Bartter and Gitelman syndromes: Questions of class

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; EAST syndrome; Gitelman syndrome; Hypokalaemia; Metabolic alkalosis; Tubulopathy.

Fig. 1.

Electrolyte transport in the TAL. The NKCC2 transporter imports one sodium, one potassium, and two chloride ions from the lumen into the cell. This transporter can be blocked by loop diuretics, inherited dysfunction causes Bartter syndrome type 1. Mutations in the gene encoding MAGE-D2 result in a transient decreased expression of NKCC2, thus causing Bartter syndrome type 5. Chloride leaves the cell via the basolateral chloride transporters CLCNKB and, presumably, CLCNKA, both of which need the Barttin subunit in order to function. Mutations in CLCNKB cause Bartter syndrome type 3 and in Barttin cause Bartter syndrome type 4a; combined dysfunction of the CLCNKA and CLCNKB channels causes Bartter syndrome type 4b. Sodium leaves the cell via the basolateral Na-K-ATPase that actively exports three sodium ions and imports two potassium ions. Potassium subsequently leaves the cell via the luminal KCNJ1 channel, mutations in which cause Bartter syndrome type 2. The luminal potassium concentration is the main driving force for the paracellular uptake of calcium and magnesium, which is facilitated by a lumen-positive transepithelial potential. Therefore, hypercalciuria with nephrocalcinosis and hypermagnesuria is typically seen in Bartter syndromes type 1 (NKCC2), type 2 (KCNJ1), and type 5 (MAGE-D2), while it can be variable in Bartter syndromes type 3 (CLCNKB), type 4a (Barttin), and type 4b (combined CLCNKA and CLCNKB)

Fig. 2.

Electrolyte transport in the DCT. The NCC transporter imports one sodium and one chloride ion from the lumen into the cell. This transporter can be blocked by thiazide diuretics. Mutations in the gene encoding NCC cause Gitelman syndrome. Chloride leaves the cell via the basolateral CLCNKB channel, which needs the Barttin subunit in order to function. Both proteins are expressed in both the TAL and DCT, and their decreased function can cause Bartter syndrome (type 3 and type 4a, respectively). Sodium can exit the cell via the basolateral Na-K-ATPase that actively exports three sodium ions while importing two potassium ions. Potassium is immediately recycled and pumped out of the cell by the basolateral potassium channel KCNJ10, mutations in which cause EAST syndrome. Calcium and magnesium are imported by TRPV5 and TRPM6, respectively.