# Bartter syndrome consensus — full text dump



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executive summary
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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
Martin Konrad1, Tom Nijenhuis2, Gema Ariceta3, Aurelia Bertholet-Thomas4, Lorenzo A. Calo5,
Giovambattista Capasso6, Francesco Emma7, Karl P. Schlingmann1, Mandeep Singh8,
Francesco Trepiccione6, Stephen B. Walsh9, Kirsty Whitton10, Rosa Vargas-Poussou11,12 and
Detlef Bockenhauer9,13
1Department of General Pediatrics, University Hospital Münster, Münster, Germany; 2Department of Nephrology, Radboud University
Medical Center, Nijmegen, The Netherlands; 3Pediatric Nephrology, Hospital Universitari Vall d’Hebron, Universitat Autonoma de
Barcelona, Barcelona, Spain; 4Université Claude Bernard Lyon 1, Lyon, France; 5Department of Medicine (DIMED), Nephrology, Dialysis,
Transplantation, University of Padova, Padua, Italy; 6Division of Nephrology, Department of Translational Medical Sciences, School of
Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy; 7Division of Nephrology, Department of Pediatric Subspecialties,
Bambino Gesù Children’s Hospital IRCCS, Rome, Italy; 8Fetal Medicine Centre, Southend University Hospital NHS Foundation Trust, Essex,
UK; 9Department of Renal Medicine, University College London, London, United Kingdom; 10London, UK; 11Hôpital Européen Georges
Pompidou, Assistance Publique Hôpitaux de Paris, Centre d’Investigation Clinique, Paris, France; 12Centre de Référence des Maladies
Rénales Héréditaires de l’Enfant et de l’Adulte, Paris, France; and 13Department of Pediatric Nephrology, Great Ormond Street Hospital for
Children NHS Foundation Trust, London, UK
Copyright ª 2020, International Society of Nephrology. Published by
Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
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.
T
he term Bartter syndrome (BS) encompasses different
inherited salt-losing tubulopathies characterized by
polyuria, hypokalemia, hypochloremic metabolic alka-
losis, and normotensive hyperreninemic hyperaldosteronism.
Five different forms (BS1–5), based on molecular genetics,
have been identified to date (Table 1).1
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 poten-
tially 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.2 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
Kidney International (2021) 99, 324–335; https://doi.org/10.1016/
j.kint.2020.10.035
KEYWORDS: Bartter syndrome; hypokalemic metabolic alkalosis; inherited
hypokalemia; salt-losing tubulopathy
Correspondence: Martin Konrad, University Children’s Hospital Münster,
Waldeyerstr.
22, D-48149 Münster,
Germany. E-mail: konradma@uni-
muenster.de
Received 3 July 2020; revised 30 September 2020; accepted 29 October
2020
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M Konrad et al.: Diagnosis and management of Bartter syndrome
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Table 1| Molecular genetics of Bartter syndrome
Characteristic
Type 1
Type 2
Type 3
Type 4a
Type 4b
Type 5
OMIM
601678
241200
607364
602522
613090
300971
Gene
SLC12A1
KCNJ1
CLCNKB
BSND
CLCNKA þ CLCNKB
MAGED2
Protein
NKCC2
KCNJ1 (ROMK or Kir1.1)
ClC-Kb
Barttin
ClC-Ka þ ClC-Kb
MAGE-D2
Inheritance
AR
AR
AR
AR
AR
XLR
AR, autosomal recessive; OMIM, Online Mendelian Inheritance in Man; XLR, X-linked recessive.
normal intravascular volume and glomerular perfusion.3 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 pros-
taglandin synthesis inhibitors, which often results in notice-
able clinical improvement.4–6
chronic hypovolemia is not well documented. Likewise, little
information exists on the incidence of secondary hyperten-
sion 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.17). The recommendations are listed
in Boxes 1–3. It is beyond the scope of this executive sum-
mary to discuss each recommendation in detail. Instead, we
highlight the significant underlying concepts. The recom-
mendations are endorsed by the European Society for Pae-
diatric Nephrology and the Working Group on Inherited
Kidney Disorders of the European Renal Association–
European Dialysis and Transplantation Association.
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,7,8 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.9 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 regu-
lating their expression (BS5). The mode of inheritance is
autosomal recessive in BS1–410–14 and X-linked recessive in
BS5.15
METHODS
The consensus process was initiated by European Rare Kidney Dis-
ease 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.17
Clinical characteristics, such as severity of biochemical
abnormalities, presence of polyhydramnios and preterm de-
livery, degree of calciuria with or without medullary neph-
rocalcinosis, 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.1
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,16 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
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.18,19 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.
Diagnosis
See Box 1. For details, see Konrad et al.17
General approach
The diagnosis of BS is primarily based on clinical, biochemical and
sonographic findings (Box 1). Even if the different subtypes of BS
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executive summary
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Figure 1 | Pathophysiology of Bartter syndrome. Schematic model of salt transport in the thick ascending limb and the distal convoluted
tubule with associated defects in Bartter syndrome (BS) indicated. In the thick ascending limb, NaCl is reabsorbed by the NaK2Cl cotransporter
NKCC2, which is mutated in BS type 1. Here, the potassium ion is recycled into the tubular lumen via the apical potassium channel KCNJ1
(ROMK), which is mutated in BS type 2. In the distal convoluted tubule, NaCl enters the tubular epithelium via the NaCl cotransporter NCC. In
both tubular segments, chloride leaves the cell on the basolateral side through chloride-permeable ion channels ClC-Ka and ClC-Kb. A
molecular defect of ClC-Kb causes BS type 3. Mutations in either the accessory subunit barttin or a combined defect of both chloride channels
ClC-Ka and ClC-Kb result in BS types 4a and 4b. Finally, transient BS type 5 is caused by mutations of MAGE-D2. MAGE-D2 stimulates trafficking
by protecting NKCC2 and NCC from intracellular degradation via HSP40 and promotes apical targeting of NKCC2 and NCC via Gs-alpha.20
can usually be characterized clinically (Table 220,21), we recommend
genetic analysis for confirmation.
specific differences between the known subtypes of BS. For
differential diagnosis, see the Differential Diagnosis section
below.
Antenatal diagnostic work-up
Early polyhydramnios of fetal origin should raise the clinical suspi-
cion 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.22 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.23,24
Age at presentation.
 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 BS2.15,20,21,25
 BS5 always presents antenatally, but symptoms spontaneously
resolve typically around the estimated date of delivery.
 BS3 usually manifests later in life. Nevertheless, a prenatal pre-
sentation does not exclude BS3. The vast majority of patients with
BS3 are diagnosed after the age of 1 year.26–32 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 pre-
senting symptom.
Postnatal diagnostic work-up
The diagnostic work-up for BS after birth should include a detailed
clinical evaluation asking for a family history of pregnancy compli-
cated 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 param-
eters 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.
 In a minority of cases, the diagnosis of BS is incidental after
noticing abnormal laboratory results, discovery of nephrocalci-
nosis, or family screening.
Salt wasting, plasma potassium, chloride, magnesium, and
bicarbonate levels.
 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.
Clinical characteristics of different types of BS
Key clinical and biochemical findings in patients with BS are
detailed below and in Table 2, with a special focus on gene-
 In some patients with BS3, hypomagnesemia may be present.
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Box 1| Recommendations for diagnosis of 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 dehy-
dration. 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.
Calciuria and nephrocalcinosis.
higher proportion of patients with BS3 because the analysis of
CLCNKB is technically challenging.
 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 situa-
tions where there is a direct therapeutic consequence, e.g., local-
ization of stones in obstructive uropathy which may occur in rare
cases in BS.
 Although large rearrangements can be detected by next-generation
sequencing, it is recommended to confirm them by a second in-
dependent method (e.g., multiplex ligation-dependent probe
amplification). Large rearrangements are particularly frequent in
the CLCNKB gene but have also been described in KCNJ1, BSND,
and MAGED2.13,21,35
 Genetic counseling should be offered to any family affected by BS.
Counseling should include cascade screening. Testing relatives is
particularly useful to identify heterozygous female carriers in
families with an index case carrying a MAGED2 mutation.
 In contrast, patients with BS3 and BS4 usually have normo-
calciuria, although hypercalciuria may occur.
 Interestingly, hypocalciuria has also been reported in patients with
BS3, and these patients mimic the phenotype of GS.
 Prenatal diagnosis and preimplantation genetic diagnosis are
technically feasible after reliable genetic counseling and may be
considered on an individual basis, according to national ethical
and legal standards.
 In transient BS5, hypercalciuria may be observed, but neph-
rocalcinosis is a rare finding.
Genetic testing.
 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.
DIFFERENTIAL DIAGNOSIS
 The differential diagnosis of BS depends on the age at
presentation and the specific context (Table 4; for details,
see Konrad et al.17).
 The detection of pathogenic variants in genes responsible for BS is
crucial
to
confirm
the
clinical
diagnosis
and
for
genetic
counseling.
 Polyhydramnios due to excessive fetal polyuria is virtually
always caused by BS. There are no reports of other inherited
tubular
disorders
causing
severe
polyhydramnios.
In
particular, polyhydramnios is not a feature in severe prox-
imal tubulopathies nor in nephrogenic diabetes insipidus.
There are reports of polyhydramnios in infants mis-
diagnosed with pseudohypoaldosteronism type I, but these
cases have later been shown to harbor KCNJ1 mutations
underlying BS2.27,36
 An early genetic diagnosis may help in resolving difficult cases
with overlapping phenotypes. In addition, the identification of the
genetic defect may prompt screening for and treatment of deafness
in patients with BS4 and for avoiding aggressive treatments in
transient BS5.
 Analytical sensitivity in BS is 90%–100%, and clinical sensitivity is
w75% in children21,27,33 but only 12.5% in adult patients.34 This
difference is possibly related to the broader differential diagnosis
(especially abuse of diuretics and laxatives) in adults and the
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 Congenital chloride diarrhea can be confused with BS.
Pregnancies are often complicated by polyhydramnios with
preterm delivery (usually not severe).37 Postnatally, this
disease
causes
pronounced
hypokalemic
and
hypo-
chloremic metabolic alkalosis secondary to watery diarrhea.
Polyuria, hypochloremia,
alkalosis,
hypokalemia
Calcium excretion
High
High
Variable
Variable
High
Nephrocalcinosis
Very frequent
Very frequent
Rare, mild
Rare, mild
Rare, mild
Plasma Cl/Na ratio
Normal
Normal
Decreased
Decreased
Increased
Other findings
Mild hypomagnesemia
Deafness, risk for CKD,
ESRD
Large for gestational age,
transient disease
Age at onset
Prenatally
Prenatally
0–5 years
Prenatally
Prenatally
Polyhydramnios
Severe
Severe
Absent or mild
Severe
Very severe
Gestational age at birth,
wks, median (IQR)
32 (29–34)
33 (31–35)
37 (36–41)
31 (28–35)
29 (21–37)
Characteristic
Type 1
Type 2
Type 3
Type 4a
Type 4b
Type 5
 Pseudo-Bartter syndrome is occasionally observed in cystic
fibrosis because of salt loss in sweat.
 Presentation beyond infancy, especially in adolescence or
even adulthood (most often BS3), makes GS a primary
consideration in those patients with hypocalciuria and/or
hypomagnesemia. Patients with hepatocyte nuclear factor
1b nephropathy may also present with hypokalemic alka-
losis and hypomagnesemia.38 Other rare tubulopathies
exhibiting metabolic alkalosis are listed in Table 4.
Polyuria, hypochloremia,
alkalosis,
hypokalemia
 Some patients with BS primarily present with neph-
rocalcinosis and/or urolithiasis. A young age at onset of
kidney stone disease should raise the clinical suspicion of a
specific underlying cause, including (incomplete) distal
renal tubular acidosis.
Hypokalemia, hypochloremia,
alkalosis,
failure to thrive
 If the presenting sign is hypokalemia, the initial differential
diagnosis is wide. In this context, it is important to distin-
guish renal from gastrointestinal potassium loss and potas-
sium shifts. If primary hyperaldosteronism and diuretic and/
or laxative use or abuse are excluded, the differential diag-
nosis narrows down to rare tubulopathies (Table 4).
Table 2| Main clinical and biochemical characteristics of different types of Bartter syndrome
 Urinary chloride excretion assessed by either fractional chlo-
ride excretion or urinary sodium/chloride ratio is helpful to
distinguish renal from extrarenal salt losses. In BS, fractional
chloride excretion is usually elevated (>0.5%).32
Polyuria, hypochloremia,
alkalosis,
transient neonatal hyperkalemia
In theory, thick ascending limb and distal convoluted tubule
function can be clinically tested by administering loop diuretics
or thiazides to better characterize the clinical diagnosis of BS.
Diuretic tests, however, are obsolete because they have been
surpassed by genetic analysis. It is important to note that there is
a potential risk of severe volume depletion in subjects with
suspected BS, especially in infancy, because of an exaggerated
response to thiazides due to the compensatory up-regulation of
salt reabsorption in the distal convoluted tubule.39 Moreover,
there remain significant uncertainties about their diagnostic
value.39–41 We therefore advise against routine tubular function
testing in patients with BS, in line with the Kidney Disease:
Improving Global Outcomes consensus statement on GS.42
CKD, chronic kidney disease; ESRD end-stage renal disease; IQR, interquartile range.
Data from Komhoff and Laghmani20 and Legrand et al.21
Leading symptoms
Polyuria, hypochloremia,
alkalosis,
hypokalemia
Nevertheless, these tests may have a role in individual chal-
lenging cases or for research purposes, together with genetic
testing, if performed in experienced (tertiary) medical centers.
THERAPY
See Box 2. For details, Konrad et al.17
Prenatal therapy
 Pregnancies complicated by polyhydramnios are at risk of
adverse outcomes, especially preterm delivery and compli-
cations of premature birth.43,44 Serial amniocenteses are
commonly used in the intention of prolonging pregnancies,
but the benefits of this strategy have not been evaluated in
prospective studies.
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Table 3| Genes recommended to be included in genetic
testing for Bartter syndrome
Table 4| Differential diagnosis of Bartter syndrome
Leading
symptom
Differential diagnosis
Additional findings
Gene
Associated disorder (MIM)
SLC12A1a
BS1 (601678)
KCNJ1a
BS2 (241200)
CLCNKBa
BS3 (607364)
BS4b (613090)
CLCNKAa
BS4b (613090)
BSNDa
BS4a (602522)
MAGED2a
BS5 (300971)
SLC12A3a
Gitelman (263800)
CASR
ADH (601198)
KCNJ10
EAST/Sesame (612780)
SLC26A3
CCD (214700)
CLDN10
HELIX (617671)
SCNN1A
PHA1B (264350)
Liddle syndrome (177200)
SCNN1B
SCNN1G
NR3C2
PHA1A (177735)
HSD11B2
AME (218030)
CYP11B1
HALD1 (103900)
CLCN2
HALD2 (605635)
KCNJ5
HALD3 (600734)
CACNA1H
HALD4 (607904)
Polyhydramnios
of fetal origin
Aneuploidia
Abnormal karyotype
Gastrointestinal tract
malformation
Variable, empty stomach
Congenital chloride
diarrhea
Dilated intestinal loops
Salt loss
Pseudohypoaldosteronism
type I
Metabolic acidosis,
hyperkalemia
Salt loss with
hypokalemic
alkalosis
Congenital chloride
diarrhea
Low urinary chloride
Pseudo-Bartter syndrome,
e.g., in CF
Low urinary chloride
Gitelman syndrome
Hypocalciuria,
hypomagnesemia
HNF1B nephropathy
Renal malformation, cysts,
MODY5, hypomagnesemia
HELIX syndrome
Hypercalcemia,
hypohidrosis, ichthyosis
Autosomal dominant
hypocalcemia
Hypocalcemia, seizures
EAST/SeSAME syndrome
Ataxia, seizures, deafness,
developmental delay
Surreptitious vomiting
Low urinary chloride
Surreptitious laxative use
Low urinary chloride
Surreptitious diuretic use
Highly variable urinary
chloride
Hypokalemic
alkalosis
without
salt loss
ADH, autosomal dominant hypocalcemia; AME, apparent mineralocorticoid excess;
BS, Bartter syndrome; CCD, congenital chloride diarrhea; EAST, epilepsy, ataxia,
sensorineural deafness, tubulopathy; HALD, familial hyperaldosteronism; HELIX,
hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, xero-
stomia; MIM, Mendelian Inheritance in Man; PHA, pseudohypoaldosteronism.
aGenes 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 pheno-
typic overlap with BS. BS2 can mimic pseudohypoaldosteronism type 1 (PHA1) in the
neonatal period. The listed hypertensive disorders can biochemically mimic BS.
Listed are genes to be considered in the (differential) diagnosis of BS and therefore
should be included in a panel of genes for genetic testing.
Primary
hyperaldosteronism;
Hypertension, low renin
Apparent
mineralocorticoid excess
Hypertension, low renin/
aldosterone
Liddle syndrome
Hypertension, low renin/
aldosterone
Nephrocalcinosis Distal renal tubular acidosis Metabolic acidosis
Proximal tubular defects
No metabolic alkalosis
Familial hypomagnesemia/
hypercalciuria
No hypokalemic metabolic
alkalosis, CKD
Apparent
mineralocorticoid excess
Hypertension, low renin/
aldosterone
 Maternal treatment with NSAIDs can be considered.
Apparent efficacy has been reported in individual cases of
polyhydramnios secondary to different causes and in idio-
pathic polyhydramnios.45 However, the treatment carries
significant risks for the fetus, especially of fetal ductus
arteriosus constriction. Therefore, close monitoring with
the use of fetal echocardiography is mandatory in all cases
of maternal NSAID therapy. Other reported complications
include neonatal intestinal perforation and necrotizing
enterocolitis.45
CF, cystic fibrosis; CKD, chronic kidney disease; EAST, epilepsy, ataxia, sensorineural
deafness, tubulopathy; HELIX, hypohidrosis, electrolyte imbalance, lacrimal gland
dysfunction, ichthyosis, xerostomia; HNF1B, hepatocyte nuclear factor 1 beta;
MODY5, maturity onset diabetes of the young type 5; SeSAME, seizures, sensori-
neural deafness, ataxia, mental retardation, electrolyte imbalance.
d has been recommended.50 Beyond infancy, some of this
supplementation may be provided by salt craving and high
spontaneous salt intake that is typical for BS.
To date, only a few cases of BS with positive outcome after
serial amniocentesis and/or prenatal indomethacin therapy
have been reported.46–49 A substantial publication bias toward
favorable outcomes cannot be excluded.
Given the above-mentioned risks and lack of prospective
studies, a formal recommendation cannot be made.
 Some patients with BS1 and BS2 have a secondary form of
nephrogenic diabetes insipidus.51,52 These patients present
a therapeutic dilemma as salt supplementation would
worsen polyuria and risk hypernatremic dehydration. We
recommend against salt supplementation in patients with
hypernatremic
dehydration
and
a
concomitant
urine
osmolality lower than plasma or a history thereof.
Potassium supplementation.
 If prenatal intervention is considered, a multidisciplinary
perinatal team is mandatory, including a maternal-fetal
medicine specialist, a neonatologist, a pediatric cardiologist
(in case of NSAID therapy), and a pediatric nephrologist.
 If potassium is supplemented, potassium chloride should
be used.32 Potassium salts (e.g., citrate) should be avoided
because they potentially worsen the metabolic disturbance
by aggravating the alkalosis.
Hypokalemia in BS can be associated with severe com-
plications,
including
paralysis,
rhabdomyolysis,
cardiac
Postnatal therapy
Salt supplementation.
 Supplementation with sodium chloride constitutes a phys-
iologic treatment that can support extracellular volume and
improve electrolyte abnormalities. At least 5–10 mmol/kg/
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M Konrad et al.: Diagnosis and management of Bartter syndrome
Box 2| Recommendations for therapy of Bartter syndrome
Prenatal period
 Before the initiation of therapeutic measures (repeated amniocentesis and/or NSAIDs) aiming at the reduction of amniotic fluid volume, we
suggest carefully weighing the intended benefit (prolongation of pregnancy) with the potential risks for the fetus, such as premature closure
of the ductus arteriosus or necrotizing enterocolitis (grade D, weak recommendation).
 Whenever prenatal therapy for the reduction of amniotic fluid is considered, we suggest involving a multidisciplinary team including a
maternal-fetal medicine specialist, neonatologist, pediatric nephrologist, and pediatric cardiologist (in case of NSAID therapy) (grade D, weak
recommendation).
Postnatal period
 We recommend considering pharmacologic doses (5–10 mmol/kg/d) of sodium chloride supplementation in patients with BS (grade C,
moderate recommendation).
 We do not recommend salt supplementation in patients with BS and secondary nephrogenic diabetes insipidus (grade D, weak
recommendation).
 We recommend using potassium chloride if potassium is supplemented (grade C, moderate recommendation).
 We do not recommend aiming for complete normalization of plasma potassium levels (grade D, weak recommendation).
 Whenever needed, we recommend using oral magnesium supplements, at best organic magnesium salts owing to their better biovailability
(grade D, weak recommendation).
 We recommend spreading out salt and electrolyte supplements throughout the day as much as possible (grade C, moderate
recommendation).
 We recommend considering treatment with NSAIDs in symptomatic patients with BS, especially in early childhood (grade B, moderate
recommendation).
 We recommend using gastric acid inhibitors together with nonselective cyclooxygenase inhibitors (grade C, moderate recommendation).
 We suggest optimizing nutritional support to facilitate optimal growth (grade D, weak recommendation).
 We do not recommend routine use of potassium-sparing diuretics, ACE inhibitors, or angiotensin receptor blockers in BS (grade D, weak
recommendation).
 We do not recommend the use of thiazides to reduce hypercalciuria in BS (grade D, weak recommendation).
ACE, angiotensin-converting enzyme; BS, Bartter syndrome; NSAID, nonsteroidal anti-inflammatory drug.
rhythm abnormalities, and sudden death.53–55 The following
recommendation, made for GS,42 applies equally to BS: Po-
tassium chloride supplements can be administered in water or
in a slow-release formulation according to each patient’s
preference. The dose will be titrated according to an indi-
vidual balance (side-effects vs. symptoms). Potassium-rich
food should be advised, with the caution that some of them
contain high amounts of carbohydrates and calories. The
target level for plasma potassium is not exactly known, but a
reasonable target level may be 3.0 mmol/l. In GS as well, a
level of 3.0 mmol/l has been suggested with the explicit
acknowledgement that this may not be achievable in some
patients.42 Realistic target values may be lower for some pa-
tients and may also change with time.
Magnesium supplementation.
in plasma levels may be more detrimental than subnormal but
steady levels. We therefore recommend dividing supplemen-
tation into as many doses as tolerable for the patient. In in-
fants receiving continuous tube feeds, supplements should be
added into the feed.
NSAIDs.
 Pharmacologic suppression of prostaglandin formation
addresses the underlying pathophysiology, and multiple
clinical observational studies have shown benefit in the
form of improved growth and electrolyte profile.57–60 The
use of selective COX-2 inhibitors has also been reported in
BS.6,61–63 Commonly used NSAIDs in BS are indomethacin
(1–4 mg/kg/d divided in 3–4 doses), ibuprofen (15–30 mg/
kg daily in 3 doses), and celecoxib (2–10 mg/kg/d in 2
doses).
 Currently, there is insufficient evidence to recommend a
specific NSAID in BS, and the risks of gastrointestinal and
cardiovascular side-effects need to be considered individu-
ally. Especially if used in the first few weeks or months of
life in premature neonates, the risk of necrotizing entero-
colitis should be carefully considered. Euvolemia should be
achieved before initiating NSAIDs, because volume status
may affect the potential nephrotoxicity.
 If magnesium needs to be supplemented (mainly in patients
with BS3), oral administration of magnesium salts should
be preferred. It is important to note that organic salts (e.g.,
aspartate, citrate, lactate) have a higher bioavailability than
magnesium oxide or hydroxide.56 Exact target levels for
plasma magnesium in BS are unknown but a level >0.6
mmol/l appears to be reasonable.
Because urinary salt and electrolyte losses are continuous,
ideal supplementation would be as close to continuous as
possible. Infrequent large doses of supplementation will cause
rapid changes in blood levels depending on timing of the
sample in relation to the last dose. Arguably, large variations
 Extended use of NSAIDs for pain is strongly associated with
chronic kidney disease.64 Whether this also applies to pa-
tients with BS has been disputed.65,66 Indeed, commence-
ment of NSAIDs in BS typically results in clinical
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Box 3| Recommendations for follow-up of patients with Bartter syndrome
Frequency and setting of visits
 We suggest that patients with BS should be followed in specialized centers with experience in renal tubular disorders to facilitate best
medical care (grade D, weak recommendation).
 We suggest that infants and young children with BS should be seen at least every 3–6 months, depending on severity of clinical problems, to
ensure adequate metabolic control, growth, and psychomotor development (grade C, weak recommendation).
 We suggest that older children with an established therapy and stable condition should be seen at least every 6–12 months (grade C, weak
recommendation).
 We suggest that adult patients should be seen every 6–12 months (grade C, weak recommendation).
We suggest evaluating QoL using age-appropriate scales from age 5 years onward at 2-year intervals (grade D, weak recommendation).
Follow-up of children
 At each follow-up visit, we suggest focusing the history and examination on dehydration, degree of polyuria, signs of muscular weakness,
growth, and psychomotor development (grade C, weak recommendation).
 We suggest that biochemical work-up should include acid-base status (either by blood gas or by measurement of venous total CO2), serum
electrolytes (including bicarbonate, chloride, and magnesium), renal function, PTH, and urinary calcium excretion (grade C, weak recommendation).
 We suggest assessing urine osmolality to test for secondary NDI (grade C, weak recommendation).
 We suggest performing renal ultrasound at least every 12–24 months to monitor nephrocalcinosis, the occurrence of kidney stones, and
signs of secondary obstructive uropathy (grade C, weak recommendation).
 For children with growth retardation despite intensified efforts for metabolic control (optimization of NSAID and salt supplementation
including potassium chloride), we suggest considering growth hormone deficiency (grade C, weak recommendation).
Follow-up of adults
 At each follow-up visit, we suggest focusing the history and examination on dehydration, degree of polyuria, signs of muscular weakness,
fatigue, and palpitations (grade C, weak recommendation).
 We suggest that biochemical work-up should include acid-base status (either by blood gas or by measurement of venous total CO2), serum
electrolytes (including bicarbonate, chloride, and magnesium), renal function, PTH, urinary calcium excretion, and microalbuminuria (grade C,
weak recommendation).
 We recommend performing renal ultrasound at least every 12–24 months to monitor nephrocalcinosis, the occurrence of kidney stones, and
signs of secondary obstructive uropathy (grade C, weak recommendation).
 We suggest performing further cardiology work-up in patients complaining of palpitations or syncope (grade C, weak recommendation).
 For pregnant women or those planning to become pregnant, we suggest the timely institution of a joint management plan involving
nephrology and obstetrics (grade C, weak recommendation).
BS, Bartter syndrome; NDI, nephrogenic diabetes insipidus; NSAID, nonsteroidal antiinflammatory drug; PTH, parathyroid hormone; QoL, quality of life.
used, there is a small risk of proton pump inhibitor–
associated hypomagnesemia that could compound renal
magnesium wasting. Conversion to H2 blockers or other
antacids (or to a COX-2 inhibitor) is recommended in
those instances.
Supportive treatment.
improvement,
including
a
stable
or
even
increased
glomerular filtration rate, likely reflecting enhanced volume
status.67 Although chronic kidney disease is a common
complication of BS, the cause is likely manifold, including
premature birth and recurrent episodes of dehydration, so
that the specific role of NSAIDs is difficult to determine.
 There are reports of “tolerance” to NSAIDs over time, as
well as of discontinuation of NSAIDs at school age owing to
a perceived lack of efficacy.32,59 It is unclear whether this is
related to insufficient dosing or a change in pathophysi-
ology and whether at some point, the risks of NSAIDs may
outweigh the benefits. Chronic use of NSAIDs should be
considered carefully in each individual patient, and tapering
or cessation may be indicated in stable patients.
Gastric acid inhibitors.
 Growth failure is a common complication of BS and often
part of the initial presentation. Dietetic support is impor-
tant to maximize caloric intake and facilitate optimal
growth. Especially in infants and young children, tube
feeding may need to be considered. A feeding tube will help
not only to achieve adequate caloric intake, but also the
administration of salt supplements.
K-sparing diuretics, angiotensin-converting enzyme inhibitors
and angiotensin receptor blockers, thiazides.
 Indomethacin and ibuprofen are nonselective inhibitors
of COX enzymes. In contrast, celecoxib primarily inhibits
COX-2. COX-1 is expressed in multiple tissues, and its
inhibition is associated with potentially serious side-
effects, which have also been reported in patients with
BS receiving NSAIDs. Thus, if nonselective COX in-
hibitors are prescribed, they should be accompanied by
gastric acid suppression. If proton pump inhibitors are
 The hypokalemic alkalosis of BS is generated in the col-
lecting duct, mediated by aldosterone (reviewed by Kleta
and Bockenhauer1). Consequently, K-sparing diuretics,
angiotensin-converting enzyme inhibitors, and angiotensin
receptor blockers can help ameliorate the electrolyte ab-
normalities in BS, and their use has been reported.30,32,68–70
However, BS is primarily a salt-wasting disorder, and the
enhanced sodium reabsorption in the collecting duct is a
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M Konrad et al.: Diagnosis and management of Bartter syndrome
would be highly desirable. The first small case series in
patients with salt-losing tubulopathies showed that quality
of life scores are directly influenced by different biochemical
parameters, such as aldosterone or potassium, and thus
may help to define better therapeutic targets in the future.75
key compensatory mechanism. Consequently, drugs that
inhibit distal sodium reabsorption worsen the salt wasting
and risk critical hypovolemia. Arguably, some of the sudden
deaths reported in BS may have been caused by hypo-
volemia rather than hypokalemia.1 We therefore do not
recommend routine use of these drugs. Instead, they should
be considered carefully in individual cases and may be
indicated in those who have severe symptoms from the
electrolyte abnormalities despite maximization of routine
treatment with NSAIDs and salt supplements.71
Long-term outcomes and complications
 Data on long-term outcomes in BS are sparse.
 Whereas nephrocalcinosis and hypercalciuria are present in
the majority of patients (except BS3), the prevalence of
symptomatic urolithiasis in BS appears to be relatively
low.30
 Thiazides are occasionally used in an attempt to reduce
calcium excretion. There are no data on their efficacy in BS.
Moreover, compensatory salt reabsorption in the distal
convoluted tubule is critical for maintenance of volume
homeostasis. Thus, thiazides in BS may lead to life-
threating
hypovolemia
and
should
not
be
routinely
administered.
Growth hormone.
 Nephrotic-range proteinuria has been reported in BS pa-
tients.28,32,76 When renal biopsies are performed, they often
show diffuse glomerular and tubulointerstitial lesions with
enlarged
glomeruli
and
focal
segmental
glomerulosclerosis.30
 Chronic kidney disease is common in BS, and patients with
BS1 and BS4 may have more severe chronic kidney disease
progression than those with BS2 and BS3.30,65 In addition
to the molecular defect itself (especially in BS4), other risk
factors potentially contributing to chronic kidney injury
could be premature birth/low birth weight, nephrocalci-
nosis, chronic dehydration state, progressive proteinuria
related to hyperfiltration due to renin-angiotensin system
activation, and treatment with NSAIDs. In BS patients,
there seems to be no correlation between serum potassium
levels and estimated glomerular filtration rate.30,77 Some
patients progress to end-stage kidney disease, but exact data
are lacking.
 Growth failure with growth hormone (GH) deficiency in
BS has been reported.28,32,72–74 Whether this is an intrinsic
part of the disorder or a secondary complication of altered
acid-base and/or electrolyte homeostasis is unclear, but
most reports of GH deficiency have concerned patients with
BS3, who have the most severe metabolic abnormalities. In
addition, elevated systemic prostaglandins may contribute
to growth failure. In one report, GH deficiency failed to
respond to recombinant human GH supplementation until
treatment with a COX inhibitor was commenced.32 Thus,
before commencement of recombinant human GH, opti-
mization of metabolic control should be attempted.
 A few kidney transplantations have been reported in the
literature.30,78–84 In all cases, electrolyte abnormalities and
polyuria were corrected and recurrent disease was not
observed.
FOLLOW-UP
See Box 3. For details, see Konrad et al.17
In BS, clinical and biochemical features and complications
vary widely depending on the underlying molecular defect
and individual patient.
 Treatment and follow-up should be tailored to the patient
on the basis of clinical manifestation, medical history, stage
of development, molecular defect, and the clinician’s expert
judgement in close contact with the patient’s local health
care provider. In addition, according to age and/or geno-
type, other professions might be involved such as dieticians,
social
workers,
psychologists,
endocrinologists,
and
otolaryngologists.
Cardiac work-up/anesthesia/sports
 Hypokalemia with or without additional hypomagnesemia
prolongs the QT interval, which could lead to an increased
risk of ventricular arrhythmias. Isolated reports on cardiac
arrhythmias, long QT interval, and sudden death have been
reported in BS patients,53,85,86 so electrocardiography
should be performed at rest to assess rhythm and QT-
interval duration. A further cardiology work-up, as previ-
ously recommended for GS,42 is indicated when patients
complain of palpitations or syncope (e.g., Holter, stress
electrocardiography), or if electrocardiographic abnormal-
ities
persist
despite
attempted
improvement
of
the
biochemical abnormalities.87
 At each follow-up visit, specific clinical features should be
addressed and biochemical work-up performed (Box 3).
 In children, there is also special emphasis on growth and
pubertal development.
 Adverse effects of NSAIDs should be looked for. In case of
intercurrent illness, it has to be kept in mind that NSAIDs
may prevent fever and thus mask the severity of infectious
diseases.
 Drugs slowing sinus rhythm or influencing the QT interval,
such as negative chronotropic drugs, or drugs potentially
inducing or exacerbating hypomagnesemia, such as proton-
pump inhibitors, macrolides, fluorchinolones, gentamicin,
or antiviral drugs, should be carefully considered.
 Renin and aldosterone levels may be helpful in assessing the
adequacy of NSAID treatment.
 During follow-up, the routine assessment of quality of life
with the use of age-specific standardized questionnaires
 Caution should be taken when patients with BS undergo
anesthesia.
Hypokalemia
and
hypomagnesemia
can
332
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M Konrad et al.: Diagnosis and management of Bartter syndrome
executive summary
potentiate the effects of anesthetic agents, such as neuro-
muscular blockade during general anesthesia and adrena-
line in regional blockade. However, there is no definitive
evidence to suggest safe preoperative plasma potassium
levels. In the general population, guidelines suggest aiming
for potassium levels >3.0 mmol/l (magnesium >0.5 mmol/
l).88
 Work performance may be limited in some patients, e.g.,
owing to muscle weakness or fatigue. Occupational thera-
pists may assist patients in finding support for their indi-
vidual situations.
 Patients may be hesitant to disclose their condition to
employers because they are afraid to lose their job. How-
ever, patients should be encouraged to share information
about the disease, ideally by providing educational material
about BS.
 There is no evidence suggesting that participation in sports
is deleterious. In any case, volume depletion should be
prevented and additional salt or electrolytes, or both, may
help. However, strenuous exercise or competition practice
should be considered carefully, particularly in cases with a
history of cardiac manifestations or prolonged QT interval.
CONCLUSIONS AND PERSPECTIVES
The identification of genes involved in BS with the conse-
quent insights into the molecular pathophysiology is relatively
recent. Therefore, long-term follow-up data from genetically
defined cohorts are limited. This highlights the need for
comprehensive patient registries. As more such data become
available, our knowledge of the natural history, treatment
response, long-term complications, and quality of life will
improve and thus directly influence patient management. We
therefore anticipate that with time, the recommendations
made here will need to be updated and revised.
Pregnancy considerations
 During normal pregnancy, serum potassium levels decrease
by 0.2–0.5 mmol/l around midgestation.9,89
 In pregnant women with BS, timely institution of a joint
management plan involving nephrology and obstetrics as
well as appropriate adaptations in therapy is mandatory.
 During pregnancy, the target level for plasma potassium is
unknown, but a level of 3.0 mmol/l has been suggested with
the explicit acknowledgement that this may not be
achievable in some patients.42
DISCLOSURE
All the authors declared no competing interests.
 In patients with BS, the occurrence of hyperemesis grav-
idarum may be particularly dangerous owing to the sub-
sequent electrolyte disturbances that may necessitate early
parenteral fluid and electrolyte supplementation.
ACKNOWLEDGEMENTS
The authors thank the European Rare Kidney Disease Reference
Network (ERKNet) for launching, organizing, and funding of this
initiative, including travel and housing costs for the core group
members. The funder had no influence on the content of the
consensus. The authors also thank Tanja Wlodkowski, Heidelberg,
Germany, for her continuous support concerning the literature search
and the panel voting procedures.
 Pregnant women with BS should be informed about
increased requirements of electrolyte supplements, that
renin-angiotensin system blockers are contraindicated, and
that NSAIDs are discouraged during pregnancy.
 Monitoring of plasma electrolyte levels is advised during
labor. Therefore, delivery in hospital might be considered to
reduce
risks
of
maternal
complications.
The
overall
outcome for women with BS and their infants described to
date is favorable.90–95
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