CNI-based Immunosuppression Research Articles

Experience with belatacept rescue therapy in kidney transplant recipients.

In kidney transplant recipients with chronic graft dysfunction, long-term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy-nine kidney transplant recipients treated with CNI-based or mTORi-based maintenance immunosuppression who had CNI-induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26.1 ± 15.0 ml/min/1.73 m2 , increasing to 34.0 ± 15.2 ml/min/1.73 m2 at 12 months postconversion (P < 0.0005). Renal function improvements were also seen in patients with low eGFR (<25 ml/min/1.73 m2 ) or high proteinuria (>500 mg/l) at conversion. The Kaplan-Meier estimates for patient and graft survival at 12 months were 95.0% and 85.6%, respectively. The discontinuation rate due to adverse events was 7.9%. One case of post-transplant lymphoproliferative disorder occurred at 17 months postconversion. For comparison, a historical control group of 41 patients converted to mTORi-based immunosuppression because of biopsy-confirmed CNI-induced toxicity was examined; eGFR increased from 27.6 ± 7.2 ml/min/1.73 m2 at baseline to 31.1 ± 11.9 ml/min/1.73 m2 at 12 months (P = 0.018). Belatacept-based immunosuppression may be an alternative regimen for kidney transplant recipients with CNI- or mTORi-induced toxicity.

Should belatacept be the centrepiece of renal transplantation?

Belatacept was developed to minimize cardiovascular risk and nephrotoxicity associated with calcineurin inhibitor (CNI)-based immunosuppression. Recently, 7-year data from the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT), a phase III study comparing belatacept with cyclosporine, have been published. While during the first year of belatacept the risk of acute rejection episodes was elevated, this seemingly had marginal consequences for long-term graft survival and function as well as patient survival.For patients at a low-immunological risk, this drug seems to be a safe and effective alternative to CNI-based immunosuppression. Whether the higher rates of acute rejection episodes in the first year outweigh the gain in long-term graft function is still debated. In particular, the lower incidence of donor-specific antibodies indicates that belatacept should not be considered as lower intensity immunosuppression over the long term.Therefore, should belatacept be the centrepiece of immunosuppression for renal patients?All randomized trials so far have focussed on patients at a low immunological risk. Furthermore, cyclosporine A (CsA), the comparator of belatacept in BENEFIT and the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT), is not the CNI of choice in modern transplantation. Furthermore, while at Year 7 the rate of cancer and infections was comparable with the CsA group, long-term data are missing on safety issues for a large number of patients. Thus, currently belatacept may be the drug of choice for a select group of patients, but not for everyone.This review highlights the benefits and uncertainties of the use of belatacept in kidney transplantation.

Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study.

The 12-month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)-based immunosuppression to a CNI-free everolimus (EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data. PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids. Patients were randomized 1:1 to receive EVR or continue CNI. Patients completing the core study could enter the extension study on their randomized treatment. A total of 81 patients entered the extension study (41, EVR; 40, CNI). At M59 post-randomization, the adjusted mean eGFR was significantly higher in the EVR group, with a benefit of 12.4 mL/min using Cockcroft-Gault (95% CI: 1.2; 23.6; p = 0.0301). Also, there was a significant benefit for adjusted and unadjusted eGFR using the four-variable Modification of Diet in Renal Disease (MDRD4) or Nankivell formula. During the extension period, treatment failure rates were similar. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in EVR and CNI groups, respectively. Compared with the CNI-based treatment, EVR-based CNI-free immunosuppression resulted in significantly better renal function and comparable patient and graft outcomes after five-yr follow-up.

Nuclear Factor of Activated T Cells-Regulated Gene Expression as Predictive Biomarker of Personal Response to Calcineurin Inhibitors.

Calcineurin inhibitors (CNIs) represent the most widely used immunosuppressive agents in kidney transplantation. Both CNIs show a narrow therapeutic window; thus, monitoring is necessary to balance efficacy and toxicity. Several approaches have been undertaken to measure the biological effects of CNI-based immunosuppression. A quantitative analysis of gene expression was established to calculate the functional effects of calcineurin inhibition, the assessment of nuclear factor of activated T cells (NFAT)-regulated gene expression. This assay is based on the quantitative analysis of interleukin-2, interferon-γ, and granulocyte macrophage colony-stimulating factor gene expression in whole blood samples collected at the time cyclosporine A/tacrolimus troughs (C0) and 2 hours after oral uptake (C2). In this comprehensive review, analytical aspects of the assay and also clinical benefits and limitations are presented and discussed. Several observational studies underline the beneficial effect of NFAT-regulated gene expression as biomarker of personal response on CNI therapy, especially in infectious complications, malignancies, and acute rejection episodes. Data are more comprehensive in cyclosporine A compared with tacrolimus therapy. However, results on prospective interventional studies are sparse. A randomized controlled study evaluating the opportunity for NFAT-guided immunosuppression is ongoing. NFAT-regulated gene expression is a promising biomarker in CNI therapy concerning infectious complications, malignancies, and acute rejection. Prospective interventional studies and randomized controlled studies are ongoing to confirm the encouraging results.

Index of microvascular resistance after early conversion from calcineurin inhibitor to everolimus in heart transplantation: A sub-study to a 1-year randomized trial

Microvascular function in transplanted hearts can be evaluated by methods used in routine left heart catheterization follow-up after heart transplantation (HTx). This sub-study of a randomized study compared the effects of everolimus (EVR) and calcineurin inhibitor (CNI) treatment on microvascular function as expressed by the index of microvascular resistance (IMR) at 1 year after HTx. A secondary objective was to compare the change in IMR from 7-11 weeks to 1 year after HTx between randomized groups. There were 70 HTx recipients included and randomly assigned to combination therapy (EVR and CNI with early CNI withdrawal) vs conventional CNI treatment. Coronary physiologic assessment was performed 7-11 weeks and 1 year after HTx. A linear mixed model was used to assess the group difference at 1 year and the difference in IMR change between 7-11 weeks and 1 year after HTx. At 1 year, there was no significant difference in IMR between the EVR group (17.5 mm Hg∙sec ± 8.9) (mean ± SD) and the CNI group (14.9 mm Hg∙sec ± 6.6, p = 0.17). The difference in IMR change between the 2 treatment arms was 1.6 mm Hg∙sec (95% confidence interval, -2.8 to 5.9; p = 0.49). Spearman's rank correlation coefficient at 1 year after HTx between IMR and maximal intimal thickness as assessed with intravascular ultrasound in the left anterior descending artery was -0.13 (p = 0.28). In this prospective, open, randomized study comparing early CNI withdrawal with mammalian target of rapamycin inhibitors immunosuppression during the first year after HTx, early transition from CNI-based immunosuppression to EVR-based treatment did not result in differences in microvascular function as assessed by the IMR.

Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study.

The primary objective of this trial was to demonstrate, based on the estimated glomerular filtration rate (eGFR), superior renal function at month 12 after conversion of maintenance kidney transplant patients from calcineurin inhibitor (CNI) therapy to everolimus, compared to continuing a standard CNI regimen. APOLLO was an open-label, 12-month, prospective, multicenter study in which 93 maintenance kidney transplant patients were randomized to convert from CNI to everolimus (n = 46) or remain on standard CNI-based immunosuppression (n = 47). The primary efficacy variable was eGFR (Nankivell formula) 12 months after randomization. The study was terminated prematurely due to slow recruitment and was thus underpowered. Mean time post-transplant was 83.5 months with everolimus and 70.1 months with CNI. Adjusted values for eGFR (Nankivell) at month 12 were 61.6 (95% CI 58.1, 65.1) mL/ min/1.73 m² with everolimus and 58.8 (95% CI 55.2, 62.3) mL/min/1.73 m² with CNI, a difference of 2.8 (95% CI -1.0, 6.7) mL/ min/1.73 m² (p = 0.145) i.e., the primary objective was not met. Using the modification of diet in renal disease (MDRD) formula, adjusted eGFR at month 12 was significantly higher with everolimus (p = 0.030). In the subpopulation who remained on the study drug (n = 52), the difference in the adjusted change from randomization was 6.6 (95% CI 1.5, 11.6) mL/min/1.73 m² (p = 0.013) in favor of everolimus. There was no biopsyproven acute rejection and no graft losses. Adverse events led to discontinuation of everolimus and CNI in 32.6% and 10.6% of patients, respectively. Conversion from CNI to everolimus to preserve renal function can be considered several years after kidney transplantation and does not compromise immunosuppressive efficacy.

Renal Function Deterioration Is Higher Within The First Year After Liver Transplantation: Results of The Italian Cross-Sectional, Multicenter Study (SURF).

Background: Previous evidence suggests that renal function (RF) deterioration occurs early after liver transplantation (LT) when exposure to calcineurin inhibitors (CNI) is higher. Materials and methods: SURF was a cross-sectional, multicenter study to investigate the prevalence of renal dysfunction (eGFR <60mL/min/1.73m2) and the retrospectively recorded evolution of RF after transplantation in maintenance (5 months (M) to 5.5 years) recipients of a primary liver graft. Results: From March 2012 to June 2013 a sample of 1,002 evaluable patients were enrolled at a mean of 28.6±16.5 M from LT. From LT to inclusion, mean eGFR decreased from 95.7±36.9 mL/min/1.73m2 to 76.9±25.7 mL/min/1.73m2. Mean yearly eGFR deterioration was -12.3±32.2 mL/min/1.73m2 which resulted from a mean of -26.2±59 mL/min/1.73m2 within 1 year after LT (n=964); -13.3±24.4 mL/min/1.73m2 between 1 and 2 years (n=675); -8.5±15.5 mL/min/1.73m2 between 2 and 3 years (n=437); -5.7±9.6 mL/min/1.73m2 between 3 and 4 years (n=244 pts); and -3.9±8.2 mL/min/1.73m2 between 4 and 5.5 years (n=98). 91% patients were on CNI-based immunosuppression at inclusion (726 TAC; 187 CsA) (monotherapy 54%; combination 46%). Mean duration of CNI monotherapy was 23.16±17.62 M, and was 26.79±18.19 M for CNI in combination. Conclusions: LT recipients experience greater RF deterioration within the first post-transplant year, and the large majority are on CNI-based immunosuppression. These data call for preventative strategies early on after transplantation to slow down RF impairment. DISCLOSURES:De Simone, P.: Speaker's Bureau, Novartis, Astellas. Cillo, U.: Speaker's Bureau, Novartis. Burra, P.: Speaker's Bureau, Novartis. Donati, D.: Speaker's Bureau, Novartis. Brusa, R.: Employee, Novartis. Fagiuoli, S.: Speaker's Bureau, Novartis.

Ten Years Experience With Belatacept-Based Immunosuppression After Kidney Transplantation

BackgroundBelatacept was approved for prevention of acute rejection in adult kidney transplantation in 2011 based on two randomized, controlled, multicenter phase 3 studies. Long-term experience over 10 years with belatacept-based immunosuppression after kidney transplantation has not been reported before.Patients and MethodsAnalyzed were 20 patients who had been included into a randomized multicenter phase 2 study by our institution between March 2001 and November 2002. For 10-year follow-up, three different groups could be analyzed: 1) patients with primary calcineurin inhibitor-based (CNI-based) immunosuppression (n = 5), 2) patients with early switch from a belatacept-based to a CNI-based regimen within the first 14 months (n = 8) and 3) patients with completely CNI-free belatacept immunosuppression (n = 7).ResultsFifteen patients received primary belatacept-based immunosuppression and five patients primary cyclosporine A (CyA). Five patients are still on belatacept. Kidney function measured by serum creatinine levels worsened in the CNI group and the belatacept to CNI switch group during long-term follow-up whereas all patients receiving belatacept throughout follow-up showed stable creatinine values. Acute rejections occurred predominantly in the first 12 months after transplantation and were responsible for four of seven switches from belatacept- to CNI-based immunosuppression within the first 14 months. Five of the 20 patients died.ConclusionsBelatacept is effective and safe in renal transplant patients and was not associated with graft loss due to chronic allograft nephropathy. Belatacept was well tolerated in all patients and caused less nephrotoxic side effects and was well accepted in most patients.

Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates

The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation.

Deferred Pre-Emptive Switch from Calcineurin Inhibitor to Sirolimus Leads to Improvement in GFR and Expansion of T Regulatory Cell Population: A Randomized, Controlled Trial

BackgroundMeasures to prevent chronic calcineurin inhibitor (CNI) toxicity have included limiting exposure by switching to sirolimus (SIR). SIR may favorably influence T regulator cell (Treg) population. This randomized controlled trial compares the effect of switching from CNI to SIR on glomerular filtration rate (GFR) and Treg frequency.MethodsIn this prospective open label randomized trial, primary living donor kidney transplant recipients on CNI-based immunosuppression were randomized to continue CNI or switched to sirolimus 2 months after surgery; 29 were randomized to receive CNI and 31 to SIR. All patients received mycophenolate mofetil and steroids. The main outcome parameter was estimated GFR (eGFR) at 180 days. Treg population was estimated by flowcytometry.ResultsBaseline characteristics in the two groups were similar. Forty-eight patients completed the trial. At six months, patients in the SIR group had significantly higher eGFR as compared to those in the CNI group (88.94±11.78 vs 80.59±16.51 mL/min, p = 0.038). Patients on SIR had a 12 mL/min gain of eGFR of at the end of six months. Patients in the SIR group showed significant increase in Treg population at 30 days, which persisted till day 180. There was no difference in the adverse events in terms of number of acute rejection episodes, death, infections, proteinuria, lipid profile, blood pressure control and hematological parameters between the two groups. Four patients taking SIR developed enthesitis. No patient left the study or switched treatment because of adverse event.ConclusionsA deferred pre-emptive switch over from CNI to SIR safely improves renal function and Treg population at 6 months in living donor kidney transplant recipients.Registered in Clinical Trials Registry of India (CTRI/2011/091/000034)

Is Cytomegalovirus Prophylaxis Dispensable in Patients Receiving an mTOR Inhibitor–Based Immunosuppression? A Systematic Review and Meta-Analysis

Cytomegalovirus (CMV) is a common opportunistic infection after solid organ transplantation. Cytomegalovirus causes increased morbidity, mortality, and reduced allograft survival. Prophylaxis may help control the virus but is associated with substantial side effects and does not completely prevent virus reactivation; relapses after cessation of the prophylaxis are frequent. Experimental and clinical data suggest that mTOR inhibitors may have an anti-CMV effect. Here, we present a meta-analysis of clinical trials after solid organ transplantation and describe potential mechanisms involved in the anti-CMV effect of mTOR-inhibitors. The current literature was reviewed for randomized controlled trials in solid organ transplantation comparing an mTOR-I with a non-mTOR-I (CNI based) treatment. The scientific quality of the trials was assessed by the Jadad score, the use of an effective allocation concealment (AC) and the existence of an intention-to-treat (ITT) analysis. Cytomegalovirus incidence was assessed in studies comparing 1) an mTOR-I-based with a CNI-based immunosuppression (10 trials, n=3,100 patients) and 2) an mTOR-I/CNI combination therapy with a CNI-based immunosuppression (15 trials, n=7,100 patients). In the first meta-analysis, CMV events after solid organ transplantation occurred significantly more often under CNIs (RR=2.27). The second meta-analysis comparing the mTOR-I + CNI combination with a CNI treatment in 15 trials of kidney, heart, and liver transplantation showed again a higher CMV incidence when patients received an mTOR-I free immunosuppression (RR=2.45). mTOR-inhibitor treatment either alone or in combination with CNIs reduces significantly the CMV incidence after organ transplantation. With the use of an mTOR-inhibitor, CMV prophylaxis may be dispensible.

PP106. Risk of long term renal graft loss after pregnancy in renal transplant recipients immunosuppressed with calcineurin inhibitors

IntroductionIntron long-term graft function are uncertain. Although there have been a large number of successful pregnancies in renal graft recipients, the effects of pregnancy and type of immunosuppressant drugs. ObjectivesTo analyze (1) the impact of pregnancy on the long term renal function and graft survival of kidney transplant recipients (KTx), and (2) the impact og the pregnancy in (KTx) immunosupressed with calcineurin inhibitors (CNI). MethodsRetrospective analysis of two cohorts: one (PG) formed by all the KTx recipients from our institution that became pregnant between 1973 and 2004, and the other one (NPG) formed by, when possible, up two KTx patients of similar demographic and clinical characteristics: patient age, donor source, donor age, interval between KTx and pregnancy (or a matched interval for NPG), baseline renal function before pregnancy, hypertension, proteinuria >1g, and CNI-based immunosuppression. but without pregnancies. Particular attention has been paid to long-term (5 and 10years) renal function and graft survival. Males were selected to complete NPG if no matched women were available. Statistical analysisAssessment of baseline homogeneity between the two cohorts was performed by appropriate analysis. Time of survival of kidney was estimated by means Kaplan–Meier method and the Cox proportional hazard model was used to perform adjusted analysis. ResultsFifty five pregnancies in 43 patients (PG) and 68 paired controls (NPG) were included in the study. The basal and functional characteristics of PG before pregnancy and NPG were not statistical and clinical significantly different. In a univariate Cox regression analysis, 10 years graft survival after pregnancy/study entry was significantly better in CG (79.9%) than PG (60.9%) (P=0.02). Multivariate analysis of graft survival showed an increased risk of long-term graft loss in pregnant women that had been treated with CNI as immunosuppressant drug compared with NP KTx that received CNIs (HR: 2.4, 95% CI, 1.17–5.00; P=0.02). In a stratified analysis, evaluating separately the recipients that had received or not CNIs, the risk of graft loss was only increased among recipients that became pregnant post-transplantation treated with CNI compared with recipients that had received CNIs but had not become pregnant (HR: 3.3, 95% CI, 1.42–7.45; P=0.005), but not among recipients that became pregnant post-transplantation and received other immunosuppressant agents (HR: 0.9, 95% CI, 0.24–3.80; P=0.94). ConclusionPregnancy in women receiving baseline immunosuppression with CNI significantly increases the risk of long-term graft loss, non observed in KTx patients treated with CNI that not became pregnant, nor in KTx patients that became pregnant but are treated with other immunosuppressant drugs . At our knowledge, this observation has not been previously reported

Randomized Trial Comparing Late Concentration-Controlled Calcineurin Inhibitor or Mycophenolate Mofetil Withdrawal

Early calcineurin inhibitor (CNI) withdrawal with mycophenolate mofetil (MMF) has not become routine practice, due to concerns about excess acute rejection. Therapeutic drug monitoring may be advantageous when the CNI or MMF is withdrawn. This prospective, randomized, concentration-controlled withdrawal study enrolled 177 stable renal transplant recipients on maintenance CNI-based immunosuppression, combined with steroids and MMF. After the feasibility phase of the study, patients were randomized to MMF-withdrawal (target area under the time-concentration curve-cyclosporine: 3250 ng·hr/mL or tacrolimus: 120 ng·hr/mL) or CNI-withdrawal (target area under the time-concentration curve-mycophenolic acid: 75 μg·hr/mL). The estimated glomerular filtration rate (modification of diet in renal disease) remained significantly better after CNI elimination (59.5±2.1 mL/min vs. 51.1±2.1 mL/min, P = 0.006) up to 3 years and resulted in less functional decline, including the subgroup with an estimated glomerular filtration rate less than 50 mL/min at baseline (P = 0.03). At 6 months, one patient in the MMF-withdrawal group (1.3%) and three in the CNI-withdrawal group (3.8%) experienced acute rejection (P = 0.62). The defined higher mycophenolic acid exposure was well tolerated. These data indicate that with time the large majority of stable renal transplant recipients can be safely reduced to dual therapy with MMF or CNIs, applying concentration-controlled dosing. CNI-free patients, including those with moderate renal allograft dysfunction, have the benefit of improved renal function, whereas the risk of acute rejection after late withdrawal is low.

Lower Malignancy Rates in Renal Allograft Recipients Converted to Sirolimus-Based, Calcineurin Inhibitor-Free Immunotherapy: 24-Month Results From the CONVERT Trial

Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen. This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275). Patients with history of posttransplant lymphoproliferative disease or known/suspected malignancy within 5 years before screening were excluded. As part of standard safety measurements, subjects were monitored for any malignancy occurrence; both skin and nonskin malignancies were reported, even if the patient discontinued from the therapy. Malignancy rates were analyzed based on exposure time to study drugs (i.e., number of events per 100 person-years of follow-up). At 2 years postconversion, the total number of malignancies per 100 person-years of exposure was significantly lower among SRL conversion patients compared with CNI continuation (2.1 vs. 6.0, P<0.001). Patients undergoing SRL-based, CNI-free therapy had significantly lower rates of the subset of nonmelanoma skin carcinomas through 2 years postconversion (1.2 vs. 4.3, P<0.001). This difference persisted after excluding patients with a history of malignancy before randomization. The rate of all other malignancies was not significantly different between treatment groups (P=0.058). In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.

Basiliximab Induction and Delayed Calcineurin Inhibitor Initiation in Liver Transplant Recipients With Renal Insufficiency

Renal insufficiency (RI) is common after liver transplantation (LT) and may worsen due to calcineurin inhibitor (CNI) use. We compared LT outcomes using basiliximab induction and delayed CNI initiation to controls with a standard CNI regimen in patients with peri-LT RI. All adults transplanted January 2004 to December 2007 with peri-LT RI (hemodialysis or creatinine ≥1.5 within 1 week of LT) were included in a retrospective nonrandomized cohort. Outcomes including 30-day and 1-year patient and graft survival and renal function were compared between basiliximab and control groups. Two hundred twenty-nine patients (102 basiliximab, 127 controls) were analyzed, mean age 54 years, 72% men, 54% with hepatitis C virus. Mean model for end-stage liver disease (28.2 vs. 20.0; P<0.001) and creatinine (1.9 vs. 1.6; P=0.001) were higher and more patients were on hemodialysis at LT (29% vs. 6%; P<0.001) in the basiliximab group. 30-day patient (99% vs. 97%; P=0.26) and graft survival (98% vs. 95%; P=0.17), 1-year patient (87% vs. 87%; P=0.89) and graft survival (86% vs. 82%; P=0.37), mean creatinine at 1-year (1.5 vs. 1.5 mg/dL; P=0.82), and treated acute rejection (6% vs. 6%; P=0.90) were similar between basiliximab and control groups, respectively. In multivariable logistic regression, basiliximab was not significantly associated with 30-day (odds ratio, 0.10; P=0.11) or 1-year (odds ratio, 0.97; P=0.94) survival, controlling for age, previous LT, model for end-stage liver disease, and hepatitis C virus. Basiliximab induction resulted in 30-day and 1-year patient, graft and renal outcomes comparable with a control group receiving standard CNI-based immunosuppression. Antibody induction with delayed CNI should be further studied prospectively.

The effect of immunosuppressive treatment on arterial stiffness and matrix Gla protein levels in renal transplant recipients

Arterial stiffness is a risk marker for cardiovascular events. In this study we aimed to compare the effect on calcineurin inhibitors (CNI) and mammalian Target of Rapamycine inhibitors (mTORi) on arterial stiffness in renal transplant patients. 81 renal transplant patients under CNI-based or mTORi-based protocol for at least 6 months were included in the study. Arterial stiffness was measured by using the SphygmoCor device (AtCor Medical, Sydney, Australia). Vitamin K-dependent, calcification inhibitor matrix Gla protein (MGP) concentrations were quantified by ELISA methods (Biomedica, Vienna, Austria). 34 patients were on mTORi-based and 47 on CNI-based immunosuppression. Mean age was 37.9 ± 10.8 (18 - 71) years and 45% were female. Age, gender, graft functions and follow-up period of the groups were similar. Augmentation index was 15.2 ± 12.6% in CNI and 18.8 ± 14.0% in mTORi groups (p > 0.05). There was no difference regarding carotid-femoral pulse wave velocity between groups. Arterial stiffness was positively correlated with age, total cholesterol, LDL cholesterol, mean arterial pressure (MAP) and proteinuria. MGP levels were higher in the mTORi group but were not predictors for carotid-femoral pulse wave velocity. Rather than specific immunosuppressive drug effects, conventional risk factors, blood pressure and proteinuria are the most important predictors for arterial stiffness in renal transplant patients.

Two-Year Outcomes in Thoracic Transplant Recipients After Conversion to Everolimus With Reduced Calcineurin Inhibitor Within a Multicenter, Open-Label, Randomized Trial

Use of the mammalian target of rapamycin inhibitor everolimus with an accompanying reduction in calcineurin inhibitor (CNI) exposure has shown promise in preserving renal function in maintenance thoracic transplant patients, but robust, long-term data are required. In a prospective, open-label, multicenter study, thoracic transplant recipients more than or equal to 1 year posttransplant with mild-to-moderate renal insufficiency were randomized to continue their current CNI-based immunosuppression or convert to everolimus with predefined CNI exposure reduction. After a 12-month core trial, patients were followed up to month 24 after randomization. Of 245 patients who completed the month 12 visit, 235 patients (108 everolimus and 127 controls) entered the 12-month extension phase. At month 24, mean measured glomerular filtration rate had increased by 3.2±12.3 mL/min from the point of randomization in everolimus-treated patients and decreased by 2.4±9.0 mL/min in controls (P<0.001), a difference that was significant within both the heart and lung transplant subpopulations. During months 12 to 24, 5.6% of everolimus patients and 3.1% of controls experienced biopsy-proven acute rejection (P=0.76). There were no significant differences in the rate of adverse events or serious adverse events (including pneumonia) between groups during months 12 to 24. Converting maintenance thoracic transplant recipients to everolimus with low-exposure CNI results in a renal benefit that is sustained to 2 years postconversion, with significantly improved measured glomerular filtration rate in both heart and lung transplant patients. Despite reductions of more than 50% in CNI exposure, there was no marked loss of efficacy. The safety profile of the everolimus-based regimen was acceptable.

Calcineurin inhibitor sparing regimens using m-target of rapamycin inhibitors: an opportunity to improve cardiovascular risk following kidney transplantation?

Maintenance therapy with calcineurin inhibitors (CNIs) increases cardiovascular risk. Use of the m-TOR inhibitors everolimus or sirolimus to minimize CNI exposure is usually undertaken to preserve renal function following kidney transplantation, but may also improve cardiovascular risk status. Recent studies of early conversion from CNI to m-TOR inhibitors have shown a numerical improvement in the incidence of hypertension, but results are not clear-cut. Dyslipidaemia, in contrast, is more frequent under m-TORs than with CNI-based immunosuppression. New-onset diabetes is rare (≤ 5%) using modern m-TOR regimens, for example, everolimus and reduced-exposure CNI. Renal function improvement with m-TOR inhibitor regimens versus CNIs would also be expected to improve cardiovascular risk. Moreover, m-TOR-based CNI-minimization regimens are not associated with proteinuria, a known cardiovascular risk factor, with the possible exception of late conversion in patients with poor renal function. Interestingly, m-TOR inhibitors may also exert cardioprotective effects. Animal data suggest that m-TORs may restrict the pathogenesis of atherosclerosis, consistent with preliminary clinical data that conversion from CNIs to everolimus can stabilize markers for arterial stiffness. In conclusion, use of m-TORs has the potential to lessen the toll of cardiovascular disease following kidney transplantation - an opportunity that merits further exploration.

Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial

The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking. In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate > or =20 mL/min/1.73m and <90 mL/min/1.73 m) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction. Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and -0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02). Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.

Calcineurin inhibitor minimization in pediatric liver allograft recipients

The use of CNI in pediatric LTx has dramatically improved the outcome for children with end-stage liver disease by significantly reducing the rate of acute and chronic rejection. Long-term concerns about CNI-induced nephrotoxicity and other adverse effects remain an issue, particularly as the emphasis moves from short-term survival to long-term quality of life. This review summarizes lessons learnt from pediatric and adult solid organ transplantation in minimizing CNI use in immunosuppression protocols in children following LTx. There are three models for CNI minimization: dose reduction, withdrawal or avoidance, supplemented by the use of IL-2 receptor blocking antibodies in the peri-transplant period, and early transition to alternate drugs such as MMF or SRL. Prospective studies evaluating reduction or withdrawal protocols in adult and pediatric LTx indicate that rejection rates are comparable with traditional CNI-based immunosuppression and that two and five yr patient and graft survival are similar, with recovery in renal function. There are few studies evaluating complete avoidance of CNI, apart from that in renal transplantation, although the benefits of long-term reduction in cardiovascular, metabolic, and possibly neoplastic side effects may justify this approach. It is not clear yet how CNI minimization will affect the development of tolerance but experimental and preliminary clinical studies indicate that CNI and steroid avoidance or minimization in the peri-operative period may favor the development of long-term graft tolerance. In summary, CNI minimization may be safe and effective in the short term but large-scale pediatric randomized studies are required to evaluate the long-term efficacy of these regimes in the development of chronic rejection, PTLD, and graft tolerance.