Approaches for transplanting the sensitized patient: biology versus pharmacology.

In 1969, Patel and Terasaki [1] reported that a positive cytotoxic crossmatch between donor lymphocytes and recipient serum was associated with early or immediate graft loss. From this seminal finding it quickly became apparent that the clinically relevant antibodies in a positive lymphocyte crossmatch were those directed against antigens encoded by the human major histocompatibility complex (MHC). These observations helped establish the human MHC as a major factor in allograft rejection. More importantly, this paper and those that followed helped solidify the belief that a positive lymphocyte crossmatch was a contraindication to renal transplantation. As a result, the field of clinical histocompatibility testing was established, driven by the need to identify the MHC proteins (called human leukocyte antigens, HLA) to which many patients possessed antibodies. It was quickly established that there were two categories of patients awaiting renal transplantation, namely those who are ‘sensitized’ (patients with HLA antibodies) and those who are ‘unsensitized’ (patients devoid of HLA antibodies). Over the next 35+ years, physicians practiced with the understanding that a positive crossmatch was a harbinger of poor transplant outcome, and many programs chose not to transplant across a positive lymphocyte crossmatch. The fallout of such decisions was that the ‘sensitized’ patient waited significantly longer for a transplant than the ‘unsensitized’ patient. Currently, in the USA, even though sensitized patients (panel reactive antibody, PRA >10%) comprise a little more than one-third of the deceased donor (DD) waitlist, they only receive ∼19% of DD transplants [2]. As a result of their prolonged time on dialysis, once transplanted, the ‘sensitized’ patient may have shorter graft survival than their ‘unsensitized’ counterparts. Since the majority of transplant candidates do not have a compatible living donor, two approaches (biological and pharmacological) have been implemented to provide these patients