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DefinitionDefinition• BS is result from a group of AR tubular disorders, BS is result from a group of AR tubular disorders, characterized by polyuria, renal NaCl loss and, as a characterized by polyuria, renal NaCl loss and, as a consequence, secondary hyperreninemic consequence, secondary hyperreninemic hyperaldo. with NL or low BP, Pkhyperaldo. with NL or low BP, Pk↓↓, M.AL result , M.AL result from defects in one of the molecules primarily or from defects in one of the molecules primarily or secondarily involved in NaCl transport across TAL.secondarily involved in NaCl transport across TAL.• Estimated Estimated prevalenceprevalence: 1 per million for BS. : 1 per million for BS. •Loop disorders Loop disorders incidenceincidence: 1/50000 live births.: 1/50000 live births.•More than 50% of the affected children are More than 50% of the affected children are products of consanguineous unions.products of consanguineous unions.

Etiology and Etiology and ClassificationClassification

•Mutations in the genes encoding proteins either in:Mutations in the genes encoding proteins either in: •Apical: NKCC2, ROMKApical: NKCC2, ROMK•Basolateral: Basolateral: -ClC-Kb (responsible for most of cases of the classical variant)-ClC-Kb (responsible for most of cases of the classical variant)

-ClC-Ka-ClC-Ka

-Digenic (ClC-Ka and ClC-Kb)-Digenic (ClC-Ka and ClC-Kb)

-Bartin (BSND, beta subunit of ClCK, which acts as an essential -Bartin (BSND, beta subunit of ClCK, which acts as an essential

beta subunit for basolateral ClC-Ka and ClC-Kb channels)beta subunit for basolateral ClC-Ka and ClC-Kb channels)

-Gain of function mutations leading to activation of -Gain of function mutations leading to activation of

ca-SRca-SR

Inherited salt wasting disorders with Inherited salt wasting disorders with secondary hypokalemiasecondary hypokalemia

DisorderDisorder InheritanInheritancece

Gene Gene locuslocus

GeneGene Protein Protein Affect- Affect- Seg Seg

Antenatal BSAntenatal BS(type 1)(type 1)

ARAR 15q15-2115q15-21 SLC12A1SLC12A1 NKCC2NKCC2 TALTAL

Antenatal BS Antenatal BS (Type 2)(Type 2)

ARAR 11q2411q24 KCNJ1KCNJ1 ROMKROMK TAL/CCDTAL/CCD

Classic BS Classic BS (type 3) (type 3)

ARAR

1p361p36 CLCNKBCLCNKB Renal CL Renal CL channelchannel

TAL+DCT1TAL+DCT1

Antenatal BS Antenatal BS (+SND): Type4(+SND): Type4

ARAR 1p311p31 BSNDBSND BartinBartin(CC sub)(CC sub)

TAL+DCT1TAL+DCT1+tAL+tAL

Antenatal BS Antenatal BS (+SND): Type4(+SND): Type4

ARARdigenicdigenic

1p361p36 CLNKA-BCLNKA-B ClCKa,bClCKa,b tAL+TAL+tAL+TAL+DCT1DCT1

Type 5 BSType 5 BS ADAD 3q13.3-3q13.3-3q213q21

CaSRCaSR Ca –SRCa –SR TAL+IMDTAL+IMD

Giltelman synd Giltelman synd ARAR 16q1316q13 SLC12A3SLC12A3 NCCNCC DCT1DCT1

Pharmacological classification of Bartter Pharmacological classification of Bartter syndrome with important clinical featuressyndrome with important clinical features

PathophysiologyPathophysiology• TAL mediates the reabsorption of 30% of the TAL mediates the reabsorption of 30% of the filtered load of salt, and produced a lumen filtered load of salt, and produced a lumen positivity that is the cause of paracellular positivity that is the cause of paracellular reabsorption of Ca++, Mg++ , Na+,… and reabsorption of Ca++, Mg++ , Na+,… and indirectly effect on function of more distal parts of indirectly effect on function of more distal parts of nephron. nephron. •In BS, defect in reabsorption in utero, produce In BS, defect in reabsorption in utero, produce polyhydramnios which may in turn contribute polyhydramnios which may in turn contribute preterm delivery with a euovolemic state due to preterm delivery with a euovolemic state due to placental function, they rapidly develop dramatic placental function, they rapidly develop dramatic IVV depletion after birth, shock and death IVV depletion after birth, shock and death

Na2ClK

K+ Cl

CLCKa2K

3Na

ClBartinBSIV

CLCKb

CLCKa and CLCKbDigenic disorder

(BS III)

Ca, Mg, K, NH4

BloodLumen

Luminal positive voltage+

NKCC2BS1

ROMKBS2

+8 mV

Thick Ascending Loop of Henle

TAL salt reabsorption

Na

Claudin 16(Paracellin)

Ca-SR

Na+ , NH4+Ca++Mg++

Pathophysiology of Bartter syndromeInternational 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

NKCC2 mutations: NKCC2 belongs to the NKCC2 mutations: NKCC2 belongs to the electroneutral solute carrier, electroneutral solute carrier, exclusively exclusively expressed in the kidneyexpressed in the kidney, with , with variant Avariant A present in all TAL. present in all TAL. Variant BVariant B is present only in is present only in the macula densa region, and the macula densa region, and variant Fvariant F is most is most highly expressed in the m.TAL.highly expressed in the m.TAL.

The affinity for transported ions is B>A>FThe affinity for transported ions is B>A>F, , ensuring the high affinity isoforms located at ensuring the high affinity isoforms located at the final TAL segment, were tubular fluid has the final TAL segment, were tubular fluid has been dilutedbeen diluted

The role of MD in the loop disorders The role of MD in the loop disorders pathogenesis: pathogenesis: capacity to activate renal PGE2 capacity to activate renal PGE2 synthesis, thereby RAAS cascade, key player in synthesis, thereby RAAS cascade, key player in coupling renal hemodynamics with tubular coupling renal hemodynamics with tubular reabsorption (by TGF). reabsorption (by TGF).

The term of blind macula densa cells The term of blind macula densa cells

ROMK mutations: Three isoforms ROMK mutations: Three isoforms (ROMK 1-3)(ROMK 1-3)

Isoform 2 ,3 Isoform 2 ,3 comprise the major apical comprise the major apical K conductance in TAL and K conductance in TAL and isoform 1isoform 1 constitute and important role of K constitute and important role of K secretion in CCD, essential for secretion in CCD, essential for maintaining K balancemaintaining K balance

Transient but important hyperkalemia Transient but important hyperkalemia within the first day of life is frequently within the first day of life is frequently observed in ROMK deficient infants and observed in ROMK deficient infants and contrasts with the typical presentation contrasts with the typical presentation of a loop disorder, of a loop disorder, later other CCD K later other CCD K channelschannels can apparently compensate can apparently compensate and all patients become hypokalemic.and all patients become hypokalemic.

ClC-Kb mutations: ClC-Kb mutations: Two highly homologous Cl channels, designated as Two highly homologous Cl channels, designated as

ClC-Ka and ClC-Kb, all are polarized to the ClC-Ka and ClC-Kb, all are polarized to the basolateral membrane.basolateral membrane.

As compared to ROMK and NKCC2, most ClC-Kb As compared to ROMK and NKCC2, most ClC-Kb patients exert an incomplete loop disorderpatients exert an incomplete loop disorder, , hydramnios, if present, is less pronounced and rarely hydramnios, if present, is less pronounced and rarely required amniocentesisrequired amniocentesis

On average, infants are born at term and rarely On average, infants are born at term and rarely exhibit severe neonatal polyuria, USG is reduced but exhibit severe neonatal polyuria, USG is reduced but not completely abolished and not completely abolished and Uca is frequently Uca is frequently normal or even lownormal or even low

FTTFTT in infancy is often the first clinical sign are in infancy is often the first clinical sign are tubular salt wasting tubular salt wasting

At first lab exam At first lab exam this patient display the most severe this patient display the most severe hypochloremia and hypokalemia, hypochloremia and hypokalemia, and in the follow up and in the follow up they have the greatest need for electrolyte they have the greatest need for electrolyte replacement replacement

ClC-Ka and ClC-Kb digenic ClC-Ka and ClC-Kb digenic mutations: mutations:

The most convincing evidence for the The most convincing evidence for the synergistic concept of ClC-Ka and ClC-synergistic concept of ClC-Ka and ClC-Kb come from two independent Kb come from two independent reports of a digenic disorder with reports of a digenic disorder with mutations in mutations in both chloride channel both chloride channel genes (with premature birth, severe genes (with premature birth, severe polyhydr, experienced severe volume polyhydr, experienced severe volume depletion immediately after birth, depletion immediately after birth, severe hypokalemia, hypochloremia)severe hypokalemia, hypochloremia), , normal Uca, no NC, normal Uca, no NC, but reduce GFR but reduce GFR even after two years, even after two years, bilateral deafness bilateral deafness in three months of age.in three months of age.

Barttin mutation: Barttin mutation: The new gene designated as BSND and its The new gene designated as BSND and its

product barttin, product barttin, a functional coupling of it a functional coupling of it with ClC-K channelswith ClC-K channels

Reported cases originate mainly from Arabic Reported cases originate mainly from Arabic countries and products of consanguineous countries and products of consanguineous unionsunions

The course of disease is most severe, by the The course of disease is most severe, by the highest perinatal mortality, and early onset of highest perinatal mortality, and early onset of CRF with one third of patients reaching ESRD CRF with one third of patients reaching ESRD in childhood is typical. in childhood is typical.

Remarkably, Remarkably, indometacin treatment is less indometacin treatment is less effectiveeffective for reasons not clarified yet. for reasons not clarified yet.

Role of bartin: Role of bartin: modulates stability, cell modulates stability, cell surface localization of ClCK channelssurface localization of ClCK channels and and biological proportion of these channels.biological proportion of these channels.

Ca-SR mutation: Ca-SR mutation: Ca-SR is a member of G protein, in the Ca-SR is a member of G protein, in the

kidney the Ca-SR is primarily expressed in kidney the Ca-SR is primarily expressed in the the basolateral cell surface in the cTALbasolateral cell surface in the cTAL, but , but also expressed in most tubule segments like also expressed in most tubule segments like in luminal surface of IMD.in luminal surface of IMD.

Activation of Ca-SR by Activation of Ca-SR by PcaPca↑↑, Pmg, Pmg↑↑, or gain of , or gain of function mutations (like ADH)function mutations (like ADH) inhibits inhibits divalent cation reabsorption in the renal divalent cation reabsorption in the renal tubule, which results in urinary loss of Ca+tubule, which results in urinary loss of Ca++, Mg++.+, Mg++.

Patients with ADH are associated withPatients with ADH are associated with a a decrease in distal tubular Fdecrease in distal tubular FRCl RCl and a renal and a renal loss of NaCl with 2loss of NaCl with 2ndaryndary hyperaldostronism hyperaldostronism and hypokalemia, mimicking a bartter and hypokalemia, mimicking a bartter syndromesyndrome

Clinical and Biochemical characteristicsClinical and Biochemical characteristics DisorderDisorder Age of Age of

onsetonsetPol-Pol-

hydrahydraP-yuriaP-yuriaP-dipsiaP-dipsia

NCNC UcaUca SmgSmg UmgUmg BphBph SkSk

Antenatal BSAntenatal BS(Type 1)(Type 1)

prenatalprenatal ++ ++ ++ ↑↑↑↑↑↑ NN NN

Antenatal BS Antenatal BS (Type 2)(Type 2)

prenatalprenatal ++ ++ ++ ↑↑↑↑↑↑ NN NN ↑↑→↓→↓

Classic BSClassic BS(Type 3)(Type 3)

InfancyInfancychildhoodchildhood

Very Very rarerare

++ Very Very rarerare

↑↑-↓-↓ N N

Antenatal BS Antenatal BS (+SND) (Type 4)(+SND) (Type 4)

PrenatalPrenatal ++ ++ ++ ↑↑↑↑↑↑ NN NN NN

Antenatal BSAntenatal BS(+SND) Type 4(+SND) Type 4digenicdigenic

PrenatalPrenatal ++ ++ NoNo NN NN NN

Type 5 BSType 5 BS InfancyInfancyAdol-AdultAdol-Adult

NoNo latelate ++ ↑↑↑↑ NN NN NN

Giltelman synd Giltelman synd AdolescenceAdolescence NoNo RareRare NoNo

DiagnosisDiagnosis The diagnosis of BS is largely one of the The diagnosis of BS is largely one of the

exclusion, made in patients who present exclusion, made in patients who present with unexplained hypokalemia and M.Al with unexplained hypokalemia and M.Al with a normal or low blood pressure.with a normal or low blood pressure.

The diagnosis is usually made with a The diagnosis is usually made with a careful history, PE, measurement of careful history, PE, measurement of urine chloride, and urine diuretic urine chloride, and urine diuretic screen.screen.

Other tests: Genetic testing, Other tests: Genetic testing, measurement of change in FEcl in measurement of change in FEcl in response to loop and thiazide diuretics, response to loop and thiazide diuretics, are not widely performed. are not widely performed. Uptodate 2013

Prenatal DiagnosisPrenatal Diagnosis The etiology of polyhydramnios is often The etiology of polyhydramnios is often

apperent from US or alfa protein assay. apperent from US or alfa protein assay. However the genetic renal or colon salt However the genetic renal or colon salt transport defect should be considered when transport defect should be considered when such studies are unrevealing.such studies are unrevealing.

Family history (renal or colonic disorder)Family history (renal or colonic disorder) Analysis of amniotic chloride concentration Analysis of amniotic chloride concentration

can be very helpful ( normal is 109 meq/l in can be very helpful ( normal is 109 meq/l in 25 weeks and 107 meq/l at 37 weeks of 25 weeks and 107 meq/l at 37 weeks of gestational age)gestational age)

Values above 112 meq/l is consistent with Values above 112 meq/l is consistent with one of neonatal forms of BS or congenital one of neonatal forms of BS or congenital chloride diarrhea.chloride diarrhea. Uptodate 2013

Differential DiagnosisDifferential Diagnosis Surreptitious vomiting (pyloric Surreptitious vomiting (pyloric

stenosis,…)stenosis,…) Surreptitious diuretic useSurreptitious diuretic use Congenital chloride diarrheaCongenital chloride diarrhea Primary aldostronism Primary aldostronism Cystic fibrosisCystic fibrosis Chloride deficient liquid formula Chloride deficient liquid formula

(Epidemic in late 1970s and 1980s) (Epidemic in late 1970s and 1980s)

Uptodate 2013

Genetic Testing who and when? 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 Treatment of patients with BS with BS (1)(1) The care of BS patients can be very challenging, loss of The care of BS patients can be very challenging, loss of

30% of the filtered salt load, 30% of the filtered salt load, transient Pk↑transient Pk↑ and and severe severe ECFV↓ ECFV↓ at birth in ROMK mutations.at birth in ROMK mutations.

Notion that BS patients often have PGE2↑, indometacin Notion that BS patients often have PGE2↑, indometacin (1-5 mg/kg/day) (1-5 mg/kg/day) is important , markedly reducing renal is important , markedly reducing renal salt loss and polyuria in many patients and ameliorating salt loss and polyuria in many patients and ameliorating systemic symptoms (systemic symptoms (fever, diarrhea, vomitingfever, diarrhea, vomiting) )

There is marked variability in PGE2 production , There is marked variability in PGE2 production , thus it thus it is difficult to predict is difficult to predict which patients will be most likely to which patients will be most likely to benefitbenefit

Aspirin 100 mg/kg/day, ibuprofen 30 mg/kg/day (less Aspirin 100 mg/kg/day, ibuprofen 30 mg/kg/day (less response than indometacin treatment)response than indometacin treatment)

Treatment of patients Treatment of patients with BS with BS (2)(2)

More selective More selective COX2 inhibitors COX2 inhibitors are ideal agents, but are ideal agents, but clinical experience is limited and rapid progression to clinical experience is limited and rapid progression to CKD change from indometacin to rofecoxib reportedCKD change from indometacin to rofecoxib reported

Patients with mutations in BSND are more venerable to Patients with mutations in BSND are more venerable to renal failure after therapy with NSAIDsrenal failure after therapy with NSAIDs

Indometacin therapy Indometacin therapy during pregnancy during pregnancy to reduce severe to reduce severe polyhydramnios, prevention of premature delivery, polyhydramnios, prevention of premature delivery, special attention has to be devoted to renal function.special attention has to be devoted to renal function.

NSAIDs may be used until GS age of 31 week, but in NSAIDs may be used until GS age of 31 week, but in

≥ ≥ 32 weeks of GS age may cause premature closure of 32 weeks of GS age may cause premature closure of PDA + intermittent drainage of amniotic fluid, repeated PDA + intermittent drainage of amniotic fluid, repeated US assessment for the development of tricuspid US assessment for the development of tricuspid regurgitation.regurgitation.

Treatment of patients Treatment of patients with BS with BS (3)(3)

Other therapeutic options: Other therapeutic options: aldo. antagonistsaldo. antagonists, , potassium potassium sparing diureticssparing diuretics, , ACEiACEi for the treatment of K↓ but can for the treatment of K↓ but can be problematic (counteract the compensatory be problematic (counteract the compensatory mechanisms for maintenance of IVV). mechanisms for maintenance of IVV).

Beta blockers (decrease renin release)Beta blockers (decrease renin release) Direct renin inhibition with AliskirenDirect renin inhibition with Aliskiren Especial therapy for type V BS.Especial therapy for type V BS. ThiazidesThiazides are not generally a suitable treatment for the are not generally a suitable treatment for the

hypercalciuria seen in BS.hypercalciuria seen in BS. Recombinent GH Recombinent GH reported to be of benefit in BSreported to be of benefit in BS Bilateral nephrectomy combined with Bilateral nephrectomy combined with R.TX.R.TX.

Indomethacin Dosages and Nephrocalcinosis in

Neonatal Bartter Syndrome

AJP Rep. 2013 May; 3(1): 21–24

Prognosis Prognosis (1)(1) Outcome in neonatal barter syndrome was Outcome in neonatal barter syndrome was

extremely poor before the establishment of extremely poor before the establishment of NICU, careful volume electrolyte establishment, NICU, careful volume electrolyte establishment, and the indometacin therapyand the indometacin therapy

As a consequence, the natural history of the As a consequence, the natural history of the disease has dramatically changed in the past 30 disease has dramatically changed in the past 30 yearsyears

Most BS patients accounted as adults did not Most BS patients accounted as adults did not have recognized signs and symptoms as neonateshave recognized signs and symptoms as neonates

Prognosis Prognosis (2)(2) Death due to difficulty in fluid and electrolyte Death due to difficulty in fluid and electrolyte

management along with progressive renal failure management along with progressive renal failure are contributing factors to early deathare contributing factors to early death

ESRD in some cases of B.S, more common in ESRD in some cases of B.S, more common in BSND typeBSND type

Renal failure due to NC, NSAID or bothRenal failure due to NC, NSAID or both Proteinuria was unexpected finding in patients Proteinuria was unexpected finding in patients

with ClCKb gene mutations, in followed up for 5-with ClCKb gene mutations, in followed up for 5-24 years.24 years.

References 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 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 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 kidney-specific 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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