Clearance of Beta-2-Microglobulin and Middle Molecules in Haemodiafiltration

Abstract

Middle molecules, consisting mostly of peptides and small proteins with molecular weight the range of 500-60,000 Da, accumulate in renal failure and contribute to the uraemic toxic state. Beta2-microglobulin (beta2-MG) with a molecular weight of 11,000 is considered representative of these middle molecules. These solutes are not well cleared by low-flux dialysis. High-flux dialysis will clear middle molecules, partly by internal filtration. This convective component of high-flux dialysis can be enhanced in a predictable way by haemodiafiltration (HDF). The convective and diffusive clearance rates of any middle molecule across any haemodiafilter can be predicted from known or measurable factors such as its sieving coefficient, bound fraction and molecular weight. The removal of middle molecules is also influenced by factors within the patient. Beta2-MG is distributed within the extracellular fluid. During HDF, beta2-MG must transfer into the intravascular compartment across the capillary walls. This transcapillary transfer at a rate of approximately 100 ml/min slows beta2-MG removal from the body. Continuing transfer after the end of a treatment session results in a significant rebound of beta2-MG levels. This intercompartment transfer and its effect on beta2-MG clearance and concentration can be predicted by a 2-compartment model. By extrapolation, the behaviour of other middle molecules can be predicted. The 2-compartment model, which takes non-dialytic beta2-MG clearance at a rate of 3 ml/min and beta2-MG generation at a rate of 0.1 mg/min into account, can predict the effect of any HDF schedule on beta2-MG levels. Low-flux dialysis results in a beta2-MG level of around 40 mg/l. Three times weekly, 4-hour HDF can reduce beta2-MG levels to around 20 mg/l. Long (nocturnal) HDF can reduce beta2-MG levels to around 10 mg/l, compared to physiological levels of less than 5 mg/l.

Serum 2-microglobulin level is a significant predictor of mortality in maintenance haemodialysis patients

“…Reduction of serum β 2 -M has been demonstrated to be effective for the treatment of dialysis-related amyloidosis, through the use of haemodiafiltration, ultrapure dialysate, high-flux membrane and adsorptive affinity column for β 2 -M [2][3][4][5][6][7]. Reduction of serum β 2 -M has been demonstrated through the use of long dialysis and daily dialysis [16,17].…”

“…Compared to low-flux haemodialysis, which does not remove circulating β 2 -M, high-flux haemodialysis is associated with a significant clearance of circulating β 2 -M [2,16]. Although primary data analysis of the HEMO study did not prove a benefit of high-flux compared to lowflux membranes [19], several studies have demonstrated better outcomes in dialysis patients treated with high-flux membranes [23][24][25][26].…”

Biomarkers for Evaluation of Clinical Outcomes of Hemodiafiltration

“…Hemodiafiltration (HDF) can efficiently remove uremic toxins, from low-molecular-weight to large-molecular-weight substances, by using a combination of diffusion and convection [1,2,3]. More specifically, the benefits of HDF can be best utilized and good therapeutic efficacy achieved in the treatment of insomnia, pruritus, irritability, restless legs syndrome (RLS), anemia, dialysis amyloidosis (DA), etc., when removal performance of low-molecular-weight protein (LMWP) is improved [4,5,6,7].…”

Long-Term Outcomes in Online Hemodiafiltration and High-Flux Hemodialysis

“…Furthermore, no large published outcome studies have directly compared survival between online HDF and high-flux HD. HDF has been demonstrated to be a superior provider of middle molecule clearance (3)(4)(5). Observational studies have suggested that increased ␤2 microglobulin clearance by high-flux HD is associated with reduced incidence of dialysis-related amyloidosis compared with low-flux HD (6,7).…”