Tuesday Clinical Case Conference

4/08Zae 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

– 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 hypokalemiaNat Clin Pract Neprol 2: 340–346 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 Assoicated gene

mutation

Neonatal Bartter’s syndrome Type 1-2

NKCC2 (Chr 15) or ROMK (Chr 11)

Classic Bartter’s syndrome Type 3 CLCNKB

Bartter’s syndrome with sensorineural deafness

Type 4 BSND

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 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.