Today, it is now well-known that patient and graft longevity are primary challenges for the liver transplant community. Over the past three decades, short-term outcomes have improved substantially while long-term outcomes have stagnated. Among adults, multiple issues have painted a somber landscape for patient longevity. First, the profile of transplant candidates has changed. Increasingly, older patients with multiple medical co-morbidities are accepted as transplant candidates. Second, more aggressive organ utilization practices have resulted in heightened ischemia/reperfusion injury that leads to tumultuous peri-transplant courses with lasting consequences. Third, our standard armamentarium of immunosuppression incurs cumulative toxicities. Moreover, the common side effects of hypertension, hyperglycemia, hyperlipidemia and nephrotoxicity often exacerbate pre-existing conditions, catapulting the risk of cardiovascular disease. Finally, loss of immunosurveillance predisposes to malignancy that is another major mortality risk, yet another example of how immunosuppression amplifies the vulnerabilities of an aged population.
The issues that plague adult liver transplant recipients as delineated above are arguably less damaging to pediatric liver transplant recipients. However, two streams of data suggest that the standard of care management of chronic immunosuppression is sub-optimal and may shorten graft or patient longevity. First, within the rigorous context of prospective, multi-center clinical trials, immunosuppression has been successfully discontinued without evidence of allograft injury in the short and mid-term. Second, multiple single center, cross-sectional, typically retrospective reports have shown that, for pediatric liver transplant recipients with normal liver tests maintained on immunosuppression, inflammation and/or fibrosis appears increase in both prevalence and severity, over time. The frequent presence of silent allograft injury has been confirmed by biopsies performed as an eligibility assessment to enter an immunosuppression withdrawal trial - arguably a cohort of “clinically ideal” patients. Moreover, emerging data suggests that biopsies with portal inflammation and interface activity express the transcriptional program of subclinical rejection. These intriguing reports of operational tolerance juxtaposed against silent chronic allograft injury suggest that, among pediatric liver transplant recipients with normal liver tests, some are maintained on too much while others are maintained on too little immunosuppression. The optimal management of immunosuppression - a personalized approach aiming at not too much or too little but just enough - is critical to simultaneously maximize both patient and allograft longevity. |
