Clearance of middle molecules during haemodialysis and haemodiafiltration: new insights

Patients with end-stage kidney disease exhibit the retention of a large variety of solutes that may affect a range of biological functions and, for instance, contribute to elevation of cardiovascular risk and modulate inflammatory responses. Such uraemic retention solutes can be classified on the basis of molecular size and protein binding as reviewed recently by the European Uraemic Toxin Work Group (EUTOX) [1]. Serum levels of uraemic retention solutes will reflect a complex interplay of changes in production or generation, reduced renal clearance and adsorption or clearance during renal replacement therapy, but could also be affected by protein binding or non-renal (e.g. hepatic) clearance. The recent EUTOX review demonstrated that new studies using state-of-the-art methodology show major differences in the concentration of some retention solutes from original reports. As nephrologists consider how to adjust dialysis therapy regimes to improve clinical outcomes, it is important to carefully consider the biological significance of elevated levels of any solute and how it may be influenced by the mode or dose (or intensity) of dialysis. For many years, attention has focused on highmolecular-weight toxins or middle molecules and their effects in dialysis patients or changes with dialysis therapy. β2-Microglobulin (β2M) is commonly measured as a representative middle molecule because its concentration is elevated significantly in end-stage kidney disease patients, it can be readily measured in serum, and it is readily cleared by high-flux membranes. Large randomized clinical trials have used either the clearance of β2M or serum β2M concentrations to define high-flux haemodialysis [2, 3] or haemodiafiltration [4]; however, these trials have failed to demonstrate that the use of high-flux membranes generally enhance patient survival in haemodialysis or haemodiafiltration therapies, although there may be benefits in certain patient subgroups [3–5]. These results were disappointing; many nephrologists expected more clear evidence of the importance of middle molecule removal in determining patient outcomes. The reasons why these large clinical trials did not more clearly demonstrate improved patient survival remain incompletely understood. One possible reason is that the trial interventions did not provide clearances of middle molecules that were large enough to improve patient survival. Mean predialysis serum β2M concentrations during the follow-up phase were 33.5 mg/L in the high-flux group during the HEMO study [6] and 26.4 mg/L in the haemodiafiltration group during the CONTRAST study [4], but these concentrations are still more than 10-fold higher than in individuals with normal kidney function. Furthermore, although the absolute levels of serum β2M were not reported in the primary outcome paper from the MPO study, serum levels of β2M for patients treated with high-flux membranes increased during the follow-up because incident patients participated in that study [3] and residual kidney function presumably dropped over time. In that study, the increase in serum β2M concentration in patients treated by highflux membranes was less than that in those treated by low-flux membranes; nevertheless, serum levels of β2M, and likely of other middle molecules, continued to increase above normal levels during the follow-up in patients treated by high-flux membranes. Although improvements to high-flux membrane performance continue