Removal Of Larger Middle Molecules Research Articles

Japanese Study of the Effects of AMG (α1-Microglobulin) Reduction Rates on Survival (JAMREDS): A Protocol of a Multicenter Prospective Observational Cohort Study

Introduction: Recent advances in dialysis therapy have made it possible to remove middle molecules. Removal of small-middle molecules, such as β2-microglobulin, can now be achieved with conventional hemodialysis (HD), and removal of large-middle molecules has become a target, particularly for α1-microglobulin (AMG, 33 kD). The AMG reduction rate has emerged as a target for improvement of various clinical symptoms, but the effects on prognosis have yet to be determined. The “Japanese study of the effects of AMG (α1-microglobulin) reduction rates on survival” (JAMREDS) was started in April 2020, with the goal of determining if the AMG reduction rate associates with the risk of mortality and cardiovascular disease (CVD) events. Methods: JAMREDS is a prospective observational study in patients on HD to examine the effects of: (1) AMG reduction rate on survival outcome and CVD events; (2) dialysis treatment modalities (HD, intermittent infusion hemodiafiltration(iHDF), pre/post-dilution online HDF) on survival and CVD events (based on AMG reduction rates with treatment mode); and (3) AMG reduction rates on survival and CVD events in patients undergoing each therapy (iHDF, pre/post-dilution online HDF). The number of planned subjects was 4,000 in preplanning. Data are collected using RED-Cap, which is an EDC system. A total of 9,930 patients were enrolled at the beginning of the study at 59 registered facilities. The JAMREDS observation period will continue until the end of 2023, after which the data will be cleaned and confirmed before analysis. Conclusion: This study may provide new evidence for the relationship between the amount of removed large-middle molecules (such as AMG) and the mortality and CVD risk. Comparisons with convection volumes will also be of interest.

Expanded hemodialysis: what's up, Doc?

In recent years there has been an increasing interest in expanded hemodialysis (HDx), an emerging renal replacement therapy based on the use of medium cut-off membranes (MCO). Thanks to the internal architecture of these types of membranes, with a higher pore size and smaller fiber inner diameter to favor internal filtration rate, they can increase the removal of larger middle molecules in conventional hemodialysis. Secondarily, several reports suggest that this therapy potentially improve the outcomes for end-stage renal disease patients. However, HDx has not been defined yet and the characteristics of MCO membranes are not well stablished. The aim of this narrative review is to define HDx and summarize the dialyzers that have been used so far to perform this therapy, collect the evidence available on its efficacy and clinical outcomes compared with other hemodialysis techniques and settle the bases for its optimal prescription.

Clinical Safety of Expanded Hemodialysis Compared with Hemodialysis Using High-Flux Dialyzer during a Three-Year Cohort.

Expanded hemodialysis (HD) equipped with a medium cut-off (MCO) membrane provides superior removal of larger middle molecules. However, there is still little research on the long-term benefits of expanded HD. Over a three-year period, this observational study evaluated the efficacy and safety profile of expanded HD for inflammatory cytokines, including IL-6. We conducted a prospective cohort study to investigate the inflammatory cytokine changes and a retrospective observational cohort study to investigate long-term clinical efficacy and safety over a three-year period. We categorized the patients according to dialyzer used: MCO and high-flux (HF) dialyzer. The inflammatory cytokines, including IFN-γ, IL-1β, IL-6, and TNF-α, were measured annually. The concentrations and changes of the four cytokines over time did not differ between the HF group (n = 15) and MCO group (n = 27). In both prospective and retrospective (HF group, n = 38; MCO group, n = 76) cohorts, there were no significant differences in either death, cardiovascular events, infections, or hospitalizations. Furthermore, the temporal changes in laboratory values, including serum albumin and erythropoietin prescriptions, did not differ significantly between the two groups in either the prospective or retrospective cohorts. In conclusion, clinical efficacy and safety outcomes, as well as inflammatory cytokines, did not differ with expanded HD compared with HF dialysis during a three-year treatment course, although the level of inflammatory cytokine was stable.

Pro-calcifying analysis of uraemic serum from patients treated with medium cut-off membrane in a prospective, cross-over study.

BackgroundThe retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the symptoms typical in uraemic patients. These molecules are defined as uraemic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put towards developing dialysis membranes that allow the removal of large middle molecules without clinically relevant albumin loss. These membranes are the medium cut-off (MCO) membranes that allow the removal of middle molecules up to ∼50 000 Da.MethodsWe performed a prospective, open-label, controlled, cross-over pilot study comparing expanded haemodialysis (HDx) (novel MCO membrane Theranova 400) and conventional haemodialysis (HD) in 20 prevalent HD patients. Ten patients used conventional HD high-flux dialyser and 10 patients used HDx for 3 months; later the patients switched and received the other treatment for a further 3 months. We then analysed the pro-calcifying effect of uraemic serum in a model of high phosphate(Pi)–induced calcification in vascular smooth muscle cells (VSMCs).ResultsIn this study, every patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential from HDx-treated patients’ serum compared with HD. Studying pathogenetic processes involved in high Pi–induced calcium deposition, we found that uraemic serum of HDx-treated patients induced less VSMC necrosis compared with uraemic serum of HD patients. Nevertheless, no differences were found between the different dialytic treatments in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC simil-osteoblastic differentiation such as bone morphogenetic protein 2, runt-related transcription factor 2, osteocalcin, matrix Gla protein, osteopontin, elastin and collagen I α1. In an effort to characterize the difference in uraemic toxin profile during the two different dialytic treatments, we measured a panel of 10 uraemic toxins and 3 precursors, finding a significant increased removal during HDx of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, tryptophane and some of its metabolites, such as 3-indoxyl sulphate, indole 3-acetic acid and kynurenine.ConclusionsThese preliminary data are promising, although larger patients’ groups are needed to better understand the effects of HDx on vascular calcification.

Efficacy and Safety of Expanded Hemodialysis with the Theranova 400 Dialyzer: A Randomized Controlled Trial.

Expanded hemodialysis therapy enabled by medium cut-off membranes may promote greater clearance of larger middle molecules that comprise putative uremic solutes than conventional high-flux dialysis. This randomized trial evaluated the efficacy and safety of hemodialysis treatment with a medium cut-off dialyzer. Clinically stable patients on maintenance hemodialysis were randomized to receive dialysis with either a medium cut-off dialyzer (Theranova 400) or a high-flux dialyzer (Elisio-17H) over 24 weeks of treatment. The primary safety end point was the predialysis serum albumin level after 24 weeks of treatment. The primary efficacy end point was the reduction ratio of free λ light chains at 24 weeks of treatment. Among 172 patients on maintenance hemodialysis, mean age was 59±13 years, 61% were men, 40% were Black, and mean dialysis vintage was 5±4 years. Of the 86 patients randomized to each dialyzer, 65 completed the trial in each group. The reduction ratio for the removal of free λ light chains was significantly higher in the Theranova 400 group compared with the Elisio-17H group after 4 weeks (39% versus 20%) and 24 weeks (33% versus 17%; both P<0.001). Among secondary end points, the Theranova 400 group demonstrated significantly larger reduction ratios at 4 and 24 weeks for complement factor D, free κ light chains, TNFα, and β2-microglobulin (P<0.001 for all), but not for IL-6. Predialysis serum albumin levels were similar between groups after 24 weeks (4 g/dl with the Theranova 400 and 4.1 g/dl with the Elisio-17H), consistent with noninferiority of the Theranova 400 dialyzer in maintaining predialysis serum albumin levels after 24 weeks of treatment. Hemodialysis therapy with the Theranova 400 dialyzer provides superior removal of larger middle molecules, as exemplified by free λ light chains, compared with a similar size high-flux dialyzer, while maintaining serum albumin level. A Multi-Center, Prospective, Randomized, Controlled, Open-Label, Parallel Study to Evaluate the Safety and Efficacy of the Theranova 400 Dialyzer in End Stage Renal Disease (ESRD) Patients, NCT03257410.

P1078IMPACT OF A MEDIUM CUT-OFF DIALYZER ON SKIN AUTOFLUORESCENCE IN HAEMODIALYSIS PATIENTS

Abstract Background and Aims Advanced glycation end-products (AGEs) are middle-sized uraemic toxins that accumulate in haemodialysis (HD) patients due to increased production, impaired excretion and insufficient removal. Previous studies have reported that the use of a medium cut-off (MCO) dialyzer promotes a greater removal of larger middle molecules (such as AGEs) than conventional high-flux HD and haemodiafiltration. However, to our knowledge, there is no published evidence regarding the effect of an MCO dialyzer on skin autofluorescence (SAF), a measure of long-term tissue AGE accumulation and independent risk factor for mortality in the HD population. We aimed to investigate the impact of using an MCO dialyzer on change in SAF over time in HD patients. Method HD patients were enrolled in a prospective observational study. SAF was measured using a validated Autofluorescence Reader at baseline, 12 and 24 months. During the initial 12 months patients dialysed using high-flux polysulphone, polyarylethersulfone or polyvinylpyrrolidone dialyzers. At a variable time after 12 months patients were switched to an MCO dialyzer (Theranova; Baxter®). Forty patients who had been using the MCO dialyzer for at least 3 months were included in this analysis. Results Mean age, baseline SAF levels and time on MCO dialyzer were 63±13 years, 3.5±0.9 arbitrary units (AU) and 124±49 days, respectively. SAF increased significantly from baseline to 12 months (3.5±0.9 vs. 3.9±1.1 AU; p&amp;lt;0.0001) but tended to decrease between 12 and 24 months, after conversion to an MCO dialyzer (3.9±1.1 vs. 3.7±0.7 AU; p=0.06). Additionally, mean ΔSAF from baseline to 12 months was positive (0.41±0.68 AU) whereas ΔSAF from 12 to 24 months was negative (-0.18±0.76 AU; p=0.002 for comparison). Furthermore, SAF at 24 months correlated negatively and significantly with time on MCO dialyzer (r= -0.384; p=0.01) though second year ΔSAF (delta from 12 to 24 months) did not (r= 0.061; p=0.7). Conclusion We found in this observational study that SAF levels decreased/stabilised in HD patients after switching to an MCO dialyzer compared to the time when patients were using conventional high-flux HD and haemodiafiltration, during which SAF levels increased. Future prospective and interventional studies with larger sample sizes and longer follow-up are needed to confirm these findings and to evaluate the impact of using an MCO dialyzer on long-term outcomes, including survival.

P1392ANALYSIS OF CALCIFYING POTENTIAL OF UREMIC SERUM FROM HAEMODIALYSIS PATIENTS TREATED WITH A MEDIUM CUT-OFF (THERANOVA) DIALYSER: A PROSPECTIVE, CROSS-OVER STUDY

Abstract Background and Aims The retention of a large number of solutes that are normally excreted or metabolized by the kidney is responsible for the classical symptoms of haemodialysis (HD) patients. These molecules are defined as uremic toxins and can be classified into three groups: small water-soluble molecules, middle molecules and protein-bound toxins. Recently, efforts were put in order to develop dialysis membranes that allow the removal of large-middle molecules without clinically relevant albumin loss. These dialysers are the medium cut-off (MCO) membranes, which allow the removal of middle molecules up to approximately 50,000 Da. We performed a prospective, open-label, controlled, cross-over pilot study comparing expanded HD (HDx) with MCO membrane Theranova and conventional HD in 20 patients. Method Ten patients underwent conventional HD high-flux dialyser and 10 patients underwent HDx for 3 months, later the patients switched and received the other treatment for a further 3 months. We then analyzed the pro-calcifying effect of patient uremic serum in a model of high-phosphate (Pi) induced calcification in vascular smooth muscle cells (VSMCs). Results In this study each patient was the control of himself and, interestingly, we found a tendency of less pro-calcifying potential of serum from patients when treated with HDx, in comparison with HD (6.6±1.1, 5.6±0.6 and 6.7±1.0, OD/mg protein, baseline HD, 0-3 HDx and 3-6 HD, months, respectively; and 4.7±0.7 vs 3.2±0.2, OD/mg protein, 0-3 HD vs 3-6 HDx, months, respectively) (Figure). Investigating the major mechanisms involved in high-Pi induced calcium deposition, we found that serum from patients when treated with HDx induced less necrosis in VSMCs, compared with HD (3.2±0.8 vs. 0.9±0.1, necrosis enrichment factor, 0-3 HD vs. 3-6 HDx, months, respectively). Nevertheless, no differences were found between the different dialysis treatment in the serum potential to induce apoptosis and to modulate the expression of a panel of genes involved in VSMC osteoblastic-differentiation such as BMP2, RUNX2, osteocalcin, MGP, OPN, and elastin. In the effort to characterize the difference in uremic toxin profile during the two different dialysis treatments, we measured a panel of protein-bound uremic toxins which have been shown to promote vascular calcification and /or bone loss and shown a significant increased removal by HDx of 3-indoxyl sulfate (30.6±13.2 vs -17.1±10.2 Δ%; 0-3 HD vs 3-6 HDx, months; p&amp;lt;0.05; and -21.1±11.4 vs 54.4±33.2 Δ%; 0-3 HDx vs 3-6 HD, months; p&amp;lt;0.05), indole 3-acetic acid (43.1±16.9 vs -2.3±10.9 Δ%; 0-3 HD vs 3-6 HDx, months; p&amp;lt;0.05), CMPF (61.8±27.6 vs -16.1±9.6 Δ%; 0-3 HD vs 3-6 HDx, months; p&amp;lt;0.05), and kynurenine (44.2±12.9 vs -0.2±6.8 Δ%; 0-3 HD vs 3-6 HDx, months; p&amp;lt;0.05). Conclusion These preliminary data suggest a role for HDx in reducing the calcifying potential of uremic serum. Our findings are promising and they need to be confirmed in larger studies.

Removal of large middle molecules via haemodialysis with medium cut-off membranes at lower blood flow rates: an observational prospective study

BackgroundOnline haemodiafiltration (OL-HDF) may improve middle molecular clearance in contrast to conventional haemodialysis (HD). However, OL-HDF requires higher convective flows and cannot sufficiently remove large middle molecules. This study evaluated the efficacy of a medium cut-off (MCO) dialyser in removing large middle molecular uraemic toxins and compared it with that of conventional high-flux (HF) dialysers in HD and predilution OL-HDF.MethodsSix clinically stable HD patients without residual renal function were investigated. Dialyser and treatment efficacies were examined during a single midweek treatment in three consecutive periods: 1) conventional HD using an HF dialyser, 2) OL-HDF using the same HF dialyser, and 3) conventional HD using an MCO dialyser. Treatment efficacy was assessed by calculating the reduction ratio (RR) for β2-microglobulin (β2M), myoglobin, κ and λ free light chains (FLCs), and fibroblast growth factor (FGF)-23 and measuring clearance for FLCs.ResultsAll three treatments showed comparable RRs for urea, phosphate, creatinine, and uric acid. MCO HD showed greater RRs for myoglobin and λFLC than did HF HD and predilution OL-HDF (myoglobin: 63.1 ± 5.3% vs. 43.5 ± 8.9% and 49.8 ± 7.3%; λFLC: 43.2 ± 5.6% vs. 26.8 ± 4.4% and 33.0 ± 9.2%, respectively; P < 0.001). Conversely, predilution OL-HDF showed the greatest RR for β2M, whereas MCO HD and HF HD showed comparable RRs for β2M (predilution OL-HDF vs. MCO HD: 80.1 ± 4.9% vs. 72.6 ± 3.8%, P = 0.01). There was no significant difference among MCO HD, HF HD, and predilution OL-HDF in the RRs for κFLC (63.2 ± 6.0%, 53.6 ± 15.5%, and 61.5 ± 7.0%, respectively; P = 0.37), and FGF-23 (55.5 ± 20.3%, 34.6 ± 13.1%, and 35.8 ± 23.2%, respectively; P = 0.13). Notably, MCO HD showed improved clearances for FLCs when compared to HF HD or OL-HDF.ConclusionsMCO HD showed significantly greater RR of large middle molecules and achieved improved clearance for FLCs than conventional HD and OL-HDF, without the need for large convection volumes or high blood flow rates. This would pose as an advantage for elderly HD patients with poor vascular access and HD patients without access to OL-HDF.Trial registrationClinical Research Information Service (CRIS): KCT 0003009. The trial was prospectively registered on the 21 Jul 2018.

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.&#x0D; 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).&#x0D; 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.&#x0D; 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.

Pyrogen retention: Comparison of the novel medium cut-off (MCO) membrane with other dialyser membranes

Haemodialysis effectively removes small solutes and smaller-sized middle molecules from the blood; however, the clearance of larger middle molecules, which have been associated with negative effects, is poor. The novel medium cut-off (MCO) dialysis membrane has larger pore sizes and a more open structure than other high-flux membranes, providing improved removal of larger middle molecules while retaining albumin. However, larger pore sizes may potentially increase permeability to pyrogens, including endotoxins and other bacterial contaminants, that could be present in the dialysis fluid. In this study, we tested the capacity of low-flux, high-flux, MCO and high cut-off dialyser membranes with different pore sizes to prevent pyrogens crossing from dialysate to the blood side in a closed-loop test system, differentiating among lipopolysaccharides, peptidoglycans and bacterial DNA using a toll-like receptor assay. Even though the bacterial contamination levels in our test system exceeded the acceptable pyrogen dose for standard dialysis fluid, levels of lipopolysaccharides, peptidoglycans and bacterial DNA in the blood-side samples were too low to identify potential differences in pyrogen permeability among the membranes. Our results suggest that MCO membranes are suitable for haemodialysis using ISO standard dialysis fluid quality, and retain endotoxins at a similar level as other membranes.

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.

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.

Effects of Hemodialysis Therapy Using Dialyzers with Medium Cut-Off Membranes on Middle Molecules.

The removal of larger middle molecules, such as free immunoglobulin light chains (FLC), is poor with most currently used dialysis technologies. While hemodiafiltration (HDF) provides enhanced clearance of middle molecules compared to high-flux hemodialysis (HD), this technique is currently not approved in some regions and, hence, not accessible for all patients. The retention of middle molecules is thought to be one factor, which contributes to excessive morbidity and mortality in HD patients. The development of medium cut-off (MCO) dialysis membranes is aimed at a more efficient clearance of larger uremic toxins while retaining albumin and may extend the benefit of enhanced solute removal to more patients. In 2 pilot studies, the removal of middle molecules using HD with an MCO dialyzer prototype was compared to (1) high-flux HD and (2) high-flux HD and HDF. The primary outcome was the overall clearance of λ FLC, and the secondary outcome was the clearance of other middle molecules and safety. Pre-to-post reduction ratios and instantaneous clearances during HD were also assessed. In both trials, the overall λ FLC clearance with MCO HD was significantly larger than with high-flux HD and HDF. Accordingly, instantaneous clearances at 30 and 120 min showed significantly higher removal of λ FLC compared to high-flux HD and HDF. MCO HD provides a more efficient removal of larger middle molecules compared to high-flux HD and HDF. A potential drawback is slightly increased albumin loss, yet preliminary data suggest that this does not lead to permanently decreased albumin levels. Thus, MCO HD may present a promising approach to further improve middle molecule removal in maintenance dialysis patients and to extend its benefit to more patients.