Cyclosporine-based Immunosuppression Research Articles

Evaluating Kaposi Sarcoma in Kidney Transplant Patients: A Systematic Review and Meta-Analysis.

Kaposi's sarcoma (KS) is a malignancy that commonly appears as lesions on the skin or mucosal surfaces but can also develop in other organs. This cancer is usually caused by the human herpesvirus 8 (HHV-8), recently known as Kaposi's sarcoma-associated herpesvirus (KSHV). KS is rare in the general population but can develop in kidney transplant recipients with varying incidence due to immunocompromised status from immunosuppression. The main aim of the present systematic review was to identify the prevalence and treatment of KS in kidney transplant patients. PubMed, Cochrane Library, and Google Scholar databases were searched for studies until October 2023. Full-text studies with similar research objectives were included, while non-English articles, reviews, case reports, ongoing clinical trials, and studies evaluating KS in HIV patients or after other solid organ transplants were excluded. All studies were observational; therefore, methodological quality was assessed using the Newcastle-Ottawa Scale. The statistical analyses were performed with the Comprehensive Meta-Analysis (CMA) software (Biostat, Inc.Englewood, NJ). The pooled analysis from the 15 studies includedshowed that KS develops in 1.5% of kidney transplant recipients and is more prevalent in African (1.7%) and Middle Eastern (1.7%) recipients than in Western recipients (0.07%). KS was also significantly more prevalent among male recipients than female recipients (OR: 2.36; p < 0.0001). Additionally, cyclosporine-based immunosuppression accounts for most KS incidences (79.6%) compared to azathioprine-based immunosuppression (28.2%). Furthermore, reduction or withdrawal of immunosuppression alone resulted in 47.8% KS complete remissions. Post-kidney transplantation KS is more frequent among males and patients of Middle Eastern and African origin. However, the gender difference may be attributed to most patients undergoing kidney transplants being male. Therefore, if gender balance is considered in future studies, then the difference might be insignificant. Based on our results, we can concur that the mainstay treatment for post-transplant KS is reduction or withdrawal of immunosuppression. However, the patients should be closely monitored to avoid KS recurrence and kidney rejection. Furthermore, there is an increased risk for KS with the use of cyclosporine-based immunosuppression. However, this does not mean that the withdrawal of this immunosuppression agent might result in improved KS outcomes because the withdrawal of azathioprine with or without cyclosporine reduction has also led to improved outcomes.

Influence of De Novo Malignancies on Long-Term Survival after Lung Transplantation.

(1) Background: Malignancies are an important cause of mortality after solid organ transplantation. The purpose of this study was to analyze the incidence of malignancies in patients receiving lung transplants (LT) and their influence on patients' survival. (2) Methods: Review of consecutive LT from 1994 to 2021. Patients with and without malignancies were compared by univariable and multivariable analyses. Survival was compared with Kaplan-Meier and Cox regression analysis. (3) Results: There were 731 LT malignancies developed in 91 patients (12.4%) with related mortality of 47% (n = 43). Native lung cancer, digestive and hematological malignancies were associated with higher lethality. Malignancies were more frequent in males (81%; p = 0.005), transplanted for emphysema (55%; p = 0.003), with cyclosporine-based immunosuppression (58%; p < 0.001), and receiving single LT (65%; p = 0.011). Survival was worse in patients with malignancies (overall) and with native lung cancer. Risk factors for mortality were cyclosporine-based immunosuppression (OR 1.8; 95%CI: 1.3-2.4; p < 0.001) and de novo lung cancer (OR 2.6; 95%CI: 1.5-4.4; p < 0.001). (4) Conclusions: Malignancies are an important source of morbidity and mortality following lung transplantation that should not be neglected. Patients undergoing single LT for emphysema are especially at higher risk of mortality due to lung cancer in the native lung.

High PIRCHE Scores May Allow Risk Stratification of Borderline Rejection in Kidney Transplant Recipients.

BackgroundThe diagnosis of borderline rejection (BLR) ranges from mild inflammation to clinically significant TCMR and is associated with an increased risk of allograft dysfunction. Currently, there is no consensus regarding its treatment due in part to a lack of biomarkers to identify cases with increased risk for immune-mediated injury.MethodsWe identified 60 of 924 kidney transplant recipients (KTRs) with isolated and untreated BLR. We analyzed the impact of predicted indirectly recognizable HLA epitopes (PIRCHE) score on future rejection, de novo DSA development, and recovery to baseline allograft function. Additionally, we compared the outcomes of different Banff rejection phenotypes.ResultsTotal PIRCHE scores were significantly higher in KTRs with BLR compared to the entire study population (p=0.016). Among KTRs with BLR total PIRCHE scores were significantly higher in KTRs who developed TCMR/ABMR in follow-up biopsies (p=0.029). Notably, the most significant difference was found in PIRCHE scores for the HLA-A locus (p=0.010). PIRCHE scores were not associated with the development of de novo DSA or recovery to baseline allograft function among KTRs with BLR (p>0.05). However, KTRs under cyclosporine-based immunosuppression were more likely to develop de novo DSA (p=0.033) than those with tacrolimus, whereas KTRs undergoing retransplantation were less likely to recover to baseline allograft function (p=0.003).ConclusionsHigh PIRCHE scores put KTRs with BLR at an increased risk for future TCMR/ABMR and contribute to improved immunological risk stratification. The benefit of anti-rejection treatment, however, needs to be evaluated in future studies.

Post-transplant Diabetes Mellitus in Kidney Transplant Recipients in Sudan: A Comparison Between Tacrolimus and Cyclosporine-Based Immunosuppression.

Hyperglycemia is a common complication among transplant patients without a history of diabetes mellitus (DM). Although new and potent immunosuppressants have improved short and long-term outcomes after transplantation, these drugs themselves may be associated with a greater risk of hyperglycemia. The present study aimed to determine the prevalence of post-transplant diabetes mellitus (PTDM) in post renal transplant patients in Sudan, and compare the effect of cyclosporine and tacrolimus-based immunosuppressive regimens. All adult kidney transplant recipients without pre-transplant diabetes who attended the transplant clinic at Ahmed Gasim Cardiac Surgery and Renal Transplant Center in Sudan were included. A total of 100 cases with functioning kidney allografts were enrolled in this study. The majority of cases were in the age range between 20 and 60 years (92%). Males and females were nearly equally distributed (56% vs 44%). Fifty-two percent of patients were on cyclosporine and 48% on tacrolimus. Overall, 18% of patients suffered from post-transplant diabetes mellitus. There was no statistically significant difference between tacrolimus and cyclosporine with regards to the prevalence of hyperglycemia (16.6% versus 13.4%; p>0.05).

Immunosuppression Regimen Use and Outcomes in Older and Younger Adult Kidney Transplant Recipients: A National Registry Analysis.

Although the population of older transplant recipients has increased dramatically, there are limited data describing the impact of immunosuppression regimen choice on outcomes in this recipient group. National data for US Medicare-insured adult kidney recipients (N = 67 362; 2005-2016) were examined to determine early immunosuppression regimen and associations with acute rejection, death-censored graft failure, and mortality using multivariable regression analysis in younger (18-64 y) and older (>65 y) adults. The use of antithymocyte globulin (TMG) or alemtuzumab (ALEM) induction with triple maintenance immunosuppression (reference) was less common in older compared with younger (36.9% versus 47.0%) recipients, as was TMG/ALEM + steroid avoidance (19.2% versus 20.1%) and mammalian target of rapamycin inhibitor (mTORi)-based (6.7% versus 7.7%) treatments. Conversely, older patients were more likely to receive interleukin (IL)-2-receptor antibody (IL2rAb) + triple maintenance (21.1% versus 14.7%), IL2rAb + steroid avoidance (4.1% versus 1.8%), and cyclosporine-based (8.3% versus 6.6%) immunosuppression. Compared with older recipients treated with TMG/ALEM + triple maintenance (reference regimen), those managed with TMG/ALEM + steroid avoidance (adjusted odds ratio [aOR], 0.440.520.61) and IL2rAb + steroid avoidance (aOR, 0.390.550.79) had lower risk of acute rejection. Older patients experienced more death-censored graft failure when managed with Tac + antimetabolite avoidance (adjusted hazard [aHR], 1.411.782.25), mTORi-based (aHR, 1.702.142.71), and cyclosporine-based (aHR, 1.411.782.25) regimens, versus the reference regimen. mTORi-based and cyclosporine-based regimens were associated with increased mortality in both older and younger patients. Lower-intensity immunosuppression regimens (eg, steroid-sparing) appear beneficial for older kidney transplant recipients, while mTORi and cyclosporine-based maintenance immunosuppression are associated with higher risk of adverse outcomes.

MO964DEATH WITH GRAFT FUNCTION AMONG EGYPTIAN KIDNEY TRANSPLANT RECIPIENTS: A SINGLE CENTER EXPERIENCE

Abstract Background and Aims Kidney transplantation is the optimal treatment of end stage renal disease (ESRD). Despite improvements in patient selection and management, every transplant carries risk of graft loss. Death with graft function (DWGF) is an important cause of long-term loss of grafts and patients. In this study, we investigated clinical characteristics and causes of DWGF among a cohort of 2953 Egyptian kidney transplant recipients. Method A total of 291 recipients who died with graft function (DWGF) were evaluated regarding causes and timing of death. Causes of death were investigated in different eras of immunosuppression; era 1 (1976-1995): steroid and azathioprine, era 2 (1996-2005): cyclosporine-based and era 3 (2006-2018): tacrolimus-based. Demographic data, original kidney disease, pre- and post-transplant co-morbidities, immunosuppression regimens, biopsy proven acute rejection episodes and graft function at last follow up were analyzed. Results Proportion of DWGF in total graft loss had changed over time. In our retrospective study, it decreases from 29.5% in era 1 to 13.7% in the most recent era of kidney transplantation. Most patients in DWGF group had diabetes mellitus, hypertension, frequently experienced more infections and more rejection episodes. cyclosporine-based immunosuppression was more prevalent. A total of 291 patients (9.9%) died with graft function. DWGF was responsible for 58.3% of a total of 499 deaths (figure 1). For this group of patients, median serum creatinine at last follow up was 1.7 mg/dl (range: 0.2 - 7 mg/dl). Out of 291 recipients who died with functioning graft, 53 patients (18.2%) died within the first year, 55 (18.9%) died within 1-5 years, 75 (25.8%) died within 5-10 years while 108 patients (37.1%) died after 10 years post transplantation. The majority of DWGF was secondary to cardio-vascular diseases (CVD) (30.9%) and serious infections (29.2%) (figure 2). Death due to malignancy was lowest within the first year (1.9%), increased thereafter but unexpectedly malignancy (22.2%) was the third main cause of death in the late period after transplantation (figure 3). Conclusion DWGF accounts for 24.5% of total graft loss. The most common cause is cardiovascular disease followed by serious infections. Pre-transplant diabetes mellitus, steroid dose and infections had most significant association with DWGF. Understanding different causes of death according to the time after transplantation is mandatory in order to improve the long-term outcomes.

Biopsy-Controlled Non-Invasive Quantification of Collagen Type VI in Kidney Transplant Recipients: A Post-Hoc Analysis of the MECANO Trial

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red; PSR); inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. β = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. β = 0.24 and 0.23, respectively) (p < 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.

Should cyclosporine be useful in renal transplant recipients affected by SARS-CoV-2?

Minimization of immunosuppression and administration of antiretrovirals have been recommended for kidney transplant recipients (KTRs) with coronavirus disease 2019 (COVID‐19). However, outcomes remain poor. Given the likely benefit of cyclosporine because of its antiviral and immunomodulatory effect, we have been using it as a strategy in KTRs diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). We studied 29 kidney transplant recipients (KTRs) who were admitted to our institution with COVID‐19 between March 15and April, 24, 2020. Mycophenolate and/or mammalian target of rapamycin inhibitors (mTORi) were discontinued in all patients. Two therapeutic strategies were compared: Group 1, minimization of calcineurin inhibitors (N = 6); and Group 2, cyclosporine‐based therapy (N = 23), with 15 patients switched from tacrolimus. Hydroxychloroquine was considered in both strategies but antivirals in none. Six patients died after respiratory distress (20.6%). Five required mechanical ventilation (17.2%), and 3 could be weaned. Nineteen patients had an uneventful recovery (65.5%). In group 1, 3 of 6 patients died (50%) and 1 of 6 required invasive mechanical ventilation (16.7%). In group 2, 3 of 23 patients died (12.5%). Renal function did not deteriorate and signs of rejection were not observed in any patient on the second treatment regime. In conclusion, immunosuppressant treatment based on cyclosporine could be safe and effective for KTRs diagnosed with COVID‐19.

GIANT CELL MYOCARDITIS: A SILENT BUT DEADLY KILLER

SESSION TITLE: Cardiovascular Cases SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/22/2019 3:45 PM - 4:45 PM INTRODUCTION: Giant cell myocarditis (GCM) usually affects previously healthy adults and is a rapidly progressive and frequently fatal disease, accounting for approximately 17% of all myocarditis fatalities. Early diagnosis is critical, with evidence showing rapidly instituted cyclosporine-based immunosuppression can improve transplant-free survival. CASE PRESENTATION: A 56 year old male with a history of Type 2 Diabetes presented with 1 week of exertional dyspnea and lightheadedness. Initial exam and tests were remarkable for a mild Troponin leak. EKG revealed Left bundle branch block and transthoracic echocardiogram (TTE) showed a normal ejection fraction (EF) and Left Ventricular (LV) internal Dimension-Diastole of 5.4cm. Stress test, nuclear imaging and Left Heart Catheterization were normal. An event monitor documented exercise induced bradycardia leading to the placement of a dual chamber pacemaker. Repeat ECHO done at the time showed normal EF and a mild circumferential pericardial effusion. In the following two months the patient developed worsening exertional dyspnea (NYHA III). A CT angiogram revealed a large pericardial effusion with tamponade physiology. The aspirate showed 304 cells with 94% monocytes, protein of 4.4g/dl, and cytology revealed reactive mesothelial and chronic inflammatory cells. CRP was elevated. Repeat ECHO showed LV EF of 30% with akinesis of inferior and inferolateral wall as well as diffuse hypokinesis and severely increased RV size and RV thrombus. He was begun on anticoagulation. Subsequently, right heart catherization showed elevated RA pressures and cardiac MRI showed Biventricular dilation and nondiagnostic delayed gadolinium enhancement imaging. Endomyocardial biopsy from RV was not suggestive of GCM. Patient subsequently developed progressive cardiogenic shock requiring dual Ventricular Assist Device placement. On analysing excised core of LV apex for cannula placement, it revealed granulomatous myocarditis with Giant cell formation and pericarditis. He was started on milrinone, high dose steroids and anticoagulation for suspected GCM. An RVAD was placed. Eventually patient returned with fulminant septic shock and died. DISCUSSION: This case reveals the rapidly progressive nature of GCM,which from presentation, has a median survival of 3 months to death or transplant without appropriate therapy. Biopsy is diagnostic in >70% cases if done early, however false negatives are frequent due to the patchy nature of the disease CONCLUSIONS: With immunotherapy, the 5-year survival rate free of transplant is between 52-72%. Transplant is an effective strategy however GCM can recur in around 25% of transplanted hearts. Reference #1: Giant Cell Myocarditis: A Brief Review ; Arch Pathol Lab Med. 2016 Dec;140(12):1429-1434 : Xu J, Brooks EG Reference #2: Diagnosis, Treatment, and Outcome of Giant-Cell Myocarditis in the Era of Combined Immunosuppression;Riina Kandolin, Jukka Lehtonen, Kaisa Salmenkivi: DOI:10.1161/CIRCHEARTFAILURE.112.969261 Reference #3: Idiopathic Giant-Cell Myocarditis — Natural History and Treatment; Leslie T. Cooper, Jr., Gerald J. Berry : N Engl J Med 1997; 336:1860-1866 DISCLOSURES: No relevant relationships by Tanya Chandra, source=Web Response No relevant relationships by Abhas Khurana, source=Web Response No relevant relationships by Osama Mukarram, source=Web Response No relevant relationships by Anand Muthu Krishnan, source=Web Response No relevant relationships by Rudra Ramanathan, source=Web Response No relevant relationships by Nitya Sthalekar, source=Web Response

Patient and Graft Outcomes Among Filipino Post-kidney Transplant Pregnancies

BackgroundKidney transplantation (KT) has been shown to improve fertility rates among women post-transplant. However, despite the favorable outcome, the impact of pregnancy on the graft and the graft’s effect on the fetus should be considered. In addition, these patients are exposed to anti-rejection medications that could affect the fetus. ObjectiveTo describe the graft and pregnancy outcomes among KT recipients. MethodologyDescriptive study of 32 post-KT recipients who were pregnant from January 1, 2001 to December 31, 2016 and were followed up 3 months post-partum. Each pregnancy was considered as an event. ResultsAmong the 32 post-KT patients there were 38 pregnancies. Mean age at conception was 34 years, with a mean interval between KT and pregnancy of 4.8 years. Around 84% took cyclosporine-based immunosuppression. The mean pre-natal serum creatinine was 1.15 mg/dL, 5.3% had ≥ 1.5 mg/dL pre-natal creatinine, and the rejection rate was 10.5%. The results of the pregnancies were as follows: 94% resulted in live births, 18.42% of mothers had pre-eclampsia, 3% had eclampsia, 3% ended in abortion, and 3% were stillbirth. Sixty-eight percent of the pregnancies were unplanned, and more complications were observed among these patients. ConclusionThe maternal and fetal outcomes and complications in this study were comparable with other studies. However, most of these complications were observed with unplanned pregnancies. Counselling prior to pregnancy should therefore be emphasized.

The carnitine-butyrobetaine-TMAO pathway after cardiac transplant: Impact on cardiac allograft vasculopathy and acute rejection

Alterations in the partly microbiota-dependent carnitine-γ-butyrobetaine (γBB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection. We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound. Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant. Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.

Inhaled Cyclosporine-Based Immunosuppression Regimen for Lung Transplant Associated Malignancy

Purpose The clinical outcome of lung transplantation has improved markedly over the last three decades after the introduction of calcineurin inhibitors. However, one of its main disadvantages appears to be calcineurin-related adverse effects including malignancy, infection and nephrotoxicity. We sought strategies to maintain lung function while decreasing the effects of systemic immunosuppression for patients who develop cancer after lung transplantation. Methods Fourteen patients were treated with propylene glycol inhaled cyclosporine at the University of Maryland Medical Center (UMMC) between February 2013 and October 2017 after cancer diagnosis, at the discretion of their lung transplant physician on a compassionate use basis. The cancers that occurred were metastatic lung (n=1), extensive/metastatic skin cancer (n=10), extensive PTLD (n=3). Results FEV1 remained stable over the twelve-month study intervals; baseline median 2.33 L/sec (IQR 1.75-2.60, n=14); three month 2.21 (1.70-2.51, n=14); six month 2.44 (IQR 1.97-2.58, n=11); twelve month 2.40 (IQR 1.98-2.88, n=9); p=0.59. CNI exposure were reduced from 6.8 (IQR 2.7-8.0) to 4.1 (IQR 3.4-4.6) at 12 month after starting inhaled cyclosporine. Cr remained stable during the follow-up with baseline 1.25 mg/dl (1.00-1.26), three month 1.40mg/dl (1.07-1.85), six month 1.34mg/dl (1.08-1.72) and twelve months 1.50mg/dl (1.33-1.62) after inhaled cyclosporine initiation; p=0.18. Conclusion Inhaled cyclosporine-based immunosuppression regimen is associated with stability of lung function in lung transplant recipients receiving reduced immunosuppression after diagnosis of malignancy

Risk factors for deterioration of liver functions after successful kidney transplantation

Increase of liver function is one of the most common complications after kidney transplantation due to the use of immunosuppressive therapy and hyperlipidemia in addition to hepatitis C virus (HCV) infection. Following the selection criteria (n = 59), the study is based on applied immunosuppressive therapy, baseline data of patients, further correlation between HCV and liver function deterioration. Patients were subjected to fasting laboratory examination to monitor serum electrolytes, uric acid and albumin levels. We looked at the effects of immunosuppressive therapy on the lipids (TG, TC, HDL, LDL) and liver enzymes (GOT, GPT, ALP, GGT). The analysis of the relationship between lipids and liver enzymes was also included in our study. The data basics were not significantly different between the tacrolimus and the cyclosporine groups. In the laboratory results, Mg levels were significantly different between the two groups (p = 0.044). The impact of HCV on the liver function was significantly different on GGT (p = 0.008). We examed the lipids and liver function level between the tacrolimus and the patients receiving cyclosporine-based immunosuppression and the total cholesterol (p = 0.005) and GOT (p = 0.05) were significantly different between the two groups. Hyperlipidemia was associated with 26% of patients taking tacrolimus-based immunosuppression, and 89% of those receiving cyclosporine; the difference was significant (p = 0.002). Regarding the effect of hyperlipidemia on liver enzymes, ALP (p = 0.006) and GGT (p = 0.0001) were significantly higher. Increases in hepatic enzymes, ALT and GGT indicate the damage to hepatocytes. Beside the increase of liver function, which is the main risk factor in hepatitis on HCV soil, the applied immunosuppressive therapy and hyperlipidemia lead to degradation of allograft function and long-term graft loss. Orv hetil. 2019; 160(5): 186-190.

Liver transplantation for hepatitis C virus (HCV) non-viremic recipients with HCV viremic donors.

In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing. Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12weeks posttreatment with DAA-based regimens, with a median time from transplant to treatment initiation of 43days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380days (IQR 263-434) posttransplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation.

Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients.

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation, and the effect of different immunosuppressive regimens on CAV is not fully understood. The randomized SCHEDULE trial (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) evaluated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine elimination can reduce CAV development. Methods and Results The SCHEDULE trial was a multicenter Scandinavian trial, where 115 de novo heart transplantation recipients were randomized to everolimus with complete cyclosporine withdrawal 7 to 11 weeks after heart transplantation or standard cyclosporine-based immunosuppression. Seventy-six (66%) patients had matched intravascular ultrasound examinations at baseline and 12 and 36 months. Intravascular ultrasound analysis evaluated maximal intimal thickness, percent atheroma volume, and total atheroma volume. Qualitative plaque analysis using virtual histology assessed fibrous, fibrofatty, and calcified tissue as well as necrotic core. Serum inflammatory markers were measured in parallel. The everolimus group (n=37) demonstrated significantly reduced CAV progression as compared with the cyclosporine group (n=39) at 36 months (Δ maximal intimal thickness, 0.09±0.05 versus 0.15±0.16 mm [ P=0.03]; Δ percent atheroma volume, 5.3±2.8% versus 7.6±5.9% [ P=0.03]; and Δ total atheroma volume, 33.9±71.2 versus 54.2±96.0 mm3 [ P=0.34], respectively]. At 36 months the number of everolimus patients with rejection graded ≥2R was 15 (41%) as compared with 5 (13%) in the cyclosporine group ( P=0.01). Everolimus did not affect CAV morphology or immune marker activity during the follow-up period. Conclusions The SCHEDULE trial demonstrates that everolimus initiation and early cyclosporine elimination significantly reduces CAV progression at 12 months, and this beneficial effect is clearly sustained at 36 months. Clinical trial registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01266148.

Adverse Events under Tacrolimus and Cyclosporine in the First 3 Years Post-Renal Transplantation in Children.

Progress in immunosuppression has reduced acute rejection, graft loss and mortality after renal transplantation. Adverse drug reactions are well described in adults but few data are available in children. Our objectives were to analyse the adverse events reported in the first 3years post-transplantation in children receiving tacrolimus or cyclosporine-based immunosuppression and compare them with the information of the Summary of Product Characteristics. This retrospective study included all children who underwent a renal transplant at Hospital Robert Debré between 2002 and 2015. Initial immunosuppression was based on induction, calcineurin inhibitor, mycophenolate mofetil and corticosteroids. Adverse events were collected from medical records and coded using the Medical Dictionary for Regulatory Activities and the implications of tacrolimus and cyclosporine analysed. Statistical analyses were performed using SAS 9.4. One hundred and twenty-five children were included. During the observation period [2.7 years (0.6-4.3)], 105 patients received tacrolimus and 39 received cyclosporine. The incidence rate for gastrointestinal disorders was 0.128 and 0.056 by patient-years of exposure (p<0.05), under tacrolimus and cyclosporine schedules. For neutropenia, it was 0.064 and 0.014 (p<0.05). The frequencies of toxic nephropathy and gastrointestinal pain were higher than those in the Summary of Product Characteristics of tacrolimus (>20%) and cyclosporine (>10%). Cosmetic events for cyclosporine and neutropenia for tacrolimus were frequently observed (18 and 14.3%, respectively), although uncommon in the Summary of Product Characteristics. The exposure-adjusted incidence rate of gastrointestinal disorders and neutropenia was higher in children under the tacrolimus schedule. Our findings contribute to the evaluation of the benefit-risk balance of immunosuppressive therapy following paediatric renal transplantation.

Giant Cell Myocarditis: A Brief Review.

Giant cell myocarditis (GCM) is a rapidly progressive and frequently fatal disease that mainly affects young to middle-aged previously healthy individuals. Early diagnosis is critical, as recent studies have shown that rapidly instituted cyclosporine-based immunosuppression can reduce inflammation and improve transplant-free survival. Before the 1980s, GCM was mainly a diagnosis made at autopsy. Owing to advancements in diagnostic and therapeutic options, it is now increasingly diagnosed on the basis of endomyocardial biopsies, explanted hearts, or apical wedge sections removed at the time of ventricular assist device placement. Histologic examination remains the gold standard for diagnosis; however, there are many possible etiologies for cardiac giant cells. Having a working knowledge of the clinicopathologic features that distinguish GCM from other giant cell-containing lesions is essential, since such lesions can have widely divergent management and outcome.

Costimulation Blockade in Kidney Transplantation: An Update.

In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.

Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients.

This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). Adult renal transplant recipients (n=361) on cyclosporine-based immunosuppression were followed for the first 6months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%). Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.

Belatacept and Long-Term Outcomes in Kidney Transplantation

BackgroundIn previous analyses of BENEFIT, a phase 3 study, belatacept-based immunosuppression, as compared with cyclosporine-based immunosuppression, was associated with similar patient and graft survival and significantly improved renal function in kidney-transplant recipients. Here we present the final results from this study.MethodsWe randomly assigned kidney-transplant recipients to a more-intensive belatacept regimen, a less-intensive belatacept regimen, or a cyclosporine regimen. Efficacy and safety outcomes for all patients who underwent randomization and transplantation were analyzed at year 7 (month 84).ResultsA total of 666 participants were randomly assigned to a study group and underwent transplantation. Of the 660 patients who were treated, 153 of the 219 patients treated with the more-intensive belatacept regimen, 163 of the 226 treated with the less-intensive belatacept regimen, and 131 of the 215 treated with the cyclosporine regimen were followed for the full 84-month period; all available data were used in the analysis. A 43% reduction in the risk of death or graft loss was observed for both the more-intensive and the less-intensive belatacept regimens as compared with the cyclosporine regimen (hazard ratio with the more-intensive regimen, 0.57; 95% confidence interval [CI], 0.35 to 0.95; P=0.02; hazard ratio with the less-intensive regimen, 0.57; 95% CI, 0.35 to 0.94; P=0.02), with equal contributions from the lower rates of death and graft loss. The mean estimated glomerular filtration rate (eGFR) increased over the 7-year period with both belatacept regimens but declined with the cyclosporine regimen. The cumulative frequencies of serious adverse events at month 84 were similar across treatment groups.ConclusionsSeven years after transplantation, patient and graft survival and the mean eGFR were significantly higher with belatacept (both the more-intensive regimen and the less-intensive regimen) than with cyclosporine. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00256750.)