Low Immunological Risk Kidney Transplant Research Articles

Utility of Routine Post Kidney Transplant Anti-HLA Antibody Screening

IntroductionDe novo DSA (dnDSA) is a strong biomarker associated with the development of antibody mediated rejection and graft loss after kidney transplantation. Although this procedure is expensive, systematic annual screening was recommended by some national organ transplant agencies or societies though its clinical utility was not clearly established. MethodsTo address this question, we retrospectively assessed the incidence of dnDSA according to the test justification (clinically indicated or systematic) in a cohort of low-immunological risk patients, defined by being non-HLA sensitized and having no prior kidney transplants. ResultsA total of 1072 patients, for whom 4611 anti-HLA tests were performed, were included in the study. During follow-up period of 8 IQR (5 ; 11) years, seventy-seven recipients developed dnDSA (prevalence of 7.2%) . Thirty-five (45.5%) of these dnDSA were detected during the first year posttransplantation. In 95% of patients with dnDSA, an immunizing event was identified in their medical records. De novo DSA was detected in 46 out of 4267 systematic screening tests performed (1.08%). Active and chronic antibody mediated rejection were frequently observed in biopsies performed after systematic DSA testing (17.9% and 15.4% respectively). ConclusionOur results suggest that the detection by systematic screening of dnDSA in low immunological risk kidney transplant patients without sensitizing events is a rare event, especially after one year. Moreover, in real life, systematic annual screening for dnDSA, seems having a limited impact to detect AMR at an earlier stage compared to patients in whom dnDSA was detected after a clinically indicated test.

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.

The impact of induction therapy in low-immunological risk kidney transplant recipients regardless of HLA matching

BackgroundInduction agents have proved to reduce the rate of acute rejection (AR) in kidney transplant recipients (KTRs) without improving long-term graft and patient survival (PS). ObjectiveThis study evaluates the utility of induction therapy in low immunological risk KTRs regardless of donor-to-recipient HLA matching. MethodsWe retrospectively reviewed the records of 218 patients undergoing kidney transplantation (KT). These patients were divided into two groups according to the usage of induction therapy: 82 did not receive any induction therapy (Group I), and 136 patients received either Anti-IL2 receptor antibodies or anti-thymocyte globulin (Group II). All patients had panel reactive antibody (PRA) < 20% and absence of donor-specific antibodies (DSA). The difference in outcomes were assessed at different intervals following KT. ResultsThe rate of bacterial infections at one year (p-value = 0.032) and the frequency of CMV disease (p-value = 0.044) were significantly higher in Group II (with induction therapy). The duration of hospital stay, the rate and severity of acute rejection, the occurrence of delayed graft function, the rate and type of surgical complications at one year, and the graft function and survival at one and three years were similar between the two groups (p-value = NS). In addition, the financial burden is much less in Group I (without induction therapy), reducing the total cost of the transplant procedure. ConclusionWe conclude that induction therapy in low-immunological risk kidney transplant patients is not a must regardless of donor-to-recipient HLA matching. Therefore, induction therapy did not yield significant health results, but had negative financial consequences.

Treatment of early borderline lesions in low immunological risk kidney transplant patients: a Spanish multicenter, randomized, controlled parallel-group study protocol: the TRAINING study

BackgroundSubclinical inflammation, including borderline lesions (BL), is very common (30–40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function.MethodsThe TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression.DiscussionThis phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL.Trial registrationclinicaltrials.gov: NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1. Protocol Version 2 of 21 January 2022. Sponsor: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org.

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.

Effect of donor-to-recipient HLA matching in low-immunological risk kidney transplant recipients without induction therapy on acute rejection, graft survival, infections, and surgical complications at 3 years: The road towards new recommendations

BackgroundDonor-to-recipient human leukocyte antigen mismatching is considered one of the strongest determinants for graft and patient survival in kidney transplant recipients (KTR). ObjectiveThis retrospective study discusses the impact of HLA matching as low immunological risk KTR without induction therapy. Material and methodsRecords of 80 adult kidney transplant patients were reviewed with three years of the follow-up. All patients had panel reactive antibodies (PRA) < 20%, absence of donor-specific antibodies (DSA) and did not receive the induction therapy. These patients were divided into two groups according to their HLA matching between donor and recipient: 55 patients with ≥ 3 HLA matches (Group I; low immunogenicity) were compared to 25 patients with <3 HLA matches (Group II; high immunogenicity). The primary endpoints included the rate and severity of acute rejection (AR) episodes, graft function (creatinine level), and survival at 1, 3, 6, 12, and 36 months. Secondary endpoints include the rate and type of infections at one-year, surgical complications at one-year, and patient survival at 1, 6, 12, and 36 months after kidney transplantation. Baseline demographic characteristics were comparable between the two groups except for recipient age, donor gender, and pre-transplant dialysis time. ResultsThere was no significant difference observed between two groups at one-year in infection rate, the length of hospital stay, AR severity, the rate of cytomegalovirus infection, and the occurrence of delayed graft function. However, the rate of AR, the graft function upon discharge, and the rate and type of surgical complications at one-year were significantly higher in Group II (high immunogenicity). The patient and graft survival at three years, the death-censored graft survival, and the serum creatinine levels at 1, 3, 6, 12, and 36 months were similar between two groups. Two deaths occurred in each group (NS). ConclusionIn our center, the donor-to-recipient HLA mismatch is not considered an immunological risk factor in low-risk kidney transplant recipients (PRA < 20% and absence of DSA).

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.

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.

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.

Induction Therapy in Half-Haplotype Low Risk Kidney Transplant Patients: Impact on Acute Rejection, Graft Survival, Infection and Surgical Complications at 3 Years

Objective: This retrospective study discusses the need for induction therapy in half haplotype low immunological risk kidney transplant patients. Material and Methods: Records of 70 adult kidney transplant patients were reviewed with 3 years follow up. All patients were half haplotype matched with their living related donors and had PRA Results: We did not find any significant difference between the 2 groups regarding the length of hospital stay, the rate and severity of acute rejection, the rate of CMV infection, the occurrence of delayed graft function and the rate and type of surgical complications at 1 year. Furthermore, the patient and graft survival as well as the serum creatinine levels upon discharge and at 1, 3, 6, 12 and 36 months were also comparable. Nevertheless, the rate and type of out of Hospital infections and 1-year infection rate as well as the treatment cost were significantly higher in Group I. Conclusion: Induction therapy might not be desirable in low-immunological risk half-haplotype kidney transplant patients.

Impact of reduced exposure to calcineurin inhibitors on the development of de novo DSA: a cohort of non-immunized first kidney graft recipients between 2007 and 2014

BackgroundIn low-immunological risk kidney transplant recipients (KTRs), reduced exposure to calcineurin inhibitor (CNI) appears particularly attractive for avoiding adverse events, but may increase the risk of developing de novo Donor Specific Antibodies (dnDSA).MethodsCNI exposure was retrospectively analyzed in 247 non-HLA immunized first KTRs by taking into account trough levels (C0) collected during follow-up. Reduced exposure to CNI was defined as follows: C0 less than the lower limit of the international targets for ≥50% of follow-up.ResultsDuring a mean follow-up of 5.0 ± 2.0 years, 39 patients (15.8%) developed dnDSA (MFI ≥1000). Patients with DSA were significantly younger (46.6 ± 13.8 vs. 51.7 ± 14.0 years, p = 0.039), received more frequently poorly-matched grafts (59% with 6–8 A-B-DR-DQ HLA mismatches vs. 34.6%, p = 0.016) and had more frequently a reduced exposure to CNI (92.3% vs. 62.0%, p = 0.0002). Reduced exposure to CNI was associated with an increased risk of dnDSA (multivariable HR = 9.77, p = 0.002). Reduced exposure to CNI had no effect on patient survival, graft loss from any cause including death, or post-transplant cancer.ConclusionsEven in a low-immunological risk population, reduced exposure to CNI is associated with increased risk of dnDSA. Benefits and risks of under-immunosuppression must be carefully evaluated before deciding on CNI minimization.

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%.

Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful.

To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors (CNI) alone or combined with everolimus. This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one (n = 59) received everolimus (target blood level, 3-8 ng/mL) and the other (n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl (MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4 (CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/mL in 2 mo, and 50-65 ng/mL thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/mL until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators. The clinical characteristics of these two cohorts were similar. During the follow up (66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group (20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate than the other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole saved 80% of cyclosporine and 56% of everolimus doses. Combining CYP3A4 modulators with CNI or mammalian target of rapamycin inhibitor, in low immunological risk kidney transplant recipients is feasible, effective, safe and affordable even in the long term.

A Prospective Randomized Trial Aimed to Reduce the Incidence of Cytomegalovirus (CMV) Infection in Kidney Transplant Recipients.

Introduction: CMV infection is associated with inferior long-term patient and graft survival. This single center prospective randomized study compares the influence of 3 immunosuppressive regimens on the incidence of CMV infection in kidney transplant recipients. Methods: This is a single center prospective randomized study included 288 low immunological risk kidney transplant recipients to receive: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure tacrolimus (TAC<5 ng/ml), everolimus (EVR: 4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), mycophenolate (MPA) and prednisone. None of the patients received any CMV prophylaxis. CMV viral replication was monitored weekly using pp65 antigenemia and PCR. The primary outcome is the incidence of CMV infection (viremia or disease) during the first year of transplantation. This report includes data of all patients up to 6 month after transplantation. Results: There were no differences in demographic characteristics including pre-transplant CMV donor/recipient serostatus. The incidence of first CMV infection episode was lower in EVR groups (4.7 vs. 7.8 vs. 35.6%, p<0.0001). There was no difference comparing mean time to first CMV infection episode or mean time of ganciclovir treatment. The total number of CMV infection episodes was also lower in EVR groups (4 vs. 14 vs. 55) because there were no recurrent episodes in G1 but 6 in G2 and 19 in G3. Twelve patients were converted from MPA to EVR due to CMV infection. There were no differences in incidence of biopsy proven acute rejection (8 vs. 20 vs. 14%, p=0.085), wound-healing adverse events (28 vs. 35 vs. 25%, p=0.2), delayed graft function (48 vs. 53 vs. 45%, p=0.4), mean estimated GFR (64±24 vs. 58±23 vs. 66±29 ml/min, p=0.06) and mean protein/creatinine ratio (0.5±1.0 vs. 0.4±0.7 vs. 0.3±0.9, p=0.5). There were 8 deaths (G1=2; G2=3; G3=3) and 6 graft losses (G1=0; G2=3; G3=3). Conclusions: This 6 month analysis indicates that patients receiving EVR are at lower risk of developing CMV infection compared to patients receiving MPA. Patients receiving EVR showed efficacy and safety profiles comparable to those receiving MPA. DISCLOSURES:Tedesco, H.: Grant/Research Support, Novartis.

Association Between Immunosuppressive Drug Concentration and the Incidence of CMV Infection or Biopsy Proven Acute Rejection (BPAR) in Kidney Transplant Recipients.

Introduction: The purpose of this analysis was to evaluate the effects of 3 immunosuppressive regimens on the incidence of CMV infection and BPAR in kidney transplant recipients. Methods: This is a single center prospective randomized study including 288 low immunological risk kidney transplant recipients randomized to: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure tacrolimus (TAC<5 ng/ml), everolimus (EVR: 4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), mycophenolate (MPA) and prednisone. None of the patients received any CMV prophylaxis. All patients were followed for 6 months after transplant. Time-average drug concentrations from day 7 to day 180 were use for this analysis. Results: There were no differences in main demographic characteristics between groups. The mean age was 45 years, 66% male, 52% caucasian and 69% recipients of grafts from deceased donors. In G1 the incidence of CMV infection was 5%. Patients with CMV infection showed higher TAC concentrations compared to those without CMV infection (6.2±0.6 vs. 5.1±1.0 ng/ml, p=0.026) with no differences in EVR concentrations (5.3±1.6 vs. 5.6±1.2 ng/ml, p=ns), respectively. In G2 the incidence of CMV infection was 8%. Patients with CMV infection showed similar TAC concentrations compared to those without CMV infection (7.7 ± 1.7 vs. 6.6 ± 1.8 ng/ml, ns) but lower EVR concentrations (4.3±1.0 vs. 5.4±1.2 ng/ml, p=0.009), respectively. In G3 the incidence of CMV infection was 36%. Patients with CMV infection showed similar TAC concentrations compared to those without CMV infection (7.7±1.6 vs. 7.5±1.1 ng/ml, ns) but higher MPA concentrations (7.2±7.7 vs. 2.3±1.6 ng/ml, p=0.037), respectively. The incidence of BPAR was 8%, 20% and 14% in G1, G2 and G3, respectively (p=0.085). There were no significant differences in TAC, EVR or MPA concentrations comparing patients with or without BPAR in each group. Conclusion: In this population receiving no CMV prophylaxis, lower incidence of CMV infection was observed among patients receiving EVR containing regimens. Higher TAC or MPA and lower EVR concentrations were associated with higher incidence of CMV infection.

Wound Healing Complications in Kidney Transplant Recipients Receiving Everolimus (EVR).

Introduction: De novo use of EVR has been associated with lower incidence of CMV infection but is associated with a concentration dependent increase in wound healing adverse events (WHAE). This study specifically evaluated WHAE within a prospective randomized trial comparing EVR and mycophenolate (MPA) in kidney transplant recipients receiving tacrolimus (TAC). Methodology: In this single center prospective randomized study 288 low immunological risk kidney transplant recipients were randomized to: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure (TAC<5 ng/ml), EVR (4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), MPA(1440 mg/day) and prednisone. All drugs were started within 24 hours of graft revascularization. None of the patients received any CMV prophylaxis. All 12 surgeons involved were not aware of the trial and therefore no specific surgical procedures were implemented. A specific case report form was developed to capture all WHAE. An ultrasound evaluation was also scheduled for all patients reaching 30 days to capture subclinical abnormalities. Results: No differences in main demographic characteristics were observed. Mean EVR concentrations at day 7 were 4.1±1.3 in G1 and 4.0±1.4 ng/ml in G2. There was no difference in the incidence of patients with at least one WHAE (28 vs. 35 vs. 25%, p=0.246) or those requiring surgical reintervention (13 vs. 13 vs. 12%, p=0,972). Total number of events was higher in G2 (35 vs. 61 vs. 42). The most frequent events observed were lymphocele (16 vs. 25 vs. 12), incisional hernia (6 vs. 11 vs. 2), urinary fistula (6 vs. 7 vs. 7) and surgical site infection (1 vs. 10 vs. 8). Ultrasound was performed in 96% of patients reaching 30 days. Among patients without previous WHAE, specific findings were observed in 13%, 11% and 4% of patients in G1, G2 and G3, respectively, mostly small fluid collections. The incidence of CMV infection was lower among patients receiving EVR (4.7 vs. 7.8 vs. 35.6, p < 0.0001), respectively. Conclusion: In this rigorous analysis involving 12 blinded surgeons the proportion of patients with any WHAE were comparable in patients receiving EVR compared to MPA, although the total number of events appears to be higher in patients receiving basiliximab induction and EVR.

De Novo Everolimus (EVR) Versus Mycophenolate (MPA) in Kidney Transplant Recipients Receiving Tacrolimus (TAC).

Introduction: Head-to-head comparison of the efficacy of de novo use of EVR or MPA has not been investigated in kidney transplant recipients receiving TAC. Methods:This is a single center prospective randomized study including 288 low immunological risk kidney transplant recipients receiving: (G1, N=85) single 3 mg/kg dose of antithymocyte globulin, reduced exposure TAC (<5 ng/ml), EVR (4-8 ng/mL) and prednisone; (G2, N=102) basiliximab, reduced exposure TAC (6 ng/ml for 3 months then <5 ng/mL thereafter), EVR (4-8 ng/mL) and prednisone; (G3, N=101) basiliximab, TAC (6-8 ng/ml), MPA(1440 mg/day) and prednisone. None of the patients received any CMV prophylaxis. All patients were followed for 6 months after transplant and 28%, 29% and 27% reached one year of follow up, respectively. This report includes detailed analysis of the incidence and characteristics of acute rejection (AR) up to one year after transplantation (mean follow up of 297±98 days). Results: There were no differences in demography including recipient age, gender, race, PRA, CMV recipient status, donor age and donor source. The incidence of delayed graft function was high but comparable among the groups (48 vs. 53 vs. 45%, p=0.391), respectively. The incidence of biopsy proven acute rejection (BPAR) was not different among the groups (8.2 vs. 19.6 vs 13.9%, p=0.085). There was no significant difference in mean time to first treated AR (64±55 vs 34±53 vs 60±113 days, p=0.419) or in the total number of BPAR episodes (10 vs. 24 vs. 17 p=0.112). Vascular involvement (grade IIA or IIB, Banff 97) was less frequent in G1 (0 vs. 29 vs. 52%, p=0.01) while the incidence of AR episodes requiring antithymocyte globulin treatment was not different (10 vs. 29 vs. 47%, p=0.07). There was no difference in the number of patients with recurrent AR episodes (3 vs. 4 vs. 3). Also, there were no differences in the number of graft losses (1 vs. 3 vs. 6) and patient death (3 vs. 3 vs. 4). The incidence of CMV infection was lower in EVR groups (4.7 vs. 7.8 vs. 35.6%, p<0.0001) with no differences in mean estimated GFR (64±24 vs. 58±23 vs. 66±29 ml/min, p=0.08 ml/min). Conclusions: In this cohort of patients receiving TAC, a single dose 3mg/kg antithymocyte globulin induction combined with reduced exposure TAC and EVR is associated with less severe AR and lower incidence of CMV infection compared to MPA.