#1657 Impact of cumulative fluid and sodium imbalance exposure on cause-specific mortality in hemodialysis
Authors: Pinter Jule , Neumaier Anne , Christa Martin , Canaud Bernard , Mayne Kaitlin , Stuard Stefano , Jardine Meg , Smyth Brendan , Genser Bernd 
Published: May 2024

Abstract

Background and Aims
Even mild fluid overload and prolonged exposure to salt excess showed to be associated with all-cause mortality in hemodialysis patients. This analysis aims to estimate the effect of fluid and sodium imbalance on cause-specific mortality.

Method
The study followed 68,196 incident hemodialysis patients from 875 clinics in 25 countries for a decade (2010-2020) using the European Clinical Database 5. Fatal events (21,644) were classified through ICD10- codes and free text descriptions into different endpoints: cardiac death (7,926 events)—with subcomponents sudden cardiac death (2,815 events), coronary death (1,705 events) and heart failure death (3,248 events); cerebrovascular death (1,516 events), non-cardiovascular death (10,898 events)—with subcomponents death by sepsis (2,054) or other infection (1,217 events), cancer death (2,095), other non-cardiovascular death (5,532 events) and death of unknown origin (1,304 events). Time-varying cumulative exposure times (in months) of relative fluid overload/-depletion, hypo-/hypernatremia and low dialysate sodium (≤ 138) were assessed and hazard ratios (HR) were calculated using a multivariate Cox model.

Results
Fluid overload showed the most consistent exposure risk associations for cardiovascular endpoints with strongest associations in cardiac causes (arrythmia death: HR peak at 7.5 (95% CI: 4.2-3.6), heart failure death: HR peak at 4.2 (95% CI: 3.3-5.4) and sudden cardiac death: HR peak at 3.8 (95% CI: 2.6-4.5)). Fluid depletion was less important but consistently associated with all causes of death. By contrast, Hyponatremia showed heterogeneity of cause specific effects. We found slightly stronger associations for non- cardiovascular causes: Death by sepsis (HR peak at 2.3 (95% CI: 1.8-2.8)) or death by other infections (HR peak at 2.1 (95% CI: 1.6-2.7)) showed the strongest cumulative exposure risk association pattern. Hypernatremia was less important with substantially smaller effects and slightly higher associations for non-cardiovascular endpoints. For low dialysate sodium, we observed evidence of heterogeneity in cause specific effects. The risk of death due to heart failure was notably pronounced with low dialysate sodium (HR peak at 5.8 (95% CI: 1.9-17.9)), while other endpoints did not show this effect. Sensitivity analysis in patients with 48 or more months of follow-up indicated that HR in higher exposure categories might be biased downwards due to non-survival of high-risk individuals.

Conclusion
Cause-specific hazard models confirm the role of fluid and sodium imbalance as independently acting risk factors for mortality. Fluid overload has the most pronounced effect on cardiac death, especially death by heart failure, arrhythmia, or sudden death. In contrast, hyponatremia is a more critical risk factor for non-cardiovascular death, particularly death caused by sepsis or other infections. The significantly increased risk in patients on low dialysate sodium prescriptions is primarily driven by a dramatic increase in risk of death by heart failure.