Alemtuzumab induction and belatacept maintenance in marginal pathology renal allografts

We performed a prospective, 12‐month, single‐center, nonrandomized, open‐label pilot study to investigate the use of belatacept therapy combined with alemtuzumab induction in renal allografts with preexisting pathology, as these kidneys may be more susceptible to additional toxicity when exposed to calcineurin inhibitors posttransplant. Nineteen belatacept recipients were matched retrospectively to a cohort of tacrolimus recipients on the basis of preimplantation pathology. The estimated glomerular filtration rate was not significantly different between belatacept and tacrolimus recipients at either 3 or 12 months posttransplant (59 vs 45, P = 0.1 and 56 vs 48 mL/min/1.72/m², P = 0.3). Biopsy‐proven acute rejection rates at 12 months were 26% in belatacept recipients and 16% in tacrolimus recipients (P = 0.7). Graft survival at 1 year was 89% in both groups. Alemtuzumab induction combined with either calcineurin inhibitor or costimulatory blockade therapies resulted in similar acceptable one‐year outcomes in kidneys with preexisting pathologic changes. Longer‐term follow‐up may be necessary to identify preferential strategies to improve outcomes of kidneys at a higher risk for poor function (ClinicalTrials.gov—NCT01496417).     

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.     

ASP2409, A Next‐Generation CTLA4‐Ig,Versus Belatacept in Renal Allograft Survival in Cynomolgus Monkeys

Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile; however, higher incidence of acute rejection and posttransplant lymphoproliferative disorder are the shortcomings of this agent. In this study, ASP2409, a new cytotoxic T‐lymphocyte associated protein 4‐immunoglobulin possessing 14‐fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys. ASP2409 monotherapy dose‐dependently prolonged renal allograft survival. Low‐dose ASP2409 in combination with a subtherapeutic dose of tacrolimus showed much longer median survival time than monotherapy. Similar allograft survival results were observed in regimens based on high‐dose ASP2409, belatacept, and therapeutic‐dose tacrolimus. The results of renal allograft histopathology with high‐dose ASP2409‐based regimens were not inferior to the belatacept‐based regimen. Moreover, higher frequencies of FoxP3‐positive regulatory T cells in renal allografts were observed in ASP2409‐ and belatacept‐based regimens compared with tacrolimus‐based regimens. No serious side effects related to ASP2409 administration were found during the study. These data suggest that ASP2409 is a promising candidate for calcineurin inhibitor‐sparing or ‐avoidance regimens.     

Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation

A majority of kidney transplant recipients receive calcineurin inhibitor‐based immunosuppression. However, some do not tolerate calcineurin inhibitors and require other immunosuppressive strategies. Until recently, alternative approaches have been associated with inferior outcomes, but recent methods have effectively utilized belatacept in calcineurin inhibitor‐intolerant patients. Though promising, belatacept uptake has been limited by higher acute rejection rates, unavailability due to production shortages, and logistical challenges as a result of intravenous infusion requirements. Interestingly, its predecessor abatacept is clinically available in subcutaneous formulation to treat autoimmune disorders but has not been used in clinical transplantation. Here we report on a series of 9 calcineurin inhibitor‐intolerant transplant recipients converted to abatacept early after transplant as rescue immunosuppression during periods of belatacept unavailability. Retrospective review revealed successful allograft salvage and 100% patient and graft survival (median 115 months) after conversion to abatacept. Patients received abatacept for a median duration of 82 months with stable, long‐term renal allograft function, a single cellular rejection episode, and no clinically apparent protective immunity concerns. Hence our findings suggest that future clinical studies utilizing abatacept either de novo or as conversion therapy in transplant recipients should be considered.     

Belatacept‐Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells

Recently, newer therapies have been designed to more specifically target rejection in an effort to improve efficacy and limit unwanted toxicity. Belatacept, a CD28‐CD80/86 specific reagent, is associated with superior patient survival and graft function compared with traditional therapy, but its adoption as a mainstay immunosuppressive therapy has been tempered by increased rejection rates. It is essential that the underlying mechanisms associated with this rejection be elucidated before belatacept is more widely used. To that end, we designed a study in a nonhuman primate kidney transplant model where animals were treated with either a belatacept‐ or a tacrolimus‐based immunosuppressive regimen. Interestingly, we found that elevated pretransplant frequencies of CD28⁺CD8⁺T_EMRA cells are associated with rejection on belatacept but not tacrolimus treatment. Further analysis showed that the CD28⁺CD8⁺T_EMRA cells rapidly lose CD28 expression after transplant in those animals that go on to reject with the allograft infiltrate being predominantly CD28^?. These data suggest that CD28⁺ memory T cells may be resistant to belatacept, capable of further differentiation including loss of CD28 expression while maintaining effector function. The unique signaling requirements of CD28⁺ memory T cells provide opportunities for the development of targeted therapies, which may synergize with belatacept to prevent costimulation‐independent rejection.     

Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept

The intent of this National Institutes of Health–sponsored study was to compare a belatacept‐based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate. Nineteen primary, Epstein–Barr virus–immune renal transplant recipients with a negative cross‐match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance mycophenolate mofetil. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 mo of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy‐proven acute cellular rejection was more frequent in the belatacept‐treated groups, with 10 treated episodes in seven participants compared with one episode in group 1; however, estimated GFR was similar between groups at week 52. There were no episodes of posttransplant lymphoproliferative disorder or opportunistic infections in any group. Protocol enrollment was halted prematurely because of a high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators, who ultimately must weigh the risks and benefits in randomized trials.     

Long‐Term Outcomes in Belatacept‐ Versus Cyclosporine‐Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT‐EXT,a Phase III Randomized Study

In the Belatacept Evaluation of Nephroprotection and Efficacy as First‐Line Immunosuppression Trial–Extended Criteria Donors (BENEFIT‐EXT), extended criteria donor kidney recipients were randomized to receive belatacept‐based (more intense [MI] or less intense [LI]) or cyclosporine‐based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent‐to‐treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI–treated, 138 of 175 belatacept LI–treated and 108 of 184 cyclosporine‐treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [CI] 0.625–1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634–1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m² for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR <20 mL/min per 1.73 m² were 0.754 (95% CI 0.536–1.061; p = 0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI 0.499–0.998; p = 0.05) for belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of belatacept‐ and cyclosporine‐based treatment were similar. De novo donor‐specific antibody incidence was lower for belatacept (p ≤ 0.0001). Relative to cyclosporine, belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.     

Belatacept‐based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective,randomized multicenter trial

Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept‐based CNIA/ESW regimens with a tacrolimus‐based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti‐thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease–calculated eGFR of <45 mL/min/1.73 m² at 12 months. Results are reported by treatment group (alemtuzumab/belatacept, rATG/belatacept, and rATG/tacrolimus). Superiority was not observed at 1 year for the primary endpoint (9/107 [8.4%], 15/104 [14.4%], and 14/105 [13.3%], respectively; P = NS) for either belatacept‐based regimen. Differences were not observed for secondary endpoints (death, death‐censored graft loss, or estimated glomerular filtration rates < 45 mL/min/1.73 m²). Differences were observed in biopsy‐proved acute cellular rejection (10.3%, 18.3%, and 1.9%, respectively) (P < .001), but not in antibody‐mediated rejection, mixed acute rejection, or de novo donor‐specific anti‐HLA antibodies. Neurologic and electrolyte abnormality adverse events were less frequent under belatacept. Belatacept‐based CNIA/ESW regimens did not prove to be superior for the primary or secondary endpoints. Belatacept‐treated patients demonstrated an increase in biopsy‐proved acute cellular rejection and reduced neurologic and metabolic adverse events. These results demonstrate that simultaneous CNIA/ESW is feasible without excessive acute rejection.     

De novo donor‐specific antibodies in belatacept‐treated vs cyclosporine‐treated kidney‐transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT‐EXT studies

Donor‐specific antibodies (DSAs) are associated with an increased risk of antibody‐mediated rejection and graft failure. In BENEFIT and BENEFIT‐EXT, kidney‐transplant recipients were randomized to receive belatacept more intense (MI)–based, belatacept less intense (LI)–based, or cyclosporine‐based immunosuppression for up to 7 years (84 months). The presence/absence of HLA‐specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid‐phase flow‐cytometry screening. Samples from anti‐HLA‐positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan‐Meier analysis, de novo DSA incidence was significantly lower in belatacept‐treated vs cyclosporine‐treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept‐based immunosuppression was associated with numerically lower MFI vs cyclosporine‐based immunosuppression. Although derived post hoc, these data suggest that belatacept‐based immunosuppression suppresses de novo DSA development more effectively than cyclosporine‐based immunosuppression.     

Ten‐year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4‐weekly or 8‐weekly

In the phase II IM103‐100 study, kidney transplant recipients were first randomized to belatacept more‐intensive‐based (n = 74), belatacept less‐intensive‐based (n = 71), or cyclosporine‐based (n = 73) immunosuppression. At 3‐6 months posttransplant, belatacept‐treated patients were re‐randomized to receive belatacept every 4 weeks (4‐weekly, n = 62) or every 8 weeks (8‐weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine‐based immunosuppression. Cumulative rates of biopsy‐proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for belatacept more‐intensive, belatacept less‐intensive, and cyclosporine, respectively (belatacept more‐intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47‐1.92; P = .89; belatacept less‐intensive vs cyclosporine: HR = 1.61; 95% CI 0.85‐3.05; P = .15). Cumulative BPAR rates from second randomization to year 10 for belatacept 4‐weekly, belatacept 8‐weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (belatacept 4‐weekly vs cyclosporine: HR = 1.06, 95% CI 0.35‐3.17, P = .92; belatacept 8‐weekly vs cyclosporine: HR = 2.00, 95% CI 0.75‐5.35, P = .17). Renal function trends were estimated using a repeated‐measures model. Estimated mean GFR values at year 10 for belatacept 4‐weekly, belatacept 8‐weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m², respectively (P<.001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2‐fold higher in patients administered belatacept every 8 weeks vs every 4 weeks.     

Belatacept during pregnancy in renal transplant recipients: Two case reports

Impaired fertility is common among patients with chronic organ failure, including end‐stage renal disease (ESRD). Women of childbearing age undergoing transplantation may experience rapid return of fertility. Pregnancy posttransplant presents numerous risks for the patient, fetus, and allograft. Maternal risks include hypertension and preeclampsia. Allograft risks include acute rejection and failure of the organ, and fetal risks include miscarriage, birth defects from immunosuppressants, premature delivery, and low birth weight. Belatacept, a selective T cell costimulation blocker, was approved for use in kidney transplant recipients in the United States in 2011. Little is known about the safety of belatacept during pregnancy in humans. We describe 2 cases of successful pregnancy and delivery with the use of belatacept‐based immunosuppression. The Transplant Pregnancy Registry International (TPR) is a voluntary registry for transplant recipients who have had pregnancies or fathered a pregnancy posttransplant. To date, these 2 cases are the only known exposures to belatacept that have been reported to the TPR. 1     

Safe Conversion From Tacrolimus to Belatacept in High Immunologic Risk Kidney Transplant Recipients With Allograft Dysfunction

There is no literature on the use of belatacept for sensitized patients or regrafts in kidney transplantation. We present our initial experience in high immunologic risk kidney transplant recipients who were converted from tacrolimus to belatacept for presumed acute calcineurin inhibitor (CNI) toxicity and/or interstitial fibrosis/tubular atrophy. Six (mean age = 40 years) patients were switched from tacrolimus to belatacept at a median of 4 months posttransplant. Renal function improved significantly from a peak mean estimated glomerular filtration rate (eGFR) of 23.8 ± 12.9 mL/min/1.73 m² prior to the switch to an eGFR of 42 ± 12.5 mL/min/1.73 m² (p = 0.03) at a mean follow‐up of 16.5 months postconversion. No new rejection episodes were diagnosed despite a prior history of rejection in 2/6 (33%) patients. Surveillance biopsies performed in 5/6 patients did not show subclinical rejection. No development of donor‐specific antibodies (DSA) was noted. In this preliminary investigation, we report improved kidney function without a concurrent increase in risk of rejection and DSA in six sensitized patients converted from tacrolimus to belatacept. Improvement in renal function was noted even in patients with chronic allograft fibrosis without evidence of acute CNI toxicity. Further studies with protocol biopsies are needed to ensure safety and wider applicability of this approach.     

De novo belatacept in clinical vascularized composite allotransplantation

Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)‐based. As such, most recipients have experienced CNI‐related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI‐based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI‐based regimen to a belatacept‐based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept‐based regimen, transitioned to a CNI–free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI‐associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA.     

Daclizumab Versus Rabbit Antithymocyte Globulin in High‐Risk Renal Transplants: Five‐Year Follow‐up of a Randomized Study

We previously reported a randomized controlled trial in which 227 de novo deceased‐donor kidney transplant recipients were randomized to rabbit antithymocyte (rATG, Thymoglobulin) or daclizumab if they were considered to be at high immunological risk, defined as high panel reactive antibodies (PRA), loss of a first kidney graft through rejection within 2 years of transplantation, or third or fourth transplantation. Patients treated with rATG had lower incidences of biopsy‐proven acute rejection (BPAR) and steroid‐resistant rejection at 1 year. Patients were followed to 5 years posttransplant in an observational study; findings are described here. Treatment with rATG was associated with a lower rate of BPAR at 5 years (14.2% vs. 26.0% with daclizumab; p = 0.035). Only one rATG‐treated patient (0.9%) and one daclizumab‐treated patient (1.0%) developed BPAR after 1 year. Five‐year graft and patient survival rates, and renal function, were similar between the two groups. Overall graft survival at 5 years was significantly higher in patients without BPAR (81.0% vs. 54.8%; p < 0.001). In conclusion, rATG is superior to daclizumab for the prevention of BPAR among high‐immunological‐risk renal transplant recipients. Overall graft survival at 5 years was approximately 70% with either induction therapy, which compares favorably to low‐risk cohorts.     

Phase I study of single‐dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients

Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12‐17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein‐Barr virus were enrolled; all completed the 6‐month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [C_max] and area under the serum concentration‐time curve from time zero extrapolated to infinity [AUC_0‐INF] were 20% and 25%, respectively). Mean half‐life (T_1/2) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady‐state (V_ss) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.     

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor–Intolerant Graft Recipients of Kidneys From Extended‐Criteria Donors

Transplant recipients receiving a kidney from an extended‐criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow‐up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.     

A Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT‐EXT Study)

Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long‐term outcomes versus CNIs. BENEFIT‐EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression Trial—EXTended criteria donors) is a 3‐year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4–7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept‐based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine‐treated patients.     

Campath,calcineurin inhibitor reduction,and chronic allograft nephropathy (the 3C Study) – results of a randomized controlled clinical trial

Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short‐term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long‐term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus‐based and 197 to tacrolimus‐based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline‐adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m² in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m² in the tacrolimus group (P = .50). Biopsy‐proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus‐based therapy, sirolimus‐based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088.     

Belatacept Conversion in an HIV‐Positive Kidney Transplant Recipient With Prolonged Delayed Graft Function

We report an HIV‐positive renal transplant recipient with delayed graft function who was converted from tacrolimus to belatacept in an attempt to improve renal function. The patient had kidney biopsies at 4 and 8 weeks posttransplant that revealed acute tubular necrosis and mild fibrosis. After 14 weeks of delayed function, belatacept was initiated and tacrolimus was weaned off. Shortly after discontinuing tacrolimus, renal function began to improve. The patient was able to discontinue dialysis 21 weeks posttransplant. HIV viral load was undetectable at last follow‐up. To our knowledge, this is the first report of belatacept use in a patient with HIV.     

Complete Regression of Psoriatic Arthritis After Belatacept Conversion in a Highly HLA‐Sensitized Kidney Transplant Patient

Costimulatory inhibitors (i.e. abatacept and belatacept) effectively abrogate T lymphocyte activation and proliferation and have been shown to be effective for disease control in certain autoimmune disorders as well as in preventing allograft rejection in kidney transplantation. Whether such immunomodulatory agents may be useful for the control of autoimmune flares and allograft acceptance, while avoiding the need of additional strong immunosuppressants, has not been shown. Here, we report the first case of a 47‐year‐old man affected by a serious debilitating form of psoriatic arthritis that presented during the course of a third, high immunological‐risk kidney transplantation. Three years after transplantation, the patient benefited by switching from tacrolimus‐ to belatacept‐based therapy, without additional immunosuppression, by showing complete regression of the arthritic symptoms as well as no progression of severe radiological lesions, which leaded to the recovery of disability and functional impairment. Remarkably, the treatment with belatacept in association with mycophenolate mofetil and steroids also provided a stable normal allograft function over time and abrogated the development of de novo circulating donor‐specific alloantibodies after 4 years of follow‐up.