Conversion of cyclosporine A to tacrolimus following heart transplantation

BACKGROUND: Cyclosporine A (CyA) is ususally the immunosuppressive drug of choice in organ transplantation; however, some side effects have limited its use. Tacrolimus is a novel immunosuppressive drug that is more potent than CyA, and has been used as a rescue agent following heart transplantation when the use of CyA is undesirable or inefficient. PATIENTS AND METHODS: Since 1996, 14 heart transplant recipients under CyA were switched to tacrolimus therapy, for refractory rejection or intolerance, to conventional immunosuppression. RESULTS: After a mean of 35+/-7 months of treatment, tacrolimus was substituted for CyA therapy. The reason for substitution was refractory rejection in six patients, gingival hypertrophy in five patients, hypertrichosis in one patient, severe arterial hypertension in one patient and hepatotoxicity in one patient. Five patients underwent a successful rescue therapy and one patient died of refractory rejection despite the use of tacrolimus. All patients with CyA side effects recovered with tacrolimus. After conversion from CyA to tacrolimus, the number of episodes of acute rejection decreased from a mean of 0.42+/-0.17 to 0.14+/-0.09 episodes/patient/month under CyA and tacrolimus therapy (P=0.11), respectively. The mean dose of prednisone was 0.18+/-0.06 mg/kg/day before compared with 0.06+/-0.01 mg/kg/day after conversion from CyA to tacrolimus (P=0.09). Creatinine serum levels averaged 124+/-7 mmol/L under CyA treatment compared with 113+/-7 mmol/L with tacrolimus therapy (P=0.002). CONCLUSION: In patients with refractory rejections or intolerance to CyA after heart transplantation, conversion to tacrolimus-based immunosuppression is safe and effective.     

Is biopsy-proven cellular rejection an important clinical consideration in heart transplantation?

PURPOSE OF REVIEW: Immunosuppression strategies to prevent allograft rejection represent the cornerstone of long-term survival after heart transplantation. Endomyocardial biopsy has defined rejection in clinical cardiac transplantation and established a threshold for therapy. With the development of more effective immunosuppression modalities and the asymptomatic nature of most histologic rejection episodes, controversy exists regarding the need to augment immunosuppression based purely on histologic findings. RECENT FINDINGS: The frequency of histologic rejection has declined with current immunosuppression. Resolution of lower grades of histologic rejection without treatment is the norm in both pediatric and adult heart transplant studies. Recurrent rejection episodes have been linked to the subsequent development of allograft coronary artery disease, and late rejection (even if asymptomatic) is associated with decreased survival in pediatric heart transplant recipients. Black race is a risk factor for recurrent rejection and reduced survival after late cellular rejection. Apoptosis of inflammatory cells is more evident during and after histologic rejection treated with corticosteroids. Despite numerous noninvasive modalities evaluated for the detection of rejection, to date noninvasive methods cannot reliably predict histologic rejection. SUMMARY: Histologic rejection appears less common with current immunosuppressive strategies, and controversy exists about the need to treat asymptomatic rejection. It remains unproven whether non-treatment of moderate or greater rejection (>/=3A) increases the likelihood of recurrent rejection, which if present, may increase the risk of allograft coronary disease and/or reduced long-term survival.     

Low incidence of transplant coronary artery disease in Chinese heart recipients.

OBJECTIVES: This study sought to assess the incidence of transplant coronary artery disease (CAD) in Chinese heart recipients. BACKGROUND: The prevalence of transplant CAD detected by angiography at 1, 2 and 4 years after heart transplantation was 11%, 22% and 45%, respectively. The incidence of transplant CAD in Chinese heart recipients has not been reported. METHODS: For those recipients surviving for more than 1 year after transplantation, coronary angiography was performed annually for surveillance of transplant CAD. The recipient characteristics, donor characteristics, rejection episodes, medication and human leukocyte antigen (HLA) mismatches were recorded. RESULTS: Fifty patients were included in this study. Thirteen (26%) recipients had ischemic heart disease. Two patients (4%) had active cytomegalovirus (CMV) infection after transplantation. The mean number of rejection episodes in the 1st year after transplantation was 1.15. Among 47 patients with complete data of donor and recipient histocompatibility antigens, there were seven patients (14.9%) with two or fewer HLA mismatches. Among 74 angiograms of 50 patients reviewed, only one patient had discrete stenosis less than 50% in the middle portion of the left anterior descending artery at 1 year after transplantation. The cumulative incidence of transplant CAD was 2% at 1 year and 2% at 2 and 4 years after transplantation. CONCLUSIONS: The incidence of transplant CAD was low in Chinese heart transplant recipients. Low percentage of ischemic heart disease in recipients, low occurrence of active CMV infection and rejection episodes after transplantation, less racial disparity, and lower HLA mismatches may be the important factors.     

Stepwise minimization of the immunosuppressive therapy in pediatric liver transplantation. A conceptual approach towards operational tolerance

The evolution of immunosuppression in pediatric liver transplantation has been characterized by a steady reduction of the immunosuppressive load, including removal of anti-lymphocyte antibodies, with the aim to reduce the incidence of EBV-related post-transplant lymphoproliferative disorders. Acute rejection rates were studied retrospectively over two decades of pediatric liver transplantation, according to the successive immunoprophylactic regimens. 318 primary pediatric liver transplant recipients, included between 1984 and 2004 in successive prospective trials, were analyzed, with respect to the impact of the immunosuppressive protocol on acute rejection occurrence. A progressive decrease of rejection incidences was observed, which corresponded to reduced immunosuppressive load and to transplant eras. Such trend might be related to changing approaches towards acute rejection histology and therapy by transplant clinicians, but also to the stepwise minimization of immunosuppressive protocols, putatively enhancing graft acceptance. We hypothesize that the recent population of liver transplant recipients with low immunosuppression might be more suitable for progressive immunosuppression withdrawal trial, with the aim to reach ultimately operational tolerance.     

Clinical value of interleukin 1- and interleukin 2-determinations in patients after kidney transplantation

In a retrospective study of allograft rejections in renal transplant recipients we examined the value of cytokine production monitoring. Interleukin 1 (IL 1) and interleukin 2 (IL 2) activities were determined in supernatants of mitogen-stimulated peripheral blood lymphocytes in 8 renal transplant recipients serially for a period up to 60 days after transplantation. LPS-induced IL 1 as well as PHA-induced IL 2 production in patients after renal transplantation were significantly decreased in comparison to healthy controls. Seven episodes of cellular rejection were diagnosed in renal allograft recipients during this time, only 4 rejection episodes, however, were associated with a rise in the IL 1 and simultaneous IL 2 production occurred for 2 up to 3 days before the diagnosis of rejection. Moreover there were 12 instances in which an elevation of IL 1 and IL 2 production was found independently from the rejection. In 8 cases the augmentation of IL 1 and IL 2 production could be associated with clinical infections. We conclude from these results that a cytokine monitoring for the diagnosis of allograft rejection does not seem to be useful.     

Endoscopies in Pediatric Small Intestinal Transplant Recipients: Five Years Experience

Objective : Intestinal transplantation has become an option as a treatment for permanent intestinal failure. Endoscopy is an essential tool in assessing the intestinal allograft after intestinal transplantation. The aim of this study was to analyze our experience using endoscopy in intestinal transplant recipients. Methods : This was a retrospective review of endoscopic and histological reports in 41 children who received an intestinal transplant between 1990 and 1995 at Children's Hospital of Pittsburgh. Results : A total of 1273 endoscopies was performed of which 760 were ileoscopies via allograft ileostomy, 273 were upper endoscopies, and 240 were colonoscopies. One hundred four rejection episodes were documented histologically in 32 patients, 6 days to >4 yr after transplantation. Most episodes were mild and easily treated with increased immunosuppression; however, severe rejection with mucosal exfoliation was seen in nine patients. Rejection sometimes involved only part of the allograft. Endoscopic appearance alone without biopsies was sensitive enough to diagnose only 63% of the rejection episodes. Epstein-Barr and cytomegalovirus infections occurred in 11 and eight patients, respectively, and involved both native bowel and allograft in some. Complications of endoscopy were few: one perforation, three episodes of bleeding, and three episodes of transient respiratory compromise. Conclusions : Endoscopy is an essential tool in the postoperative assessment of intestinal transplant recipients. Frequent surveillance ileoscopies with biopsies should be performed after transplantation. If patients clinically deteriorate with fever, diarrhea, bacteremia, or gastrointestinal bleeding and a clear cause is not elucidated by ileoscopy, an upper endoscopy with biopsies is indicated.     

Determinants of left ventricular function one year after cardiac transplantation.

Left ventricular systolic function was assessed by radionuclide angiography in 107 consecutive transplant recipients who were alive one year after operation. Mean (SEM) ejection fraction was 62.4 (4.6) at rest and 68.8 (5.4) on exercise. The influence of donor-related factors (donor age and sex, ischaemia time), recipient-related factors (recipient age and sex, frequency of acute rejection), type of immunosuppression (cyclosporin/azathioprine or prednisolone/azathioprine), and frequency of hypertension on left ventricular function one year after operation was examined by univariate and multivariate analysis. There was a close association both at rest and on exercise between a higher ejection fraction and treatment with cyclosporin/azathioprine. There was a trend for lower donor and recipient age, shorter ischaemia time, and fewer rejection episodes to be associated with better left ventricular function, but this was not statistically significant. Left ventricular systolic function was well maintained in most patients a year after cardiac transplantation. The type of immunosuppression used had a strong influence on the left ventricular systolic function of the transplanted heart.     

Determinants of left ventricular function one year after cardiac transplantation

Left ventricular systolic function was assessed by radionuclide angiography in 107 consecutive transplant recipients who were alive one year after operation. Mean (SEM) ejection fraction was 62.4 (4.6) at rest and 68.8 (5.4) on exercise. The influence of donor-related factors (donor age and sex, ischaemia time), recipient-related factors (recipient age and sex, frequency of acute rejection), type of immunosuppression (cyclosporin/azathioprine or prednisolone/azathioprine), and frequency of hypertension on left ventricular function one year after operation was examined by univariate and multivariate analysis. There was a close association both at rest and on exercise between a higher ejection fraction and treatment with cyclosporin/azathioprine. There was a trend for lower donor and recipient age, shorter ischaemia time, and fewer rejection episodes to be associated with better left ventricular function, but this was not statistically significant. Left ventricular systolic function was well maintained in most patients a year after cardiac transplantation. The type of immunosuppression used had a strong influence on the left ventricular systolic function of the transplanted heart.     

Heart transplantation: intraoperative management, postoperative therapy and complications

Currently, heart transplantation (HTX) is performed as an orthotopic cardiac replacement according to the technique of Lower and Shumway in over 95% of the cases with good results. Survival after heterotopic HTX, by contrast, remain poor (one year survival: 50%). Postoperative therapy compiles primarily prophylactic measures to prevent complications, especially organ rejection and infections. Immunosuppressive prophylaxis generally includes a triple drug therapy consisting of cyclosporin, prednisolone, and azathioprine for maintenance therapy. Initially there is often an additional application of poly- or monoclonal antibodies. The prime measure to prevent infection during the initial hospital stay will be reversed isolation of the recipient. Initial antibiotic prophylaxis resembles that of conservative cardiac surgery, but in addition antiviral and antifungal prophylaxis is applied. The most common postoperative complication following HTX is cardiac rejection, which is detected by routine endomyocardial biopsies. At our institution the incidence of rejection decreases from 3.07 episodes per patient in the first 3 months to 1.97 episodes during the last 6 months of the first year after HTX. In general, acute rejection is treated by methylprednisolone (3 x 500 mg/day) or anti-T-cell-antibodies. Infections often occur following intervals of increased immunosuppression, usually early postoperatively and following therapy of acute rejections. Often, invasive diagnostic measures have to be taken rapidly in order to allow for specific therapy (antibiotics, antimycotic treatment, virostatic agents). Close follow-up of the heart transplant recipient and rapid therapy of possible postoperative complications enable the current one-year survival rates of 80% or more.     

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.     

Antibody Elimination by Apheresis in Living Donor Liver Transplant Recipients

Abstract: In the present study, we investigated retrospectively the indications and the efficacy of the elimination of preexisting antiallogeneic antibodies in liver transplant recipients. Three patients who were ABO blood type incompatible were subjected to plasmapheresis and double filtration plasmapheresis before the living donor liver transplantation (LDLTx), and the titers decreased to less than 8. After transplantation, plasmapheresis was also performed in 3 cases, and continuous hemodiafiltration in 1 case, and in 2 out of these 3 patients acute rejection was recognized. Two patients who were crossmatch positive were subjected to plasmapheresis before transplantation, and the T warm titers were reduced to less than Score 2. These 2 patients had no acute rejections after transplantation. We conclude that in liver transplant patients apheresis is effective to prevent acute rejection induced by preexisting anti‐A and/or anti‐B antibodies and anti‐donor specific antibodies before transplantation, but it is not effective in a patient with accelerated humoral rejection occurring after transplantation.     

Cytomegalovirus infection after liver transplantation： Current concepts and challenges

Cytomegalovirus （CMV） is a common viral pathogen that influences the outcome of liver transplantation. In addition to the direct effects of CMV syndrome and tissue-invasive diseases, CMV is associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. Risk factors for CMV disease are often interrelated, and include CMV D＋/R- serostatus, acute rejection, female gender, age, use of high-dose mycophenolate mofetil and prednisone, and the overall state of immunity. In addition to the role of CMV-specific CD4＋ and CD8＋ T lymphocytes, there are data to suggest that functionality of the innate immune system contributes to CMV disease pathogenesis. In one study, liver transplant recipients with a specific polymorphism in innate immune molecules known as Toll-like receptors were more likely to develop higher levels of CMV replication and clinical disease. Because of the direct and indirect adverse effects of CMV disease, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component in improving the outcome of liver transplantation. In the majority of transplant centers, antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in CMV-seronegative recipients of liver allografts from CMV-seropositive donors （D＋/R-）. However, the major drawback of antiviral prophylaxis is the occurrence of delayed-onset primary CMV disease. In several prospective and retrospective studies, the incidence of delayed-onset primary CMV disease ranged from 16% to 47% of CMV D＋/R- liver transplant recipients.Current data suggests that delayed-onset CMV disease is associated with increased mortality after liver transplantation. Therefore, optimized strategies for prevention and novel drugs with unique modes of action are needed. Currently, a randomized controlled clinical trial is being perf     

Thoracic imaging in heart transplantation

Heart transplantation remains the best treatment option for patients with end-stage heart failure refractory to standard management. Thoracic imaging plays an important role in the preoperative and postoperative evaluation of cardiac transplant recipients. This article reviews the major complications of cardiac transplantation, including acute allograft rejection. Advances in the treatment of organ rejection have improved the long-term survival of cardiac transplant recipients. Rejection is now detected earlier with the help of endomyocardial biopsy and treated aggressively with improved immunosuppressive therapies. The estimated 1-year and 5-year survival rates of heart transplant recipients are 79% and 65%, respectively (2).     

Incidence of cancer after immunosuppressive treatment for heart transplantation

Prolonged or intensive immunosuppressive therapy used after organ transplantation is complicated by an increased incidence of cancer. Striking differences in incidence are observed in heart and heart-lung transplant recipients when compared with renal transplant patients. The most significant increase was in the incidence of lymphomas in cardiac versus renal patients. Moreover, a two-fold greater increase of all neoplasms was found in cardiac recipients, with nearly a six-fold increase in visceral tumors. Several factors may account for these differences. In cardiac allograft recipients, intensive immunosuppression is frequently used to reverse acute rejection and the highest number of cardiac transplants was performed in the era of polypharmacy, usually consisting of triple therapy.     

Improved outcome following renal transplantation with reduction in the immunosuppression therapy for rejection episodes

Renal transplantation is superior to hemodialysis in terms of rehabilitation and cost, but it is offered to only a minority of patients with end-stage renal failure because of complications related to immunosuppression therapy. To reduce morbidity, we modified our therapy of patients with transplant rejection from high dose intravenous methylprednisolone (group A: January 1968–September 1972) to lower dose oral prednisone (group B: September 1972–December 1977). Patient survival in group B was significantly improved over that in group A, both in recipients of cadaver transplants (91 per cent versus 81 per cent, respectively, at one year, p < 0.0009) and in recipients of transplants from living related donors (99 per cent versus 86 per cent, respectively, at one year p < 0.001). The improvement in patient survival was the result of a significant decrease in the incidence of infections. Patients with multiple rejection episodes, a very high risk group, experienced an 18 per cent increase in patient survival in group B. With reduction and rapid tapering of corticosteroids for the treatment of patients with acute rejection and curtailment of the therapy of patients with multiple rejection episodes, survival after renal transplantation becomes comparable to that following hemodialysis; in addition, graft function is not compromised.     

Evaluation of viral load and antigenemia as markers for relapse cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) is a pathogen, commonly found in the donors and recipients of solid organ transplantation. CMV is one of the major causes of morbidity and mortality in these patients. Relapsing episodes of CMV infection occur in 23-33% of transplant patients which is likely a reflection of incomplete suppression of viral replication following antiviral treatment with intravenous ganciclovir. We have studied CMV DNA load and antigenemia as markers for relapse of CMV infection in 49 renal transplant patients out of 68 with CMV infection who received a course of intravenous ganciclovir among 300 transplants carried out between January of 2001 and June of 2005. Viral load and antigenemia were measured in blood samples obtained before, during and at the completion of treatment. We also studied different viral load as predictors of relapse CMV infection. Twelve (24.5%) of 49 recipients developed relapsing CMV infection. The relapsing group had higher viral loads after treatment than the no relapsing group. There was no difference in antigenemia level between both groups. The viral loads before and during the treatment, the age and sex of donors and recipients, inmunosupresión, percentage of seronegative recipients with seropositive donors, duration of the therapy and the percentage of patients with heavy immunosuppression were similar in the two groups, but the incidence of acute rejection was higher in the relapsing group. We also evaluated the range of viral load after treatment which is able to trigger the relapse of CMV infection. We conclude that CMV DNA load after treatment is a useful marker for individualizing antiviral treatment of CMV infection in renal transplant recipients. Acute rejection is a risk factor to the relapsing CMV infection.     

Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.

STUDY OBJECTIVES: The efficacy of antithymocyte induction therapy in lung transplantation is controversial, and its use varies from center to center. We hypothesized that rabbit antithymocyte globulin (RATG) induction therapy would decrease acute rejection after lung transplantation, and we designed a single-center, randomized, prospective study to test this hypothesis. DESIGN: A total of 44 single or bilateral adult lung transplant recipients were randomly assigned to receive either RATG induction therapy (dosage, 1.5 mg/kg/d for 3 days) at the time of transplantation, along with conventional immunosuppression (cyclosporine, azathioprine, and prednisone), or conventional immunosuppression alone with no induction therapy. RESULTS: Although a similar number of biopsies were performed in each group, the number of patients experiencing biopsy-proven grade II or greater acute rejection was significantly reduced in the group receiving RATG induction therapy (23% incidence), as compared to the patients treated with conventional immunosuppression alone (55% incidence; p = 0.03). In addition, there was a nonsignificant reduction in the incidence of bronchiolitis obliterans syndrome at the conclusion of the study in patients who received RATG induction (20%), as compared to patients in the control group (38%). The incidence of posttransplant infections and malignancies were similar between the two groups. CONCLUSION: Induction therapy with RATG significantly reduces the incidence of acute allograft rejection after lung transplantation.     

Pediatric heart transplantation: immunosuppression and its complications

PURPOSE OF REVIEW: Advances in immunosuppression have contributed to the significant improvements in outcome for pediatric heart transplant recipients in the past two decades. The large increase in the number of available immunosuppressive agents in the past few years mandates that those caring for this complex group of patients remain up to date in this rapidly advancing field. RECENT FINDINGS: In this review, we evaluate recent studies of immunosuppressive efficacy, end-organ toxicities, and side effects of nonspecific immunosuppression with currently used regimens. In addition, we examine new findings that attempt to define the genetic contribution to rejection profiles, immunosuppressive efficacy, and drug disposition after heart transplantation in children. SUMMARY: The continuous evaluation of new immunosuppressive regimens will help to elucidate the optimal treatment regimens for pediatric heart transplant recipients. Unfortunately, the small number of transplantations means that it is unlikely that pivotal randomized, controlled trials will ever be performed in this population. Extrapolation from adult controlled trials and experience from other pediatric solid organ transplant recipient populations will continue to provide important contributions to our knowledge base. Understanding the genetic contribution to graft and patient outcomes may help us tailor immunosuppressive therapy for the individual patient.     

Rejection theraples

One hundred thirty-eight primary liver allograft recipients received cyclosporine and prednisolone immunosuppression with azathioprine added during the induction phase. All rejections were biopsy-confirmed clinical rejections. Acute rejection was seen in 58.7% of the patients. The treatment of acute rejection was successful in 88.9% of treated patients. Rejection-related death was seen in 4.3%, and retransplantation was performed for acute or chronic rejection in 2.2% of the patients. The risk for dying increased with the number of rejection treatments.     

The role of the electrocardiogram in the recognition of cardiac transplant rejection: A systematic review and meta‐analysis

BackgroundIn cardiac transplant recipients, the electrocardiogram (ECG) is a noninvasive measure of early allograft rejection. The ECG can predict an acute cellular rejection, thus shortening the time to recognition of rejection. Earlier diagnosis has the potential to reduce the number and severity of rejection episodes.MethodologyA systematic literature review was conducted to identify and select the original research reports on using electrocardiography in diagnosing cardiac transplant rejection in accordance with the PRISMA guidelines. Studies included reported sensitivity and specificity of ECG readings in heart transplant recipients during the first post‐transplant year. Data were analyzed with Review manager version 5.4. p‐value was used in testing the significant difference.ResultsAfter the removal of duplicates, 98 articles were eligible for screening. After the full‐text screening, a total of 17 papers were included in the review based on the above criteria. A meta‐analysis of five studies was done.ConclusionIn heart transplant recipients, a noninvasive measure of early allograft rejection has the potential to reduce the number and severity of rejection episodes by reducing the time and cost of surveillance of rejection and shortening the time to recognition of rejection.