Low-dose Calcineurin Inhibitors Research Articles

Programmed Cell Death 1 (PD-1) Inhibitors in Renal Transplant Patients with Advanced Cancer: A Double-Edged Sword?

Given advancements in cancer immunity, cancer treatment has gained breakthrough developments. Immune checkpoint inhibitors, such as programmed cell death 1 (PD-1) inhibitors, are the most promising drugs in the field and have been approved to treat various types of cancer, such as metastatic melanoma, head and neck squamous cell carcinoma, and urothelial carcinoma. However, whether PD-1 inhibitors should be administered to renal transplant patients with advanced cancer remains unclear because the T-cells produced after administration of these inhibitors act against not only tumor antigens but also donor alloantigens. Thus, the use of PD-1 inhibitors in kidney-transplanted patients with advanced cancer is limited on account of the high risk of graft failure due to acute rejection. Hence, finding optimal treatment regimens to enhance the tumor-specific T-cell response and decrease T-cell-mediated alloreactivity after administration of a PD-1 inhibitor is necessary. Thus far, no recommendations for the use of PD-1 inhibitors to treat cancer in renal transplant patients are yet available, and very few cases reporting kidney-transplanted patients treated with PD-1 inhibitors are available in the literature. Therefore, in this work, we review the published cases and suggest feasible approaches for renal transplant patients with advanced malignancy treated by a PD-1 inhibitor. Of the 22 cases we obtained, four patients maintained intact grafts without tumor progression after treatment with a PD-1 inhibitor. Among these patients, one maintained steroid dose before initiation of anti-PD1, two received immunosuppressive regimens with low-dose steroid and calcineurin inhibitor (CNI)-elimination with sirolimus before initiation of anti-PD-1 therapy, and one received combined anti-PD-1, anti-vascular endothelial growth factor (VEGF), and chemotherapy with unchanged immunosuppressive regimens. mammalian target of rapamycin (mTOR) inhibitors and anti-VEGF may act as regulators of tumor-specific and allogenic T-cells. However, more studies are necessary to explore the optimal therapy and ensure the safety and efficacy of PD-1 inhibitors in kidney-transplanted patients.

Brain metabolic alterations in patients with long-term calcineurin inhibitor therapy after liver transplantation.

Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism. To investigate CNI-related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long-term CNI treatment after liver transplantation. Eighty-two patients (19 CNI free, 34 CNI low-dose and 29 standard-dose CNI immunosuppression) 10years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents. The MRS results were correlated with psychometric data assessing cognitive function. Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low-dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209±0.012 vs 0.222±0.010; P<0.001) and a significant increase in PCr (0.344±0.026 vs 0.321±0.017; P<0.001) compared to controls. Myo-Inositol in the CNI free group (2.719±0.549 institutional unit [iu]) was significantly lower compared to controls (3.181±0.425 iu; P=0.02), patients on low-dose (3.130±0.513 iu; P<0.05) and standard-dose CNI therapy (3.207±0.632 iu; P<0.02). Glutamate and glutamine levels correlated negatively with cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status Total Scale: R=-0.362, P=0.029). Long-term CNI therapy after liver transplantation might be associated with alterations of brain metabolites.

Early Switch to Mammalian Target of Rapamycin Inhibitors Is a Sustainable Treatment Approach in Renal Transplant Recipients: 7-Year Results

ObjectiveThe aim of this study was to investigate the safety and sustainability of mammalian target of rapamycin inhibitor (m-TORi)-based treatment protocols in renal transplant patients. MethodsWe retrospectively evaluated a total of 206 patients who were switched to low-dose calcineurin inhibitors (CNI) + m-TORi or mycophenolate mofetil (MMF) + m-TORi treatment protocols in the first 3 months of renal transplantation between January 2010 and August 2011 in our center. Demographic and laboratory features of the patients were recorded. ResultsOf the patients included in the study, 89 (43.2%) were female and 117 (56.8%) were male. The mean age was 41.9 ± 13.8 years. Panel reactive antibody was negative in 95% of the recipients. One hundred thirty-four (65%) patients received anti-thymocyte globulin induction therapy. Initially, 108 patients were treated with cyclosporine and 98 (47.6%) were treated with tacrolimus-based regimens. One hundred thirty-five patients (65.5%) were switched to low-dose CNI + m-TORi and 71 patients (34.5%) were switched to MMF + m-TORi. The mean switching time was 3 months. At the end of the study, 161 patients (78.2%) were still continuing the m-TORi treatment protocol and 45 patients (21.8%) could not continue for various reasons (11.4% proteinuria, 5.5% edema, 2.9% acute rejection, 1% acne + oral aphthae, 1% neuropathy). The biopsy-proven acute rejection rate was 4.5% (n = 9). The mean duration of sustainability of m-TORi treatment protocol was 84.15 ± 6.79 months. Mean serum creatinine of patients who were still continuing m-TORi was 1.42 ± 1.09 mg/dL. ConclusionSwitching to m-TORi in the early posttransplant period is a safe and sustainable treatment approach.

Dual antibody induction and de novo use of everolimus enable low-dose tacrolimus with early corticosteroid withdrawal in simultaneous pancreas-kidney transplantation

BackgroundTo be an optimal immunosuppressive regimen after simultaneous pancreas kidney transplantation (SPK), low dose calcineurin inhibitor and early withdrawal of corticosteroids are desired. MethodsImmunosuppressive regimen as such has been conducted consecutively in SPK recipients since 2009 in authors' institute. In addition to tacrolimus in low trough level and early corticosteroid withdraw, dual induction with basiliximab and low-dose thymoglobulin in combination with everolimus are the important components of the protocol. Results25 consecutive primary SPK recipients were included in the study. Lymphocyte depletion by low dose thymoglobulin was limited to two weeks, and CD25 coating with basiliximab was detectable for 4 weeks. The BPAR within the first 12 months was 13%. During a median follow-up of 58 months, new-onset diabetes mellitus and renal function deterioration were rare events. No cytomegalovirus activation was encountered. The patients, pancreas and kidney graft survival at 1-year and 5-year was 100% and 94.4%, 95.8% and 95.8%, 100% and 100% respectively.

Efficacy and safety of everolimus plus low-dose calcineurin inhibitor vs. mycophenolate mofetil plus standard-dose calcineurin inhibitor in renal transplant recipients: A systematic review and meta-analysis .

To seek an optimized immunotherapy which can preserve renal function while maintaining low acute rejection rates, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of everolimus (EVR) plus low-dose calcineurin inhibitor (CNI) vs. mycophenolate mofetil (MMF) plus standard-dose CNI regimen after kidney transplantation (KT). We searched for RCTs comparing the outcomes of EVR plus low-dose CNI and MMF plus standard-dose CNI regimen after KT and identified eligible RCTs according to strict inclusion and exclusion criteria. Two authors independently assessed the quality of included studies and performed a meta-analysis using RevMan5.3. Eleven RCTs with 850 renal transplant recipients were included. This meta-analysis showed that EVR plus low-dose CNI regimen was associated with comparable renal function (standardized mean difference (SMD) 0.16, 95% CI (-0.03, 0.35), p=0.09) and a similar rate of acute rejection (risk ratio (RR) 1.16, 95% CI (0.96, 1.42), p=0.13), graft loss (RR 0.89, 95% CI (0.63, 1.24), p=0.49) and mortality (RR 1.19, 95% CI (0.69, 2.08), p=0.53) compared to MMF plus standard-dose CNI regimen. In addition, EVR plus low-dose CNI regimen could reduce the rate of cytomegalovirus and infection, whereas a lower rate of other adverse events were noted in MMF plus standard-dose CNI regimen. EVR plus low-dose CNI regimen was similar in efficacy and safety to MMF plus standard-dose CNI regimen after KT. However, this should be confirmed by further studies. .

Effect of Early Immunosuppression Therapy on De Novo Anti–Human-Leukocyte-Antigen Antibody After Kidney Transplantation

The aim of the study was to investigate the effect of immunosuppression therapy early after kidney transplantation, particularly exposure of mycophenolic acid (MPA) and calcineurin inhibitor (CNI), on posttransplantation de novo HLA antibody production. MethodsA single-center retrospective cohort study was performed at the First Affiliated Hospital of Sun Yat-sen University, enrolling the kidney transplant or pancreas-kidney transplant recipients who had surgery between January 2010 and February 2016. ResultsA total of 214 recipients were included in the study with a median follow-up period of 1.06 years. A total of 30 recipients (14.0%) were positive in HLA antibody detection posttransplant with a median follow-up period of 1.46 years. Ten recipients (4.7%) lost their allograft function during follow-up, and 6 of them (60%) developed de novo HLA antibody after graft failure. Multivariate analysis showed that acute rejection significantly increased the risk of de novo HLA antibody (hazard ratio [HR], 2.732). Intensified MPA dosing therapy reduced the risk by 59.8% (HR, 0.402); low-dose CNI therapy increased the risk by 33.3% (HR, 1.333), and the effect of extremely low-dose CNI therapy was even larger (HR, 2.242). ConclusionThe risk of de novo HLA antibody can be decreased by reducing the risk of acute rejection. A tendency was seen in low-dose CNI therapy to increase the risk of de novo HLA antibody, but intensified MPA dosing therapy may provide an umbrella protection effect by reducing the risk. Prospective study was required to confirm the effects.

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients.

Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients.

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

The objective of this review is to explore the available literature on solid renal masses (SRMs) in transplant allograft kidneys to better understand the epidemiology and management of these tumors. A literature review using PubMed was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. Fifty-six relevant studies were identified from 1988 to 2015. A total of 174 SRMs in 163 patients were identified, with a mean tumor size of 2.75 cm (range 0.5-9.0 cm). Tumor histology was available for 164 (94.3%) tumors: clear cell renal cell carcinoma (RCC; 45.7%), papillary RCC (42.1%), chromophobe RCC (3%), and others (9.1%). Tumors were managed by partial nephrectomy (67.5%), radical nephrectomy (19.4%), percutaneous radiofrequency ablation (10.4%), and percutaneous cryoablation (2.4%). Of the 131 patients (80.3%) who underwent nephron-sparing interventions, 10 (7.6%) returned to dialysis and eight (6.1%) developed tumor recurrence over a mean follow-up of 2.85 years. Of the 110 patients (67.5%) who underwent partial nephrectomy, 3.6% developed a local recurrence during a mean follow-up of 3.12 years. The current management of SRMs in allograft kidneys mirrors management in the nontransplant population, with notable findings including an increased rate of papillary RCC and similar recurrence rates after partial nephrectomy in the transplant population despite complex surgical anatomy.

Neurotoxic Side Effects of Calcineurin Inhibitors in Patients After Liver Transplantation: Preliminary Results of a Quantitative MRI Study of the Brain

Background: Calcineurin inhibitors (CNI) are the most often used immunosuppressive drugs for the prevention of graft rejection after liver transplantation (LT). Long-term CNI treatment, however, is associated with cardiovascular disease and renal dysfunction. Considering the high frequency of neurotoxic side effects during the first weeks after treatment onset, long-term effects upon brain tissue structure and brain function must be expected. Aiming to estimate the long-term influence of CNI on cerebral microstructure and function after LT we carried out this quantitative MR study. Methods: Ninety patients (mean age: 58 ± 8) with a history of at least 3 years after liver transplantation were studied. They were divided into three groups according to their medication of the last two years: 23 patients without CNI, 36 patients with reduced dose of CNI (stable tacrolimus blood trough levels below 5 μg/l or stable cyclosporine A blood trough levels below 50 μg/l) and 31 patients with standard dose of CNI. Four patients were excluded due to incomplete examinations or artefacts. Thirty-two healthy gender- and age-adjusted volunteers served as reference group. All subjects underwent neuropsychological testing with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and MR examinations at 3 T (Verio, Siemens, Erlangen). The MR protocol included a T1 weighted GRE with 2 flip angles, a T2 weighted TSE with three echoes, a T2* weighted GRE with triple TE. Quantitative T1, relative proton density (PD, in ratio to water phantom), T2 and T2* maps were obtained on-the-fly on the MR system with an extended image reconstruction provided by the manufacturer, using monoexponential fitting to the signal intensity decay curves of the T1 GRE, T2 TSE and T2 GRE sequences, respectively, for region of interest (ROI) measurements, which were made in 18 ROIs located in cerebellum, brainstem, and cerebral gray and white matter. One-way ANOVA with Bonferroni corrected post hoc tests (α = 0.05) were used to compare the qMRI data and Kruskal–Wallis test to compare the RBANS scores between groups. Results: RBANS scores revealed that patients receiving CNI owned a significantly worse visuospatial/constructional ability, and patients with low dose CNI an overall impaired cognitive function compared to controls. qMRI revealed significant microstructural changes, especially in frontal white matter, with higher PD and T2 (CNI free) and higher T2* (CNI free and low dose), indicating increased free water (PD and T2) and reduced metabolism (T2*) within brain tissue of these patients compared to controls. Interestingly, little change has been found in patients with standard CNI dose, indicating probably different phenotypes between patients, by considering that the CNI dose was applied depending on patients’ tolerability to CNI medication. Conclusion: These preliminary results showed that long term medication with CNI affects tissue microstructure in human brain and the brain function after liver transplantation (Figure 1). The authors have none to declare.

Acute Graft-vs-Host Disease After Liver Transplantation: Experience at a High-volume Liver Transplantation Center in Korea

BackgroundAcute graft-vs-host disease (GVHD) is a rare but life-threatening complication of orthotopic liver transplantation (OLT). We present 6 cases of GVHD after OLT. MethodsAmong our 4294 OLT recipients, we identified 6 patients (0.14%) who were diagnosed with GVHD. Their medical records were reviewed retrospectively. ResultsLiver graft types included deceased donor whole liver graft (n = 3) and right liver graft from son (n = 3). Mean recipient and donor ages were 57.2 ± 6.6 years and 32.7 ± 10.8 years, respectively. Onset of GVHD symptoms occurred 14 to 32 days after OLT, and initial symptoms were skin rash (n = 5) and fever (n = 1). GVHD was pathologically confirmed by skin or rectal biopsy. Chimerism of donor lymphocytes was identified in all 3 patients who underwent the short tandem repeat polymerase chain reaction assay. Attempts were made to treat the GVHD in all 6 patients by corticosteroids with or without low-dose calcineurin inhibitor, but we had to stop early or reduce these agents due to aggravation of pancytopenia and septic complications. Ultimately, 5 patients died 6 to 106 days after the onset of GVHD, and only 1 patient recovered. This surviving patient was diagnosed earlier and had been administered the recommended dosage of corticosteroid for a longer period with aggressive infection prophylaxis compared to the other cases. ConclusionsBecause of very poor outcomes of GVHD after OLT, early diagnosis and vigorous treatment should be emphasized, although no effective treatment modality has been established yet. We strongly suggest performing aggressive infection prophylaxis during GVHD treatment.

The efficacy and safety of intensified enteric-coated mycophenolate sodium with low exposure of calcineurin inhibitors in Chinese de novo kidney transplant recipients: a prospective study.

The aim of this study was to investigate the efficacy and safety of a transient intensified enteric-coated mycophenolate sodium (EC-MPS) dosing regimen with low exposure of calcineurin inhibitors (CNIs) in Chinese de novo kidney transplantation. In a 6-month prospective study, a total of 97 recipients were enrolled and assigned to either an intensified EC-MPS dosing (IS) regimen or a standard EC-MPS dosing (SD) regimen. The area under the curve (AUC) of MPA was assessed at week 1 post transplant. The incidences of acute rejection, patient and graft survival, renal allograft function and adverse events were analysed. The IS regimen displayed a trend of acute rejection risk reduction (IS 2.7% vs. SD 13.3%, p=0.061) and allograft function improvement (IS 62.8±14.0ml/min per 1.73m(2) vs. SD 56.6±18.3ml/min per 1.73m(2) , p=0.084) after 6-month follow-up. MPA-AUC0-12h was substantially higher in the intensified EC-MPS group than the standard EC-MPS group, though without a significant difference (71.4±41.7 vs. 53.0±27.0mg·h/l, p=0.107). The IS regimen did not increase the incidence of adverse effects (IS 54.1% vs. 45.0%, p=0.39), including diarrhoea or leucopenia. The intensified EC-MPS dosing regimen maintaining low-dose CNIs in this study may be beneficial for Chinese adult de novo kidney transplant recipients in terms of acute rejection and allograft function and is safe within 6months post transplant.

Early Initiation of Everolimus After Liver Transplantation: A Single-Center Experience.

Evidence relating to early everolimus use after liver transplantation remains limited. Ninety-one adult patients undergoing liver transplantation at our center during 2007-2012 in whom everolimus therapy was initiated <3 months post-transplant were analyzed retrospectively. Everolimus was started on days 1-5 in 50 patients (group 1) and after day 5 in 41 patients (group 2). Most patients continued to receive low-dose cyclosporine (59.3%, target 50-80 ng/ml) or low-dose tacrolimus (25.3%; target 3-5 ng/ml). Mean follow-up was 4.6 years. One-, three- and five-year patient survival rates were 80.5%, 74.2%, and 70.5%, respectively, and did not differ between groups 1 and 2. Six patients (6.6%) developed biopsy-proven acute rejection after a median of 47 days (range 27-356 days). Everolimus was discontinued due to adverse events in 21 patients (23.1%). Incisional hernia repair occurred in 14.0% and 9.4% of patients in group 1 and 2, respectively. Renal function remained stable during follow-up, despite poor baseline function. Everolimus with very low-dose calcineurin inhibitor given immediately after liver transplantation appears safe and effective, achieving a low rejection rate with well-preserved renal function.

Sirolimus-Based Immunosuppressive Regimens in Renal Transplantation: A Systemic Review

Sirolimus (SRL)-based immunosuppressive regimens have been used for preventing rejection after kidney transplantation. This review analyzes their merits and demerits compared with other conventional regimes from the aspects of acute rejection rate, graft function, as well as patient/graft survival rates. In general, SRL is mostly recommended to be used as conversion therapy from calcineurin inhibitor (CNI) after kidney transplantation in most studies. Minimization or withdrawal of cyclosporine A (CsA) could also be considered when it was combined with SRL. SRL can replace mycophenolate mofetil (MMF), and the CNI dose should be reduced appropriately in this setting. Quadruple maintenance regimens containing SRL need future study to clarify their superiority. De novo use of low-dose CNI combined with SRL has no apparent merits and thus is not recommended. De novo use of standard-dose CNI combined with SRL followed by maintenance, de novo use of CNI-free regimens, as well as SRL use in delayed graft function (DGF) patients who spare antibody induction and postpone CNI administration should also be avoided. SRL supports steroids withdrawal after kidney transplantation, and SRL combined with tacrolimus is recommended in this setting. Loading dose is recommended when initiating SRL treatment and its trough blood level should be routinely monitored.

Place of mTOR inhibitors in management of BKV infection after kidney transplantation.

Context: BK virus (BKV) viremia and BKV-associated nephropathy (BKVAN) have become a serious nuisance to kidney transplant (KT) patients since the mid-nineties, when the incidence of this disease has increased significantly. Evidence Acquisition: Directory of open access journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science have been searched. Results: Many hypothesis have been made as to why this phenomenon has developed; it is of general opinion that a more potent immunosuppression is at the core of the problem. The use of the association of tacrolimus (TAC) with mycophenolic acid (MPA) has gained momentum in the same years as the increase in BKV viremia incidence making it seem to be the most likely culprit. m-TOR inhibitors (m-TORIs) have been shown to have antiviral properties in vitro and this fact has encouraged different transplant teams to use these agents when confronted with BKV infection (viremia or nephropathy). However, the results are mitigated. There had been conflicting results for example when converting from TAC-to sirolimus-based immunosuppression in the setting of established BKVAN. Conclusions: In order to prevent BKV infection we have to minimize to some extent immunosuppression, but it is not always possible, e.g. in high immunological risk patients. Conversely, we could use m-TORIs associated with low-dose calcineurin inhibitors (CNIs). This could be actually the key to a safe immunosuppression regimen both from the immunological stand point and from the viral one.

Suppressive effects of conversion from mycophenolate mofetil to everolimus for the development of cardiac allograft vasculopathy in maintenance of heart transplant recipients

BackgroundWhether converting to everolimus (EVL) from mycophenolate mofetil (MMF) during the maintenance period after heart transplantation (HTx) reduces cardiac allograft vasculopathy (CAV) progression remains unclear. We sought to determine the effect of converting from MMF with standard-dose calcineurin inhibitors (CNIs) to EVL with low-dose CNIs on CAV progression. MethodsWe retrospectively reviewed the medical records of 63 HTx recipients who survived at least at 1year after HTx. Twenty-four recipients were converted from MMF to EVL (EVL group, 2.2±2.3years after HTx), while 39 recipients were maintained on MMF (MMF group, 2.4±2.2years after HTx). The EVL group underwent three-dimensional intravascular ultrasound (3D-IVUS) analysis before and 1year after conversion to EVL, and these data were compared with data from 2 consecutive IVUS in the MMF group. ResultsIVUS indices in the EVL group at 1year after conversion did not show increased CAV development, whereas a significant increase in %plaque volume (p=0.006) and decrease in lumen volume (p<0.001) were observed in the MMF group. EVL conversion was significantly associated with smaller increases in %plaque volume (p=0.004) and smaller decreases in lumen volume (p=0.017). IVUS indices in the late EVL conversion group (≥2years) also did not exhibit increased CAV development, while those in the MMF group did. ConclusionsConversion to EVL from MMF in maintenance periods after HTx may decrease the rate of CAV progression based on IVUS indices.

De novo mTOR inhibitor-based immunosuppression in ABO-incompatible kidney transplantation.

ABO-incompatible (ABOi) kidney transplantation (KTx) has become an accepted therapeutic option in renal replacement therapy for patients without a blood group-compatible living donor. Using different desensitization strategies, most centers apply B-cell depletion with rituximab and maintenance immunosuppression (IS) with tacrolimus and mycophenolic acid. This high load of total IS leads to an increased rate of surgical complications and virus infections in ABOi patients. Our aim was to establish ABOi KTx using an immunosuppressive regimen, which is effective in preventing acute rejection without increasing the risk for viral infections. Therefore, we selected a de novo immunosuppressive protocol with low-dose calcineurin inhibitor and the mTOR inhibitor everolimus for our ABOi program. Here, we report the first 25 patients with a complete three-yr follow-up treated with this regimen. Three-yr patient survival and graft survival were 96% and 83%. The rate of acute T-cell-mediated rejections was low (12%). Cytomegalovirus (CMV) infection was evident in one patient only (4%). Surgical complications were common (40%), but mild in 80% of cases. We demonstrate that ABOi KTx with a de novo mTOR inhibitor-based regimen is feasible without severe surgical or immunological complications and a low rate of viral infections.

Everolimus in de novo liver transplant recipients: a systematic review

Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients. Randomized controlled trials comparing everolimus for de novo liver transplant in PubMed, the Cochrane Library, and ScienceDirect published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval (95% CI) for renal function, relative risk (RR) and 95% CI for treated biopsy-proven acute rejection (tBPAR), graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with RevMan version 5.10. A total of four randomized controlled trials covering 1119 cases were included. The meta-analyses revealed that compared with standard exposure of calcineurin inhibitors (CNIs), everolimus combined with reduced CNIs improved creatinine clearance (calculated with the Cockcroft-Gault formula) by 5.13 mL/min at one year (95% CI: 0.42-9.84; P=0.03), and decreased tBPAR (RR: 0.56; 95% CI: 0.35-0.90; P=0.02). Everolimus initiation with CNIs elimination improved glomerular filtration rate (GFR, measured with the modification of diet in renal disease formula) of 10.42 mL/min/1.73 m2 (95% CI: 3.44-17.41; P<0.01) one year after treatment, but increased tBPAR (RR: 1.71; 95% CI: 1.15-2.53; P<0.01). Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant (RR: 0.60; 95% CI: 0.34-1.03; P=0.06), but was associated with greater risk of adverse events which resulted in drug discontinuation (RR: 1.98; 95% CI: 1.49-2.64; P<0.01). Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of tBPAR one year after liver transplant, but everolimus administered without CNIs increases tBPAR.

Immunosuppressive minimization with mTOR inhibitors and belatacept.

Immunosuppressive therapy after kidney transplantation consists of a calcineurin inhibitor (CNI)-based therapy in combination with mycophenolic acid and steroids in most cases. In spite of low acute rejection rates and excellent graft survival, it is associated with major long-term complications, such as cardiovascular events, malignancy, and nephrotoxicity, and does not favor tolerogenic processes. Mammalian target of rapamycin (mTOR) inhibitors in combination with low-dose CNI offer good rejection rates and acceptable allograft function; however, de novo mTOR inhitibor-based treatment in combination with mycophenolate is not widely used due to higher acute rejection rates. Early conversion from a CNI to an mTOR inhibitor is a feasible option in selected patients with a slightly higher acute rejection rate, but equal or better GFR. Costimulation blockade has been proven to facilitate antirejection prophylaxis without CNI-associated side effects. So far, belatacept has been approved in combination with mycophenolate and steroids with better graft function, however, a slightly higher acute rejection rate. Recently, the combination of an mTOR inhibitor and belatacept with lymphocyte-depleting antibody induction and without maintenance steroids has been explored in two pilot studies with very low acute rejection rates, very good graft function, and an acceptable side effect profile.

Everolimus Associated With Low-Dose Calcineurin Inhibitors, an Option in Kidney Transplant Recipients of Very Old Donors

BackgroundDespite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010. MethodsAssociated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group. ResultsThere were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36–49 mL/min and 51–55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty-nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively. ConclusionsInduction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED.

Abstract 11167: Effects of Conversion to Everolimus With Low-Dose Calcineurin Inhibitors From Mycophenolate Mofetil on Cardiac Allograft Vasculopathy in Maintenance Heart Transplant Recipient: Serial Three-Dimensional Intravascular Ultrasound Analysis at 2 Years

Introduction: Everolimus (EVL) has been shown to reduce the severity of CAV in de novo heart transplant (HTx) recipients. However, there is still little knowledge about the effects of conversion from mycophenolate mofetil (MMF) to EVL with reducing calcineurin inhibitor (CNI) dose on cardiac allograft vasculopathy (CAV) in maintenance HTx recipients. To evaluate this hypothesis, we performed a retrospective study. Methods: We examined 63 consecutive HTx recipients who were investigated with three-dimensional intravascular ultrasound (3D-IVUS) analysis every year. 24 recipients were converted to EVL with low-dose CNI from MMF with standard-dose CNI (EVL group) while the others maintained on MMF with standard-dose CNI (MMF group). 3D-IVUS analyses in a year after conversions to EVL with low-dose CNI was compared with those just before the conversions in EVL group, while recent two 3D-IVUS analyses at one year interval were compared in the control group. Results: At the former analyses, plaque volume (PVI) and %plaque volume (%PVI, PVI/vessel volume percent) were significantly greater and lumen volume (LVI) was smaller in the EVL group in comparison with those in the MMF group. %PVI increased (10.37±7.53 versus 12.95±9.83, P=0.008) and LVI (10.57±2.63 versus 9.52±2.42 mm 3 /mm, P&lt;0.001) reduced significantly in the control group but not in the EVL group. The increase in %PVI during one year was suppressed and the decrease in LVI preserved in the EVL group compared with the control group (2.60±0.92 vs -0.66±1.14 %, p=0.031, -1.05±0.26 vs 0.05±0.19 mm 3 /mm, p=0.007, respectively). These effects were sustained at 2 years (p=0.042 and p=0.005). Conclusions: Compared with persistent MMF therapy, EVL conversion with low-dose CNI significantly reduce the severity of luminal narrowing in maintenance HTx recipients.