Defining the Optimal Ultrafiltration Rate to Reduce Mortality in Hemodialysis: Target Trial Emulation in a Multinational Cohort

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Background: While insufficient ultrafiltration may lead to fluid overload and cardiovascular complications, overly aggressive fluid removal increases the risk of intradialytic hypotension, ischemic injury, and death. Despite growing evidence that high ultrafiltration rates (UFR) are associated with increased mortality, the optimal UFR remains undefined—particularly in relation to sex-specific outcomes. Methods: Using target trial emulation, we assessed the association between UFR (ml/h/kg, normalized to post-dialysis weight) and all-cause mortality in incident patients receiving hemodiafiltration or high-flux hemodialysis at NephroCare centers across eight European countries (2014–2019). Patients with residual kidney function were excluded. The cohort was drawn from the European Clinical Database 5, an electronic health record repository. Six UFR categories were compared: <6, 6–<8, 8–<10, 10–<12, 12–<14, and ≥14 ml/h/kg (reference group). A nested target trial design and inverse probability of treatment weighting across 45 covariates—including demographics, comorbidities, dialysis parameters, labs, vitals, and medications—were applied to emulate randomization. Results: Among 19,539 patients (35,455 person-years), 4,125 deaths occurred, yielding a mortality rate of 11.9/100 person-years (95% CI: 11.5–12.2). On average, the UFR was 12.8 ± 4.9 ml/h/kg. Compared to the reference group, we observed a stepwise linear inverse reduction in hazard of all-cause mortality, from 0.83 (95% CI 0.76-0.90) on a rate of 12-14 ml/h/kg to 0.53 (95%CI 0.44-0.63) on a rate of < 6ml/h/kg (figure 1). There was no evident effect modification by gender (lack of substantial heterogeneity, I2 values: 0% to 27.1%). Conclusion: Lower UFR are strongly and independently associated with improved survival in hemodialysis patients, regardless of sex. These findings support individualized fluid management strategies that prioritize lower UFR while preventing chronic fluid overload.