Haemodiafiltration at increased plasma ionic strength for improved protein-bound toxin removal

Aim: Protein-bound uraemic toxin accumulation causes uraemia-associated cardiovascular morbidity. Enhancing the plasma ionic strength releases toxins from protein binding and makes them available for removal during dialysis. This concept was implemented through high sodium concentrations ([Na+]) in the substituate of pre-dilution haemodiafiltration at increased plasma ionic strength (HDF-IPIS). Methods: Ex vivo HDF-IPIS with blood tested increasing [Na+] to demonstrate efficacy and haemocompatibility. Haemocompatibility was further assessed in sheep using two different HDF-IPIS set-ups and [Na+] between 350 and 600mmolL(-1). Safety and efficacy of para-cresyl sulphate (pCS) and indoxyl sulphate (IS) removal was further investigated in a randomized clinical pilot trial comparing HDF-IPIS to HD and HDF. Results: Compared to [Na+] of 150mmolL(-1), exvivo HDF-IPIS at 500mmolL(-1) demonstrated up to 50% higher IS removal. Haemolysis in sheep was low even at [Na+] of 600mmolL(-1) (free Hb 0.0160.001gdL(-1)). In patients, compared to HD, a [Na+] of 240mmolL(-1) in HDF-IPIS resulted in 40% greater reduction (48.7 +/- 23.6 vs. 67.8 +/- 7.9%; P=0.013) in free IS. Compared to HD and HDF (23.0 +/- 14.8 and 25.4 +/- 10.5 mLmin(-1)), the dialytic clearance of free IS was 31.6 +/- 12.8 mLmin(-1) (P=0.017) in HDF-IPIS, but [Na+] in arterial blood increased from 132 +/- 2 to 136 +/- 3mmolL(-1) (0 vs. 240min; P<0.001). Conclusion: HDF-IPIS is technically and clinically feasible. More effective HDF-IPIS requires higher temporary plasma [Na+], but dialysate [Na+] has to be appropriately adapted to avoid sodium accumulation.