Bartter’s and Gitelman’s Syndromes

Nirmala Baskaran

Selayang Hospital

• Inherited tubular defects

• Autosomal recessive

• Primary defect is impaired sodium reabsorption

• Characteristic set of metabolic abnormalities: low K, metabolic alkalosis, high renin, high aldosterone, low Mg, hyperplastic juxtaglomerular apparatus.

Pathogenesis

Tubular defect

--- > salt and water loss

--- > activation of the renin-angiotensin-aldosterone system

--- > hyperaldosteronism and increased distal flow

--- > enhanced K+ and H+ losses

--- > Low K+ and metabolic alkalosis

Bartter’s Syndrome

• Defects of sodium reabsorption in the thick ascending limb of the LOH.

• 5 types, based on the underlying molecular defect.

Loop of Henle

• Generation and maintenance of the medullary osmotic gradient

• Absorption of 40% Na and 25% water• Descending limb – highly water permeable

aquaporin-1• Thin ascending limb – passive Na

absorption• Thick ascending limb – active Na

absorption

Clinical presentation-Bartter’s

• Types 1 and 2 : Present early with severe symptoms (antenatal with maternal polyhydramnios, prematurity, nephrocalcinosis, severe volume depletion)

• Type 3 : Milder sx, similar to Gitelman’s• Type 4 : Gene mutation -- > abnormal barttin ( a

beta-subunit of chloride channels in LOH and inner ear) --- > sensorineural deafness and renal failure

• Type 5 : Mutation in the chloride channel itself.

The Role of Prostaglandins

• Renal overproduction of PGE2

• Impaired entry of chloride into the macula densa cells --- > increased COX2 expression --- > increased PGE2

• Directly stimulates renin release --- > hyperaldosteronism

• Vasodilatation --- > normotension

• Not significant in Gitelman’s

Gitelman’s Syndrome

• Primary defect in the thiazide-sensitive Na:Cl cotransporter in the DCT

• Some heterogenecity from mutations in the genes for Cl channels

• More benign condition

• Presents in late childhood or adulthood

Ion transport in DCT

• DCT : Only 7% of NaCl reabsorption --- > less significant volume loss

• Decreased intracellular Na activates the basolateral Na:Ca exchanger --- > hypocalciuria +/- hyperMguria --- > more fatigue, cramps

Phenotypic variations

• Intrafamilial phenotype variability in Gitelman’s due to increase number and conductance of Cl channel in other area. Am J of Kidney Ds 2004,43:304-12

• Post-transcriptional compensation in heterozygotes with regulated increase in movement of cytoplasmic protein to luminal membrane. J Am Soc Nephrol 2002,13:604-10

• Mutants with residual transport activity. J Am Soc Nephrol 2006,17:2136-42

• ROMK mutants with hyperprostaglandin E syndrome. KI 2001,59:1803-11

Differential diagnosis

• Primary hyperaldosteronism – low renin, high BP

• Vomiting/bulemia – low urine chloride (<20meq/L)

• Diuretic use – history, urine chloride, urine diuretic assay

• Autosomal dominant hypocalcemia – due to a gain-of-function mutation in the CaSR (---> inhibits luminal K channel in the TAL) – low Ca, Mg

• Gentamicin-indued – due to activation of the CaSR, resolves 2-6/52 after stopping Rx

Urinary Calcium

• Can be useful in differentiating between Bartter’s and Gitelman’s. J Pediatr 1992;120:38-43, Bettinelli A et al

• Urinary Ca:Creatinine ratio > 0.20 -- > B < 0.20 -- > G• Not always reliable as1. Persistent low K --- > secondary medullary

damage and reduced Ca excretion 2. Treatment of hypokalemia corrects

hypercalciuria in B

Treatment

• The tubular defect cannot be corrected• Rx aims at:

1) block PGE2 (Indomethacin)

2) block aldosterone (Spiranolactone)

3) replace K and Mg• Combinations of NSAIDs and pottassium-

sparing diuretics• ACE inhibitors useful , transient hypotension,

some deterioration in GFR

Chemical chaparones

• Aim to up-regulate number or function of remaining transporters.

• Glycerol

• 4-phenylbutyrate, a transcriptional regulator

• Thapsigangin, a specific inhibitor of sarco-endoplasmic reticulum Ca-ATPase --- > increases expression of wild-type hNCC