Available online 8 October 2025, 102055

The syndrome of inappropriate antidiuresis (SIAD) is caused by increased renal water retention due to excessive arginine vasopressin (AVP) release from the posterior pituitary, enhanced kidneys sensitivity to AVP, or ectopic secretion of AVP or AVP-like peptides. Consequently, augmenting water clearance is a key therapeutic strategy, achievable either through osmotic diuresis or aquaresis. Osmotic diuresis has traditionally been induced with oral urea powder, however, two randomized placebo-controlled trials have demonstrated that glucosuria, induced by the SGLT2 inhibitor empagliflozin, effectively raises plasma sodium levels in both inpatients and outpatients with SIAD. An indirect urea-driven osmotic diuresis has also been observed in a controlled open-label study evaluating high-protein supplementation in outpatients with chronic SIAD. Aquaresis can be achieved with AVP receptor antagonists (vaptans) and, to a lesser extent, with loop diuretics. Moreover, preclinical and preliminary clinical data suggest that apelin, an endogenous neuropeptide that counteracts AVP in salt and water homeostasis, is effective in increasing plasma sodium levels in SIAD.

hyponatremia

syndrome of inappropriate antidiuretic hormone secretion

apelin

arginine vasopressin

water-electrolyte balance

urea

urea transporter proteins

aquaporins

vasopressin receptor antagonists

sodium-glucose transporter 2 inhibitors

osmotic diuresis

© 2025 The Author(s). Published by Elsevier Ltd.