CKDu and Heat Stress Nephropathy Across Eras: Regional Heterogeneity, Occupational Evidence, and Prevention in a Warming World.

BACKGROUND: Chronic kidney disease of uncertain etiology (CKDu), increasingly framed as heat stress nephropathy (HSN) in endemic settings, has evolved from a regional enigma into a climate-health concern. Affecting young workers outside the diabetes-hypertension axis, it shows how heat, labor, dehydration, and social vulnerability converge on the kidney. CKDu/HSN is best approached as heterogeneous kidney disease phenotypes: occupational heat stress is strongly supported in Mesoamerica and selected populations, whereas co-exposures, water insecurity, vulnerability, and genetic or developmental susceptibility may modify risk elsewhere. SUMMARY: This review traces CKDu/HSN from agricultural communities to its relevance as a nephrology and public-health priority. We discuss the shift from unstable definitions and geographic labels toward a clinicopathologic and policy framework. Available data support a layered model in which recurrent heat exposure, dehydration, workload, subclinical acute kidney injury, tubular stress, endogenous fructogenesis, oxidative injury, and co-exposures may contribute with different weights across settings. However, human causal validation remains incomplete, and CKDu should not be treated as a single etiologic diagnosis. We synthesize biomarker and histopathologic evidence supporting a tubulointerstitial phenotype and examine how climate change is expanding heat-related kidney risk. KEY MESSAGES: CKDu/HSN has preventable and measurable components at the intersection of climate, work, and kidney health. The strongest interventional evidence comes from occupational programs, water-rest-shade or rest-shade-hydration-hygiene strategies in sugarcane workers, including the Adelante Initiative, which improved kidney-related outcomes without clear loss of operational viability. Nephrology must translate this evidence into prevention, early detection, resilient kidney care, and climate-conscious planning.