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Bartter Gitelman Syndrome


									Tuesday Clinical Case Conference

    Zae Kim, MD
 Bartter-like salt losing tubulopathies
• 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
• 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
• 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
• 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
   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 Neprol 2: 340–346 doi:10.1038/ncpneph201

Hypokalemic salt-losing tubulopathies_Zelikovic_Nephrology Dialysis Transplant_2003
BSND – a model of K+ secretion in the
            inner ear

            Bartter syndrome_Herbert_CurrOpinHTNNeph_2003
Hypokalemic salt-losing tubulopathies_Zelikovic_Nephrology Dialysis Transplant_2003
           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

• 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

• 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
Blood and urine biochemical data in
          patient groups
Group results of HCT test
Individual hydrochlorothiazide test results
    (as maximal increase in fractional chloride clearance)
• Traditional parameters
   – Age, plasma Mg and urine Ca excretion lack
• Blunted natriuretic and chloruretic response to
  HCT correctly recognizes GS from BS and from
• Small number of BS and PB in the study

• Antenatal BS / Classic
  – Replacement therapy
     • Fluid loss may surpass 50cc/kg/d with very large loss of Na
     • K supplement
  – Rx
     • Prostaglandin synthetase inhibitors (indomethacin)
• Gitelman
  – Mg / K supplement
  – Spironolactone or amiloride

              Name            Number       Assoicated
                                         gene mutation
Neonatal Bartter’s syndrome   Type 1-2   NKCC2 (Chr 15)
                                         or ROMK (Chr
Classic Bartter’s syndrome    Type 3     CLCNKB

Bartter’s syndrome with       Type 4     BSND
sensorineural deafness
Gitelman’s syndrome                      NCCT (SLC12A3)
                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

Mechanism of disease the kidney-specific chloride channesl_Kramer_NatureClinicPractNeph_2007
        Bartter Syndrome – clinical
• 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
   – 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.
• 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
           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.

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