Clinical relevance of abstruse transport phenomena in haemodialysis

Abstract

Haemodialysis (HD) utilizes the bidirectional properties of semipermeable membranes to remove uraemic toxins from blood while simultaneously replenishing electrolytes and buffers to correct metabolic acidosis. However, the nonspecific size-dependent transport across membranes also means that certain useful plasma constituents may be removed from the patient (together with uraemic toxins), or toxic compounds, e.g. endotoxin fragments, may accompany electrolytes and buffers of the dialysis fluids into blood and elicit severe biological reactions. We describe the mechanisms and implications of these undesirable transport processes that are inherent to all HD therapies and propose approaches to mitigate the effects of such transport. We focus particularly on two undesirable events that are considered to adversely affect HD therapy and possibly impact patient outcomes. Firstly, we describe how loss of albumin (and other essential substances) can occur while striving to eliminate larger uraemic toxins during HD and why hypoalbuminemia is a clinical condition to contend with. Secondly, we describe the origins and mode of transport of biologically active substances (from dialysis fluids with bacterial contamination) into the blood compartment and biological reactions they elicit. Endotoxin fragments activate various proinflammatory pathways to increase the underlying inflammation associated with chronic kidney disease. Both phenomena involve the physical as well as chemical properties of membranes that must be selected judiciously to balance the benefits with potential risks patients may encounter, in both the short and long term.

Keywords: albumin loss; endotoxin; haemodialysis membranes; hypoalbuminemia; transport.

Figure 1:

The essence of HD therapy: four phenomena, having common modes of transport across the membrane wall, may occur simultaneously during every HD session. The net effect of all the events determines the overall efficacy of treatment, affecting patient well-being as well as long-term outcomes.

Figure 2:

The removability by standard ‘high-flux’ membranes during HD of non-uraemic toxins, i.e. compounds that do not contribute to the uraemic syndrome. The selection of the substances is arbitrary, and includes proteins having not only plasma-based functionality, but also proteins released into the blood from tissues and cells due to physiological events, and not necessarily involved in, or the result of, specific disease processes [59]. These ‘essential’ proteins that are common and well discussed compounds in various fields of medicine and diagnostics are in a similar size range as the known uraemic compounds targeted for removal in HD.

Figure 3:

Histogram depicting the molecular weight distribution of 697 observed plasma proteins analysed by Schenk et al. [59] Most of the proteins are under 60 000 Da, i.e. below the size range of the albumin molecule, removal of which during dialysis in large amounts is generally considered undesirable as it negatively impacts patient outcomes. As most of the known uraemic toxins are well below this size range and targeted for removal in HD, several essential proteins (i.e., non-toxins) could inadvertently be eliminated during dialysis with highly porous membranes.

Figure 4:

The size range of bacterium-derived substances that could prevail in dialysis fluids should they be contaminated by Gram-negative bacteria (from Jofré et al. [64]). Both endotoxins and exotoxins of the size range of most of the uraemic toxins targeted for removal in HD are present. Because of the bidirectionality of membranes and separation processes being size based, these substances have the potential to enter the patients’ bloodstream to induce pro-inflammatory reactions. A = LPS (>100 000 Da); B = lipid A (2000–4000 Da); C = other LPS fragments (<8000 Da); D = peptidoglycans (1000 to 20 000 Da); E = muramyl peptides (400–1000 Da). Secreted bacterial toxins such as exotoxin A (71 000 Da) or its fragment (<1000 Da) and other exotoxins (20 000 to 50 000 Da) may also be present, but their role in HD is less well defined. Other cellular components (bacterial DNA) of variable sizes have also been shown to pass into the blood stream during dialysis).

Figure 5:

The mechanism by which endotoxin fragments interact with certain regions of the membrane polymer. Hydrophobic regions (acyl chains) of the lipid A part of the LPS molecule adsorb to hydrophobic domains (–CH₃ groups) of the polysulfone membrane polymer, while electrostatic interactions occur between the –SO₂ groups of polysulfone and the sugar residues, core and O-antigen part of the lipid A molecule. Such interactions thus offer a degree of safety to the patient each time this type of dialysers are used for dialysis treatment. Further, such interactions have been used to develop special ultrafilters used in the dialysis fluid circuit as endotoxin adsorbers to assure high microbiological purity of dialysis fluids.