Regenerative medicine continues to flourish. Yet it is still a major breakthrough when new techniques are demonstrated to be both safe and effective in humans. One area with great promise is in the successful grafting of blood vessels in patients with renal disease.
Medscape spoke with Laura Niklason, MD, who, along with colleagues, recently published a paper in the Lancet reporting results from two clinical trials investigating the application of a new vessel grafting technique.
Medscape: Let’s begin by having you explain a bit about the issues facing patients with end-stage renal disease who must undergo dialysis. What are the particular challenges for this group of people?
Dr Niklason: Patients who are on dialysis for kidney failure have a really challenging existence. They have to go to dialysis centers three times a week, for 3-5 hours each session, so that they can have their blood cleansed in the dialysis machine. It’s a big burden for them and also very expensive for the healthcare system. It probably costs $80,000-90,000 a year for Medicare to care for each dialysis patient. It’s burdensome for the patients, and it’s also expensive for the system.
One of the key drivers of patient discomfort and difficulty is failure of what we call “dialysis access.” In order to do dialysis, we have to be able to withdraw blood from the patient at a high rate, around 1 L/min, to run it through a dialysis machine and clean the blood. In order to do that, we need a conduit, a connection between the patient’s artery and the vein that is sitting underneath the skin. That conduit gets punctured with large-bore needles three times a week in order to draw blood out of a patient, clean it, and then return it to the patient.
One of the things that really contributes to the difficulties of the dialysis patients is when this dialysis conduit fails. When they become clotted, otherwise obstructed, or infected, then this conduit has to be removed, replaced, or intervened upon. And that contributes to morbidity and overall patient misery.
What we’re hoping to achieve with this new product, the human acellular vessel, is to hopefully have a graft that will suffer fewer of these complications and/or last longer, so that patients can go substantially longer before they have to get a new conduit placed.
Medscape: Given the difficulties with viable biological alternatives, tell us about how you and your co-investigators settled on culturing acellular vessels.
Dr Niklason: I think, as a comparison to other biological materials, there are two real distinctions of our vessel vs other products or other things that have been tested in man.
Many other biological conduits are derived from animal sources—typically, pig sources or bovine sources, although there are some conduits that are also grown in sheep. For all of those xenogeneic constructs, they all have to undergo crosslinking, often with glutaraldehyde, in order to limit the immunogenicity of the product. When you do that, it becomes very difficult for the patient’s own self to repopulate, remodel, and maintain the graft. In some instances, those grafts undergo dilatation and basically flow mechanical failure because the host can’t repopulate the tissues.
In contrast, there are some autologous engineered blood vessels that have been tested in recent years. These vessels were most commonly made from the patient’s own cells. They were living constructs that were grown in vitro from a tissue biopsy from the patient. This has the obvious advantage of being autologous, but it has the disadvantage that it was necessary to grow an individual graft for each patient; the waiting time was quite long, and the expense was high.
We threaded the needle here a little bit with this product. Because it is a human product, it’s engineered from human cells and doesn’t have to be crosslinked; it’s not immunogenic. But it does not require tissue biopsy from the patient. We used a donor cell bank to grow this engineered vessel, and we then decellularize them at the end of the process. So, we’ve got a nonliving human-based tissue that doesn’t have to be cross-linked and can be remodeled by the host.
Medscape: Once the acellular vessels were engineered, how did you go about testing these in humans?
Dr Niklason: Our first interest for this study was really to document safety; that was really primarily goal number one. But we also sought to understand efficacy in terms of how well these things function for dialysis. So, in terms of the study design, we were most interested in capturing events that would have a negative impact on safety.
For example, we looked for mechanical failure, dilatation, rupture, and bleeding. We were also interested in capturing whether or not these graft provoked any immune responses in the patients. We had multiple blood draws, like panel-reactive antibodies, to determine whether or not we were synthesizing these patients against the implanted tissue. From a safety standpoint, we were very encouraged. We had no instances of true aneurysm formation or mechanical failure in these grafts, so they appear to be very mechanically robust. And we had essentially no evidence of important immunogenicity. We had no instance where the graft was rejected by the patient. It was encouraging from the standpoint of safety in these 60 patients.
The other aspect of the trial design, though, had to do with the function of the graft aside from safety. And that really spoke to blood flow rates that we observed in the graft, how well the graft responded to being punctured with needles repeatedly over weeks and months and years, whether the graft maintained mechanical integrity after all those assaults, and also propensity for infection and other forms of failure, like internal hypoplasia.
Again, from the functional standpoint, these grafts seem to function pretty well. They withstood needle puncture three times a week quite well; and, in fact, we have some histologic evidence that there’s actually healing after needle puncture, so whole cells migrate into the needle tracks and help to heal the tissue actively on an ongoing basis. We think that’s encouraging and exciting. And the blood flow rates through these grafts were quite high. They were over 1 L/min typically. This meant that they were very well suited for dialysis and could withstand the high pressures of high blood flow rates that are required for these conduits.
Medscape: These are some very promising findings, not only for nephrology but for any specialties that seek to use aspects of regenerative medicine. What is next for your group, and to what sorts of applications do you see this technology being applied elsewhere?
Dr Niklason: As far as the first part of the question, we definitely plan to proceed with the phase 3 pivotal trial where we’re doing a prospective randomized comparison head to head against a standard of care in the field, which is polytetrafluoroethylene. We anticipate beginning that trial actually pretty shortly in the coming months, and we’re very excited about that. That trial will hopefully serve as our pivotal trial to really examine the comparative efficacy of this new material vs current standard of care.
As far as what it means for regenerative medicine on the whole, I think in particular the long-term mechanical function and the repopulation of these implants by patient cells means that we may be looking at a new paradigm here. If we’re interested in replacing connective tissue in patients, it may be possible to engineer the correct matrix, which we can then implant and which then gets repopulated. Blood vessels are connective tissue, but there are many other connective tissues in the body as well—intestine, trachea, tendon, ligament, skin. There may be many instances where engineering the correct matrix in the lab and creating an acellular implant may get us to off-the-shelf tissue replacement for a variety of diseases. I personally think that’s very exciting.