
There are two ways to treat a failed kidney: replace it with a working one (transplant) or use an artificial kidney to do its job (dialysis). The former works best but is often inaccessible, due to costs, lack of donors, and more. That leaves dialysis, the main therapy used for kidney failure since the early 20th century. Most of these patients will receive haemodialysis, where the blood is taken from the body and passed through a filter called a dialyser so it can be cleaned of toxins and excess fluids before being re-infused. There’s also peritoneal dialysis, where the lining of the abdomen is used as a filter instead, though this is much less commonly used.
Yet haemodialysis only replaces part of a healthy kidney’s function. It can clear small and sometimes medium-sized waste molecules – but leaves larger toxins behind in the blood. Even worse, survival rates are low, even as complications like cardiovascular disease can also arise.
“Dialysis has saved the lives of many patients with kidney failure,” is how Dr Cristian Pedreros- Rosales, a nephrologist and associate professor at the department of internal medicine at the University of Concepción in Chile, puts it. “But it is an insufficient purification method.”
2million+
The number of patients worldwide currently reliant on dialysis to stay alive.
National Kidney Foundation
In recent decades, however, a new technique has emerged that promises to be more effective: highvolume haemodiafiltration (HDF). Studies have shown it to outperform haemodialysis (HD) at clearing larger toxins – and better yet, to have a lower risk of mortality. Today, uptake of high-volume HDF is broadly on the rise in hospitals around the world. And according to many in the field, it’s only a matter of time before it becomes the standard of care everywhere.

More ways to clean the blood
The limitations of haemodialysis can plausibly be understood in a single word: diffusion. “In haemodialysis,” explains Bernard Canaud, a nephrologist at the Montpellier School of Medicine and a senior chief scientist at Fresenius Medical Care, “you only have diffusive action. In haemodiafiltration, you have diffusive plus convective clearance. That’s what makes the difference.”
Diffusion and convection are both methods of removing toxins from the blood. With the former, waste products move from the solution with a higher concentration of particles (blood) into one with a lower concentration (dialysate) – as if they were being pulled from a crowded room into one that’s empty. This, in turn, happens inside the dialyser. Here, blood is separated from dialysate – a solution of purified water, electrolytes and salt – by a semipermeable membrane. For their part, blood and dialysate flow in opposite directions. Small waste molecules can then move from the blood to dialysate, but those that are too large to pass through the membrane’s pores stay behind. You can improve clearance by using membranes with bigger pores, a process known as high-flux HD. But for this to work, you can only make the pores so big, otherwise you risk essential large proteins like albumin accidentally passing through and leaving the patient with a deficiency.
High-flux HD allows some medium-sized molecules, including the inflammatory protein beta two microglobulin, to escape, and is currently considered the standard of care. Yet as Pedreros- Rosales concedes, it still leaves bigger waste products in the blood. “These larger toxins,” he explains, “are more cardiotoxic than smaller ones like urea, and are linked to higher mortality and cardiovascular events – the most significant issues for dialysis patients.”
Haemodiafiltration, for its part, uses high-permeability membrane too. But it also cleans the blood via convection, whereby the water in the blood is pulled across the membrane due to differences in pressure between the fluids on either side. Waste products are then dragged through the membrane with it. Modern dialysis machines will automatically calculate and generate the necessary pressure based on the volume of water you want to remove from the blood. In practice, this means that convection offers better clearance of middle-sized toxins, says Francesco Locatelli, a professor of nephrology at the Alessandro Manzoni Hospital near Milan – though how effective it is depends on the total volume of fluid taken from the blood over the session. When the volume is high enough, Locatelli explains, “this is the only way of removing toxins of molecular weight higher than urea – the so-called ‘small’ molecules – and to also remove the middle molecules until the size of approximately 20 [kilodaltons].”
High volume, higher clearance
The ‘high volume’ part of ‘high-volume HDF’ refers to the large amount of fluid removed from the patient’s blood during one session – known as the ‘convective volume’. Studies have shown 23L to be the point where patients start to see a beneficial effect from HDF, with Pedreros-Rosales explaining that’s why it’s the recommended minimum convective dose. These bigger volumes, adds Canaud, allow for more clearance of waste. With high-flux HD, “I’d say that usually you would get 50-70ml per minute of beta two microglobulin clearance, which is already substantial. If you move to high-volume haemodiafiltration, you get 120-150ml.”
But for the patient to maintain their fluid balance, you have to replace the water that’s removed before the blood is re-infused: if you take 23L out, you need to put 23L back in. This fluid you add in is called substitution fluid. Today’s dialysis machines enable the use of such high convective volumes because they can produce substitution fluid live, by sterilising and filtering fresh dialysate.
“This is the way to make sure that we have no limitation in the substitution volume that we deliver to the patient,” Canaud explains. In the past, substitution fluid was a bagged sterile solution that was hooked up to the machine. Here, you’d be limited to using around 8-10L per session.
Substitution fluid can be added into the blood either before (pre-dilution) or after (post-dilution) it passes through the dialyser. Both methods will do the job, though the pre-dilution method requires about twice as much fluid to get the same level of clearance given it dilutes the blood before it’s filtered. “Postdilution,” Locatelli stresses, “is the more efficient way for improving the removal of toxins.”
The recommended 23L figure is in relation to the post-dilution mode, though this doesn’t include the weight gained by the patient between dialysis sessions due to fluid retention. To put it differently, Locatelli says, you’d need to remove this amount from the blood on top of the 23L. “All together, theoretically, we’d have to remove 25, 26, or even 27 litres.”
23%
The percentage by which highvolume HDF reduced the risk of all-cause mortality compared to high-flux HD.
The New England Journal of Medicine
What, however, if you increase the convective dose beyond 23L? As Canaud says, the data we have so far shows that clearance improves as convective volume goes up. But we don’t know whether there’s a maximum volume where the beneficial effect tapers off. Practically speaking, however, the convective volume will be limited by the length of the session (usually four hours) and the blood flow from the patient. “In four hours,” Canaud adds, “it’s difficult to get more than 30L.”
The future of high-volume HDF
These questions notwithstanding, you get the sense that HDF is here to stay. To quote Pedreros-Rosales: “HDF has enough evidence showing benefits in multiple areas, particularly in primary outcomes such as survival, that it should soon be considered a ‘standard.’”
A case in point is the so-called ‘CONVINCE’ trial. Published last June in the New England Medical Journal – and boasting Canaud as an author – it found that high-volume HDF reduced the risk of all-cause mortality by 23% compared to high-flux HD. A 2024 meta-analysis of five trials, including a pooled total of 4,143 patients with end-stage kidney disease, found that HDF reduced the risk of death from any cause by nearly 20% compared to the HD group.
So what’s stopping more clinics from switching to HDF? For one, regulatory approval may be lacking. This is certainly the case in the US – at the time of writing, only one HDF system has received the green light from the FDA. Another barrier, suggests Pedreros-Rosales, is the cost of therapy. That’s shadowed, Canaud adds, by the slow pace of change across medicine generally. “I think it will take ten years to get 80% or more [of clinics to use high-volume HDF], depending on the country.”
In the meantime, there’s plenty of scope to fine-tune the technique. For instance, innovations in membrane design can help prevent albumin from being dragged from the blood along with the toxins. Renal care giant Fresenius reports that their optimised FX CorAL filters can reduce the loss of albumin to under 1.4g in one four-hour HDF session.
Feedback systems can also be used to automatically adjust infusion rates based on the pressure inside the dialyser. Because the amount of water removed from the blood depends on this pressure, it can be used to calculate how much substitution fluid is needed. The Max-Sub feature on Nipro’s Surdial X dialysis machine uses this principle to determine the highest possible substitution volume for a given patient.
On the research front, trials and studies are underway to further investigate the benefits of highvolume HDF. The H4RT trial at the University of Bristol is currently examining the clinical and costeffectiveness of the treatment compared to high-flux HD in people with end-stage kidney disease. There’s research interest in other impacts of the procedure, such as quality of life and cognitive function.
That’s echoed by what remains a primary focus: achieving the best possible clearance of waste products. “Step by step,” Locatelli says, “we are moving to try and equal the native kidneys.”