Society of Diabetic Nephropathy Prevention Journal of Nephropharmacology 2345-4202 16 1 2027 01 01 Recurrent dehydration and chronic kidney disease; molecular pathways linking osmotic stress, tubular injury and fibrotic progression e12894 e12894 10.34172/npj.12894 EN Eleonora Tashkenbaeva https://orcid.org/0000-0001-5705-4972 Maftuna Abdulloeva https://orcid.org/0009-0002-0911-0890 Iroda Salieva https://orcid.org/0009-0003-6358-519X Sabokhat Tuychieva https://orcid.org/0009-0005-0889-7320 Laziz Yorbulov https://orcid.org/0009-0009-8721-2199 Sadriddin Mukhtarov https://orcid.org/0009-0000-2511-4133 Farida Khasanjanova https://orcid.org/0009-0006-5049-6333 Journal Article 10.34172/npj.12894 2026 04 28 2026 06 23 Recurrent dehydration has detected as a significant, modifiable risk factor for the development and progression of chronic kidney disease, particularly in populations exposed to occupational heat stress or limited fluid access. This overview sought to consider current findings on the molecular pathways linking episodic volume depletion to sustained renal dysfunction, emphasizing osmotic stress as the primary catalyst for tubular epithelial injury. Repeated hyperosmolar insults disrupt cellular homeostasis, provoking mitochondrial dysfunction, endoplasmic reticulum stress, and excessive reactive oxygen species production. These perturbations activate conserved signaling cascades, notably p38 MAPK, NF-κB, and the NLRP3 inflammasome, which drive pro-inflammatory cytokine release and sustained leukocyte infiltration. Concurrently, osmotic stress potently upregulates transforming growth factor-beta and connective tissue growth factor, precipitating epithelial-to-mesenchymal transition and myofibroblast differentiation. The consequent extracellular matrix accumulation, compounded by defective autophagy and maladaptive proliferative responses, establishes a self-sustaining loop of tubulointerstitial fibrosis. Recurrent dehydration further amplifies intrarenal renin-angiotensin-aldosterone system activity and endothelin-1 signaling, accelerating peritubular capillary loss and hypoxia-driven fibrogenesis. Recent data further implicate urea transporter dysregulation and tonicity-responsive enhancer-binding protein activation in exacerbating tubular cell cycle arrest and cellular senescence. Interpretation of these interconnected molecular networks reveals promising therapeutic targets that could interrupt the transition from acute osmotic injury to irreversible architectural damage. Finally, integrating mechanistic insights with clinical epidemiology reinforces the urgent need for evidence-based hydration protocols and novel antifibrotic strategies to mitigate the rising global incidence of dehydration-related chronic kidney disease.