Project Aims to Clear Path for Hemodiafiltration in the United States

Bridget M. Kuehn
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A growing number of patients in Europe and Asia are receiving a new form of renal replacement therapy called hemodiafiltration instead of hemodialysis. In fact, about one-third of patients in Europe currently receive hemodiafiltration, and that number is growing by about 6% a year, according to Bernard Canaud, MD, chief medical scientist at Fresenius Medical Care in Germany.

Hemodiafiltration’s growing popularity abroad is being driven in part by European studies suggesting that the newer technique leaves patients feeling better with less fatigue and fewer cramps and because of emerging data suggesting that it may also offer cardiovascular benefits, Canaud explained.

Until recently, the U.S. Food and Drug Administration (FDA) had not approved any hemodiafiltration devices, so it hasn’t been an option for patients in the United States. But the Kidney Health Initiative (KHI), a public–private partnership that includes the American Society of Nephrology, the FDA, makers of hemodiafiltration equipment, and other stakeholders have been working to change that.

KHI aims to stimulate innovation and research on kidney diseases, and the treatment of kidney diseases has been one area that has lagged behind in terms of research and new treatment options, said Stephen Ash, MD, a member of the KHI hemodiafiltration work group and medical director at Hemocleanse, Inc. Dialysis.

KHI has brought together nephrologists, regulators, patients, and companies to try to identify and overcome challenges that stand in the way. One of the biggest hurdles to bringing hemodiafiltration to the United States has been that there wasn’t a clear pathway for companies to gain clearance from the FDA for marketing hemodiafiltration devices.

“That was the biggest impediment to the improvements in that area,” Ash said.

Removing big particles

Hemodialysis was invented in the early part of the 20th century. It is very effective at removing small molecules like urea, creatinine, and potassium from the blood, explained Ash.

In layman’s terms, hemodialysis works basically the same way as a tea bag, said Richard Ward, MD, a retired professor of medicine from the University of Louisville, in Kentucky. The small molecules from the blood naturally diffuse through the dialysis membrane to the water on the other side of the membrane. But larger molecules, especially those that are attached to proteins, may not make it through the dialysis membrane.

“There are quite a few larger molecules that accumulate in people without kidney function that are probably contributing to the toxicity of the disease,” Ward said. Ash noted that these larger molecules have been linked to hypertension, cardiovascular disease, and ill effects on the immune system.

Hemodiafiltration, developed in the 1980s, was designed to overcome this limitation of dialysis by combining diffusion of molecules across a membrane with convection to help remove some of the larger molecules.

Again, in layman’s terms, Ward said, hemodiafiltration works in much the same way a press coffee pot works: by forcing fluid and molecules through a membrane under pressure. The pressure greatly increases the amount of fluid being removed during treatment, Ash said. So instead of removing 2 to 3 liters over 3 to 4 hours as dialysis does, hemodiafiltration removes 20 to 30 liters in the same period. To counteract that large amount of fluid loss, patients are simultaneously infused with an equal amount of sterile fluid. Ash said the intent of hemodiafiltration is to keep patients healthier by creating a renal replacement therapy that more closely resembles the way the kidney works.

“It’s really replicating the kind of hemofiltration system that is present in the human body,” he said.

Data from four clinical trials have had mixed results, according to a review by the KHI work group.

A Spanish study found that patients treated with hemodiafiltration had a 30% lower risk of cardiovascular disease and of death resulting from all causes. Two other studies failed to show a statistically significant reduction in deaths among individuals receiving hemodiafiltration. A fourth study showed no difference in mortality rates or quality of life in patients over 65 years old, but it did find lower rates of low blood pressure during renal replacement therapy, and fewer muscle cramps. Ash noted that there was a trend toward benefit in all the studies, but some studies may have been too small to enable a statistically significant difference to be found.

“There’s no doubt that there’s something there that’s benefiting patients,” Ash said.

A meta-analysis of data from all the trials suggests that the benefits of hemodiafiltration hinge on how much fluid is filtered, Ward noted. The Spanish study also filtered a higher volume than did the other studies.

“It does look like there’s a relationship between survival benefit and volume,” said Ward.

To provide more definitive evidence, Canaud is launching an 1800-patient randomized trial comparing hemodialysis and high-volume hemodiafiltration in Europe. So far, nephrologists in the United States haven’t been able to conduct clinical trials to test the potential value of hemodiafiltration because of the dearth of devices cleared for use in the U.S.

“Right now, the United States is locked out of it,” Ward said.

Clarifying the pathway

One of the challenges to gaining FDA clearance for hemodiafiltration devices has been the need to demonstrate that large volumes of safe sterile fluid can be reliably produced to balance out fluid removal.

Ash explained that the FDA’s stated standard is less than one bacterium per 1000 liters of fluid. Production facilities that produce large amounts of sterile fluids can meet this standard by taking small samples over time until they add up to 1000 liters. But proving that hemodiafiltration machines, which produce at most 20 or 30 units of sterile fluid per treatment, meet the standard by that method is not practical, he said.

“The requirements, quite frankly, for sterile fluid needed for that therapy as written [are] impossible to meet,” Ash said. He noted that European regulators instead used a statistical process to prove that the machines and their reusable filters would produce sufficiently sterile fluids.

As the KHI hemodiafiltration project was getting started, a company called Nephros became the first to win FDA clearance for its hemodiafiltration device, as documented in KHI’s review of regulation of these devices. Douglas Silverstein, MD, a medical officer at the FDA and co-chair of the KHI project, said the 510k clearance pathway used by Nephros “required and benefited from a strong collaboration between the FDA and the firm.”

Now, the company is participating in the KHI project to establish a clear pathway for other hemodiafiltration devices through the FDA’s regulatory process. Silverstein helped coordinate the FDA’s contributions to this KHI project.

“Together, FDA personnel provided and clarified the regulatory framework for review of these devices,” Silverstein said. He noted that the FDA has partnered with KHI on many projects, “helping KHI and the renal community better understand medical device performance characteristics, develop position papers, discuss clinical trial design, and consider study endpoints. We are poised to continue to work with all stakeholders in the renal community.”

The approval pathway recommended by the KHI project relies on testing protocols to prove that the devices can reliably produce fluids that meet the FDA requirements for sterility.

“It turns out to be a very logical pathway, probably the only scientifically sound pathway,” Ash said.

Now, the ball is in the manufacturers’ court to submit their devices for approval and for the FDA to consider them.

“The FDA is always open to stakeholder input,” Silverstein said. “The information we have already and will continue to gain from stakeholders in the renal community has and will undoubtedly strengthen our knowledge and enhance future collaborative efforts.”

Ash cautioned that even if more devices are approved, there remain other hurdles to the widespread availability of hemodiafiltration. He noted that hemodiafiltration was easier to adopt in Europe, where dialysis units had already adopted water purification systems that produce ultrapure dialysate.

“It’s not easy to implement this therapy in a dialysis unit; that’s a caveat,” Ash said. “You really have to improve the space and water quality beyond what we usually have in the United States, but toward what is required in Europe.”

Still, the proposed approval pathway makes it possible for this new renal replacement option to begin tests and potentially to be offered in the United States.

“The pathway is a step forward,” Ward said.