Calcineurin Inhibitors Group Research Articles

MTOR INHIBITORS ENHANCE ANTITUMOR ACTIVITY OF LIVER NATURAL KILLER CELLS IN MICE

Background: Liver transplantation (LT) is the best available option for patients with end stage liver disease and HCC. However, recipients are at high risk of cancer recurrence and infection, due to immunosuppressive (IS) therapy. IS used in LT commonly consist of calcineurin inhibitor (CNI) or a mechanistic target of rapamycin (mTOR), anti-metabolite and corticosteroids. Liver is an important immunological organ with a unique microenvironment. Innate and adaptive immune responses shapes the balance between immune tolerance and activation. It is well-known that IS drugs targeting the adaptive component of immunity, while innate immune cells become the only self-defense mechanism against neoplastic cells and infectious agents. However, the effect of IS drugs on liver resident immune cells are not well known. In this study, we analyzed the effect of two main IS drugs, calcineurin inhibitors and mTOR inhibitors on adaptive and innate immune components of the liver in mice Method: C57/BL6 mice were treated by intraperitoneal injection of mTORi (rapamycin and everolimus) and CNI (cyclosporine) for 7 days. Twenty-four hours after the last injection, liver mononuclear cells (LMNCs), splenocytes were collected. The proportion of T cells, NKT cells and NK cells and various functional molecules were analyzed by flow cytometry. Result: The proportion of TCR+NK1.1- T cells, TCR+NK1.1+ NKT cells in LMNC did not differ in both CNI mTORi treated groups. TCR-NK1.1+NK fraction in LMNCs was significantly increased in mTORi group (9.5 in mTORi groups versus 7.8 in control group), CNI treatment had no effect on NK cells frequency. mTORi treatment significantly upregulated the TRAIL positive NK cells (38.5%±4.0 in mTORi group vs 21.0%±8.3 in untreated, p =0.003). CNI treatment oppositely significantly decreased the TRAIL positive NK cell population (16.4%±4.2 in CNI group vs 21.0%±8.3 in untreated, p <0.05). CD 69 and Nkp46 expression on liver NK cells were not changed significantly in both mTORi and CNI treated groups in comparison to control group. Moreover, liver NK cells from mTORi treated mice showed significantly higher cytotoxicity against TRAIL-sensitive Hepa1-6 cells (30.1% ± 13.0 vs 13.5 %± 6.0, p=0.009). Cytotoxicity against TRAIL resistant YAC-1 mouse lymphoma was not significantly enhanced after mTORi treatment (53.6 % ± 4.4 vs 39.9% ± 1.2). Conclusion: mTOR inhibitors has ability to enhance liver resident NK cell activity. This result suggests that mTOR inhibitors might be useful to maintain anti-microbe and anti-tumor immunity even under immunosuppressive condition after transplantation.

THE FEATURE OF MDSCS IN THE LONG-TERM STABLE KIDNEY TRANSPLANT RECIPIENTS AFTER DIFFERENT IMMUNOSUPPRESSION THERAPY

Objective: Myeloid-derived suppressor cells (MDSCs) play an important role in immune tolerance. The aim of this study is to investigate different feature of MDSCs in the long-term survival with kidney transplant recipients. Methods: From January 1989 to November 2008, a total number of 35 Recipients operated in kidney transplantation department of the first affiliated hospital of Xi’an Jiaotong university, were selected. They all had stable kidney function now. Recipients were divided into 4 Four three groups: Aza +Pred (n=5; Tacrolimus inhibitors group (FK506 + MMF + Pred) (n=10; Cyclosporine inhibitors group (CsA + MMF + Pred) (n=10); rapamycin group (RAPA + MMF + Pred) (n=10). The expression of MDSCs in peripheral blood was determined by flow cytometry. The expression of serum HLA-G5 and sCD30 was detected by ELLISA. MDSCs of mice were also induced in vitro, which were also treated with different immunosuppression as above. Results: The percentage of MDSCs was significantly higher in calcineurin inhibitors group than rapamycin inhibitors group. The level of MDSCs between Cyclosporine group and tacrolimus group was no significant difference. Rapamycin significantly reduces the immunosuppressive function of MDSCs on T cells compared with CNI group and reduces the number of MDSCs induced in vitro. No significant difference was observed between Cyclosporine group and tacrolimus group. Conclusions: 1. Rapamycin inhibits the differentiation and function of MDSCs in vitro and in vivo, which maybe bad for immune tolerance. When select rapamycin as immunosuppression, should be careful in Long-term survival with kidney transplant recipients. 2. MDSCs, HLA-G5, CD30 may act an effective method to evaluate immune status of kidney recipients.

Assessing the effect of immunosuppressive agents for immune-related adverse event management on tumor response.

3066 Background: High grade immune-related adverse events (irAEs) to cancer immune checkpoint inhibitors (ICI) require considerable immunosuppression (IS) with high-dose steroids and steroid-sparing IS (SSIS) for steroid-dependent cases. T lymphocyte-specific IS has generally been avoided or used with significant caution due to the fear that these agents may negatively impact ICI efficacy. We sought to determine whether T cell-specific IS agents, such as calcineurin inhibitors (CNIs), have an adverse effect on tumor control when compared to other immunomodulatory drugs (IMDs). Methods: We retrospectively analyzed clinical annotations of adult patients treated with ICIs for malignancy from 1/1/2000-12/31/2019, highlighting patients who were managed with SSIS, specifically those most commonly used for autoimmune disease therapy. Topical IS use was excluded. Patients were categorized as tumor responders or non-responders, and irAEs were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Progression-free survival (PFS) was assessed via Kaplan-Meier curve. Results: 1331 unique individuals were prescribed ≥1 ICIs, with 526 prescribed systemic steroids (39.5%) and 90 (6.8%) patients prescribed SSIS agents, 25 patients with &gt;1 SSIS: mycophenolate (39), methotrexate (26), leflunomide (5), azathioprine (3), rituximab (24), tocilizumab (3), infliximab (8), etanercept (1), adalimumab (1), golimumab (1) and CNIs (18): cyclosporine, tacrolimus. IMDs hydroxychloroquine (6) and sulfasalazine (5) were also prescribed. The objective response rate was 50.0% in the CNI group compared to 45.5% in the IMD cohort and 45.4% in the irAE group (CTCAE grade matched) with steroids alone without any SSIS. Median PFS were compared between CNI cohort (5.4 months, range 1.3-34 months) to IMD (1.1 months, range 0.4-6.4, p=0.02) and steroid alone (2.4 months, range 0.69-17.7, p=0.48). Multiple regression analysis identified irAE presence as an independent correlates to tumor response (p=0.02). Conclusions: T cell-specific IS should not be excluded from irAE treatment algorithm as we observed that PFS was comparable to immunomodulators and similar efficacy was observed compared to steroids alone. Rapid identification and management of irAEs can help mitigate morbidity but there are virtually no reliable clinical trials to guide irAE management with SSIS. These findings support the need for larger, prospective evaluation of immunosuppression use for high grade irAE therapy.

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 ...

Invasive haemodynamics in de novo everolimus vs. calcineurin inhibitor heart transplant recipients.

AimsInvasive haemodynamic profiles at rest and during exercise after heart transplantation (HTx) have never been described in a randomized trial where de novo everolimus (EVR)‐based therapy with early calcineurin inhibitor (CNI) withdrawal has been compared with conventional CNI treatment. We report central invasive haemodynamic parameters at rest and exercise during a 3 year follow‐up after HTx in a sub‐study of the SCandiavian Heart transplant Everolimus De novo stUdy with earLy calcineurin inhibitor avoidancE trial. We hypothesized that the nephroprotective properties, the less development of cardiac allograft vasculopathy (CAV), and the antifibrotic properties of EVR, in comparison with CNI‐based immunosuppression, would demonstrate favourable invasive haemodynamic profiles in patients at rest and during exercise.Methods and resultsNinety of 115 HTx recipients randomized to EVR or CNI treatment performed right heart catheterization at rest and 68 performed right heart catheterization at exercise up to 3 years after HTx. Haemodynamic profiles were compared between EVR and CNI treatment groups. Resting haemodynamics improved in both groups from pre‐HTx to the first follow‐up at 7–11 weeks post‐HTx and thereafter remained unchanged up to 3 years of follow‐up. During follow‐up, cardiac reserve during exercise increased with higher levels of maximum heart rate (118 to 148 b.p.m., P < 0.001), mean arterial pressure (103 to 128 mmHg, P < 0.001), and cardiac output (10.3 to 12.2 l/min, P < 0.001). No significant differences in haemodynamic parameters were observed between the EVR and CNI groups at rest or exercise. Isolated post‐capillary pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≥ 15 mmHg, and pulmonary vascular resistance <3) were measured in 11% of the patients at 7–11 weeks, 5% at 12 months, and 6% at 36 months after HTx. The EVR group had significantly better kidney function (76 mL/min/1 vs. 60 mL/min/1, P < 0.001) and reduced CAV (P < 0.01) but an increased rate of early biopsy‐proven treated rejections (21.2% vs 5.7%, P < 0.01) compared with the CNI group at any time point. The differences in renal function, CAV, or early biopsy‐proven treated acute rejections were not associated with altered haemodynamics.Conclusions De novo EVR treatment with early CNI withdrawal compared with conventional CNI therapy did not result in differences in haemodynamics at rest or during exercise up to 3 years after HTx despite significant differences in renal function, reduced CAV, and number of early biopsy‐proven treated rejections.

Efficacy and safety of everolimus treatment on liver transplant recipients: A meta-analysis.

Everolimus is an effective immunosuppressant in organ transplantation without impaired renal function. The present study aimed to evaluate the efficacy and safety of everolimus therapy in liver transplant recipients. A systematic literature search was conducted to identify the eligible studies. The quality of the included studies was assessed. The outcomes of interest were biopsy-proven acute rejection (BPAR), graft loss, death, renal function and adverse events. Eight trials involving 1570 participants were included. Compared to the standard exposure to calcineurin inhibitors (CNIs), the incidences of BPAR, graft loss and death were not increased in the everolimus combined with reduced CNIs group. The renal function was significantly improved after everolimus combined with reduced CNI therapy, and the glomerular filtration rate (GFR) was estimated to be elevated by 5.59 (95% CI: 2.17-9.01, P=.001) as compared to the standard exposure to CNIs. The risk of any adverse event was increased by everolimus combined with reduced CNI therapy (RR=1.22, 95% CI: 1.04-1.42, P=.01) as compared to the standard exposure to CNIs. The likelihood of infection was not associated with the regimen. Any publication bias was not identified. Although everolimus combined with reduced CNI therapy significantly improved the renal function in liver transplant recipients, it did not influence the incidence of BPAR, graft loss and death. This regimen might be associated with an increased risk of adverse events, which needs to be elucidated further.

SUN-107 mTORI VERSUS CNI BASED IMMUNOSUPPRESSIVE REGIMENS FOR PAEDIATRIC KIDNEY TRANSPLANTATION

Mammalian target of rapamycin inhibitors (mTORi) have been proposed as an alternative to calcineurin inhibitors (CNI) in long term immunosuppression regimens for kidney transplantation. Their potential benefits include avoidance of the nephrotoxic effects of CNIs and lower rates of viral infection. However, some studies have shown an increased risk of rejection. Little data exists on kidney transplant outcomes in children receiving mTORi. We compared the outcomes of kidney transplantation in children on mTORi containing immunosuppressive regimens versus CNI containing regimens. Data for patients <18 years who received their first transplant between 1 January 2000 to 31 December 2015 were extracted from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. A matched cohort study design was used to compare graft survival for patients who switched from CNI to mTORi between 2 and 24 months post transplantation and continued on the mTORi for 12 months or greater and a control group matched on age, gender, year of transplant and donor source who were receiving CNI based immunosuppression. Kaplan-Meier method with Cox regression was used to compare graft survival in the first 10 post-transplant years. Of 590 first kidney transplants in patients < 18 years of age, 40 patients switched from CNI to mTORi between 2-24 months post-transplant and remained on the mTORi for 12 months or greater. These patients were matched to 120 patients who remained on CNI. There were 4 graft losses in the mTORi group and 32 in the CNI group. Graft survival was greater in the mTORi group with 10-year graft survival 87% and 72.5% in the matched control group (X21=5.22, p =0.02). Graft survival at 10 years post first kidney transplant in paediatric patients on mTORi containing immunosuppressive regimens appears to be superior to those on CNI containing regimens. Our study is limited by small numbers and short duration of mTORi exposure in some patients. Further studies in this population are needed to determine if mTORi based immunosuppressive regimens are superior to CNI based regimens in paediatric kidney transplantation.

Tacrolimus therapy after renal transplantation. Current questions of concentration/dose ratio

Tacrolimus is an important part of immunosuppressive therapy after solid organ transplantation. The therapeutic range of the drug from the calcineurin inhibitor group is narrow. Adjustment of the blood concentration can be very complicated but to be able to avoid the occurrence of side effects or ineffective immunosuppression it is inevitable. This article summarizes the properties of tacrolimus pharmacokinetics, pharmacogenetics and pharmacodynamics. We will focus on individual variations of cytochrome enzymes. In the following part, a new method for screening high risk patients will be introduced. We will present the publications of the determination of the concentration/dose (C/D) ratio. By determining the C/D ratio, researchers identify fast and slow metabolizing patient groups. Fast metabolizers require higher doses in general and the occurrence of complications is also more frequent in this group. Long-term results are lagging behind the slow metabolizing group. The long-term results of renal transplantation nowadays contribute to the postoperative period and the later years rather than the surgery itself. It includes the proper management of previous illnesses (e.g., hypertension, diabetes, endocrinological problems), detection of complications (e.g., infections, malignancies), and the precise regulation of immunosuppressive therapy. Orv Hetil. 2019; 160(30): 1178-1183.

Incidence of Malignancies in Patients Treated With Sirolimus Following Heart Transplantation

BackgroundMalignancy is a major cause of late post-heart transplantation (HT) mortality. Sirolimus (SRL) exerts antiproliferative properties and its long-term use in HT as primary immunosuppression (IS) is associated with decreased mortality risk that is not fully explained by attenuation of cardiac allograft vasculopathy progression. ObjectivesThis study sought to examine whether conversion from calcineurin inhibitor (CNI)-based to SRL-based IS was associated with decreased risk of malignancy post-HT. MethodsOverall, 523 patients underwent HT between 1994 and 2016 at a single institution. The main outcomes included incidence of overall de novo malignancies (excluding non-melanoma skin cancers [NMSCs]), post-transplantation lymphoproliferative disorders (PTLD), and first and subsequent primary occurrences of NMSC post-HT. ResultsThe study identified 307 patients on SRL-based and 216 on CNI-based maintenance IS. Over a median follow-up of 10 years after HT, overall de novo malignancies (non-NMSC) occurred in 31% of CNI patients and in 13% of SRL patients (adjusted hazard ratio [HR]: 0.34; 95% confidence interval [CI]: 0.18 to 0.62; p < 0.001). The incidence of the first NMSC was similar in the SRL and CNI groups (HR: 0.92; 95% CI: 0.66 to 1.28; p = 0.62). However, conversion to SRL was significantly associated with a decreased risk of subsequent primary occurrences of NMSC compared with that of CNI (adjusted HR: 0.44; 95% CI: 0.28 to 0.69; p < 0.001). The adjusted PTLD risk was significantly decreased in the SRL group (HR: 0.13; 95% CI: 0.03 to 0.59; p = 0.009). Late survival post-HT was markedly decreased in patients who developed non-NMSC, PTLD, or non-PTLD compared with patients who did not develop these malignancies, whereas NMSC had no significant effect on survival. ConclusionsConversion to SRL was associated with a decreased risk of all de novo malignancies, PTLD, and subsequent primary occurrences of NMSC after HT. These findings provided further explanation of the late survival benefit with long-term SRL use.

A randomized trial of everolimus-based quadruple therapy vs standard triple therapy early after lung transplantation.

Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus‐based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open‐label, 12‐month multicenter trial was conducted at 8 German sites. Patients 3‐18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3‐5 ng/mL) with reduced CNI (tacrolimus 3‐5 ng/mL or cyclosporine 25‐75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy‐proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325.

Efficacy of Glucocorticoids and Calcineurin Inhibitors for Anti-aminoacyl-tRNA Synthetase Antibody-positive Polymyositis/dermatomyositis-associated Interstitial Lung Disease: A Propensity Score-matched Analysis.

The optimal treatment strategy for anti-aminoacyl-tRNA synthetase antibody-positive polymyositis/dermatomyositis-associated interstitial lung disease (anti-ARS-PM/DM-ILD) is yet to be established. We aimed to evaluate the efficacy of glucocorticoids and calcineurin inhibitors (CNI) in patients with ARS-PM/DM-ILD. Progression-free survival (PFS) and overall survival rates were retrospectively evaluated in 32 consecutive patients with ARS-PM/DM-ILD. Disease progression was defined as deterioration in PM/DM-ILD (including recurrence). Predictive factors associated with PFS were analyzed by Cox hazards analysis. The efficacy of first-line prednisolone (PSL) plus CNI therapy was compared with that of PSL monotherapy using propensity score-matched analysis. Overall, 20 (62.5%) and 12 (37.5%) patients received first-line therapy with PSL + CNI and PSL, respectively. The 2-year PFS and 5-year survival rates in the overall cohort were 68.8% and 96.9%, respectively. On multivariate analysis, arterial oxygen pressure (HR 0.86) and PSL monotherapy (vs PSL + CNI; HR 7.29) showed an independent association with PFS. Baseline characteristics of propensity score-matched PSL + CNI and PSL groups were similar. The 2-year PFS rate was significantly higher in the matched PSL + CNI group than in the matched PSL group. All patients who experienced disease progression during first-line therapy were subsequently treated with second-line therapies. The 5-year survival rates of both the matched PSL + CNI and PSL groups were favorable. Propensity score-matched analysis demonstrated that first-line PSL + CNI therapy for patients with ARS-PM/DM-ILD significantly improved the PFS compared with PSL monotherapy, although there was no significant difference regarding longterm survival.

Calcineurin Inhibitors With Reduced-Dose Steroids as First-Line Therapy for Focal Segmental Glomerulosclerosis

IntroductionHigh-dose corticosteroids remain the first-line therapy for focal and segmental glomerulosclerosis (FSGS), whereas calcineurin inhibitors (CNIs) are reserved for those patients resistant to corticosteroid therapy.MethodsThis is a retrospective cohort analysis in patients with primary FSGS diagnosed between 2007 and 2014. According to the administered treatment, patients were segregated into 3 groups: high-dose prednisone, first-line CNIs plus low-dose prednisone, and rescue CNIs. Cumulative corticosteroid doses were compared as well as response to therapy and long-term renal survival by Cox regression analysis.ResultsA total of 66 patients were included (39 treated with high-dose prednisone, 11 treated with first-line CNI, 16 treated with high-dose prednisone followed by rescue CNI). Cumulative doses of prednisone in the high-dose group were 9.3 g (interquartile range [IQR] = 7.5−12.5 g), compared to 2.5 g (IQR = 1.82−3.12 g) in the first-line CNI plus low-dose corticosteroid group and 13.8 g (IQR = 9.2−15.8 g) rescue CNI groups, respectively (P < 0.001). Time under corticosteroid management was also higher in the high-dose prednisone group compared to the first-line CNI group. There was a response to treatment in 76.9%, 72.7%, and 87.5% of high-dose prednisone, first-line CNI and rescue CNI groups, with complete remission in 48.7%, 36.4%, and 31.3% respectively. There was no difference in relapse incidence after treatment (48.4%, 44.4%, and 46.7%) or in 5-year renal survival (87.2%, 81.8%, and 87.5%). Baseline proteinuria, biopsy chronicity score, and response to therapy were independent predictors of renal survival.ConclusionAn initial CNI plus low-dose corticosteroid approach in primary FSGS reduces corticosteroid exposure with a response-to-therapy rate similar to that of the currently recommended high-dose corticosteroid regimen. These findings justify a randomized trial to formally test this hypothesis.

Aortic root dilation in kidney transplant recipients.

INTRODUCTION Aortic root (AoR) dilation is associated with cardiac damage and higher cardiovascular risk. Cardiovascular disease is the most common cause of death in patients after kidney transplantation (KTx ). OBJECTIVES The aim of this study was to assess the prevalence of enlarged AoR diameter in KTx recipients. Patients with bicuspid aortic valve, significant valvular disease, or evidence of connective tissue disorder were excluded. PATIENTS AND METHODS A total of 87 KTx recipients were divided into 2 groups depending on immunosuppressive regimen: 41 patients receiving mammalian target of rapamycin inhibitors (mTORi) and 46 patients treated with calcineurin inhibitors (CNIs). In all patients, echocardiography was performed, laboratory and clinical markers of cardiovascular risk were assessed, and the AoR diameter was calculated. RESULTS There were no differences between groups in age, sex, body surface area, body mass index, frequency of diabetes, hypertension, dyslipidemia, time after replacement therapy, creatinine levels, and estimated glomerular filtration rate. In the CNI group, the observed and calculated AoR diameters were similar (P = 0.8). In the mTORi group, the observed AoR diameter was higher than the calculated one (P = 0.002). The concentric and eccentric left ventricular hypertrophy was similar in both groups (P = 0.12 and P = 0.69, respectively). In the stepwise regression analysis, the AoR diameter was associated with body surface area and mTORi treatment. CONCLUSIONS KTx recipients have a high prevalence of AoR dilation. Immunosuppressive regimen based on mTORi increases the incidence of AoR enlargement.

Cost analysis on the use of rituximab and calcineurin inhibitors in children and adolescents with steroid-dependent nephrotic syndrome.

Rituximab (RTX) is increasingly being used in place of calcineurin inhibitors (CNI) in pediatric patients with steroid-dependent nephrotic syndrome (SDNS). However, despite its favorable safety profile, its unit cost is prohibitive. We therefore compared the healthcare costs associated with the use of both agents in a retrospective cohort. This study was a retrospective analysis of data retrieved from the medical charts and electronic databases of pediatric patients (age range 2-18years) with SDNS who were treated with either CNI or RTX from January 2008 to December 2012 at Children's Hospital of New Orleans, Louisiana. The minimum follow-up period was 12months. Of the 18 patients whose medical data were analyzed, ten received RTX and eight were treated with CNI. The annualized healthcare cost for the rituximab group was $197,031 versus $189,857 (all values in US dollars) for the CNI group (p>0.05). At the 12-month follow-up, more patients in the RTX group were in remission (40 vs. 25%). Duration of freedom from steroid use was longer in the RTX group, while body mass index was higher in the CNI arm (p>0.05). No significant adverse events occurred in either group. The expenditure for the RTX and CNI groups was comparable, but there were fewer clinical encounters in the former group, potentially reducing the burden of healthcare on the patient's family.

Impact of the Trough Level of Calcineurin Inhibitor on the Prevalence of Donor-Specific Human Leukocyte Antigen Antibodies During Long-Term Follow-Up After Pediatric Liver Transplantation: Antibody Strength and Complement-Binding Ability.

BackgroundIn pediatric patients, long-term immunosuppression after liver transplantation (LT) is typically minimal. However, posttransplant donor-specific HLA antibodies (DSAs) may be prevalent under these conditions. Here, we evaluated the effects of minimized calcineurin inhibitor (CNI) on DSA development to assess the validity of minimized/withdrawn immunosuppression.MethodsWe retrospectively examined 66 patients who underwent pediatric LT at our institution between July 1991 and October 2013. Patients were divided into 2 groups based on the CNI trough level. The cutoff trough levels were 3 and 30 ng/mL for tacrolimus and cyclosporine, respectively. Luminex single-antigen bead assays were performed, and the cutoff for a positive reaction was set at a mean fluorescence intensity (MFI) of at least 1000.ResultsThe mean recipient ages at the time of LT were 29.1 and 77.2 months for the low and regular CNI groups, respectively (P = 0.0007). Univariate logistic regression analysis revealed that recipient age at LT younger than 3 years (P = 0.0099) and low CNI (P < 0.0001) were significantly associated with DSA development. In multivariate analysis, low CNI was an independent risk factor of DSA development (P = 0.0011). Of 15 high-MFI DSAs, 3 were anti-DR, and 12 were anti-DQ. Two of 3 anti-DR DSAs and 11 of 12 anti-DQ DSAs had complement-binding ability and high MFIs.ConclusionsCNI minimization was an independent risk factor for posttransplant DSA during long-term follow-up after pediatric LT. Adjusting CNI to appropriate levels is a safe first step to prevent the immunological effects of DSA.

Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial.

Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain. In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514). The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively. Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

Cognitive function after heart transplantation: Comparing everolimus‐based and calcineurin inhibitor‐based regimens

Studies have shown conflicting results concerning the occurrence of cognitive impairment after successful heart transplantation (HTx). Another unresolved issue is the possible differential impact of immunosuppressants on cognitive function. In this study, we describe cognitive function in a cohort of HTx recipients and subsequently compare cognitive function between subjects on either everolimus- or calcineurin inhibitor (CNI)-based immunosuppression. Cognitive function, covering attention, processing speed, executive functions, memory, and language functions, was assessed with a neuropsychological test battery. Thirty-seven subjects were included (everolimus group: n=20; CNI group: n=17). The extent of cerebrovascular pathology was assessed with magnetic resonance imaging. About 40% of subjects had cognitive impairment, defined as performance at least 1.5 standard deviations below normative mean in one or several cognitive domains. Cerebrovascular pathology was present in 33.3%. There were no statistically significant differences between treatment groups across cognitive domains. Given the high prevalence of cognitive impairment in the sample, plus the known negative impact of cognitive impairment on clinical outcome, our results indicate that cognitive assessment should be an integrated part of routine clinical follow-up after HTx. However, everolimus- and CNI-based immunosuppressive regimens did not show differential impacts on cognitive function.

Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial

In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. 36-month follow-up of the intention-to-treat population. CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m2). At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89). Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed. Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy. Serious adverse events occurred in 33 (39%) belatacept-treated patients and 36 (40%) patients in the CNI group. Treatment exposure-adjusted incidence rates for serious infections (belatacept vs CNI, 10.21 vs 9.31 per 100 person-years) and malignancies (3.01 vs 3.41 per 100 person-years) were similar. More patients in the belatacept versus CNI group had any-grade viral infections (14.60 vs 11.00 per 100 person-years). No posttransplantation lymphoproliferative disorder was reported. Belatacept-treated patients had a significantly greater estimated gain in mean eGFR (1.90 vs 0.07mL/min/1.73m2 per year; P for time-by-treatment interaction effect= 0.01). The probability of acute rejection was not significantly different for belatacept (8.38% vs 3.60%; HR, 2.50 [95% CI, 0.65-9.65; P=0.2). HR for the comparison of belatacept to the CNI group for time to death or transplant loss was 1.00 (95% CI, 0.14-7.07; P=0.9). Exploratory post hoc analysis with a small sample size. Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

Effect of Immunosuppressive Treatment on Carotid Atherosclerosis in Renal Transplant Recipients

BackgroundThe aim of this study was to compare the effect of immunosuppressive regimens using either mammalian target of rapamycin inhibitors (mTORi) or calcineurin inhibitors (CNI) on the risk of atherosclerosis in renal transplant patients. Materials and MethodsThe study involved a group of 24 recipients treated with mTORi (mTORi group) and a group of 20 recipients treated with immunosuppressive regimen based on CNI (CNI group). Laboratory and clinical markers of cardiovascular risk in both groups were investigated. Carotid atherosclerosis was evaluated by measurement of the intima media thickness (IMT) of the common and internal carotid artery walls and detection of carotid plaques by a high-resolution ultrasonography. The study was performed 3–24 years after transplantation. ResultsThe mTORi group showed higher level of total cholesterol (242 vs 201 mg/dL; P < .004), low-density lipoprotein cholesterol (140 vs 116 mg/dL; P < .05), and triglycerides (226 vs 168 mg/dL; P < .01). Posttransplant diabetes developed in 34% of mTORi group compared with 25% in the CNI group. The mean of IMT (left and right) of common and internal carotid arteries was similar in both groups. Carotid plaques were detected in 46% of patients from the mTORi group and 25% from CNI group (P < .02). The presence of carotid plaques combined with an IMT of >0.9 mm were associated with male gender, mTORi treatment (P = .03), and cardiovascular events. The incidence of coronary heart disease was higher in mTORi group than in CNI group (53% vs 20%; P = .03). ConclusionsThere was not beneficial effect of immunosuppressive treatment with mTORi on carotid atherosclerosis in renal transplant patients.

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.