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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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Tuesday Clinical Case Conference 4/08 Zae Kim, MD
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 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 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 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
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 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
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 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)
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 • 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 • 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 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.
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 • 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.