Pathophysiology and clinical presentations of salt-losing tubulopathies

At least three renal tubular segments are involved in the pathophysiology of salt-losing tubulopathies (SLTs). Whether the pathogenesis starts either in the thick ascending limb of the loop of Henle (TAL) or in the distal convoluted tubule (DCT), it is the function of the downstream-localized aldosterone sensitive distal tubule (ASDT) to contribute to the adaptation process. In isolated TAL defects (loop disorders) ASDT adaptation is supported by upregulation of DCT, whereas in DCT disorders the ASDT is complemented by upregulation of TAL function. This upregulation has a major impact on the clinical presentation of SLT patients. Taking into account both the symptoms and signs of primary tubular defect and of the secondary reactions of adaptation, a clinical diagnosis can be made that eventually leads to an appropriate therapy. In addition to salt wasting, as occurs in all SLTs, characteristic features of loop disorders are hypo- or isosthenuric polyuria and hypercalciuria, whereas characteristics of DCT disorders are hypokalemia and (symptomatic) hypomagnesemia. In both SLT categories, replacement of urinary losses is the primary goal of treatment. In loop disorders COX inhibitors are also recommended to mitigate polyuria, and in DCT disorders magnesium supplementation is essential for effective treatment. Of note, the combination of a salt- and potassium-rich diet together with an adequate fluid intake is always the basis of long-term treatment in all SLTs.