Tuesday Clinical Case Conference

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Tuesday Clinical Case Conference
4/08 Zae Kim, MD
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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
• Endocrinologists approach adrenalectomy
• Hyperplasia of the zona glomerulos
• Renal bx hyperplasia of the juxtaglomerular
  apparatus

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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)

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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

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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

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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 340346
doi10.1038/ncpneph201
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Pathyphysiology
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Pathophysiology
Hypokalemic salt-losing tubulopathies_Zelikovic_Ne
phrology Dialysis Transplant_2003
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BSND a model of K secretion in the inner ear
Bartter syndrome_Herbert_CurrOpinHTNNeph_2003
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Hypokalemic salt-losing tubulopathies_Zelikovic_Ne
phrology Dialysis Transplant_2003
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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

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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?

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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, n41
• 19 pediatric and 22 adult patients
• BS, n7
• five type I, two type III
• pseudo-BS, n3
• 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

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Blood and urine biochemical data in patient groups
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Group results of HCT test
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Individual hydrochlorothiazide test results(as
maximal increase in fractional chloride clearance)
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• 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

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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

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Pathophysiology
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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

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Age at manifestation and primary symptoms of
genetically defined salt-wasting kidney disorders
Mechanism of disease the kidney-specific chloride
channesl_Kramer_NatureClinicPractNeph_2007
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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.

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• 3 or 4 types of Bartters have been identified
• Defects in the luminal Na-K-Cl transporter
• Defects in the luminal potassium channel
• Defects in the basolateral chloride channel

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Gitelmans syndrome

• Like Bartters 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.