Proliferation Signal Inhibitors Research Articles

A quantitative assessment of renal function utilizing albuminuria in pediatric heart transplant recipients.

Kidney disease is common after pediatric heart transplantation. Serum creatinine-based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients. This was a cross-sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin-to-creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019. In 115 patients at a median duration of 10.2 years post-transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria. Albuminuria is a prevalent finding in medium-term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria.

Assessment of the adverse effects of sirolimus versus everolimus in pediatric heart transplant recipients

Literature is limited comparing adverse effects (AEs) of the proliferation signal inhibitors (PSIs) sirolimus (SRL) and everolimus (EVL) in pediatric heart transplant (HTx) recipients. Single-center, observational cohort analysis assessing first use of SRL or EVL in pediatric HTx recipients <21 years of age with up to 2 years follow-up between 2009 and 2020. Eighty-seven patients were included, with 52 (59.8%) receiving EVL and 35 (40.2%) receiving SRL. Tacrolimus with PSI was the most common regimen. Intergroup comparison revealed lower baseline estimated glomerular filtration rate (eGFR) and greater increase in eGFR from baseline to 6 months and latest follow-up in SRL cohort compared to EVL cohort. There was greater increase in HDL cholesterol in SRL cohort compared to EVL cohort. Intragroup analysis revealed eGFR and HDL cholesterol increased significantly within SRL cohort, triglycerides and glycosylated hemoglobin increased in EVL cohort, and LDL cholesterol and total cholesterol increased in both cohorts (all p < .05). There were no differences in hematological indices or rates of aphthous ulcers, effusions, or infections between cohorts. Incidence of proteinuria was not significantly different among those screened within cohorts. Of those included in our analysis, one patient in SRL cohort (2.9%) and two in EVL cohort (3.8%) had PSI withdrawn due to AE. Low-dose PSIs in calcineurin inhibitor minimization regimens appear well-tolerated with low withdrawal rate secondary to AE in pediatric HTx recipients. While incidence of most AE was similar between PSI, our results suggest EVL may be associated with less favorable metabolic impact than SRL in this population.

Drug Levels After Proliferation Signal Inhibitors Initiation and Short-Term Outcomes in Ambulatory Heart Transplant Recipients

<h3>Purpose</h3> This study evaluated the impact of proliferation signal inhibitors (PSI) initiation on rejection and renal function based on drug levels in ambulatory heart transplant recipients. <h3>Methods</h3> This is a retrospective cohort study of heart transplant recipients (1994-2019) at Toronto General Hospital who were on tacrolimus (TAC) and initiated on PSI with TAC at any time after 6 months post-transplant. We collected baseline characteristics, renal function prior and post initiation, and episodes of treated cellular rejection 6 months prior to conversion and post conversion. Post-PSI initiation combined PSI and TAC levels were expressed as percentage increase or decrease at a month after PSI initiation in reference to TAC levels prior to PSI. Patients were in 3 groups according to relative drug levels post-PSI: decrease(>15% decrease), increase(>15% increase), and stable (-15% to +15%). Renal function was evaluated in relative terms comparing pre- and post-PSI glomerular filtration rate (GFR). We compared risk of rejection and mortality for one year follow-up post-PSI initiation using chi-square and renal function using one-way ANOVA. <h3>Results</h3> There were 99 recipients, median age of 53 (25th-75th percentile, 41-59), median time from transplant of 1.5 years (1.1-3.2). 28 of these patients experienced rejection 6 months prior to initiation. The median eGFR prior to initiation was 54 ml/min (42-71). Reasons for PSI were CAV (65%), impaired kidney function (16%), cancer (14%), and spurious (5%). 9 patients had decreased drug levels, 75 increased and 15 stable. Post-PSI combined levels were significantly higher in patients with increased levels (17±7 vs 11±4 in stable vs 19±3ng/ml in decreased, p<0.01) There were no differences in drug levels based on reasons for the change. Relatively eGRF 1-month post-PSI initiation increased significantly in patients with decreased levels (47%±89% increase in eGFR) compared to patients with stable (10%±21%) and decreased levels (4%±27%, p=0.01). There was no difference in risk of rejection across groups with different drug levels or reasons for PSI initiation. <h3>Conclusion</h3> We found that the main reason for PSI initiation in combination with TAC reduction was related to CAV followed by impaired kidney function. After PSI initiation, a relative decrease in drug levels was associated with improved renal function.

Feasibility of Prolonged Calcineurin-Inhibitor Free Immunosuppression After Lung Transplantation - A Retrospective Single Center Analysis

<h3>Purpose</h3> Data on Calcineurin-inhibitor (CNI) free Immunosuppression (IS) after lung transplantation is limited to case reports. Various IS agents are reproted as alternative to CNI including proliferation signal inhibitors (PSI), belatacept and induction agents. Aim of this study was to investigate indications and outcome of CNI-free IS in a large LTx cohort. <h3>Methods</h3> A retrospective single center analysis. All patients during in follow-up after LTx with a maintenance IS without CNI were included. Reasons for conversion to CNI-free IS, complications and outcome after conversion were recorded. <h3>Results</h3> Among 2,099 patients in follow-up, 51 (2.4 %) were identified on a CNI-free IS regimen. All 51 patients (29 males, median 56 years and 6.2 years after LTx at conversion) were converted to a triple drug regimen including PSI (n=7 sirolimus, n=44 everolimus), prednisolone and an antimetabolite (n=49 mycophenolate, n=2 azathioprine). Seventeen patients had pre-existing chronic lung allograft dysfunction (CLAD) before conversion. 26 patients (52 %) had malignancy without a curative intention as a reason for conversion from conventional IS with a 1-year survival of 36%. In 11 patients with malignancy and a curative approach survival was 100% and 64% after 1 and 5 years, respectively. 7 of these were re-converted to a CNI-based regimen later. In 14 patients without malignancy, CNI-free IS was used for median 985 days. Most common non-malignant indications were polyneuropathy (n=5) and infections (n=5). 4 of these patients were re-converted to a CNI-based regimen after 97 to 338 days. In patients without malignancy and those with malignancy and curative intention (n=25), survival was 96 and 84%,1 and 5 year after conversion to CNI-free IS respectively. Four of these patients developed CLAD 146 to 1,044 days after conversion. Neuropathy improved in all affected patients. In 31 evaluable patients, median glomerular filtration rate (GFR, CKD-EPI formula) declined from 55 to 51 and 48 ml/min/1.73 m² 6 and 12 months after conversion, respectively. <h3>Conclusion</h3> Prolonged CNI-free IS based on a PSI triple regimen is feasible in selected LTx-patients. Improvement was observed in patients with neurological complications. No significant changes in GFR were noted after conversion. The role of CNI-free IS in a palliative setting of malignancy is unclear.

A rare drug fever due to everolimus use in a patient with liver transplantation: a case report during the Covid-19 pandemic

Drug-induced fever (DIF) is an uncommon, difficult-to-diagnose complication which is one of the possible causes of fever of unknown origin (FUO). In addition, Covid-19 infection is also a cause of fever in these pandemic days we live. Everolimus (EVR), an inhibitor of the mammalian target of rapamycin (mTOR), is employed as an immunosuppressant in combination with calcineurin inhibitors, following a procedure of organ transplantation, and as a proliferation signal inhibitor coated on a drug-eluting stent and in cancer therapy. EVR has many adverse effects that require follow-up, but fever is not one of the well-known adverse effects thereof. In our literature search, we have found only a single case of fever due to EVR use which had been reported in a patient following a cardiac transplantation in 2004. On the other hand, our case is a patient with a diagnosis of alcohol-induced liver cirrhosis and hepatocellular carcinoma (HCC) who has been subjected to a liver transplantation (LT) has developed fever in the course of our follow-up just after the initiation of EVR treatment at the third month post-transplantation and during the covid-19 pandemic.

Donor Heart Coronary Calcification: Do We Take This Donor Heart?

<h3>Purpose</h3> The donor shortage in heart transplantation (HTx) has led to programs accepting older donors. Coronary calcification is common in older people and is known to correlate with underlying coronary artery disease. It is not known whether these donors with coronary calcification impart an increased risk for the recipient to develop cardiac allograft vasculopathy. <h3>Methods</h3> Between 2010 and 2017, we assessed 31 heart transplant patients who were found to have coronary calcification within the first 3 months after heart transplantation, either by coronary angiography or chest CT scans. These patients were compared to a contemporary cohort of 192 patients (transplanted with donors >30 years old) without coronary calcification for the following outcomes: 3-year survival, 3-year freedom from cardiac allograft vasculopathy (CAV, as defined by stenosis ≥30% by angiography), 3-year non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke), and 1-year freedom from any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). <h3>Results</h3> Those patients with donor coronary calcification compared to those without had a significantly lower 3-year freedom from CAV (64.5% vs 85.9%, P=0.001). There was no significant difference in 3-year survival, freedom from NF-MACE, and 1-year rejection episodes. The severity of CAV observed in the donor coronary calcification group included: CAV1 = 13, CAV2 = 1, CAV3 = 0. <h3>Conclusion</h3> Donor coronary artery calcification appears to be a marker for greater risk for developing CAV after heart transplantation. Caution must be taken to accept these organs and if accepted, early modification of immunosuppression with a proliferation signal inhibitor may be indicated.

Mechanistic Target of Rapamycin (mTOR) Inhibitors.

Mechanistic target of rapamycin (mTOR) inhibitors are macrocyclic lactone antibiotics derived from Streptomyces hygroscopicus that prevent T lymphocyte activation and B cell differentiation. Unlike calcineurin inhibitors (CNIs) that inhibit cytokine production, mTOR inhibitors block the cytokine signal transduction to arrest cells in the G1 to S phase. This class of drugs is commonly used for post-transplantation and cancer management because of its immunosuppressive and antiproliferative properties, respectively. The potential uses of mTOR inhibitors are heavily explored because of their impact on cell growth and proliferation. However, mTOR inhibitors have a broad range of effects that can result in adverse reactions, but side effects can occur with other immunosuppressive agents as well. Thus, the performance of mTOR inhibitors is compared to the outcomes and adverse effects of other immunosuppressive drugs or the combination of other immunosuppressants and mTOR inhibitors. Because mTOR regulates many downstream pathways, mTOR inhibitors can affect these pathways to manage various diseases. Sirolimus (rapamycin) is approved by the Food and Drug Administration (FDA) to treat post-renal transplantation and lymphangioleiomyomatosis (LAM). Everolimus is approved by the FDA to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC), renal angiomyolipoma (AML) and tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation. Temsirolimus is approved by the FDA to treat advanced RCC. Opportunities to use mTOR inhibitors as therapy for other transplantation, metabolic disease, and cancer management are being researched. mTOR inhibitors are often called proliferation signal inhibitors (PSIs) because of their effects on proliferation pathways.

Heart Transplant Immunosuppression Strategies at Cedars-Sinai Medical Center.

Heart transplant is the optimal treatment for selected patients with end-stage heart failure. Immunosuppression after heart transplantation has significantly reduced the incidence of rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes as well. The goal of induction therapy is to provide intense immunosuppression when the risk of allograft rejection is highest. Most maintenance immunosuppressive protocols employ a 3-drug regimen consisting of a calcineurin inhibitor, an antimetabolite agent and glucocorticoids. The management of rejection proceeds in a stepwise fashion based on the severity of rejection detected on biopsy and the patient's clinical presentation. This review will cover induction, maintenance, rejection therapy and some special considerations including sensitization, renal sparing protocol, and corticosteroid weaning. It will end in consideration of potential future directions in immunosuppressive strategies to promote patient and graft survival.

Risk factors for early development of cardiac allograft vasculopathy by intravascular ultrasound.

Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss. While there are numerous post-transplant factors which may increase the risk of the development of CAV, there is a paucity of data on the impact of donor-derived atherosclerosis (DA), early discontinuation of prednisone, and early initiation of proliferation signal inhibitors (PSI) as assessed by intravascular ultrasound (IVUS). Retrospective single-center study of all adult transplant patients (2008-2017) with serial IVUS at baseline and annually for 5years. DA was defined as a baseline maximal intimal thickness (MIT) ≥0.5mm, and CAV development was defined as MIT ≥1mm or an increase in MIT ≥0.5mm at year 1 compared with baseline or an increase in 0.3mm annually thereafter. Clinical risk factors for CAV were identified using multivariable hazard regression. Separate multistate models were applied to assess the association of prednisone discontinuation and PSI initiation and CAV. Of 282 patients screened, 186 patients had a 1-year angiogram. The mean age of those included in the cohort was 51±11years, 70% were male, 58% were Caucasian, and 27% were supported by a left ventricular assist device. Donor atherosclerosis was present in 40%. The cumulative incidence of CAV at 5years is 41% in DA- vs. 59% in DA + (p=.012). Donor age was a strong predictor of DA (p=.016). Significant risk factors for CAV included male sex (HR=4.141, p=.001), non-Caucasian race (HR=1.98, p=.011), BMI<18kg/m2 (HR=4.596, p=.042), longer ischemic time (HR=1.374, p=.028), older donor age (HR=1.158, p=.009), and rejection with hemodynamic compromise within the first year (HR=2.858, p=.043). Prednisone discontinuation within 1year was associated with a lower risk of CAV (HR 0.58 p=.047). Initiation of proliferation signal inhibitors (PSI) within 2years resulted in fewer cases of CAV (HR 0.397 p<.001). In patients with an angiogram at 1year, those with DA were significantly more likely to develop CAV. Lower incidence of CAV by IVUS was seen in patients who discontinued prednisone in the first year or had initiation of a PSI within two years of transplantation. Knowledge of early IVUS may allow a more tailored approach to patient management.

Outcomes after Early Initiation of mTOR-Inhibitors in Adult Cardiac Transplant Recipients

Purpose The effect of mTOR-inhibitors initiated as maintenance immunosuppression early after cardiac transplant is not well-established. Current outcomes data are limited to small, single-center studies. Methods 22,173 adult cardiac transplant recipients from the United Network for Organ Sharing database between 2008 and 2018 were included in current study. Propensity-matching was carried out to match 184 patients started on proliferation signal inhibitor (PSI) maintainence therapy (sarolimus or everolimus) before discharge with 184 controls. Outcomes included mortality/graft failure, development of coronary artery disease, infection, and acute rejection. Results PSI and No PSI cohorts were well-matched with regards to age (40.4 vs. 50.6), gender (32% vs. 30% females), race (60% vs. 63% white), LVAD use (28% vs. 30%), UNOS status (54% vs 55% 1A), HF etiology (32% vs 31% ischemic), and other immunosuppressive medication use (all p=NS). Compared to controls, PSI group had significantly lower rates of coronary artery disease (17.8%, 95% CI 12.1%-24.4% versus 27.9%, 95% CI 20.9%-35.5; P=0.04) (Figure). However, risk of hospitalization for rejection (36.1% vs. 23.7%, p=0.043) and hospitalization for infection (40.6% vs. 28.8%, p=0.011) at 5 years were significantly higher in the PSI group. Mortality and graft failure rates were comparable between PSI and No PSI groups. Conclusion mTOR-inhibitors initiated early as part of a maintenance immunosuppression regimen may reduce the long-term risk of developing coronary artery disease at the expense of higher risk of rejection and infection in adult cardiac transplant recipients. These findings suggest that switching to PSI at a later time point may be a more effective strategy in minimizing post-transplant complications compared to early initiation of PSI.

The Gift That Keeps on Giving? The Impact of Donor Coronary Atherosclerosis on the Development of Coronary Allograft Vasculopathy by IVUS

Purpose Cardiac allograft vasculopathy (CAV) is a leading cause of late graft loss . While there are numerous risk factors for the development of CAV, there is a paucity of data on the impact of donor derived atherosclerosis (DA), particularly as assessed by intravascular ultrasound (IVUS). Methods Retrospective single center study of all adult transplant patients (2008-2017) with serial IVUS at baseline and annually upto 5 years. DA was defined as a baseline maximal intimal thickness (MIT) ≥ 0.5 mm, CAV development was defined as MIT ≥ 1 mm or an increase in MIT ≥ 0.5 mm at year 1 or an increase in 0.3 mm annually thereafter. Clinical risk factors for CAV were identified using parametric hazard regression. Separate multistate models were applied to assess the association of prednisone discontinuation, proliferation signal inhibitors (PSI) initiation with CAV. Results Of 284 patients transplanted, 186 patients survived and had an IVUS at 1 year. Mean age of 51 ± 11 years, 70% male, 58% Caucasian with 27% supported by LVAD and 40% had DA. Patients who developed CAV at 1-year had longer ischemic times (4 vs. 3.7 hours, p=0.03), DA+ (65% vs. 39%, p=0.047) and older donor age (40 vs. 33 years, p=0.03). The 5-year cumulative incidence of CAV 41% in DA- vs. 59% in DA+ (Fig 1A). Significant risk factors for CAV were male sex HR 4.1, non-Caucasian race HR 2, underweight (BMI hemodynamic rejection within 1 year HR 2.9. Initiation of PSI within 2 years for reasons other than CAV resulted in fewer cases of CAV HR 0.40 p Conclusion In patients with a baseline and yearly IVUS, DA was more prevalent HR 2 in recipients who developed CAV. Reductions in CAV were seen in patients who discontinued prednisone in the first year or had early PSI initiation for reasons other than CAV. Early IVUS results may allow physicians to tailor immunosuppression and potentially delay progression of CAV.

The Major Adverse Transplant Events (MATE) Score Applied to a Cohort of Pediatric Heart Transplant Recipients

Purpose The MATE score evaluates a surrogate end-point comprised of MATEs that predict graft loss. The first major pediatric heart transplant (PHTX) drug study, TEAMMATE, will use the MATE score as a primary end point. We have applied a calcineurin inhibitor (CNI) minimization strategy via early transition to a proliferation signal inhibitor (PSI) since 03/11, similar to the protocol employed in the TEAMMATE study. We sought to apply the MATE score to our population. Methods All PHTX patients between 03/11-12/14 surviving to 4-mo post-HTX with 36-mo of follow-up formed the study cohort. An equal number of HTX patients from a similar prior period formed the control cohort. Study subjects followed the early transition to PSI protocol, while the control subjects remained on mycophenolate (MMF). Statistical analyses were similar to those described for the TEAMMATE study. Results Twenty-seven subjects formed each group. At study end, 77% of study subjects vs. 24% of control subjects remained on protocol. A baseline-adjusted comparison of mean MATE-3 scores at 36-mo post-HTX did not suggest a difference in efficacy between the groups (ANCOVA p = 0.50). The longitudinal linear mixed effects regression (lmer) model assessing differences in MATE-3 scores over time was not different between the groups either (p = 0.74). Safety, assessed by Tukey's Honest Significant Difference between 36-mo MATE-6 scores, was similar between the groups as well. An upper 95% confidence limit difference of +0.56 was found and is within the acceptable safety range. Lower age ( Conclusion In this small group of PHTX patients following treatment regimens similar to those found in the TEAMMATE study with a high control cross over rate, safety and efficacy seem to be similar. In older patients however, early transition to a PSI-based regimen may improve long-term outcomes.

Undue Infection Risk from Proliferation Signal Inhibitors When Initiated Later after Heart Transplantation

Purpose Proliferation signal inhibitors (PSIs) have been shown to decrease the incidence of cardiac allograft vasculopathy (CAV) and rejection in clinical trials when given at the time of heart transplantation. These trials have also demonstrated that patients on PSIs have a reduced risk of CMV infection post-transplant. However, the effect of PSIs on overall infection rates when given later post-transplant has not been clearly delineated. We sought to evaluate the incidence of infection post-PSI initiation at our single center. Methods Between 2010 and 2015 we assessed 550 heart transplant patients, 187 of which were initiated on a PSI (sirolimus or everolimus) over a five-year period after heart transplant. Endpoints included subsequent 2-year survival and subsequent 2-year freedom from infection (including CMV). A control population with patients not initiated on a PSI (n=363) was also included. Results 187/550 (34.0%) of heart transplant patients were initiated on a PSI over a five-year period after heart transplant. Patients were initiated on a PSI due to rejection, malignancy, CMV viremia, CAV, circulating antibodies, renal insufficiency and infection. The average time to PSI initiation was 1.3 years. Patients on a PSI compared to patients on no PSI had significantly reduced subsequent 2-year survival and reduced subsequent 2-year freedom from infection (see table). There was no difference in subsequent 2-year freedom from CMV infection. Conclusion PSI initiation later after heart transplant is associated with less than optimal outcomes. However, as PSI is used in high-risk patients, the outcomes are not unexpected but PSI use may have increased infection risk. PSI should be used with caution in these patients.

Thrombotic events with proliferation signal inhibitor‒based immunosuppression in cardiac transplantation.

Some literature exists potentially linking proliferation signal inhibitors (PSIs) to venous thromboembolism (VTE). We sought to determine the impact of PSIs on development of VTE in heart transplant (HT) patients while controlling for other risk factors. The incidence and predisposing factors of VTE were analyzed in this retrospective review of patients >18 years who underwent HT January 2000 to October 2016. Re-transplants, multiorgan transplants, or patients that expired within 30 days post-HT were excluded. VTE incidence rates are reported as number of events per 100 person-years. Cox proportional hazards models were used to assess the relationship between PSI exposure (time-varying covariate) and VTE. Of 561 HT recipients, 112 received PSIs, started a median of 1.5 years post-HT. There were 102 total VTE events: 78 in PSI-naive patients during 2,547 patient-years (3.0 events per 100 person-years) vs 24 in PSI-exposed patients during 544 patient-years (4.4 events per 100 person-years). Cox proportional hazards models with PSI exposure as a time-varying covariate indicated the increased risk was statistically significant (unadjusted hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.31 to 3.49, p = 0.002). A VTE history was significantly associated with increased risk of VTE post-HT (HR 1.58, 95% CI 1.07 to 2.35, p = 0.022); however, the risk remained significant when adjusting for potential confounders, including previous VTE (HR 2.0, 95% CI 1.18 to 3.38, p = 0.010). Exposure to PSIs is associated with a significant increase in risk for VTE even when controlling for other risk factors. When considering the use of PSI-based immunosuppression after HT, the risk of VTE over time should be weighed against the potential benefit.

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.

Review of Major Drug-Drug Interactions in Thoracic Transplantation

The first human lung transplant surgery in the world was done in 1963, followed by the first heart transplant in 1967, making this year its 50th anniversary. Since then, there has been great advancement in immunotherapy, with the adoption of calcineurin inhibitors (CNI), mycophenolate mofetil, and proliferation signal inhibitors (PSI). However, while these medications are crucial to maintenance of allograft function and prevention of allograft rejection, they have many toxicities and side effects, which make therapeutic dose monitoring and recognition of drug-drug interactions of critical importance. Most of drug-drug interactions in transplant medicine can be explained through the mechanism of CYP3A4 and P-glycoprotein. A large component of the medical management of post-transplant care is in the appropriate utilization of immunosuppression drugs while minimizing side effects and drug-drug interactions.

Thrombotic Events With PSI Based Immunosuppression in Cardiac Transplantation

Proliferation signal inhibitors (PSIs) are often introduced after heart transplant (HT) in patients with renal dysfunction or cardiac allograft vasculopathy (CAV). Limited literature exists potentially linking PSIs to venous thromboembolism (VTE). We sought to determine the impact of PSI on development of VTE in a large population of HT recipients.

The Effect of Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal on Allograft Vasculopathy in De-Novo Heart Transplant Recipients: Results of the Schedule Trial after 6 Years

The SCHEDULE (Scandinavian heart transplant everolimus de-novo study with early calcineurin inhibitors avoidance) trial has sought to evaluate whether initiation of the proliferation signal inhibitor everolimus and total early cyclosporine elimination can significantly reduce the development of CAV in de-novo HTx recipients. We have previously reported that patients treated with everolimus demonstrated significantly reduced CAV progression when compared to cyclosporine therapy at both 12 and 36 months (12-month IVUS examination revealed ∆Maximal Intimal Thickness (MIT) 0.02±0.05 versus 0.08±0.12 mm (p<0.01), ∆Percent Atheroma Volume (PAV) 1.2±2.0 versus 3.7±4.1% (p<0.01), ∆Total Atheroma Volume (TAV) -0.13±20.5 mm3 versus 11.1±27.6 mm3 (p=0.08) and 36-month examination showed ∆MlT 0.09±0.05 versus 0.15±0.16 mm (p=0.01), ∆PAV 5.4±3.1 versus 7.6±5.9% (p=0.02), ∆TAV 33.9±71.2 mm3 versus 54.2±96.0 mm3 (p=0.26), respectively). Treatment according to study arm has been further extended to a total treatment period of 6 years and the IVUS results of this follow-up period will be presented. In addition, Virtual Histology (VH) data will be included to assess the morphological changes associated with everolimus treatment.

Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance (Schedule): Results After 6 Years of Follow-up

The SCHEDULE trial investigated whether initiation of the proliferation signal inhibitor everolimus and early cyclosporine avoidance could improve renal function and reduce cardiac allograft vasculopathy in de-novo heart transplant recipients. After 12 months, we reported significantly higher measured glomerular filtration rates (mGFR) among patients treated with everolimus vs. conventional cyclosporine (79.8±17.7 vs. 61.5±19.6 mL/kg/1.73 m2; p<0.001), and significantly reduced incidence of cardiac allograft vasculopathy (CAV) (50.0% vs. 64.6%; p=0.003) and CAV progression (Δ maximal intimal thickness; 0.03±0.06 vs. 0.08±0.12 mm; p<0.01) assessed by IVUS. Both developments in mGFR and CAV remained significantly in favor of everolimus treatment also in our reports after 36 months. With a further extension of the treatment period to 6 years, results of renal function and CAV according to study arm will be presented.

Role for primary immunosuppression with everolimus after pulmonary transplantation

PurposeEverolimus is a proliferation signal inhibitor used for triple immunosuppressive therapy following solid organ transplantation. Its positive benefits, such as reduction of acute rejection episodes and reduced nephrotoxicity have been shown in kidney- as well as heart transplantation. However the role of everolimus is less well defined in lung transplantation. We thus wished to study the effect of primary immunosuppression with everolimus in a preclinical large animal lung transplantation model. MethodsLeft-sided single lung transplantation from MHC-mismatched donors was performed in 11 adult minipigs. Intravenous pharmacologic immunosuppression was maintained for 28 days with 1.5 mg/kg/d methylprednisolone, 1.0 mg/kg/d azathioprine and cyclosporine A (blood levels 300-500 ng/ml; CsA group; n = 5). A further group (CsA + Ev; n = 6) received methylprednisolone, CsA (200–300 ng/ml) and Everolimus (5–10 ng/ml). Immunosuppression was discontinued on postoperative day (POD) 28. Graft survival was monitored by sequential chest X-rays, bronchoscopies and transbronchial biopsy histology. ResultsAll animals survived the 28 day course of immunosuppressive therapy and showed healthy grafts on POD 28. Median allograft survival in the CsA group was 55 ± 15 days. CsA + Ev grafts showed median survival of 49 ± 86 days (p = 0.37). ConclusionWhereas everolimus might be advantageous as maintenance immunosuppressive agent, this data does not support an important role for everolimus in the immunosuppressive induction phase following lung transplantation.