Kidney failure is a prevalent and severe chronic noncommunicable disease that is increasingly common worldwide. Hemodiafiltration and hemodialysis are two widely accepted therapies for patients with this condition. While practice variations exist across continents, hemodialysis is the more commonly utilized method overall. As per the New England Journal Of Medicine, multiple randomized controlled trials have sought to determine whether hemodiafiltration provides superior survival outcomes compared to hemodialysis.
However, three of these trials yielded inconclusive results, while the fourth demonstrated a survival advantage for hemodiafiltration. Observers from the scientific and nephrology communities raised concerns about attrition during follow-up in these trials. A meta-analysis of individual participant data from the four trials suggested that high-dose hemodiafiltration, with a convection volume of at least 23 liters per session, delivered in post dilution mode, may offer a survival benefit.
However, the analysis did not predefine dose dependency, leaving room for confounding based on medical indications for treatment. Study-level meta-analyses that included additional studies with various dialysis methods also failed to provide conclusive evidence. Given the prevailing uncertainty, a pragmatic, open-label, randomized controlled trial was initiated to investigate the potential survival benefits of high-dose hemodiafiltration compared to conventional high-flux hemodialysis.
The trial revealed a lower risk of all-cause mortality among patients with kidney failure who underwent high-dose hemodiafiltration, compared to those receiving conventional high-flux hemodialysis. Previous meta-analyses of various convective dialysis therapies versus hemodialysis had shown a reduction in cardiovascular mortality but no effect on all-cause mortality, nonfatal cardiovascular events, or hospitalization.
Another individual-participant data analysis of four randomized controlled trials further supported the survival benefit of hemodiafiltration, particularly among patients receiving high-dose treatment. However, this beneficial effect was attributed to potential confounding due to indication, as healthier patients with lower event risks were more likely to achieve higher convection volumes.
What sets this trial apart from previous studies is its enrollment of patients who were highly likely candidates for high-dose hemodiafiltration. The trial did not identify any specific patient characteristic or vascular access type associated with failure to achieve the high-dose target. Thus, the results provide further support for the clinically significant survival benefit of high-dose hemodiafiltration. Importantly, being both randomized and controlled, the trial’s findings suggest that confounding by indication is unlikely to explain the observed association.
Historically, pharmacologic intervention studies targeting patients with kidney failure have often yielded neutral results. This may be attributed to the limited efficacy of interventions focused on modifying a single late-stage mechanism in patients with multiple concurrent illnesses. In contrast, hemodiafiltration is a nonselective intervention with the potential to engage multiple mechanisms, including increased removal of uremic toxins and other physiological processes.
Although sub analyses indicate a potential benefit of hemodiafiltration for infection-related and cardiovascular deaths, interpreting these findings is complicated by the addition of COVID-19 diagnoses during the trial. Distinguishing between COVID-19-related deaths and deaths from other causes, such as cardiovascular events, in patients diagnosed with COVID-19 remains challenging. Therefore, caution should be exercised when interpreting these subanalyses.
While the trial design aimed to provide an unbiased effect estimate by ensuring complete follow-up of mortality and avoiding data censoring after key events like renal transplantation, certain limitations should be acknowledged. The achieved sample size was lower than initially calculated due to recruitment difficulties during the COVID-19 pandemic and related lockdowns. Moreover, the overall risk of death was lower than generally reported, partly due to the selection of patients likely to achieve high convection volumes, indicating relatively good vascular access. The trial’s findings of an association between hemodiafiltration and reduced all-cause mortality remain valid despite the overall lower risk of death among the trial patients.
To impact clinical practice, the generalizability of the trial’s findings must be considered. The trial’s pragmatic design, with fewer exclusion criteria, supports its applicability. However, the inclusion criteria may have resulted in a trial population that was healthier than the broader hemodialysis population in Europe and the United States. Additionally, data on race or ethnic groups were not collected for the European patients, limiting the generalizability of the findings to non-White patients with kidney failure.
Furthermore, the absolute survival advantage of hemodiafiltration may vary among individual patients within the treatment group. Previous reports have indicated that younger patients without diabetes or cardiovascular disease, with increased serum creatinine and albumin levels, derive the most benefit from hemodiafiltration.
Updating the hemodiafiltration-pooling project with individual-participant data from the present trial and other trials would enable a more precise exploration of treatment effects across various subgroups. Overall, the trial’s results, combined with findings from other trials and large observational studies, support the acceptable safety profile of hemodiafiltration when hygienic and microbiologic rules are strictly followed.
In this trial, conducted over a median follow-up period of 30 months, high-dose hemodiafiltration demonstrated a lower risk of death among patients with kidney failure compared to conventional high-flux hemodialysis. These findings contribute to the growing body of evidence supporting the survival benefits of hemodiafiltration.
