Acute Heart Transplant Rejection Research Articles

(294) - Mixed Acute Cellular Rejection and Antibody Mediated Rejection in Heart Transplantation: A Retrospective Study in a Single Transplant Center

(294) - Mixed Acute Cellular Rejection and Antibody Mediated Rejection in Heart Transplantation: A Retrospective Study in a Single Transplant Center

Identification of Common Blood Gene Signatures for the Diagnosis of Renal and Cardiac Acute Allograft Rejection

To test, whether 10 genes, diagnostic of renal allograft rejection in blood, are able to diagnose and predict cardiac allograft rejection, we analyzed 250 blood samples from heart transplant recipients with and without acute rejection (AR) and with cytomegalovirus (CMV) infection by QPCR. A QPCR-based logistic regression model was built on 5 of these 10 genes (AR threshold composite score>37% = AR) and tested for AR prediction in an independent set of 109 samples, where it correctly diagnosed AR with 89% accuracy, with no misclassifications for AR ISHLT grade 1b. CMV infection did not confound the AR score. The genes correctly diagnosed AR in a blood sample within 6 months prior to biopsy diagnosis with 80% sensitivity and untreated grade 1b AR episodes had persistently elevated scores until 6 months after biopsy diagnosis. The gene score was also correlated with presence or absence of cardiac allograft vasculopathy (CAV) irrespective of rejection grade. In conclusion, there is a common transcriptional axis of immunological trafficking in peripheral blood in both renal and cardiac organ transplant rejection, across a diverse recipient age range. A common gene signature, initially identified in the setting of renal transplant rejection, can be utilized serially after cardiac transplantation, to diagnose and predict biopsy confirmed acute heart transplant rejection.

Left ventricular myocardial performance index change for detection of acute cellular rejection in pediatric heart transplantation

EMB, the gold standard for diagnosis of ACR, poses unique risks in children. Limited cross-sectional data have associated LV MPI with ACR. We hypothesize that a relative change in MPI from baseline without ACR to the time of ACR will better detect ACR than an absolute threshold LV MPI value. We identified 40 children with ACR ≥60days post-transplant matching them by age and time from transplantation to 40 children without ACR. There was a significant increase in LV MPI at time of ACR vs. baseline (0.59±0.17 vs. 0.41±0.11; p<0.001). There was no difference in LV MPI between baseline and follow-up (0.41±0.11 vs. 0.42±0.11; p=0.65). An absolute increase in LV MPI of ≥0.47 had 82.5% sensitivity and 85% specificity for ACR, whereas an increase in LV MPI from baseline of ≥20.4% was 90% sensitive and 100% specific. Serial measurement of LV MPI appears to be a sensitive and specific marker of ACR. LV MPI shows good interobserver agreement and increases at the time of EMB-proven ACR with subsequent resolution to baseline measurements upon EMB-proven resolution of ACR. Future studies in larger, prospective cohorts should be undertaken to validate these findings.

Ultrasound Molecular Imaging of Acute Cellular Cardiac Allograft Rejection in Rat With T-Cell–Specific Nanobubbles

Acute rejection (AR) is one of the main obstacles of cardiac transplantation; however, a noninvasive diagnostic method, which reflects its pathologic nature, has not been developed yet. In this study, we prepared a specific nanobubbles targeting to the activated T cells and applied it in the ultrasound molecular imaging of AR in heart transplantation by myocardial contrast echocardiography (MCE). Nanobubbles loading anti-CD25 antibody (NB(specific)) or isotype control antibody (NB(nonspecific)) were prepared and then applied in the ultrasound molecular imaging by MCE in a rat model. MCE was performed in 24 allografts and 18 isografts that were divided into three groups, including days 2, 4, and 6 after transplantation. Confocal laser scanning microscopy was used to evaluate the binding of nanobubbles and T cells in four allografts and four isografts. MCE with NB(specific) in allograft showed a "delayed enhancement," and the time-intensity curve presented a second peak. The intensity and time of second peak were both positively correlated with the transplant time (P<0.01) and the pathologic grade of AR (P<0.01). Confocal laser scanning microscopy demonstrated the binding of nanobubbles and lymphocytes in myocardium post-MCE with NB(specific). Ultrasound molecular imaging of AR after heart transplantation can be achieved by using MCE with the nanobubbles targeted to T cells. The appearance of delayed enhancement indicates the occurrence of AR, and the intensity and time of the second peak in time-intensity curve provide potential quantitative indications for diagnosis and severity of AR.

Abstract 19697: Left Ventricular Unloading by Impella® Microaxial Flow Pump for Treatment of Left Ventricular Overload in Venoarterial Ecmo Supported Cardiogenic Shock Patients

Background Venoarterial (VA)-ECMO is an established support for refractory cardiogenic shock (CS), but may be complicated by an increase of cardiac afterload leading to left ventricular (LV) distension with consecutive pulmonary edema and deterioration of left ventricular function. Methods VA-ECMO was instituted in patients with refractory CS of different etiology. Progressive LV overload was detected by clinical signs of pulmonary edema and critical elevated LV end diastolic pressure (LVEDP). LV unloading by Impella ® 2.5 via femoral access was established. Patients were followed up for heart rate, catecholamine demand, white blood cell count (WBC) and serum lactate levels before and after 24 hours (h). Fatal bleeding complications, signs of limb ischemia and 28-day mortality were assessed. Data are presented as mean±SD. Results Six patients, SAPS II-Score on admission 56±15, age 61±18 yrs are presented. Three MI patients complicated with refractory CS. One patient with myocarditis, one due to acute heart failure complicated by septic shock and one due to acute heart transplant rejection. Five/6 patients were on mechanical ventilation and all showed clinical and radiologic signs of pulmonary edema (LVEDP before LV unloading 35±15 mmHg). Under Impella ® support (5±2 days) heart rate decreased after 24 h from 120±15 to 104±20/min. After 24h catecholamine demand decreased (dobutamine and epinephrine p=n.s.; norepinephrine 0.44±0.38 to 0.20±0.19 µg/kg/min, p=0.04). Serum lactate levels declined from 5.5±4.8 to 2.5±1 mmol/l at 24 h and 1.3±0.3 mmol/l at 72 h. WBC declined from 22±6 to 18±6 thd/µl (p=0.004) after 24 h. No fatal bleeding complications or limb ischemia occurred. 28-day mortality was 17 %. One patient with myocarditis died in multiorgan failure. Conclusion VA-ECMO treatment of CS complicated by LV overload can safely and efficiently be treated by LV unloading using microaxial flow pump Impella ® 2.5. This biventricular decompression rapidly reduces catecholamine demand and lactate levels indicating an improved organ function followed by a resolution of SIRS due to cardiac shock (reduced WBC).

Identification and Classification of Acute Cardiac Rejection by Intragraft Transcriptional Profiling

Treatment of acute rejection (AR) in heart transplantation relies on histopathological grading of endomyocardial biopsies according to International Society for Heart and Lung Transplantation guidelines. Intragraft gene expression profiling may be a way to complement histological evaluation. Transcriptional profiling was performed on 26 endomyocardial biopsies, and expression patterns were compared with the 1990 International Society for Heart and Lung Transplantation AR grades. Importantly, transcriptional profiles from settings with an equivalent AR grade appeared the same. In addition, grade 0 profiles could not be distinguished from 1A profiles, and grade 3A profiles could not be distinguished from 3B profiles. Comparing the AR groupings (0+1A, 1B, and 3A+3B), 0+1A showed more striking differences from 1B than from 3A+3B. When these findings were extrapolated to the 2005 revised guidelines, the combination of 1A and 1B into a single category (1R) appears to have brought together endomyocardial biopsies with different underlying processes that are not evident from histological evaluation. Grade 1B was associated with upregulated immune response genes, as 1 categorical distinction from grade 1A. Although grade 1B was distinct from the clinically relevant AR grades 3A and 3B, all of these grades shared a small number of overlapping pathways consistent with common physiological underpinnings. The gene expression similarities and differences identified here in different AR settings have the potential to revise the clinical perspective on acute graft rejection, pending the results of larger studies.

Relative reductions in soluble CD30 levels post-transplant predict acute graft function in islet allograft recipients receiving three different immunosuppression protocols

Despite advances in islet transplantation, challenges remain in monitoring for anti-islet immune responses. Soluble CD30 (sCD30) has been investigated as a predictor of acute rejection in kidney, lung, and heart transplantation as well as in a single study in human islet cell recipients. In this study, sCD30 levels were retrospectively assessed in 19 allograft recipients treated with three different immunosuppression induction therapies. Soluble CD30 levels were assessed at pre-transplant; early post-transplant (day 4–day 7); one-month post-transplant; and late post-transplant (day 90–day 120) and then correlated with eventual graft outcomes at 1-year follow-up. Results showed no correlation between mean serum sCD30 levels at any point in time pre- or post-transplant and graft function at 1-year follow-up. However, analysis demonstrated that mean sCD30 levels at day 28 or day 90–day 120 decreased from pre-transplant levels in recipients with long-term islet allograft function compared to recipients with partial or non-graft function (a decrease of 43.6 ± 25.6% compared to 16.7 ± 35.2%, p < 0.05). In another finding, immunosuppression with the ATG protocol led to a greater reduction in sCD30 levels post-transplant overall. A larger reduction post-transplant correlated with full graft function. The results demonstrate that a relative reduction in sCD30 levels post-transplant may be applicable as a biomarker to monitor graft function in islet allograft recipients. Additionally, knowledge of the impact of various immunosuppression protocols on the timing and extent of changes in post-transplant sCD30 levels could aid in patient-specific tailoring of immunosuppression.

Pre-implantation Basiliximab Reduces Incidence of Early Acute Rejection in Pediatric Heart Transplantation

Basiliximab is an anti-CD25 monoclonal antibody used as induction therapy in solid-organ transplantation. In this study we aim to determine whether pre-operative administration of basiliximab is beneficial in preventing early heart allograft rejection. In this investigation we assess the effect of pre-implantation basiliximab on CD25 count and on acute rejection in children undergoing cardiothoracic transplantation. The notes of all children undergoing cardiothoracic transplantation at the Great Ormond Street Hospital between January 2000 and June 2007 were retrospectively reviewed. One hundred twenty-one heart transplant recipients were included: 29 patients did not receive basiliximab; 33 patients received basiliximab after coming off cardiopulmonary bypass (CPB); and 59 patients received basiliximab prior to organ implantation. All patients receiving basiliximab had an effectively suppressed CD25 count (<0.2%) on Days 1 and 10 post-transplant. Freedom from Grade 3A or greater rejection in the first year was significantly greater in the pre-implantation basiliximab group than in the post-implantation and no-basiliximab groups (95%, 70% and 72%, respectively; p = 0.02). Induction regimen was the only significant explanatory variable after multivariate Cox regression. The results of this study confirm that basiliximab is effective at suppressing CD25 count whether given pre- or post-CPB. Basiliximab before transplantation appeared to reduce acute rejection, whereas post-CPB administration did not suggest similar effects. These findings require independent validation in randomized trials and further studies should seek to mechanistically delineate these observations.

Synergistic effects of Isatis tinctoria L. and tacrolimus in the prevention of acute heart rejection in mice

Although immunosuppressive treatments are available for acute cardiac rejection no viable treatment exists for long-term cardiac graft failure. Moreover, the extended use of calcineurin inhibitor immunosuppressants, the mainstay of current treatment for cardiac transplantation, leads to significant side effects such as nephrotoxicity and an increased risk of cardiac disease. Because some agents used in Traditional Chinese Medicine (TCM) have strong immunosuppressive effects coupled with low toxicity, we investigated the effect of Compound K (K), the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., either as a single treatment or combined with tacrolimus (FK-506) on acute cardiac allograft rejection. We compared the ability of K alone, or in combination with FK-506, to inhibit acute heart transplant rejection both in vitro and in vivo. We found that the inhibition of lymphocyte proliferation was positively correlated with K concentration. K significantly reduced IL-2 and IFN-γ expression levels and significantly inhibited lymphocyte proliferation in both a lymphocyte transformation test and a mixed lymphocyte reaction (MLR). We also found that the inhibitory effect of a combination of K and a sub-therapeutic dose of FK-506 (SubFK-506) was stronger than that of full-dose FK-506 alone. Oral administration of K reduced acute cardiac allograft rejection in mice and had no apparent toxicity. In vivo, the immunosuppressive effect of K combined with a half-dose of FK-506 was equivalent to that of a full-dose of FK-506 alone. K combined with a half-dose of FK-506 reduced the expression levels of IL-2 and IFN-γ (both within the graft and in the recipients' serum) more effectively than a full-dose of FK-506. These results show that K has significant immunosuppressive effects both in vitro and in vivo. When used as a combination therapy with FK-506 we see a powerful inhibition of rejection with no obvious toxic side effects. The mechanism of action is postulated to involve the inhibition of IL-2 and IFN-γ expressions by lymphocytes, rather than the activation of Tr1 cells via the production of IL-10.

Eotaxin/CCL11 expression by infiltrating macrophages in rat heart transplants during ongoing acute rejection

Eotaxin/CCL11 chemokine is expressed in different organs, including the heart, but its precise cellular origin in the heart is unknown. Eotaxin is associated with Th2-like responses and exerts its chemotactic effect through the chemokine receptor-3 (CCR3), which is also expressed on mast cells (MC). The aim of our study was to find the cellular origin of eotaxin in the heart, and to assess whether expression is changing during ongoing acute heart transplant rejection, indicating a correlation with mast cell infiltration which we observed in a previous study. In a model of ongoing acute heart transplant rejection in the rat, we found eotaxin mRNA expression within infiltrating macrophages, but not in mast cells, by in situ-hybridization. A five-fold increase in eotaxin protein in rat heart transplants during ongoing acute rejection was measured on day 28 after transplantation, compared to native and isogeneic control hearts. Eotaxin concentrations in donor hearts on day 28 after transplantation were significantly higher compared to recipient hearts, corroborating an origin of eotaxin from cells within the heart, and not from the blood. The quantitative comparison of eotaxin mRNA expression between native hearts, isografts, and allografts, respectively, revealed no statistically significant difference after transplantation, probably due to an overall increase in the housekeeping gene's 18S rRNA during rejection. Quantitative RT-PCR showed an increase in mRNA expression of CCR3, the receptor for eotaxin, during ongoing acute rejection of rat heart allografts. Although a correlation between increasing eotaxin expression by macrophages and mast cell infiltration is suggestive, functional studies will elucidate the role of eotaxin in the process of ongoing acute heart transplant rejection.

Predictive Role of Pretransplant Serum CXCL10 for Cardiac Acute Rejection

The detection of acute rejection in heart transplantation remains an important feature of transplant management, especially in the early phase. Frequent surveillance with endomyocardial biopsy is necessary, even though it is an invasive procedure and carries a certain risk. Hence, noninvasive biomarkers able to predict acute rejection could be a further helpful tool in patient management. The interferon-gamma-inducible chemokine CXCL10 is required for initiation and development of graft failure caused by acute or chronic rejection. It has been reported that CXCL10 serum level is predictive of graft loss in kidney graft recipients. In the present study, we investigated whether pretransplant CXCL10 serum level may be a predictive noninvasive biomarker in heart transplant (HTx) recipients, as well. Sera from 143 patients undergoing orthotopic heart transplantation were collected before surgery and tested for CXCL10 and CCL22 and compared with serum samples from healthy subjects. We found that basal CXCL10 serum levels in HTx recipients were significantly higher than in healthy subjects, whereas no difference was seen in CCL22 levels. Among HTx recipients, CXCL10 serum levels of rejectors were significantly higher than in nonrejectors. Our results showed that CXCL10 was a significant independent risk factor of several variables and had the highest predictive value for early acute heart rejection, with 160 pg/mL cutoff value. In HTx recipients, measurement of pretransplant CXCL10 serum levels could be a clinically useful tool for predicting cardiac acute rejection, especially in the early posttransplant period.

Cardiovascular magnetic resonance in the diagnosis of acute heart transplant rejection: a review.

BackgroundScreening for organ rejection is a critical component of care for patients who have undergone heart transplantation. Endomyocardial biopsy is the gold standard screening tool, but non-invasive alternatives are needed. Cardiovascular magnetic resonance (CMR) is well suited to provide an alternative to biopsy because of its ability to quantify ventricular function, morphology, and characterize myocardial tissue. CMR is not widely used to screen for heart transplant rejection, despite many trials supporting its use for this indication. This review summarizes the different CMR sequences that can detect heart transplant rejection as well as the strengths and weaknesses of their application.ResultsT2 quantification by spin echo techniques has been criticized for poor reproducibility, but multiple studies show its utility in screening for rejection. Human and animal data estimate that T2 quantification can diagnose rejection with sensitivities and specificities near 90%. There is also a suggestion that T2 quantification can predict rejection episodes in patients with normal endomyocardial biopsies.T1 quantification has also shown association with biopsy proven rejection in a small number of trials. T1 weighted gadolinium early enhancement appeared promising in animal data, but has had conflicting results in human trials. Late gadolinium enhancement in the diagnosis of rejection has not been evaluated.CMR derived measures of ventricular morphology and systolic function have insufficient sensitivity to diagnose mild to moderate rejection. CMR derived diastolic function can demonstrate abnormalities in allografts compared to native human hearts, but its ability to diagnose rejection has not yet been tested.There is promising animal data on the ability of iron oxide contrast agents to illustrate the changes in vascular permeability and macrophage accumulation seen in rejection. Despite good safety data, these contrast agents have not been tested in the human heart transplant population.ConclusionT2 quantification has demonstrated the best correlation to biopsy proven heart transplant rejection. Further studies evaluating diastolic function, late gadolinium enhancement, and iron oxide contrast agents to diagnose rejection are needed. Future studies should focus on combining multiple CMR measures into a transplant rejection scoring system which would improve sensitivity and possibly reduce, if not eliminate, the need for endomyocardial biopsy.

Genetic Polymorphisms Impact the Risk of Acute Rejection in Pediatric Heart Transplantation: A Multi-Institutional Study

The objective of this study was to determine the association between the genetic polymorphisms of proinflammatory and regulatory cytokines and long-term rates of repeat and late acute rejection episodes in pediatric heart transplant (PHTx) recipients. Three hundred twenty-three PHTx recipients: 205 White non-Hispanic, 43 Black non-Hispanic, and 75 Hispanic were analyzed for time to first repeat and late acute rejection episodes by race, age at transplantation, and gene polymorphism (interleukin [IL]-6, -174 G/C, IL-10, -1082 G/A, -819 C/T, 592 C/A; vascular endothelial growth factor (VEGF) -2578 C/A, -460 C/T, +405 C/G; tumor necrosis factor alpha (TNF-alpha)-308 G/A). Recipient black race and older age at transplant were risk factors for both repeat and late rejections, though black race was more significantly related to late rejection (P=0.006). Individually, TNF-alpha high, IL-6 high, VEGF high, and IL-10 low phenotypes did not impact the risk of repeat or late rejection. However, the combination VEGF high/IL-6 high and IL-10 low was associated with increased estimated risk of late rejection (P=0.0004) and only marginally with repeat rejection (P=0.051). In a multivariate analysis, adjusting for age and race, VEGF high/IL-6 high and IL-10 low still remained an independent risk factor for late acute rejection (RR=1.91, P<0.001). This is the largest multicenter study to document the impact of genetic polymorphism combinations on PHTx recipients' outcome. The high proinflammatory (VEGF high/IL-6 high) and lower regulatory (IL-10 low) cytokine gene polymorphism profile exhibited increased risk for late rejection, irrespective of age and race/ethnicity.

40-OR: The combination high VEGF/high IL-6 and low IL-10 gene polymorphism impact the risk of acute rejection in pediatric heart transplantation – a multicenter study

40-OR: The combination high VEGF/high IL-6 and low IL-10 gene polymorphism impact the risk of acute rejection in pediatric heart transplantation – a multicenter study

31-P: HLA-A and HLA-B amino-acid triplet mismatching is associated with increased frequency of acute rejection in pediatric heart transplantation

31-P: HLA-A and HLA-B amino-acid triplet mismatching is associated with increased frequency of acute rejection in pediatric heart transplantation

Update on Cardiac Transplantation Pathology

The endomyocardial biopsy is the mainstay for monitoring acute allograft rejection in heart transplantation. Objective and accurate assessment of cellular and humoral types of rejection is important to optimize immunosuppressive therapy, avoid therapeutic complications, and improve patient outcome. The grading system for evaluation of heart transplant biopsies published in 1990 was revised in 2004 after more than a decade of implementation. In this review, we focus on a practical approach to the evaluation of human heart transplant biopsies as diagnostic surgical pathologic specimens. We discuss the revised International Society of Heart and Lung Transplantation working formulation. We reviewed pertinent literature, incorporating ideas and vast experience of participants in various work groups that led to the revision of the 1990 grading system. The grading system for cellular rejection is presented with detailed light microscopic morphology and comparison of the 1990 and 2004 International Society of Heart and Lung Transplantation working formulations. We show how the pathologic recognition of cellular rejection and antibody-mediated rejection has evolved. We emphasize the interpretation of immunostains for complement components C4d and C3d in the diagnosis of antibody-mediated rejection. Evidence of regulation of complement activation in human heart transplant biopsies is presented in this context. We also discuss the pitfalls, caveats, and artifacts in the interpretation of allograft endomyocardial biopsies. Lastly, we discuss the pathology of human cardiac allograft vasculopathy in practical detail.

Probrain Natriuretic Peptide and C-Reactive Protein as Markers of Acute Rejection, Allograft Vasculopathy, and Mortality in Heart Transplantation

N-terminal probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are useful in risk stratification of patients with congestive heart failure. They could also be markers of distinctly altered hormonal and immunological milieus, but the combined prognostic value of these biomarkers in heart transplant (HTx) recipients has not been assessed previously. We sought to assess the individual and combined value of NT-proBNP and CRP as markers of acute rejection, cardiac allograft vasculopathy (CAV) and all-cause mortality in HTx recipients. We evaluated 101 patients for acute rejection and 210 patients for CAV and all-cause mortality. Patients evaluated for rejection had serial endomyocardial biopsies and plasma sampling performed during the first year postHTx. All other patients had plasma samples taken upon inclusion at an annual visit. Median follow-up for CAV and all-cause mortality was 2.2 years and 5.4 years, respectively. Altogether, 1131 biopsy procedures were performed, and increased NT-proBNP and CRP levels were not useful markers of acute cellular rejection. In total, 78 (37%) patients developed CAV, and 39 (19%) patients died. Neither biomarker was a predictor of CAV, but both were independent predictors of mortality. When combining both biomarkers, elevated levels of both NT-proBNP and CRP identified patients at highest risk for CAV (HR 2.10, P=0.01) and all-cause mortality (HR 3.14, P=0.01). In HTx recipients, NT-proBNP and CRP are not useful as markers of acute cellular rejection during the first year postHTx, but combined analysis adds significantly to their predictive value for development of CAV and all-cause mortality.

Rat chemokine CXCL11: Structure, tissue distribution, function and expression in cardiac transplantation models

CXCL11 is thought to play a critical role in allograft rejection. To clarify the role of CXCL11 in the rat transplantation model, we cloned CXCL11 cDNA from rat liver tissue and used it to study CXCL11 structure, function and expression. The rat CXCL11 gene encodes a protein of 100 amino acids and spans approximately a 2.8 kb DNA segment containing 4 exons in the protein coding region. Tissue distribution of rat CXCL11 was analyzed by quantitative RT-PCR and showed that rat CXCL11 mRNA is expressed in various tissues and, in particular, at high levels in the spleen and lymph nodes. COS-1 cells were transfected with a plasmid vector encoding rat CXCL11 and used to study CXCL11 effects on cell migration and internalization of CXCR3, the CXCL11 receptor. The recombinant CXCL11 showed chemotactic properties and induced CXCR3 internalization in CD4(+) T cells. Expression of CXCL11 mRNA also was measured in rat acute (ACI to LEW) and chronic (LEW to F344) heart transplant rejection models. CXCL11 mRNA expression in allografts increased in both models, compared with controls, and was primarily observed in infiltrating macrophages and donor endothelial cells. These results indicate that, like the other CXCR3 chemokines, rat CXCL11 seems to have a role in the homing of CD4(+) T cells in both acute and chronic rejection models of heart allotransplantation.

322: P-glycoprotein expression on peripheral blood mononuclear cells and biopsy proven acute rejection in heart transplantation

P-glycoprotein (P-Gp), the membrane bound efflux pump encoded by the multi drug resistance (MDR1) gene may be one reason for poor response to immunosuppression in heart transplant recipients. This study set out to test the hypothesis that peripheral blood mononuclear cell expression of P-Gp is associated with increased levels of biopsy proven rejection, cyclosporine levels and nephrotoxicity in heart transplant recipients.

Everolimus (Certican) in Heart Transplantation: Optimizing Renal Function Through Minimizing Cyclosporine Exposure

The proliferation signal inhibitor everolimus is efficacious for reducing the incidence of acute rejection and cardiac allograft vasculopathy (CAV) in heart transplantation; and it has the potential to facilitate cyclosporine (CsA) minimization in this setting. Reducing CsA dose in heart transplantation is dependent on everolimus trough blood levels of 3 to 8 ng/mL being achieved. Physicians experienced in the use of everolimus aim for CsA trough blood levels of 175 to 200 ng/mL in everolimus-treated patients during the initial 3 months following heart transplantation. Modeling data from the heart pivotal study suggest that CsA trough blood levels of 100 ng/mL at 6 months posttransplant could be targeted without loss of efficacy, and antibody induction therapy may assist with this approach. Target CsA trough blood levels for maintenance patients could possibly be reduced from the current 80 to 100 ng/mL to 50 to 80 ng/mL. Maintenance patients with renal dysfunction or CAV may benefit from conversion to everolimus and subsequent reduction in CsA trough blood levels (eg, by 50%). Initial experience of everolimus with reduced CsA trough blood levels in heart transplantation is favorable, but there is scope for further study.