Exploring the Clinical Relevance of Providing Increased Removal of Large Middle Molecules

Abstract

Dialysis technologies have continued to advance over recent decades; however, these advancements have not always been met with improved patient outcomes. In part, the high morbidity and mortality associated with dialysis have been attributed to a group of uremic toxins, which are described as "difficult to remove." With a new generation of hemodialysis membranes now making meaningful clearance of these molecules possible, it is an apt time to review the clinical relevance of these middle molecules. Our review describes the developments in membrane technology that enable the removal of large middle molecules (molecular mass >15 kD) that is limited with high-flux dialysis membranes. Of the known 58 middle molecules, a literature search identified 27 that have molecular mass >15 kD. This group contains cytokines, adipokines, hormones, and other proteins. These molecules are implicated in chronic inflammation, atherosclerosis, structural heart disease, and secondary immunodeficiency in the literature. Single-center safety and efficacy studies have identified that use of these membranes in maintenance dialysis populations is associated with limited loss of albumin and increased clearance of large middle molecules. Larger, robustly conducted, multicenter studies are now evaluating these findings. After completion of these safety and efficacy studies, the perceived clinical benefits of providing clearance of large middle molecules must be assessed in rigorously conducted, randomized clinical studies.

Keywords: Adipokines; Albumins; Artificial; Atherosclerosis; Chronic inflammation; Heart Diseases; Inflammation; Kidneys; Molecular Weight; cardiovascular disease; chronic dialysis; cytokines; hemodialysis; immune deficiency; malnutrition; renal dialysis; uremia.

Figure 1.

Medium cut-off membranes provide clearance of large middle molecules without albumin loss. Schematic of pore size distribution in dialysis membranes. As membranes have been developed to allow the removal of large middle molecules (MMs) without albumin loss, the distribution of the pore sizes has had to be “tightened.” The pink bar represents the distribution of large MMs before albumin is lost. The solid line indicates low flux, the dotted line indicates high flux, the dot-dash line indicates high cutoff (HCO), and the large dashed line indicates medium cutoff (MCO).

Figure 2.

Large middle molecules are pathologically involved in atherosclerosis. Large middle molecules and atherosclerosis. The cytokines IL-6, IL-18, and TNF-α result in increased expression of inflammatory genes, which are proatheroma formation. Advanced glycosylation end products (AGEs), TNF-α, IL-6, and adiponectin all result in increased expression of adhesion molecules on the vascular endothelium. Elevated levels of IL-1b result in increased expression of IL-1 receptors, which in turn, results in monocyte recruitment, macrophage activation, and the proliferation of smooth muscle cells (SMCs) and endothelium. In addition, prolactin stimulates SMC proliferation.