Immunosuppression In Cardiac Transplantation Research Articles

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.

Incidence of cytomegalovirus in cardiac transplant recipients receiving induction immunosuppression with antithymocyte globulin.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in cardiac transplant recipients. Use of induction immunosuppression in cardiac transplantation may have an impact on the incidence of CMV, but literature is limited. Single-center, retrospective cohort study comparing the risk of CMV infection and disease in cardiac transplant patients receiving antithymocyte globulin (ATG) induction therapy to those receiving no antibody induction. A total of 75 patients were included in our analysis, 50 who received ATG induction and 25 who did not. CMV infection occurred in 10 (20%) and 5 (20%) patients in the ATG and No ATG groups, respectively (P > 0.99). CMV disease occurred in 10 (20%) and 4 (16%) patients in the ATG and No ATG groups, respectively (P = 0.763). The median time from transplant to CMV infection was 200.0 [142.5, 364.5] days in the ATG group vs 221.0 [192.0, 299.0] days in the No ATG group (P = 0.723). The median time from end of CMV prophylaxis to CMV infection was 94.5 [66.5, 151.0] days in the ATG group vs 53.0 [41.0,149.5] days in the No ATG group (P = 0.202). Freedom from CMV infection was highest in the D+/R+ group and lowest in the D+/R- group. In cardiac transplant recipients, ATG induction was not associated with an increased incidence of CMV infection or disease in the setting of valganciclovir prophylaxis and an initial maintenance immunosuppression regimen of primarily steroids, mycophenolate mofetil, and tacrolimus.

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.

Quest for Lower Immunosuppression in Cardiac Transplantation: an Analysis of the TICTAC Trial

Evaluation of: Baran DA, Zucker MJ, Arroyo LH et al.: A prospective, randomized trial of single versus dual drug immunosuppression in heart transplantation: the Tacrolimus in Combination, Tacrolimus Alone Compared (TICTAC) trial. Circ. Heart Fail. 4(2), 129-137 (2011). Success in cardiac transplantation has been attributed to improved immunosuppressive regimens. Conventionally, patients are treated with a triple regimen following transplantation, consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), antiproliferative agent (mycophenolate mofetil) and corticosteroids. These agents, however, are associated with a significant morbidity which has prompted a quest for minimization of immunosuppressive regimens; a challenging goal, given the potential for allograft rejection particularly early after transplantation. This article reviews a recent study by Baran and colleagues who boldly challenged the notion that triple immunosuppression is a prerequisite for success after cardiac transplantation. The authors successfully demonstrate the feasibility of weaning corticosteroids and mycophenolate mofetil early after cardiac transplantation, maintaining patients solely on monotherapy with tacrolimus. This evaluation focuses on the findings and limitations of the study and provides the historical background which led to this promising clinical trial.

305: Mid-Term Results of Campath Induction and Steroid-free Maintenance Immunosuppression in Cardiac Transplantation

305: Mid-Term Results of Campath Induction and Steroid-free Maintenance Immunosuppression in Cardiac Transplantation

Induction Immunosuppression with Anti-CD25 Monoclonal Antibody (Basiliximab) Allows Delayed Initiation and Uptitration of Calcineurin Inhibitor Post Cardiac Transplant

Background:The role of anti-CDmonoclonal antibodies in induction immunosuppression for cardiac transplantation remains unclear. This study sought to determine if basiliximab allows delayed commencement, slower uptitration and reduced nephrotoxicity or allograft rejection with cyclosporin. Methods: We performed retrospective analysis of cardiac transplant patients on cyclosporin, mycophenolate mofetil, and corticosteroids and compared the results depending on whether they received basiliximab post transplant. Data was collected for 21 days post transplant. Exclusion criteria: <18 yrs old, alternative immunosuppression, multi-organ transplant. Results: 39 patients studied (basiliximab: 22; nonbasiliximab: 17). More patients in the non-basiliximab group were ex-smokers (71% vs. 32%, p= 0.025) and type 2 diabetics (35% vs. 4.5%, p= 0.03) but had similar demographics for stroke, hypertension, mechanical support and indication for transplant. No patients received OKT3 or antithymocyte globulin. Time to cyclosporin initiation (mean± 1SD) was 0.12± 0.35 days for non-basiliximab versus 1.50± 2.54 days for basiliximab (p= 0.003). Therapeutic cyclosporin levels (250–300mg/L) were reached later in the basiliximab arm (11.1± 3.7 days) versus (17.1± 7.4 days) (p= 0.003). There was a trend to decreased Grade 3 rejection on day 14 in the basiliximab arm (p= 0.09). There were no significant differences in average creatinine clearance between the groups within the initial 21 days (p= 0.71). Conclusion: Post cardiac transplant, basiliximab allowed delayed initiation and time to therapeutic trough levels of cyclosporin with a trend to decreased severe rejection on day 14. Nephrotoxicity was not reduced. A larger study group is needed to evaluate basiliximab’s effect on rejection rate and renal function.

Immunosuppression in cardiac transplantation: state of the art and new drugs

Immunosuppression in cardiac transplantation: state of the art and new drugs

Analysis of an antibody pharmaceutical, tocilizumab, by capillary electrophoresis using a carboxylated capillary

Antibody pharmaceuticals are becoming more and more prevalent due to their excellent effectiveness in clinical medications, and are expected to allow tailor-made medical treatment for rheumatic diseases, immunosuppression in cardiac transplantation, and cancer. Antibody-type pharmaceuticals of immunoglobulin G (IgG) commonly have N-glycosylated carbohydrate chains attached to heavy chains. The carbohydrate chains play important roles in the effectiveness of antibodies. Therefore evaluation of a glycosylated species is important in the first step of quality control of antibody pharmaceuticals. In the present work, we examined capillary electrophoresis with a newly developed, chemically modified capillary, the inner surface of which is modified with carboxyl groups, for evaluation of IgG molecular species which have carbohydrate chains; tocilizumab was used as a model. The analytical system developed in the present study is useful for determining the content of non-glycosylated peptides. In the analysis of tocilizumab, the ratio of non-glycosylated peptide was estimated to be 1.23% with a relative standard deviation of 3.05%. The method affords high reproducibility with simple operation, and analysis can be completed within 6 min.

Increased rejection rates in cardiac transplant associated with dexamethasone

Background Peri-operative immunosuppression in cardiac transplantation includes the use of intravenous methylprednisolone. During a national shortage, intravenous dexamethasone was substituted for methylprednisolone at standard equivalencies. Methylprednisolone and dexamethasone are used interchangeably in many clinical settings; however, their equivalency has not been demonstrated. Methods Forty-two consecutive cardiac transplant patients were studied retrospectively. All patients received standard triple immunosuppression. Eighteen patients received dexamethasone and 24 methylprednisolone. Twelve patients were included for comparison after the methylprednisolone shortage resolved. Endomyocardial biopsy (EMB) results graded as ≥1B (ISHLT classification) were considered positive for acute cellular rejection. Results More patients who received dexamethasone as induction had cellular rejection (12/17; (70%) vs. 14/33; (42%); p = 0.05). Four patients were excluded because of deaths unrelated to cardiac function. The increased rate of rejection seen during dexamethasone substitution declined after reinstitution of methylprednisolone ( p = 0.05). Conclusions Peri-operative high-dose dexamethasone in cardiac transplants was associated with higher rates of acute cellular rejection. The equivalencies of dexamethasone and methylprednisolone differ from accepted standards when used in pulse doses. Peri-operative use of glucocorticoids may rely on mechanisms that are different from those considered in the standard equivalency measures. Pulse doses of dexamethasone and methylprednisolone in transplantation may not be interchangeable at standard equivalencies.

Tacrolimus in cardiac transplantation

The availability of effective immunosuppressive agents has allowed cardiac transplantation to become an accepted treatment for patients with end-stage heart disease. In recent years, tacrolimus has emerged as a useful alternative to cyclosporine, combined with either azathioprine or the newer antiproliferative agents, mycophenolate mofetil or sirolimus. A number of randomized clinical trials have shown tacrolimus to be comparable with cyclosporine regarding survival and the drug also demonstrates equivalent or improved prophylaxis against acute rejection. The adverse effects of tacrolimus differ from cyclosporine and the drug demonstrates a particularly improved profile with respect to hypertension and dyslipidemia. These data have recently led to regulatory approval of tacrolimus for primary immunosuppression in cardiac transplantation in the USA.

Does a sirolimus - based immunosuppression in calcineurin inhibitor-free regime improve chronic renal failure in cardiac transplant recipients independent from blood pressure?

The standard immunosuppression in cardiac transplantation (CTX) includes calcineurin inhibitors (CNI) to prevent allograft vasculopathy as limiting factor of graft survival. The most important side effect of CNI is the multifactorial pathogenesis of chronic renal failure after HTX. Progression to end-stage renal failure is worsening the cardiac transplant outcome. To prevent of futher nephrotoxicity, immunosuppression in cardiac transplant recipients has been changed to a CNI-free immunosuppressive regime with sirolimus. Sirolimus (SIR) is one of the new powerful immunosuppressants with antiproliverative and antimigratory properties on cells by binding to FK 506-binding protein. In our prospective observational study 26 patients (1 female, 25 male) with chronic renal failure, grade II-III, 2 to 13 years after cardiac transplantation have been included and switched overlapping from a former triple drug CNI-containing regime containing mycophenolate mofetil or azathioprine and prednisolone to a drug regime with sirolimus instead of CNI. The blood pressure, s-creatinine and creatinine clearance was measured regularly before and after CNI withdrawal and switch to SIR. During the 17- to 27-month follow-up cardiac transplant status including blood pressure and renal function was examined every 1–3 months. No acute CTX-rejection occured during follow-up. Prior to conversion the serum-creatinine ranged from 1.9 – 3.9 mg/dl. Without significant changing of the blood pressure after withdrawal of CNI to SIR, CTX patients with CNI-induced renal failure showed a recovery of the renal function within the first months. The decrease of s-creatinine was up to 1.1 mg/dl. Nevertheless, in the following month, an increase in s-creatinine was observed again. In CTX-recipients with CNI-induced chronic renal failure, conversion from CNI to SIR is safe, shows no significant effect to the blood pressure and anticipates cardiac graft rejection. CNI withdrawal and SIR introduction can slow progression of renal failure. To prevent CNI nephrotoxicity after CTX, SIR-based immunosuppression should be considered in earlier stages of renal failure.

Immunosuppression for cardiac transplantation—the past, present and future

The field of cardiac transplant immunosuppression is rapidly developing and has evolved over the past 35 years. Anecdote, experience and registry based practice is giving way to an increasing bounty of well designed, randomized controlled trials which will guide future therapy. Current therapy is based on triple therapy with corticosteroids, a calcineurin inhibitor and an antimetabolite, but these regimens may be replaced by substitution or addition of newer antiproliferative agents. The true nemesis is coronary graft vasculopathy, which affects 50% of patients at 5 years and until recently had very few preventive therapeutic options. Renal toxicity remains among the most challenging adverse effects of immunosuppression to be overcome.

The challenge of rejection and cardiac allograft vasculopathy.

Since the first human heart transplantation was performed in 1967, the field of heart transplantation has advanced to the point where survival and acceptable quality of life are commonplace. Despite remarkable progress in the clinical management of rejection, rejection continues to limit survival and quality of life in the heart transplant population. This review will discuss the biologic processes involved in hyperacute rejection, acute rejection, and humoral (vascular) rejection. The development of endomyocardial biopsy techniques represented a significant advancement in the diagnosis of cardiac rejection, and endomyocardial biopsy remains the 'gold standard' in the diagnosis of cellular rejection. To date, no noninvasive parameters will diagnose rejection with adequate sensitivity and specificity. Biopsy frequency and immunosuppressive therapies may be tailored to the risk of rejection. Immunosuppression for cardiac transplantation can be divided into three major phases: 1) perioperative immunosuppression; 2) maintenance immunosuppression, and; 3) treatment of rejection. The strategy for treating transplant rejection should be influenced by several variables: 1) Histologic grade of rejection; 2) Evidence of hemodynamic compromise by ejection fraction or right heart catheterization; 3) Severity of previous rejection episodes and types of immunosuppressives used; and 4) Risk factors for rejection, including time after transplantation. Future rejection therapy will involve more sophisticated attempts to alter host responses toward the donor organ in a more specific and selective way. Despite considerable advances in the care of the heart transplant recipient, long-term survival is limited by cardiac allograft vasculopathy. The final section of this chapter will review the pathology, immunopathology, nonimmunologic risk factors, diagnosis, prevention and treatment of allograft vasculopathy.

Cardiac Transplant Patient at One Year: Cyclosporine vs Conventional Immunosuppression

From March 1, 1979 thru September 30, 1984 we performed 56 cardiac transplants (Tx). The first 32 patients received conventional immunosuppression therapy consisting of azathioprine/prednisone (I/P), while the subsequent 24 patients received cyclosporine/prednisone (C/P). Twenty-one of 32 I/P patients ages 39 +/- 3 years (SEM), and 16 of 24 eligible C/P patients ages 36 +/- 3 years, survived one year with follow-up through September 30, 1985. The one year post-transplant course of these 37 patients was evaluated by chart review. While donor ages are similar, ischemic time was shorter in the conventionally treated patients. The initial hospital stay for I/P vs C/P was 67 +/- 6 vs 33 +/- 3 days (p less than .05), at a total cost of $49,900 +/- $5,800 vs $53,800 +/- $10,000. During the first year following transplantation, the I/P patients required an additional 34 +/- 7 days of hospitalization, while C/P patients required 16 +/- 10 days. Over the first year, the number of infections and rejections differed at 2.8 +/- 0.6 per I/P patient vs 1.2 +/- 0.3 per C/P patient, and 2.5 +/- 0.4 per patient vs 1.5 +/- 0.3 per patient respectively (p less than .05). Renal function test results were better in the I/P group. Results of cardiac catheterization performed at one year were similar except for cardiac index and stroke volume index, both being higher in the C/P group. Coronary anatomy was considered normal in all. These data indicate that while overall survival is similar, a shortened post-transplant hospital course with fewer necessary hospitalizations, rejection episodes and infection episodes characterizes the first year in survivors receiving C/P immunosuppression. While both groups had multiple hemo-dynamic abnormalities as compared to normal subjects, cardiac index and stroke volume index were improved in the C/P group. Therapy with C/P represents an advance in immunosuppression for cardiac transplantation as compared to I/P; however, decreased renal function and diastolic hypertension were problems in the C/P group.

Improved Immunosuppression for Cardiac Transplantation: Immune Monitoring and Individualized Modulation of Recipient Immunity by In Vitro Testing

These studies demonstrate that immune monitoring and individualized modulation of recipient immune reactivity using a quality-controlled preparation of rabbit antithymocyte globulin can improve results of cardiac transplantation. The most valuable assay in individualizing drug doses was the serial measurement of T-cell levels using a complete lymphocyte profile technique and monitoring with phytohemagglutinin to rule out false low T-cell levels. Using this system, the incidence and severity of early rejections were markedly reduced and no grafts were lost to rejection in the first month. The recent first-year graft survival has been about 60%, an improvement largely related to a reduction in early rejection and infection. This technique of immunosuppression appears quite promising for improving the results of future cardiac transplantations.