Kidney paired donation (KPD) was first suggested in 1986, but it was not until 2000 when the first paired donation transplant was performed in the USA. In the past decade, KPD has become the fastest growing source of transplantable kidneys, overcoming the barrier faced by living donors deemed incompatible with their intended recipients. This review provides a basic overview of the concepts and challenges faced by KPD as we prepare for a national pilot program with the United Network for Organ Sharing. Several different algorithms have been creatively implemented in the USA and elsewhere to transplant paired donors, each method uniquely contributing to the success of KPD. As the paired donor pool grows, the problem of determining allocation strategies that maximize equity and utility will become increasingly important as the transplant community seeks to balance quality and quantity in choosing the best matches. Financing for paired donation is a major issue, as philanthropy alone cannot support the emerging national system. We also discuss the advent of altruistic or non-directed donors in KPD, and the important role of chains in addition to exchanges. This review is designed to provide insight into the challenges that face the emerging national KPD system in the USA, now 5 years into its development.

No statistically significant differences in pancreas transplant outcomes were demonstrated when recipients were stratified by recipient age. These results suggest that older recipients can successfully undergo pancreas transplantation and expect five-yr outcomes similar to those seen in younger recipients.

Belatacept is used to prevent allograft rejection, but fails to do so in a sizable minority of patients due to inadequate control of costimulation-resistant T cells. We have reported control of costimulation-resistant rejection when belatacept is combined with perioperative alemtuzumab-mediated lymphocyte depletion and rapamycin (ABR). To assess the means by which the ABR regimen controls belatacept-resistant rejection, we studied 20 ABR-treated patients, characterizing peripheral lymphocyte phenotype and functional responses to donor, third-party, and viral antigens using flow cytometry, intracellular cytokine staining, and CFSE-based lymphocyte proliferation. Compared to conventional immunosuppression in 10 patients, lymphocyte depletion evoked substantial homeostatic lymphocyte activation balanced by regulatory T and B cell phenotypes. The reconstituted T cell repertoire was enriched for CD28+ naïve cells, notably diminished in belatacept-resistant CD28- memory subsets, depleted of polyfunctional donor-specific T cells, but able to respond to third-party and latent herpes viruses. B cell responses were similarly favorable, without alloantibody development, and a reduction in memory subsets—changes not seen in conventionally treated patients. ABR regimen uniquely alters the immune profile, producing a repertoire enriched for CD28+ T cells, hyporesponsive to donor-alloantigen, and competent in its protective immune capabilities. The resulting repertoire is permissive for control of rejection with belatacept monotherapy. TRIAL REGISTRATION ClinicalTrials.gov - NCT00565773

The innate immune system is a critical regulator of the adaptive immune responses that lead to allograft rejection. It is increasingly recognized that endogenous molecules released from tissue injury and cell death are potent activators of innate immunity. Mitochondria, ancestrally related to bacteria, possess an array of endogenous innate immune activating molecules. We have recently demonstrated that extracellular mitochondria are abundant in the circulation of deceased organ donors and that their presence correlates with early allograft dysfunction. Here we demonstrate the ability of mitochondria to activate ECs, the initial barrier between a solid-organ allograft and its host. We find that mitochondria exposure leads to the upregulation of EC adhesion molecules and their production of inflammatory cytokines and chemokines. Additionally, mitochondrial exposure causes DCs to upregulate costimulatory molecules. Infusion of isolated mitochondria into heart donors lead to significant increase in allograft rejection in a murine heterotopic heart transplantation model. Finally, co-incubation of human PBMCs with mitochondria treated ECs results in increased numbers of effector (IFN-γ + , TNF-α +) CD8 + T cells. These data indicate that circulating extracellular mitochondria in deceased organ donors may directly activate allograft ECs and promote graft rejection in transplant recipients.

Antigen-experienced T cells, also known as memory T cells, are functionally and phenotypically distinct from naive T cells. Their enhanced expression of adhesion molecules and reduced requirement for co-stimulation enables them to mount potent and rapid recall responses to subsequent antigen encounters. Memory T cells generated in response to prior antigen exposures can cross-react with other nonidentical, but similar, antigens. This heterologous cross-reactivity not only enhances protective immune responses, but also engenders de novo alloimmunity. This latter characteristic is increasingly recognized as a potential barrier to allograft acceptance that is worthy of immunotherapeutic intervention, and several approaches have been investigated. Calcineurin inhibition effectively controls memory T-cell responses to allografts, but this benefit comes at the expense of increased infectious morbidity. Lymphocyte depletion eliminates allospecific T cells but spares memory T cells to some extent, such that patients do not completely lose protective immunity. Co-stimulation blockade is associated with reduced adverse-effect profiles and improved graft function relative to calcineurin inhibition, but lacks efficacy in controlling memory T-cell responses. Targeting the adhesion molecules that are upregulated on memory T cells might offer additional means to control co-stimulation-blockade-resistant memory T-cell responses.