CNI-based Immunosuppression Research Articles

Long-Term Outcome after Early Mammalian Target of Rapamycin Inhibitor-Based Immunosuppression in Kidney Transplant Recipients.

Background: The use of mammalian target of rapamycin inhibitors (mTORis) in kidney transplantation increases the risk of donor-specific human leukocyte antigen (HLA) antibody formation and rejection. Here, we investigated the long-term consequences of early mTORi treatment compared to calcineurin inhibitor (CNI) treatment. Methods: In this retrospective single-center analysis, key outcome parameters were compared between patients participating in randomized controlled immunosuppression trials between 1998 and 2011, with complete follow-up until 2018. The outcomes of eligible patients on a CNI-based regimen (n = 384) were compared with those of patients randomized to a CNI-free mTORi-based regimen (n = 81) and 76 patients randomized to a combination of CNI and mTORi treatments. All data were analyzed according to the intention-to-treat (ITT) principle. Results: Deviation from randomized immunosuppression for clinical reasons occurred significantly more often and much earlier in both mTORi-containing regimens than in the CNI treatment. Overall patient survival, graft survival, and death-censored graft survival did not differ between the treatment groups. Donor-specific HLA antibody formation and BPARs were significantly more common in both mTORi regimens than in the CNI-based immunosuppression. Conclusions: The tolerability and efficacy of the mTORi treatment in kidney graft recipients are inferior to those of CNI-based immunosuppression, while the long-term patient and graft survival rates were similar.

Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits.

Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.

Rescue Everolimus Post Lung Transplantation is Not Associated With an Increased Incidence of CLAD or CLAD-Related Mortality.

Everolimus (EVE) has been used as a calcineurin inhibitor (CNI) minimization/ elimination agent or to augment immunosuppression in lung transplant recipients (LTR) with CNI-induced nephrotoxicity or neurotoxicity. The long-term evidence for survival and progression to chronic lung allograft dysfunction (CLAD) is lacking. The primary aim was to compare survival outcomes of LTR starting EVE-based immunosuppression with those remaining on CNI-based regimens. The secondary outcomes being time to CLAD, incidence of CLAD and the emergence of obstructive (BOS) or restrictive (RAS) phenotypes. Single center retrospective study of 91 LTR starting EVE-based immunosuppression matched 1:1 with LTR remaining on CNI-based immunosuppression. On multivariate analysis, compared to those remaining on CNI-based immunosuppression, starting EVE was not associated with poorer survival [HR 1.04, 95% CI: 0.67-1.61, p = 0.853], or a statistically significant faster time to CLAD [HR 1.34, 95% CI: 0.87-2.04, p = 0.182]. There was no difference in the emergence of CLAD (EVE, [n = 57, 62.6%] vs. CNI-based [n = 52, 57.1%], p = 0.41), or the incidence of BOS (p = 0.60) or RAS (p = 0.16) between the two groups. Introduction of EVE-based immunosuppression does not increase the risk of death or accelerate the progression to CLAD compared to CNI-based immunosuppression.

Targeting Calcineurin Inhibitor-Induced Arterial Hypertension in Liver Transplanted Children Using Hydrochlorothiazide.

Arterial hypertension (AH) is the most common toxic effect of calcineurin inhibitor (CNI)-based immunosuppression in children after liver transplantation (LT). Activation of the renal sodium chloride cotransporter (NCC) by CNIs has been described as a major cause of CNI-induced AH. Thiazides, for example, hydrochlorothiazide (HCTZ), can selectively block the NCC and may ameliorate CNI-induced AH after pediatric LT. From 2005 thru 2015 we conducted a retrospective, single-center analysis of blood pressure in 2 pediatric cohorts (each n = 33) with or without HCTZ in their first year after LT. All patients received CNI-based immunosuppression. According to AAP guidelines, AH was defined as stage 1 and stage 2. Cohort 1 received an HCTZ-containing regimen to target the CNI-induced effect on the NCC, leading to AH. Cohort 2 received standard antihypertensive therapy without HCTZ. In children who have undergone LT and been treated with CNI, AH overall was observed less frequently in cohort 1 vs cohort 2 (31% vs 44%; ns). Moreover, severe AH (stage 2) was significantly lower in cohort 1 vs 2 (1% vs 18%; p < 0.001). Multivariate analysis revealed HCTZ as the only significant factor with a protective effect on occurrence of severe stage 2 AH. While monitoring safety and tolerability, mild asymptomatic hypokalemia was the only adverse effect observed more frequently in cohort 1 vs 2 (27% vs 3%; p = 0.013). Targeting NCC by HCTZ significantly improved control of severe CNI-induced AH and was well tolerated in children who underwent LT. This effect may reduce the risk of long-term end-organ damage and improve quality of life.

Humoral response to SARS-CoV-2 is well preserved and symptom dependent in kidney transplant recipients

Data on the immune response to SARS-CoV-2 in kidney transplant recipients are scarce. Thus, we conducted a single-center observational study to assess the anti-SARS-CoV-2 IgG seroprevalence in outpatient kidney transplant recipients (KTR; n=1037) and healthcare workers (HCW; n=512) during the second wave of the COVID-19 pandemic in fall 2020 and evaluated the clinical variables affecting antibody levels. Antibodies against S1 and S2 subunit of SARS-CoV-2 were evaluated using immunochemiluminescent assay (cut off 9.5AU/ml, sensitivity of 91.2% and specificity of 90.2%). Anti-SARS-CoV-2 IgG seroprevalence was lower in KTR than in HCW (7% vs. 11.9%, p=.001). Kidney transplant recipients with SARS-CoV-2 infection were younger (p=.001) and received CNI-based immunosuppression more frequently (p=.029) than seronegative KTR. Anti-SARS-CoV-2 IgG positive symptomatic KTR had a higher BMI (p=.04) than asymptomatic KTR. Interestingly, anti-SARS-CoV-2 IgG levels were higher in KTR than in HCW (median 31AU/ml, IQR 17-84 vs. median 15AU/ml, IQR 11-39, p<.001). The presence of moderate to severe symptoms in KTR was found to be the only independent factor affecting IgG levels (Beta coefficient = 41.99, 95% CI 9.92-74.06, p = .011) in the multivariable model. In conclusion, KTR exhibit a well-preserved symptom-dependent humoral response to SARS-CoV-2 infection.

Time-dependent blood eosinophilia count increases the risk of kidney allograft rejection.

BackgroundGrowing evidence suggest that type 2 immune effectors play a role in solid organ transplantation. The aim of this study was to evaluate the impact of blood count eosinophils (BCEo) on immunological outcomes in kidney transplant recipients with stable graft function after 3 months post-transplant.MethodWe performed cause-specific Cox model considering BCEo, the use of calcineurin inhibitors and systemic corticoids as time-dependent explicative variables on a prospective cohort of 1013 kidney transplant patients who experienced kidney allograft rejection and/or the appearance of de novo donor specific antibodies after excluding common causes of increased BCEo..FindingsBCEo ≥ 0.3 G/L was associated with a 3-fold increased risk of rejection independent of immunosuppressive regimen after 3 months post-transplant in patients without pre-transplant DSAs and with CNI-based immunosuppression. No association between BCEo either with donor specific antibodies or graft survival was noticed.InterpretationThese observations in this large cohort support the hypothesis of eosinophils in allo-immunity in human and claim for further mechanistic research.FundingThis study was supported by the French National Research Agency, The “Institut de Recherche en Santé Respiratoire des Pays de la Loire” and the University hospital of Nantes.

Viral load-guided immunosuppression after lung transplantation (VIGILung)\u2014study protocol for a randomized controlled trial

BackgroundImmunosuppression including high-dose calcineurin inhibitors (CNI) is essential after lung transplantation. Dosing is usually guided by therapeutic drug monitoring adjusted to target trough levels of CNIs to keep the balance between over-dose causing severe toxicity and increased risk of infections or under-dose with a risk of graft injury. Adaptation of CNI-based immunosuppression by monitoring of torque teno virus (TTV), a latent nonpathogenic DNA virus, measured in the whole blood in addition to conventional therapeutic drug monitoring may reduce the toxicity of immunosuppression with similar efficacy.Methods/designAn open-label, randomized, controlled, parallel-group, multicenter trial in lung transplant recipients will be conducted to investigate the safety and efficacy of immunosuppression guided by TTV monitoring as an add-on to conventional therapeutic drug monitoring. Adult lung transplant recipients 21 to 42 days after transplantation are eligible to participate. Patients (N = 144) will be randomized 1:1 to the experimental intervention (arm 1: immunosuppression guided by TTV monitoring in addition to conventional therapeutic drug monitoring of tacrolimus trough levels) and control intervention (arm 2: conventional therapeutic drug monitoring). Outcomes will be assessed 12 months after randomization with the change in glomerular filtration rate as the primary endpoint. Secondary endpoints will be additional measurements of renal function, allograft function, incidence of acute rejections, incidence of chronic lung allograft dysfunction, graft loss, and infections.DiscussionThe results of this randomized controlled trial may reduce the toxicity of immunosuppression after lung transplantation while maintaining the efficacy of immunosuppression. Study results are transferable to all other solid organ transplantations.Trial registrationClinicalTrials.gov NCT04198506. Registered on 12 December 2019

Optimization of de novo belatacept-based immunosuppression administered to renal transplant recipients.

Kidney transplant recipients administered belatacept‐based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor‐specific antibodies (DSAs), and improved renal function and long‐term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)‐based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept‐based regimen than with CNI‐based immunosuppression. Although these early co‐stimulation blockade‐resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept‐based maintenance regimens. Steroid‐sparing, belatacept‐based immunosuppression (following T cell–depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI‐based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept‐based regimen for minimizing early cellular AR occurrence.

MP52-09 CARDIAC FUNCTION IMPROVEMENT IN KIDNEY TRANSPLANTS PATIENTS AFTER THE EARLY ADDITION OF EVEROLIMUS WITH CALCINEURIN INHIBITOR MINIMIZATION

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery II (MP52)1 Apr 2020MP52-09 CARDIAC FUNCTION IMPROVEMENT IN KIDNEY TRANSPLANTS PATIENTS AFTER THE EARLY ADDITION OF EVEROLIMUS WITH CALCINEURIN INHIBITOR MINIMIZATION Naoki Yokoyama*, Takeshi Ishimura, Takahito Endo, Shun Nishioka, Teruyuki Oda, Satoshi Ogawa, and Masato Fujisawa Naoki Yokoyama*Naoki Yokoyama* More articles by this author , Takeshi IshimuraTakeshi Ishimura More articles by this author , Takahito EndoTakahito Endo More articles by this author , Shun NishiokaShun Nishioka More articles by this author , Teruyuki OdaTeruyuki Oda More articles by this author , Satoshi OgawaSatoshi Ogawa More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000914.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In patients with chronic kidney disease, cardiac function has been shown to improve after kidney transplantation (KTx) in accordance with kidney function recovery. In contrast, KTx patients are exposed to de novo risk factors for cardiac dysfunction such as calcineurin inhibitors (CNIs). Recently, everolimus (EVR)-based CNI-minimization regimens have been reported to reduce cardiac abnormalities during heart transplants. Moreover, EVR itself has been reported to confer direct cardioprotective effects. However, the details concerning the long-term effects of KTx have not been elucidated. METHODS: This study included 75 patients who underwent KTx and were initially treated with CNI, mycophenolate mofetil, and methylprednisolone between 2010 and 2016. Thirty-seven patients started to receive EVR along with a CNI reduction 3 months after KTx (EVR group) and 38 patients were continued on CNI-based immunosuppression without EVR (CNI group). All patients underwent echocardiography before, and at 3 months and 3 years after KTx. We analyzed several parameters such as ejection fraction (EF), left ventricular diastolic diameter (LVDd), and left ventricular mass index (LVMI, g/m2) and compared these parameters between groups. Additionally, we regarded patients who had an LVMI≥125 and ≥110 in male and females, respectively, as having left ventricular hypertrophy (LVH). The prevalence of LVH was also compared between the EVR and CNI groups. RESULTS: The EF and LVDd did not show any apparent changes from pre-KTx to 3 years after KTx. The mean LVMI before, and at 3 months and 3 years after KTx were 118.7 ± 54.7, 102.1 ± 23.3, and 100.6 ± 23.7, respectively. We observed significant improvements in LVMI values from pre-KTx to 3 months after KTx (p=0.02). The change in LVMI values and prevalence of LVH did not show any differences between the EVR and CNI groups. Since the change in LVMI values of patients who already had LVH 3 months after KTx tended to be considerably affected by kidney function improvements regardless of immunosuppressant, we performed a subgroup analysis on 62 patients without LVH at 3 months after KTx. The LVMI in the EVR group showed greater improvement than the CNI group (-1.7 ± 21.5 vs 9.2 ± 18.4, p=0.03) and the ratio of patients with LVH was significantly higher in the EVR group than in the CNI group 3 years after KTx (5.8% vs 21.4%, p=0.05). CONCLUSIONS: The early addition of EVR and reduction of CNI after KTx may reduce myocardial hypertrophy and improve long-term cardiac function. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e775-e775 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naoki Yokoyama* More articles by this author Takeshi Ishimura More articles by this author Takahito Endo More articles by this author Shun Nishioka More articles by this author Teruyuki Oda More articles by this author Satoshi Ogawa More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement PDF downloadLoading ...

MP59-19 ANTI-ATHEROSCLEROTIC EFFECT OF EVEROLIMUS IN KIDNEY-TRANSPLANTED PATIENTS

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation & Vascular Surgery III (MP59)1 Apr 2020MP59-19 ANTI-ATHEROSCLEROTIC EFFECT OF EVEROLIMUS IN KIDNEY-TRANSPLANTED PATIENTS Takeshi Ishimura*, Takahito Endo, Shun Nishioka, Naoki Yokoyama, Teruyuki Oda, Satoshi Ogawa, and Masato Fujisawa Takeshi Ishimura*Takeshi Ishimura* More articles by this author , Takahito EndoTakahito Endo More articles by this author , Shun NishiokaShun Nishioka More articles by this author , Naoki YokoyamaNaoki Yokoyama More articles by this author , Teruyuki OdaTeruyuki Oda More articles by this author , Satoshi OgawaSatoshi Ogawa More articles by this author , and Masato FujisawaMasato Fujisawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000928.019AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cardiovascular disease (CVD) is the major cause of death after kidney transplantation (KTx). Everolimus (EVR) is an immunosuppressive agent now widely used in KTx that is also known for its anti-atherosclerotic effect. The Ankle–Brachial Index (ABI), Carotid Artery Intima–Media Thickness (IMT), and Cardioankle Vascular Index (CAVI) provide indicators of atherosclerosis and are utilized as surrogate CVD markers in many diseases such as chronic kidney disease and diabetes. In this study, we explored the potential anti-atherosclerotic effect of EVR in KTx by sequentially assessing the ABI, IMT, and CAVI. METHODS: This study included 107 patients who recently underwent KTx with triple immunosuppression therapy consisting of calcineurin inhibitor (CNI, either tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. Three months after KTx, EVR was added in 52 patients (EVR+ group), and 55 patients remained on conventional CNI-based immunosuppression therapy without EVR (EVR- group). The ABI, IMT (mm), and CAVI were examined 3 months and 1 year after KTx, and the mean of the right and left values of each test were regarded as an index of atherosclerosis. The changes in the values of each test from 3 months to 1 year were compared between the EVR+ and EVR- groups. Additionally, we determined the prognostic significance of EVR use in the progression of atherosclerosis as well as other clinical parameters. RESULTS: Overall, the mean ABI, IMT, and CAVI 3 months and 1 year after KTx were 1.125 ± 0.087 (n=107) and 1.137 ± 0.091 (n=100), 0.650 ± 0.199 (n=107) and 0.633 ± 0.310 (n=92), and 7.579 ± 1.348 (n=70) and 7.493± 1.623 (n=63), respectively; no significant differences from 3 months to 1 year were observed in each test. The changes in the ABI, IMT, and CAVI in the EVR+ vs. EVR- groups were 0.044 ± 0.093 vs. -0.011 ± 0.087 (p=0.003), -0.022 ± 0.127 vs. 0.033 ± 0.361, and 0.023 ± 1.487 vs. -0.173 ± 1.322, respectively. The ABI in the EVR- group showed a significant reduction from 3 months to 1 year than that in the EVR+ group. Furthermore, EVR non-use, high total cholesterol 3 months after KTx, and cyclosporine use were revealed as prognostic factors for a reduction in the ABI; however, the only independent prognostic factor determined on multivariate analysis was high total cholesterol 3 months after KTx. CONCLUSIONS: The results suggest that the early addition of EVR may prevent atherosclerosis progression after KTx. Further studies in more patients with a longer observation period may provide evidence of the anti-atherosclerotic effect of EVR. Source of Funding: none © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e888-e888 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takeshi Ishimura* More articles by this author Takahito Endo More articles by this author Shun Nishioka More articles by this author Naoki Yokoyama More articles by this author Teruyuki Oda More articles by this author Satoshi Ogawa More articles by this author Masato Fujisawa More articles by this author Expand All Advertisement PDF downloadLoading ...

Rescue Everolimus Post Lung Transplantation is Not Associated with an Increased Incidence of CLAD or CLAD Related Mortality

Calcinuerin inhibitor (CNI) based immunosuppression (IS) regimens remain the cornerstone of IS protocols post lung transplantation (LTx). Everolimus (EVE) has been used to augment IS in LTx patients or as a CNI minimization/ elimination agent in those with renal impairment or recurrent CMV infection. There is limited evidence to support EVE based IS regimens and the impact on progression to chronic lung allograft dysfunction (CLAD). The primary aim was to compare patients who remained on CNI-based IS to those who switched to EVE-based IS and assess the impact of EVE-based IS on time to CLAD and ultimately survival. Single centre retrospective study of 91 patients who were initiated on EVE from 1550 consecutive LTx recipients between 1993 and 2018. Each EVE patient was matched with a patient who remained on CNI-based IS. Criteria for matching included indication for LTx, gender, LTx procedure and age at LTx. A survival analysis was performed in the EVE cohort. 182 LTx recipients [91 EVE & 91 CNI-based IS, mean age 51 ±15 years, 70% male, 82% BSLTx, LTx diagnosis: COPD 35%, ILD 22%, CF 22%, PAH 8%]. The incidence of CLAD was similar across the groups (51% EVE-based vs 48% CNI-based). Patients with CLAD at initiation of EVE had a 3.6 times higher risk of death than those without CLAD [HR 3.60, 95% CI: 2.16 - 6.01, p = 0.0001]. However there was no significant difference in the risk of developing CLAD between EVE-based IS and CNI-based IS [HR 1.05, 95% CI: 0.65 - 1.71]. The incidence of the RAS phenotype of CLAD was higher in the EVE-based group (56% EVE-based vs 39%- CNI-based) but not significant. The risk of death is not significant between EVE-based IS and CNI-based IS from time of switch [HR 1.22, 95% CI: 0.77 - 1.88]. The median days from CLAD to death was significantly higher (p = 0.01) in the EVE-based IS group (1127, IQR: 504 - 2210) compared to the CNI-based group (427, IQR: 236 - 1229). The survival analysis noted a higher mortality with 1) Earlier initiation post LTx (2% / month closer to LTx, 95% CI 1.0 - 3.0%, p = 0.001), 2) Increasing age at initiation (3% /year of age, 95% CI, 0 - 5%, p = 0.029). 3) Diabetes at the time of initiating EVE (HR 2.74 [1.48 - 5.09], p = 0.001). EVE-based IS can be successfully utilized for second-line IS for CNI minimization / elimination and was not associated with an increase in CLAD incidence or CLAD related mortality.

Survival in Lung Transplant Recipients on a Calcineurin Free Regimen: Is It Possible?

Calcineurin inhibitors (CNI) are the cornerstone of immunosuppression in lung transplantation. The International Heart and Lung Transplant registry data estimates that almost 99% of patients are on a CNI-based immunosuppression regimen. The population of lung transplant (LTx) recipients not on a calcineurin inhibitor is exceedingly rare and their outcomes have not been previously examined in a systematic way. An IRB-approved, retrospective, observational, cohort study of LTx recipients who received CNI-free, everolimus (EVR)-based immunosuppression at the University of Colorado from January 1, 1995 - October 1, 2019. The health system's electronic medical records was queried to identify and collect data on eligible LTx recipients. All continuous variables are presented as median(range). Seven of 12 were single LTx (ILD, COPD), five were bilateral LTx,(ILD, COPD, CF) and one was a re-transplant. The majority (8/12) of patients were transitioned to CNI-free, EVR-based immunosuppression due to renal insufficiency, 3/12 due to metastatic cancer, and 1/12 due to both renal failure and cancer. Five of 12 were maintained on three agents (EVR, corticosteroid, and either methotrexate or azathioprine) and the others were on corticosteroids with EVR alone. The median time to transition to CNI-free immunosuppression was 8.8 (2.3 to 21.3) years. Median age at CNI cessation was 67 years old (40-72 years old). Median survival on CNI-free immunosuppression for all comers was 1.6 years with median survival in the deceased cohort (n=8) of 1 year (4 days to 4.6 years) and median survival in the living cohort (n=4) of 2.1 years (1.2 years to 8.2 years). At least three patients were treated with high dose steroids for presumed acute rejection after stopping the CNI. This review demonstrates that in certain situations withdrawal of CNI and transition to CNI-free, EVR- based immunosuppression may result in durable patient survival. Larger multicenter cohort analysis may be the next step in understanding the safety, efficacy and role of CNI-free immunosuppression, as equipoise would be impossible to achieve in a randomized controlled trial.

Mild acute cellular rejection and development of cardiac allograft vasculopathy assessed by intravascular ultrasound and coronary angiography in heart transplant recipients-a SCHEDULE trial substudy.

To evaluate the association between mild acute cellular rejection (ACR) and the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). Substudy of the SCHEDULE trial (n=115), where de novo HTx recipients were randomized to (i) everolimus with early CNI elimination or (ii) CNI-based immunosuppression. Seventy-six patients (66%) were included based on matched intravascular ultrasound (IVUS) examinations at baseline and year 3 post-HTx. Biopsy-proven ACR within year 1 post-HTx was recorded and graded (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post-HTx. Median age was 53years (45-61), and 71% were male. ACR was recorded in 67%, and patients were grouped by rejection profile: no ACR (33%), only 1R (42%), and ≥2R (25%). Median ∆MIT (maximal intimal thickness)BL-3Y was not significantly different between groups (P=0.84). The incidence of CAV was 49% by IVUS and 26% by coronary angiography with no significant differences between groups. No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.025, P=0.83). The number of 1R was not a significant predictor of ∆MITBL-3Y (P=0.58), and no significant interaction with treatment was found (P=0.98). The burden of mild ACR was not associated with CAV development.

Mild Acute Cellular Rejection is Not Associated with Development of Cardiac Allograft Vasculopathy Assessed by Intravascular Ultrasound and Coronary Angiography in Heart Transplant Recipients - A Substudy of the SCHEDULE Trial

Purpose The impact of mild (1R) acute cellular rejection (ACR) on the development of cardiac allograft vasculopathy (CAV) after heart transplantation (HTx) remains unclear. We aimed to investigate the association between mild ACR within 1 year of HTx and development of CAV at 3 years post HTx. Methods This is a substudy of the SCHEDULE trial (n=115) in which de novo HTx recipients were randomized to either (i) everolimus or (ii) conventional CNI-based immunosuppression. 76 patients (66%) were eligible for inclusion based on matched intravascular ultrasound (IVUS) examinations at baseline (BL) and 3 years post HTx. Biopsy proven ACR within year 1 was recorded and graded according to ISHLT criteria (1R, 2R, 3R). Development of CAV was assessed by IVUS and coronary angiography at year 3 post HTx. Results Median age was 53 years (45-61) and 71% were male. In 67% of patients ACR was recorded during year 1 (1R in 63%, 2R in 24%, and 3R in 3% of patients, respectively). Patients were grouped by rejection profile: no ACR (33%), only 1R (42%), at least one 2R/3R (25%). At 3 years post HTx 49% of patients had CAV on IVUS (maximal intimal thickness, MIT ≥ 0.5 mm) with no difference in the incidence of IVUS-CAV between groups (p=0.43). Median ∆MITBL-3Y was 0.09 mm (0.05-0.15) with no significant difference among groups (p=0.84) (figure 1). At 3 years post HTx angiographic CAV was present in 26% of patients with no significant between group difference (no ACR: 40%, only 1R: 24%, at least one 2R/3R: 7%; p=0.06). No correlation was found between number of 1R and ∆MITBL-3Y (r=-0.03, p=0.83). Number of 1R did not predict ∆MITBL-3Y in an adjusted linear regression model (p=0.69). No significant interaction with treatment regimen (everolimus/CNI) was found (p=0.84). Conclusion Mild ACR within 1 year of HTx was not associated with development of CAV assessed by IVUS and coronary angiography at year 3 post HTx.

New insights into immune mechanisms of antiperlecan/LG3 antibody production: Importance of T cells and innate B1 cells.

Autoantibodies against perlecan/LG3 (anti‐LG3) have been associated with increased risks of delayed graft function, acute rejection, and reduced long‐term survival. High titers of anti‐LG3 antibodies have been found in de novo renal transplants recipients in the absence of allosensitizing or autoimmune conditions. Here, we seek to understand the pathways controlling anti‐LG3 production prior to transplantation. Mice immunized with recombinant LG3 produce concomitantly IgM and IgG anti‐LG3 antibodies suggesting a memory response. ELISpot confirmed the presence of LG3‐specific memory B cells in nonimmunized mice. Purification of B1 and B2 subtypes identified peritoneal B1 cells as the major source of memory B cells reactive to LG3. Although nonimmunized CD4‐deficient mice were found to express LG3‐specific memory B cells, depletion of CD4+ T cells in wild type mice during immunization significantly decreased anti‐LG3 production. These results demonstrate that B cell memory to LG3 is T cell independent but that production of anti‐LG3 antibodies requires T cell help. Further supporting an important role for T cells in controlling anti‐LG3 levels, we found that human renal transplant recipients show a significant decrease in anti‐LG3 titers upon the initiation of CNI‐based immunosuppression. Collectively, these results identify T cell targeting interventions as a means of reducing anti‐LG3 levels in renal transplant patients.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n=93) or to tacrolimus-based therapy (n=95), both with basiliximab induction and enteric-coated mycophenolate sodiumwith or withoutsteroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1vs. -13.3mL/min per 1.73m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p<0.001). Mean eGFR at week 24 was 95.8versus 76.0mL/min per 1.73m2 for everolimus versus tacrolimus (p<0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p=0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p=0.026); the rate of treated BPAR was 8.9% versus 2.2% (p=0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Immunosuppression Modification by Everolimus With Minimization of Calcineurin Inhibitors Recovers Kidney Graft Function Even in Patients With Very Late Conversion and Also With Poor Graft Function

BackgroundAlthough kidney graft survival within 5 years after transplantation is now achieved in >95% of recipients, chronic graft deterioration remains a factor limiting long-term survival. Chronic nephrotoxicity induced by calcineurin inhibitors (CNIs) is one of the major causes of chronic graft injury; thus, minimization of CNIs by administration of everolimus (EVR) is expected to relieve their toxic effects. MethodsFifty-six kidney transplant recipients receiving CNI-based immunosuppression (tacrolimus, n = 34; cyclosporine, n = 22) were analyzed. The average posttransplant period at conversion was 7.4 years and no less than 3 years. Conversion of immunosuppression was accomplished by reducing CNI by 40% in dose and beginning EVR at 1 or 1.5 mg. Changes in graft function were examined, and adverse effects were evaluated. ResultsSignificant improvement in graft function was observed quickly after EVR administration, and it had persisted for 1 year after conversion as a 7% increase in estimated glomerular filtration rate. No obvious acute rejection was observed. Further analyses concerning “timing of EVR conversion” and “graft function at conversion” were performed. Graft function was significantly improved even in patients with late conversion at 2 to 10 years. The estimated glomerular filtration rate was significantly improved even in patients with poor function. ConclusionsWe concluded that this modification to the immunosuppressive regimen, as expected, reduced CNI nephrotoxicity. Our results showed that even patients with very late conversion or poor graft function also benefited from EVR conversion with CNI minimization.

The CECARI Study: Everolimus (Certican®) Initiation and Calcineurin Inhibitor Withdrawal in Maintenance Heart Transplant Recipients with Renal Insufficiency: A Multicenter, Randomized Trial.

In this 3-year, open-label, multicenter study, 57 maintenance heart transplant recipients (>1 year after transplant) with renal insufficiency (eGFR 30–60 mL/min/1.73 m2) were randomized to start everolimus with CNI withdrawal (N = 29) or continue their current CNI-based immunosuppression (N = 28). The primary endpoint, change in measured glomerular filtration rate (mGFR) from baseline to year 3, did not differ significantly between both groups (+7.0 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.18). In the on-treatment analysis, the difference did reach statistical significance (+9.4 mL/min in the everolimus group versus +1.9 mL/min in the CNI group, p = 0.047). The composite safety endpoint of all-cause mortality, major adverse cardiovascular events, or treated acute rejection was not different between groups. Nonfatal adverse events occurred in 96.6% of patients in the everolimus group and 57.1% in the CNI group (p < 0.001). Ten patients (34.5%) in the everolimus group discontinued the study drug during follow-up due to adverse events. The poor adherence to the everolimus therapy might have masked a potential benefit of CNI withdrawal on renal function.

Pubertal Development in Pediatric Kidney Transplant Patients Receiving Mammalian Target of Rapamycin Inhibitors or Conventional Immunosuppression.

Data regarding the onset of puberty in children receiving mammalian target of rapamycin (mTOR) inhibitors are limited. Kidney transplant patients aged <14 years were analyzed retrospectively to a maximum age of 18 years, with a minimal observation period of 1 year. Immunosuppression comprised (1) standard CNI-based regimen or (2) low-exposure mTOR inhibitor with reduced-exposure CNI, initiated either de novo or in the maintenance phase. Of 108 children analyzed, 67 received an mTOR inhibitor (56 everolimus, 11 sirolimus) and 41 did not. The age at which girls reached Tanner stage P2 was similar with mTOR inhibitor therapy (median 11.6 years) or without (median 11.1 years) (P = 0.262), as was age at stage B2 (median 11.6 vs. 11.2 years; P = 0.753). In boys, both the age of attaining Tanner stage P2 (median 12.9 vs. 13.0 years; P = 0.796) and Tanner stage G2 (median 13.1 vs. 12.9 years; P = 0.344) were also similar with or without an mTOR inhibitor. Age at menarche in girls, and age at spermarche in boys, did not differ between the 2 groups. In this retrospective analysis, sexual maturation ages and reproductive hormone levels were comparable in adolescent kidney transplant patients receiving low-exposure mTOR inhibitors and reduced CNI therapy or conventional CNI-based immunosuppression.

Effect of mammalian target of rapamycin inhibitors on cytomegalovirus infection in kidney transplant recipients receiving polyclonal antilymphocyte globulins: a propensity score-matching analysis.

Mammalian target of rapamycin inhibitors (mTORi) prevents cytomegalovirus (CMV) infection in kidney transplant (KT) patients. From May 2010 to December 2013, all KT recipients were retrospectively analysed. Maintenance immunosuppression regimen was divided into mTORi or calcineurin inhibitors (CNI)-based regimen. Since June 2011, CMV-seropositive recipients (R+) treated with high-intensity immunosuppression and mTORi did not receive anti-CMV prophylaxis. We analysed 350 consecutive patients, of which 95 (27%) received mTORi and 255 (73%) CNI-based immunosuppression. A Cox-regression multivariate analysis showed that the use of mTORi-based immunosuppression during all follow-up reduced the risk of CMV infection (HR 0.36, 95% CI 0.15-0.89, P = 0.028) and confirmed in a propensity score-matched cohort (HR 0.4, 95% CI 0.1-0.9, P = 0.047). Early discontinuation of mTORi increased the risk of CMV infection (HR 3.2; 95% CI 1.7-6.0) in univariate analysis. The incidence of CMV infection was not higher among CMV R+ patients on mTORi and requiring high-intensity immunosuppression when CMV prophylaxis was not given. The use of mTORi protected for CMV infection in KT patients, allowing to avoid antiviral prophylaxis for R+ patients receiving high-intensity immunosuppression. The increased risk of CMV infection after early discontinuation of mTORi warrants further research.