Solid Organ Transplantation - Toward More Individualized, Proactive Patient Management
There are numerous challenges to achieving successful organ transplantation. Dr. Terry Strom, Director, Transplant Research Center, Beth Israel Deaconess Medical Center, discusses how more precise patient monitoring following transplantation could provide the basis for more individualized, and more proactive, therapy.
He looks ahead to the potential use of biomarkers to provide warning of possible rejection and to reduce the burden of immunosuppression therapy.
Immunosuppression Therapy – Striking the Right Balance
“The primary challenge following transplantation,” observes Dr. Strom “is to walk the tightrope between over- and under- immunosuppression.” Current guidelines, he explains, are largely based on the patient’s clinical status and drug levels: administer a high level of immunosuppression following transplantation and then withdraw slowly, recognizing that patients who fare well early on are likely to tolerate dose reductions or even elimination of certain therapies.
“The shortfall of this approach,” says Dr. Strom “is that the guidelines are not nearly as sharp as, for example, the guidelines for managing somebody with hypertension. For that patient you give a drug, measure the blood pressure and, if the blood pressure isn’t where you want it, you adjust the dose of the medication. The feedback on your therapy for that patient is quite precise because there is a total reckoning of whether you're giving enough or too much medication because you’re looking at the outcome.” With transplant patients this is not the case: physicians observe whether the organ is working well and take measurements of the amount of drug that is in the circulation but they do not measure the impact of medication on a patient’s immune system.
“So our ability to manage patients is extraordinarily imprecise,” cautions Dr. Strom. “It’s likely that we give many of our patients too much immunosuppression for too long a period of time. Yet others, for one reason or another, will slip through the barrier imposed by immunosuppressant medications and reject the transplant.” Given the variability in patients’ immune systems one of the many challenges in clinical transplantation is to get the balance right in terms of administering enough immunosuppression to protect the patient from rejection, while having the means to determine whether medications have been reduced too quickly.
A More Proactive Approach – The Promise of Biomarkers
The current approach to therapy is reactive. The first indication that there has been insufficient immunosuppression is when the graft loses function. “It’s often said that you can treat rejection successfully,” observes Dr. Strom “but the truth of the matter is that in many cases, while you don’t lose the transplant at that moment, you do lose some function and memory-type activated T cells are accrued in the host, which are much more resistant to immunosuppressive therapy than cells that have not been fully activated.”
The goal for patient monitoring is to move to what Dr Strom terms “a truly informative, individualized approach”. This would, for example, alert you that a patient is experiencing a rejection episode and would allow you to avoid performing biopsies, which are time-consuming, expensive and not totally benign. Even better would be a means to predict that the patient is going to experience a rejection episode, based on immune response, and warn that an intervention is needed. “It’s impossible to believe that malfunction of the transplant precedes heightening of immune activity in the host,” says Dr. Strom. “Rejection of a kidney transplant, which could be viewed as a kidney disease, is in fact caused by a heightened immune response against the donor and has to occur before the situation escalates with palpable loss of function.”
Identifying appropriate biomarkers could provide the basis for a more proactive approach to patient management. “There is considerable consensus in the transplant community that we have the ability to diagnose rejection with biomarkers.” This would provide clinicians with a “molecular signature” indicating that rejection is likely, allowing preventative steps to be taken. A reliable molecular signature that forewarns of rejection would also enable safe and in many cases expedited reductions in the intensity of immunosuppression. Many in the field are working on validation studies to demonstrate that rejection can be anticipated by a significant period of time – by weeks, or even months.
Molecular Signatures – The Key to Reduced Immunosuppression
Looking ahead, Dr. Strom is optimistic biomarkers will help identify patients suitable for total withdrawal of therapy – biomarkers that are consistent with so-called “immune-tolerance”. “A lot of people consider the ultimate goal to be the creation of immune tolerance in transplant patients - the state in which the immune system protects rather than attacks the organ. I, and others, believe we're on the cusp of being able to deliver this.”
An intermediate goal is to have the ability to maintain a patient on extremely low levels of immunosuppression. “There’s a lot of activity in this regard and it’s likely molecular signatures will be very important in making this happen. It may not be tolerance but it would drastically minimize the likelihood the immunosuppressive therapies are going to cause problems.”