Assessing proximate intermediates between ambient temperature, hospital admissions, and mortality in hemodialysis patients.

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Typical thermoregulatory responses to elevated temperatures among healthy individuals include reduced blood pressure and perspiration. Individuals with end-stage kidney disease (ESKD) are susceptible to systemic fluctuations caused by ambient temperature changes that may increase morbidity and mortality. We investigated whether pre-dialysis systolic blood pressure (preSBP) and interdialytic weight gain (IDWG) can independently mediate the association between ambient temperature, all-cause hospital admissions (ACHA), and all-cause mortality (ACM). The study population consisted of ESKD patients receiving hemodialysis treatments at Fresenius Medical Care facilities in Philadelphia County, PA, from 2011 to 2019 (n=1981). Within a time-to-event framework, we estimated the association between daily maximum dry-bulb temperature (TMAX) and, as separate models, ACHA and ACM during warmer calendar months. Clinically measured preSBP and IDWG responses to temperature increases were estimated using linear mixed effect models. We employed the difference (c-c') method to decompose total effect models for ACHA and ACM using preSBP and IDWG as time-dependent mediators. Covariate adjustments for exposure-mediator and total and direct effect models include age, race, ethnicity, blood pressure medication use, treatment location, preSBP, and IDWG. We considered lags up to two days for exposure and 1-day lag for mediator variables (Lag 2-Lag 1) to assure temporality between exposure-outcome models. Sensitivity analyses for 2-day (Lag 2-only) and 1-day (Lag 1-only) lag structures were also conducted. Based on Lag 2- Lag 1 temporal ordering, 1°C increase in daily TMAX was associated with increased hazard of ACHA by 1.4% (adjusted hazard ratio (HR), 1.014; 95% confidence interval, 1.007-1.021) and ACM 7.5% (adjusted HR, 1.075, 1.050-1.100). Short-term lag exposures to 1°C increase in temperature predicted mean reductions in IDWG and preSBP by 0.013-0.015% and 0.168-0.229mmHg, respectively. Mediation analysis for ACHA identified significant indirect effects for all three studied pathways (preSBP, IDWG, and preSBP+IDWG) and significant indirect effects for IDWG and conjoined preSBP+IDWG pathways for ACM. Of note, only 1.03% of the association between temperature and ACM was mediated through preSBP. The mechanistic path for IDWG, independent of preSBP, demonstrated inconsistent mediation and, consequently, potential suppression effects in ACHA (-15.5%) and ACM (-6.3%) based on combined pathway models. Proportion mediated estimates from preSBP+IDWG pathways achieved 2.2% and 0.3% in combined pathway analysis for ACHA and ACM outcomes, respectively. Lag 2 discrete-time ACM mediation models exhibited consistent mediation for all three pathways suggesting that 2-day lag in IDWG and preSBP responses can explain 2.11% and 4.41% of total effect association between temperature and mortality, respectively. We corroborated the previously reported association between ambient temperature, ACHA and ACM. Our results foster the understanding of potential physiological linkages that may explain or suppress temperature-driven hospital admissions and mortality risks. Of note, concomitant changes in preSBP and IDWG may have little intermediary effect when analyzed in combined pathway models. These findings advance our assessment of candidate interventions to reduce the impact of outdoor temperature change on ESKD patients.