Large Middle Molecules Research Articles

Advantages of expanded hemodialysis (HDx) over standard hemodialysis

Chronic kidney disease leads to the accumulation of a wide range of uremic toxins. Negative effects of uremic toxins are most likely due to the combined effects of many uremic solutes, including small molecules, middle molecules, and soluble protein-linked substances. Large and medium-sized molecules are directly associated with chronic inflammation and adverse effects, including major cardiovascular risks and consequently poor prognosis.
 Recent advances in chemical composition and new production techniques led to improved biocompatibility and selective permeability of dialysis membranes. Specifically, the creation of a new class of membranes provided the possibility to improve the clearance of medium to high molecular weight (MW) solutes (i.e. uremic toxins in the range of 5–50 kDa).
 The new HDx therapy (expanded HD) is the next evolution in hemodialysis, as it effectively targets the removal of large middle molecules. The HDx therapy is enabled by the THERANOVA dialyzer featuring an innovative membrane that combines a higher permeability than regular high-flux dialyzers with effective selectivity for large proteins.
 Expanded hemodialysis is an advanced therapy targeting large and medium-sized molecules that are currently not possible to remove by modern dialysis methods including traditional hemodialysis (HD) and hemodiafiltration (HDF). HDx became possible due to THERANOVA, a new dialyzer with an innovative membrane. The THERANOVA-based HDx provides a great new opportunity for dialysis patients, providing unique high-efficiency hemodialysis with the usage of already available infrastructure and standard HD workflows.

Long-term effect of medium cut-off dialyzer on middle uremic toxins and cell-free hemoglobin.

The medium cut-off (MCO) dialyzer has shown good clearance of large middle molecules, but its long-term effects are unclear. We investigated whether MCO hemodialysis (HD) over one year could reduce middle molecule levels and cell-free hemoglobin (CFH), without albumin loss. A prospective cohort study in 57 hemodialysis patients was conducted. The patients were assigned to the MCO dialyzer group or the high-flux dialyzer group, according to the HD machine they used. The reduction ratio (RR) and one-year changes in small and middle molecules and CFH were analyzed. Over a 12-month follow-up, MCO HD did not reduce the serum levels of middle molecules (lambda free light chain [FLC], from 135.7 ± 39.9 to 132.0 ± 39.1 mg/L; kappa FLC, from 168.2 ± 58.5 to 167.7 ± 65.8 mg/L; β2-microglobulin, from 25.6 ± 9.6 to 28.4 ± 4.8 mg/L) or albumin (from 3.96 ± 0.31 to 3.94 ± 0.37 g/dL). MCO HD provided excellent RR of lambda FLC (49.3 ± 10.3%), kappa FLC (69.6 ± 10.4%) and β2-microglobulin (80.9 ± 7.3%), compared to high-flux HD. CFH was also removed well during an MCO HD session (RR of CPH, 85.5 [78.7–97.3] %), but long-term change was not significant (from 57.8 [46.2–79.1] to 62.0 [54.6–116.7] mg/L). The MCO dialyzer can be used effectively and safely in conventional HD settings, but long-term effects on large middle molecules and CFH were not significant. Further studies are needed to verify clinical benefits of the MCO dialyzer.

Medium Cut-Off Dialyzer versus Eight Hemodiafiltration Dialyzers: Comparison Using a Global Removal Score

Background: A novel class of membranes, medium cut-off (MCO) membranes, has recently been designed to achieve interesting removal capacities for middle and large middle molecules in hemodialysis (HD) treatments. The few studies published to date have reported contradictory results regarding middle-sized molecules when comparing MCO dialyzers versus dialyzers used in online hemodiafiltration (OL-HDF). Methods: A prospective, single-center study was carried out in 22 patients. Each patient underwent 9 dialysis sessions with routine dialysis parameters, one with an MCO dialyzer in HD and the other 8 with different dialyzers in OL-HDF. The removal ratio (RR) of urea, creatinine, β₂-microglobulin, myoglobin, prolactin, α₁-microglobulin, α₁-acid glycoprotein, and albumin was intraindividually compared. Albumin loss in dialysate was measured. We propose a global removal score ([urea_RR + β₂-microglobulin_RR + myoglobin_RR + prolactin_RR + α₁-microglobulin_RR + α₁-acid glycoprotein_RR]/6 – albumin_RR) as a new tool for measuring dialyzer effectiveness. Results: No significant differences in the RRs of small and middle molecular range molecules were observed between the MCO vs. OL-HDF dialyzers (range 60–80%). Lower RRs were found for α₁-microglobulin and α₁-acid glycoprotein without significant differences. The albumin RR was < 11% and dialysate albumin loss was < 3.5 g in all situations without significant differences. The global removal score was 54.9 ± 4.8% with the MCO dialyzer without significant differences. Conclusions: Removal of a wide range of molecular weights, calculated with the proposed global removal score, was almost equal with the MCO dialyzer in HD treatment compared with 8 high-flux dialyzers in high-volume OL-HDF without relevant changes in albumin loss. The global removal score could be a new tool to evaluate the effectiveness of dialyzers and/or different treatment modalities.

Large uremic toxins: an unsolved problem in end-stage kidney disease.

Patients with end-stage kidney disease (ESKD) on maintenance hemodialysis are subject to a high burden of inflammation and cardiovascular disease, driven at least in part by retention of uremic solutes. Existing dialysis technologies using high-flux membranes offer limited clearance of solutes >15 kDa. New approaches to improve the removal of large uremic toxins include the novel medium cut-off dialysis membranes with pores larger than those in high-flux membranes. These new membranes provide the potential to improve the clearance of large middle molecules up to 50 kDa. In this review, we discuss 18 uremic toxins with molecular weights between 15 and 60 kDa that are retained in ESKD, for which there is evidence of a link to inflammation and/or cardiovascular disease. These include inflammatory proteins, cytokines, adipokines and other signaling proteins. Improved clearance of this group of difficult to remove molecules has the potential to lead to improved outcomes in dialysis patients by reducing the burden of cardiovascular disease, which now needs to be assessed in robust clinical trials.

Chronic inflammation in end-stage renal disease and dialysis.

Under normal conditions, inflammation is a protective and physiological response to various harmful stimuli. However, in several chronic debilitating disorders, such as chronic kidney disease, inflammation becomes maladaptive, uncontrolled and persistent. Systemic persistent inflammation has, for almost 20 years, been recognized as a major contributor to the uraemic phenotype (such as cardiovascular disease, protein energy wasting, depression, osteoporosis and frailty), and a predictor of cardiovascular and total mortality. Since inflammation is mechanistically related to several ageing processes (inflammageing), it may be a major driver of a progeric phenotype in the uraemic milieu. Inflammation is likely the consequence of a multifactorial aetiology and interacts with a number of factors that emerge when uraemic toxins accumulate. Beside interventions aiming to decrease the production of inflammatory molecules in the uraemic milieu, novel strategies to increase the removal of large middle molecules, such as expanded haemodialysis, may be an opportunity to decrease the inflammatory allostatic load associated with retention of middle molecular weight uraemic toxins.

Design and methods of the REMOVAL-HD study: a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HaemoDialysis patients

BackgroundRemoval of uraemic toxins is inadequate using current dialysis strategies. A new class of dialysis membranes have been developed that allow clearance of larger middle molecules. The REMOVAL-HD study (a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HaemoDialysis patients) will address safety, efficacy and the impact on patient-centred outcomes with the use of a mid cut-off (MCO) dialyser in a chronic haemodialysis (HD) population.MethodsREMOVAL-HD is an open label, prospective, non-randomised, single-arm, multi-centre device study in 85 chronic HD participants. All visits will be conducted during regular HD sessions and participants will undergo a 1 month wash-in period using a standardised high flux dialyser, 6 months of intervention with a MCO dialyser and 1 month of wash-out using a high flux dialyser. The primary endpoint is change in pre-dialysis concentrations of serum albumin, with secondary endpoints including the efficacy of clearance of free light chains and β-2 microglobulin, and patient-centred outcomes including quality of life, symptom burden, functional status, nutritional status, hospitalisation and death.DiscussionMCO dialysers are a novel form of HD membrane. The REMOVAL-HD study is a pivotal study designed to monitor the immediate and medium-term effects following exposure to this dialyser.Trial registrationAustralian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482. Date of registration - 21/06/2016.

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

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.

Large Middle Molecule and Albumin Removal: Why Should We Not Rest on Our Laurels?

Large middle molecules (LMM) are an important subclass of uremic toxins. Many of them have been linked with poor outcomes in hemodialysis (HD) patients. The onset of high-flux membranes and convective techniques allowed to dramatically improve their clearance but without a clear and undebatable reduction of mortality in HD patients. Despite the real effect on the removal of selected toxins, little is known about the influence of modern HD techniques on the global removal of uremic toxins. Mostly explained by a lack of knowledge and selective assays, LMM removal is not evaluated appropriately. The development of highly sensitive and widespread detection techniques such as mass spectrometry could increase our knowledge about the real state of their removal in HD. Nevertheless, these techniques remain cost effective and are difficult to handle. On the contrary, the improvement of LMM removal raises the question of a tolerable albumin removal. Indeed, increasing membrane permeability can significantly increase LMM removal accompanied by a higher albumin loss. However, in chronic kidney disease and particularly in HD patients, albumin can be modified, and it subsequently exerts detrimental effects. This could be avoided by the clearance of the modified forms in HD, but future efforts should be done to investigate the real impact of their removal.

Clinical studies and chronic kidney disease: what did we learn recently?

This article summarizes relevant clinical studies that recently were devoted to the role of uremic toxins in outcomes of patients with chronic kidney disease and uremia. We summarize observational data linking uremic toxins (phosphate, the dimethylarginines, uric acid, and several large peptidic middle molecules and protein-bound solutes) to outcomes in observational studies. Interventional studies that evaluate the impact of different removal strategies on uremic toxin concentration in end-stage renal disease are then summarized along with clinical outcome studies with different dialysis strategies. Finally, we focuse on interventions in chronic kidney disease patients who are not yet on dialysis. We conclude that although there are more and more data on how to better remove uremic toxins by dialysis and nondialysis strategies, convincing evidence of the impact of these strategies on hard outcomes is much scarcer.

Removal of water-soluble and protein-bound solutes with reversed mid-dilution versus post-dilution haemodiafiltration

Convective dialysis strategies are superior in the removal of protein-bound uraemic retention solutes. Mid-dilution and mixed-dilution haemodiafiltration (HDF), both combining pre-dilution and post-dilution, are promising options to further improve removal capacity and have been shown of additional benefit for large middle molecules. In this study, we compared the removal of small water-soluble and protein-bound solutes in post-dilution versus mid-dilution HDF. Fourteen chronic haemodialysis (HD) patients were included in this crossover study. Patients were kept for 4 weeks on high-flux HD. On the mid-week session of Weeks 3 and 4, either post-dilution or reversed mid-dilution HDF were applied, in random order. Blood and dialysate flows were maintained at 300 and 800 mL/min, while the substitution flow was 75 mL/min in post-dilution and 150 mL/min in mid-dilution HDF. Based on the data collected during the sessions under study, extraction ratio (ER) and reduction ratio (RR) of small water-soluble and protein-bound solutes were calculated, as well as total solute removal (TSR) based on spent dialysate. No differences were observed for TSR, ER and RR for protein-bound solutes. For small water-soluble solutes, ER in post-dilution HDF was significantly higher than in mid-dilution HDF: 0.92 ± 0.02 versus 0.87 ± 0.04 for urea (P < 0.001), 0.92 ± 0.02 versus 0.88 ± 0.02 for creatinine (P < 0.001) and 0.84 ± 0.02 versus 0.82 ± 0.03 for uric acid (P = 0.009). TSR and RR were, however, not different due to the lower inlet concentrations with post-dilution HDF. TSR of mid-dilution and post-dilution HDF was not different for both small water-soluble and protein-bound compounds. Both strategies in the setting as applied in this study are as adequate for the removal of these solutes.