and pubertal delay and short stature may relate to the GH and insulin-like growth factor type 1 (IGF-I) axis [15]. Hypomagnesaemia and hypokalaemia are associated with glucose intolerance and insulin resistance [15]. In a Beijing cohort of 132 patients, 21.2 % had hyperuricaemia, associated with higher body mass index and lower fractional uric acid excretion [69]. Glomerular proteinuria and CKD may occur, attributed to chronic hypokalaemia (tubulointerstitial nephritis, vacuolisation, cysts) or volume depletion with RAAS activation; abdominal pain is frequent, due to intestinal paresis or supplement intolerance [15].

Age-related differences. In a Chinese series of 95 patients aged 2 to 52 years, those aged 16 years or younger had more febrile episodes (20.4 % versus 4.3 %) and nausea or vomiting (12.2 % versus 0 %), and less paraesthesia (20.4 % versus 43.5 %) and palpitations (8.2 % versus 37.0 %), with higher potassium and magnesium [63]. In two Chinese paediatric series of 30 children each, hypomagnesaemia was present in 90 %; in one, fatigue occurred in 43.3 % and short stature in 36.7 %, and in the other muscle weakness in 50 % and severe hypokalaemia (< 2.5 mmol/L) was associated with tetany [51, 60].

Quality of life. Quality of life is significantly reduced, to a degree comparable to congestive heart failure or diabetes, according to a Yale study cited by KDIGO [15]. In a Japanese study published in 2026 with 128 patients referred for suspected Gitelman (66 with biallelic SLC12A3 variants and 62 with pseudo-Gitelman, without causal variants) and 70 controls, quality of life was similarly impaired in both patient groups; nocturnal enuresis was more marked in genetic Gitelman and persisted, in 50 %, at least until entry to primary school [70].

3.6. Treated disease and natural history

Available data come almost exclusively from patients treated with supplements and, in Bartter, NSAIDs. There are no untreated natural history cohorts in antenatal forms, whose course without treatment is potentially fatal [1]. Figures for CKD, growth and nephrocalcinosis cited in sections 3 and 11 therefore describe treated disease and combine the effects of the molecular defect, prematurity, dehydration episodes and drugs [1]. In Gitelman, most described severe manifestations come from reports with clinical rather than genetic diagnosis, with possible confusion with classic Bartter [15].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

The ERKNet consensus recommends considering antenatal Bartter in polyhydramnios of fetal origin (grade C, weak recommendation) [1]. Polyhydramnios due to excessive fetal polyuria is virtually always caused by Bartter: it has not been described in severe proximal tubulopathies or nephrogenic diabetes insipidus [1]. Polyhydramnios is defined by a deepest vertical pocket greater than 8 cm, occurs in 1–2 % of pregnancies and is idiopathic in up to 60 % of cases, with a 2- to 5-fold increase in perinatal mortality; approximately 8 % have additional fetal anomalies on ultrasound [66]. In the French series of 464 isolated polyhydramnios cases with amniotic fluid biochemistry, 28 (6 %) represented Bartter [71]. Severe, early (from 19–20 weeks) polyhydramnios recurring in pregnancies with structurally normal male fetuses, often large for gestational age, should prompt consideration of BS5 [47, 55]. Recurrent ‘idiopathic’ polyhydramnios in a family may correspond to MAGED2 variants [13, 66].

4.2. Neonatal period and infancy

The consensus recommends considering Bartter with renal salt wasting, polyuria, rapid weight loss and dehydration; beyond the neonatal period, with failure to thrive, recurrent vomiting, repeated fever, hypochloraemic hypokalaemic metabolic alkalosis and nephrocalcinosis (grade C, moderate recommendation) [1]. Other signs are salt craving, muscle weakness, low blood pressure and delayed puberty; growth charts are very useful [1]. In an infant with growth retardation and a history of polyhydramnios, plasma aldosterone helps guide diagnosis [41]. Plasma potassium may initially be normal and, in BS2, transient hyperkalaemia occurs, so potassium should be measured before assuming hypokalaemia and starting supplementation [41, 43]. There is no newborn screening programme for these diseases in the sources consulted.

4.3. Child, adolescent and adult

In Gitelman, suggestive complaints include salt craving (preference for salty food from childhood), muscle weakness, fatigue and poor exercise endurance, syncope, cramps, tetany, paraesthesia, carpopedal spasms, growth and pubertal delay, short stature, thirst and abdominal pain; in adults, also dizziness, vertigo, polyuria, nocturia, palpitations, arthralgia and visual disturbances [15]. Disease is frequently discovered incidentally in routine blood tests, and KDIGO recommends measuring potassium and magnesium in the assessment of epilepsy, growth retardation, delayed puberty and neuromuscular diseases [15]. Presentation after the first year, in adolescence or adulthood, with hypocalciuria or hypomagnesaemia, makes Gitelman the leading hypothesis, but BS3 and HNF1B nephropathy enter the differential [1]. In women, pregnancy may reveal the disease: potassium below 2.8 mmol/L in the first trimester should be investigated [26].

4.4. Warning and emergency signs

Emergencies include severe dehydration with shock in the newborn (especially in BS5 and antenatal types), hypernatraemic dehydration in a patient with secondary nephrogenic diabetes insipidus, and profound hypokalaemia with arrhythmia, quadriplegia, respiratory failure or rhabdomyolysis, requiring intravenous potassium with electrocardiographic monitoring [1, 15, 47]. Acute tetany requires intravenous magnesium [15]. Gastroenteritis with vomiting or diarrhoea is dangerous because it prevents taking supplements and worsens volume depletion; the French PNDS recommends alert when potassium falls by more than 0.5 mmol/L during gastroenteritis [15, 25]. In pregnant women, hyperemesis gravidarum is particularly dangerous [1]. NSAIDs may mask fever and the severity of intercurrent infections [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Biochemical and imaging assessment of Bartter

For initial assessment (grade C, moderate), the ERKNet consensus recommends a history of polyhydramnios, prematurity, growth failure and family history; biochemistry including serum sodium, chloride, potassium, calcium and magnesium, acid–base balance, renin, aldosterone, creatinine, fractional chloride excretion (FECl) and urinary calcium/creatinine ratio; and renal ultrasound for medullary nephrocalcinosis and stones [1]. FECl is usually above 0.5 % in Bartter and distinguishes renal from extrarenal losses; the urinary Na/Cl ratio also helps [1]. In the Great Ormond Street series, FECl was above 0.5 % in all patients before supplementation [67]. The urinary calcium/creatinine ratio should be interpreted against age-specific reference values [5]. Urinary PGE2 is informative but requires a refrigerated 24-hour collection and specialist laboratory, making it impractical for routine use [1, 5]. Repeated urinary chloride measurement distinguishes Bartter (persistently elevated) from concealed vomiting or bulimia (low) and diuretic abuse (highly variable) [1, 43]. No biochemical test is confirmatory; the consensus recommends confirmation by genetic analysis whenever possible (grade B, moderate) [1].

5.2. Criteria for suspicion and diagnosis of Gitelman syndrome

Source: KDIGO Table 2 [15]. KDIGO itself cautions that hypertension (in middle-aged or older adults) and presentation before 3 years do not exclude the diagnosis, and that renal cysts have been described [15]. Paediatric calcium/creatinine ratio values appear in a KDIGO supplementary table that could not be obtained; interpretation in children should use the laboratory's age-specific reference values. If the patient takes supplements and electrolytes are normal or nearly normal, they should be stopped at least 48 hours before sampling; plasma and urine should be collected simultaneously and a spot urine sample is sufficient [15]. Kidney biopsy is unnecessary except, for example, with significant proteinuria [15]. Hypocalciuria and hypomagnesaemia with hypokalaemic alkalosis constitute the signature distinguishing Gitelman from Bartter, with the caveat that BS3 may mimic Gitelman [8, 16].

5.3. Algorithm for secondary hypokalaemia

In hypokalaemia, it is necessary to distinguish renal loss, gastrointestinal loss and transcellular shift; after excluding primary hyperaldosteronism and diuretic or laxative use, the differential narrows to rare tubulopathies [1]. GeneReviews on hypokalaemic periodic paralysis proposes an algorithm based on blood pressure, urinary potassium and bicarbonate [72].

Source: GeneReviews, Table 4 [72]. The algorithm describes Bartter as normomagnesaemic, a simplification: some BS3 patients have hypomagnesaemia [1, 8].

5.4. Functional diuretic tests

The ERKNet consensus does not recommend tubular furosemide or thiazide tests when genetic testing is accessible (grade D, moderate): they are considered obsolete, carry a risk of severe volume depletion, especially in infants, in whom the thiazide response is exaggerated by compensatory DCT upregulation, and their diagnostic value is uncertain; they may have a role in difficult cases or research in tertiary centres [1]. KDIGO considers the hydrochlorothiazide test no longer recommended because of the risk of acute volume depletion in loop defects, limitations in children and under other drugs, and risk of interstitial nephritis or hypersensitivity [15]. The thiazide test is based on a blunted FECl response in Gitelman [73]. Only BS1 showed a blunted furosemide response in a small study, and results depend on age and glomerular filtration rate [5].

5.5. Genetic testing

Indication and panel. KDIGO recommends offering genetic testing to all patients with clinical suspicion who meet the minimum criteria, in an accredited laboratory [15]. For Gitelman, it recommends an NGS panel with at least SLC12A3, CLCNKB and HNF1B; if only one variant is found, MLPA deletion testing of the other allele; and, if only Sanger sequencing is available, the sequence SLC12A3 → CLCNKB → HNF1B with MLPA [15]. For Bartter, the ERKNet consensus defines the minimum panel and differential diagnosis genes presented in the following table [1].

BS2 may mimic pseudohypoaldosteronism type 1 in the neonatal period and hypertensive disorders may biochemically mimic Bartter, justifying inclusion of differential diagnosis genes [1]. Exome or genome sequencing with targeted analysis is viewed as the future preferred test [15]. In BS5, confirmation is ideally by rapid trio exome or genome sequencing during pregnancy or neonatal admission [47].

Yield and sensitivity. Analytical sensitivity for exons and exon–intron boundaries is 90–100 % and specificity 100 %; in Gitelman, clinical sensitivity is 65–80 %, depending on methods, because non-coding variants or variants in other genes are excluded [15]. In 15–20 % of Gitelman patients, even after MLPA, only one pathogenic variant is detected; the second defect may lie in regulatory or intronic regions or another gene, and is investigated only in specific cases (severe cases, Asian ancestry, counselling) [15]. In Bartter, clinical sensitivity is approximately 75 % in children but only 12.5 % in adults, in whom the differential is broader (diuretic and laxative abuse) and the proportion of BS3, technically difficult to analyse because of CLCNKA-CLCNKB homology, is higher [1]. A 37-gene panel applied to 384 index children from three national networks (174 with Bartter or Gitelman and 76 with distal tubular acidosis) obtained a genetic diagnosis in 245 (almost two thirds) and changed the clinical diagnosis in 16 [74]. In 1033 adults from three European centres (744 with clinical tubulopathy), genetic diagnosis was obtained in 29 %, half the paediatric rate [75]. In the French antenatal Bartter cohort (171 families), 75 % had variants in BS1–BS4 genes; MAGED2 accounted for 9 % overall, 38 % of cases without another cause and 44 % of negative male probands, justifying inclusion of MAGED2 in screening the most severe forms [54]. In Laghmani's series, all 13 infants with transient antenatal Bartter had a MAGED2 variant [13].

Technical limitations. A negative result does not exclude the diagnosis. Short-read NGS calling only single-nucleotide variants and small indels misses CLCNKB deletions and hybrid alleles, and mapping ambiguity between CLCNKA and CLCNKB paralogues compounds the problem; MLPA is necessary but describes complex rearrangements as simple deletions [42, 52]. In Gitelman, rearrangement testing (MLPA) and intronic variant testing (lymphocyte cDNA analysis) increase yield [15]. In MAGED2, copy number analysis and intronic assessment should follow a negative exome when the phenotype is convincing [47]. The proportion of detectable alleles is not equivalent to clinical sensitivity: analytical sensitivity of 90–100 % coexists with clinical sensitivity of 65–80 % in Gitelman and 12.5 % in adult Bartter [1, 15].

Report content and interpretation. The report should state the gene, versioned reference transcript (preferably MANE Select, for example NM_001126108.2 for SLC12A3), the variant in HGVS (Human Genome Variation Society) nomenclature, zygosity, class according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria and, for genes with paralogues, the copy number analysis method [1, 49]. Phase of the two variants should be confirmed by parental testing. Variant reclassification is possible and, for variants of uncertain significance (VUS), in vitro functional studies may be considered [15]. Historical one-letter protein notation (for example ‘R642C’) should be converted to HGVS with a transcript before comparison between laboratories [49, 61].

5.6. Prenatal diagnosis

The ERKNet consensus does not recommend measuring electrolytes or aldosterone in amniotic fluid (grade C, moderate), because high chloride and aldosterone did not distinguish Bartter-related polyhydramnios from other causes or controls in larger studies [1]. Molecular genetic testing is applicable to prenatal diagnosis, adapted to national ethical and legal standards and with counselling (grade D, weak), and is the most reliable method [1]. Without genetic testing, the ‘Bartter index’, the product of amniotic fluid alpha-fetoprotein and total protein, may be considered (grade C, weak) [1]. In the French series of 464 isolated polyhydramnios cases (2008–2012), in which 136 fetuses (29.3 %) had severe disease (46 chromosomal anomalies, 28 Bartter, 23 other genetic syndromes, 22 swallowing disorders, 17 uronephrological diseases), the index identified Bartter with 85.7 % sensitivity (24/28) and 84.2 % specificity [71]. Sensitivity of 93 % and specificity of 100 % attributed to the index derivation study circulate in secondary databases attributing them to the full ERKNet consensus version; that version was inaccessible and the executive summary cites only the 464-case series, so these values should be read as coming from a derivation series without external validation [1, 5]. Both methods require amniocentesis, with a risk of complications [1]. Investigation of polyhydramnios includes molecular testing, preferably in a fetal trio, by panel, exome or genome [66].

6. Differential Diagnosis

The differential is organised into four contexts: polyhydramnios of fetal origin, salt wasting with hypokalaemic alkalosis, hypokalaemic alkalosis without salt wasting (with hypertension), and nephrocalcinosis or hypomagnesaemia [1]. Among the subtypes themselves, hypercalciuria points to BS1 or BS2, hypocalciuria with hypomagnesaemia to Gitelman or BS3, deafness to BS4a or BS4b, neonatal hyperkalaemia to BS2 and spontaneous resolution in a boy to BS5 [1, 47].

Congenital chloride diarrhoea is the most difficult differential diagnosis prenatally, because pregnancy is also complicated by polyhydramnios and premature birth, usually less severe; in the newborn, hypokalaemic hypochloraemic alkalosis results from watery diarrhoea and urinary chloride is low [1]. Distinguishing Gitelman from BS3 has practical consequences: classic Bartter is more likely with onset before 3 years, failure to thrive, polyuria and normal magnesium, but the two diseases may be clinically indistinguishable and only genetic testing separates them [8, 15]. HNF1B nephropathy may present with renal-wasting hypomagnesaemia as the initial and predominant manifestation: in the series assembled by GeneReviews, 46 of 107 patients (43 %) with a 17q12 deletion had hypomagnesaemia, up to 59 % in children using age-specific standards, and FEMg above 2 % with normal kidney function indicates tubular magnesium wasting [77]. CASR-related autosomal dominant hypocalcaemia is distinguished by hypocalcaemia and low PTH; more than 50 % of patients have symptomatic hypocalcaemia and more than 30 % renal or intracerebral calcifications [40]. Gitelman-like tubulopathy without causal variants (pseudo-Gitelman) is frequent among referred adults: in a Japanese study, almost half of patients with hypokalaemia and alkalosis had no SLC12A3 variants [70]. A Bartter-like picture has also been described in severe congenital insulin resistance due to INSR variants [83].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no authorised aetiological treatment for any form of Bartter or Gitelman, and no medicine has these diseases as an indication approved by the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA); potassium chloride is the only drug whose generic indication (hypokalaemia with or without metabolic alkalosis) covers its use [84, 85]. All other drugs mentioned for these diseases are used off-label. Recommendations rest on observational studies, case reports and expert opinion; for Bartter there is no randomised trial, and for Gitelman there is a single small randomised crossover trial [1, 15, 86]. Patients should be followed in centres experienced in tubulopathies (grade D, weak) [1].

7.2. Bartter syndromes: salt and electrolyte supplementation

Sodium chloride. The ERKNet consensus recommends considering pharmacological sodium chloride doses of at least 5–10 mmol/kg/day (grade C, moderate); beyond infancy, some requirements are covered by spontaneous salt craving [1]. The French PNDS gives 5–10 mmol/kg/day, potentially reaching 50 mmol/kg/day, without restricting spontaneous intake, and warns about salt–water balance in the polyuric infant, in whom relative water deficit may cause hypernatraemia [25]. Salt supplementation should not be given in patients with secondary nephrogenic diabetes insipidus, that is, hypernatraemic dehydration with urinary osmolality below plasma osmolality, or a history thereof (grade D, weak) [1].

Potassium chloride. If potassium supplementation is necessary, chloride should be used (grade C, moderate), because the lost anion is chloride and other salts, such as citrate, worsen alkalosis [1]. Complete potassium normalisation should not be sought (grade D, weak); a reasonable target is 3.0 mmol/L, extrapolated from KDIGO for Gitelman, and realistic targets may be lower and vary over time, because hypokalaemia may cause paralysis, rhabdomyolysis, arrhythmias and sudden death [1]. In adults, the French PNDS suggests starting 3–4 g/day KCl (40–52 mmol) in 2–3 doses with meals; above 8 g/day there is no additional benefit and intolerance increases; potassium gluconate is reserved for short periods (less than 2 weeks) and intravenous KCl for acute situations, without aiming for normalisation [25]. In a Korean cohort, mean KCl dose was 5.0 mEq/kg/day before 18 years and 2.1 mEq/kg/day thereafter [87].

Magnesium. Oral magnesium should be given when necessary, particularly in BS3, preferably as organic salts (aspartate, citrate, lactate) because of greater bioavailability (grade D, weak); the optimal target is unknown and a value above 0.6 mmol/L is considered reasonable [1]. In adults, the PNDS suggests 300–400 mg/day elemental magnesium in 2–4 doses [25].

Dose distribution. Salt and electrolytes should be spread throughout the day as much as possible (grade C, moderate): losses are continuous, and large infrequent doses cause fluctuations potentially more harmful than stable subnormal levels; in continuously tube-fed infants, supplements may be mixed with feeds [1].

7.3. Bartter syndromes: prostaglandin synthesis inhibitors

The ERKNet consensus recommends considering NSAIDs in symptomatic patients, particularly in early childhood (grade B, moderate); they are the mainstay of treatment at least in the first years, except in transient BS5, and observational studies show better growth and electrolyte profiles [1]. Evidence is insufficient to select among NSAIDs, so choice should weigh gastrointestinal and cardiovascular risks; in preterm infants, during the first weeks and months, the risk of necrotising enterocolitis (NEC) should be considered; euvolaemia should be achieved before initiation, because nephrotoxicity depends on volume status [1]. Labels for these drugs do not include Bartter [88, 89].

Gastric protection. The consensus recommends combining acid secretion inhibitors with non-selective COX inhibitors (grade C, moderate) [1]. Proton pump inhibitors (PPIs) carry a small hypomagnesaemia risk, worsening renal magnesium wasting; in that case, H2 antagonists, other antacids or a COX-2 inhibitor may be used [1]. With prolonged use, gastrointestinal effects may be severe and warrant endoscopic surveillance [90].

NSAIDs and kidney function. Prolonged NSAID use for pain is strongly associated with CKD in the general population, but in Bartter NSAID initiation typically results in clinical improvement with stable or increased GFR through improved volume status [1]. CKD is frequent in Bartter and multifactorial (prematurity, dehydration episodes), and the specific contribution of NSAIDs is difficult to isolate [1]. NSAID ‘tolerance’ and discontinuation at school age because of perceived lack of efficacy have been described; reduction or withdrawal may be considered in stable patients [1]. In adults, indometacin is rarely maintained because of uncertain benefit, gastrointestinal effects and possible CKD [25]. Renin and aldosterone may help assess adequacy of the NSAID dose [1].

7.4. Bartter syndromes: nutrition, growth and other drugs

Nutritional support should be optimised for growth (grade D, weak), and nasogastric or gastrostomy tube feeding should be considered in infants and young children to ensure calories and salt administration [1, 25]. GH deficiency has been described mainly in BS3; systemic prostaglandins may contribute, and in one report deficiency responded to recombinant GH only after starting a COX inhibitor [1]. In children with growth retardation despite optimised treatment (NSAIDs, salt, KCl), GH deficiency should be considered (grade C, weak), after optimising metabolic control [1]. The sources consulted give no disease-specific GH dosing.

The consensus does not recommend routine potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) (grade D, weak), because they worsen salt wasting and critical hypovolaemia risk; some sudden deaths in Bartter may result more from hypovolaemia than hypokalaemia; these drugs are reserved for individual cases with severe symptoms despite maximised NSAIDs and salt [1]. Thiazides should not be used to reduce hypercalciuria (grade D, weak), because of absent efficacy data and potentially fatal hypovolaemia risk [1]. A 2018 review takes a different position: it considers amiloride preferable among potassium-sparing agents (avoiding spironolactone-induced gynaecomastia) and allows ACEi to correct potassium and reduce proteinuria, with minimal starting doses because of hypotension and acute kidney injury risk in polyuric patients [90]. The French PNDS reserves ACEi for very severe abnormalities despite maximisation of all treatment and, in adults, allows low-dose ACEi or ARBs with proteinuria, with blood pressure surveillance; potassium-sparing agents only after multidisciplinary discussion [25]. In Korean practice, 68 % of patients received potassium-sparing agents [87]. In extremely severe, uncontrollable forms, bilateral nephrectomy has been used exceptionally; after kidney transplantation, electrolyte abnormalities and polyuria are corrected without recurrence [1, 25].

7.5. Bartter type 5 (MAGED2)

BS5 management differs from other forms because disease is transient. Pregnancy should be managed as high-risk, with serial ultrasound and delivery in a centre caring for extremely preterm infants [47]. In the newborn, replacement of fluid, NaCl and potassium should be aggressive with close monitoring, treating dehydration and shock [47]. The decisive point is active, monitored tapering of supplements and any NSAID as tubulopathy regresses, rather than maintaining a lifelong regimen; early genetic diagnosis avoids unnecessary aggressive treatment [1, 47]. Follow-up addresses consequences of prematurity and nephrocalcinosis, and growth and kidney function until demonstrated normalisation [47].

7.6. Prenatal management

Before repeated amniocenteses or maternal NSAIDs to reduce amniotic fluid, benefit (prolonging pregnancy) should be weighed against fetal risks (premature ductus arteriosus closure, NEC), with a decision by a multidisciplinary team including maternal–fetal medicine, neonatology, paediatric nephrology and, if NSAIDs are used, paediatric cardiology (grade D, weak) [1]. Serial amniocenteses are common but their benefit has not been prospectively assessed; maternal NSAIDs require fetal echocardiography because of ductus arteriosus constriction risk and are associated with neonatal intestinal perforation and NEC; only a few cases with good outcomes are published, with possible publication bias, and a formal recommendation is not possible [1]. The French PNDS recommends amniodrainage (up to 2 L) for uterine distension with threatened preterm labour and limits prenatal indometacin, when indispensable, to 48 hours, by multidisciplinary decision, with delivery in a level 3 maternity unit [25]. FDA NSAID labelling states that, from 20 weeks, they may cause fetal renal dysfunction with oligohydramnios and, from 30 weeks, premature ductus arteriosus closure; dose and duration should be limited between 20 and 30 weeks and use avoided from 30 weeks [88].

In BS5, a Chinese series of three pregnancies with hemizygous MAGED2 showed that the two pregnancies with therapeutic amnioreduction reached 35+2 and 37+1 weeks without severe neonatal complications, whereas expectant management ended at 32+6 weeks with transient brain injury requiring rehabilitation; this is an uncontrolled case series [91]. In another series, two boys were born at 33 weeks after repeated amnioreductions, with normal neurodevelopment at 3–4 years [55].

7.7. Gitelman syndrome: salt, potassium and magnesium

Salt. KDIGO advises NaCl intake ad libitum, following the patient's salt appetite; in 2017, the benefit of additional pharmacological NaCl supplements had not been tested [15]. In children, the French PNDS considers pharmacological NaCl (compounded capsules) frequently necessary, potentially exceeding 4–5 mmol/kg/day, adjusted to electrolytes, RAAS and growth; in adults, it does not systematically recommend it but advises against salt restriction [26]. A NaCl versus placebo trial in patients aged 16 years or older (NCT04995627, n = 21) was completed in 2024, with no published results found [92].

Potassium and magnesium: principles. Individualised lifelong oral potassium and/or magnesium supplementation is the mainstay of treatment [15]. With hypomagnesaemia, magnesium should be corrected first, because this facilitates potassium replacement and reduces tetany [15]. No correlation between serum levels and symptoms has been demonstrated; targets considered reasonable are potassium 3.0 mmol/L and magnesium 0.6 mmol/L (1.46 mg/dL), and realistic targets may be lower [15]. High doses cause gastric ulceration, vomiting and diarrhoea, and cost and reimbursement, varying by country, influence adherence [15]. In children, the French PNDS recommends potassium supplementation in all cases, even asymptomatic, targeting potassium of at least 3 mmol/L, and advocates magnesium even without hypomagnesaemia to improve potassium correction and prevent chondrocalcinosis [26]. In adults, the PNDS states that oral supplementation typically raises potassium only 0.2–0.3 mmol/L and the theoretical target is often unattainable [26].

Available formulations vary by country. The French PNDS lists, for potassium, KCl syrup with glycerophosphate (11.25 mmol per sachet), Diffu-K® 600 mg capsules (8 mmol) and Kaleorid® prolonged-release 600 mg (8 mmol) and 1000 mg (13 mmol) tablets, considering potassium gluconate less preferable because it contains sucrose and worsens alkalosis, reserving it for transient situations such as gastroenteritis; for magnesium, lactate (2 mmol per 50 mg tablet), Magnésium B6® (1.92 mmol), effervescent oxide (6 mmol), pidolate MAG 2® in an ampoule (4.8 mmol) or sachet (7.6 mmol) and carbonate (4 mmol), as well as compounded magnesium carbonate 400 mg capsules [26]. In France, magnesium is not systematically reimbursed [26]. Availability of these formulations in Portugal and Brazil was not verified in the sources consulted.

7.8. Gitelman syndrome: second-line treatment

If symptomatic hypokalaemia persists despite good adherence, or adverse effects are unacceptable, KDIGO allows potassium-sparing diuretics (amiloride, spironolactone, potassium canrenoate, eplerenone), RAAS blockers (ACEi or ARBs) or indometacin, alone or combined [15]. Potassium-sparing agents worsen salt wasting and should be started cautiously because of hypotension risk, potentially with concomitant salt; ACEi and ARBs worsen sodium loss and hypovolaemia risk and should be withheld in vomiting or diarrhoea [15]. Spironolactone has antiandrogenic effects (gynaecomastia, hirsutism, erectile dysfunction, menstrual irregularities), problematic in adolescents and young people; eplerenone is selective and lacks these [15]. Indometacin is rarely used in Gitelman, in which urinary PGE2 is usually normal; rofecoxib has been used in refractory hypokalaemia, limited by cardiovascular effects [15]. The French PNDS allows indometacin in children with persistent growth retardation despite optimal ionic balance, starting at a low dose and increasing, if necessary, to 1–3 mg/kg/day in 2 doses, and ACEi or ARBs in adults with Gitelman and hypertension [26]. If growth retardation persists despite adequate supplementation, puberty and GH should be assessed; GH is probably beneficial in true deficiency, with optimised biochemical control [15, 26].

7.9. Chondrocalcinosis

Chondrocalcinosis is prevented by magnesium supplementation [15]. Acute attacks may be treated with oral NSAIDs, with renal caution, or low-dose oral colchicine, which may increase magnesium's laxative effect; intra-articular steroids are an alternative when other drugs are contraindicated, and intermittent systemic steroids or methotrexate have been proposed for severe cases [15]. The sources provide no doses for these drugs for this indication.

7.10. Drugs to avoid or use cautiously

Source: KDIGO Table 3, ERKNet consensus and French PNDS [1, 15, 26].

7.11. Education, physical activity, school and work

KDIGO and ERKNet recommend specific education (leaflets, forums), a medical identification bracelet, a travel medical letter with supplements in hand luggage and ‘sick-day rules’ for intercurrent illness [1, 15]. Sport has not been shown to be harmful; during endurance or competitive activity, volume depletion should be prevented with additional salt and electrolytes, and cardiological assessment performed with long QT or cardiac history [1, 15]. Adjustments at school and work may be justified (breaks, reduced hours, remote working; difficulty with shift work), educational support for comorbidities of extreme prematurity and occupational therapist involvement, encouraging informed disclosure to the employer [1, 15]. Renal treatment does not correct BS4 deafness, which requires its own audiological screening and management, enabled by early genetic diagnosis [1, 10].

7.12. Differences between guidelines

The four reference guidelines agree on principles (salt, potassium chloride, magnesium, divided doses, NSAIDs in Bartter but not first-line in Gitelman), but differ on specific points [1, 15, 25, 26].

7.13. Regulatory status

National summaries of product characteristics (INFARMED, ANVISA) were not consulted; United States label doses concern other indications and serve only as safety references.

7.14. Clinical trials

In the Blanchard trial, indometacin significantly reduced eGFR and renin; eplerenone and amiloride tripled aldosterone, slightly increased renin and worsened sodium depletion, without significant change in eGFR or blood pressure; there were 8 early withdrawals, 6 for gastrointestinal intolerance to indometacin and 2 for hypotension with eplerenone [86]. Mean potassium gains (0.15 to 0.38 mmol/L) start from a baseline of 2.8 mmol/L, so no drug normalised potassium in most patients. The trial is small, open-label and short-term, did not assess clinical outcomes (arrhythmias, quality of life, CKD) and used an eplerenone dose above the label dose; its results cannot be transferred to Bartter or children. There are no randomised NSAID trials in Bartter, and comparison between the three drugs is valid only within this trial. Trials without published results permit no efficacy conclusions, and absence of results in a search does not prove they have not been published.

7.15. Developments over the last 12 months and research

Between October 2025 and October 2026, a ClinicalTrials.gov search found no active phase 2 or 3 trial targeting Bartter or Gitelman, and no regulatory process, authorisation or orphan designation was identified in the United States or European Union [85, 92]. A negative search does not prove absence of preclinical programmes. Publications from the period are classified as follows.

Chaperone or proteostasis-modulating approaches for ROMK variants retained in the endoplasmic reticulum are preclinical; rescue with the Hsp90 inhibitor 17-AAG has been shown in cells only for mutant barttin [43]. Calcilytics target CASR-related autosomal dominant hypocalcaemia [40]. The French Gitelman PNDS was updated in February 2025; no update to KDIGO 2017 or ERKNet 2021 was identified [26].

7.16. Pregnancy, lactation, perioperative care and transition

Pregnancy. In normal pregnancy, serum potassium falls by 0.2–0.5 mmol/L in mid-gestation; in affected women, hypokalaemia and hypomagnesaemia worsen and a joint, timely nephrology–obstetric plan is mandatory, with supplement adjustment (grade C, weak) [1, 15]. The potassium target is unknown; ERKNet suggests 3.0 mmol/L and the French Gitelman PNDS 2.5–3.0 mmol/L, with magnesium above 0.6 mmol/L, monthly monitoring and follow-up in a level 3 maternity unit [1, 26]. RAAS blockers are contraindicated and NSAIDs discouraged; the Bartter PNDS also contraindicates aldosterone antagonists and maintains only salt, potassium and magnesium [1, 25]. Some authors have proposed amiloride or eplerenone with strict volume monitoring, a position diverging from the rest of the PNDS and KDIGO [26]. Electrolytes should be monitored during labour, and baseline supplementation resumed postpartum [1, 15]. Reported maternal–fetal outcomes are favourable, without serious maternal or fetal arrhythmias [15]. In a French series of 12 pregnancies in 5 patients, mean KCl dose was 9 g/day (4–10 g/day) and elemental magnesium dose 460 mg/day (300–900) [26]. In the Chinese registry, 12 of 43 women had children after symptom onset, with generally uneventful pregnancies, lower first-trimester potassium and increased potassium and magnesium postpartum [64]. In a Beijing series of 5 pregnant women (clinical diagnosis), there were 3 vaginal births and 2 caesarean sections, without postpartum haemorrhage, and children were healthy at 6 months–5 years [97]. The complications most reported without control are third-trimester oligohydramnios, arrhythmias and muscle weakness [26].

Lactation. The sources consulted contain no specific breastfeeding recommendations for these diseases.

Anaesthesia and surgery. Hypokalaemia and hypomagnesaemia potentiate local and general anaesthetics, neuromuscular blockade and the effect of adrenaline in regional blocks [1, 15]. There is no evidence regarding safe preoperative levels; general consensus suggests potassium above 3.0 mmol/L and magnesium above 0.5 mmol/L [1, 15]. The French PNDS, citing the UK Renal Association and Royal College of Anaesthetists (2016), gives potassium of at least 2.8 mmol/L for planned minor surgery and, for major surgery, potassium of at least 3.0 mmol/L with magnesium above 0.5 mmol/L, or potassium of at least 3.3 mmol/L if magnesium is below 0.5; surgery should be postponed below these values [26]. It recommends electrocardiogram (ECG), potassium and magnesium within the preceding 24 hours; avoiding β2 agonists, insulin, laxatives, PPIs, class III antiarrhythmics, fluoroquinolones, macrolides and haloperidol; using induction and analgesia without QT prolongation (midazolam, fentanyl) and antiemetics such as metoclopramide; avoiding rapid correction of stable chronic abnormalities; and postoperative monitoring with continuous ECG and attention to ileus [26].

Transition. Transition from paediatrics to adult services is particularly important and should be organised, with the disease re-explained at each stage [15, 26]. There are no therapeutic studies in adults with Bartter, and treatment derives from paediatric practice [25].

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

The ERKNet consensus recommends offering genetic counselling to families with a clinical and/or genetic diagnosis, including cascade screening (grade D, weak), and KDIGO recommends it for all patients and parents of affected children, with testing of parents, siblings and partner [1, 15]. Risks depend on the inheritance pattern [3, 14, 17, 40].

The French PNDS considers Gitelman transmission risk very low outside consanguinity, because the partner is rarely a carrier [26].

8.2. Cascade testing and carriers

Testing relatives is particularly useful to identify heterozygous carrier women in families with a MAGED2 variant, because diagnosis changes management of future pregnancies, which become high-risk [1, 47]. BS5 diagnosis retrospectively explains recurrent ‘idiopathic’ polyhydramnios and changes antenatal counselling: if the child is delivered safely, persistent kidney disease is not usually expected [47, 66]. In families with CLCNKB deletions, testing parents and carriers requires a copy number analysis method, because sequencing does not detect the deleted allele [42]. In populations with founder variants (Amish, Romani, Costa Rican), targeted testing of those variants may be the first step [22–24]. SLC12A3 heterozygotes did not differ from non-carriers in blood pressure in Taiwanese and Japanese studies [61, 62].

8.3. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and preimplantation genetic testing (PGT) are technically possible when both pathogenic variants, or the MAGED2 variant, have been identified, and should be considered individually according to each country's ethical and legal standards [1, 15]. In Gitelman, in the KDIGO panel's experience, they are rarely requested given most patients' good prognosis, but may be discussed in very severe cases [15]. In severe antenatal Bartter forms, particularly BS4 with deafness and BS5 with extreme prematurity risk, early diagnosis allows planning of delivery location and fetal surveillance [1, 47]. Amniotic fluid biochemistry is less reliable than genetic testing [1, 71].

8.4. Counselling minors and consultation content

Testing a patient's minor siblings has direct clinical benefit, because early AR diagnosis allows treatment before complications, and in BS4 allows deafness screening [1]. Carrier status testing in asymptomatic minors without immediate clinical benefit should generally be deferred until they can decide; this general guidance is not specifically discussed in the guidelines consulted. Consultation should explain the mechanism, phenotypic variability even with identical variants, lifelong treatment in AR forms and transient BS5 [15, 47]. Resources for families with polyhydramnios include the British organisation Antenatal Results and Choices [66].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Available estimates measure different things: annual incidence, birth prevalence, expert-estimated point prevalence and prevalence calculated from allele frequencies in genomic databases. None comes from a genetically based population study with clinical confirmation.

9.2. Founder populations and diversity

In Pennsylvania Amish, complete CLCNKB deletion accounts for virtually all BS3 alleles and SLC12A3 c.1924C>G p.(Arg642Gly) has a calculated allele frequency of 1/51 [22]. In the European Romani population, SLC12A3 c.1180+1G>T accounts for approximately 75 % of alleles and c.1939G>A p.(Val647Met) approximately 25 % [24, 57, 58]. In Costa Rica, SLC12A1 c.1875G>A p.(Trp625Ter) accounts for 57 % of BS1 alleles, with an estimated carrier frequency of approximately 1/145 [23, 59]. In China, SLC12A3 p.(Thr60Met) and p.(Asp486Asn) are hotspots, and a Yi population homozygous for the variant NM_001126108.2:c.1262G>T p.(Cys421Phe) (published designation p.C421F) has been described [48, 51, 60]. In Japan and Taiwan, SLC12A3 carrier frequencies are much higher than European frequencies [27, 61, 62]. In Korea, BS3 predominates among genetically confirmed Bartter cases (33 of 39) [87]. High consanguinity explains the higher prevalence in Kuwait [99].

The reference European series come from France (Brochard, Seys, Legrand, Vargas-Poussou, Allaf), the United Kingdom (Walsh) and European consortia (Ashton, Hureaux) [7, 8, 50, 54, 67, 71, 74, 75]. The sources consulted contain no prevalence, recurrent variant or cohort data from Portugal or Brazil, or United States data beyond Amish populations; absence from these sources does not demonstrate that such data do not exist.

9.3. Special populations

In adults, genetic diagnosis is less frequent (29 % of tubulopathies, 12.5 % of clinical Bartter cases) and the pseudo-Gitelman proportion is high, making exclusion of concealed diuretics and laxatives essential [1, 70, 75]. BS3 may be diagnosed in older people, with a risk of confusion with renovascular hypertension or hyperaldosteronism [28]. Preterm infants with antenatal Bartter have increased NEC risk under NSAIDs and prematurity-related comorbidities requiring educational support [1]. In women, pregnancy may reveal Gitelman [26]. BS4 patients need hearing rehabilitation [1].

9.4. Reference networks and patient organisations

The relevant European reference network is ERKNet (European Rare Kidney Disease Reference Network; https://www.erknet.org/), whose tubulopathies working group wrote the 2021 consensus and which maintains the ERKReg registry and patient information [1, 29]. In France, the ORKiD network and MARHEA centres publish PNDS documents, and the GitelBart association (https://www.gitelbart.fr/) provides information, emergency cards and children's materials [26, 100]. In the United Kingdom, the UK Kidney Association maintains patient information on Gitelman and Bartter type 3 and the RaDaR registry; this information states that these patients will rarely need dialysis or transplantation, contrasting with CKD observed in 25 % of French BS3 patients [8, 101]. No dedicated associations in Portugal or Brazil were identified in the sources consulted.

10. Illustrative Clinical Case

In 2026, Okura and colleagues described in Case Reports in Endocrinology a Japanese woman aged 66 years with Bartter type 3 diagnosed in later life [28]. She had had no childhood symptoms and had taken a statin for hypercholesterolaemia since 60 years. At 65 years, routine blood tests showed potassium 2.0 mmol/L. She was 150 cm tall and weighed 53 kg; initial blood pressure was 157/88 mmHg, with heart rate 116/min, but subsequent measurements were around 120/70 mmHg, interpreted as white-coat hypertension. Biochemistry showed sodium 141 mmol/L, potassium 2.0 mmol/L, chloride 96 mmol/L, calcium 9.9 mg/dL, magnesium 1.8 mg/dL (0.74 mmol/L, normal), creatinine 0.59 mg/dL and eGFR 77 mL/min/1.73 m²; pH was 7.429 and bicarbonate 27.1 mmol/L; plasma renin activity was 9.9 ng/mL/h and aldosterone 47.9 pg/mL; urinary calcium/creatinine ratio was 0.65 mmol/mmol, without hypocalciuria. Initial suspicion of renovascular hypertension led to magnetic resonance angiography (mild renal artery narrowing), contrast-enhanced computed tomography, Doppler and captopril renography, which excluded significant stenosis. ECG showed prominent U waves (Figure 5 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13248106/figure/fig-0005/).

To distinguish BS3 from Gitelman, the authors performed diuretic tests: with thiazide, FECl change was 3.4 % (above the 2.3 % threshold, indicating functional NCC and favouring Bartter) and, with furosemide, chloride reabsorption was 10.1 % [28]. The genetic panel identified homozygous CLCNKB NM_000085.5:c.1830G>A p.(Trp610Ter) (NC_000001.11:g.16055508G>A; NP_000076.2:p.(Trp610Ter), validated in VariantValidator), without BSND variants or deafness, establishing BS3 diagnosis [28, 49]. According to the authors, ClinVar associates this variant with BS3 and BS4b.

Treatment evolved in stages (Figure 6 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13248106/figure/fig-0006/). KCl was increased from 3 to 6 and then 9.9 g/day without normalising potassium; low-dose enalapril (1.25–2.5 mg/day) raised potassium to 3.2 mmol/L, but systolic blood pressure fell to 100 mmHg; spironolactone alone (12.5–25 mg/day) was insufficient; the combination of enalapril 2.5 mg/day and spironolactone 12.5 mg/day with KCl 9.9 g/day stabilised potassium at approximately 4.0 mmol/L without persistent hypotension, during follow-up from November 2022 to January 2025 [28]. The vertical axis of Figure 6 is labelled ‘Potassium (mg/dl)’, apparently a unit error because the values are consistent with mmol/L. In the discussion, the authors assemble other adult-diagnosed BS3 cases and state that only 46 % of adults with a clinical Gitelman diagnosis have genetic confirmation [28].

The case illustrates three points: BS3 may remain undiagnosed until the seventh decade and mimic secondary hypertension; normal magnesium and absence of hypocalciuria argue against Gitelman; and genetic confirmation is decisive. Management should not be read as recommended practice: diuretic tests are not recommended by ERKNet or KDIGO when genetic testing is accessible, and combining ACEi with an aldosterone antagonist diverges from the ERKNet recommendation against their routine use [1, 15].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis of Bartter syndromes

Long-term data are limited and come from treated patients [1]. CKD is frequent and multifactorial: contributing factors include the molecular defect (especially in BS4), prematurity and low birth weight, nephrocalcinosis, chronic dehydration, hyperfiltration proteinuria associated with RAAS activation and NSAIDs; BS1 and BS4 may have more severe progression than BS2 and BS3, and serum potassium does not correlate with eGFR [1]. Some patients progress to ESKD; the few described kidney transplants corrected electrolyte abnormalities and polyuria without recurrence [1]. Nephrocalcinosis and hypercalciuria persist in most (except BS3), but symptomatic stones are relatively uncommon; nephrotic proteinuria and glomerular and tubulointerstitial lesions, including focal segmental glomerulosclerosis, have been described [1].

In BS5, tubulopathy resolves completely and residual morbidity results from prematurity [13, 47]. In BS4, deafness is permanent and CKD and ESKD risk is highest [1].

11.2. Prognosis of Gitelman syndrome

In 2017, there was no evidence of reduced life expectancy, but long-term data on metabolic syndrome, arrhythmias, CKD, blood pressure and chondrocalcinosis were lacking [15]. Symptoms may increase with age independently of hypokalaemia control, and hypokalaemia may become easier to control after menopause [15]. Quality of life is reduced [15, 70]. Chondrocalcinosis is the long-term joint complication and was documented radiologically in approximately 42 % of a Chinese adult cohort [68]. CKD may occur, although less frequently than in Bartter [15, 102].

11.3. Surveillance

Depending on age and genotype, the team should include dietitians, social workers, psychologists, endocrinologists, otorhinolaryngologists, cardiologists and rheumatologists [1, 26].

12. Summary and Final Considerations

Bartter and Gitelman syndromes are salt-wasting tubulopathies with hypokalaemic metabolic alkalosis and normotensive hyperreninaemic hyperaldosteronism. Bartter results from TAL defects in the loop of Henle and is divided into five molecular types: BS1 (SLC12A1), BS2 (KCNJ1), BS3 (CLCNKB), BS4a (BSND), BS4b (CLCNKA with CLCNKB) and BS5 (MAGED2); Gitelman results from biallelic SLC12A3 variants in the DCT. Current numbering assigns type 5 to MAGED2, and the former ‘type 5’ designation for CASR gain of function now corresponds to a differential diagnosis.

Types 1, 2, 4 and 5 manifest in utero through polyhydramnios and prematurity and, after birth, through polyuria, dehydration and growth retardation; BS1 and BS2 have hypercalciuria and nephrocalcinosis, BS2 transient neonatal hyperkalaemia, BS4 sensorineural deafness and greater CKD risk, and BS5 spontaneous resolution around term. BS3 usually presents in early childhood but encompasses a spectrum from prenatal life to old age, with approximately one quarter of patients having a Gitelman-like phenotype. Gitelman presents mainly in adolescence or adulthood, with salt craving, cramps, fatigue, hypomagnesaemia, hypocalciuria, prolonged QT and chondrocalcinosis, and reduces quality of life.

Diagnosis rests on simultaneously collected plasma and urine biochemistry and genetic confirmation through a panel including all group genes, with copy number analysis, particularly for CLCNKB, whose genomic architecture with deletions and hybrid genes escapes short-read sequencing. Clinical sensitivity is approximately 75 % in children and much lower in adults, so a negative result does not exclude the diagnosis and requires reassessment of acquired causes. Diuretic tests are obsolete when genetic testing is accessible.

Bartter treatment rests on sodium chloride, potassium chloride, magnesium when necessary and NSAIDs in the early years, with divided doses, gastric protection and nutritional optimisation; in BS5, tapering supplements is essential. Gitelman treatment rests on unrestricted salt, lifelong potassium chloride and magnesium, with targets around 3.0 and 0.6 mmol/L, and second-line drugs whose benefit, demonstrated in a single randomised trial of 30 patients, is modest and accompanied by adverse effects. All drugs except potassium chloride are used off-label, and there are no orphan designations or active phase 2 or 3 trials. The ERKNet and KDIGO consensus statements and French PNDS documents differ on specific points, such as the indometacin ceiling, use of potassium-sparing agents and pregnancy potassium target.

AR forms have a 25 % recurrence risk and BS5 follows X-linked inheritance, with particular interest in identifying carrier women. Epidemiology is poorly known: estimates range from expert classes to historical series and genomic database calculations, and there are Amish, Romani and Costa Rican founder populations, with much higher SLC12A3 carrier frequencies in Japan and Taiwan. The sources consulted contain no Portuguese or Brazilian data. Prognosis depends on type: CKD affects approximately one quarter of BS3 patients after a median 8 years of follow-up, is more severe in BS1 and BS4, and is less frequent in Gitelman; regular follow-up in experienced centres linked to ERKNet organises biochemical, renal, cardiac, auditory and growth surveillance.

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