Tuesday Clinical Case Conference

1
Tuesday Clinical Case Conference
4/08 Zae Kim, MD
2
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

3
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)

4
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

5
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

6
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
7
Pathyphysiology
8
Pathophysiology
Hypokalemic salt-losing tubulopathies_Zelikovic_Ne
phrology Dialysis Transplant_2003
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
BSND a model of K secretion in the inner ear
Bartter syndrome_Herbert_CurrOpinHTNNeph_2003
14
Hypokalemic salt-losing tubulopathies_Zelikovic_Ne
phrology Dialysis Transplant_2003
15
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

16
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?

17
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

18
Blood and urine biochemical data in patient groups
19
Group results of HCT test
20
Individual hydrochlorothiazide test results(as
maximal increase in fractional chloride clearance)
21

• 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

22
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

23
(No Transcript)
24
(No Transcript)
25
Pathophysiology
Name Number Assoicated gene mutation
Neonatal Bartters syndrome Type 1-2 NKCC2 (Chr 15) or ROMK (Chr 11)
Classic Bartters syndrome Type 3 CLCNKB
Bartters syndrome with sensorineural deafness Type 4 BSND
Gitelmans syndrome NCCT (SLC12A3)
26
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

27
Age at manifestation and primary symptoms of
genetically defined salt-wasting kidney disorders
Mechanism of disease the kidney-specific chloride
channesl_Kramer_NatureClinicPractNeph_2007
28
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.

29

• 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

30
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.