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The term Bartter syndrome denotes a group of renal diseases which share a
common denominator of hypokalaemia and metabolic alkalosis. The patch
clamp technique has made possible the analysis of single ion channels,
improving our understanding of the molecular physiopathology of all the
Bartterlike syndromes. enetic mapping of each defect has further clari!ed
the mutations involved and the possible modes of inheritance. This improved
understanding has opened new avenues for therapy, improving mortality and
morbidity in these patients. "nother group of illnesses, the pseudoBartter
syndrome, may produce a hypokalaemic metabolic alkalosis without primary
renal disease. The underlying illness needs to be identi!ed and treated.
#revious $ection %e&t $ection
Introduction
'n ()*+, ,rederic Bartter and his colleagues wrote their seminal paper
(
based
on two patients with hypokalaemic metabolic alkalosis, hyperaldosteronism,
normal blood pressure, decreased pressor responsiveness to angiotensin ''
infusion and hyperplasia of the -u&taglomerular apparatus. $ubsequently, a
wide variety of hypokalaemic metabolic alkalotic states, with di.erent clinical
and laboratory !ndings as well as agerelated presentations, have been
reported, leading to confusing variations in nomenclature. Terms such as
Bartterlike syndrome do little to help the clinician identify the speci!c
metabolic defect and treat the patient/s illness correctly. 't may be better to
subclassify Bartter syndrome by renal pathophysiological abnormality. By this
method, Bartter syndrome falls into four subgroups0 1i2 antenatal Bartter
syndrome 1hyperprostaglandin 3+ syndrome24 1ii2 the itleman variety of
Bartter syndrome 1itleman syndrome24 1iii2 classical Bartter syndrome4 and
1iv2 pseudoBartter syndrome. 5e address the clinical and pathological
aspects, and the genetics, of each of the above in detail, hoping to clarify the
path to early diagnosis and appropriate treatment.
#revious $ection %e&t $ection
Antenatal Bartter syndrome (hyperprostaglandin E2 syndrome)
The signs and symptoms of antenatal Bartter $yndrome may be present and
identi!able in utero.
+,6,),((,(7,
,
++
8ne&plained polyhydramnios between +7 and 9*
weeks of gestation is a welldocumented early sign of this syndrome
according to most investigators.
+,(7,
,
6(
"nother important !nding at this stage is
biochemical abnormality of the amniotic :uid, with normal sodium, potassium
and prostaglandin levels, but consistently elevated chloride levels.
+;6
The
infants are usually born prematurely.
+,
,
9<
"fter birth, the most important clinical
!nding is hyposthenuria 1urine of low speci!c gravity2 and rapid weight
loss.
+,
,
6
=ethargy and poor feeding often develop. 'n the !rst week of life,
laboratory investigation shows a metabolic alkalosis associated with
hypokalaemia. The urine has low speci!c gravity with very high sodium,
chloride and calcium levels, while potassium is normal.
+
>owever, after (;9
weeks, the level of potassium in the urine rises to considerably above normal,
with relatively less sodium than in the !rst week of life.
+
#rostaglandin levels
are high, both in blood and in urine.
+,?;(<
>yperprostaglandin 3+ is a secondary
phenomenon due to :uid and electrolyte loss, and will be suppressed by
appropriate :uid and electrolyte replacement over a period of
time.
+
Therefore, calling this entity hyperprostaglandin 3+ syndrome
?
rather
than antenatal Bartter syndrome seems inappropriate, since the
hyperprostaglandism is secondary to the basic pathology.
+,
,
+9
=evels of renin
and aldosterone are also very high, and important in establishing the
diagnosis.
+,
(<;(+
8ntreated infants will fail to thrive, and may die in a few days
as a result of dehydration, poor feeding and@or severe electrolyte disturbance.
Aild mental retardation has been observed in some children with this disease4
however, we have not encountered such retardation in our infant patients who
were diagnosed and treated early, and the putative brain insult may therefore
be linked to delay in diagnosis and treatment. There are also reports of special
facial features, such as a triangular face characteriBed by prominent forehead,
large eyes, protruding ears and drooping mouth.
(*,(C,
,
9(
$trabismus may also be
present.
(C
There are now reports of sensorineural deafness in a Bedouin
family
(*
and also in one from Dosta Eica.
(C
#revious $ection %e&t $ection
Pathophysiology of antenatal Bartter syndrome
The pathophysiology of antenatal Bartter syndrome can only be e&plained if
one !rst looks at the renal handling of sodium, potassium and chloride at the
nephron level. ,iltration of electrolytes in the glomeruli is complete0 the
concentration of %a
F
, G
F
, Dl
H
, >DI9
H
, Da
+F
1ioniBed calcium comprising *<J of
total serum Da2 and other electrolytes in the Bowman/s capsule is the same as
in whole blood.
(?,
,
()
"t the level of the pro&imal tubule, *CJ of !ltered %a
F
and
G
F
is reabsorbed, while at the level of the thick ascending limb of loop of
>enle, +<J of !ltered %a
F
and G
F
is reabsorbed. Eeabsorption of Dl
H
in this
segment is closely related to that of G
F
and %a
F
. The pro&imal tubule and thick
ascending limb of loop of >enle reabsorb )<J of !ltered Da
+F
. Eeabsorption of
Da
+F
is a passive process and is coupled to %a
F
reabsorption. "ny defect in the
normal function of the thick ascending loop of >enle is relevant to %a
F
, G
F
, and
Dl
H
, and will impair their absorption. This will have a secondary e.ect on the
osmolality of the peritubular space and subsequently reduce the movement of
water from the descending limb of the loop of >enle in the direction of the
tubular space to the interstitium. The !nal result of such a phenomena is the
:ooding of the distal tubule with diluted urine with a high content of %a
F
, G
F
,
Dl
H
and Da
+F
.
'n the thick ascending loop of >enle, %a
F
G
F
+D'
H
1site (, ,igure(2 in the form
of an electroneutral cotransport passes through the apical membrane of the
tubule into the tubular cell.
();+(
"t the basolateral cell membrane are the %a
F
G
F
pumps which, when active, pump sodium out of the cell into the
interstitium and then the blood, and potassium from the interstitium into the
cell.
+C;+)
The function of these pumps is an active process using "T#, and they
are thus called %a
F
G
F
"T#ase pumps 1site 9, ,igure(2. 'ntracellular G
F
needs
to move out of the cell to the blood as well as into the luminar space.
Aovement of potassium into the luminar space is of the utmost importance
for the process of reabsorption of +<J of the !ltered %a 1(7<meq@l2 which
takes place in this segment of the loop of >enle. 3ach molecule of
%a
F
requires one molecule of G
F
in the electroneutral passage through the
luminal membrane in the form of %a
F
G
F
+D'
H
. Inly +<J of !ltered G
F
16
meq@(2 is reabsorbed in the thick ascending loop of >enle. This will not
provide the necessary G
F
ions
7,+6,
,
+*
for reabsorption of sodium. The passage and
movement of G
F
ions takes place through channels known as G
F
channels 1site
+, ,igure(2 or EIAG 1rat outer medulla G
F
channel2. Their opening and closure
are under the control of the Da
+F
content of the cell and its "T# level. 5hen
the %a
F
G
F
"T#ase pump 1site 9, ,igure(2 becomes active, cell "T# falls, and
this opens the potassium channels, facilitating movement of G
F
from the
intracellular space to the lumen as well as into the interstitium. Aovement of
G
F
from the intracellular space into the intraluminal space provides the
potassium molecules necessary for %a
F
G
F
+D'
H
cotransport and subsequent
absorption of %a
F
and Dl
H
from the luminal space of the thick ascending loop
of >enle. Thus recirculation of G
F
through the potassium channels facilitates
electroneutral movement of %a
F
G
F
+D'
H
through the apical cell membrane.
#ositive potential of the lumen also acts as a driving force for the passage of
G
F
and %a
F
through the paracellular pathways 1intercellular spaces2 into the
blood 1site *, ,igure(2. Dalcium and magnesium also pass through these
paracellular spaces 1site *, ,igure(2. #assage of Dl
H
from the cell into the
interstitium can take place through kidneyspeci!c chloride channels 1D'DGb2
1site 6, ,igure(2, and via G
F
@Dl
H
cotransport system 1site 7, ,igure(2. 'n the
apical membrane, there is also an e&change of %a
F
@>
F
. This is summariBed
schematically in ,igure(.
Thus the handling of chloride ions by the thick ascending loop of >enle is an
intimate part of the normal function of %a
F
G
F
+D'
H
electroneutral cotransport,
as well as G
F
channels 1EIAG2 and Dl
H
channels 1D'DGb2. 'n other words,
defects in Dl
H
transport may result from any loss or altered function of %a
F
G
F
+D'
H
cotransporter and@or G
F
channels, as well as chloride channels. >owever,
no defect in chloride channels has been identi!ed which relates to the
pathogenesis of antenatal Bartter syndrome. The longterm use of loop
diuretics such as frusemide produces electrolyte blood and urine changes
resembling those of antenatal Bartter syndrome,
99,97,9?,
,
7*
and this is an e&le
of altered function. =oss of function can result from mutations in any of the
genes encoding either the %a
F
G
F
+Dl
H
cotransporter or G
F
channels. The locus
of the gene responsible for %a
F
G
F
+D'
H
cotransport 1NKCC22 in apical cell
membranes 1site (, ,igure(2 has been identi!ed by $imon et al. in ())* on
chromosome (6q(6+(.
9C
$i& independent mutations were identi!ed in their
patients with antenatal Bartter syndrome.
enetic study of another group of patients with antenatal Bartter syndrome
with a normal gene for %a
F
G
F
+D'
H
cotransport revealed a mutation in the
gene involving G
F
channels.
9);7(
The locus of the gene responsible for these
inwardly rectifying G
F
channels 1ROMK2 1site +, ,igure(2 was identi!ed in
chromosome ((q+7+6.
7<,
,
7(
>ere again eleven independent mutations were
mapped, indicating genetic heterogenicity.
9)
$tudy of familial cases of
antenatal Bartter syndrome revealed a de!nite autosomal recessive pattern.
Lefects in either %a
F
G
F
+D'
H
cotransport or G
F
channels will result in
malreabsorption of %a
F
, G
F
, Dl
H
, and Da
+F
in the thick ascending limb of loop of
>enle primarily, with subsequent reabsorption of >+I in the descending loop
of >enle. The result of such a defect will be the delivery of large volumes of
urine with a high content of %a
F
, G
F
, Dl
H
and Da
+F
to the distal tubule. 'n the
distal tubule, part of the delivered %a
F
will be reabsorbed in e&change for
intracellular G
F
. By this action, partial but incomplete concentration of the
intraluminal :uid will be accomplished, while more potassium wasting
becomes evident. >owever, this impaired sodium absorption in the thick
ascending limp of loop of >enle will result in increased levels of prostaglandin
3+.
9?,?),
,
)(
This interrelation has been documented in normal individuals using
loop diuretics.
9?
'ncreased prostaglandin 3+ levels will e&acerbate the primary
defect of chloride transport in the thick ascending loop of >enle which will0 1i2
stimulate the reninangiotensinaldosterone a&is causing hypokalemia due to
increased aldosterone activity4 1ii2 impede EIAG channel activity and hence
decrease %aDl transport4 and 1iii2 impede >+I reabsorption in the collecting
ducts due to a secondary e.ect on vasopressin activity, resulting in
hyposthenuria.
Molume contraction will activate the reninaldosterone a&is. This can be seen
by the high levels of both renin and aldosterone in both blood and urine of
patients with antenatal Bartter syndrome. The action of aldosterone in the
distal tubule is twofold. ,irst, the increased movement of %a
F
from the
luminal space intracellularly in e&change for intracellular G
F
via the principal
cells of the late distal tubule and the collecting duct, hence enhancing
potassium wasting. This is accomplished by increasing the activity of the %a
F
G
F
"T#ase pumps at the basolateral cell membrane 1site 9, ,igure(2, which
pump %a
F
out of the tubular cell into interstitium and G
F
into the cell from the
interstitium. This increases intracellular G
F
, creating more of a
G
F
concentration gradient with respect to the lumen, and henceforth more loss
of G
F
into the lumen through the apical membrane and !nally into the urine.
$econdly, aldosterone stimulates the intercalated cells of the late distal tubule
and collecting duct to e&change intracellular >
F
for intraluminal G
F
, with
subsequent e&aggeration of the metabolic alkalosis due to >
F
loss.
The ne&t question to be answered is why these patients, who have high levels
of renin and angiotensin, do not develop high blood pressureN Dould this be
due to nonresponsiveness of their blood vessels to angiotensin as suggested
by Bartter 1endorgan failure2N 't has now been demonstrated that patients
with Bartter syndrome will show a normal response to vasopressor agents
once their volume is restored to normal.
+
"nother equally important !nding in antenatal Bartter syndrome is
hypercalciuria. The cause of calcium loss has already been described. $uch a
continuous loss of calcium results in nephrocalcinosis and secondary renal
impairment in many of these patients.
7);6(
'ndeed, calcium deposits in the
kidney of these patients can be picked up by either ultrasonographic
e&amination of the kidneys as early as + months
(<
or simple abdominal Oray.
#revious $ection %e&t $ection
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Figure 1.
Transport sites in the thick ascending limb of the loop of >enle. 1(2
3lectroneutral %a
F
,G
F
,+Dl
H
cotransport in the apical membrane. 1+2 G
F
channel
1Eat outer medulla potassium channel2 in the apical and the basolateral cell
membrane. 192 %a
F
@G
F
"T#ase pump in the basolateral cell membrane. 172
G
F
@Dl
H
cotransporter in the basolateral cell membrane. 162 Dl
H
channel 1D'DGb2
in the basolateral cell membrane. 1*2 'ntercellular space.
#revious $ection %e&t $ection
Gitleman syndrome
This phenotype of Bartter syndrome is characteriBed by a milder course than
in the antenatal variety. Inset is late, usually after the age of +< years.
#atients present with fatigue, muscle weakness and recurrent episodes of
tetany.
+7,69,67,6*,
,
6C
Biochemically, there is metabolic alkalosis, 1serum bicarbonate
P+)meq@(2 profound hypokalaemia, 1serum potassium Q9meq@l4 normal
P9.6meq@(2 hypomagnesaemia 1serum magnesium Q<.6meq@l4 normal <.?;
(.<meq@(2 and hypocalciuria, 1urinary calcium Q+mg@kg per day4 normal +;C
mg@kg per day2.
69;66
8rinary concentrating ability in this disease is mildly
impaired.
#revious $ection %e&t $ection
Pathophysiology of Gitleman syndrome
The basic pathology in this disease is an impaired %aDl cotransporter in the
distal nephron. Listal tubule and collecting duct together reabsorb about (+J
of the !ltered %a
F
. The early distal tubule, also called the cortical diluting
segment, is the site of absorption of %aDl by %a
F
Dl
H
cotransport 1%DDT2 1site
(, ,igure+2 and is the site of action of thiaBide diuretics.
7+,79,
,
66
" similar
biochemical abnormality can be seen in longterm use of thiaBide diuretics in
an otherwise normal individual. %aDl wasting in this part of the distal nephron
will lead to mild hypovolaemia, and stimulation of the reninangiotensin
a&is.
7
$imon et al.
6?
showed that there is a complete linkage of itleman
syndrome to the locus encoding the renal thiaBide sensitive %a
F
Dl
H
cotransporter on chromosome (*q(9, with an autosomal recessive pattern
and a ))J penetrance.
*C
Autant alleles in this disease have been reported by
$imon and others.
6?,**;*?
The late distal tubule and collecting duct have two
kinds of cells, each with special feature and function. Principal cells reabsorb
%a
F
and >+I 1site (, ,igure92 and secrete G
F
1site +, ,igure92. "ldosterone acts
on principal cells to increase %a
F
reabsorption and increase
G
F
secretion. Intercalated cells secrete >
F
ions in e&change for reabsorption of
G
F
ions 1site 7, ,igure92. "ldosterone increases >
F
ion secretion by
intercalated cells.
'mpairment of %a
F
Dl
H
cotransport in the early part of the distal tubule results
in e&cessive amounts of %a
F
ion in the late distal tubule. Aa&imal reabsorption
of %a
F
and >+I and ma&imal secretion of G
F
ion by the principal cells takes
place in this segment.
(),
,
+<
"t the same time, >
F
is e&creted by intercalated
cells and this, together with impaired Dl
H
reabsorption in the early distal
tubule, results in metabolic alkalosis. The reason for hypocalciuria, as well as
hypomagnesaemia, is not clear. The available literature attributes the high
intake of Da
+F
in distal tubule and hence hypocalciuria to 1a2 decreased apical
%a
F
uptake driving basolateral %a
F
@Da
+F
e&change with subsequent increase of
Da
+F
uptake at the apical membrane level and 1b2 decreased intracellular
Dl
H
content increasing the polarity of the apical cell membrane, which
stimulates Da
+F
uptake.
7,*<,
,
*(
>ypomagnesaemia in itleman syndrome is
perhaps due to magnesium wasting in distal convoluted tubules of the
nephron due to inhibition of Ag
+F
uptake in the presence of hypokalaemia.
*+;
*6
't has also been suggested that the metabolic alkalosis may be an important
cause of hypomagnesaemia by increasing the resistance of distal tubular cells
to Ag
+F
uptake.
7,
,
*9
5ith low Ag
+F
levels in the blood, magnesium wasting has
been observed in patients with itleman syndrome, indicating a toolow renal
Ag
+F
threshold.
7,
,
*7
#revious $ection %e&t $ection
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Figure 2.
Transport sites in the early distal tubule. 1(2 3lectroneutral %a
F
, Dl
H
cotransport
in the apical membrane. 1+2 G
F
channel 1Eat outer medulla potassium channel2
in the apical and the basolateral cell membrane. 192 %a
F
@G
F
"T#ase pump in
the basolateral cell membrane. 172 G
F
@Dl
H
cotransporter in the basolateral cell
membrane. 162 'ntercellular space.
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Figure 3.
Transport sites in the late distal tubule with two kind of cells. 1#rincipal cell
and intercalated cell2. 1(2 %a
F
channel. 1+2 G
F
channel 1Eat outer medulla
potassium channel2 in the apical and the basolateral cell membrane. 192
%a
F
@G
F
"T#ase pump in the basolateral cell membrane. 172 $ite of G
F
@>
F
1>
F