by George Taniwaki
Two weeks ago, I posted a blog entry with an update on advances in artificial organs. I try not to cover a topic in my blog too frequently, so as to not overemphasize any one area of research. Thus, I wasn’t planning to write about regenerative medicine again for several months. However, last week an exciting paper was published and I’ve decided not to put it in my pile for discussion later.
Scientists at the Massachusetts General Hospital (MGH) in Boston have created a functioning kidney and transplanted it into a rat, where it began making urine. The process is described in detail in Nature Medicine May 2013 (subscription required) and summarized in The New York Times Apr 2013.
The bioengineered kidney starts with a kidney from a rat cadaver. The kidney is perfused with detergent to remove the kidney cells to leave behind a scaffold called an extracellular matrix. One of the authors of the current study is Dr. Harald Ott, who was one of the developers of this decellularization process while at the University of Minnesota. (His decellularization process is described in an Aug 2010 blog post).
In previous research into constructing an artificial kidney, the decellularization process caused severe damage to the vascular, glomerular, and tubular structures. In the MGH process, much lower pressures were used to better preserve these important structures.
Further, previous research made no attempt to repair these structures after decellularization. The group at MGH seeded the kidney scaffold with a small number of human epithelial stem cells. These cells can grow to repair the blood vessels, glomeruli, and tubules. (See the Apr 2013 blog post for a more controlled way to form blood vessels and tubules using a 3D printer.)
The MGH group then seeded the kidney scaffold with newborn rat kidney cells by perfusing it with a whole-organ culture (see image below). After several days, the kidney was able to produce urine at about 10% of the efficiency of a biological rat kidney.
As a final test, the kidney was transplanted into a live rat where it continued to work.
Bioengineered rat kidney incubating in whole-organ culture. Photo courtesy of MGH
This is a first successful attempt to create a working artificial kidney. It is a logical next step based on knowledge gained from earlier experiments, but it is still a remarkable achievement. Several hurdles must be overcome to turn it into a possible therapy.
First, the incubation process must be perfected to allow the bioengineered kidneys to perform for extended periods of time (hopefully for the normal lifespan of the animal) after transplant. Often, transplanted organs can suffer damage called reperfusion injury once they are connected to the living blood supply.
Second, the efficiency of the kidney needs to be significantly increased above the current 10%. The goal would be to have one or two artificial kidneys able to supply the capacity needed for normal function. This may require applying the correct cell type to each area of the kidney rather than bathing the entire kidney in a mixed culture.
Third, the kidneys need to be scaled up to human size. Larger mammals have about the same size cells as smaller ones. So large mammals, such as humans, have several thousand-fold more cells than smaller ones. Each cell needs to have access to blood from capillaries. Thus, large mammals have much more complex branching in their circulatory network than smaller mammals. Similarly, large mammal kidneys have many more tubules than those in smaller mammals.
Finally, another issue in creating human-sized artificial kidneys is the limited availability of human-sized kidneys for creating the extracellular matrix. As readers of this blog know, there is a severe shortage of deceased donor human kidneys available for transplant. However, this may be overcome by the fact that the kidneys used as scaffolds do not need to be of transplant quality. The supply of scaffolds may be increased further by using pig kidneys, which are a similar size to human ones and readily available.
If these problems can be solved, and I believe they can, then the first clinical trials of artificial kidneys may begin within the next few years.
An interview with Dr. Ott is available on YouTube.
Harald Ott discusses artificial organs. Video still from Nature Medicine
In addition to not wanting to run a story on regenerative medicine so soon because of topic fatigue, I was also worried about the impact the story may have on kidney patients and potential donors.
If you are a kidney patient, do not let the rapid progress in the development of artificial kidneys deter you from seeking a live donor. You want to take control of your medical outcome and improve your quality of life now, not wait for a scientific breakthrough some day in the future.
Similarly, if you are considering becoming an organ donor, don’t turn down the opportunity to give the gift of life. People need transplants now.
There will be many clinical trials before the enough data is submitted to the FDA for it to approve implanting artificial kidneys in humans. It may be over a decade before the first products come to market.