Bartter syndrome

A. 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 three main clinical variants, as
follows:

Neonatal (or antenatal) Bartter syndrome

Classic Bartter syndrome

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 identified to date. Such advances may result in the development of new
therapies (see the image below).[1](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 (sodiumpotassium 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 three main anatomic and pathophysiologic disturbances that lead to the salt-losing
tubulopathy. They are as follows (see Etiology, Prognosis, Presentation, and Workup)[2] :

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 gene). Most recently, a mutation in the basolateral calcium sensing receptor was
identified as causing milder symptoms of classic Bartter syndrome. [3]

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 genesCLCNKB and CLCNKA or their beta
subunit BSND.

B. 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
havehypomagnesemia, 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.[4]

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.

C. 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.[5]
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.[6, 7, 8] 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.[7, 9, 10] 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 potassium ion rich
endolymph.[6] 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.[11]
Type IVb Bartter syndrome
Type IVb Bartter syndrome is a recently renamed form. It is associated with sensorineural
deafness but is not caused by mutations in the BSND gene.
Type V Bartter syndrome
Type V Bartter syndrome has been shown to be a digenic disorder resulting from loss-offunction mutations in the genes that encode the chloride channel subunits ClC-Ka and ClCKb.[11] 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).
An etiology of Bartter syndrome that is usually known as autosomal dominant hypocalcemia or
autosomal dominant hypoparathyroidism has been described. This type V Bartter syndrome has a
gain-of-function mutation in the calcium-sensing receptor (CaSR). The CaSR is expressed in the
basolateral membrane of the thick ascending limb of loop of Henle. When this receptor is
activated, rate of potassium efflux from ROMK channel is reduced, leading to reduction of NaK-2Cl cotransporter activity. The lack of luminal positive charge leads to increased level of
calcium and magnesium in the urine. The end result is mild renal sodium, chloride, potassium,
calcium and magnesium wasting.
This form of Bartter syndrome has additional phenotypic presentation of hypocalcemia and
hypomagnesemia.[3, 12]
A summary of currently identified genotype-phenotype correlations in Bartter syndrome is in the
table below.

Table 1. Bartter Syndrome Genotype-Phenotype Correlations

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 IVb CLCNKB and CLCNKA Neonatal with deafness

Bartter type V

CaSR

Classic

D. 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.[13]
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.[14, 15]

E. 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

F. 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.