به نام جان جهان و به نام ایران

1. به نام جان جهان و به نام ایران

2. 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.

3. 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 basolateralClC-Ka and ClC-Kb channels) -Gain of function mutations leading to activation of ca-SR

4. Inherited salt wasting disorders with secondary hypokalemia

5. Pharmacological classification of Bartter syndrome with important clinical features

6. Pathophysiology 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

7. Thick Ascending Loop of Henle Lumen Blood + Luminal positive voltage Na 3Na 2Cl NKCC2 BS1 K 2K CLCKa K+ Cl CLCKa and CLCKb Digenic disorder BS2 ROMK Bartin BSIV Cl CLCKb (BS III) Ca, Mg, K, NH4 +8 mV

8. TAL salt reabsorption Na+ , NH4+ Ca++ Mg++ Na Ca-SR Claudin 16 (Paracellin)

9. Pathophysiology of Bartter syndrome International journal of pediatrics, 2012

10. Schematic representation of the prostaglandin cascade and its inhibition with NSAID in relation to the tubular salt-wasting and clinical symptoms in HPS/aBS

11. Pathophysiologic relationships of defect tubular salt reabsorption in the medullary thick ascending limb of Henle's loop

12. 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

13. 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 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.

14. ClC-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

15. ClC-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.

16. 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.

17. 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 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

18. Clinical and Biochemical characteristics

19. Diagnosis 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

20. Prenatal Diagnosis 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

21. Differential Diagnosis 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

22. 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

23. Treatment of patients with BS (1) 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)

24. Treatment of patients with BS (2) 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.

25. Treatment of patients with BS (3) 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.

26. Indomethacin Dosages and Nephrocalcinosis in Neonatal Bartter Syndrome AJP Rep. 2013 May; 3(1): 21–24

27. Prognosis (1) 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

28. Prognosis (2) 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.

29. 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

30. 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.

31. 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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