Loop disorders: insights derived from defined genotypes

Great progress has been made in the last 15 years in the characterization and the pathophysiological understanding of renal salt and water wasting associated with inherited disorders of the thick ascending limb (TAL) of Henle's loop, the loop disorders. Besides careful clinical observations and innovative physiological concepts, molecular genetics have made this progress possible. So far, mutations in five different genes may be responsible for the loop disorders. These gene products are as follows: NKCC2 symporter, ROMK, ClC-Ka, ClC-Kb, and barttin, a β-subunit to both chloride channels. The key symptoms, such as polyhydramnios secondary to fetal polyuria, postnatal volume depletion with hypotension, iso- or hyposthenuria, hyperprostaglandinuria and hypercalciuria followed by hypokalemic alkalosis secondary to hyperaldosteronism, are typical features of loop disorders that are restricted to TAL, such as in disorders with NKCC2 and ROMK mutations. However, transient perinatal hyperkalemia in infants with ROMK mutations suggests an additional function of ROMK for K secretion in the cortical collecting duct. The extremely rare human ClC-Kamutation has only been described in combination with ClC-Kb mutations. Similar to barttin mutations, this double knockout of transepithelial salt transport in TAL and in distal convoluted tubule (DCT) leads to a severe loop disorder with deafness. In contrast, the isolated ClC-Kb mutation predominantly appears as an incomplete loop disorder with features similar to an isolated DCT defect, because ClC-Kb function in TAL can in part be compensated by ClC-Ka. This compensation does not exist in DCT. Besides these defined genotypes, the type and the severity of mutation as well as the onset and quality of medical care are important determinants for the patients' outcome. Considering a few variables, such as transient hyperkalemia, disease onset beyond neonatal period, profound hypochloremia and hypokalemia, or congenital hearing loss, might be helpful to guide genetic testing efficiently.