Scientists have previously shown that embryonic tissue transplants can be used to grow new kidneys inside rats. In their latest study, though, they put the new kidneys to an unprecedented and critical test, removing the rat's original kidneys and placing the new kidneys in position to take over for them. The new kidneys were able to successfully sustain the rats for a short time.
"We want to figure out how to grow new kidneys in humans, and this is a very important first step," says Marc R. Hammerman, M.D., the Chromalloy Professor of Renal Diseases and leader of the study. "These rats lived seven to eight days after their original kidneys were removed, long enough for us to know that their new kidneys worked."
The study will appear in the July/August issue of Organogenesis, a new scientific journal. It is also available online.
Hammerman is a leader in the burgeoning field of organogenesis, which focuses on growing organs from stem cells and other embryonic cell clusters known as organ primordia. Unlike stem cells, organ primordia cannot develop into any cell type--they are locked into becoming a particular cell type or one of a set of cell types that make up an organ.
"Growing a kidney is like trying to construct an airplane--you can't just make a single part like a propeller, you have to build several different parts and systems and get them all working together properly," Hammerman explains. "Fortunately, kidney primordia already know how to grow different parts and self-assemble into a kidney--we just have to give them the right cues and a little assistance at various points."
For the study, Hammerman and coauthor Sharon Rogers, research instructor in medicine, gave renal primordia transplants to 5- and 6-week-old rats. Prior to insertion, scientists soaked the transplant tissue in a solution that included several human growth factors, proteins and hormones. One of the rats' original kidneys was removed at the same time.
Three weeks after the transplant, researchers connected the new kidneys to the bladder and administered a second dose of growth factors.
Approximately five months after the transplants, scientists removed the remaining original kidney in control and experimental rats. To help resolve uncertainty about which kidney functions are critical to sustaining life, scientists cut the connections between the bladder and the new kidneys in a subset of the experimental rats.
Rats with no new kidneys lived for two to three days, and rats whose new kidneys were disconnected from their bladders lived no longer. However, the rats with new kidneys connected to their bladders lived seven to eight days.
"This tells us that the urine-producing functions of the kidney are key to preservation of life," says Rogers.
"Seven to eight days may not seem like a long time," adds Hammerman. "However, what we have done is akin to building the first airplane and showing that it can fly, if only for a few minutes. It's just as revolutionary."
In this study and in other previous research, Hammerman and Rogers have established that the newly grown kidneys can perform many essential renal functions.
"For example, we've shown that they can excrete inulin, an inert sugar that we inject into a rat's bloodstream," Hammerman says. "This demonstrates that the kidneys are filtering the blood."
When scientists injected the rats with another compound known as p-aminohippurate, the kidney began to secrete it into the urine.
In addition to excretion and filtration, the new kidney also has to reabsorb salts, water and key nutrients. The researchers have shown that the new kidneys can reabsorb both water and the nutrient phosphorus.
Hammerman, who is director of the Renal Division at the school's affiliate Barnes-Jewish Hospital, hopes to use animal-to-human transplants, known as xenotransplants, as a solution for chronic organ donation shortages.
"Every year, approximately 10,000 kidneys become available for transplant into patients with end-stage kidney disease," Hammerman says. "But the waiting lists for kidney transplants can run as high as 100,000 individuals, and most patients die of the disease before an organ becomes available."
Kidney function in pigs is similar to that in humans, and Hammerman's eventual goal is to use embryonic pig tissue transplants to help renal failure patients live longer.
Working with embryonic tissues that grow into organs inside the patient lets Hammerman avoid hyperacute and acute vascular rejection, two immune system responses that can destroy xenotransplants. In both of these responses, the body's immune system recognizes the blood vessels of transplanted tissue as foreign and attacks them.
"Those two types of rejection have so far made it impossible to xenotransplant fully grown kidneys," Hammerman explains. "However, we can avoid this by transplanting embryonic kidneys before blood vessels develop."
The primordia are small enough that survival can be maintained after transplantation through diffusion of oxygen and nutrients. The transplanted cells attract the growth of new blood vessels from the host as they grow into a mature organ.
Hammerman notes that recipients of embryonic xenotransplants will still have to take immune suppression drugs to prevent acute rejection, a third type of immune response that directly attacks transplanted tissues. But recipients of human kidney transplants also must take immune suppression drugs.
Hammerman and Rogers published their first report on growing kidneys in 1998. They are currently working to perfect pig-to-rat xenotransplantation of kidney primordia. If they can extend life in pig-to-rat transplants, the next steps are pig-to-primate and then pig-to-human transplants.
"Therapies based on growing new organs will be part of mainstream medical practice by the middle of the 21st century," predicts Hammerman, who is also working to develop approaches for growing a new pancreas as a treatment for diabetes.
Rogers SA, Hammerman MR. Prolongation of life in anephric rats following de novo renal organogenesis. Organogenesis, July/August 2004.
Funding from the National Institutes of Health.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.