Salt-Losing Tubulopathies in Children: What's New, What's Controversial?

Abstract

Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders.

Keywords: Bartter-s syndrome; Cell & Transport Physiology; Gitelman-s syndrome; children; kidney tubule.

Figure 1.

Sodium and water reabsorption along the nephron. Knockouts of distinctive proteins in particular nephron segments lead to distinctive disease in man, as indicated.

Figure 2.

Simplified diagram of a PT cell. Sodium reabsorption in the PT is mainly accomplished by NHE3, which exchanges sodium for protons. Other sodium-coupled transporters use the chemical and electrical gradient of sodium for the reabsorption of molecules (X stands for, e.g., glucose, amino acids, phosphate).

Figure 3.

Simplified diagram of a TAL cell. Sodium is reabsorbed electroneutrally via NKCC2 (defective in Bartter type 1), together with one potassium and two chloride ions. The transporter can only function with all four ions bound and, because of its luminal concentration, potassium binding becomes the rate-limiting step. Therefore, potassium is recycled through the potassium channel ROMK1 (defective in Bartter type 2) to ensure an adequate luminal supply of potassium. This also generates a lumen positive transepithelial potential, providing the driving force for paracellular absorption of calcium and magnesium. Sodium exits the cell on the basolateral (blood side) via the Na-K-ATPase, whereas chloride exits through the chloride channels CLCNKB (defective in Bartter type 3) and CLCNKA; both require Barttin (defective in Bartter type 4) for proper membrane localization. NKCC2 can be inhibited by loop diuretics, such as furosemide.

Figure 4.

Simplified diagram of a DCT cell. Sodium is reabsorbed electroneutrally via a sodium-chloride cotransporter (NCC) and can then exit toward the blood side via the Na-K-ATPase, whereas chloride can pass through the basolateral chloride channel CLCKNB. KCNJ10 indirectly regulates Na-K-ATPase activity by providing a supply of potassium dependent on basolateral potassium concentration. NCC can be inhibited by thiazides. Impaired salt reabsorption in DCT indirectly affects magnesium uptake via TRPM6, explaining the renal magnesium wasting for salt-losing disorders of the DCT.

Figure 5.

Simplified diagram of a principal cell and type 1 intercalated cell in the cortical CD. Sodium reabsorption occurs electrogenically through ENaC and Na-K-ATPase and thus facilitates potassium and proton secretion through ROMK and the H⁺-ATPase, respectively. Aldosterone indirectly affects the activity of these proteins via the mineralocorticoid receptor MRCR. ENaC can be inhibited by amiloride.