Bartter’S And Gittleman’S Syndromes

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Dr Nirmala Baskaran

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    http://masala4maza.blogspot.com/2008/11/degeorge-syndrome-details.html

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Bartter’S And Gittleman’S Syndromes

  1. 1. Bartter’s and Gitelman’s Syndromes Nirmala Baskaran Selayang Hospital
  2. 2. <ul><li>Inherited tubular defects </li></ul><ul><li>Autosomal recessive </li></ul><ul><li>Primary defect is impaired sodium reabsorption </li></ul><ul><li>Characteristic set of metabolic abnormalities: low K, metabolic alkalosis, high renin, high aldosterone, low Mg, hyperplastic juxtaglomerular apparatus. </li></ul>
  3. 3. Pathogenesis <ul><li>Tubular defect </li></ul><ul><li>--- > salt and water loss </li></ul><ul><li>--- > activation of the renin-angiotensin-aldosterone system </li></ul><ul><li>--- > hyperaldosteronism and increased distal flow </li></ul><ul><li>--- > enhanced K + and H + losses </li></ul><ul><li>--- > Low K + and metabolic alkalosis </li></ul>
  4. 4. Bartter’s Syndrome <ul><li>Defects of sodium reabsorption in the thick ascending limb of the LOH. </li></ul><ul><li>5 types, based on the underlying molecular defect. </li></ul>
  5. 6. Loop of Henle <ul><li>Generation and maintenance of the medullary osmotic gradient </li></ul><ul><li>Absorption of 40% Na and 25% water </li></ul><ul><li>Descending limb – highly water permeable aquaporin-1 </li></ul><ul><li>Thin ascending limb – passive Na absorption </li></ul><ul><li>Thick ascending limb – active Na absorption </li></ul>
  6. 10. Clinical presentation-Bartter’s <ul><li>Types 1 and 2 : Present early with severe symptoms (antenatal with maternal polyhydramnios, prematurity, nephrocalcinosis, severe volume depletion) </li></ul><ul><li>Type 3 : Milder sx, similar to Gitelman’s </li></ul><ul><li>Type 4 : Gene mutation -- > abnormal barttin ( a </li></ul><ul><li>beta-subunit of chloride channels in LOH and inner ear) --- > sensorineural deafness and renal failure </li></ul><ul><li>Type 5 : Mutation in the chloride channel itself. </li></ul>
  7. 11. The Role of Prostaglandins <ul><li>Renal overproduction of PGE2 </li></ul><ul><li>Impaired entry of chloride into the macula densa cells --- > increased COX2 expression --- > increased PGE2 </li></ul><ul><li>Directly stimulates renin release --- > hyperaldosteronism </li></ul><ul><li>Vasodilatation --- > normotension </li></ul><ul><li>Not significant in Gitelman’s </li></ul>
  8. 12. Gitelman’s Syndrome <ul><li>Primary defect in the thiazide-sensitive Na:Cl cotransporter in the DCT </li></ul><ul><li>Some heterogenecity from mutations in the genes for Cl channels </li></ul><ul><li>More benign condition </li></ul><ul><li>Presents in late childhood or adulthood </li></ul>
  9. 13. Ion transport in DCT
  10. 14. <ul><li>DCT : Only 7% of NaCl reabsorption --- > less significant volume loss </li></ul><ul><li>Decreased intracellular Na activates the basolateral Na:Ca exchanger --- > hypocalciuria +/- hyperMguria --- > more fatigue, cramps </li></ul>
  11. 16. Phenotypic variations <ul><li>Intrafamilial phenotype variability in Gitelman’s due to increase number and conductance of Cl channel in other area. Am J of Kidney Ds 2004,43:304-12 </li></ul><ul><li>Post-transcriptional compensation in heterozygotes with regulated increase in movement of cytoplasmic protein to luminal membrane. J Am Soc Nephrol 2002,13:604-10 </li></ul><ul><li>Mutants with residual transport activity. J Am Soc Nephrol 2006,17:2136-42 </li></ul><ul><li>ROMK mutants with hyperprostaglandin E syndrome. KI 2001,59:1803-11 </li></ul>
  12. 17. Differential diagnosis <ul><li>Primary hyperaldosteronism – low renin, high BP </li></ul><ul><li>Vomiting/bulemia – low urine chloride (<20meq/L) </li></ul><ul><li>Diuretic use – history, urine chloride, urine diuretic assay </li></ul><ul><li>Autosomal dominant hypocalcemia – due to a gain-of-function mutation in the CaSR (---> inhibits luminal K channel in the TAL) – low Ca, Mg </li></ul><ul><li>Gentamicin-indued – due to activation of the CaSR, resolves 2-6/52 after stopping Rx </li></ul>
  13. 18. Urinary Calcium <ul><li>Can be useful in differentiating between Bartter’s and Gitelman’s. J Pediatr 1992;120:38-43, Bettinelli A et al </li></ul><ul><li>Urinary Ca:Creatinine ratio > 0.20 -- > B </li></ul><ul><li>< 0.20 -- > G </li></ul><ul><li>Not always reliable as </li></ul><ul><li>Persistent low K --- > secondary medullary damage and reduced Ca excretion </li></ul><ul><li>Treatment of hypokalemia corrects hypercalciuria in B </li></ul>
  14. 19. Treatment <ul><li>The tubular defect cannot be corrected </li></ul><ul><li>Rx aims at: </li></ul><ul><li>1) block PGE2 (Indomethacin) </li></ul><ul><li>2) block aldosterone (Spiranolactone) </li></ul><ul><li>3) replace K and Mg </li></ul><ul><li>Combinations of NSAIDs and pottassium-sparing diuretics </li></ul><ul><li>ACE inhibitors useful , transient hypotension, some deterioration in GFR </li></ul>
  15. 20. Chemical chaparones <ul><li>Aim to up-regulate number or function of remaining transporters. </li></ul><ul><li>Glycerol </li></ul><ul><li>4-phenylbutyrate, a transcriptional regulator </li></ul><ul><li>Thapsigangin, a specific inhibitor of sarco-endoplasmic reticulum Ca-ATPase --- > increases expression of wild-type hNCC </li></ul>

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