Toronto Lung Transplant Program
By: Grace Jacobs
An interview with Dr. Shaf Keshavjee,
Surgeon-in-Chief at University Health Network (UHN), Director of the Toronto Lung Transplant Program
The Toronto Lung Transplant Program has reached many milestones over the last four decades with its innovative thinking and research. Groundbreaking achievements in lung preservation, transplant surgery, assistive devices, and post-transplant outcomes have made Toronto the centre of the world in the field of thoracic surgery. However, many complex challenges continue to face lung transplantations today.
First and foremost, there is a shortage of lungs viable for transplant. The yearly mortality rate on the waiting list is between 18-20%. Only around one in six donated lungs are healthy enough to be used, often due to an increase in pro-inflammatory cytokines that is associated with higher rates of patient death.1 However, the recent development and implementation of the Toronto Ex Vivo Lung Perfusion (EVLP) System, which allows lungs to be preserved at body temperature, has opened a realm of possibilities. Prior to the EVLP system, lungs were preserved through cooling to slow down metabolism and deterioration. However, cold preservation prevents proper assessment of graft quality. Thus, donor lungs might be rejected solely on the basis of an inability to assess marginal organs. With the advent of EVLP, marginal organs can be monitored and assessed individually to help transplant surgeons select lungs that are suitable for transplantation. This effectively expands the donor pool of available lungs to patients in need of a transplant. In addition, the physiologic conditions of EVLP enable implementation of therapeutic strategies that would not be possible during cold storage. Thus, EVLP has served as a platform by which to improve viability by repairing inflammation and injury. Surgeon-in-Chief at University Health Network (UHN), Director of the Toronto Lung Transplant Program, and developer of EVLP, Dr. Shaf Keshavjee explains: “This is how we’ve been able to transform transplantation, [and] move into the realm of personalized medicine.”
Dr. Keshavjee hopes that one day, a molecular diagnostic nanochip will assess biomarkers of lung function, with results for one lung available in as little as 20 minutes. This is a much-needed improvement from current diagnostic tools—usually designed for chronic diseases—that take a day to get results. Currently, lungs can only be kept on ex vivo perfusion for a maximum of 12-18 hours, although research is focusing on how to improve oxygen delivery, nutrition, and perfusion to increase this timeframe. Looking forward, Dr. Keshavjee indicates that most researchers hope to extend lung survival to 24 hours; however, he hopes to eventually reach 48 hours.
Another major obstacle in lung transplantation is post-transplant tissue injury caused by chronic rejection, and viral, fungal, and bacterial infections that result from systemic immunosuppression (a requirement for surgery). Injuries are particularly problematic if recovery is abnormal, which can result in the formation of fibrous tissue in place of healthy lung tissue. This can ultimately lead to lung failure. Additionally, acute or chronic rejection of the organ can be caused by differences in major histocompatibility complex proteins between donor and recipient. Current research is focusing on gene therapy as a potential solution to these problems. The goal is to genetically modify lungs to improve anticipation of, and adaption to, the process of transplantation. These improvements could reduce incidences of post-surgical rejection that can occur in recipients throughout their lives. Already, techniques have been developed that use adenoviral vector-delivered gene therapy to upregulate interleukin 10, which reduces inflammation in the donor lung.2
In the future, lungs might be grown using recipient stem cells; or, cells could be transferred onto a lung graft, which would avoid organ rejection completely. Dr. Keshavjee expresses confidence in the development of these techniques: “[In coming years], we will make a new trachea repopulated with your own cells and transplant it. One day, we will grow a new lung.” The thoracic surgery program in Toronto has had many successes, especially in systematically translating solutions effectively from bench to bedside. Considering the next steps, Dr. Keshavjee expresses a belief in encouraging the next generation of clinician-scientists. “[It’s about] creating people who will continue to think like this in the future, and enabling them. Just because it’s not possible now, doesn’t mean it won’t [ever] be.”