Mechanistic models for intermittent haemodialysis and haemodiafiltration clearance

Haemodialysis has been used clinically for more than 70 years, but data regarding the clearance of medicines during dialysis are often based on studies with outdated, less efficient dialysers. Moreover, dialysis clearance is still frequently estimated using empirical approaches which lack mechanistic interpretability, are not readily generalizable across medicines or dialysis modalities and may underestimate medicine clearance with contemporary dialysers. Furthermore, the increasing use of haemodiafiltration, which combines diffusion and convection, limits the applicability of haemodialysis models that account only for diffusion clearance. We therefore developed a mechanistic, theory-based framework to quantify both diffusion and convection clearance during haemodialysis or haemodiafiltration. Dialysance, described by Michaels in 1966, was extended to demonstrate its applicability to both obsolete recirculating and contemporary single-pass dialysis systems. Diffusion clearance was described using blood and dialysate flow rate and the mass transfer-area coefficient. Convection clearance was described using convection volume, plasma water flow and sieving coefficients. We introduce a dimensionless metric for dialysis efficiency, which we show is equivalent to the well-known hepatic extraction ratio. This metric provides a bounded, physiologically interpretable measure of dialyser performance that avoids ambiguity associated with traditional solute clearance-based efficiency metrics. The proposed framework supports a mechanistic approach to estimation of dialysis clearance applicable to population pharmacokinetic models. This approach offers a theoretically generalizable method for quantifying dialysis clearance and a target concentration approach to individualized dosing of medicines during haemodialysis or haemodiafiltration.