Advances in our understanding of uremic retention solutes, and improvements in hemodialysis membranes and other techniques designed to remove uremic retention solutes, offer opportunities to readdress the definition and classification of uremic toxins. A consensus conference was held to develop recommendations for an updated definition and classification scheme on the basis of a holistic approach that incorporates physicochemical characteristics and dialytic removal patterns of uremic retention solutes and their linkage to clinical symptoms and outcomes. The major focus is on the removal of uremic retention solutes by hemodialysis. The identification of representative biomarkers for different classes of uremic retention solutes and their correlation to clinical symptoms and outcomes may facilitate personalized and targeted dialysis prescriptions to improve quality of life, morbidity, and mortality. Recommendations for areas of future research were also formulated, aimed at improving understanding of uremic solutes and improving outcomes in patients with CKD.

Classification of Uremic Toxins and Their Role in Kidney Failure.

Background and objectives 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. Design, setting, participants, & measurements 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. Results 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 Conclusions 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. Clinical Trial registry name and registration number 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.

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

Hypoalbuminemia results when compensatory mechanisms are unable to keep pace with derangements in catabolism/loss and/or decreased synthesis of albumin. Across many disease states, including chronic kidney disease (CKD), hypoalbuminemia is a well-established, independent risk factor for adverse outcomes, including mortality. In the setting of CKD, reduced serum albumin concentrations are often a manifestation of protein-energy wasting, a state of metabolic and nutritional alterations resulting in reduced protein and energy stores. The progression of CKD to kidney failure and the initiation of maintenance hemodialysis (HD) further predisposes an already at-risk population toward hypoalbuminemia such that approximately 60% of HD patients have albumin concentrations <4.0 g/dl. Albumin loss into the dialysate through the dialyzer appears to be a potentially modifiable cause of hypoalbuminemia in some patients. A group of newer dialyzers for maintenance HD-sometimes termed protein-leaking or medium cut-off membranes-aim to improve clearance of middle molecules (vs high flux dialyzers) but are associated with increased albumin losses. In this article, we will examine the impact of dialyzer selection on albumin losses during conventional HD, including the clinical relevance of such losses on serum albumin levels. Data on the clinical relevance of albumin losses during dialysis and current gaps in the evidence base are also discussed.

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Slipping Through the Pores: Hypoalbuminemia and Albumin Loss During Hemodialysis.

The reduction of the dismally high mortality of current end-stage renal disease patients maintained on conventional standard haemodialysis (HD) remains an unmet medical need. Online haemodiafiltration (HDF) modes with various sites of fluid substitution (post-, pre-, mixed- and mid-dilution) are increasingly used worldwide as promising alternatives to conventional HD. Large scale cohort studies, post hoc analyses of randomized trials, and individual participant meta-analyses suggest that post-dilution and pre-dilution, especially with high substitution volumes, improve outcomes compared with conventional standard HD. However, there is no definitive proof of a survival advantage of HDF over standard HD. The different modes of high-volume HDF should be considered a therapeutic platform allowing to personalize and tailor routine HDF treatment. The selection of the HDF mode should be made according to individual patient characteristics. Utilizing high retention onset membranes, expanded haemodialysis (HDx) can achieve the same solute removal performance as HDF. Subgroups of high-volume OL-HDF patients could benefit from HDx. Ongoing and future trials should provide definitive proof for the superiority of high-volume OL-HDF over conventional HD or HDx to give guidance for the most favourable mode of dialytic therapy for clinical use.

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High-volume online haemodiafiltration treatment and outcome of end-stage renal disease patients: more than one mode

Chronic kidney disease (CKD) is characterized by the retention of solutes named uremic toxins, which strongly associate with high morbidity and mortality. Mounting evidence suggests that targeting uremic toxins and/or their pathways may decrease the risk of cardiovascular disease in CKD patients. Dialysis therapies have been developed to improve removal of uremic toxins. Advances in our understanding of uremic retention solutes as well as improvements in dialysis membranes and techniques (HDx, Expanded Hemodialysis) will offer the opportunity to ameliorate clinical symptoms and outcomes, facilitate personalized and targeted dialysis treatment, and improve quality of life, morbidity and mortality.

Expanded Haemodialysis as a Current Strategy to Remove Uremic Toxins

Background: A new class of dialysis membrane, the mid cut-off (MCO) dialyzer, has been developed to improve the clearance of uremic toxins in hemodialysis (HD). The a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) study aimed to determine if regular use of MCO dialyzer was safe and specifically did not result in a significant loss of albumin. Methods: This investigator initiated, crossover, longitudinal, device study was conducted across 9 centers in Australia and New Zealand (n = 89). Participants had a 4-week wash-in with high-flux HD, followed by 24-week intervention with MCO HD and a subsequent 4-week wash-out with high-flux HD. The primary outcome was change in serum albumin between weeks 4 and 28. Secondary outcomes included trends in serum albumin, changes in kappa- and lambda-free light chains (FLC), 6-min walk test (6MWT), malnutrition inflammation score (MIS), restless legs score and quality of life. Results: Participants had a mean age of 66 ± 14 years, 62% were men, 45% were anuric, and 51% had ­diabetes. There was no reduction in serum albumin following treatment with MCO HD (mean reduction –0.7 g/L, 95% CI –1.5 to 0.1). A sustained, unexplained reduction in serum albumin (>25%) was not observed in any participant. A reduction in FLC was observed 2 weeks into MCO HD (lambda-FLC: Δ –9.1 mg/L, 95% CI –14.4 to –3.7; kappa-FLC: Δ –5.7 mg/L, 95% CI –9.8 to –1.6) and was sustained for the rest of the study intervention. Both FLC increased after the cessation of MCO use. There was no improvement in restless legs symptoms, quality of life, 6MWT or MIS scores. Conclusions: Regular HD using the MCO dialyzer did not result in a significant fall in serum albumin. There were no effects on quality of life, functional status or nutrition. Trial Registration: Australian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482.

Muhgeot Wong

Papers

A tRial Evaluating Mid Cut-Off Value Membrane Clearance of Albumin and Light Chains in HemoDialysis Patients: A Safety Device Study.