Bartter Syndrome

Author: Lynda A Frassetto, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN
Background
Bartter syndrome, originally described by Bartter and colleagues in 1962, represents a set of
closely related, autosomal recessive renal tubular disorders characterized by hypokalemia,
hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure. The
underlying renal abnormality results in excessive urinary losses of sodium, chloride, and
potassium. (See Prognosis and Presentation.)
Bartter syndrome has traditionally been classified into 3 main clinical variants: neonatal (or
antenatal) Bartter syndrome, classic Bartter syndrome, and Gitelman syndrome. Advances in
molecular diagnostics have revealed that Bartter syndrome results from mutations in numerous
genes that affect the function of ion channels and transporters that normally mediate
transepithelial salt reabsorption in the distal nephron segments. Hundreds of mutations have been
indentified to date. Such advances may result in the development of new therapies (see the image
below).
[22]
(See Pathophysiology and Etiology.)
Normal transport mechanisms in the thick ascending limb of the loop
of Henle. Reabsorption of sodium chloride is achieved with the sodium chloride/potassium chloride
cotransporter, which is driven by the low intracellular concentrations of sodium, chloride, and
potassium. Low concentrations are maintained by the basolateral sodium pump (sodium-potassium
adenosine triphosphatase), the basolateral chloride channel (ClC-kb), and the apical potassium channel
(ROMK).
A modern, and more clinically relevant, classification of Bartter syndrome takes into account the
3 main anatomic and pathophysiologic disturbances that lead to the salt-losing tubulopathy. They
are as follows (see Etiology, Prognosis, Presentation, and Workup)
[28]
:
Classic Bartter syndrome and Gitelman syndrome - The first type involves the thick ascending
limb of the loop of Henle (TALH) or distal convoluted tubule (DCT) dysfunction that leads to
hypokalemia; this condition takes the form of either classic Bartter syndrome (caused by
mutations in the CLCNKB gene) or Gitelman syndrome (caused by mutations in the NCCT r atal
(or antenatal)r this is sensorineural deafness - e-betahydoxysteroid dehydrogenase, which leads
to elevated endogenous mgene)
Neonatal (or antenatal) Bartter syndrome - The second type involves polyuric loop dysfunction
that is more severe; this form of Bartter syndrome is characterized by defects in the NKCC2 and
ROMK genes
Neonatal (or antenatal) Bartter syndrome with sensorineural deafness - The third type involves
the most severe combined loop and distal convoluted tubule dysfunction; it is caused by defects
in the chloride channel genes CLCNKB and CLCNKA or their beta subunit BSND.
Pathophysiology
Bartter and Gitelman syndromes are renal tubular salt-wasting disorders in which the kidneys
cannot reabsorb chloride in the TALH or the DCT, depending on the mutation.
Chloride is passively absorbed along most of the proximal tubule but is actively transported in
the TALH and the distal convoluted tubule (DCT). Failure to reabsorb chloride results in a
failure to reabsorb sodium and leads to excessive sodium and chloride (salt) delivery to the distal
tubules, leading to excessive salt and water loss from the body.
Other pathophysiologic abnormalities result from excessive salt and water loss. The renin-
angiotensin-aldosterone system (RAAS) is a feedback system activated with volume depletion.
Long-term stimulation may lead to hyperplasia of the juxtaglomerular complex.
Angiotensin II (ANG II) is directly vasoconstrictive, increasing systemic and renal arteriolar
constriction, which helps to prevent systemic hypotension. It directly increases proximal tubular
sodium reabsorption.
ANG IIinduced renal vasoconstriction, along with potassium deficiency, produces a
counterregulatory rise in vasodilating prostaglandin E (PGE) levels. High PGE levels are
associated with growth inhibition in children.
High levels of aldosterone also enhance potassium and hydrogen exchange for sodium.
Excessive intracellular hydrogen ion accumulation is associated with hypokalemia and
intracellular renal tubule potassium depletion. This is because hydrogen is exchanged for
potassium to maintain electrical neutrality. It may lead to intracellular citrate depletion, because
the alkali salt is used to buffer the intracellular acid and then lowers urinary citrate excretion.
Hypocitraturia is an independent risk factor for renal stone formation.
Excessive distal sodium delivery increases distal tubular sodium reabsorption and exchange with
the electrically equivalent potassium or hydrogen ion. This, in turn, promotes hypokalemia,
while lack of chloride reabsorption promotes inadequate exchange of bicarbonate for chloride,
and the combined hypokalemia and excessive bicarbonate retention lead to metabolic alkalosis.
Persons with Bartter syndrome often have hypercalciuria. Normally, reabsorption of the negative
chloride ions promotes a lumen-positive voltage, driving paracellular positive calcium and
magnesium absorption. Continued reabsorption and secretion of the positive potassium ions into
the lumen of the TALH also promotes reabsorption of the positive calcium ions through
paracellular tight junctions. Dysfunction of the TALH chloride transporters prevents urine
calcium reabsorption in the TALH. Excessive urine calcium excretion may be one factor in the
nephrocalcinosis observed in these patients.
Calcium is usually reabsorbed in the DCT. Theoretically, chloride is reabsorbed through the
thiazide-sensitive sodium chloride cotransporter and transported from the cell through a
basolateral chloride channel, reducing intracellular chloride concentration. The net effect is
increased activity of the voltage-dependent calcium channels and enhanced electrical gradient for
calcium reabsorption from the lumen.
In Gitelman syndrome, dysfunction of the sodium chloride cotransporter (NCCT) leads to
hypocalciuria and hypomagnesemia. In the last several years, the understanding of magnesium
handling by the kidney has improved and advances in genetics have allowed the differentiation
of a variety of magnesium-handling mutations.
While patients the variants that make up Bartter syndrome may or may not have
hypomagnesemia, this condition is pathognomonic for Gitelman syndrome. The mechanism of
the impaired magnesium reabsorption is still unknown; studies in NCCT knockout mice
demonstrate increased apoptosis of DCT cells, which would then lead to diminished reabsorptive
surface area.
[13]

Sensorineural deafness
The ClC-Kb channel is found in the basolateral membrane of the TALH, while the barttin
subunits of ClC-Ka and ClC-Kb are found in the basolateral membrane of the marginal cells of
the cochlear stria vascularis.
In the inner ear, an Na-K-2Cl pump, called NKCC1, on the basolateral membrane increases
intracellular levels of sodium, potassium, and chloride. Potassium excretion across the apical
membrane against a concentration gradient produces the driving force for the depolarizing influx
of potassium through the ion channels of the sensory hair cells required for hearing. The sodium
ion is excreted across the basolateral membrane by the Na-K-adenosine triphosphatase (ATPase)
pump, and the ClC-K channels allow the chloride ion to exit to maintain electroneutrality.
Sensorineural deafness associated with type IV Bartter syndrome, a neonatal form of the disease
(see Etiology), is due to defects in the barttin subunit of the ClC-Ka and CIC-Kb channels.
Mutations in only the ClC-Kb subunit, as occurs in type III Bartter syndrome, do not result in
sensorineural deafness.
Etiology
Defects in either the sodium chloride/potassium chloride cotransporter or the potassium channel
affect the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of
Henle (TALH). The result is the delivery of large volumes of urine with a high content of these
ions to the distal segments of the renal tubule, where only some sodium is reabsorbed and
potassium is secreted.
Familial and sporadic forms of Bartter and Gitelman syndromes exist. When inherited, these
syndromes are passed on as autosomal recessive conditions.
Neonatal (type I and type II) Bartter syndrome
An autosomal recessive mode of inheritance is observed in some patients with neonatal Bartter
syndrome, although many cases are sporadic.
At least 2 genotypes have been identified in neonatal Bartter syndrome. Type I results from
mutations in the sodium chloride/potassium chloride cotransporter gene (NKCC2; locus
SLC12A1 on chromosome bands 15q15-21). (See the first image below.) Type II results from
mutations in the ROMK gene (locus KCNJ1 on chromosome bands 11q24-25). (See the second
image below.)
Type I neonatal Bartter syndrome. Mutations in the sodium
chloride/potassium chloride cotransporter gene result in defective reabsorption of sodium, chloride,
and potassium. Type II neonatal Bartter syndrome. Mutations in the
ROMK gene result in an inability to recycle potassium from the cell back into the tubular lumen, with
resultant inhibition of the sodium chloride/potassium chloride cotransporter.
Classic (type III) Bartter syndrome
Some patients have an autosomal recessive mode of inheritance in classic Bartter syndrome,
although many cases are sporadic.
In classic Bartter syndrome, the defect in sodium reabsorption appears to result from mutations
in the chloride-channel gene (on band 1p36). The consequent inability of chloride to exit the cell
inhibits the sodium chloride/potassium chloride cotransporter. (See the image below.)
Classic Bartter syndrome. Mutations in the ClC-kb chloride channel
lead to an inability of chloride to exit the cell, with resultant inhibition of the sodium chloride/potassium
chloride cotransporter.
Increased delivery of sodium chloride to the distal sites of the nephron leads to salt wasting,
polyuria, volume contraction, and stimulation of the renin-angiotensin-aldosterone axis. These
effects, combined with biologic adaptations of downstream tubular segments, specifically the
distal convoluted tubule (DCT) and the collecting duct, result in hypokalemic metabolic
alkalosis.
[2]

The hypokalemia, volume contraction, and elevated angiotensin levels increase intrarenal
prostaglandin E2 (PGE2) synthesis, which contributes to a vicious cycle by further stimulating
the renin-aldosterone axis and inhibiting sodium chloride reabsorption in the TALH.
Type IV Bartter syndrome
Studies have identified a novel type IV Bartter syndrome.
[10, 23, 24]
This is a type of neonatal
Bartter syndrome associated with sensorineural deafness and has been shown to be caused by
mutations in the BSND gene.
[23, 25, 26]
BSND encodes barttin, an essential beta subunit that is
required for the trafficking of the chloride channel ClC-K (ClC-Ka and ClC-Kb) to the plasma
membrane in the TALH and the marginal cells in the scala media of the inner ear that secrete
po
[10]
Thus, loss-of-function mutations in barttin cause Bartter
syndrome with sensorineural deafness.
In contrast to other Bartter types, the underlying genetic defect in type IV is not directly in an
ion-transporting protein. The defect instead indirectly interferes with the barttin-dependent
insertion in the plasma membrane of chloride channel subunits ClC-Ka and ClC-Kb.
Type V Bartter syndrome
Other observations have identified type V Bartter syndrome. This is another type of neonatal
Bartter syndrome that is associated with sensorineural deafness, but it is not caused by mutations
in the BSND gene. Type V Bartter syndrome has been shown to be a digenic disorder resulting
from loss-of-function mutations in the genes that encode the chloride channel subunits ClC-Ka
and ClC-Kb.
[27]
The specific genetic defect includes a large deletion in the gene that encodes
ClC-Kb (ie, CLCNKB) and a point mutation in the gene that encodes ClC-Ka (CLCNKA).
A summary of currently identified genotype-phenotype correlations in Bartter syndrome is in the
table below. For completion, the genetic defect found in Gitelman syndrome (the thiazide-
sensitive sodium chloride cotransporter, encoded by the gene NCCT) is also included.
Table 1. Bartter Syndrome Genotype-Phenotype Correlations (Open Table in a new window)
Bartter Syndrome Genotype-Phenotype Correlations
Genetic Type Defective Gene Clinical Type
Bartter type I NKCC2 Neonatal
Bartter type II ROMK Neonatal
Bartter type III CLCNKB Classic
Bartter type IV BSND Neonatal with deafness
Bartter type V CLCNKB and CLCNKA Neonatal with deafness
Gitelman syndrome NCCT Gitelman syndrome
Epidemiology
International occurrence
Bartter syndrome is rare, and estimates of its occurrence vary from country to country. In the
United States, the precise incidence is unknown.
In Costa Rica, the frequency of neonatal Bartter syndrome is approximately 1.2 cases per
100,000 live births but is higher if all preterm births are considered. No evidence of
consanguinity was found in the Costa Rican cohort.
In Kuwait, the prevalence of consanguineous marriages or related families in patients with
Bartter syndrome is higher than 50%, and prevalence in the general population is 1.7 cases per
100,000 persons.
In Sweden, the frequency has been calculated as 1.2 cases per 1 million persons. Of the 28
patients Rudin reported, 7 came from 3 families; the others were unrelated.
[14]

Age-related demographics
Neonatal Bartter syndrome can be suspected before birth or can be diagnosed immediately after
birth. In the classic form, symptoms begin in neonates or in infants aged 2 years or younger.
Gitelman syndrome is often not diagnosed until adolescence or early adulthood.
[15, 16]

Prognosis
Bartter and Gitelman syndromes are autosomal recessive disorders, and neither is curable. The
degree of disability depends on the severity of the receptor dysfunction, but the prognosis in
many cases is good, with patients able to lead fairly normal lives.
The effects of prostaglandin synthetase inhibition include an increase in the plasma potassium
concentration (however, this rarely exceeds 3.5 mEq/L), a decrease in the magnitude of polyuria,
and improved general well-being.
With treatment, plasma renin and aldosterone levels normalize. Therapy improves the patient's
clinical condition and allows catch-up growth.
Bone age is usually appropriate for chronological age, and pubertal and intellectual development
are normal with treatment.
The effectiveness of long-term use of prostaglandin synthetase inhibitors is well established.
Some patients may experience a recurrence of hypokalemia, which can be managed by adjusting
the indomethacin dose or with potassium supplementation. The disease does not recur in the
patient with a transplanted kidney.
Morbidity and mortality
Significant morbidity and mortality occur if Bartter syndrome is untreated. With treatment, the
outlook is markedly improved; however, long-term prognosis remains guarded because of the
slow progression to chronic renal failure due to interstitial fibrosis.
Sensorineural deafness
Sensorineural deafness associated with Bartter syndrome IV is due to defects in the barttin
subunit of the ClC-Ka and CIC-Kb channels.
Nephrocalcinosis
A review of 61 cases of Bartter syndrome reported 29 with nephrocalcinosis, a condition that is
often associated with hypercalciuria.
Renal failure
Renal failure is fairly uncommon in Bartter syndrome. In a review of 63 patients, 5 developed
progressive renal disease requiring dialysis or transplantation.
In 2 reports of patients who underwent biopsies before developing end-stage renal disease
(ESRD), 1 patient had interstitial nephritis, and the other had mesangial and interstitial fibrosis.
One report relates the case of a patient developing reversible acute renal failure from
rhabdomyolysis due to hypokalemia.
Short stature/growth retardation
Nearly all patients with Bartter syndrome have growth retardation. In a review of 66 patients, 62
had growth retardation, often severe (below the fifth percentile for age). Treatment with
potassium, indomethacin, and growth hormone (GH) has been effective.
Additional complications
Other complications in Bartter syndrome include the following:
Cardiac arrhythmia and sudden death - May result from electrolyte imbalances
Failure to thrive and developmental delay - Common in untreated patients
Significant decrease in bone mineral density - Has been documented in patients with either the
neonatal or classic form
Patient Education
Patients and their parents must understand that no cure exists for the constellation of mutations
that causes the various forms of Bartter syndrome. This chronic condition requires taking
medications consistently, as prescribed, which is often difficult for children and adolescents.
Patients should be aware of potential adverse effects of medical therapy, especially
gastrointestinal (GI) irritation and bleeding.
Patients tend to become volume depleted if they are sodium and water restricted. Adequate fluid
and electrolyte replacement should be available, especially in hot weather and during exercise.
Patients should avoid strenuous exercise because of the danger of dehydration and functional
cardiac abnormalities secondary to potassium imbalance.
With regard to diet, patients should be educated about which foods have high potassium content.
Bartter and Gitelman syndromes are autosomal recessive disorders; ie, mutations are required on
each allele in the chromosome pair. Offspring carry at least 1 mutated allele. In consanguineous
marriages or in marriages between closely related families, genetic counseling may be advisable.
For patient education information, see Growth Hormone Deficiency, Growth Failure in Children,
Growth Hormone Deficiency in Children, and Growth Hormone Deficiency FAQs.
Proceed to Clinical Presentation

History
Neonatal Bartter syndrome
Maternal polyhydramnios, secondary to fetal polyuria, is evident by 24-30 weeks' gestation.
Delivery often occurs before term. The newborn has massive polyuria (rate as high as 12-50
mL/kg/h).
The subsequent course is characterized by life-threatening episodes of fluid loss, clinical volume
depletion, and failure to thrive. Volume depletion increases thirst, and the normal response is to
increase fluid intake.
A subset of patients with neonatal Bartter syndrome (types IV and V) develop sensorineural
deafness.
Classic Bartter syndrome
Patients have a history of maternal polyhydramnios and premature delivery. Symptoms include
the following:
Polyuria
Polydipsia
Vomiting
Constipation
Salt craving
Tendency for volume depletion
Failure to thrive
Linear growth retardation
Other symptoms, which appear during late childhood, include fatigue, muscle weakness, cramps,
and recurrent carpopedal spasms.
Developmental delay and minimal brain dysfunction with nonspecific electroencephalographic
changes are also present.
Physical Examination
Neonatal Bartter syndrome
Patients are thin and have reduced muscle mass and a triangularly shaped face, which is
characterized by a prominent forehead, large eyes, protruding ears, and drooping mouth.
Strabismus is frequently present. Blood pressure is within the reference range.
A subset of patients with Bartter syndrome (types IV and V) develop sensorineural deafness,
which is detectable with audiometry.
Classic Bartter syndrome
The patient's facial appearance may be similar to that encountered in the neonatal type. However,
this finding is infrequent.
Proceed to Differential Diagnoses

Diagnostic Considerations
Patients with Gitelman syndrome tend to have milder symptoms than do those with Bartter
syndrome and to present in adolescence and early adulthood. Often, patients have minimal
symptomatology and lead relatively normal lives.
[14]

Consider possible renal tubular disorder if patients, especially dehydrated infants and young
children, are found to have hypokalemia and a high serum bicarbonate concentration that do not
correct with potassium and chloride replacement treatment.
Conditions to consider in the differential diagnosis of Bartter syndrome include the following:
Diuretic abuse
Gitelman syndrome
Hyperprostaglandin E syndrome
Familial hypomagnesemia with hypercalciuria/nephrocalcinosis
Activating mutations of the CaSR calcium-sensing receptor
Cyclical vomiting
Congenital chloride diarrhea
Gullner syndrome - Familial hypokalemic alkalosis with proximal tubulopathy
Mineralocorticoid excess
Pyloric stenosis
Hypomagnesemia
Cystic fibrosis
Hypochloremic alkalosis
Hypokalemia
Proceed to Workup

Approach Considerations
The severity and site of the mutation determines the age at which symptoms first develop.
Completely dysfunctional mutations in the receptors and ion channels in the thick ascending
limb of the loop of Henle (TALH) are probably not compatible with life.
Most cases of Bartter syndrome are discovered in infancy or early adolescence. Bartter syndrome
can also be diagnosed prenatally, when the fetus develops polyhydramnios and intrauterine
growth retardation. Many of the neonates are born prematurely. Children diagnosed early in life
usually have more severe electrolyte disorders and symptoms. Because of Bartter syndrome's
heterogeneity, patients with minimal symptomatology may be discovered relatively late.
Electrocardiography
An electrocardiogram (ECG) may reveal changes characteristic of hypokalemia, such as
flattened T waves and prominent U waves.
Histologic findings
Although renal biopsy is not usually required, histologic findings may be useful in confirming
the diagnosis of Bartter syndrome.
In neonatal and classic Bartter syndrome, the cardinal finding is hyperplasia of the
juxtaglomerular apparatus. Less frequently, hyperplasia of the medullary interstitial cells is
present.
Glomerular hyalinization, apical vacuolization of the proximal tubular cells, tubular atrophy, and
interstitial fibrosis may be present as a consequence of chronic hypokalemia.
Inpatient care
For patients initially diagnosed in the hospital, the goal is to stabilize the patient sufficiently for
discharge. This includes stabilization of potassium and other electrolytes, as well as volume and,
perhaps, acid-base parameters.
Consultations
Contact a nephrologist or pediatric nephrologist whenever a patient fitting the clinical picture of
Bartter or Gitelman syndrome is identified. The specialist can assist with the initial diagnosis and
carry out periodic outpatient evaluation of growth, development, renal function, serum
electrolytes, and response to therapy.
Monitoring
Patients initially need frequent outpatient follow-up care until the metabolic abnormalities
caused by the renal tubular transporter mutation are stabilized with medications. The length of
time to stability depends on the severity of the mutation and the degree of patient compliance.
Laboratory Studies
Potassium
Initiate timed urine collection to determine potassium levels. In hypokalemia, normal kidneys
retain potassium.
[18]
Elevated urinary potassium levels with low blood potassium levels suggest
that the kidneys are having problems retaining potassium.
Aldosterone
Next, initiate timed urine collection to determine aldosterone levels. Aldosterone levels should
be high in volume-replete patients. If urinary aldosterone levels are high despite volume
replacement, there is an abnormal stimulation of aldosterone.
Patients with primary hyperaldosteronism in a volume-replete state usually have normal to high
blood pressure. Low or low-normal blood pressure with high aldosterone excretion suggests that
the primary problem is something else and that the aldosterone response is secondary to the
undiagnosed primary abnormality.
Chloride
Next, initiate a timed urine collection to determine chloride levels. Extrarenal volume depletion
is a possible reason for low blood pressure, high aldosterone excretion, and potassium loss. In
this case, the kidneys retain sodium and chloride, and urinary chloride concentrations should be
low.
High urine chloride levels with low blood pressure, high aldosterone secretion, and high urinary
potassium levels are found only with long-term diuretic use and Bartter or Gitelman syndrome. If
diuretic abuse is suspected, a urine screen for diuretics can be ordered. Otherwise, the diagnosis
is Bartter or Gitelman syndrome.
Calcium/magnesium
Patients with Bartter syndrome have high urinary excretion of calcium and normal urinary
excretion of magnesium.
In patients with Gitelman syndrome, the opposite is true, with tests showing low urinary
excretion of calcium and high urinary excretion of magnesium.
Hyperuricemia
Hyperuricemia is present in 50% of patients with Bartter syndrome, whereas in Gullner
syndrome, hypouricemia, secondary to impaired proximal tubular function, is present.
Complete blood count
Polycythemia may be present from hemoconcentration.
Mutations
Mutations in the different transporters cause Bartter syndrome. The older methods of
determining the presence of mutations require more detailed physiologic investigations,
including determination of serum magnesium levels and further urine collections to assess
calcium, magnesium, and PGE2 levels.
In Bartter syndrome, urine calcium excretion is high, leading to nephrocalcinosis, while serum
magnesium levels are normal.
With the transporter mutations that cause Gitelman syndrome, hypomagnesemia is common and
is accompanied by hypocalciuria.
Genetic analysis has become the preferred methodology for determining if a mutation in one of
the transporters has occurred. An analysis of the genes for the transporters shows multiple
problems leading to abnormal gene function, including missense, frame-shift, loss-of-function,
and large deletion mutations. (Not all mutations lead to a marked loss of function.)
[3, 4, 5, 6, 19, 20]

Amniotic fluid
If the diagnosis is being made prenatally, assess the amniotic fluid. The chloride content may be
elevated in either Gitelman or Bartter syndrome.
Glomerular filtration rate
The glomerular filtration rate (GFR) is preserved during the early stages of the disease; however,
it may decrease as a result of chronic hypokalemia. One study, however, hypothesizes that GFR
is affected more by secondary hyperaldosteronism than by hypokalemia.
[29]

Imaging Studies
Neonatal Bartter syndrome can be diagnosed best prenatally by ultrasonography. The fetus may
have polyhydramnios and intrauterine growth retardation. Amniotic chloride levels may be
elevated.
[21]

After birth, especially if the disease is diagnosed in older patients who have hypercalciuria,
consider a renal ultrasonogram or flat plate of the abdomen for nephrocalcinosis. Sonographic
findings include diffusely increased echogenicity, hyperechoic pyramids, and interstitial calcium
deposition.
Because continued calcium loss may affect bones, dual-energy radiographic absorptiometry
scans to determine bone mineral density may be advisable in older patients.
Nephrocalcinosis can occur and is often associated with hypercalciuria. It can be diagnosed with
abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral
computed tomography (CT) scans.
Proceed to Treatment & Management

Approach Considerations
Since first described in 1962, several types of medical treatment have been used, including the
following:
Sodium and potassium supplements - Used for the electrolyte imbalances
Aldosterone antagonists and diuretic spironolactone - Are mainstays of therapy
Angiotensin-converting enzyme (ACE) inhibitors - Used to counteract the effects of angiotensin II
(ANG II) and aldosterone
Indomethacin - Used to decrease prostaglandin excretion
Growth hormone (GH) - Used to treat short stature
Calcium or magnesium supplements - May occasionally be needed if tetany or muscle spasms
are present
Pregnancy-related considerations
Reports associated with Bartter syndrome in pregnant women are limited because Bartter
syndrome is a rare disease. Complications related to electrolyte loss (eg, hypokalemia,
hypomagnesemia) responded well to supplementation. Fetuses were unaffected and carried to
term.
In Rudin's report of 28 pregnant patients, no problems were noted except asymptomatic
hypokalemia.
[14]
In another study, of 40 patients, 30 reported normal pregnancies and terminated
by normal parturition; however, many of the patients who were pregnant probably had Gitelman
syndrome.
Renal Transplantation
Bartter and Gitelman syndromes, by themselves, do not lead to chronic renal insufficiency;
however, in patients with these syndromes who develop end-stage renal disease (ESRD) for
other reasons, transplants from living relatives are an option and result in normal urinary
handling of sodium, potassium, calcium, and magnesium.
Reports of renal transplants from living relatives in ESRD patients with Bartter syndrome
suggest that many endocrinologic abnormalities in Bartter syndrome improve or normalize after
transplantation.
Because the genetic abnormality in Bartter syndrome may be found only in the kidneys (which is
certain in Na-K-Cl cotransporter but may not be the case for some of the other mutations),
transplantation corrects the problem by replacing unhealthy kidneys with normal ones.
Donors
Bartter syndrome is an autosomal recessive disorder. Both parents carry at least 1 gene for the
disorder. Statistically, only 1 of 4 siblings will be completely healthy. Whether carrying 1 gene
for this abnormality leads to long-term problems late in life if 1 kidney is removed is unknown.
Transplants from living, unrelated persons or cadavers are options for patients with ESRD.
Preemptive Surgery
One approach to the management of severe Bartter syndrome involves preemptive nephrectomy
and renal transplantation.
[30]
The rationale for this approach lies in the fact that Bartter syndrome
is an incurable genetic disease, and the poorly controlled forms may result in frequent life-
threatening episodes of dehydration and electrolyte imbalances. Preemptive bilateral
nephrectomies and successful kidney transplantation prior to the onset of ESRD has resulted in
correction of metabolic abnormalities and excellent graft function.
Special Surgical Concerns
Electrolytes
Special attention should be paid to correcting electrolyte abnormalities when patients with
Bartter syndrome undergo surgical procedures.
Anesthesia
The multiple biochemical abnormalities that occur in patients with Bartter syndrome may present
a challenge to anesthesiologists when general anesthesia is used. Potential problems include
difficulties in fluid and electrolyte management, acid-base abnormalities, and a decreased
response to vasopressors.
Renal function must be monitored carefully, and dose adjustments must be made for drugs
dependent on renal excretion if renal function declines. Moreover, metabolic alkalosis has been
reported to alter drug protein binding for some anesthetic agents.
Patients with Bartter syndrome may also have platelet dysfunction if routinely treated with
nonsteroidal anti-inflammatory agents.
Diet and Activity
Diet
Adequate salt and water intake is necessary to prevent hypovolemia, and adequate potassium
intake is essential to replace urinary potassium losses. Patients should consume foods and drinks
that contain high levels of potassium (eg, tomatoes, bananas, orange juice).
With growth retardation, adequate overall nutritional balance (protein-calorie intake) is
important. Whether other dietary supplements (eg, citrate, magnesium, vitamins) are helpful is
not clear.
Activity
No restriction on general activity is required, but precautions against dehydration should be
taken. Patients should avoid strenuous exercise avoided because of the danger of dehydration and
functional cardiac abnormalities secondary to potassium imbalance.
Proceed to Medication

Medication Summary
Salt and water depletion due to an inability to conserve sodium in the thick ascending limb of the
loop of Henle (TALH) or the distal convoluted tubule (DCT) leads to activation of the renin-
angiotensin-aldosterone system (RAAS) and high aldosterone levels. This helps the kidneys
retain sodium distal to the site of the mutation, but at the expense of losing potassium.
Aldosterone inhibitors and angiotensin-converting enzyme (ACE) inhibitors help to block the
RAAS and to prevent potassium loss in the distal tubules. The body conserves potassium, and
less oral potassium supplementation is needed.
Short stature and growth failure are common in Bartter syndrome. Exogenous growth hormone
(GH) increases the growth rate and helps patients with GH deficiency attain normal height.
Although not well studied, at least 1 report describes a patient with low GH levels and Gitelman
syndrome who was below the third percentile for height and whose growth rate improved 4-fold
during GH treatment. Dose depends on brand used. Somatropin (up to 0.3 mg/kg weekly SC) and
somatropin (rDNA origin, 0.1 mg/kg daily SC) have been used.
Potassium Supplements
Class Summary
These are used to treat hypokalemia associated with Bartter syndrome. Correction of
hypokalemia is the most important goal of medical therapy.
View full drug information
Potassium chloride (K-Dur, Klor-Con, Micro K)

Dosage depends on the degree of receptor dysfunction and hypokalemia. Serum potassium levels
often run in the range of 2-3 mEq/L, which may require several hundred milliequivalents of
potassium per day.
Potassium can be administered in various formulations, but chloride salt is recommended
because of coexisting chloride deficiencies in patients with Bartter syndrome. Potassium is
essential for the transmission of nerve impulses, the contraction of cardiac muscle, the
maintenance of intracellular tonicity, skeletal and smooth muscles, and the maintenance of
normal renal function.
Diuretics, Potassium-Sparing
Class Summary
These medications enhance the effect of potassium supplementation by decreasing urinary
potassium losses.
View full drug information
Spironolactone (Aldactone)

Spironolactone is a specific antagonist of aldosterone, primarily by competitively binding to
receptors at the aldosterone-dependent sodium-potassium exchange site in the DCT. This agent
increases water excretion while retaining potassium and hydrogen ions.
View full drug information
Amiloride

Amiloride inhibits sodium reabsorption at the DCT, cortical collecting tubule, and collecting
duct. This decreases the net negative potential of the tubular lumen and reduces potassium and
hydrogen secretion and their subsequent excretion.
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Triamterene (Dyrenium)

Triamterene interferes with potassium/sodium exchange (active transport) in the distal tubule,
cortical collecting tubule, and collecting duct by inhibiting sodium/potassium adenosine
triphosphatase (ATPase). This agent decreases calcium excretion and increases magnesium loss.
ACE Inhibitors
Class Summary
ACE inhibitors block the conversion of angiotensin I (ANG I) to ANG II and prevent the
secretion of aldosterone from the adrenal cortex.
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Captopril

Captopril prevents the conversion of ANG I to ANG II, a potent vasoconstrictor, resulting in
lower aldosterone secretion. It is also helpful in preventing potassium loss.
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Enalapril (Vasotec)

Enalapril is a competitive inhibitor of ACE. It reduces ANG II levels, decreasing aldosterone
secretion.
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Lisinopril (Prinivil, Zestril)

Lisinopril prevents the conversion of ANG I to ANG II, a potent vasoconstrictor, resulting in
lower aldosterone secretion.
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Benazepril (Lotensin)

Benazepril prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor,
resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
When pediatric patients are unable to swallow tablets or the calculated dose does not correspond
with tablet strength, an extemporaneous suspension can be compounded. Combine 300 mg (15
tablets of 20-mg strength) in 75 mL of Ora-Plus suspending vehicle, and shake well for at least 2
minutes. Let the tabs sit and dissolve for at least 1 hour, then shake again for 1 minute. Add 75
mL of Ora-Sweet. The final concentration is 2 mg/mL, with a total volume of 150 mL. The
expiration time is 30 days with refrigeration.
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Fosinopril

Fosinopril is a competitive ACE inhibitor. It prevents conversion of angiotensin I to angiotensin
II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in
aldosterone secretion. It decreases intraglomerular pressure and glomerular protein filtration by
decreasing efferent arteriolar constriction.
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Quinapril (Accupril)

Quinapril is a competitive ACE inhibitor. It reduces angiotensin II levels, decreasing aldosterone
secretion.
NSAIDs
Class Summary
These medications blunt prostaglandin overproduction, which is responsible for the pressor
resistance to ANGII and norepinephrine, hyperreninemia, and increased sympathoadrenal
activity. By inhibiting PGE2 synthesis, these agents also contribute to the correction of the
hemoconcentration defect.
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Indomethacin (Indocin)

Indomethacin is a nonsteroidal drug with anti-inflammatory, antipyretic, and analgesic properties
that are thought to be mediated by its potent prostaglandin inhibitory effect; ensuing
hyporeninemic hypoaldosteronism is thought to be responsible for potassium retention.
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Naproxen (Anaprox, Aleve, Naprosyn, Naprelan)

Naproxen is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and
pain by decreasing the activity of the enzyme cyclo-oxygenase (COX), which results in
prostaglandin synthesis.
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Sulindac (Clinoril)

Sulindac decreases COX activity and, in turn, inhibits prostaglandin synthesis. This results in
decreased formation of inflammatory mediators.
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Meloxicam (Mobic)

Meloxicam decreases COX activity and this, in turn, inhibits prostaglandin synthesis. These
effects decrease the formation of inflammatory mediators.
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Ketoprofen

Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are
indicated initially in small patients, elderly patients, and patients with renal or liver disease.
Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with
caution, and closely observe the patient's response.
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Flurbiprofen

Flurbiprofen may inhibit COX, thereby, in turn, inhibiting prostaglandin biosynthesis. These
effects may result in analgesic, antipyretic, and anti-inflammatory activities.
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Ibuprofen (Motrin, Advil, Ultraprin, Addaprin)

Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.