Miriam Zacchia, Giovanna Capolongo, Luca Rinaldi, Giovambattista Capasso

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 (Ca2+) and magnesium (Mg2+) 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+, Ca2+, Mg2+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.