Researchers find innovative ways to replicate natural renal function.
NEW YORK—Despite many advances over the years, dialysis and transplantation remain imperfect solutions to renal replacement. One of every five dialysis patients dies every year, and the shortage of live and cadaver donor organs shows no sign of ending or even abating. Xenotransplantation—long considered the holy grail of renal replacement—has so far yielded little success. Fortunately, researchers are coming up with creative new ways to replicate the function of the kidneys. Here’s a look at some of the most promising developments now underway.
The membraneless artificial kidney
Although still on the laboratory bench, a wearable, microfluidic artificial kidney being developed
at ColumbiaUniversity in New York City has exciting potential. The device, about the size of a
deck of cards, incorporates small, nanopore filters, a battery, and a pump. Designed to be worn on the inner arms at all times, the membraneless kidney will enable patients to dialyze themselves at will, whether it’s sleeping, working at a desk, driving, or watching TV.
Invented by a team headed by Edward F. Leonard, PhD, the device is called membraneless because it uses a layer of “sheath” fluid instead of a traditional membrane to extract toxic molecules from blood. “The idea is to make blood flow through layers no thicker than 50 microns,” says Dr. Leonard, a professor of chemical engineering. “We will, in effect, create a ‘sandwich,’ with layers of sheath fluid on top and bottom; the ‘meat’ of the sandwich is the layer of blood.”
The molecular components of the blood will diffuse into the sheath fluid, which will carry away the toxins. “We will dialyze the sheath fluid and return proteins and other necessary elements back into the patient’s bloodstream,” Dr. Leonard says.
The membraneless kidney will be worn on the arm, permanently connected to the bloodstream, and attached via thin plastic tubes to a wastebasket-sized container of dialyzing solution. Patients would connect the kidney’s tubes to the solution, and when they want to take a break, they can disconnect. Each patient might have two or three of the solution containers for use in different locations, such as home, office, and car.
Dr. Leonard says good candidates for his device will be “active, ambulatory patients who want to live normal lives” and don’t want to be tied to a dialysis clinic three times a week. Within the next year, Dr. Leonard hopes to have a working prototype that he can test by “piggybacking” it onto an ordinary dialysis machine in a clinic. Once he’s sure the membraneless kidney is working properly, he will promote wider testing using the device on its own. Although there are a number of obstacles to overcome, Dr. Leonard says he believes the membraneless kidney could be available for widespread use in the next five years. Infoscitex Inc., of Waltham, Mass., is collaborating with Columbia on the project.
The Wearable Artificial Kidney (WAK)
The Wearable Artificial Kidney (WAK)—a miniaturized hemodialysis machine worn around the waist—could become a must-have accessory for 21st-century kidney failure patients. The WAK, whose development is being spearheaded by Victor Gura, MD, associate clinical professor of medicine at the University of California in Los Angeles, consists of a 5-lb continuously worn belt containing a high-flux dialyzer, a pulsatile pump that propels blood and dialysate, and sorbent cartridges that purify and regenerate the dialysate. The entire system is powered with a nine-volt battery. When the device is used for ultrafiltration only, it has the ability to remove excess salt and water in patients with fluid overload due to congestive heart failure. In this configuration, the device weighs only 2 lb.
Dr. Gura says creating the WAK required looking for new solutions to old problems and keeping an open mind. “This is not similar to current technology,” he explains. For one thing, the WAK uses a novel pump. “Conventional dialysis machines use one pump for blood and another for dialysate,” says Dr. Gura, who is also an attending physician at Cedars-SinaiMedicalCenter in Los Angeles. “The pump we use weighs less than 1 lb and operates on small batteries. It has a unique alternate pulsating mechanism to circulate blood and dialysate through the system.”
The WAK is designed to provide continuous dialysis 24 hours a day, seven days a week. Dr. Gura and his team believe the device also has the potential for treating patients with congestive heart failure.
WAK testing has already begun in animals and humans. In one recent study, six patients with fluid over-load due to renal or cardiac failure used the WAK for six hours. Blood flow averaged 116 mL/min and fluid removal ranged from 120 to 288 mL/h. The WAK removed an average of 9 grams of salt per pa-tient, and all of the patients’ vital signs remained constant. There were no complications. Further human studies are underway.
“We have had considerable FDA guidance, and we could be in the market in the next couple of years,” Dr. Gura says. “The ESRD population in the U.S. is approaching 400,000, and given the fact that current annual mortality is 20%, we’re talking about saving 40,000 lives a year. To me that’s pretty exciting.”
The Human Nephron Filter
Enlarged photos of the Human Nephron Filter (HNF), a molecularly engineered nanomembrane, resemble a group of interlocking snowflakes. But HNF researcher Allen Nissenson, MD, says the filter’s delicate appearance actually belies an underlying strength. “Ordinary dialysis membranes are fairly stupid,” explains Dr. Nissenson, professor of medicine and director of the dialysis program at the David Geffen School of Medicine at UCLA. By this he means that conventional hemodialysis’ ability to remove toxins and return usable agents to the blood is relatively primitive. In contrast, “nano-technology can create membranes that are really very smart,” said Dr. Nissenson, who chairs the scientific advisory board of Philtre, the company developing the HNF.
The HNF, he observes, is highly selective. It can remove specific substances from the blood while leaving others behind, even if all of the substances have the same molecular weight and charge. Dr. Nissenson and his team have been using nanochemistry to create the tiny-pored membranes. So far, they have created small sections of porous membrane and they are now attempting to populate entire membranes with pores, which will then be tested them in the lab. “We haven’t conducted laboratory studies with actual fluid and complete membranes to verify our computer model results,” he says, “But we’re almost at that point.” Down the road, he says, the HNF can serve as the key component of “a continuously functioning, wearable or implantable artificial kidney.”
Before that can happen, however, a number of issues need to be resolved. “We know that individual pores function properly; the key is to construct an entire membrane and have it work,” Dr. Nissenson says. “Also, in order for this to work, there must be a way for the patient’s blood to flow through the device and back into the bloodstream. We’ve given some thought to this problem of vascular access, but will need to devote more attention to it.”
Dr. Nissenson’s group already has performed computer modeling to compare conventional hemodialysis with dialysis using the HNF. To do this, they input data about theoretical patients, including their size, weight and protein intake. They calculate how much potassium, urea, or fluid will be removed in a given period by a commercial dialyzer used for standard dialysis (three times a week, four hours per session). “Then we take our device and input the same parameters. The computer then calculates how well each method works to remove solute from the blood.”
So far, Dr. Nissenson’s team has computer-tested a number of possible regimens using the HNF—24 hours for six days per week, 24 hours for seven days a week, and so on—and the HNF has performed well, although he says when he begins animal testing, other issues may develop that cannot be predicted now.
Dr. Nissenson says he hopes to begin such HNF testing in the next two to three years, probably in pigs or dogs. Assuming those trials go well, he says, testing on humans could begin within three years at the earliest.
The initial iteration of an HNF-containing device would be worn in a shoulder holster under one arm (see illustration at left); later versions could be implantable. “Implantable versions are a minimum of five years off, and that may be optimistic,” he says. Even so, Dr. Nissenson is confident that his ideas are on the right track. “Ultimately,” he predicts, “this has the potential to be transformational.”
The bioartificial kidney
The bioartificial kidney, under development by David Humes, MD, professor of internal medicine at the University of Michigan in Ann Arbor, looks like a typical hemofiltration cartridge. But with its key component—the renal tubule assist device (RAD), which is filled with living cells—it represents a breakthrough in hemofiltration. It’s the first time the function of the tubule has ever been approximated by technology.
The clear, plastic canister of the RAD is filled with hollow fibers whose walls are dotted with microscopic pores and lined with living renal proximal tubule (RPT) cells (see illustration, opposite page). These cells are grown in the lab from salvaged adult stem cells taken from unusable donor kidneys. Once inside the RAD, the RPT cells can assume many of the kidney’s reabsorptive functions and, even more importantly, metabolic and endocrine functions. Among others, these include influencing cytokine levels to help prevent inflammation and activating vitamin D to enhance the patient’s nutritional status. “Traditional dialysis is not complete renal replacement; the RAD is much closer,” Dr. Humes says. “In addition to purifying the blood, the kidney is a solid organ, and it must add critical metabolic and hormonal substances that we’re not yet aware of.”
Currently, the RAD is used in tandem with traditional renal dialysis in the ICU to treat critically
ill patients with acute renal failure. In this setting, patients are hooked up to the bioartificial kidney, where one cartridge filters the blood as in traditional dialysis and then shunts it to the RAD, where it is further purified before being returned to the patient.
In the past two years, several human trials have been carried out with the RAD, and the results
have been promising. In a phase II study in late 2005, Dr. Humes randomized ICU patients to traditional dialysis or dialysis plus treatment with the RAD, and found that use of the RAD reduced 28-day mortality from 61% to 34%. These results, he says, “were remarkable and exceeded our expectations.”
Soon, Dr. Humes plans to evaluate the RAD in patients with ESRD, where treatment will extend to months or years rather than days, and end points will be less clear-cut. In the future, Dr. Humes hopes to shrink the RAD enough to make it wearable and, eventually, im-plantable. To that end, part of his team is working on a micro-electro-mechanical system (MEMS) nanofabrication process. “In the next couple of years we’ll be trying to miniaturize these devices,” Dr. Humes says. “If miniaturizing is successful, we will do large-animal testing to see how it can work in chronic renal failure. If that is successful, we will test it clinically in humans.” If everything goes smoothly, he adds, “We could have bioartificial kidneys ready for human trials in five years.”
Dr. Humes says he hopes a wearable device may be ready for widespread use in the next 10 years, while fully implantable versions may take 20-30 years. Ultimately, he says, his and Dr. Nissenson’s technologies may converge. “Dr. Nissenson is trying to produce porous nanofabricated membranes that duplicate the tubules’ filter and reclamation process; I think what he’s doing is attractive and innovative. If he can produce these membranes in a robust fashion with selective characteristics, perhaps adding our living cells to his membranes might be the way to go.”