Pathology of Chronic Rejection: An Overview of Common Findings and Observations About Pathogenic Mechanisms and Possible Prevention.

Definition, Clinical Presentation and Suspected Etiology Very good to excellent one year patient and graft survival rates at most experienced transplant centers has shifted considerable attention in research away from short term complications like acute rejection to chronic rejection (CR), which is the major obstacle to long-term, morbidity-free survival (reviewed in detaiF). In comparison to acute rejection, chronic rejection is a more indolent. but progressive form of allograft injury, which is largely irreversible and eventually results in allograft failure. Although the term "chronic" implies a temporally prolonged course, many cases of chronic rejection clearly evolve from severe or inadequately controlled acute rejection episodes because of noncompliance or an inability to maintain immunosuppression, or to monitor the allograft for rejection. Such patients experience a progressive decline in organ function over a period of weeks to months. Another significant cohort of patients slowly develop graft dysfunction and eventual failure over a period of years from chronic rejection. This may be attributable to .. clinically silent" rejection episodes that go undetected or to other factors. A third cadre of patients become trapped in a disheartening cycle that alternates between rejection and infection (e.g .• CMY, polyoma virus"). in which the immunosuppressive therapy is repeatedly increased then decreased. Each turn of the cycle further damages the organ. which eventually fails with features of chronic rejection. Three lines of evidence best support the contention that alloimmunity is the major etiologic factor. as originally suspected_J ·• First, isografts rarely, if ever, suffer the same set of changes seen in allografts with chronic rejection. although some isografts do develop chronic arterial lesions. but they are delayed in onset and less severe in comparison [Q allografts.5-a Secondly, patients who are at high risk of severe or persistent acute rejection:9-1~ and those inadequately immunosuppressed have a higher rate of chronic rejection. 17.[8This is likely related to an increased risk of alloreactivity like that seen with donor/recipient racial or ethnic mismatches. [9-23 sex mismatching. [414 viral infections"5-32 and in patients treated with immune activating drugs.33 Finally. greater MHC mismatching results in a higher rate of long term