Tuesday Clinical Case Conference 4/08 Zae Kim, MD

Tuesday Clinical Case Conference 4/08 Zae Kim, MD

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 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 Bartter-like salt losing tubulopathies History 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 History 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

History 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 1997 BS II = ROMK channel Lifton

2001 BS III = mutation of gene on chr 1 = ClCNkb 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: 340346 doi:10.1038/ncpneph201

Pathyphysiology 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 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 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 Pathophysiology Name Number Neonatal Bartters syndrome

Type 12 NKCC2 (Chr 15) or ROMK (Chr 11) Classic Bartters syndrome Type 3

CLCNKB Bartters syndrome with sensorineural deafness Type 4 BSND Gitelmans syndrome

Assoicated gene mutation 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 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 Bartters have been identified: Defects in the luminal Na-K-Cl transporter Defects in the

luminal potassium channel Defects in the basolateral chloride channel 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.

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