Editorial: Endocrine regulation of homeostasis of water, electrolytes and organic solutes

termed nephrogenic diabetes insipidus) results from peripheral insensitivity to AVP signaling and is frequently iatrogenic (i.e., chronic lithium therapy) 7 . In their review article, Flynn et al. provide updated insights into the diagnosis and management of these conditions, including the differential diagnosis of the polyuria-polydipsia syndrome. Both AVP deficiency and resistance pose clinical challenges, as delayed diagnosis and treatment may lead to dehydration, hypernatremia and substantial morbidity and mortality. For decades, the water deprivation test followed by desmopressin administration represented the diagnostic gold standard, although it is limited by low accuracy and requires inpatient monitoring. In the recent years, a copeptin-based diagnostic approach has been proposed, enabling a more straightforward and robust diagnostic process, albeit with some limitations that warrant consideration 6,8,9 . Elevated basal copeptin levels can exclude AVP resistance, while its measurement under appropriate stimulation tests (i.e., hypertonic saline or arginine infusion) allows accurate identification of AVP deficiency. Nevertheless, ongoing efforts aim to optimize the timely and safe management of hospitalized patients with AVP disorders and to develop shorter, better-tolerated diagnostic protocols that maintain high diagnostic accuracy 10 . On the other hand, hypotonic hyponatremia is the most common electrolyte disorder among hospitalized patients and is independently associated with prolonged length of stay, worse clinical outcomes and increase mortality 11 . In most cases ECF volume is preserved, and hyponatremia results from a chronic reduction in free-water clearance leading to dilutional hyponatremia due to the syndrome of inappropriate antidiuresis (SIAD). The underlaying persistent V2R signaling despite hypotonicity may arise from a wide range of diseases, medications and systemic conditions; however, its pathophysiology remains incompletely understood 12,13 . In his minireview Prof. Soleimani summarizes current evidence regarding acid-base homeostasis in SIAD-associated hyponatremia. Notably, despite low serum sodium and chloride concentrations, acid-base balance in SIAD is typically near normal, with preserved serum bicarbonate levels, reflecting effective renal compensatory mechanisms. One hypothesis is that an initial dilutional acidosis secondary to ECF expansion may trigger a compensatory renal acid excretion. Additionally, both hypotonicity and V1aR activation have been shown to stimulate renal H⁺-ATPase and, together with enhanced ammoniagenesis, may contribute to the maintenance of systemic acid-base balance. Beyond its pathogenesis, SIAD still lacks broadly applicable, well tolerated and affordable treatment strategies capable of effective and sustainably increasing free-water clearance [14][15][16] . In his insightful opinion, Prof. Tzoulis critically examines the advantages and limitations of the recently proposed therapeutic approach using empagliflozin in SIAD. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are oral glucose-lowering agents approved for the treatment of type 2 diabetes mellitus, heart failure and CKD. By inducing persistent glycosuria, they promote osmotic diuresis and are associated with substantial cardiovascular and renal benefits. In the context of SIAD, small randomized controlled trials conducted in both inpatient and outpatient settings have demonstrated a modest increase in serum sodium levels, potentially allowing relaxation of fluid restriction regimens, which are often poorly tolerated 14 . Although several aspects remain to be clarified, SGLT2 inhibitors may emerge as an adjunctive therapy to oral urea or adequate dietary protein intake, potentially improving tolerability and adherence in patients with mild-to-moderate hyponatremia, without the cost associated with AVP receptor antagonists. Taken together, this collection offers valuable examples of contemporary approaches to evaluating the systemic consequences of disrupted regulation of hydro-electrolyte and organic solute homeostasis.