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Tuesday Clinical Case Conference. 4/08 Zae Kim, MD. Bartter-like salt losing tubulopathies History. In 1962, Frederic Bartter Reported two patients with Hypokalemic alkalosis normal blood pressure despite high aldosterone production Growth and mental retardation

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bartter like salt losing tubulopathies history
Bartter-like salt losing tubulopathiesHistory
  • In 1962, Frederic Bartter
    • Reported two patients with
      • Hypokalemic alkalosis
      • normal blood pressure despite high aldosterone production
      • Growth and mental retardation
      • Muscle weakness and cramps
      • Salt craving and constipation
      • Polydipsia and polyuria
    • Lab:
      • K 2-2.2 meq/L, HCO3 30-34 mmol/L, sCl 75-66 meq/L
    • Endocrinologist’s approach = adrenalectomy
      • Hyperplasia of the zona glomerulos
      • Renal bx: hyperplasia of the juxtaglomerular apparatus
bartter like salt losing tubulopathies history3
Bartter-like salt losing tubulopathiesHistory
  • Works of McCredie, Fanconi, Dillion
    • Two quite distinct clinical presentations of BS identified within the group of pediatric Bartter patient
      • Neonatal variant of BS
        • The most severe form
        • Polyhydramnios, premature delivery
        • Growth retardation
        • marked hypercalciuria leading to nephrocalcinosis
      • Classical Bartter syndrome
        • Insidious onset in infancy
        • Present with failure to thrive
        • Nephrocalcinosis is typically absent (hypercalciuria to lesser extent)
bartter like salt losing tubulopathies history4
Bartter-like salt losing tubulopathiesHistory
  • Gitelman syndrome
    • Reported in 1966
    • “a new familial disorder characterized by hypokalemia and hypomagnesemia” in two adult sisters
    • Clinically:
      • Often present in early adulthood
      • Predominantly musculoskeletal symptom
        • Carpopedal spasm and normal growth
    • Biochemical
      • Hypokalemia, but less marked than BS
      • Hypomagnesemia is constant finding
      • Pronounced hypocalciuria, where as BS have nl-to-high
      • BS with polyuria, 2/2 reduction of urinary concentrating ability, not present in Gitelman patients
bartter like salt losing tubulopathies history5
Bartter-like salt losing tubulopathiesHistory
  • Contribution by geneticists
    • 1996
      • Simon et al
        • Gitelman disease = mutation of gene on Chr 16 = NaCl
        • neonatal variant of BS (BS I) = mutations of gene on on Chr 15 = NaK2Cl cotransporter
      • Lifton
        • BS II = ROMK channel
    • 1997
      • Lifton
        • BS III = mutation of gene on chr 1 = ClCNkb
    • 2001
      • Landau
        • BSND = mutation of gene on ch 1 = “Barttin”
    • Knock-out animal model exist for Gitelman and Bartter type I and II
    • Genetic testing – hampered by…
      • Large gene dimensions, lack of hot-spot mutations, heavy workup time, and costs
slide6
Clinical and biochemical features of Gitelman's syndrome and the various types of Bartter's syndrome

Phillips DR et al. (2006) A serum potassium level above 10 mmol/l in a patient predisposed to hypokalemia

Nat Clin Pract Neprol2:340–346 doi:10.1038/ncpneph201

pathophysiology
Pathophysiology

Hypokalemic salt-losing tubulopathies_Zelikovic_Nephrology Dialysis Transplant_2003

bsnd a model of k secretion in the inner ear
BSND – a model of K+ secretion in the inner ear

Bartter syndrome_Herbert_CurrOpinHTNNeph_2003

cascade of events
Cascade of events

Salt loss

Volume depletion

Renin/aldosterone secretion / JGA hyperplasia

autonomous hyperreninemic hyperaldosteronism

Enhanced K and H secertion at the collecting tubule

Hypokalemia and metabolic alkalosis result

diagnosis
Diagnosis
  • Clinical history and biochemical workup may not allow definite diagnosis
    • Especially concerning the different types of tubular disorders
  • Genetic diagnosis
    • Costly, cumbersome, and time-consuming because
      • Great dimension of most genes
        • Five exonic regions for ROMK to 26 exons for SLC12A1 and SLC12A3
      • Lack of hot-spot mutations
        • Recognized mutations evenly distributed along the whole gene
      • And very large number of mutations
  • Test with diuretic?
a thiazide test for the diagnosis of renal tubular hypokalemic disorders colussi et al cjasn 2007
A Thiazide Test for the Diagnosis of Renal Tubular Hypokalemic DisordersColussi, et. Al, CJASN, 2007
  • In cohort of patients with genetically proven GS or BS diagnosis, sensitivity and specificity of diuretic test with oral HCTZ was evaluated
    • GS, n=41
      • 19 pediatric and 22 adult patients
    • BS, n=7
      • five type I, two type III
    • “pseudo-BS”, n=3
      • two from surreptitious diuretic intake and one from vomiting
  • TEST: administration of HCTZ and measurement of the maximal diuretic-induced increase over basal in the subsequent 3h of chloride fractional clearance
individual hydrochlorothiazide test results as maximal increase in fractional chloride clearance
Individual hydrochlorothiazide test results(as maximal increase in fractional chloride clearance)
slide21
Traditional parameters
    • Age, plasma Mg and urine Ca excretion lack specificity
  • Blunted natriuretic and chloruretic response to HCT correctly recognizes GS from BS and from PB
  • Small number of BS and PB in the study
treatment
Treatment
  • Antenatal BS / Classic
    • Replacement therapy
      • Fluid loss may surpass 50cc/kg/d with very large loss of Na (~45meq/kg/day)
      • K supplement
    • Rx
      • Prostaglandin synthetase inhibitors (indomethacin)
  • Gitelman
    • Mg / K supplement
    • Spironolactone or amiloride
gitelman syndrome
Gitelman syndrome
  • Reported by Gitelman few years after Bartter
    • Similar syndrome characterized by
      • Hyperreninemia, metabolic alkalosis, and impaired renal conservation of Mg and K
    • In contrast
      • Often diagnosed in adolescence or early adulthood
      • Asymptomatic finding on routine lab test
      • Predominant muscular symptoms
  • Mutation
    • Inherited as autosomal recessive
    • Inactivating mutations in the SLC12A3 gene
      • Loss of function of NCCT in DCT
      • chr 16q13
age at manifestation and primary symptoms of genetically defined salt wasting kidney disorders
Age at manifestation and primary symptoms of genetically defined salt-wasting kidney disorders

Mechanism of disease the kidney-specific chloride channesl_Kramer_NatureClinicPractNeph_2007

bartter syndrome clinical manifestation
Bartter Syndrome – clinical manifestation
  • typically manifests early in life with
    • polyhydramnios, failure to thrive, growth retardation, polydipsia, dehydration, salt craving, and marked muscle weakness.
    • Blood pressure is characteristically low or normal.
    • The GFR is normal, but there is inadequate urinary acid excretion after NH4Cl challenge.
    • Nephrogenic diabetes insipidus also may be seen.
    • Sodium transport in erythrocytes and salivary glands is impaired
    • As early as 1975 Kurtzman and Gutierrez (281) postulated that Bartter syndrome resembled one of inhibited function of the thick ascending limb
      • most recent genetic studies seem to confirm this proposal.
      • Renal biopsy demonstrates hyperplasia and hypertrophy of the juxtaglomerular cells as well as of the medullary interstitial cells, the site of prostaglandin E2 synthesis.
slide29
3 or 4 types of Bartter’s have been identified:
    • Defects in the luminal Na-K-Cl transporter
    • Defects in the luminal potassium channel
    • Defects in the basolateral chloride channel
gitelman s syndrome
Gitelman’s syndrome
  • Like Bartter’s an autosomal recessive disorder, but not usually diagnosed early in life.
  • Findings mimic administration of a thiazide diuretic: the defect is in the Na-Cl transporter.
  • Patients may complain of polyuria, cramps.
  • They do not have hypercalciuria, but typically have low serum magnesium levels.