A colourless, odourless and toxic gas to humans may hold a rather counter-intuitive key to extending the lives of kidney transplant recipients, Western researchers say.
Kidney disease strikes 2.6 million Canadians, with an average of 16 people per day experiencing kidney failure of some sort. Despite improvements in immunosuppressive therapy, the long-term survival of kidney transplant patients has not increased dramatically over the past decade.
“More than 95 per cent of kidney transplants are successful through the first year. But overall survival over time hasn’t changed too much,” said Patrick Luke, a Surgery professor in the Schulich School of Medicine & Dentistry. “I tell people, for a deceased donor kidney, it would be between 11-15 years as an average. We’d like to see this become 20 or 25 years.”
Luke, along with research associate Rabindra Bhattacharjee and others at the Matthew Mailing Centre for Translational Transplant Studies, are pioneering a unique treatment using carbon monoxide-releasing molecules (CORM) in an attempt to meet that aggressive target.
The researchers are part of a $10 million Canadian National Transplant Research Program project, the first in the world to unite the solid organ transplant, bone marrow transplant and donation/critical care research communities together. More than 100 researchers and 86 collaborators at 13 centres and universities in nine provinces are coming together over six nationwide research projects to improve clinical outcomes for transplant recipients.
After 14 hours, in cold solution, the kidney on the right produced 1.5 litres of urine over six hours, compared to the untreated kidney on the left, which produced just 400 ml.
Luke and Bhattacharjee also have a Physicians’ Services Incorporated Foundation grant ($169,000) to assist their research.
Normally, when you breathe carbon monoxide, the gas enters the lungs and binds to the hemoglobin in the red blood cells. As the level of carbon monoxide increases, the amount of oxygen the blood carries to the body’s cells decreases, leading to oxygen starvation.
However, in a lab setting, treating kidneys with a synthesized form of carbon monoxide, CORM, has improved kidney transplant function and survival when added directly to the kidney storage solution prior to transplantation. At the time of the transplant, CORM is no longer present – thanks to its short half life – which means no danger to the patient.
Kidney transplant patient survival is mostly dependent upon the damage that occurs during kidney removal from the donor and prolonged preservation in a cold solution, Bhattacharjee said.
“Lack of blood supply during the entire transplantation processes deprives the kidney from getting oxygen, which provokes inflammation in this organ,” he said. “In small animal models, we have shown CORM improves kidney function and survival when given to the kidney donor or when added directly to the kidney storage solution.”
CORM acts as an anti-inflammatory. It dilates the blood vessels and prevents the death of cells. Luke believes this could also lead to the reduction of toxic immunosuppressive drug use required for transplant patients.
“The point of all these studies is to set up the immune system so that when we do the transplants, we are going to condition these kidneys in a way that the immune system doesn’t attack it (kidney) and take years off it at the outset,” Luke said. He noted more than 4,500 Canadians are waiting for an organ transplant. As less than 50 per cent of those people will receive an organ, three die each day while waiting for an organ.
For Bhattacharjee – who called working with Luke “wonderful ground to grow my plant” – he sees no issues to keep this idea from the bedside in the near future. Western is currently approving its human ethics protocol.
“The good thing with CORM and kidney preservation is we are not directly treating the patient, but the kidneys after donation,” he said. “If CORM works positively in kidney preservation, it would work equally for other organs, too.”
At the one-year mark of transplantation, if a biopsy was done, you could expect to see 40 to 60 per cent showing interstitial fibrosis and tubular atrophy, or abnormalities in the kidney’s function, Luke added.
“With this early treatment, we are trying to set up for success 10, 15, 20 years down the road, so we don’t have to re-transplant. If we are able to condition them with something like carbon monoxide, and prevent the immune system from being revved up, and reduce inflammation, I think that is exciting.”
Working on this for almost a decade, Luke has looked at this at the cellular level, in small animals, large animals and now has grant proposals written to bring his research to humans.
“I don’t want to cure any mice,” Luke said, noting success in humans could come as soon as five years. “The ultimate goal is to create the best situation for patients. If I could do one thing in my lifetime that changes the practice of medicine, if I can say we’ve done this, that every one getting a kidney transplant will use this method, that’s so exciting.”
