Geographic differences and their influence on tolvaptan treatment in patients with ADPKD

Introduction: Tolvaptan is the only FDA- and EMA approved disease-modifying treatment for autosomal dominant polycystic kidney disease (ADPKD), although its tolerability is associated by hydration status and aquaretic adverse effects. Environmental and climatic conditions may affect thirst perception and fluid loss; however, their influence on tolvaptan treatment outcomes has not been adequately investigated. Methods : This retrospective multicenter observational cohort study included 205 adults with ADPKD from 11 nephrology centers in Türkiye who received tolvaptan therapy for at least 12 months between 2020 and 2022. Demographic, clinical, laboratory, and imaging data were collected from medical records. Meteorological parameters including temperature, humidity, sunshine duration, latitude, and longitude were obtained from the Turkish National Meteorology Institute. Correlations between climatic variables and treatment-related parameters were evaluated using Spearman correlation analysis. Results: Treatment interruption occurred in 27.6% of patients, mainly because of aquaretic symptoms, nephrotoxicity, or hepatotoxicity. Estimated glomerular filtration rate significantly decreased over the 2-year follow-up period (p < 0.001), while serum creatinine levels increased significantly (p < 0.001). Maximum tolerated tolvaptan dose was negatively correlated with annual average temperature (r=-0.615, p < 0.05). Serum sodium levels were positively associated with humidity and negatively associated with annual sunshine duration. Serum uric acid levels were inversely correlated with latitude; serum calcium levels showed no significant correlation with temperature parameters. Conclusion : Geographic and climatic factors significantly associate with tolvaptan tolerability and biochemical responses in ADPKD. High temperatures were associated with reduced tolvaptan tolerance, whereas humidity increased and sunshine duration decreased serum sodium levels, both indicating an elevated hypernatremia risk in hot, humid, and less sunny environments. Incorporating environmental parameters into individualized tolvaptan dose adjustments may improve safety and adherence. Larger climate-diverse studies using thermal stress indices such as the Universal Thermal Climate Index (UTCI) are warranted.