Bartter and Gitelman syndromes: Questions of class
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REVIEW
Bartter and Gitelman syndromes: Questions of class Martine T. P. Besouw 1
&
Robert Kleta 2,3 & Detlef Bockenhauer 2,3
Received: 2 July 2019 / Revised: 28 August 2019 / Accepted: 17 September 2019 # The Author(s) 2019
Abstract Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution. Keywords Bartter syndrome . Gitelman syndrome . EAST syndrome . Tubulopathy . Metabolic alkalosis . Hypokalaemia
Introduction Physiology and pathophysiology Small solutes like sodium and potassium are freely filtered by the glomerulus and will subsequently be reabsorbed in different parts of the nephron. Approximately 99% of the total amount of filtered sodium will be reabsorbed: around 70– 80% in the proximal tubule (PT), 10–20% in the thick ascending limb of the loop of Henle (TAL), another 5–10% in the distal convoluted tubule (DCT), and around 2–5% in the collecting duct (CD). The percentages of potassium being reabsorbed in the PT and TAL are more or less comparable to those of sodium. However, in the more distal DCT and the CD, also known as the aldosterone-sensitive part of the
* Martine T. P. Besouw [email protected] 1
Department of Pediatric Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
2
Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
3
Department of Renal Medicine, University College London, London, UK
nephron, potassium can be actively secreted. Inherited or acquired factors (the latter including drugs) that disrupt the function of specific transporters in these nephron segments can cause a range of symptoms, the most common being polyuria and polydipsia, electrolyte abnormalities, and acid-base disturbances [1–4].
Salt reabsorption in the TAL In the TAL, sodium is reabsorbed from the tubular lumen into the cell together with potassium and two chloride molecules by the luminal sodium-potassium-2 chloride cotransporter (NKCC2), which can be blocked by loop diuretics (Fig. 1). Next, chloride leaves the cell via basolateral
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