Transcript barrter syndrome

‫به نام جان جهان و به نام ایران‬
Definition
BS is result from a group of AR tubular disorders,
characterized by polyuria, renal NaCl loss and, as a
consequence, secondary hyperreninemic hyperaldo.
with NL or low BP, Pk↓, M.AL result from defects
in one of the molecules primarily or secondarily
involved in NaCl transport across TAL.
• Estimated prevalence: 1 per million for BS.
•Loop disorders incidence: 1/50000 live births.
•More than 50% of the affected children are
products of consanguineous unions.
•
Etiology and Classification
•Mutations
in the genes encoding proteins either in:
•Apical: NKCC2, ROMK
•Basolateral:
-ClC-Kb (responsible for most of cases of the classical variant)
-ClC-Ka
-Digenic (ClC-Ka and ClC-Kb)
-Bartin (BSND, beta subunit of ClCK, which acts as an essential
beta subunit for basolateral ClC-Ka and ClC-Kb channels)
-Gain of function mutations leading to activation of
ca-SR
Inherited salt wasting disorders with
secondary hypokalemia
Disorder
Inheritance
Gene locus
Antenatal BS
(type 1)
AR
15q15-21
SLC12A1
NKCC2
TAL
Antenatal BS
(Type 2)
AR
11q24
KCNJ1
ROMK
TAL/CCD
Classic BS
(type 3)
AR
1p36
CLCNKB
Renal CL TAL+DCT1
channel
Antenatal BS
(+SND): Type4
AR
1p31
BSND
Bartin
(CC sub)
TAL+DCT1
+tAL
Antenatal BS
(+SND): Type4
AR
digenic
1p36
CLNKA-B
ClCKa,b
tAL+TAL+
DCT1
Type 5 BS
AD
3q13.3-3q21 CaSR
Ca –SR
TAL+IMD
16q13
NCC
DCT1
Giltelman synd AR
Gene
SLC12A3
Protein
Affect- Seg
Pharmacological classification of Bartter syndrome with
important clinical features
Pathophysiology
TAL mediates the reabsorption of 30% of the
filtered load of salt, and produced a lumen
positivity that is the cause of paracellular
reabsorption of Ca++, Mg++ , Na+,… and
indirectly effect on function of more distal parts of
nephron.
•In BS, defect in reabsorption in utero, produce
polyhydramnios which may in turn contribute
preterm delivery with a euovolemic state due to
placental function, they rapidly develop dramatic
IVV depletion after birth, shock and death
•
Thick Ascending Loop of Henle
Lumen
Blood
Luminal positive voltage +
BS1
NKCC2
3Na
Na
2Cl
K
2K
K+
BS2
ROMK
Cl
Bartin
BSIV
Cl
CLCKa
CLCKa and CLCKb
Digenic disorder
CLCKb (BS III)
Ca, Mg, K, NH4
+8 mV
TAL salt reabsorption
Na+ , NH4+
Ca++
Mg++
Na
Claudin 16
(Paracellin)
Ca-SR
Pathophysiology of Bartter syndrome
International journal of pediatrics, 2012
Schematic representation of the prostaglandin cascade and its inhibition with NSAID
in relation to the tubular salt-wasting and clinical symptoms in HPS/aBS
Pathophysiologic relationships of defect tubular salt reabsorption in the medullary thick
ascending limb of Henle's loop
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NKCC2 mutations: NKCC2 belongs to the electroneutral
solute carrier, exclusively expressed in the kidney, with
variant A present in all TAL. Variant B is present only in
the macula densa region, and variant F is most highly
expressed in the m.TAL.
The affinity for transported ions is B>A>F, ensuring the
high affinity isoforms located at the final TAL segment,
were tubular fluid has been diluted
The role of MD in the loop disorders pathogenesis:
capacity to activate renal PGE2 synthesis, thereby RAAS
cascade, key player in coupling renal hemodynamics
with tubular reabsorption (by TGF).
The term of blind macula densa cells
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ROMK mutations: Three isoforms (ROMK 1-3)
Isoform 2 ,3 comprise the major apical K
conductance in TAL and isoform 1 constitute and
important role of K secretion in CCD, essential for
maintaining K balance
Transient but important hyperkalemia within the
first day of life is frequently observed in ROMK
deficient infants and contrasts with the typical
presentation of a loop disorder, later other CCD K
channels can apparently compensate and all
patients become hypokalemic.
ClC-Kb mutations:
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Two highly homologous Cl channels, designated as ClC-Ka and
ClC-Kb, all are polarized to the basolateral membrane.
As compared to ROMK and NKCC2, most ClC-Kb patients exert
an incomplete loop disorder, hydramnios, if present, is less
pronounced and rarely required amniocentesis
On average, infants are born at term and rarely exhibit severe
neonatal polyuria, USG is reduced but not completely abolished
and Uca is frequently normal or even low
FTT in infancy is often the first clinical sign are tubular salt
wasting
At first lab exam this patient display the most severe
hypochloremia and hypokalemia, and in the follow up they have
the greatest need for electrolyte replacement
ClC-Ka and ClC-Kb digenic mutations:
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The most convincing evidence for the synergistic
concept of ClC-Ka and ClC-Kb come from two
independent reports of a digenic disorder with
mutations in both chloride channel genes (with
premature birth, severe polyhydr, experienced
severe volume depletion immediately after birth,
severe hypokalemia, hypochloremia), normal
Uca, no NC, but reduce GFR even after two
years, bilateral deafness in three months of age.
Barttin mutation:
 The new gene designated as BSND and its product
barttin, a functional coupling of it with ClC-K channels
 Reported cases originate mainly from Arabic countries
and products of consanguineous unions
 The course of disease is most severe, by the highest
perinatal mortality, and early onset of CRF with one
third of patients reaching ESRD in childhood is typical.
 Remarkably, indometacin treatment is less effective for
reasons not clarified yet.
 Role of bartin: modulates stability, cell surface
localization of ClCK channels and biological proportion
of these channels.
Ca-SR mutation:
 Ca-SR is a member of G protein, in the kidney the Ca-SR
is primarily expressed in the basolateral cell surface in
the cTAL, but also expressed in most tubule segments
like in luminal surface of IMD.
 Activation of Ca-SR by Pca↑, Pmg↑, or gain of function
mutations (like ADH) inhibits divalent cation
reabsorption in the renal tubule, which results in urinary
loss of Ca++, Mg++.
 Patients with ADH are associated with a decrease in
distal tubular FRCl and a renal loss of NaCl with 2ndary
hyperaldostronism and hypokalemia, mimicking a
bartter syndrome
Clinical and Biochemical characteristics
Disorder
Age of
onset
PolP-yuria
hydra P-dipsia
NC
Uca Smg
Umg
Bph
Sk
Antenatal BS
(Type 1)
prenatal
+
+
+
↑↑↑
N
N


Antenatal BS
(Type 2)
prenatal
+
+
+
↑↑↑
N
N

↑→↓
Classic BS
(Type 3)
Infancy
childhood
Very
rare
+
Very
rare
↑-↓
N



Antenatal BS
(+SND) (Type 4)
Prenatal
+
+
+
↑↑↑
N
N

N
Antenatal BS
(+SND) Type 4
digenic
Prenatal
+
+
No
N
N
N


Type 5 BS
Infancy
Adol-Adult
No
late
+
↑↑
N
N

N
Giltelman synd
Adolescence
No
Rare
No
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
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
Diagnosis
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The diagnosis of BS is largely one of the
exclusion, made in patients who present with
unexplained hypokalemia and M.Al with a normal
or low blood pressure.
The diagnosis is usually made with a careful
history, PE, measurement of urine chloride, and
urine diuretic screen.
Other tests: Genetic testing, measurement of
change in FEcl in response to loop and thiazide
diuretics, are not widely performed.
Uptodate 2013
Prenatal Diagnosis
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The etiology of polyhydramnios is often apperent
from US or alfa protein assay. However the
genetic renal or colon salt transport defect should
be considered when such studies are unrevealing.
Family history (renal or colonic disorder)
Analysis of amniotic chloride concentration can
be very helpful ( normal is 109 meq/l in 25 weeks
and 107 meq/l at 37 weeks of gestational age)
Values above 112 meq/l is consistent with one of
neonatal forms of BS or congenital chloride
diarrhea.
Uptodate 2013
Differential Diagnosis
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Surreptitious vomiting (pyloric stenosis,…)
Surreptitious diuretic use
Congenital chloride diarrhea
Primary aldostronism
Cystic fibrosis
Chloride deficient liquid formula (Epidemic in
late 1970s and 1980s)
Uptodate 2013
Genetic Testing who and when?
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Barter syndrome: Specific gene mutated can often be
deduced from the clinical presentation
BS more frequently occur in the setting of parental
consanguineous, as a result homozygotys across disease
loci can be a useful addition screen to identify the
responsible gene.
If definite mutations can be identified in the first case,
prenatal diagnosis may be useful for parental decisions
Treatment of patients with BS (1)
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The care of BS patients can be very challenging, loss of
30% of the filtered salt load, transient Pk↑ and severe
ECFV↓ at birth in ROMK mutations.
Notion that BS patients often have PGE2↑, indometacin
(1-5 mg/kg/day) is important , markedly reducing renal
salt loss and polyuria in many patients and ameliorating
systemic symptoms (fever, diarrhea, vomiting)
There is marked variability in PGE2 production , thus it
is difficult to predict which patients will be most likely to
benefit
Aspirin 100 mg/kg/day, ibuprofen 30 mg/kg/day (less
response than indometacin treatment)
Treatment of patients with BS (2)
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More selective COX2 inhibitors are ideal agents, but
clinical experience is limited and rapid progression to
CKD change from indometacin to rofecoxib reported
Patients with mutations in BSND are more venerable to
renal failure after therapy with NSAIDs
Indometacin therapy during pregnancy to reduce severe
polyhydramnios, prevention of premature delivery,
special attention has to be devoted to renal function.
NSAIDs may be used until GS age of 31 week, but in
≥ 32 weeks of GS age may cause premature closure of
PDA + intermittent drainage of amniotic fluid, repeated
US assessment for the development of tricuspid
regurgitation.
Treatment of patients with BS (3)
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Other therapeutic options: aldo. antagonists, potassium
sparing diuretics, ACEi for the treatment of K↓ but can
be problematic (counteract the compensatory
mechanisms for maintenance of IVV).
Beta blockers (decrease renin release)
Direct renin inhibition with Aliskiren
Especial therapy for type V BS.
Thiazides are not generally a suitable treatment for the
hypercalciuria seen in BS.
Recombinent GH reported to be of benefit in BS
Bilateral nephrectomy combined with R.TX.
Indomethacin Dosages and Nephrocalcinosis in
Neonatal Bartter Syndrome
AJP Rep. 2013 May; 3(1): 21–24
Prognosis (1)
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Outcome in neonatal barter syndrome was
extremely poor before the establishment of
NICU, careful volume electrolyte establishment,
and the indometacin therapy
As a consequence, the natural history of the
disease has dramatically changed in the past 30
years
Most BS patients accounted as adults did not
have recognized signs and symptoms as neonates
Prognosis (2)
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Death due to difficulty in fluid and electrolyte
management along with progressive renal failure
are contributing factors to early death
ESRD in some cases of B.S, more common in
BSND type
Renal failure due to NC, NSAID or both
Proteinuria was unexpected finding in patients
with ClCKb gene mutations, in followed up for 524 years.
References
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Bartter and Gitelman syndrome, Up to date 2013.
Genetics of type III BS in Sapin, proposed
diagnostic algoritms, PLOS, 2013
Understanding BS and Gitelman syndrome,
World J of pediatr 2012
Pseudo bartter syndrome, pattern and
correlation with other CF features, Journal of
kidney disease and transplantation, 2013.
Barrter syndrome, Medscape 2012
Antenatal bartter syndrome a review,
International journal of pediatrics 2012
Bartter syndrome treatment, management
emedicine 2013
References
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Genetic disease of the kidney, 2009
Up to date 2011
A novel CLCN5 mutation in a boy with bartter
like syndrome and partial growth hormone
deficiency, pediatric nephrology journal, 2010,
2363-2368
Bartin mutations in in antenatal barter syndrome
with hearing loss, pediat nephrology journal, 2006
Pediatric nephrology Avner, 2009
Inherited forms of renal hypomagnesemia,
pediatr Nephrol, 2009.
References
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Genetic Disorders of NaCl Transport in the Distal Convoluted
Tubule, Nephron Physiol 2011;118:p15–p21
Calcium-sensing Receptor Decreases Cell Surface Expression of
the Inwardly Rectifying K Channel Kir4.1, JOURNAL OF
Biological Chemistry, Jan 2011
Bartter Syndrome Prenatal Diagnosis Based on Amniotic Fluid
Biochemical Analysis, Pediatric Research: March 2010 - Volume
67 - Issue 3 - pp 300-303
Genetics of calcium-sensing--regulation of calcium levels in the
body , Curr Opin Pharmacol. 2003 Jun;3(3):291-4
Loop Disorders: Insights Derived from Defined Genotypes,
Nephron Physiol 2011;118:p7–p14
Regulation of ROMK channel and K+ homeostasis by kidneyspecific WNK1 kinase, J Biol Chem (2009)
Long-term follow-up of patients with Bartter syndrome type I and
II , Nephrol Dial Transplant. 2010
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