Leading Causes of Kidney Graft Loss Over Time
Dr. Manuel Pascual, Assistant Professor of Medicine, Harvard Medical School, and colleagues reviewed the state-of-the-art in medical management after kidney transplantation as well as future directions in transplantation research, focusing on strategies for low toxicity immunosuppression. The following is an interview with Dr. Pascual, Director of Clinical Research in Transplantation at Massachusetts General Hospital, conducted by Dr. Susan Smith, site editor and program director of Medscape Transplantation.

Dr. Smith: At the American Society of Transplant Surgeons 2nd Annual Winter Symposium in January 2002, a significant amount of evidence was presented in support of the previously underestimated contribution of nonimmune factors (primarily related to ischemia reperfusion injury). What pharmacologic strategies do you believe hold the greatest promise for improving long-term allograft function and survival?

Dr. Pascual: At present, we are examining pharmacologic strategies to decrease ischemic injury to the allograft. The major effort in that regard that needs to be made (and, by the way, that we aren't very good at) should be prevention of ischemic injury by decreasing cold ischemia time. We routinely transplant cadaveric kidneys with cold ischemia times of 20-24 hours. The group at Washington University in St. Louis, Missouri, showed a significant decrease in delayed graft function by decreasing the mean cold ischemia time to 12-13 hours. So, optimization of the quality of the donor organ from the beginning is key, as is using minimally nephrotoxic immunosuppressive drug regimens. Both of these approaches should contribute to improved long-term survival.

Dr. Smith: Three randomized, double-blind clinical trials demonstrated that mycophenolate mofetil (MMF) lowers the incidence of acute rejection at 6 months by approximately 50%. But by 3 years after transplantation, only a limited beneficial effect of MMF on the survival of the graft was observed in only 1 of the trials. Yet in a recent retrospective study, MMF therapy emerged as a protective factor, independent of the presence or absence of acute rejection, supporting observations from previous studies in animals that MMF prevents chronic rejection. Why do you suppose that the retrospective study of the effect of MMF on long-term graft survival yielded different results from the 3 randomized clinical trials? And how important are the retrospective data?

Dr. Pascual: The 3 randomized trials were not designed to answer questions about chronic rejection. Follow-up was not sufficient and statistical power was not adequate to truly address long-term outcomes. This would take at least 5 years of follow-up and would require a larger sample size. The retrospective study, although inherently limited by design, is important because it supports data from animal models that MMF prevents chronic rejection. To overcome the problem of conducting large long-term studies, we need to establish good surrogate markers, such as allograft function and proteinuria, that are predictive of long-term outcomes.

Dr. Smith: The transplant community appears to be heading down the road to elimination of calcineurin inhibitors and/or corticosteroids from the posttransplant immunosuppressive drug regimen. How close do you predict we are? How might this be best accomplished? And in this regard, what are the implications of the Edmonton islet cell protocol for kidney transplantation?

Dr. Pascual: Recent preliminary data suggest that avoidance or elimination of corticosteroids may be feasible, but that avoidance or elimination of calcineurin inhibitors may be more difficult because more acute rejection has been seen after discontinuation of calcineurin inhibitors. However, we do not have long-term data for either.

Examples of avoidance regimens (of corticosteroids) require induction therapy with polyclonal or monoclonal antibodies in combination with tacrolimus (TAC) plus MMF or TAC plus sirolimus. We need to be careful, though, that what is feasible in the short term will not be detrimental in the long term (5-10 years), and right now we just don't know.

During the last 20 years, organ transplantation has been successful as a result of using calcineurin inhibitors, so we need to be extremely cautious in this area. We need well-designed, randomized clinical trials with long-term follow-up or we may get "burned" down the road. Importantly, patients in these trials must be extremely well informed about what they are participating in (ie, what exactly it is that they will be avoiding or eliminating and the potential risks).

The Edmonton protocol was designed for islet cell transplantation and used low levels of TAC. This protocol needs to be validated in kidney transplant recipients, as it is a potentially interesting regimen.

Dr. Smith: A number of strategies have been postulated to decrease the toxic consequences of current immunosuppressive regimens and improve long-term graft function and survival. What large, randomized clinical trials do you believe are most needed to pave the way for a new era in low-toxicity transplant immunosuppression?

Dr. Pascual: In the next 5 years, the standard of care (which still includes calcineurin inhibitors and corticosteroids) needs to be compared with double-therapy or monotherapy regimens designed to avoid or eliminate calcineurin inhibitors and/or corticosteroids. These new regimens will need to include induction agents, either polyclonal or monoclonal agents.

In 5 years, we may be able to induce "hyporesponsiveness" with a new "palette" of induction agents including polyclonal antibodies, monoclonal antibodies such as the IL-2-receptor blockers, or new agents that inhibit T-cell costimulatory pathways (this new class of agents should become available in 2-4 years).

An active area of research is designing regimens to induce stable allotolerance. Upcoming clinical trials of these regimens will need to include clinically acceptable conditioning regimens and be designed for long-term follow-up, notably to ensure that late-onset chronic rejection does not develop.

Dr. Smith: What are the implications of this paper for how we might need to change the way we evaluate and report outcomes in transplantation?

Dr. Pascual: Ideally, clinical trials need to be designed for longer follow-up. As I said earlier, we also need to find surrogate markers that will predict long-term outcomes. In addition, we need to expand our thinking beyond immune-related outcomes (eg, acute rejection) to also include cardiovascular morbidity and mortality outcomes. This also has implications for patient selection and pretransplant interventions. There is currently an epidemic of cardiovascular disease in the end-stage renal disease population. Screening for cardiovascular disease must be carefully done during the evaluation process, and patients with significant coronary artery disease should undergo revascularization procedures before transplantation.

When you look at the recent history of transplantation, we have shown in the 1990s that we can safely decrease the rates of acute rejection. The challenge for the upcoming 10-20 years is to improve long-term outcomes.