Bartter’S And Gittleman’S Syndromes
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Bartter’S And Gittleman’S Syndromes

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Dr Nirmala Baskaran

Dr Nirmala Baskaran

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Bartter’S And Gittleman’S Syndromes Bartter’S And Gittleman’S Syndromes Presentation Transcript

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