Comparisons Of Biochemical And Clinical Outcomes Of Hemodialysis Patients Treated With Middle Cut-Off Dialyzers Versus High-Flux Hemodialysis Or Hemodiafiltration

The CONCORDIA study is an observational, real-world evidence investigation designed to evaluate the comparative effectiveness of dialysis modalities, specifically focusing on medium cut-off (MCO) dialyzers (Theranova) versus high-flux hemodialysis (HF-HD) and hemodiafiltration (HDF). The study is motivated by the persistently high mortality rates among hemodialysis patients and the substantial variation in outcomes across regions, suggesting that treatment practices may play a key role in influencing patient outcomes.

Conventional hemodialysis effectively removes small uremic toxins but is limited in clearing larger middle molecules, which are believed to contribute to morbidity and mortality. HDF improves clearance of these molecules but requires more complex infrastructure and higher costs. MCO membranes, such as Theranova, have been developed to enhance removal of middle and large middle molecules without requiring significant changes to dialysis delivery, representing a potentially scalable alternative.

The primary objective of the CONCORDIA study is to determine whether the use of Theranova dialyzers is associated with lower all-cause mortality compared to HF-HD. Secondary objectives include assessing whether Theranova improves biochemical outcomes relative to HF-HD and whether it is non-inferior to HDF in terms of both clinical and biochemical outcomes. Additional analyses will explore patient characteristics associated with Theranova use.

The study adopts a retrospective observational design, leveraging the extensive infrastructure of the Dialysis Outcomes and Practice Patterns Study (DOPPS) as a control cohort. Patients treated with Theranova will be recruited from non-DOPPS facilities with high utilization of MCO dialyzers, primarily in Europe. The expected sample includes approximately 500-1000 Theranova patients, compared with DOPPS cohorts of HF-HD and HDF patients.

Eligible participants are adults (≥18 years) receiving in-center maintenance hemodialysis. Data will be collected retrospectively from March to June 2026 and include demographics, comorbidities, laboratory values, dialysis prescriptions, medication use, and clinical outcomes such as mortality, cardiovascular events, infections, and hospitalizations. Data are pseudonymized to ensure patient confidentiality, including date shifting and variable binning techniques.

The primary outcome is all-cause mortality. Secondary outcomes include major adverse cardiovascular events (MACE), infection-related events, hospitalizations, and a range of biochemical parameters (e.g., hemoglobin, ferritin, phosphorus, CRP, beta-2 microglobulin). Additional outcomes include measures of volume status, blood pressure, and medication utilization.

Analytically, the study will use Cox proportional hazards models with sequential adjustment for confounders, including demographics, comorbidities, and treatment factors. Matching and multivariable adjustment will be employed to mitigate confounding by indication. Both superiority (Theranova vs HF-HD) and non-inferiority (Theranova vs HDF) analyses will be conducted. The non-inferiority margin is informed by prior randomized trial data comparing HDF and HF-HD.

Overall, CONCORDIA aims to generate robust real-world evidence on the comparative effectiveness of MCO dialyzers, informing clinical practice and supporting future trial design.