Comparison of Utilization and Clinical Outcomes for Belatacept- and Tacrolimus-Based Immunosuppression in Renal Transplant Recipients.

The performance of belatacept in a real clinical setting has not been reported. A retrospective cohort study was conducted using registry data comparing 1-year clinical outcomes between belatacept- and tacrolimus-treated adult kidney transplant recipients (KTRs) from January 6, 2011, through January 12, 2014. Of 50 244 total patients, 417 received belatacept plus tacrolimus, 458 received belatacept alone, and 49 369 received tacrolimus alone at discharge. In the overall study cohort, belatacept alone was associated with a higher risk of 1-year acute rejection, with the highest rates associated with non-lymphocyte-depleting induction (adjusted hazard ratio 2.65, 95% confidence interval 1.90-3.70, p < 0.0001). There was no significant difference in rejection rates between belatacept plus tacrolimus and tacrolimus alone. In KTRs who met inclusion criteria for the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), 1-year kidney function was higher with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (mean estimated GFR 65.6, 60.4 and 54.3 mL/min per 1.73 m2 , respectively; p < 0.001). The incidence of new-onset diabetes after transplantation was significantly lower with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (1.7%, 2.2%, and 3.8%, respectively; p = 0.01). Despite improved graft function and metabolic complications with belatacept alone, it may be advisable to add short-term tacrolimus in the first year after transplant and to consider lymphocyte-depleting induction in patients with high rejection risk, as the risk-benefit ratio allows.

Pre-transplant myeloid dendritic cell deficiency associated with cytomegalovirus infection and death after kidney transplantation.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells critical for immunity. We previously demonstrated a significant association between pre-transplant blood myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) deficiency and post-transplant BK viremia in renal transplant recipients. In the current post-hoc analysis, we studied the association of these same pre-transplant DC levels with other post-transplant outcomes. METHODS: Pre-transplant peripheral blood mDC and pDC levels were quantified using flow cytometry in 78 patients undergoing kidney transplantation. Post-transplant outcomes were analyzed, including infection, rejection, and patient death, with a median follow-up of 5.3 years. Associations between DC levels and outcomes were assessed using logistic regression analysis and Cox proportional hazards models. RESULTS: An independent association of mDC levels with post-transplant cytomegalovirus infection (adjusted odds ratio 7.0, P = 0.01) and patient death (adjusted hazard ratio 13.0, P = 0.015) was found. No associations were demonstrated between levels of either DC subtype and bacterial infections or rejection. CONCLUSIONS: Pre-transplant mDC deficiency is significantly associated with CMV infection and death after kidney transplantation.

Stem cell factor, interleukin-16, and interleukin-2 receptor alpha are predictive biomarkers for delayed and slow graft function.

INTRODUCTION: Delayed graft function (DGF) and slow graft function (SGF) due to ischemic and reperfusion injury (IRI) are common complications of deceased donor kidney transplantation. We tested whether a panel of serum and urine cytokines represent early biomarkers for DGF and SGF. METHODS: We collected serum and urine samples from 61 patients 48 hours posttransplantation and used a multiplex enzyme-linked immunosorbent assay (ELISA) technique to measure levels of 23 cytokines. Fourteen patients developed poor graft function (PGF), with 6 having DGF and 8 with SGF. RESULTS: Area under receiver operation characteristics curve (AUC) demonstrated the following: serum levels of SCF (0.88) and interleukin (IL) 16 (0.74). CONCLUSIONS: This study showed that a select panel of cytokines measured early post kidney transplantation may predict poor graft function.

Listing for expanded criteria donor kidneys in older adults and those with predicted benefit.

Certain patient groups are predicted to derive significant survival benefit from transplantation with expanded criteria donor (ECD) kidneys. An algorithm published in 2005 by Merion and colleagues characterizes this group: older adults, diabetics and registrants at centers with long waiting times. Our goal was to evaluate ECD listing practice patterns in the United States in terms of these characteristics. We reviewed 142 907 first-time deceased donor kidney registrants reported to United Network for Organ Sharing (UNOS) between 2003 and 2008. Of registrants predicted to benefit from ECD transplantation according to the Merion algorithm ('ECD-benefit'), 49.8% were listed for ECD offers ('ECD-willing'), with proportions ranging from 0% to 100% by transplant center. In contrast, 67.6% of adults over the age of 65 years were ECD-willing, also ranging from 0% to 100% by center. In multivariate models, neither diabetes nor center waiting time was significantly associated with ECD-willingness in any subgroup. From the time of initial registration, irrespective of eventual transplantation, ECD-willingness was associated with a significant adjusted survival advantage in the ECD-benefit group (HR for death 0.88, p < 0.001) and in older adults (HR 0.89, p < 0.001), but an increased mortality in non-ECD-benefit registrants (HR 1.11, p < 0.001). In conclusion, ECD listing practices are widely varied and not consistent with published recommendations, a pattern that may disenfranchise certain transplant registrants.

Recent developments in kidney transplantation--a critical assessment.

Rapid advances have been made in decreasing acute rejection rates and improving short-term graft survival in kidney transplant recipients. Whether these advances ultimately will lead to a commensurate improvement in long-term survival is not yet known. In recent years, greater attention has been placed on defining the precise etiology of graft loss, determining how far and with what agents we can minimize immunosuppression, and delineating the nature of both T-cell-mediated as well as antibody-mediated rejection. In addition, with the growing disparity of available organs and patients in need of a transplant, greater attention has been placed on optimizing allocation. In this minireview, we will focus on developments over the last couple of years, paying particular attention to insights, studies and observations that may attempt to elucidate some of these open questions.

Immunosuppression reduction for BK virus nephropathy: a case for caution.

BK virus nephropathy (BKVN) is increasingly recognized as a major cause of renal allograft failure. Recent reports demonstrate that prompt reduction of immunosuppression upon detection of persistent viremia can be associated with resolution of viremia, with minimal risk of acute rejection (AR). However, these experiences in general have occurred in centers with low baseline risks of AR. It is possible that a finer balance between overimmunosuppression and the risk of AR may exist in centers that routinely transplant patients with higher risk of AR. Thus the risk/benefit of this strategy may be altered in these centers. We report a case of antibody-mediated rejection that followed reduction of immunosuppression for BKVN diagnosed more than 3 months after the onset of viremia. This rejection episode resulted in a greater decrease in graft function than the initial BKVN episode. Issues relevant to the management of these patients are discussed, including the need for improved immune monitoring assays to determine more accurately the balance between infection and rejection.

Preemptive retransplantation for BK virus nephropathy: successful outcome despite active viremia.

BK virus nephropathy (BKVN) is now recognized as a major cause of renal allograft loss. Recent reports suggest that retransplantation in patients with graft loss due to BKVN is safe after return to dialysis. Since early transplantation is associated with improved outcomes, it would be advantageous if this procedure could be performed prior to ultimate graft loss. However, little data are available regarding the safety of this approach during active viremia. In this report, we describe successful preemptive retransplantation with simultaneous allograft nephrectomy in two patients with active BKVN and viremia at the time of surgery. With 21- and 12-month follow-up, respectively, both patients have stable allograft function and no evidence for active viral replication. We conclude that preemptive retransplantation can be considered in patients with failing allografts due to BKVN.

The effects of renal transplantation on circulating precursor dendritic cells.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells that induce and regulate immune responses. Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid DC populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. METHODS: Using flow cytometry, PBDC levels were quantified in patients with end-stage renal disease (ESRD) undergoing renal transplantation. RESULTS: PBDC levels were significantly reduced in ESRD patients pretransplantation compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving antilymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pretransplant values concurrent with overall reduction of immunosuppression. Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall immunosuppression. CONCLUSIONS: Our findings suggest that PBDC levels may reflect the degree of immunosuppression in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss, and infectious complications.

Involvement of the direct and indirect pathways of allorecognition in tolerance induction.

It is generally accepted that there are two pathways of allorecognition, direct and indirect, that together contribute to allograft rejection. Although it has been suggested that the direct pathway predominates during early acute rejection and that the indirect pathway provides a continuous supply of alloantigen responsible for chronic rejection, the true relative contribution of each pathway to the overall rejection process is still not entirely known. It is clear, however, that any strategies designed to achieve the ultimate goal in transplantation, the induction of tolerance, will need to take into account both pathways. This review seeks to explore the involvement of the direct and indirect pathways of allorecognition on a mechanistic level as it relates to the induction of tolerance. A brief historical perspective is included for each pathway as well as a comprehensive review of the mechanisms felt to be active during tolerance induction.

Tolerance and chronic rejection.

The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity called chronic rejection (CR). Recent reports suggest an improvement in long-term renal allograft survival, although it is not clear from these data whether a true reduction of biopsy-proven CR has occurred. Although newer immunosuppressive medications have greatly reduced the incidence of acute rejection (AR) in the early post-transplantation period, the ideal therapy for both AR and CR would be to achieve a state of tolerance. By definition, such a state should allow for indefinite allograft survival, with no histopathological evidence of CR, despite immunocompetence in the host (i.e. without the need for chronic immunosuppression). Although several experimental studies are able to achieve tolerance, with clear improvement in allograft survival, detailed studies on graft function and morphology are often not included. This review will discuss possible ways that tolerance induction could lead to a CR-free state. General mechanisms of CR and transplantation tolerance induction are discussed as well as the difficulties in translating small animals studies into large animals and humans.

Regulatory functions of self-restricted MHC class II allopeptide-specific Th2 clones in vivo.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy.

Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the alpha(1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/-1.7 vs. 54.7 +/-3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.

Indirect allorecognition of mismatched donor HLA class II peptides in lung transplant recipients with bronchiolitis obliterans syndrome.

A correlation between indirect allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOS+ and nine BOS-lung transplant recipients were cultured with synthetic peptides corresponding to the beta-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOS+ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS- patients (p=0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOS+ patients than in BOS- patients (p=0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.

Chronic allograft dysfunction: mechanisms and new approaches to therapy.

Renal allograft failure is the most common cause of end-stage renal disease beyond the early posttransplantation period, accounting for 25% to 30% of patients awaiting renal transplantation. Despite recent advances in immunosuppressive therapy, improvements in long-term graft survival have not been commensurate with those observed in 1-year graft survival. The most common cause of chronic allograft loss is an incompletely understood clinicopathological entity sometimes called chronic rejection, chronic allograft dysfunction or in the case of kidneys, chronic allograft nephropathy. Although the precise mechanism(s) responsible for the characteristic pathological changes are still unclear, it is generally agreed that both alloantigen-dependent and alloantigen-independent factors influence the development of chronic allograft nephropathy. This article will address the potential mechanisms responsible for the pathogenesis of chronic dysfunction in solid organ grafts and the current approaches to management, including newer therapies designed to prevent the progression of the disease.

Blockade of CD28-B7, but not CD40-CD154, prevents costimulation of allogeneic porcine and xenogeneic human anti-porcine T cell responses.

Despite increasing use of swine in transplantation research, the ability to block costimulation of allogeneic T cell responses has not been demonstrated in swine, and the effects of costimulatory blockade on xenogeneic human anti-porcine T cell responses are also not clear. We have compared the in vitro effects of anti-human CD154 mAb and human CTLA4IgG4 on allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses. Both anti-CD154 mAb and CTLA4IgG4 cross-reacted on pig cells. While anti-CD154 mAb and CTLA4IgG4 both inhibited the primary allogeneic pig MLRs, CTLA4IgG4 (7.88 microg/ml) was considerably more inhibitory than anti-CD154 mAb (100 microg/ml) at optimal doses. Anti-CD154 mAb inhibited the production of IFN-gamma by 75%, but did not inhibit IL-10 production, while CTLA4IgG4 completely inhibited the production of both IFN-gamma and IL-10. In secondary allogeneic pig MLRs, CTLA4IgG4, but not anti-CD154 mAb, induced Ag-specific T cell anergy. CTLAIgG4 completely blocked the indirect pathway of allorecognition, while anti-CD154 mAb blocked the indirect response by approximately 50%. The generation of porcine CTLs was inhibited by CTLA4IgG4, but not by anti-CD154 mAb. Human anti-porcine xenogeneic MLRs were blocked by CTLA4IgG4, but only minimally by anti-CD154 mAb. Finally, CTLA4IgG4 prevented secondary xenogeneic human anti-porcine T cell responses. These data indicate that blockade of the B7-CD28 pathway was more effective than blockade of the CD40-CD154 pathway in inhibiting allogeneic pig T cell responses and xenogeneic human anti-pig T cell responses in vitro. These findings have implications for inhibiting cell-mediated immune responses in pig-to-human xenotransplantation.

Transplantation tolerance: the concept and its applicability.

Recent advances have enabled researchers to induce tolerance in animal transplant models. Although it has been relatively easy to do so in rodents, it has been much more difficult to translate such strategies into primates. Understanding the cellular and molecular mechanisms of the alloimmune response has prompted the development of novel strategies that may obviate the need for immunosuppression in humans. Mechanisms of tolerance and promising new therapies, as well as the inherent difficulties in bringing them into clinical practice, are reviewed.