The importance of the thick ascending limb of Henle’s loop in renal physiology and pathophysiology

The thick ascending limb (TAL) of Henle’s loop is a crucial segment for many tasks of the nephron. Indeed, the TAL is not only a mainstay for reabsorption of sodium (Na(+)), potassium (K(+)), and divalent cations such as calcium (Ca(2+)) and magnesium (Mg(2+)) from the luminal fluid, but also has an important role in urine concentration, overall acid–base homeostasis, and ammonia cycle. Transcellular Na(+) transport along the TAL is a prerequisite for Na(+), K(+), Ca(2+), Mg(2+) homeostasis, and water reabsorption, the latter through its contribution in the generation of the cortico-medullar osmotic gradient. The role of this nephron site in acid–base balance, via bicarbonate reabsorption and acid secretion, is sometimes misunderstood by clinicians. This review describes in detail these functions, reporting in addition to the well-known molecular mechanisms, some novel findings from the current literature; moreover, the pathophysiology and the clinical relevance of primary or acquired conditions caused by TAL dysfunction are discussed. Knowing the physiology of the TAL is fundamental for clinicians, for a better understanding and management of rare and common conditions, such as tubulopathies, hypertension, and loop diuretics abuse.