Disparity in the regulation and prevention of water versus sodium imbalance in heat-stress nephropathy: a phylogenetic perspective.

The progressive rise in global temperature has led to an increase in heat-related illness and has brought heat-stress nephropathy (HSN) to the forefront as an emerging cause of both acute kidney injury (AKI) and chronic kidney disease (CKD). HSN is characterized by tubulo-interstitial damage and linked to disturbances in water and sodium homeostasis. Observational studies indicate that young, otherwise healthy workers exposed to heat are less likely to develop AKI when hypovolaemia due to sweating is corrected with sodium chloride-containing solutions rather than water alone. This narrative review first summarizes the clinical spectrum, epidemiology, pathophysiology, and prevention of HSN in the context of climate change and the broader epidemic of heat-associated CKD described in several tropical and temperate regions. Then, it examines, in a phylogenetic perspective, the evolution of the two main regulatory systems governing body fluid homeostasis: the antidiuretic hormone (ADH)-thirst axis (water balance) and the renin-angiotensin-aldosterone system (RAAS)-salt appetite axis (sodium balance). In aquatic environments, large external osmotic gradients drove early renal adaptations primarily focused on water handling. Approximately 600 million years ago, ADH-like nonapeptides emerged, enabling tight regulation of plasma osmolality. With the transition to terrestrial life, the development of long loops of Henle, a hypertonic renal medulla, and exquisitely sensitive thirst mechanisms allowed mammals to conserve water very efficiently. By contrast, the RAAS system, central to sodium conservation and effective circulating volume, appeared later (around 400 million years ago) and remains slower and less sensitive, with no behavioural drive equivalent to thirst. The mineralocorticoid receptor is present in fish, but its specific ligand aldosterone first appears in terrestrial vertebrates. The net result is a phylogenetically more refined defence of water than of sodium. We propose that this evolutionary asymmetry underlies the particular renal vulnerability observed in HSN, in which inadequate sodium replacement and suboptimal control of volaemia may predispose to ischaemic tubular injury. Understanding these evolutionary roots may help explaining why, in the era of global warming, the prevention of HSN requires not only water but also appropriate salt replacement and targeted protection of vulnerable populations.