Liver, kidney and lung transplantation results in excellent patient survival and has become the standard of care for patients with end-stage organ failure. However, the demand for transplantation exceeds by far the number of available organs, resulting in a long waiting time for these life-saving procedures.
Our research focuses on improving organ preservation, which will allow us to extend the donor pool and reduce the waiting time of our patients for a life-saving transplantation. Our new technology, Ex Vivo Perfusion, allows us to assess and treat the liver, lungs, and kidneys outside of the body prior to transplantation. This technique will provide more and better grafts for our patients, reducing morbidity and mortality on the waiting list and after transplantation. Ex Vivo Perfusion will help us increase the number of organs that can be transplanted, improve the survival of organs that are transplanted by inducing tolerance, and develop new ways of treating existing diseases.
To achieve the above, we are focusing our research on the following:
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Marginal Grafts
One strategy to improve the organ shortage is the use of suboptimal (marginal) grafts, such as organs retrieved after circulatory death (DCD), or organs from older donors. Unfortunately, marginal grafts poorly tolerate the preservation techniques of cold static storage, often resulting in a severe graft injury and poor graft function. Using Ex Vivo Perfusion, we can assess and repair marginal grafts, increasing the numbers that are usable for transplantation.
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Viral Infections
Chronic viral infections affecting potential donors for organ transplantation are also very common. While some types of infection in donors, such as hepatitis C (HCV), make using donated organs impossible, others, such as Epstein-Barr virus (EBV) and Human cytomegaloviruses (CMV) can have an adverse effect on patient outcomes after transplantation, including acute and chronic graft dysfunction, and malignancies, but do not stop the transplant entirely. With the new techniques, we have been able to assess and treat existing diseased organs that otherwise would have been turned down for transplantation.
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Immune Tolerance
Our goal is to treat end-stage organ diseases with a single organ transplant procedure, and restore function and quality of life without the need for immunosuppressive drugs.
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Treatment of Diseases (Cancer)
Another potential use for Ex Vivo Perfusion is the treatment of cancer. We can remove a diseased organ from the body, treat it in ways that are not possible if the organ is inside the body (for example, with high dose chemotherapy, high dose nanoparticle delivery, etc.) and then return the treated organ to the body using transplantation techniques.
Ex Vivo Lung Perfusion (EVLP) is a novel method of donor lung preservation and treatment developed in Toronto, which allows donor lungs to be treated for at least 12 hours under protective physiological conditions. This essentially creates a critical time window in which donor lungs can be optimally repaired prior to lung transplantation. In Toronto, EVLP has been an integral part of our clinical lung transplant program since 2008. In 2012, Health Canada approved this strategy and subsequently, the Ministry of Health and Long-Term Care started to reimburse our hospital for EVLP costs. In 2013, our lung transplant activities increased by 28% in one year, with EVLP being the major responsible factor for that increase, considering that our multi-organ donor pool number and characteristics did not change. We now have significant experience with over 110 patients that have received EVLP lungs in Toronto. This group of patients enjoys very low rates of severe primary graft dysfunction (PGD), and a 5-year survival of 70% in comparison to 63% in contemporaneous conventional transplants. With the ability to treat infected donor lungs, we are increasing the number of viable transplants.
In Vivo Lung Perfusion (IVLP) is a surgical technique developed to deliver high-dose chemotherapy to the lung, minimizing systemic exposure by selectively delivering an agent though the pulmonary artery and selectively diverting blood. IVLP has the distinct advantage of delivering high-dose drug treatment to the lung while limiting exposure of sensitive critical organs, therefore avoiding severe complications. With In Vivo Lung Perfusion, it is possible to vary parameters such as drug delivery, temperature, ventilation, and other physiological parameters, thus creating a fully customizable environment.
For the liver and kidney transplantation, we’ve developed the
Normothermic Ex Vivo Liver and Kidney perfusion circuits. These maintain the grafts at a physiological temperature (37°C), saturating them with oxygen and a solution that contains blood, minerals, nutrients, amino acids, glucose, antibiotics and drugs. With these techniques, we avoid the negative effects of cold storage, which does not allow graft assessment prior to transplantation and is unsuitable for graft repair strategies.
Using Normothermic perfused preservation, we can reduce preservation injury, and are able to assess liver and kidney function prior to transplantation. In addition, the liver and kidney have a normal function and metabolism during the preservation period, allowing us to apply novel strategies and modify grafts according to the recipient needs. We have already shown that Ex Vivo Liver and Kidney perfusion are safe in our transplantation population, and have performed multiple liver and kidney transplants following Ex Vivo Perfusion.
Liver:
By using the novel warm perfusion technique for the liver storage, we avoid the organ injury, which normally occurs when the liver is cooled on ice. In addition, during warm perfusion, the liver has an active function outside the human body, which allows us to test its function before transplantation. By using warm perfusion, we are able to safely transplant liver grafts that were previously declined for transplantation. This allows us to provide more livers for our patients on the waiting list, also shortening the waiting time for this life-saving procedure.
Kidney:
We have recently started our clinical trial using warm kidney perfusion for transplantation. Our first experience provided excellent kidney function after transplantation, indicating that this new technique has great promise for our patients on the waiting list. We hope that warm perfusion will allow us to provide better kidney function and use more kidneys for transplantation.
Lungs:
Our studies focus on the following:
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Ex Vivo Lung Perfusion (EVLP) system
In a landmark study, we successfully showed that previously unusable “marginal” human lungs assessed during 4 hours of EVLP could be used for clinical transplantation with excellent post-transplant outcomes comparable to conventional donor lungs. This contribution to the lung transplant field enabled the expansion of the donor lung pool worldwide and serves as a foundation for research in the preservation and regenerative repair of donor lungs ex vivo.
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Modification of the donor lung using gene therapy before transplantation
We have proved the concept that genetic modification of the donor lung prior to implantation can lead to improved function of the graft after transplantation. We developed a novel strategy for using gene therapy as a potential mechanism to repair injured donor lungs ex vivo before transplantation.
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Introducing the concept of semi-elective lung transplantation using Ex Vivo Lung Perfusion
We have demonstrated that combining properly performed cold static preservation and normothermic EVLP can substantially prolong donor lung preservation times from 6 to 8 hours to 18 to 24 hours without adverse effects to recipients. This provides multiple advantages to transplant teams and patients.
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Lung donation after cardiac death (DCD)
Donation after cardiac death (DCD) has the potential to overcome one of the major limitations of organ transplantation today: the increased gap between available donors and patients in need for transplantation. We have determined best practices in DCD lung transplantation and demonstrated the advantages of routinely using EVLP for assessment of DCD donors to improve the outcomes of lung transplantation.
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Innovation with the use of organs from lung donors infected with HCV (hepatitis C)
We have demonstrated for the first time the safety of transplanting HCV-positive donors into HCV-negative recipients. We have achieved this by using innovative technology to inactivate HCV from donor organs using light-based therapies. This will have an impact bringing a large number of donor organs not previously available.
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Development of a new method for delivery of localized chemotherapy to the lungs: In Vivo Lung Perfusion
We are often limited in our ability to treat cancer that has metastasized to the lung, because the dose of chemotherapy drug needed to effectively kill the cancer is so high that it would be impossible to give it to a patient. With In Vivo Lung Perfusion we can give the drugs exclusively to the diseased lungs, protecting the patient from their side effects and increasing the effectiveness of the treatment.
