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Pathophysiology and clinical presentations of salt-losing tubulopathies

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Abstract

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.

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Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, Philipps University, Marburg, Germany

    Hannsjörg W. Seyberth

  2. Lazarettgarten 23, 76829, Landau, Germany

    Hannsjörg W. Seyberth

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Answers

1: C. For the boy, the DC1 type of SLT is the most likely diagnosis based on the combination of tetany with normal urine osmolality after dehydration. For the adult, the combination of tetany with isothenuria and hypochloremia best fits the diagnosis of a tubular disorder of the DC2 type. A loop disorder can definitely be excluded.

2: B. The triad of hypokalemia, hypomagnesemia, and almost normal specific gravity in a random urine specimen is characteristic for a DCT-like disorder in all three patients. However, the additional sign of hypochloremia in the unrelated young woman leads to the diagnosis of a DC2 type disorder.

3: A. Children with hypercalciuria and potassium-losing nephropathy fulfill all of the critical criteria for the diagnosis of a loop disorder, particularly when they had been born prematurely after a pregnancy that had been complicated by polyhydramnios. As hypokalemia was not necessarily present when the infants were first examined, one can assume that the most likely diagnosis is a L2 type disorder with ROMK defect. This SLT type is often associated with transient hypoaldosteronism in the postnatal period.

4: B. The (additional) function of ClC-Ka can be best demonstrated by comparing the clinical presentation of patients with isolated ClC-Kb defect (DC2 type) directly with the presentation of patients with a combined ClC-Ka and ClC-Kb defect (L-DC1 type).

5: E. Na-K-ATPase is the only functional protein that is expressed at the basolateral and not at the apical/luminal cell membrane. Therefore it cannot be stimulated directly by increased urine flow.

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Seyberth, H.W. Pathophysiology and clinical presentations of salt-losing tubulopathies. Pediatr Nephrol 31, 407–418 (2016). https://doi.org/10.1007/s00467-015-3143-1

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