Advances in Long-Term Immunosuppression and Improving Outcomes

This edition of The Immunology Report focuses on the choices now available for improving clinical outcomes and long-term patient and graft survival, from minimizing ischemic reperfusion injury post transplant through adapting best practices for managing the complications of immunosuppression.

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Dixon B. Kaufman, MD, PhD, FACS
Dixon B. Kaufman, MD, PhD

Successful solid-organ transplantation demands a lifelong commitment to each recipient by a team of highly trained professionals that will carefully monitor and care for the recipient to ensure the health of the transplanted organ and that of the patient.

Once an organ is transplanted, the transplantation team must devise the best possible regimen to prevent graft rejection and to avoid or minimize the many adverse effects of long-term immunosuppressive therapy. Even under the best of circumstances, there can be daunting challenges. The only truism is to "expect the unexpected."

Physicians, surgeons, nurses, pharmacists, and others involved in the transplant process strive to manage the patient's immunosuppressed state to prevent rejection and cause the least possible harm in the process. Just as importantly, they must educate and encourage their patients to adhere to their immunosuppressive regimen, or even their best efforts will be for naught.

This edition of The Immunology Report is based upon selected presentations delivered during the 2014 World Transplant Congress, which was held July 26–31, 2014, in San Francisco, California. During this meeting, healthcare professionals in the transplant community attended workshops, seminars, and symposia; sat through oral presentations of exciting new research; and viewed hundreds of scientific posters describing predictors of transplant-patient outcomes, the process of organ rejection and preservation, and the body's immune response. In addition, they learned about new strategies to deal with organ rejection and the role of biomarkers in personalizing drug therapy.

Speakers at these sessions also provided a close look at ways to optimize the long-term management of patients after kidney transplantation, including the risk factors for allograft failure, development of donor-specific antibodies, and immunosuppressive toxicity.

Michael D. Rizzari, MD, of the University of Wisconsin–Madison School of Medicine and Public Health, provides an update on belatacept, a fusion protein used with other medications to prevent rejection of kidney transplants. When used with basiliximab induction, mycophenolate mofetil, and corticosteroids, belatacept therapy has proven clinically equivalent to the use of cyclosporine in preventing organ rejection. However, how well it fares compared with the more widely used drug tacrolimus or other immunosuppressive agents, such as sirolimus or everolimus, has not been established in large clinical trials.

Dr. Rizzari reviews the results of the pivotal clinical trials involving this drug and their long-term extension studies, discusses important considerations for its use in kidney-transplant recipients, and outlines ongoing trials evaluating the drug as an alternative to calcineurin inhibitors.

Between the time that an organ is removed from a donor and transplanted into an awaiting recipient, changes related to ischemia affect tissues and, ultimately, graft function. Imran Javed, MD, of the University of Washington Medical Center in Seattle, discusses ischemic reperfusion injury (IRI) and methods of maximizing the function of organs most affected by this phenomenon. Recently, use of nitric oxide, an antioxidant and anti-inflammatory agent, has proven to affect cell signaling, inhibit nuclear proteins, and limit IRI. When inhaled by lung-transplant recipients, nitric oxide therapy has proven superior to the use of other vasodilators in terms of hemodynamics. The pharmacology and physical effects of this promising treatment continue to be studied.

As successful as solid-organ transplant may be, late allograft failure always lurks as a medical complexity. Ultimately, the organ-transplantation team strives to improve both the patient's lifespan and quality of life. In the second of his two articles for this edition, Dr. Javed delves into anticipating and controlling comorbidities that contribute to organ failure. Selection of pharmacotherapeutics may make all the difference in preventing damage to transplanted tissue. Finally, Dr. Javed discusses the use of biomarkers and other screening tools to follow patients and the health of their allografts.

The use of novel immunosuppressants has led to a lower rate of early graft rejection; however, as previously noted, late allograft loss is still a major problem. Thin Thin Maw, MBBS, of the Washington University School of Medicine in St. Louis, takes a close look at the reasons for allograft failure and current options to optimize immunosuppressant therapy. Her article reviews the history of immunosuppression in kidney transplantation, discusses the reasons for allograft loss over the long term, and reports on the outcomes of studies investigating novel approaches to anticipating and preventing organ failure.

Jonathan C. Berger, MD, MHS, of The University of Michigan Hospital and Health System in Ann Arbor, covers a symposium dedicated to improving patient and graft survival and promoting quality of life of individuals who receive allografts. Beginning with a definition of the goals for patient survival, aside from the obvious, Dr. Berger then confronts the causes of patient death in renal-transplant recipients, the risk factors that may predict these causes, and the possibilities for preserving organ function and patient health in the face of imminent graft failure. In addition, he discusses practical approaches to monitoring graft and patient outcomes and the possibilities of using biomarkers to identify graft rejection early.

Immunosuppressant agents preserve the function of transplanted organs, but they also may cause patients to develop other health problems that can threaten the viability of the graft and the patient. Robert R. Redfield, MD, of the University of Wisconsin–Madison School of Medicine and Public Health, describes the threat of cancer development among recipients of different types of organ grafts and current methods of minimizing this risk. In addition, he discusses the threat to patient health posed by the metabolic syndrome, diabetes, and hypertension in patients who have undergone transplant surgery and how best to manage them. Finally, Dr. Redfield reviews the vulnerability to infection of graft recipients receiving immunosuppressive therapy and provides solid recommendations on who needs to be vaccinated and with what vaccines, especially those patients who are planning to travel outside the United States.

We thank our authors for bringing us up to date on so many subjects that are so important to improving and optimizing the long-term care of transplant recipients. Future editions of The Immunology Report certainly will shed even more light on these pressing issues and how to protect our patients better from infection and other comorbidities, prevent graft injury, and enhance their quality of life.

Dr. Kaufman is the Ray D. Owen Professor of Surgery and Chairman, Division of Transplantation, University of Wisconsin–Madison School of Medicine and Public Health, Madison, Wisconsin.

Supported by an educational grant from Astellas Pharma US, Inc., Bristol-Myers Squbb, and Ikaria, Inc.