In the last few years, the number of hemodialysis patients with inadequate blood flow (Qb) rates has increased due to vascular access problems. To avoid a clinical status of underdialysis, these patients need long-lasting dialysis sessions. However, other factors aimed to optimize the dialysis dose have to be considered. High-efficiency convective therapies, such as online hemodiafiltration (HDF), are claimed to be superior to high-flux hemodialysis (HF-HD) in improving the dialysis efficacy, but treatment efficacy is strongly related to blood flow rate and infusion volumes. Online mid-dilution (HDF-MD) with the Nephros OL-pure MD190 represents a new HDF concept to increase the removal of middle molecules. In a cross-over clinical trial, 8 patients, with Qb eff <300 mL/min, received either online HDF-MD or HF-HD; Qd was 700 mL/min, the time duration was 240 min, and the filtration volume in HDF-MD was 112+/-7 mL/min. No differences were found for Kt/V, urea, and creatinine clearances. Clearance of both small phosphate (P) large beta(2)-microglobulin (beta(2)m), and leptin (L) solutes was significantly greater for MD (P 217+/-32, beta(2)m 85.5+/-10, L 42.6+/-18 mL/min) than for HF-HD (P 178+/-32, beta(2)m 71.9+/-13, L 32.1+/-12 mL/min). The results of this study indicate that HDF remains the best means of providing increased removal of large-molecular weight solutes even in patients with vascular access problems.