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 hyperreninemichyperaldo. 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.
Mutations in the genes encoding proteins either in:
Apical: NKCC2, ROMK
-ClC-Kb (responsible for most of cases of the classical variant)
-Digenic (ClC-Ka and ClC-Kb)
-Bartin (BSND, beta subunit of ClCK, which acts as an essential
beta subunit for basolateralClC-Ka and ClC-Kb channels)
-Gain of function mutations leading to activation of
TAL mediates the reabsorption of 30% of the filtered load of salt, and produced a lumen positivity that is the cause of paracellularreabsorption 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 important clinical features
Luminal positive voltage
CLCKa and CLCKb
Ca, Mg, K, NH4
TAL salt reabsorption important clinical features
Na+ , NH4+
Pathophysiology of Bartter syndrome important clinical features
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
NKCC2 mutations: NKCC2 belongs to the reabsorption in the medullary thick 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
ROMK mutations: Three reabsorption in the medullary thick 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 hyperkalemiawithin 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 reabsorption in the medullary thick -Kb mutations:
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 reabsorption in the medullary thick -Ka and ClC-Kb digenic mutations:
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: reabsorption in the medullary thick
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: reabsorption in the medullary thick
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 cationreabsorption in the renal tubule, which results in urinary loss of Ca++, Mg++.
Patients with ADH are associated with a decrease in distal tubular FRCland a renal loss of NaCl with 2ndaryhyperaldostronism and hypokalemia, mimicking a bartter syndrome
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.
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.
Surreptitious vomiting (pyloric stenosis,…)
Surreptitious diuretic use
Congenital chloride diarrhea
Chloride deficient liquid formula (Epidemic in late 1970s and 1980s)
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)
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.
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 reabsorption in the medullary thick
Neonatal Bartter Syndrome
AJP Rep. 2013 May; 3(1): 21–24
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
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 5-24 years.
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.
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
میهن reabsorption in the medullary thick
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