End-stage renal disease (ESRD) is a chronic condition that disproportionately affects communities of color and diabetics. Hallmark burdens include the lack of essential renal functions and routine life-saving dialysis treatments to filter and remove toxic wastes from the body. Given their compromised survival advantage, the ESRD population is vulnerable to adverse complications associated with acute environmental exposures. However, little is known about the effect of extreme heat events (EHE), air pollution, and ambient temperature on this targeted population. This dissertation focused on ESRD patients receiving hemodialysis treatments at Fresenius Medical Care facilities within the Northeastern United States region (n=60,717). Using longitudinal study design methods, we investigated the association between acute environmental exposures and the risk of all-cause mortality (ACM) and all-cause hospital admissions (ACHA).We applied case-crossover methods to estimate acute EHE effects on mortality and hospital admissions stratified by latitude, race/ethnicity, and comorbidities. Overall, risks varied, but same-day ACM and ACHA risks were most pronounced. ESRD patients with cardiovascular disease (rate ratio [RR], 2.14; 95% CI:1.91-2.40) and cerebrovascular disease (RR, 1.47; 95% CI:1.26-1.71) had notably increased risks of same-day EHE-related mortality. We furthered our investigation by studying PM2.5 and O3 effects using a similar study design but considered the role of EHE as a modifier and incorporated distributed lag nonlinear modeling to account for cumulative lag structures. Pooled same-day EHE-adjusted models estimated an 8% ACM rate increase when O3 concentrations exceeded air quality standards during warmer months. Our data suggest that EHE can act as a modifier between O3 and ACM. Though, no effect modification by EHE was observed for acute air pollutant exposures and ACHA. Lastly, this dissertation explored the mediating role of selected thermoregulatory responses to increased temperature on ACM or ACHA outcomes using traditional mediation analyses. Systolic blood pressure before dialysis treatment (preSBP) and interdialytic weight gain change (IDWG) were identified as significant pathways. However, we observed inconsistent mediation in the IDWG pathway for ACM (-6.26%) and ACHA (-2.67%). Concomitant physiological changes in preSBP and IDWG may have little intermediary effect in combined pathway models. Overall, this research provided additional lines of evidence for enhancing patient response protocols and early warning systems to improve healthcare delivery in an era of a changing climate specific to subpopulations living with ESRD.