Abstract
BackgroundBeta-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.MethodsHerein we undertook a systematic review of existing studies reporting patient level data concerning generation, elimination and distribution of β2M in order to develop a population model of β2M kinetics. We used this model and previously determined relationships between predialysis β2M concentration and survival, to simulate the population distribution of predialysis β2M 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).ResultsWe identified 9 studies of 106 individuals and 156 evaluations of or more compartmental kinetic parameters of β2M. These studies used a variety of experimental methods to determine β2M 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 β2M. In large scale (N = 10000) simulations of individuals drawn from the population of β2M kinetic parameters, we found that, higher dialytic removal materially affects β2M exposures only when RRF (renal clearance of β2M) 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 β2M generation rate.ConclusionsPreservation 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 β2M may allow personalization of hemodialysis prescription and/or facilitate the design of such studies by identifying patients with higher β2M generation rate.
Highlights
In patients initiating conventional high flux (HF) hemodialysis, total loss of Residual renal function (RRF) was predicted to be associated with a relative risk (RR) of death of more than 20%
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
Beta 2 Microglobulin (β2M) is an 11.6 kDa protein expressed in the surface of every nucleated cell, where it non-covalently associates with the alpha-chain of the Major Histocompatibility Complex I (MHC-I)/Human Leukocyte Antigen I (HLA-I) to facilitate antigen presentation. [1,2] It has long been appreciated that glomerular filtration is the major pathway for the elimination of β2M. [3,4,5,6,7] Residual renal function (RRF), inflammation and malnutrition appear to affect β2M concentration in patients with chronic kidney disease (CKD) [8,9,10,11] and end-stage renal disease (ESRD) [12,13,14,15,16,17]
Summary
Beta 2 Microglobulin (β2M) is an 11.6 kDa protein expressed in the surface of every nucleated cell, where it non-covalently associates with the alpha-chain of the Major Histocompatibility Complex I (MHC-I)/Human Leukocyte Antigen I (HLA-I) to facilitate antigen presentation. [1,2] It has long been appreciated that glomerular filtration is the major pathway for the elimination of β2M. [3,4,5,6,7] Residual renal function (RRF), inflammation and malnutrition appear to affect β2M concentration in patients with chronic kidney disease (CKD) [8,9,10,11] and end-stage renal disease (ESRD) [12,13,14,15,16,17]The main recognized manifestation of β2M accumulation in patients receiving long-term dialysis is dialysis-related amyloidosis [18,19,20,21,22], but more recently β2M has been linked to higher mortality in hemodialysis (HD) patients [14,23,24], to aortic calcification and cardiovascular mortality in patients with non-dialysis dependent CKD [25]. More efficient dialytic removal of β2M has not equivocally translated into improved outcomes in randomized controlled trials (RCT) of High Flux membranes [14,26] and on-line hemodiafiltration (HDF) [27,28,29] creating uncertainty regarding the clinical effectiveness of enhanced middle molecule removal Understanding of these discrepant findings and their implication for the middle molecule toxin theory that has been the driving biological hypothesis for the majority of randomized trials to date, requires one to simultaneously consider the ability of the available dialysis modalities to remove β2M and the considerable intra-individual, biological, variability in the kinetics of β2M. This report aims to develop a population kinetic model incorporating the intra-individual variability in generation, distribution and extrarenal elimination of β2M, which is used to describe the disposition of β2M under different HD regimes and levels of RRF To develop this population kinetic model, we first undertook a patient-level review and synthesis of the literature of clinical studies (either observational or interventional) regarding these kinetic parameters of β2M in humans. A quantitative description of the relative importance of factors determining β2M concentrations among patients with impaired kidney function is currently lacking
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