Middle Molecule Clearance: Facts and the Path Forward

Middle molecule clearance represents the next frontier in dialysis care, offering compelling advantages in patient outcomes^1,2,3 and quality of life.^4,5,6  At DaVita, we’re committed to establishing and scaling clinical practices that rapidly extend these benefits to as many physicians and appropriate patients as possible. 

What are middle molecules and why do they matter? 

Middle molecules are larger uremic toxins with a molecular weight typically ranging from 0.5 to 60 kDa. Examples of middle molecules include β2-microglobulin, free light chains and cytokines. In patients with kidney failure, these toxins can build up in the blood over time. 

Middle molecule buildup are associated with a range of negative health impacts in ESKD patients:^7,8 

• Systemic inflammation, weakened immune response and higher cardiovascular and all-cause mortality risk 

• Quality of life impediments like fatigue, severe itching, restless legs, decreased appetite, and poor sleep 

• Longer recovery times following dialysis treatment 

Why is middle molecule innovation a priority?  

A growing body of research points to the benefits of middle molecule clearance, yet traditional high-flux hemodialysis does not sufficiently address this next-level care opportunity.

Traditional Hemodialysis Filters and Particle Size  

Conventional high-flux dialyzers excel in removing waste products of up to 25 kDa, including very small waste particles of less than .5 kDa.  This means we are excellent at removing urea, creatinine and other small solutes. This capability has been a tremendous advancement that extends life and improves quality of life for ESKD patients.   

Today, the next frontier in dialysis care is the removal of larger middle molecules (typically ranging from 15-60 kDa) which are not effectively removed by conventional high-flux dialyzers. 

The Added Challenge of Protein Binding 

It’s important to differentiate between free middle molecules of larger size and the molecular complexes that are formed when small waste products bind to protein in the blood. These protein-bound toxins are not typically cleared effectively by any currently available technology, and remain an important area of research. 

What are the most promising pathways to middle molecule clearance? 

For several months, DaVita has been actively engaged in research and dialogue exploring two leading technologies for advanced middle molecule clearance. 

• Expanded hemodialysis (Expanded HD) 

• Hemodiafiltration (HDF) 

Multiple analyses, including the recent landmark MOTheR study, confirm that both therapies offer superior middle molecule clearance compared to conventional dialysis, resulting in similar improvements in mortality and quality-of-life benefits.⁹

Expanded HD: Today’s Path Forward 

Our goal is to ensure that every physician and appropriate patient who wants advanced middle molecule clearance gains access to it in the coming months.​ While both therapies are safe and effective, only Expanded HD can be rolled out broadly to all DaVita centers on this accelerated timeline – making it the only practical choice to bring advanced clearance to the most physicians and patients, today. 

By elevating Expanded HD as the primary approach in our centers, we are extending a new choice to physicians and their patients in months, rather than years, while also continuing to explore the potential of HDF as a promising complementary therapy in cases where it is clinically appropriate. 

How does Expanded Hemodialysis (Expanded HD) work?  

Same Machine, New Dialyzer 

Expanded HD uses the same basic equipment and software as conventional high-flux hemodialysis, but the dialyzer itself is more technologically advanced. These advanced filters are referred to as medium cut-off membranes or super high-flux dialyzers. 

Superior Mechanical Filtration  

In comparison to traditional filters, the dialyzers used in Expanded HD can be thought of as “super sieves.”  These membranes feature a sophisticated design that optimizes pore structure, size and distribution, as well as the diameter of the fibers from which the filter is constructed, to positively influence the relationship between fluid movement and middle molecule clearance. Specifically, Expanded HD filters allow a wider range of larger molecules to pass through, improving middle molecule clearance, while selectively retaining essential proteins like albumin.^10,11,12

Clinically Comparable to HDF 

Both Expanded HD and HDF have been shown in multiple studies to be safe and effective treatments for ESKD.^1,3,8,9 Recent clinical milestones such as the MOTheR trial⁹ — one of the most rigorous head-to-head trials of middle molecule therapies — found that Expanded HD is safe and non-inferior to HDF in its composite endpoint of all-cause mortality and major cardiovascular events.  

How does hemodiafiltration (HDF) work? 

An Emerging U.S. Therapy with New Equipment Requirements
 
Unlike traditional dialysis and Expanded HD which are primarily diffusion-based, HDF combines standard diffusion with high-volume convection. This approach uses an entirely different type of machine and removes a much higher volume of fluid during treatment. As a result, centers adopting this modality must invest in specific HDF machines.  

Uses High Fluid Volume to Clear Middle Molecules  

Because HDF relies on removing and replacing a very high volume of fluid (often more than 23 liters) to “drag” or “flush” larger molecules from the blood, it may be most suitable for patients with higher blood flow rates. 

An Additional Path to Improved Outcomes  

Studies such as the MOTheR⁹and CONVINCE⁴ trials, among others, support HDF as a safe and effective therapy for advanced middle molecule clearance.  

Expanded HD vs HDF at a Glance 

In assessing two clinically comparable approaches to middle molecule clearance,^1,3,8,9 advantages in scalability, access and practicality of implementation come to the fore. In light of recent FDA equipment approval and operational learnings from our own Expanded HD pilots and initiatives, our assessment confirms Expanded HD as the evidence-based advancement that can reach the highest number of physicians and their patients today. 

Looking Ahead to a New Scalable Standard 

At DaVita, we’re committed to elevating Expanded HD as the immediate, scalable standard for middle molecule clearance. Even as we begin to operationalize this promising therapy, we are also continuing to evaluate all clinically validated pathways to advance patient outcomes. 

Ultimately, we’re working to expand meaningful clinical choice—making this advanced treatment option accessible to physicians and appropriate patients across every DaVita center. 

Are you a patient looking for information on your treatment options? Read our patient guide to Understanding Expanded Hemodialysis (Expanded HD).

^[1]Blankestijn PJ, Vernooij RWM, Hockham C, et al. Effect of Hemodiafiltration or Hemodialysis on Mortality in Kidney Failure. N Engl J Med. 2023;389(8):700-709. doi:10.1056/NEJMoa2304820 

^[2] Abe, M., Masakane, I., Wada, A. et al. High-performance dialyzers and mortality in maintenance hemodialysis patients. Sci Rep 11, 12272 (2021). https://doi.org/10.1038/s41598-021-91751-w 

^[3] Castillo JC, Vesga J, Rivera A, et al. Survival Differences in Patients with High-Flux Hemodialysis versus Expanded Hemodialysis: A Cohort Study. Blood Purif. 2025;54(12):772-781. doi:10.1159/000548158 

^[4] Rose M, Fischer FH, Liegl G, et al. The CONVINCE randomized trial found positive effects on quality of life for patients with chronic kidney disease treated with hemodiafiltration. Kidney Int. 2024;106(5):961-971. doi:10.1016/j.kint.2024.07.014 

^[5] Lim, JH., Park, Y., Yook, JM. et al. Randomized controlled trial of medium cut-off versus high-flux dialyzers on quality of life outcomes in maintenance hemodialysis patients. Sci Rep 10, 7780 (2020). https://doi.org/10.1038/s41598-020-64622-z    

^[6] Penny JD, Gozdzik D, Tamasi T, et al. Impact of Expanded Hemodialysis on Subjective Experience Using Dynamic Patient-Reported Outcome Measurement Tool. Kidney Med. 2025;7(12):101134. Published 2025 Oct 10. doi:10.1016/j.xkme.2025.101134 

^[7] Wolley MJ, Hutchison CA. Large Uremic Toxins: An Unsolved Problem in End-Stage Kidney Disease. Nephrology, Dialysis, Transplantation. 2018;33(suppl_3):iii6-iii11.  

^[8] Pecoits-Filho R, Ferraro PM, et al. The CONCORDIA Study: All-Cause Mortality with HDx with Theranova Compared with Hemodiafiltration Using DOPPS as an External Real-World Comparator. Abstract presented at: ERA Congress; 2026. 

^[9] De Sequera Ortiz P, Pérez García R, Martínez-Vaquera S, et al. MOTheR HDx Study: A MOPR Study to Explore Morbidity and Mortality in Patients Dialyzed with Theranova HDx Compared with OL-HDF. Abstract presented at: ERA Congress; 2026. 

^[10] Kirsch AH, Lyko R, Nilsson LG, et al.. Performance of Hemodialysis With Novel Medium Cut-Off Dialyzers. Nephrology, Dialysis, Transplantation 2017;32(1):165-172. 2.

^[11] Masakane I, Sakurai K.. Current Approaches to Middle Molecule Removal: Room for Innovation. Nephrology, Dialysis, Transplantation: 2018;33(suppl_3):iii12-iii21. 3.

^[12] Ronco C, Marchionna N, Brendolan A, et al.. Expanded Haemodialysis: From Operational Mechanism to Clinical Results. Nephrology, Dialysis, Transplantation :2018;33(suppl_3):iii41-iii47.