Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future

Abstract

Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization. Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization. CNIs, such as cyclosporine and tacrolimus, have served as the backbone of transplant immunosuppression for the vast majority of renal transplant recipients over the past 40 years. The advent of CNI therapy undoubtedly ushered in the modern era of transplantation, establishing renal transplant as the gold-standard therapy for end-stage renal failure. However, although CNI therapy has secured exceptional short-term outcomes with transplantation, progress in improving long-term renal allograft survival has stagnated for many years,1Lamb K.E. Lodhi S. Meier-Kriesche H.U. Long-term renal allograft survival in the United States: a critical reappraisal.Am J Transplant. 2011; 11: 450-462https://doi.org/10.1111/j.1600-6143.2010.03283.xAbstract Full Text Full Text PDF PubMed Scopus (719) Google Scholar spurring interest in other immunosuppressive strategies. The nephrotoxicity and well-defined adverse metabolic effects of CNIs have also driven a desire to explore alternative immunosuppressive agents.2Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection.Drugs. 2009; 69: 2227-2243https://doi.org/10.2165/11319260-000000000-00000Crossref PubMed Scopus (248) Google Scholar, 3Malat G. Culkin C. The ABCs of immunosuppression: a primer for primary care physicians.Med Clin North Am. 2016; 100: 505-518https://doi.org/10.1016/j.mcna.2016.01.003Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 4Naesens M. Kuypers D.R. Sarwal M. Calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol. 2009; 4: 481-508https://doi.org/10.2215/CJN.04800908Crossref PubMed Scopus (1090) Google Scholar Costimulation blockade emerged as a promising immunosuppression strategy based on seminal work in the 1990s demonstrating that blockade of critical costimulatory pathways (such as CD28-CD80/86 and CD40-CD154 interaction) could substantially prolong allograft survival in murine transplant models.5Larsen C.P. Elwood E.T. Alexander D.Z. et al.Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.Nature. 1996; 381: 434-438https://doi.org/10.1038/381434a0Crossref PubMed Scopus (1285) Google Scholar, 6Lin H. Bolling S.F. Linsley P.S. et al.Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.J Exp Med. 1993; 178: 1801-1806https://doi.org/10.1084/jem.178.5.1801Crossref PubMed Scopus (475) Google Scholar, 7Pearson T.C. Alexander D.Z. Winn K.J. Linsley P.S. Lowry R.P. Larsen C.P. Transplantation tolerance induced by CTLA4-Ig.Transplantation. 1994; 57: 1701-1706https://doi.org/10.1097/00007890-199457120-00002Crossref PubMed Scopus (330) Google Scholar Whereas the clinical development of anti-CD154 was initially halted because of the development of unexpected thrombotic complications (later attributed to cross-linkage of platelet-expressed CD154),8Koyama I. Kawai T. Andrews D. et al.Thrombophilia associated with anti-CD154 monoclonal antibody treatment and its prophylaxis in nonhuman primates.Transplantation. 2004; 77: 460-462https://doi.org/10.1097/01.TP.0000110291.29370.C0Crossref PubMed Scopus (99) Google Scholar the pursuit of drugs to disrupt CD28-B7 interaction culminated in the development and clinical trials of belatacept, a potent CD28 antagonist.9Larsen C.P. Pearson T.C. Adams A.B. et al.Rational development of LEA29Y (Belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.Am J Transplant. 2005; 5: 443-453https://doi.org/10.1111/j.1600-6143.2005.00749.xAbstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar Subsequent clinical trials have validated the promise of belatacept, demonstrating superior long-term outcomes of graft and patient survival compared to renal transplant recipients treated with cyclosporine-based immunosuppression.10Vincenti F. Rostaing L. Grinyo et and long-term outcomes in kidney J Med. 2016; PubMed Scopus Google F. et study of immunosuppression regimens cyclosporine in renal transplant recipients J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar However, early and logistical associated with have the adoption of this In this review, we explore the history of costimulation blockade in renal transplantation, the of belatacept in transplant recipients, and the future of costimulatory blockade in The of emerged in the and as a for PubMed Scopus Google Scholar that of interaction with costimulatory and of costimulation to the for including and of costimulatory also to to Adams A.B. Pearson T.C. and Nephrol. PubMed Scopus Google The of costimulatory in the of J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar murine transplant that is on the interaction CD28 on and on C.P. Elwood E.T. Alexander D.Z. et al.Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.Nature. 1996; 381: 434-438https://doi.org/10.1038/381434a0Crossref PubMed Scopus (1285) Google Scholar a of the of to the of emerged as of the drugs to this interaction through that to with than CD28 to M. a novel inhibitor of 2004; PubMed Scopus Google Scholar However, has to a clinically for such as and A.B. Larsen C.P. Costimulation blockade in and transplantation: the CD28 2016; PubMed Scopus Google Scholar demonstrated to prolong allograft survival in nonhuman et effects of CTLA4Ig in a of PubMed Google et and renal allograft rejection in PubMed Scopus Google Scholar the development of belatacept, has of the backbone for belatacept to the for CD28 C.P. Pearson T.C. Adams A.B. et al.Rational development of LEA29Y (Belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.Am J Transplant. 2005; 5: 443-453https://doi.org/10.1111/j.1600-6143.2005.00749.xAbstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar belatacept more renal allograft survival in nonhuman transplant C.P. Pearson T.C. Adams A.B. et al.Rational development of LEA29Y (Belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties.Am J Transplant. 2005; 5: 443-453https://doi.org/10.1111/j.1600-6143.2005.00749.xAbstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar by promising the clinical development of belatacept The of belatacept in renal transplant recipients in that of patients treated with belatacept and treated with cyclosporine-based a in associated with belatacept F. Larsen C. et blockade with Belatacept in renal J Med. 2005; PubMed Scopus Google Scholar The clinical development of belatacept was by the Belatacept of and as the clinical of transplant immunosuppression F. et study of immunosuppression regimens cyclosporine in renal transplant recipients J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar The BENEFIT of belatacept more and a the to clinical a of renal transplant recipients treated with conventional cyclosporine-based immunosuppression. along with the BENEFIT-EXT of belatacept in recipients of Grinyo et outcomes a study of Belatacept cyclosporine in recipients of J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar demonstrated that renal transplant recipients treated with belatacept demonstrated superior compared to recipients treated with conventional cyclosporine-based immunosuppression was also a in the of allograft in the belatacept-treated compared to CNI in the BENEFIT study for more belatacept for F. et study of immunosuppression regimens cyclosporine in renal transplant recipients J Transplant. Full Text Full Text PDF PubMed Scopus Google this in allograft was in the BENEFIT-EXT Pearson T. et study of Belatacept cyclosporine in kidney J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar The for this are this could to the early of the in the early in could to benefits of belatacept compared to CNI than a in to is also that early benefits in allograft by the of more allografts in the BENEFIT-EXT study as compared to the and in the BENEFIT The BENEFIT that this graft was the of a incidence and of in recipients treated with belatacept incidence of rejection F. et study of immunosuppression regimens cyclosporine in renal transplant recipients J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar increased risk of acute rejection was to the early because the of the BENEFIT rejection in the belatacept after F. Larsen C.P. et outcomes a study in kidney transplant J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar the or BENEFIT-EXT acute rejection with Grinyo et outcomes a study of Belatacept cyclosporine in recipients of J Transplant. Full Text Full Text PDF PubMed Scopus Google Pearson T. et study of Belatacept cyclosporine in kidney J Transplant. Full Text Full Text PDF PubMed Scopus Google S. et al.Long-term outcomes in recipients of a J Transplant. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar In addition, a incidence of was in belatacept-treated renal transplant recipients for the of transplant patients on belatacept patients on in a to on the of belatacept in this of transplant The BENEFIT and BENEFIT-EXT trials culminated in clinical approval of belatacept for renal transplant recipients by the and and the in C. R. of the approval of J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar The study of the BENEFIT that renal transplant recipients treated with belatacept and survival compared to treated with cyclosporine-based in risk of or graft as a was for the belatacept-treated patients compared to with a in F. Rostaing L. Grinyo et and long-term outcomes in kidney J Med. 2016; PubMed Scopus Google Scholar The in patient and graft survival with belatacept was in this long-term and the in associated with belatacept may as that the vast majority of with a graft by the of study and the of risk more in long-term allograft belatacept have clinical of the belatacept cyclosporine for immunosuppression in renal transplant recipients also that to the BENEFIT belatacept was associated with long-term of renal allografts by an increased incidence of early F. G. et outcomes in a study of kidney transplant recipients Belatacept or J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar potential of belatacept emerged the BENEFIT of of in the BENEFIT and BENEFIT-EXT patient and in belatacept-treated compared to F. S. of Belatacept on of and the BENEFIT and BENEFIT-EXT PubMed Scopus Google Scholar of the patients in the BENEFIT and BENEFIT-EXT also that compared to the the belatacept-treated and a of after transplant et regimens are associated with cardiovascular and metabolic risk compared with cyclosporine in kidney transplant recipients and BENEFIT-EXT 2011; PubMed Scopus Google Scholar in validated in a that tolerance to that renal transplant recipients treated with belatacept a of or compared to recipients on et after kidney transplantation: and with J 77: Full Text Full Text PDF PubMed Scopus Google Scholar study using a validated risk of major adverse cardiac in renal transplant recipients the BENEFIT and BENEFIT-EXT to that belatacept may in a in major adverse cardiac compared to CNI as well as an to in cardiovascular I. H. et of the cardiovascular risk for renal transplant to BENEFIT and BENEFIT-EXT PubMed Scopus Google Scholar promising a to the impact of belatacept conversion on cardiovascular risk in renal transplant of renal transplant patients in the and with graft to on or to to belatacept. The patients to and on immunosuppression to of the validated cardiovascular risk was Although belatacept was associated with a in and a to in was in the risk of major adverse cardiac the conversion and the patients on M. et risk conversion to Belatacept a calcineurin inhibitor in kidney transplant a clinical Med. Full Text Full Text PDF PubMed Scopus Google Scholar However, this was to the that the belatacept conversion in to the findings of other belatacept conversion In addition, that this patients to is that the cardiovascular benefits of belatacept conversion because the adverse metabolic of CNI may have into the cardiovascular and risk associated with belatacept is of belatacept is its to and Larsen C.P. Pearson T.C. Belatacept and CD28 costimulation and over the Transplant PubMed Scopus Google Scholar of the long-term of clinical trials a incidence of donor-specific antibody in the patients treated with belatacept cyclosporine years of the of in the BENEFIT and in the BENEFIT-EXT R. et donor-specific in of the BENEFIT and BENEFIT-EXT J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar in renal transplant recipients that belatacept may by the of the major in and blocking of C. C. et of in renal by Belatacept on a on and Am Soc Nephrol. PubMed Scopus Google Scholar is that belatacept could the of after compared to cyclosporine R. et in donor-specific antibody after cyclosporine-based immunosuppression: of BENEFIT and J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar for this was also by the the of belatacept in renal transplant recipients with recipients in this acute and a of patients in the belatacept-treated a of compared to a treated with C. M. et in renal transplant with risk a study J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar of the BENEFIT and BENEFIT-EXT trials is that the of patients cyclosporine-based than because tacrolimus is associated with of acute rejection and than et tacrolimus and cyclosporine in the of renal allograft a of the PubMed Scopus Google Scholar Although this was for the potential clinical approval of belatacept, the of the clinical benefits of belatacept therapy compared to patients treated with immunosuppression. In et et clinical Belatacept with tacrolimus after kidney PubMed Scopus Google Scholar a study of tacrolimus belatacept for renal transplant immunosuppression. the BENEFIT this in the belatacept and was a increase in the incidence of associated with belatacept in graft in the belatacept of this was that was and to in treatment In addition, as discussed more the experience with patients Emory long-term benefits in in patients immunosuppression compared to A.B. C. et with calcineurin inhibitor therapy rejection and long-term renal allograft J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar Belatacept a for transplant immunosuppression. immunosuppressive agent has demonstrated as an in patient and renal allograft survival as belatacept has the of CNIs its adoption has by logistical barriers as well as concerns of increased short-term incidence of ACR. of the of Transplant that to the of patients immunosuppression increased to G. C. R. et and of Belatacept in kidney transplant recipients in the United Scopus Google Scholar However, than of transplant belatacept in renal transplant and of transplant in over of the adoption of belatacept in G. C. R. et and of Belatacept in kidney transplant recipients in the United Scopus Google Scholar in the of Transplant of renal transplant recipients in a immunosuppression and a of patients have et J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar The of associated with belatacept is undoubtedly of its barriers to and a of clinical trials and have to the to this with Adams A.B. et of immunosuppression to renal transplant J Transplant. Full Text Full Text PDF PubMed Scopus (18) Google Scholar have more with or belatacept with a short-term of low-dose CNI to long-term CNI-free immunosuppression. trials have to a and immunosuppression based on belatacept with such as or In early the of patients to or R. Grinyo F. et with regimens in kidney transplant J Transplant. 2011; 11: Full Text Full Text PDF PubMed Scopus Google Scholar as immunosuppression after kidney patients with and a course of The a risk of rejection in the compared to of the of patients in the belatacept on CNI-free and regimens and the belatacept a that was than the patients in the of and immunosuppression by et H. et using Belatacept without or calcineurin J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar treated kidney transplant recipients with belatacept, and patients also to or patients of immunosuppression patients on belatacept was in 10 patients and in Although of in the first of rejection in of of this patient a patient and graft survival of and with of patients in to belatacept R. H. et using and J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar The early of trials in Transplant The in was a of CNI and using belatacept and However, this was early because of the incidence of rejection and in the compared to the Larsen C.P. et early of a of calcineurin inhibitor and using J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar The in also demonstrated the potential of immunosuppression regimens based on belatacept. compared a and tacrolimus with belatacept and belatacept and the other a course of tacrolimus, and therapy with and belatacept. Although this study the of in the in was also because of the of in the belatacept therapy of the et of CNI and using of the in Transplantation J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar of and immunosuppression was the a of immunosuppression that renal transplant recipients to belatacept with belatacept with or tacrolimus with et immunosuppression with calcineurin inhibitor and early a J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar Whereas was in of the and was in of the However, this was with a of acute rejection in the and compared to the et for calcineurin inhibitor and immunosuppression of a J Am Soc Nephrol. PubMed Scopus Google Scholar The of and immunosuppression was a study that and a tapered by and compared renal transplant recipients belatacept and recipients treated with conventional tacrolimus and immunosuppression. study rejection and in the belatacept and tacrolimus was in regimens L. et of renal transplant recipients with calcineurin Belatacept plus PubMed Scopus Google Scholar Although promising based on rejection the of in renal by belatacept with and inhibitor may for this belatacept was as the of care for renal transplant recipients and approval in for patients or a history of we first belatacept using the as the BENEFIT we a increase in in a of Emory renal transplant recipients treated with a of rejection the first of to a strategy of belatacept with a low-dose course of tacrolimus to the renal allograft early of ACR. The of a course of tacrolimus that was to in a more incidence of A.B. C. et with calcineurin inhibitor therapy rejection and long-term renal allograft J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar with using immunosuppression. In belatacept-treated patients or without tacrolimus on a immunosuppression demonstrated superior compared to the of patients the Emory belatacept has continued to renal transplant recipients tacrolimus and and and belatacept is and are to a of by is and belatacept is and is to a of to for to and to for to with a in tacrolimus by with a in tacrolimus by and a of tacrolimus novel have acute rejection with the and the of rejection of to efforts to regimens, immunosuppressive that may with belatacept to and the development of to patients or risk of rejection on belatacept the to the clinical of belatacept. of belatacept into immunosuppression regimens that the long-term of and graft survival with an of clinical of belatacept has that for immunosuppression. the BENEFIT and BENEFIT-EXT trials that belatacept in recipients to a of of in M. D. of associated with of J PubMed Scopus Google Scholar of the risk of associated with belatacept, we also administration of belatacept to patient with a history of on risk of allograft rejection in and the of patients the BENEFIT and BENEFIT-EXT have administration of belatacept to patient with a history of the of belatacept in recipients has D. S. Belatacept in a kidney transplant J Transplant. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, G. et immunosuppressive in kidney transplant PubMed Scopus Google Scholar, G. et to Belatacept immunosuppression in kidney transplant Scopus Google Scholar and its in this to In addition, is that belatacept with to recipients are a for recipients of associated risks of In study of transplant recipients belatacept-treated patients and belatacept in patients was associated with a incidence of years a of to and a to compared to recipients treated with G. et and outcomes in kidney transplant recipients treated with J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar was a to graft survival in patients with treated with belatacept, was demonstrating that renal transplant recipients, belatacept-treated recipients a of compared to recipients, and in for than recipients et of Belatacept and tacrolimus on and in and kidney transplant PubMed Scopus Google Scholar with belatacept administration in recipients (such as primary or thrombotic is and alternative immunosuppression because the to this also R. R. et Belatacept for and PubMed Scopus Google Scholar Finally, is that immunosuppression may a for recipients have to that transplant recipients treated with belatacept antibody and cellular to after to of et and after of in kidney transplant recipients treated with PubMed Scopus Google Scholar, M. et antibody to of in kidney transplant recipients treated with J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar, et and cellular to a of in kidney transplant recipients PubMed Scopus Google Scholar, D. Rostaing L. in kidney transplant recipients PubMed Scopus Google Scholar, et and after in kidney transplant recipients PubMed Scopus Google Scholar, S. et to and of in kidney transplant Clin Med. 11: PubMed Scopus Google Scholar, R. C. and cellular of transplant recipients to a of a and PubMed Scopus Google Scholar have that patients that by risk of ACR. a nonhuman renal transplant et et rejection is associated with J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar that of than was with allograft rejection on belatacept a was in recipients treated with immunosuppression. using renal allograft recipients that patients with a of more to rejection on belatacept the potential of in the of costimulatory transplant M. et of rejection in renal transplant J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar of have also in transplant rejection in renal transplant are also in kidney allografts and F. G. et allograft J Transplant. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar clinical and have to clinically for to belatacept such as M. et for the of kidney allograft Nephrol. PubMed Scopus Google M. et for kidney allograft after conversion to Clin Med. PubMed Scopus Google Scholar and C. the of PubMed Scopus Google Scholar may also in patients for or conversion of belatacept, although are to in patients belatacept an of by that belatacept may the risk for acute and based on risk that could to immunosuppression that belatacept may associated with superior long-term allograft outcomes has also the development of conversion patients conventional immunosuppression regimens to belatacept. have in patient and for as to the development of of the allograft by allograft or to the development of acute CNI the development of thrombotic S. conversion to Belatacept after thrombotic in kidney transplant PubMed Scopus Google Scholar of or graft D. S. F. conversion tacrolimus to Belatacept for graft renal in kidney transplant Scopus Google The to garner the long-term renal benefits of belatacept and the early rejection risk interest in conversion trials of CNIs to belatacept. The the conversion of renal transplant recipients on immunosuppression to belatacept with a primary outcome of in to L. et calcineurin regimens to a in renal transplant a J Am Soc Nephrol. 2011; PubMed Scopus Google Scholar risk patients to after transplant to on immunosuppression on or to immunosuppression. patients to belatacept renal without increased or graft and rejection the first and rejection in the belatacept in on with of in renal et in renal in kidney transplant recipients cyclosporine or tacrolimus to the long-term of a PubMed Scopus Google Scholar The of this study demonstrated increase in adverse or M. et and outcomes years after to Belatacept a calcineurin inhibitor in kidney transplant a J 69: Full Text Full Text PDF PubMed Scopus Google Scholar The belatacept conversion a in compared to the to on M. et and outcomes years after to Belatacept a calcineurin inhibitor in kidney transplant a J 69: Full Text Full Text PDF PubMed Scopus Google Scholar by et R. H. et calcineurin to immunosuppression in Transplant a Am Soc Nephrol. PubMed Scopus Google Scholar kidney transplant recipients to to on immunosuppression of patients on or to belatacept. Whereas graft survival was in was in the belatacept with of a of a incidence of the for belatacept conversion therapy is allograft CNI or development of H. et therapy of PubMed Scopus Google Scholar, G. D. et conversion tacrolimus to Belatacept in risk kidney transplant recipients with allograft J Transplant. Full Text Full Text PDF PubMed Scopus Google Scholar, G. M. D. et of Belatacept conversion on kidney transplant and PubMed Scopus Google Scholar, D. M. et of Belatacept conversion on renal and in kidney transplant patients with antibody-mediated PubMed Scopus Google Scholar, D. M. et conversion in kidney transplant recipients with a Transplant. PubMed Scopus Google Scholar, et tacrolimus to Belatacept renal in kidney transplant patients with in allograft PubMed Scopus Google Scholar, C. et conversion tacrolimus to a in kidney transplant recipients renal and Nephrol. PubMed Scopus Google Scholar, M. F. et is a risk in kidney transplant recipients with conversion calcineurin regimens to Nephrol. PubMed Scopus Google Scholar, M. D. S. conversion to Belatacept after kidney transplantation: outcome and PubMed Scopus Google Scholar The vast majority of that belatacept conversion therapy or in this patient with allograft study in associated with conversion years CNI to belatacept in renal transplant recipients with CNI nephrotoxicity S. I. D. of conversion to Belatacept in kidney transplant recipients for tacrolimus Transplant. PubMed Google Scholar study of conversion tacrolimus to belatacept in renal transplant patients with rejection that conversion in a in compared to a of patients on D. M. et of Belatacept conversion on renal and in kidney transplant patients with antibody-mediated PubMed Scopus Google Scholar study of renal transplant recipients with and graft demonstrating that conversion to belatacept was associated with a in graft survival in the with and increase in the of D. M. et conversion in kidney transplant recipients with a Transplant. PubMed Scopus Google Scholar However, the of belatacept conversion in this patient that a study of patients with failed

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