Grade 3A Rejection Research Articles

Medication Adherence in Patients Who Undergo Cardiac Transplantation

BackgroundHeart transplant patients are required to take medication for life, both immunosuppressants to prevent rejection and any required for other illnesses. Treatment compliance can be measured quantitatively or qualitatively. Compliance measurement is not easy owing to different factors. The aim of this study was to assess the prevalence of therapeutic compliance in heart transplant patients. MethodsWe undertook a cross-sectional observational descriptive study. The sample comprised patients who received a heart transplant from 2001 to 2011. Of the 203 patients in total, we studied 99. We used the Morisky-Green test as an indirect method and recorded the immunosuppressant blood levels as a direct method. ResultsThe mean age of the patients was 50 ± 12 years, and 84% were male. According to the Morisky-Green test, 33% of the patients were noncompliant, of whom 30% said they rarely forgot to take their medication. Patients took an average of 8 ± 3 drugs per day, but only 85% knew what the drugs were for; 24% of the patients had grade 3A rejection, and 65% had graft vessel disease. ConclusionsTransplanted patients in this study showed a high level of therapeutic adherence that did not differ from other transplant series, either cardiac or other organs, nor from other chronic diseases. The results for defaulters were higher than that expected from these patients. The defaulter results were expected to be lower, given the information that the patients were supposed to have, both before and after the transplantation, and with the strict medical monitoring. Therefore, we have to stress therapeutic compliance, both medical and dietary-hygiene measures, and seek new strategies to improve the results.

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Aim The initial ischemia/reperfusion injury (IRI) may have impact on the recipient immune response after transplantation. Allograft inflammatory factor-1 (AIF-1), an evolutionary conserved structural protein has been implicated in the regulation of inflammation, associated with rejection. AIF-1 is either passively released from injured tissue cells during procurement, or actively secreted by allograft infiltrating cells contributing to allograft rejection. We investigated the impact of ischemia/reperfusion in association with the presence of AIF-1, IL-18, TLR-2 and TLR-4, markers with the goal to demonstrate the presence of these markers in donor tissue during IRI, and in peripheral blood and biopsy specimen with allograft rejection. Methods Tissue from donor atrium was subjected to IRI using 1X PBS for 90 minutes. Tissue array was prepared for immunohistochemistry (IHC) stains. Recipients peripheral blood mononuclear cells (MNCs) and endomyocardial specimens were tested by RT-PCR and IHC stains for identification of AIF-1, TLR2, -4, and IL-18 markers. Results Only AIF-1 and IL-18 specific immunoreactivity were detected in cardiomyocytes and interstitial tissues after IRI. The TLR-2 immunoreactivity was strongly detected in infiltrating MNCs and CMCs in grade 3A rejection. IL-18 immunoreactivity was strongly detected in grade 3A rejection. In peripheral blood MNCs, AIF-1 expression was 4.2-fold-increased in the group with 3A rejection as compared with grade 1A or 0. The mRNA expression levels were varied significantly for TLR-2 in MNCs with different ISHLT grades (grades 3A ® 1A rejection: mean ± SEM both peripheral blood and local tissue was 64.0 ± 3.8; vs. 38.4 ± 3.5, p Conclusions AIF-1 and IL-18 are initial inflammatory markers associated with IRI present in the donor. The expression profile of the recipient AIF-1, TLR-2 and IL-18 were correlated with biopsy-proven allograft rejection, suggesting a potential for diagnostic biomarkers for early detection of allograft rejection.

Effect of Blood Product Transfusion–Induced Tolerance on Incidence of Cardiac Allograft Rejection

Background Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial. Objective To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection. Patients and Methods Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation. Results Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups. Conclusions Blood transfusions within the first 2 weeks post-transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies.

Combined Analysis of Allograft Inflammatory Factor-1, Interleukin-18, and Toll-Like Receptor Expression and Association with Allograft Rejection and Coronary Vasculopathy

In cardiac transplantation settings, the initial myocardial ischemia and reperfusion may cause myocyte tissue injury and the release of allograft inflammatory factor-1 (AIF-1). This in part may trigger the innate immune response through the modulation of Toll-like receptor-2 (TLR-2) and AIF-1 expression and function, causing the release of proinflammatory cytokines. The goal was to demonstrate these markers in the peripheral blood and biopsy specimen from recipients with cardiac allograft rejection and coronary vasculopathy (CV). Peripheral blood and endomyocardial specimens were tested by reverse transcriptase-polymerase chain reaction and immunohistochemistry stains for identification of TLR-2, -4, interleukin-18, and AIF-1 markers and analyzed against clinical rejection grades for rejection. The differences for mRNA transcript levels were determined by one-way analysis of variance. The mRNA expression levels were significantly varied for TLR-2 in monocytes with different rejection grades (P < 0.0001). The mean +/- SEM level of mRNA expression for 3A grade rejection was 64.21 +/- 3.8; grade 1A, 38.4 +/- 3.5; and for Grade 0 was 38.46 +/- 2.8. The TLR-4 mRNA expression was increased but the specificity was not statistically significant. The TLR-2 immunoreactivity was strongly detected in infiltrating mononuclear cells and cardiac myocytes in Grade 3A rejection. AIF-1 expression was increased significantly in the group with 3A rejection and Grade III CV as compared with Grade 0 or 1A. Interleukin-18 receptors were strongly detected in Grade 3A rejection and CV. The expression profiles of AIF-1, TLR-2, and interleukin-18 were correlated with biopsy-proven allograft rejection in both peripheral blood and local tissue, suggesting a potential for diagnostic biomarkers for early detection of allograft rejection.

Native BK viral nephropathy in a pediatric heart transplant recipient

BK viral nephropathy is a well-documented clinical entity in kidney transplant recipients and a significant cause of morbidity and allograft loss in affected patients. BK viral nephropathy in native kidneys of non-kidney transplant recipients is relatively uncommon, but has been reported in adult patients. We report the occurrence of BK viral nephropathy in a pediatric heart transplant recipient. A 10-yr-old boy with past history of Ewing's sarcoma underwent heart transplantation for dilated cardiomyopathy induced by previous chemotherapy with doxorubicin. Post-transplant course was complicated by grade 3A rejection and CMV colitis. He was diagnosed with native BK viral nephropathy approximately 18 months post-transplant due to mild, but persistent, elevation in serum creatinine associated with proteinuria. BK viral nephropathy affects non-kidney transplant recipients, and a high index of suspicion is necessary for early diagnosis and management of this condition.

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.

Aggressive steroid weaning after cardiac transplantation is possible without the additional risk of significant rejection

Chronic steroid use after cardiac transplantation (CTX) is accompanied by co-morbidities that are dependent on length of exposure. A retrospective review of all CTX without induction therapy from 1999-2004. After 2001, an aggressive strategy of steroid weaning was introduced. A total of 165 patients underwent CTX, 82 from 1999-2001 (group 1) and 83 from 2002-2004 (group 2). There were no significant differences in recipient or donor characteristics between group 1 and group 2. The baseline calcineurin was cyclosporine in 41% and 5% (p < 0.0001) and tacrolimus in 59% and 95% (p < 0.0001), respectively. The mean duration of steroid use was 1023 d in group 1 and 383 d in group 2 (p < 0.0001). The overall incidence of any > or =ISHLT grade 3A rejection per year after CTX for group 1 vs. group 2 was as follows: year 1: 40% vs. 49% (p = NS) and year 2: 7.4% vs. 9.2% (p = NS). Steroid withdrawal by one yr after CTX using a contemporary immunosuppressive regimen is possible in most patients. In comparison with a slower steroid wean, a faster wean is not associated with an excess of significant rejection in the first two yr post CTX.

198: Renal Dysfunction before Ventricular Assist Impacts Renal Function Post-Transplant, Despite Improvements in Renal Function during Ventricular Support

inflammation.T-regs and inflammation were positively correlated (Spearman correlation coefficient 0.68; p 0.001). Among biopsies with low T-regs, the majority showed low inflammation: 77% (10/13) of those with FOXP3 score of 0 had an inflammation score of 1, as did 80% (24/30) of those with FOXP3 score of 1. By contrast, biopsies with more T-regs showed greater inflammation. In biopsies with a T-regs score of 2, 73% (16/22) had an inflammation score of 2, and those with a score of 3, 89% (8/9) had an inflammation score of 3. Table 2 shows the association between inflammation and the grade of rejectionInflammation correlated with the grade of rejection. Among biopsies with a high degree of inflammation (3), 46% (6/13) had grade 3A rejection and 38% (5/13) grade 2. By contrast, with less inflammation (1), 51% (19/37) had grade 1A. Conclusions: In heart transplants, T-regs increased with greater inflammation. Higher inflammation scores correlated with higher grades of rejection. Thus, T-regs increased with higher grades of rejection and reflected anti-allograft reactivity. Table 1

Sirolimus-Based Immunosuppression After Cardiac Transplantation: Predictors of Recovery From Calcineurin Inhibitor-Induced Renal Dysfunction

Proliferation signal inhibitors (PSI) facilitate reduction in calcineurin inhibitor exposure resulting in an improvement in creatinine clearance (CrCl) in cardiac transplant recipients with renal dysfunction. Predictors of improvement in renal function after conversion to PSI-based treatment remain unknown. We studied estimated CrCl (eCrCl) before and after initiating sirolimus and concomitant lowering (n = 20) or discontinuing (n = 18) calcineurin inhibitor in 38 patients with renal dysfunction (eCrCl < 50 ml/min) who had undergone cardiac transplantation a median (25%-75% percentiles) 81.8 months (17.4-129.5 months) earlier. The median sirolimus starting dose was 2.0 mg, and the blood level after 1 month was 8.0 ng/ml (4.5-13.4 ng/ml). Median eCrCl at conversion was 22.9 ml/min (19.1-30.6 ml/min), which increased after 1, 3, and 6 months to 25.9 (18.6-37.1), 25.6 (17.9-34.5), and 28.8 (18.7-38.7) ml/min, respectively. Age, gender, eCrCl at baseline, CNI reduction vs discontinuation, and presence or absence of diabetes or hypertension did not predict improvement in eCrCl after conversion. Only time from transplantation to conversion and eCrCl 3 months before conversion were correlated to the improvement in renal function after conversion to sirolimus (p < 0.05 and p < 0.01 for correlation after 1 month, respectively). Five patients (13%) experienced a grade 3A rejection episode while being treated with sirolimus. Treatment with sirolimus facilitates CNI lowering or discontinuation associated with a significant improvement in renal function after 1 month. Better renal function 3 months before conversion and a shorter time from transplant to conversion were associated with a greater improvement in renal function after conversion to sirolimus.

Decreased recipient survival following orthotopic heart transplantation with use of hearts from donors with projectile brain injury

Background Fatal gunshot injury to the brain can cause significant alterations in the neuroendocrine state and myocardial dysfunction. Therefore heart allografts from these donors may result in graft failure following orthotopic heart transplantation (OHTx). We evaluated whether receiving a heart from a donor who died from fatal gunshot wound to the brain independently affected the outcome of transplantation. Methods A retrospective review of 113 consecutive patients undergoing OHTx at a university hospital from 1996 to 2002 was performed. Group 1 received hearts from donors with fatal gun shot brain injury ( n = 17), and Group 2 received hearts from donors who died from other causes ( n = 96). Results Recipient age, gender, United Network for Organ Sharing (UNOS) status, indication for transplantation, and other co-morbid conditions were similar in both groups. Young male donors pre-dominated in Group 1, but other donor characteristics were not significantly different. The incidence of Grade 3A rejection was higher in Group 1 than Group 2 (35% vs 6.3%, p = 0.003), as was the incidence of post-operative infection (35% vs 7.2%, p = 0.004). Actuarial survival at 1 and 5 years was significantly lower in Group 1 than in Group 2 (81% and 74% vs 97% and 94%, respectively, p = 0.005). Multivariate logistic regression analysis also demonstrated that fatal gunshot brain injury, as cause of donor death, was a risk factor for recipient mortality ( p = 0.01). Conclusion Receiving a heart from a donor with fatal gunshot brain injury is a significant risk factor for recipient mortality following OHTx. Cautious use of heart allograft from these donors, especially in low-risk recipients, may lead to improved outcome following heart transplantation.

Initial experience with sirolimus and mycophenolate mofetil for renal rescue from cyclosporine nephrotoxicity after heart transplantation

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. We evaluated a CNI elimination protocol in 14 patients with renal impairment at 48.3 ± 36.0 months after heart transplantation. The mean serum creatinine was 321 ± 107 μmol/L; cyclosporine ( n = 13) or tacrolimus ( n = 1) was discontinued with sirolimus commenced immediately, initially aiming for a target trough level of 16 (12 to 20) ng/mL. If patients were not receiving mycophenolate (MMF) this was initiated at 1 g bid. The transfer period was covered with a tapering course of corticosteroids. In addition to monitoring clinical status, hematology, biochemistry, and sirolimus levels, graft function was assessed by echocardiography, ECG, and, where indicated, endomyocardial biopsy. Renal function improved in 12 patients (with 6 having a greater than 40% decrease in serum creatinine), remained unchanged in 1, and deteriorated in 1. Two patients who were converted at 15 and 139 months after transplantation experienced grade 3A rejection. One patient experienced a fall in ejection fraction without histologic evidence of rejection. Sirolimus was discontinued in three patients because of side effects: bone marrow suppression, presumed lymphocytic pneumonitis, and generalized acneform rash complicated by an axillary abcess; 50% of patients continue on sirolimus. In conclusion, withdrawal of CNIs after heart transplantation resulted in an improvement in renal function in most patients: 43% experienced a substantial improvement. CNI elimination protocols need to be refined to reduce the risk of breakthrough rejection and to minimize side effects while protecting renal function after heart transplantation.

A randomized clinical trial of tacrolimus [PROGRAF®] and cyclosporine [NEORAL®] immunosuprression in pediatric heart recipients

While Tacrolimus [Tac] and Cyclosporine [Cya] immunosuppression are used after heart transplantation (tx), few studies evaluate them in pediatrics. We randomized 26 heart recipients in a prospective, open label trial to Tac (n = 14) or Cya (n = 12) to compare their efficacy. Both groups received initial adjunct therapy of azathioprine and steroids. Mean age at tx was 4 yrs for Tac and 5.8 yrs for Cya. Mean follow-up was 26 mos (11–39 mos) for Tac and 24 mos for Cya (13–33 mos). Mortality for Tac was 14%; both deaths occurred day 8, 1 of sepsis, 1 of multiorgan failure. Mortality in the Cya group was 42%; 3 deaths < 1 month of primary graft failure, 1 late death (11 mos) of infection and 1 (7 mos) of accelerated graft vasculopathy. Four pts on Cya required switch to Tac; 3 for ongoing rejection, 1 for renal impairment and hyperlipidemia 1.2 yrs post tx. Two Tac pts required switch to Cya; 1 for leukopenia and oral ulcers, 1 for refractory anemia. Both resolved on Cya. Of the 12 Tac and 9 Cya survivors > 1 month post-tx, freedom from acute allograft rejection at 3, 6, and 12 mos was 0.33 vs 0.44, 0.58 vs 0.78, and 0.83 vs 0.78, respectively. 58% (7/12) Tac pts and 44% on Cya (4/9) had at least 1 grade 3A rejection or worse in the first 3 mos post-tx; 1 Tac pt had vascular rejection with eosiniphils, edema and poor ventricular function < 1 month post-tx (resolved with aggressive therapy). At 12 mos 12 pts were on Tac and 4 on Cya. No difference in incidence of bacterial or viral infections, though infection accounted for a late Cya death. Seizures occurred in 1 Tac and 1 Cya pt < 1 month post-tx. At 12 mos, 25% Tac and 50% Cya had hyperlipidemia, and 17% Tac and 50% Cya pts had anemia; 20% on Tac were off steroids while all 4 on Cya remained on steroids. Our experience suggests both are efficacious in pediatrics. Conversion from Cya to Tac was useful for refractory rejection, though a lower incidence of cellular rejection was not observed in the Tac group.

Is everolimus useful in preventing allograft rejection and vasculopathy after heart transplant?

The main cause of illness and death after the first year of heart transplantation is vasculopathy of the cardiac allograft, probably initiated by early immunological and non-immunological endothelial damage. The incidence of multiple episodes of grade 3A rejection 6 months after primary heart transplantation was lower with everolimus (1.5 mg, 8.1% and 3 mg, 6.6%) than in the azathioprine group (14%). Allograft vasculopathy was less frequent with everolimus than azathioprine. A follow-up study is necessary to determine whether these effects translate into the important end points of reduced incidences of death, graft loss or a second transplantation.

INOS and peroxynitrite formation during acute rejection after human heart transplantation

endomyocardial biopsy (EMB) beyond 2 years post-transplant remains uncertain. We performed a retrospective analysis reflecting our singleinstitution experience with 4041 biopsies (188 patients) from 1986-2001. Late ISHLT grade 3A rejection ocurring beyond 2 years posttransplant was detected in 24% of cardiac transplant recipients (33 of 139 patients) up to 10 years post-transplant. Late rejection could not be attributed to subtherapeutic levels of immunosuppression or other established parameters. Late rejection was only marginally correlated with the incidence of moderate rejection within the first 2 posttransplant years (p 0.09). Unlike the incidence of moderate rejection in the first post-transplant year showing a steady decline toward more recent years (2.1430.13), the incidence of late rejection appeared not to be influenced by transplant era (mean 0.11 0.056) over a 10 year observation period (1989-1999). Spontaneous resolution of moderate rejection beyond 2 years post-transplant occurred in all 17 patients in whom specific anti-rejection therapy had been electively withheld. Mortality beyond 2 years post-transplant was slightly lower (p 0.033) in the late rejecting group (n 33) than in the control group (n 106), no difference was found in the prevalence of transplant vasculopathy diagnosed by coronary angiography. EMB continues to detect episodes of moderate rejection even very late after heart transplantation without a close correlation with the rejection frequency in the early posttransplant period. Late rejection may represent a distinct biological entity as evidenced by its spontaneous resolution, lack of an era effect as is found for early rejection and no negative impact on survival. The future role of late EMB will depend on its predictive value for diagnosis and risk stratification of chronic graft dysfunction.

In Vivo Imaging of Acute Cardiac Rejection in Human Patients Using 99mTechnetium Labeled Annexin V

Annexin V binds phosphatidylserine moieties on apoptotic cells. This study reports the initial experience at Stanford University Medical Center with 99mTc-labeled annexin V imaging as a noninvasive measure of apoptosis in acute cardiac rejection. Ten cardiac transplant patients had 99mTc Annexin V imaging and endomyocardial biopsy (EMB) performed within 24 h. No complications related to 99mTc annexin V administration occurred. Eight patients had ISHLT grade of acute rejection of 1A or less. Five patients had two or more areas of uptake noted in the right ventricle on imaging studies. Two of these patients had positive biopsies: one patient had grade 2 rejection with two focal uptake areas and another had grade 3A rejection with three foci. An additional five patients had either one or zero hot spot areas and corresponding negative EMBs. 99mTc-annexin V appears to be well tolerated and may identify patients with acute cardiac rejection.

Routine surveillance endomyocardial biopsy continues to detect significant rejection late after heart transplantation

Background The need for continued surveillance endomyocardial biopsies beyond the first year after cardiac transplantation is controversial. We evaluated the incidence of rejections requiring treatment (International Society Heart and Lung Transplantation grade 3A or greater) in patients 5 years or more after heart transplantation. Methods We conducted a retrospective chart review of all patients who underwent at least 1 endomyocardial biopsy at our center 5 years or more after heart transplantation. Results A total of 461 biopsies were performed in 77 patients 5 or more years after heart transplantation. Nine episodes of grade 3A or greater rejection were identified in 8 of 77 patients (10%). During the first year, 7.6% of biopsies were grade 3A or greater. Grade 3A rejection occurred in approximately 3.5% to 4% of biopsies during years 2 to 7. The overall incidence of procedural related complications at our institution was < 0.5%. Conclusion Endomyocardial biopsies continue to detect clinically significant rejection beyond 5 years after cardiac transplantation. The overall incidence of procedural related complications requiring treatment was low and none was life threatening. The absence of early rejection does not predict freedom from late rejection. Therefore, we continue to recommend surveillance biopsies in cardiac transplant recipients late after transplantation.

A clinical trial combining donor bone marrow infusion and heart transplantation: Intermediate-term results

Background: Donor chimerism (the presence of donor cells of bone marrow origin) is present for years after transplantation in recipients of solid organs. In lung recipients, chimerism is associated with a lower incidence of chronic rejection. To augment donor chimerism with the aim to enhance graft acceptance and to reduce immunosuppression, we initiated a trial combining infusion of donor bone marrow with heart transplantation. Reported herein are the intermediate-term results of this ongoing trial. Methods: Between September 1993 and August 1998, 28 patients received concurrent heart transplantation and infusion of donor bone marrow at 3.0 × 10 8 cells/kg (study group). Twenty-four contemporaneous heart recipients who did not receive bone marrow served as controls. All patients received an immunosuppressive regimen consisting of tacrolimus and steroids. Results: Patient survival was similar between the study and control groups (86% and 87% at 3 years, respectively). However, the proportion of patients free from grade 3A rejection was higher in the study group (64% at 6 months) than in the control group (40%; P = .03). The prevalence of coronary artery disease was similar between the two groups (freedom from disease at 3 years was 78% in study patients and 69% in controls). Similar proportions of study (18%) and control (15%) patients exhibited in vitro evidence of donor-specific hyporesponsiveness. Conclusions: The infusion of donor bone marrow reduces the rate of acute rejection in heart recipients. Donor bone marrow may play an important role in strategies aiming to enhance the graft acceptance. (J Thorac Cardiovasc Surg 2000;119:673-81)

Oral steroid pulse without taper for the treatment of asymptomatic moderate cardiac allograft rejection

Background: The most frequently administered treatment for asymptomatic ISHLT Grade 3A cardiac allograft rejection is intravenous steroids or oral steroid pulse with a taper. This study analyzes the efficacy of 3-day 100-mg course of prednisone without a tapered regimen for the treatment of asymptomatic moderate cardiac allograft rejection. Methods All new episodes of asymptomatic ISHLT Grade 3A rejections were treated with oral steroid pulse without taper, consisting of 100 mg of prednisone for 3 consecutive days followed by resuming the pre-rejection steroid dose on the fourth day. We retrospectively reviewed the histologic response of all treated episodes among all cardiac transplant recipients transplanted between January 1995 through December 1997 who were treated with triple therapy consisting of cyclosporine, azathioprine and steroids. Patients receiving additional or alternative immunosuppressives were excluded from the study. The treated episodes were analyzed as responders if the follow-up biopsy were Grade 0, 1A, 1B, or 2; treatment was counted as non-responders if the follow-up biopsy showed Grade 3A or higher. Results Of 230 cardiac transplant recipients, 100 patients received a 3-day 100 mg course of prednisone without taper for 174 new episodes of asymptomatic ISHLT Grade 3A rejection. The overall response rate was 75% (130/174 rejection episodes). A significant difference in the response rate was observed depending on the number of days post transplant. A comparison of the success rates among rejections which occurred > 90 days post transplant versus < 30 days revealed responses to be 88% versus 70% ( p = 0.02); for rejections treated > 60 days post transplant versus < 30 days showed success rates of 84% versus 70% ( p = 0.04). The mean age of the recipient revealed a trend to be lower among the non-responder group (49 ± 12 years versus 53 ± 9 years, p = 0.07). Having left ventricular assist device as a bridge to transplant did not significantly affect the treatment outcome. The response rates were 69% for the patients who required the assist device versus 77% for those not bridged ( p = ns). There was no significant difference in the gender or the baseline immunosuppressive doses between the responders and non-responders. The cost of a 3-day outpatient, visiting nurse supervised intravenous steroid therapy versus 3 days of oral prednisone was $861 vs $6.88. Conclusion Oral steroid pulse without taper is an effective and economical way to treat asymptomatic moderate grade cardiac allograft rejection. A 3-day course of 100 mg of prednisone without taper should be considered as first line of therapy for clinically stable form of moderate cardiac allograft rejection occurring > 60 days post transplant.

The Meaning of Mild Rejection During Corticosteroid Weaning in Heart Transplant Recipients.

398 Corticosteroid weaning after heart transplant has increased in popularity and has been performed early and late (> 6 months) after heart transplantation. The actual weaning schedule has varied from program to program (over 1 week to 5 months). Some heart transplant programs will reinstitute corticosteroids if routine endomyocardial biopsy during weaning reveals mild rejection. However, it has not been established whether mild rejection progresses to a more severe form of rejection at a higher rate during corticosteroid weaning. To answer this question, we reviewed 165 heart transplant patients between April 1989 and July 1997 who were undergoing corticosteroid weaning beginning at 6 months after transplant and decreasing by 1 mg per month from a 5 mg baseline dose. Only endomyocardial biopsy grades of ≥3A were treated with reinstitution of corticosteroids at high doses. During this corticosteroid-weaning period, there were a total of 835 endomyocardial biopsies performed. Of the total, 558 were grade 0, 238 were grade 1A, 9 were grade 1B, 25 were grade 2, 4 were grade 3A, and 1 was grade 3B. The 4 patients with grade 3A rejection had either grade 0 or grade 1A on their previous endomyocardial biopsies. The patient with grade 3B rejection had previous endomyocardial biopsy demonstrating grade 1B rejection. This meant 1/9 (11%) grade 1B rejections and only 2/238 (0.8%) grade 1A rejection progressed to ≥ grade 3A rejection. Four patients were withdrawn from the corticosteroid-weaning protocol due to LVEF decreasing to ≤ 45% (range 20-45%) and all 4 patients had either grade 0 or grade 1A on their endomyocardial biopsy at the time of removal from the corticosteroid-weaning protocol. Other patients were not successfully weaned due to adverse effects of weaning including myalgias, headaches, arthritis, and fatigue. Corticosteroid weaning was successful in 83.6% of patients. Conclusion: Corticosteroid weaning late after heart transplantation is successful in a majority of patients. Endomyocardial biopsies during the steroid-weaning protocol revealing grade 1A mild rejection rarely progress to a more severe from of rejection and therefore do not support removing the patient from the corticosteroid-weaning protocol. Endomyocardial biopsy grade 1B rejection during corticosteroid weaning should have close observation with follow-up endomyocardial biopsy.

Revision of the 1990 working formulation for cardiac allograft rejection: the Sheffield experience

ObjectiveTo audit the 1990 International Society for Heart and Lung Transplantation cardiac rejection criteria and to evaluate the impact on classification and clinical outcomes of a modification in which grade...