Evaluation of the efficacy of an interdialytic "ethanol 40% v/v - enoxaparin 1000 U/mL" lock solution to prevent tunnelled catheter infections in chronic hemodialysis patients: a multi-centre, randomized, single blind, parallel group study.

BACKGROUND: Tunnelled dialysis catheter (TC) infections are a major health complication and are associated with increased antibiotic consumption, hospital stays, health costs and mortality. Experimental data provide evidence that Ethenox, a mixture of enoxaparine 1000 U/mL in 40% v/v ethanol, could be a promising lock solution. The aim of the study is to compare an interdialytic lock solution of Ethenox with reference lock solutions, unfractionated heparin (UFH) or citrate 4% for the prevention of TCI in hemodialysis patients. METHOD: This study will monitor a multicentre, prospective, single blind, randomized, controlled, parallel group trial. The main inclusion criteria are patients > 18 years old with end-stage renal disease, treated with chronic hemodialysis/hemodiafiltration three times a week, with incident or prevalent non-impregnated internal jugular TCs inserted for at least 2 weeks and able to give informed consent. Exclusion criteria are TCI in the previous 4 weeks and anti-infective treatment for TCI in the previous 2 weeks. Patients will be randomized to receive either study treatment Ethenox in the intervention group or reference solutions in the control group, unfractionated heparin (UFH) or citrate 4% w/v according to usual practice. The primary outcome measure will be time to first TCIs assessed by an endpoint adjudication committee blinded to the study arm according to predefined criteria. Patients will receive the study treatment for up to 12 months. Intention-to-treat analysis of the primary endpoint will be performed with a marginal Cox proportional hazard model. Prospective power calculations indicate that the study will have 90% statistical power to detect a clinical significant two-fold increase in median infection-free survival if 200 patients are recruited into each arm over a period of 24 months. DISCUSSION: Firm evidence of the efficacy of the Ethenox lock in preventing TCI could be of major clinical benefit for patients. The results of this study will allow the development of new guidelines based on a high level of evidence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03083184 , date of registration March 17 2017 and European Clinical Trials Database Identifier: EudraCT 2016-A00180-51), date of registration July 11 2016.

Protein-bound uraemic toxin removal in haemodialysis and post-dilution haemodiafiltration.

BACKGROUND: The accumulation of larger and protein-bound toxins is involved in the uraemic syndrome but their elimination by dialysis therapy remains difficult. In the present study, the impact of the albumin permeability of recently introduced advanced high-flux dialysis membranes on the removal of such substances was tested in haemodialysis and online post-dilution haemodiafiltration. METHODS: Two types of polyethersulfone membranes only differing in albumin permeability (referred as PU- and PU+) were compared in eight patients on maintenance dialysis in a prospective cross-over manner. Treatment settings were identical for individual patients: time 229 +/- 22 min; blood flow rate 378 +/- 33 mL/min; dialysate flow rate 500 mL/min; substitution flow rate in haemodiafiltration 94 +/- 9 mL/min. Removal of the protein-bound compounds p-cresyl sulfate (pCS) and indoxyl sulfate (IS) was determined by reduction ratios (RRs), dialytic clearances and mass in continuously collected dialysate. In addition, the elimination of the low-molecular weight (LMW) proteins beta(2)-microglobulin, cystatin c, myoglobin (myo), free retinol-binding protein (rbp) and albumin was measured. RESULTS: Plasma levels of the protein-bound toxins were significantly decreased by all treatment forms. However, the decreases were comparable between dialysis membranes and between haemodialysis and haemodiafiltration. The RRs of total pCS ranged between 40.4 +/- 25.3 and 47.8 +/- 10.3% and of total IS between 50.4 +/- 2.6 and 54.6 +/- 8.7%. Elimination of free protein-bound toxins as assessed by their mass in dialysate closely correlated positively with the pre-treatment plasma concentrations being r = 0.920 (P < 0.001) for total pCS and r = 0.906 (P < 0.001) for total IS, respectively. Compared to haemodialysis, much higher removal of all LMW proteins was found in haemodiafiltration. Dialysis membrane differences were only obvious in haemodialysis for the larger LMW proteins myo and rbp yielding significantly higher RRs for PU+ (myo 46 +/- 9 versus 37 +/- 9%; rbp 18 +/- 5 versus 15 +/- 5%; P < 0.05). Additionally, the albumin loss varied between membranes and treatment modes being undetectable with PU- in haemodialysis and highest with PU+ in haemodiafiltration (1430 +/- 566 mg). CONCLUSIONS: The elimination of protein-bound compounds into dialysate is predicted by the level of pre-treatment plasma concentrations and depends particularly on diffusion. Lacking enhanced removal in online post-dilution haemodiafiltration emphasizes the minor significance of convection for the clearance of these solutes. Compared to LMW proteins, the highly protein-bound toxins pCS and IS are less effectively eliminated with all treatment forms. For a sustained decrease of pCS and IS plasma levels, alternative strategies promise to be more efficient therapy forms.

Mid-dilution on-line haemodiafiltration in a standard dialyser configuration.

BACKGROUND: Mid-dilution haemodiafiltration (HDF) results in an improved middle molecule removal compared with standard HDF. The OLpur MD 190 haemodiafilter represents a new dialyser design exclusively for mid-dilution on-line HDF. Compared with standard haemodialysers, structural changes in the headers allow the infusion of high replacement fluid volumes after a first post-dilution and before a second pre-dilution stage. METHODS: We compared in vitro the new device [blood flow (QB) 400 ml/min, substitution flow (QS) 100 and 200 ml/min, dialysate flow (QD) 800 ml/min] with a conventional high-flux dialyser of the same surface area in haemodialysis (HD) (QD 500 ml/min) and post-dilution HDF (at QS 60, QD = 500 ml/min and at QS 100, QD = 800 ml/min) modes. Subsequently, we performed an initial clinical application of the new device in six mid-dilution HDF treatments of five end-stage renal disease patients (QB 400 ml/min, QS 200 ml/min, QD 800 ml/min, treatment duration 205+/-23 min). RESULTS: In vitro urea and beta2-microglobulin clearances in mid-dilution HDF were, respectively, 309.2+/-5.5 and 144.4+/-15.2 ml/min (QS 100) and 321.6+/-4.1 and 204.9+/-4.1 ml/min (QS 200), compared with 278.6+/- 17.2 and 94.0+/-7.6 ml/min in HD, and 310.8+/-10.2 and 123.0+/-6.5 ml/min (QS 60) and 323.6+/-11.2 and 158.0+/-10.3 ml/min (QS 100) in post-dilution HDF. The in vivo trials showed the clinical utility of the device and confirmed the in vitro data: urea and beta2-microglobulin clearances were, respectively, 324.6+/- 10.9 and 207.9+/-29.3 ml/min, while reduction ratios were 75.0+/-5.5 and 83.6+/-4.7%. CONCLUSION: Our preliminary results need confirmation in a prospective cross-over study. However, the Nephros MD 190 haemodiafilter promises to be a true technological step ahead in terms of improved beta2-microglobulin removal.