High Cutoff Membranes for Mediators Removal

Cytokines are middle molecular weight molecules having autocrine, paracrine, and/or endocrine effects. These molecules regulate the hormonal, metabolic, and immunologic responses to external (e.g., infection, trauma) or internal (e.g., ischemia, cancer) aggressions. After an insult, patients produce and release a vast amount of these mediators and, in some cases, may overexpress them in relation to the etiologic stimulus. This impairment in regulation of cytokines is recognized as a main pathophysiologic mechanism in the systemic inflammatory syndromes (i.e., sepsis or severe acute pancreatitis), common among critically ill patients. A number of attempts have been made in the past to attenuate the clinical expression of the dysregulation through the suppression of specific mediators implicated in either inflammatory or antiinflammatory pathways. However, those efforts failed to produce required clinical improvement because of the redundant and pleiotropic effects of the cytokines. Instead, the nonselective contemporary removal of various mediators has been recognized as the effective alternative. The latter is actually able to modify inflammatory and antiinflammatory effects in different metabolic pathways. During the last decade, the extracorporeal removal of cytokines has been proposed as one of the therapeutic options to reduce these overexpressed molecules. Numerous theories have been offered to explain the role of this in modulating the inflammatory pathways. The “peak concentration hypothesis” states that by preventing the early peak of circulating molecules, these techniques are capable of preventing and modulating the clinical effects of inflammatory and antiinflammatory responses. This extracorporeal removal reduces the serum concentration of different cytokines in the same pathways preventing its clinical manifestation (“threshold immunomodulation hypothesis”). The reduction in serum concentration achieved by high-volume fluid exchange treatments, which is accompanied by an increased lymphatic flow, leads to a proportional reduction in tissue cytokine concentration as mentioned in the “mediator delivery hypothesis.” Furthermore, the reduction in the circulating level of molecules could restore the concentration gradient necessary to guide the reticuloendothelial system to the main production site (i.e., the source of infection), improving the efficiency of the immune system (cytokinetic model). Finally, a direct immune-homeostatic role has been demonstrated for some extracorporeal blood purification therapies that modulate the HLA-DR expression, correlating with cell activation and interaction with some cell reproductive systems.

Numerous types of blood purification therapies have been described in last few years for the mediator removal in the hyperinflamed patients in the intensive care unit (ICU), but none is recognized as superior over others. The use of high cutoff membranes (HCO) in the extracorporeal circuit for renal replacement therapy has been proposed as a valuable therapeutic choice for hyperinflamed patients with acute kidney injury (AKI) in the ICU.

The effects of HCO for the mediator removal in hyperinflamed patients with AKI have been tested previously, with conflicting results seen in the literature. The lack of a standardized definition of HCO and the different settings and treatment modalities in studies undertaken are possible explanations for these nonhomogeneous clinical results. Indeed, many terms have been used to categorize these membranes (e.g., high permeability, super high-flux), causing major confusion to compare results. In fact, although several randomized clinical trials and observational studies claim to have used an HCO, they failed to actually express all the membrane characteristics including pore size or cutoff value. Moreover, studies often miss specifying the treatment settings as blood flow or effluent dose rendering them useless for comparative purposes. On a systematic review recently published, Villa et al. have showed these pitfalls ; in particular, these authors have performed a systematic review using all possible terminology related to HCO (e.g., high cutoff, high permeability, super high flux, large pore). With this search strategy, the authors obtained 98 studies; nevertheless, most of them were excluded for the lack of specific information about the treatment setting or because, although the authors declared to have used an HCO, the actual membrane cutoff was lower than 60 kDa. Interestingly, at the end of the screening process, only three case reports, three studies on animals, 11 in vitro/ex vivo studies, and six randomized clinical trials/observational studies fulfilled the optimum criteria.

Most international scientific societies agree that a univocal definition of the membrane cutoff and HCO should be adopted.

Engineering Characteristics of High Cut-off Membrane

The development of HCO represents one of the most recent advances in membrane technology for renal replacement therapy. Their indications encompass all clinical conditions in which an effective removal of substances in the range of 20 kDa to 50 kDa is desired. The sieving coefficient (SC) profile slightly differs from that observed in the physiologic glomerular filtration barrier, and a comparable clearance may be obtained for molecules such as myoglobin, free light chain immunoglobulins, or cytokines.

The high transmembrane clearance for middle molecular weight molecules achievable with a HCO is due mainly to the increase in the pore size (>0.01 µm, around double that of a standard high-flux membrane, Fig. 173.1 ) and thus to the increased membrane porosity for middle molecular weight molecules. As a consequence, an increased cutoff usually is perceived.

The cutoff value for a membrane is identified with the range of molecular weights of the smallest solutes cleared by the membrane. Otherwise stated, considering the normal distribution of membranes' pore size, the statistical cutoff value is identified as the molecular weight of the solute with an SC of 0.1. Currently, HCO are identified clinically as membranes with a cutoff value that approximates the molecular weight of albumin (i.e., 60 KDa). This feature is important to achieve clinically relevant clearance of “filterable” toxins such as multiple myeloma light chains, myoglobin, or inflammatory mediators.

On the other hand, HCO showed an increased retention onset, defined as the mean value of the molecular weight of those molecules with an SC equal to 0.9. Retention onset is clinically represented by the molecular weight of the smallest molecules that are subjected to transmembrane retention. The higher retention onset allows the clinician to increase and maintain clearance of molecules with a lower molecular weight for longer periods of time (i.e., myoglobin [18KDa], β2-microglobulin [12KDa], interleukin-8 [8 KDa]). The adhesion of proteins to the membrane surface commonly occurs during the treatment, and this new layer (“protein cake”) acts as a barrier that further affects the transmembrane clearance by means of pore occlusion. This phenomenon leads to the so-called membrane fouling. The increase in the retention onset by increasing pore size diminishes the membrane fouling effect, allowing a prolonged clearance for molecules with lower (up to 20KDa) molecular weight.