Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects

Abstract

Salt-losing tubulopathies with secondary hyperaldosteronism (SLT) comprise a set of well-defined inherited tubular disorders. Two segments along the distal nephron are primarily involved in the pathogenesis of SLTs: the thick ascending limb of Henle's loop, and the distal convoluted tubule (DCT). The functions of these pre- and postmacula densa segments are quite distinct, and this has a major impact on the clinical presentation of loop and DCT disorders - the Bartter- and Gitelman-like syndromes. Defects in the water-impermeable thick ascending limb, with its greater salt reabsorption capacity, lead to major salt and water losses similar to the effect of loop diuretics. In contrast, defects in the DCT, with its minor capacity of salt reabsorption and its crucial role in fine-tuning of urinary calcium and magnesium excretion, provoke more chronic solute imbalances similar to the effects of chronic treatment with thiazides. The most severe disorder is a combination of a loop and DCT disorder similar to the enhanced diuretic effect of a co-medication of loop diuretics with thiazides. Besides salt and water supplementation, prostaglandin E2-synthase inhibition is the most effective therapeutic option in polyuric loop disorders (e.g., pure furosemide and mixed furosemide-amiloride type), especially in preterm infants with severe volume depletion. In DCT disorders (e.g., pure thiazide and mixed thiazide-furosemide type), renin-angiotensin-aldosterone system (RAAS) blockers might be indicated after salt, potassium, and magnesium supplementation are deemed insufficient. It appears that in most patients with SLT, a combination of solute supplementation with some drug treatment (e.g., indomethacin) is needed for a lifetime.

Fig. 1

Salute reabsorption in the thick ascending limb (TAL) of Henle`s loop, the distal convoluted tubule (DCT), and the aldosterone-sensitive distal nephron (ASDN). In the TAL (a), sodium chloride is reabsorbed by furosemide-sensitive sodium–potassium-2-chloride co-transporter (NKCC2) together with potassium, which has to be recycled via the renal outer medullary potassium channel, Kir 1.1 (ROMK) into the tubular lumen. Calcium and magnesium are reabsorbed passively via the paracellular pathway driven by lumen-positive transepithelial potential. In the DCT (b), salt reabsorption occurs via thiazide-sensitive sodium cotransporter (NCCT). As in the TAL, sodium is extruded basolaterally by sodium–potassium–adenosine triphosphatase (Na-K-ATPase), and chloride leaves the cell through chloride channels (ClC). Reabsorption of magnesium and calcium in the DCT is active and transcellular in nature, consisting of uptake through selective ion channels (TRPM6 and TRPV5, respectively). In the ASDN (c), ROMK potassium channels – in addition to their role in the TAL – are essential for potassium ion secretion in exchange for the electrogenic reabsorption of sodium via amiloride-sensitive epithelial sodium channels (ENaC) under the influence of aldosterone

Fig. 2

Simplified scheme to explain how prostaglandin E₂ (PGE₂) plays a pivotal role in the pathogenesis of salt and water wasting in loop disorders. The genetic knockout of active transcellular transport impairs salt (chloride) detection by low intracellular salt content and cell shrinkage in the macula densa (MD), with the consequence of cyclooxygenase-2 (COX-2) and prostaglandin E2-synthase (PGES) activation. Overproduced PGE₂ interferes with tubuloglomerular feedback (TGF) through disinhibition of glomerular filtration, which increases glomerular filtration rate (GFR). In parallel, PGE₂ inhibits antidiuretic hormone (ADH) action on water reabsorption at the level of the collecting duct (CD) and activates the renin–angiotensin–aldosterone system (RAAS) in an attempt to increase salt reabsorption. However, PGE₂ antagonizes this by inhibiting tubular salt reabsorption in addition to the genetic defect directly at the tubular site and thereby actually aggravates renal salt wasting. cTAL cortical thick ascending limb of Henle’s loop, mTAL medullary thick ascending limb of Henle's loop