Revisiting the Middle Molecule Hypothesis of Uremic Toxicity: A Systematic Review of Beta 2 Microglobulin Population Kinetics and Large Scale Modeling of Hemodialysis Trials In Silico

BACKGROUND: Beta-2 Microglobulin (β2M) is a prototypical “middle molecule” uremic toxin that has been associated with a higher risk of death in hemodialysis patients. A quantitative description of the relative importance of factors determining β2M concentrations among patients with impaired kidney function is currently lacking. METHODS: Herein we undertook a systematic review of existing studies reporting patient level data concerning generation, elimination and distribution of β(2)M in order to develop a population model of β(2)M kinetics. We used this model and previously determined relationships between predialysis β(2)M concentration and survival, to simulate the population distribution of predialysis β(2)M and the associated relative risk (RR) of death in patients receiving conventional thrice-weekly hemodialysis with low flux (LF) and high flux (HF) dialyzers, short (SD) and long daily (LD) HF hemodialysis sessions and on-line hemodiafiltration at different levels of residual renal function (RRF). RESULTS: We identified 9 studies of 106 individuals and 156 evaluations of or more compartmental kinetic parameters of β(2)M. These studies used a variety of experimental methods to determine β(2)M kinetics ranging from isotopic dilution to profiling of intra/inter dialytic concentration changes. Most of the patients (74/106) were on dialysis with minimal RRF, thus facilitating the estimation of non-renal elimination kinetics of β(2)M. In large scale (N = 10000) simulations of individuals drawn from the population of β(2)M kinetic parameters, we found that, higher dialytic removal materially affects β(2)M exposures only when RRF (renal clearance of β(2)M) was below 2 ml/min. In patients initiating conventional HF hemodialysis, total loss of RRF was predicted to be associated with a RR of death of more than 20%. Hemodiafiltration and daily dialysis may decrease the high risk of death of anuric patients by 10% relative to conventional, thrice weekly HF dialysis. Only daily long sessions of hemodialysis consistently reduced mortality risk between 7–19% across the range of β(2)M generation rate. CONCLUSIONS: Preservation of RRF should be considered one of the therapeutic goals of hemodialysis practice. Randomized controlled trials of novel dialysis modalities may require large sample sizes to detect an effect on clinical outcomes even if they enroll anuric patients. The developed population model for β(2)M may allow personalization of hemodialysis prescription and/or facilitate the design of such studies by identifying patients with higher β(2)M generation rate.