Immunological Risk Kidney Transplant Recipients Research Articles

Antibody-mediated rejection diagnosed in early protocol biopsies in high immunological risk kidney transplant recipients.

Renal transplant recipients with donor-specific anti-HLA antibodies are at an increased risk of antibody-mediated rejection (AMR). Early protocolized renal biopsies may serve as a strategy to improve diagnosis in this patient population. We evaluated 155 highly sensitized renal transplant recipients with cPRA class I+II>90% pre-transplant from 2015 to 2022. Patients with protocol biopsies within the first two weeks post-transplant were included. A total of 122 patients were included in the study. Of these, 13 (10.6%) were diagnosed with very early antibody-mediated rejection (veABMR) within the first two weeks post-transplant. This corresponds to 52% (13/25 patients) of all ABMR cases reported during the follow-up of this population. The graft survival rates at one and three years were significantly lower in patients with veABMR (p<0.001) compared to patients without rejection in the early protocol biopsy. In terms of severity, the veABMR cohort exhibited a hazard ratio (HR) of 10.33 (95% CI 3.23-33.06; p<0.001) for graft failure. The presence of donor-specific antibodies (DSA) class II on the day of transplantation and a higher percentage of eplet mismatch (EpMM), particularly EpMM DQA1, correlated with the development of veABMR. Early protocol biopsies play a pivotal role in the early detection of veABMR in high-risk immunological patients. Patients with veABMR face significant risks of graft loss, despite early treatment of rejection.

#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience

Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P &amp;lt; 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.

Single-dose antithymocyte globulin in standard immunological risk kidney transplant recipients: efficacy and kinetics of peripheral blood CD3+ T lymphocyte modulation.

Polyclonal anti-T cell antibodies (ATG or thymoglobulin®) are used as induction therapy in kidney transplant recipients. This study evaluates the safety, efficacy, and CD3+T lymphocyte modulation of two ATG regimens. The trial included two cohorts of kidney transplant recipients that were followed for one year. The study group, including standard immunological risk recipients, received one 3mg/kg dose of ATG. The comparator group, including standard and high immunological risk kidney transplant recipients, received a fractionated dose regimen (up to four 1.5mg/kg doses). Patient and graft outcomes and the kinetics of CD3+T lymphocyte modulation in the peripheral blood were evaluated. One hundred kidney transplant recipients were included in each group. The one-year incidence of treated acute rejection, and patient and graft survival did not differ between groups. Bacterial infections were significantly more frequent in fractionated-dose group patients (66%versus 5%; P = 0.0001). At one-year follow-up, there was no difference in the incidence of cytomegalovirus infection (P = 0.152) or malignancies (P = 0.312). CD3+T lymphocyte immunomodulation in the single-dose group was more effective in the first two days after transplantation. After the third post-transplant day, CD3+T lymphocyte modulation was more efficient in the fractionated dose group. Both regimens resulted in low rejection rates and equivalent survival. The single and reduced dose regimen protects from the occurrence of bacterial infections. CD3+T lymphocyte modulation occurred with different kinetics, although it did not result in distinct outcomes.

Three-year Outcomes After Conversion From Monthly to Every 2-month Belatacept Maintenance Therapy in Kidney Transplant Recipients: Results From a Randomized Controlled Trial.

To determine whether every 2-mo (q2m) belatacept is noninferior to standard q1m maintenance, we conducted a prospective, single-center randomized trial in low-immunologic-risk, stable renal transplant recipients. Here, post hoc analysis of 3-y outcomes, including renal function and adverse events, are reported. One hundred sixty-three patients received treatment in the q1m control group (n = 82) or q2m study group (n = 81). Renal allograft function as measured by baseline-adjusted estimated glomerular filtration rate was not significantly different between groups (time-averaged mean difference of 0.2 mL/min/1.73 m2; 95% confidence interval: -2.5, 2.9). There were no statistically significant differences in time to death or graft loss, freedom from rejection, or freedom from donor-specific antibodies (DSAs). During the extended 12- to 36-mo follow-up, 3 deaths, 1 graft loss occurred in the q1m group, compared with 2 deaths, and 2 graft losses in the q2m group. In the q1m group, 1 patient developed DSAs and acute rejection. In the q2m group, 3 patients developed DSAs and 2 associated with acute rejection. Based on the similar renal function and survival at 36 mo compared with q1m, q2m belatacept is a potentially viable maintenance immunosuppressive strategy in low immunologic risk kidney transplant recipients that may facilitate increased clinical utilization of costimulation blockade-based immunosuppression.

311.4: Every 2-Month Belatacept Maintenance Therapy in Kidney Transplant Recipients: 3-Year Follow-up of a Randomized, Non-inferiority Trial

Introduction: Maintenance immunosuppression with belatacept following kidney transplantation results in improved long-term graft function as compared to calcineurin inhibitors. However, broad application of belatacept has been limited, in part related to logistical barriers surrounding a monthly (q1m) IV infusion requirement. Our center conducted a randomized, non-inferiority trial comparing every 2-month (q2m) dosing to standard q1m maintenance. At twelve month follow up, q2m dosing was noninferior to standard q1m dosing as determined by renal function (eGFR). Two-month dosing was safe and well tolerated without a significant incidence of immunologic events in subjects adherent to the study protocol, but longer term follow-up is of interest to better elucidate patient and graft outcomes. Here, we present the 3-year outcomes from this study. Methods: Low immunologic risk, stable renal transplant recipients a minimum of 1 year post-transplant were randomized to q1m or q2m belatacept maintenance therapy. 36-month follow-up was conducted as intention-to-treat on the population that initiated the study protocol. An autoregressive model using baseline-adjusted means with a random effect for subject was used to compare renal function between groups. Kaplan Meier survival analysis was performed for analysis of adverse and immunologic events. Results: 163 patients initiated the study protocol and received treatment in the q1m control group (n=82) or q2m study group (n=81). Renal allograft function as measured by baseline adjusted eGFR was not significantly different between groups at 36 months (mean [95% CI], q1m: 73.43[70.37, 76.49] vs. q2m: 72.46[69.08, 75.84].There were no statistically significant differences in time to death or graft loss (cumulative survival at 36 months, q1m: 92.6%, q2m: 95.0%, p=0.49; freedom from rejection (q1m: 98.7%, q2m: 92.4%, p=0.06), or freedom from DSA (q1m: 98.7%, q2m: 92.4%, p=0.06). During the extended 12-36 month follow-up period, 3 deaths, 1 graft loss occurred in the q1m group, compared to 2 deaths, 2 graft losses in the q2m group. In the q1m group, one patient developed DSA and acute rejection. In the q2m group, 3 patients developed DSA, 2 associated with acute rejection. All acute rejections in both groups were associated with documented medication nonadherence.Conclusions: Based on similar renal function and adverse event rates at 36 months compared to q1m, q2m belatacept is a viable and safe maintenance immunosuppressive strategy in low immunologic risk kidney transplant recipients with potential to facilitate increased clinical utilization of costimulation blockade-based immunosuppression. (ClinicalTrials.gov NCT02560558) James O. Robbins Foundation. James M. Cox Foundation. Carlos and Marguerite Mason Trust.

Standard induction with basiliximab versus no induction in low immunological risk kidney transplant recipients: study protocol for a randomized controlled trial

BackgroundInduction therapy with IL-2 receptor antagonist (IL2-RA) is recommended as a first-line agent in low immunological risk kidney transplant recipients. However, the role of IL2-RA in the setting of tacrolimus-based immunosuppression has not been fully investigated.AimsTo compare different induction therapeutic strategies with 2 doses of basiliximab vs. no induction in low immunologic risk kidney transplant recipients as per KFSHRC protocol.MethodsProspective, randomized, double blind, non-inferiority, controlled clinical trialExpected outcomes1. Primary outcomes:Biopsy-proven acute rejection within first year following transplant2. Secondary outcomes:a. Patient and graft survival at 1 yearb. eGFR at 6 months and at 12 monthsc. Emergence of de novo donor-specific antibodies (DSAs)Trial registrationThe study has been prospectively registered at clinicaltrials.gov (NTC: 04404127). Registered on 27 May 2020.

Long-term Efficacy and Safety of Everolimus Versus Mycophenolate in Kidney Transplant Recipients Receiving Tacrolimus.

The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking. This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101). There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103). In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.

INCIDENCE OF CYTOMEGALOVIRUS DISEASE IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING EVEROLIMUS AND REDUCED TACROLIMUS DOSES: A COHORT RETROSPECTIVE ANALYSIS

Introduction: Cytomegalovirus (CMV) is the most common viral pathogen occurring in postrenal transplantation. CMV infection usually develops during the first few months after transplantation. The success of CMV prophylaxis with antivirals has resulted in a decrease in the incidence of CMV infection. However, CMV remains a significant pathogen, associated with allograft rejection and loss, mortality, interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies, and increased post-transplant costs. Purpose: To determine the incidence of cytomegalovirus disease in kidney transplant recipients receiving Everolimus and reduced Tacrolimus doses. Material and Methods: All low immunological risk patients, >18 years old whom received kidney transplantation at Santa Casa de Misericordia de Juiz de Fora between January 2013 and February 2017 were retrospectively assessed. The first group received induction therapy with Basiliximab, and the post-operative maintenance regimen included Tacrolimus, Mycophenolic acid and Prednisone (BAS/MPS), and the second group received Polyclonal antilymphocyte globulins (2,25mg/kg) as induction therapy, and then low dose of Tacrolimus (2mg/10kg/day), Everolimus and Prednisone as maintenance regimen (r-ATG/EVR). None of the patients received pharmacological prophylaxis or preemptive therapy against CMV. Results: Patients receiving EVR showed a lower incidence of CMV when compared to those receiving MPS (4.2% x 17.5%, p=0.005). There was an important difference in the time of hospitalization to treat CMV disease. Patients of the MPS stayed hospitalized for about 20 days more than the EVR group (p=0.005). There was no difference as to the incidence of rejection, delayed graft function or graft survival. Conclusion: Results from this trial conducted in low immunological risk kidney transplant recipients receiving no CMV prophylaxis demonstrated that EVR was associated to a decrease in CMV disease incidence when compared to MPS. These data suggest that kidney transplant recipients receiving EVR may not need CMV prophylaxis.

Induction and Donor Specific Antibodies in Low Immunologic Risk Kidney Transplant Recipients.

Optimal induction for patients without pretransplant donor-specific antibodies (DSAs) is poorly defined. The goal of this study was to compare the incidence of de novo DSA (dnDSA) and graft outcomes between induction therapies in patients with a negative virtual crossmatch (VXM). A retrospective chart review was performed, identifying 782 patients with a negative VXM who underwent kidney transplantation at a single, high-volume institution between January 2013 and May 2017. Kaplan-Meier analysis was used to assess the incidence of dnDSA and allograft survival between induction therapies in this group. dnDSA is defined as the development of new post-transplant DSA, at any MFI level. Induction therapy included alemtuzumab (N=87, 11%), basiliximab (N=522, 67%), and anti-thymocyte globulin (ATG; N=173, 22%). One-year graft survival was similar between groups (alemtuzumab, 100%; basiliximab, 98%; ATG, 99%). Incidence of acute rejection at 1 year was <2% and not different between the three groups. Alemtuzumab was associated with the highest incidence of dnDSA at 14%, compared with 5% and 8% in basiliximab and ATG groups, respectively, at 1 year (P=0.009). In multivariate regression analyses, alemtuzumab retained its significant association with a dnDSA HR of 2.5 (95% CI, 1.51 to 4.25; P=0.0004). In summary, alemtuzumab was associated with a higher rate of dnDSA development in patients with a negative VXM; however, this finding was not associated with rejection or graft failure.

Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients.

De novo donor-specific antibodies (dnDSA) play an important role in antibody-mediated rejection (ABMR) and graft failure, yet their development in kidney transplant recipients (KTx) of higher immunological risk has not been characterized. We prospectively determined the incidence of dnDSA at 3 and 12months posttransplant and assessed their associations with outcomes in recipients stratified by low, moderate, and high immunological risk. Adult KTx were screened for DSA pretransplant, months 3 and 12 posttransplant, and when clinically indicated. Outcomes included incidence of dnDSA, death-censored graft survival (DCGS), and ABMR. Of 371 recipients, 154 (42%) were transplanted across a pretransplant DSA that became undetectable by 12months posttransplant in 78% of cases. dnDSA were detected in 16% (95% confidence interval [CI]: 12-20%) by 3months and 23% (95% CI: 18-29%) by 12months posttransplant. Incidence at 12months was higher in the moderate (30%) and high-risk groups (29%) compared to the low-risk group (16%). dnDSA were associated with an increased risk of ABMR (hazard ratio [HR] 2.2; 95% CI: 1.1-4.4; P=.04) but were not an independent risk factor for DCGS. In conclusion, dnDSA were more frequent in transplant recipients of higher immune risk and associated with an increased risk of ABMR.

Induction Therapy With ATG Compared With Anti-IL2 Basiliximab in Low–Immunologic Risk Kidney Transplant Recipients

Practically all kidney allograft recipients require immunosuppressive therapy to prevent rejection and loss of the allograft. The aim of this study was to determine the occurrence of biopsy-proven acute rejection in low–immunologic risk kidney transplant recipients according to the type of induction (basiliximab vs low-dose of rabbit antithymocyte globulin [rATG], 3.5 mg/kg). Materials and MethodsA total of 125 patients after primary kidney transplant were included in the retrospective analysis with 6-month follow-up. The immunosuppression regimen included tacrolimus, mycophenolic acid, and corticoids. ResultsWe did not find any significant difference in the occurrence of acute rejection or difference in the occurrence of infection complications. Patients in the rATG group had a significantly longer period of cold ischemia, more frequently received kidney transplants from expanded criteria donors, and had significantly more mismatches in HLA-DR. Delayed graft function (DGF) was identified as an independent risk factor for biopsy-proven acute rejection (hazard ratio, 3.4859; P = .003). There was comparable incidence of DGF between the 2 groups despite that there were several factors that are more commonly associated with DGF in the rATG group. ConclusionPatients with low immunologic risk and high risk of DGF benefit from the rATG induction in dose of 3.5 mg/kg without the increased risk of infection complications with the assumption of good graft function in long-term post-transplant period.

P161 Clinical features and outcomes using rituximab for high immunologic risk kidney transplant recipients with historic DSA

P161 Clinical features and outcomes using rituximab for high immunologic risk kidney transplant recipients with historic DSA

Evidence-based practice: Guidance for using everolimus in combination with low-exposure calcineurin inhibitors as initial immunosuppression in kidney transplant patients.

The mammalian target of rapamycin (mTOR) inhibitor, everolimus, in combination with reduced-exposure calcineurin inhibitor (CNI), has been demonstrated in clinical trials to have comparable efficacy in low-to-moderate immunological risk kidney transplant recipients to the Standard of Care, mycophenolic acid (MPA) in combination with standard-exposure CNI. Current treatment guidelines consider mTOR inhibitors to be a second-line therapy in the majority of cases; however, given that everolimus-based regimens are associated with a reduced rate of viral infections after transplantation, their wider use could have great benefits for kidney transplant patients. In this evidence-based practice guideline, we consider the de novo use of everolimus in kidney transplant recipients. The main outcomes of our consideration of the available evidence are that: 1. Everolimus, in combination with reduced-exposure CNI and low dose steroids, is a suitable regimen for the prophylaxis of kidney transplant rejection in the majority of low-to-moderate immunological risk adult patients, with individualized management; 2. Induction with either basiliximab or rabbit anti-thymocyte globulin is an effective therapy for kidney transplant recipients when initiating an everolimus-based, reduced-exposure CNI regimen; and 3. An individualized approach should be adopted when managing kidney transplant recipients on everolimus-based therapy.

Thymoglobulin Versus Basiliximab Induction Therapy in Low-Risk Kidney Transplant Recipients: A Single-Center Experience

BackgroundThe Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that T-cell–depleting agents should be used only for kidney transplant (KT) recipients at high immunologic risk. However, the effects of thymoglobulin induction therapy in low–immunologic risk KT recipients on tacrolimus, mycophenolic acid, and steroid have not been elucidated yet. MethodsWe retrospectively collected 6 months postoperative clinical data, for low–immunologic risk KT recipients at Soonchunhyang University Hospital. Recipients were divided into thymoglobulin and basiliximab groups, based on the induction agent used. Low–immunologic risk recipients were defined as those with panel-reactive antibody level <30% at the time of kidney transplantation. The incidence of biopsy-proven acute rejection and borderline change was compared between the two groups. ResultsOf the 46 low–immunologic risk patients, 25 received thymoglobulin. The incidence of biopsy-proven acute rejection was 0% (n = 0) and that of borderline change was 8% (n = 2) in the thymoglobulin group. The basiliximab group had a significantly higher incidence of rejection (23.8%; n = 5; P = .015) and borderline change (42.9%; n = 9; P = .006). No significant difference in estimated glomerular filtration rate was found between the two groups at 6 months after kidney transplantation. Cytomegalovirus (CMV) infection occurred more frequently in the thymoglobulin group than in the basiliximab group. All patients with CMV infection in both groups were effectively treated with pre-emptive intravenous ganciclovir therapy. ConclusionsIn low–immunologic risk KT recipients who received tacrolimus, mycophenolic acid, and steroid therapy, thymoglobulin induction therapy significantly reduced the incidence of biopsy-proven acute rejection and borderline change compared with basiliximab induction therapy.

Role of induction therapy in low immunological risk-kidney transplant recipients: A mate-kidney analysis.

We aimed to evaluate the impact of induction on outcomes in low-immunological risk kidney transplant recipients (KTRs) using a mate-kidney model. Using OPTN/UNOS database, we identified three groups of low-immunological risk KTRs (first transplant, panel reactive antibody <20%, human leukocyte antigen mismatches ≤3) with each group containing recipients of mate-kidneys from same donor and differed by induction received: group 1: no induction vs interleukin-2 receptor antibody (IL2RA) induction; group 2: no induction vs depleting antibody induction; group 3: IL2RA vs depleting antibody induction. Outcomes were compared between mate-kidney recipients in each group in an adjusted model. Total of 1034 mate-kidney recipients were identified: group 1, n=192; group 2, n=362 and group 3, n=480. Adjusted risk for DGF was higher (OR 1.89, 95% CI 1.09-3.25,.P=0.02) and one-year acute rejection trended lower (OR 0.53, 95% CI 0.25-1.11, P=0.09) among depleting antibody induced patients in group 2. Adjusted five-year graft survivals were similar between mate-kidney recipients in all three groups. Adjusted patient death risk was significantly lower in depleting antibody induced patients in group 2 (HR 0.48, 95% CI 0.26-0.88, P=0.02) and trended lower in IL2RA induced patient in group 1 (HR 0.32, 95% CI 0.10-1.01, P=0.05). Perioperative antibody induction was associated with lower patient death risk in low-immunologic risk KTRs.

Predictive Factors of Acute Rejection in Low Immunologic Risk Kidney Transplant Recipients Receiving Basiliximab.

The optimal immunosuppressive induction therapy in kidney transplant recipients with low immunologic risk of acute rejection (AR) is still controversial. The use of basiliximab (BSX) has led to a significant decrease of AR with a low side effect profile. This study sought to evaluate predictive risk factors for AR in low immunologic risk patients subjected to immunosuppressive induction therapy with BSX. We reviewed all low immunologic risk patients (panel reactive antibody [PRA] level<50%, who had undergone a first deceased-donor transplant) subjected to immunosuppressive induction therapy with BSX, calcineurin inhibitor, mycophenolate mofetil, and prednisolone (n= 346). AR was defined as any rejection occurring until 12 months posttransplantation. Predictive risk factors for AR were evaluated by logistic regression and, to find the best cut-off of PRA related to a higher incidence of AR, receiver-operator characteristic (ROC) curve analysis was performed. The rate of AR was 7.8%. Multivariate logistic regression analysis identified age at the time of transplantation (P= .040) and PRA level (P= .001) as independent risk factors for AR. ROC curve analysis confirmed that PRA >10% was related to an increased incidence of AR (19.2% vs 6.0%, P= .005). A higher incidence of AR was observed in low immunologic risk kidney transplant patients with a PRA level >10%. These data support the use of more intensive immunosuppressive induction therapy in patients with low immunologic risk and a PRA level >10%.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

Effects of Ideal Versus Total Body Weight Dosage of Rabbit Antithymocyte Globulin on Outcomes of Kidney Transplant Patients With High Immunologic Risk.

The optimal dose of rabbit antithymocyte globulin induction therapy in kidney transplant recipients with high immunologic risk lacks consensus. The purpose of this study was to evaluate the effect of using ideal body weight rather than total body weight for the weight-based dose calculations in this patient population. Data were retrospectively collected on 89 adult patients who received rabbit antithymocyte globulin induction therapy for high immunologic risk kidney transplant. Hospital protocol changed from the use of cumulative rabbit antithymocyte globulin doses of 7.5 mg/kg total body weight to 7.5 mg/kg ideal body weight in 2009. Patients were separated into 2 cohorts based on the amount of rabbit antithymocyte globulin (in mg/kg total body weight) received. Rate of biopsy-proven acute rejection, patient survival, and allograft function were evaluated at 90 days and 1 year after transplant. Cost of induction therapy was also evaluated. Baseline demographics were predominantly similar between the 2 cohorts. No significant difference in maintenance immunosuppression was identified. Rates of biopsy-proven acute rejection at 90 days and 1 year were similar between ideal and total body weight cohorts (4.2% vs 0% at 90 days, P = .5; 8.7% vs 0% at 1 year, P = .13). Patient survival and allograft function were also similar. Median cost of rabbit antithymocyte globulin induction therapy per patient was lower in the ideal body weight cohort, but this difference was not statistically significant ($17 542 vs $19 934; P = .3). Our results suggest that use of ideal body weight for dose calculations of rabbit antithymocyte globulin induction therapy in high immunologic risk kidney transplant recipients at 7.5 mg/kg results in low rates of acute rejection with a safety profile similar to that shown with a total body weight dosage. Use of ideal body weight for lower cumulative doses may still need further evaluation in this patient population.

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 m(2) prior to the switch to an eGFR of 42 ± 12.5 mL/min/1.73 m(2) (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.

83 Serum BAFF levels and B cell subsets in secondary lymphoid organs after rituximab administration: Its association with clinical outcomes

INTRODUCTION AND OBJECTIVES: Rituximab (RIT), antiCD20 antibody, has been applied to kidney transplantation because of its potent B-cell depleting effect. Although CD20+ cells in peripheral blood (PB) and spleen are consistently depleted in patients receiving RIT, the clinical effects are heterogeneous, probably related to differences in the depleting effects of secondary lymphoid organs (SLOs), such as peripheral lymph nodes (LNs). Meanwhile, B cell activation factor of the TNF family (BAFF) promotes B cell development and antibody secretion, and also serum BAFF levels increase after RIT administration. The aim of this study was to investigate the relationship between serum BAFF levels and B cell subsets in different lymphoid organs after RIT administration and its association with clinical outcomes. METHODS: Since April 2005, 50 patients with immunological high risks [ABO-incompatible (ABOI) or donor specific anti-HLA antibody (DSA) positive or both] received a single dose of RIT with 200 mg/ body at 3 weeks before kidney transplantation. They received 3 to 4 sessions of apheresis prior to transplantation. The induction immunosuppressive therapy was consisted of tacrolimus, MMF, steroid, and basiliximab. In all patients, the several pelvic LNs were dissected at the time of transplantation. Of those, 2 ABOI (induction period of RIT) and 6 DSA positive patients received splenectomy concurrently with transplantation. Immunohistochemical intensity of B cell subsets (CD20, CD27, CD79a, and CD138) in both LN and spleen was scored. Serum BAFF levels at day -7, 7, and 28 post-transplant were measured by ELISA. RESULTS: Acute antibody-mediated rejection (AAMR) developed in 9 patients (19%) in this series. The intensity score of CD138 in LNs was significantly higher in AMR patients (p<0.01) than those in non-AMR patients. No significant difference was found in the intensity scores of all B cell subsets in spleen among the patients with or without AMR. The serum BAFF levels at day -7 (p<0.01), 7 (p<0.05), and 28 (p<0.01) post-transplantation were significantly lower in AMR patients than in non-AMR patients. The existence of DSA before transplant, the intensity score of CD138 in LNs, and low serum BAFF level at 7 days before transplant were significantly associated with the occurrence of AAMR. CONCLUSIONS: In immunological high risk kidney transplant recipients receiving RIT before transplant, the plasma cell intensity in LNs and low serum BAFF level were risk factors of AAMR.