The influence of late acute rejection episodes on long-term graft outcome after liver transplantation

Acute cellular rejection represents the most important single risk factor for the occurrence of chronic rejection after organ transplantation. We correlated late acute rejections with the occurrence of chronic graft failure after liver transplantation. We followed 1426 liver transplants for late acute rejection episodes defined as occurring >3 months after OLT. The overall incidence of chronic rejection in our patient population was 3.7%. In summary, we observed a predictive increase of transaminase levels prior to routine biopsies among patients with histologic evidence of late acute rejections. In contrast to other organ systems, late acute rejection episodes were not associated with the occurrence of chronic graft deterioration in liver grafts.     

心脏移植术后冠状动脉病变的相关因素分析

目的探讨心脏移植术后长期存活的患者冠状动脉病变的相关危险因素。方法回顾性分析32例心脏移植术后长期存活患者的临床资料,并对相关的临床因素进行评价,筛选出移植心冠状动脉病变的独立危险因素。结果高脂血症、热缺血时间、巨细胞病毒(CMV)抗体阳性、移植后时间及慢性排斥反应是移植心冠状动脉病变的危险因素,而年龄、高血压和糖尿病与移植心冠状动脉病变的相关性不明显;多元Losgitic回归分析,移植后时间和慢性排斥反应是移植心冠状动脉病变的独立危险因素(P<0.001,P=0.003)。结论心脏移植术后冠状动脉病变的实质是慢性排斥反应;与供心的热缺血时间、高脂血症及巨细胞病毒感染等相关。     

Intragraft heme oxygenase-1 and coronary artery disease after heart transplantation

Peri-operative tissue injury triggers the development of Transplant Coronary Artery Disease (TCAD). Animal studies have shown that induction of heme oxygenase (HO)-1 protects the donor organ from the development of TCAD. To investigate the role of HO-1 in TCAD after clinical heart transplantation, we measured intragraft mRNA expression of HO-1, HIF-1alpha, TGF-beta, FLIP, and the Bcl-2/Bax balance. Immunohistochemical staining of HO-1 was performed to determine its origin. Myocardial biopsies taken at the end of the transplantation procedure (time 0), at 1 week and at 10 months after transplantation were studied from recipients with or without angiographic signs of accelerated TCAD, diagnosed after 1 year. At time 0, no differences in mRNA expression for any of the measured parameters were found between TCAD positive and negative patients. At 1 week, mRNA expression of HO-1 and TGF-beta was higher in grafts that developed accelerated TCAD (p=0.001 and p=0.0002). These higher mRNA levels were accompanied by a pro-apoptotic shift in Bcl-2/Bax (p=0.02), suggesting proneness for apoptosis via the mitochondrial pathway. Immunohistochemical staining showed that HO-1 was mainly produced by infiltrating macrophages. At 10 months, again HO-1 and TGF-beta levels were high in TCAD positive patients (p=0.02 and p=0.05), but the expression of apoptotic markers was comparable at this time point. Our results suggest that a higher HO-1 by macrophages in our patient population might be an adaptive response to tissue injury and inflammation, reflecting damage due to the transplantation procedure that finally results in TCAD.     

Risk factors for the development of coronary artery disease of a grafted heart as detected very early after orthotopic heart transplantation

Orthotopic heart transplantation (OHTx) represents a well established method of end-stage heart failure treatment. Allograft coronary artery disease (CAD) still remains to be one of the most important limiting factors for OHTx recipients' long-term survival. Unfortunately, allograft CAD can be detected very early after OHTx. Our study was designed to identify risk factors for early allograft CAD development. Eighty-three OHTx recipients (18 females, 65 males, mean age 50.55 +/- 11.04 years) with coronary intravascular ultrasound examination performed early after OHTx (29.81 +/- 12.45 days) formed the study population. The impact of a number of pre-, peri- and early post-transplant possible risk factors on early allograft CAD development was studied. By multivariate analysis, only higher donor age (P < 0.001) and higher recipient's body mass index (P = 0.003) were found to represent risk factors for the early development of allograft CAD.     

Acute rejection episodes after renal transplantation in children

46 renal transplants performed in children at the Medizinische Hochschule Hannover between 1975 and 1980 are evaluated for the occurrence of acute rejection episodes. 33 patients received cadaveric donor grafts (CAD) and 13 living donor grafts (LD). Immunosuppression was carried out with prednisone and azathioprine. 14 patients were treated additionally with antilymphocyte globulin (ALG). A total of 68 acute rejection episodes occurred, 38% of them within the first week of transplantation, and the latest 3 years after transplantation. The most important signs of acute rejection were a rise in serum creatinine concentration, a decrease in urine output and fever. Patients with living donor grafts and full-house matched kidneys had fewer reversible and irreversible rejection episodes than did patients with grafts from cadaveric donors and with grafts with 1-4 mismatches. The value of ALG treatment is doubtful: only 1 out of 14 patients who received ALG treatment experienced no rejection episodes compared to 12 out of 33 patients who did not have ALG treatment. 2.4 rejection episodes/patient occurred in patients who had cadaver grafts and had received ALG compared to 1.17 episodes/patient in similar patients who had not received ALG. Irreversible rejection episodes occurred in 4 out of 9 ALG-treated and in 3 out of 23 non-ALG-treated recipients of cadaver grafts.     

Beating heart coronary artery bypass surgery after orthotopic heart transplantation

Beating-heart coronary artery bypass surgery was performed in a 52-year-old man with accelerated transplant coronary artery disease 10 years after orthotopic heart transplantation. Transplant coronary artery disease was first detected in the left circumflex coronary artery 9 years after transplantation. Rapid progression to triple vessel disease occurred within 1 year, and the patient developed worsening symptoms of shortness of breath and chest pain. He underwent off-pump "beating heart" left internal mammary artery to left anterior descending coronary artery bypass surgery. The circumflex coronary artery was not graftable due to diffuse and truncated small vessel disease. His postoperative course was uneventful and he was discharged on the fifth postoperative day. Coronary angiography 3 months after the surgery revealed a widely patent left internal mammary artery to left anterior descending artery bypass. He is alive and symptom free more than 1 year after his surgery.     

血管紧张素转换酶抑制剂对心脏移植后冠状血管增殖病变的影响

目的通过建立大鼠心脏移植后冠状血管增殖病变的模型,观察血管紧张素转换酶抑制剂(ACEI)对心脏移植后冠状血管增殖病变的影响。方法设立对照组、结扎组、ACEI+结扎组,观察2周后各组大鼠血液、心肌AngⅡ含量,心肌AngⅡ受体密度,及血管病理学结果。结果各组血液AngⅡ含量差异无统计学意义,结扎组心肌AngⅡ含量明显增高(17．42±5．49)fmol／mg．蛋白P<0．001比对照组,ACEI+结扎组AngⅡ含量明显下降(5．35±1．95)fmol／mg。蛋白P< 0．01比结扎组,结扎组AngⅡ受体密度增高(48．80±4．32)fmol／mg蛋白P<0．01比对照组,ACEI +结扎组内膜增生比结扎组明显减轻[内膜厚度(21．01±4．55)μm比(60．34±9．32)μm,P< 0．01)。结论心脏局部肾素-血管紧张素系统,AngⅡ及AngⅡ受体参与移植后冠状血管病变,A- CEI明显抑制移植后冠状血管病增殖变。     

Pravastatin prevents the progression of accelerated coronary artery disease after heart transplantation in a rabbit model

Abstract  This study was designed to investigate the effects of pravastatin (Pr) on accelerated coronary arteriosclerosis in transplanted hearts. The rabbit hearts were transplanted to the recipients' neck heterotopi-cally, and received FK506. The rabbits in group 1 were fed a normal diet (ND), and cholesterol-rich diet (CD) in group 2 and 3. Pr (10 mg/kg) was given to group 3. They were sacrificed at 4 weeks and the severity of m%cardial rejection and arteriosclerosis was assessed and scored histologically. The serum lipid levels were significantly elevated by a CD. However, addition of Pr had no effect on the levels of LDL and total cholesterol (TC). There was no significant difference in m%cardial rejection in each group. Transplanted hearts in group 2 showed more severe arteriosclerotic lesions than those in group 1. Pr treatment in group 3 diminished the severity of coronary arteriosclerosis. Pr may prevent the accelerated coronary arteriosclerosis after heart transplantation without significant changes in TC and LDL.     

Non-invasive detection of coronary artery disease by dobutamine-stress echocardiography in children after heart transplantation.

BACKGROUND: Coronary vasculopathy is the main cause of cardiac graft failure. Because yearly coronary angiography is invasive in children, a non-invasive method for detecting graft vasculopathy is needed. The aim of this study was to test dobutamine-stress echocardiography in a pediatric population to determine its feasibility, safety and reliability in the detection of graft coronary artery disease. METHODS: Eighteen patients, aged 2 days to 16.8 years at transplantation (mean 8.4 years), underwent 44 dobutamine-stress echocardiography (DSE) exams, at a follow-up of 1.1 to 11.8 years (mean 5.1 years). Selective coronary angiography was performed for comparison. Echocardiographic recordings were obtained in 4 standard views of the left ventricle and measurements carried out within the frames of a 16-segment model. Segmental scores of contractility were obtained for each segment and a total segmental contractility index was calculated at each stage. RESULTS: All patients reached the maximum dose stage. Maximum heart rate was 57% to 90% of predicted maximum. Maximum systolic blood pressure reached 190 mmHg. Segmental scores were normal in 37 and abnormal in 7 cases. Echographic results were concordant with angiography in 82% and discordant in 18% of the cases (4 negative DSEs with minor angiographic lesions, 2 positive DSEs with normal angiography), but there was no significant angiographic lesion with normal DSE. CONCLUSIONS: DSE is a safe and highly feasible non-invasive technique in transplanted children. A normal DSE study successfully predicts the absence of significant coronary artery disease in the post-transplant population.     

The influence of gender on survival after heart transplantation

Because of a shortage of deceased donors, more than one-third of patients die during the waiting period for transplantation. This study was conducted to analyze the influence of gender on survival after heart transplantation. We retrospectively reviewed the recipients after primary orthotopic heart transplantation. According to gender, patients were divided into four groups: male donor to male recipient, male donor to female recipient, female donor to male recipient, and female donor to female recipient. Kaplan-Meier survival curves were plotted with log-rank tests. Cox regression analysis with dummy variables were used to examine the effects of donor gender, recipient gender, and donor-recipient gender combinations on survival after heart transplantation. The data did not show any significant effect of donor gender, recipient gender, or donor-recipient gender combinations on patient survival, using the methods of log-rank test and Cox regression with dummy variables. Based on our results, we concluded that gender was not an important factor in organ allocation.     

Donor polymorphisms in Toll-like receptor-4 influence the development of rejection after renal transplantation

BACKGROUND: Although innate immunity is crucial to host defense against pathogens, the extent to which innate immune mechanisms participate in the rejection of allogenic tissues in humans is unknown. We hypothesize that activation of innate immunity through Toll-like receptors (TLRs) critically regulates the development of renal allograft rejection. We have recently demonstrated decreased acute rejection in lung transplant recipients heterozygous for either of two functional polymorphisms in TLR4 associated with endotoxin hyporesponsiveness. In the present investigation, we sought to evaluate the role of innate immune activation through TLR4, in either donor or recipient, upon the development of renal allograft rejection. METHODS: Patients and donors were screened for the TLR4 functional polymorphisms (Asp299Gly and Thr399Ile) by polymerase chain reaction (PCR) using sequence-specific primers. RESULTS: The incidence of biopsy-proven acute renal allograft rejection was significantly reduced in patients receiving donor grafts heterozygous for the Asp299Gly or Thr399Ile alleles, when compared with wild type (22% vs. 0%, respectively, p = 0.02). There was no association with recipient TLR4 allele and rejection. CONCLUSIONS: The results suggest activation of innate immunity through TLR4 in the donor kidney contributes to the development of acute rejection after renal transplantation.     

Prevalence of donor-transmitted coronary artery disease and its influence on heart transplant outcomes

Background

It is uncertain whether donor-transmitted coronary artery disease (DTCAD) affects heart transplant (HT) recipients.

Methods

This retrospective analysis includes records of all patients who underwent a HT at our center over an 8-year period, who survived for at least 1 month, and who were examined by coronary angiography within 2 months post-HT. We distinguished angiographically from keep ultrasonography (IVUS) detected DTCAD. Major adverse cardiovascular events (MACE) comprised death, myocardial infarction, unstable angina, coronary revascularization, and admission because of heart failure not due to an acute rejection episode.

Results

Among the 171 patients of mean age 53 ± 13 years and including 83% men, 65 (38%) were evaluated by IVUS. Donors were aged 40 ± 14 years (range = 14-73). Angiographic DTCAD affected seven patients (4.1%), and IVUS-detected DTCAD, 35 (53.8% of those examined by IVUS). DTCAD donors were older than non-DTCAD donors, by an average of 13 years (P = .001) for angiographic DTCAD and 18 years (P < .0001) for IVUS-detected DTCAD. Two patients underwent percutaneous revascularization upon detection of angiographic DTCAD. The angiographic- and IVUS-detected DTCAD groups did not differ significantly from the corresponding non-DTCAD groups as regards MACE incidence during 54 ± 41 and 38 ± 20 months follow-up, respectively. Cox regression analysis with adjustment for relevant confounders confirmed that IVUS-detected DTCAD was not a predictor of MACE (hazard ratio 1.2, 95% confidence interval 0.2-8.1).

Conclusions

Among HT patients surviving ≥ 1 month, angiographic- and IVUS-detected DTCAD showed prevalences of <10% and >50%, respectively. Neither detection method was associated with a greater long-term incidence of MACE.     

Late rejection episodes more than 1 year after pediatric heart transplantation: risk factors and outcomes.

BACKGROUND: Little is known about late rejection episodes after pediatric heart transplantation. We determined the frequency of late rejection episodes (>1 year) after pediatric heart transplantation, defined risk factors for its occurrence, and evaluated outcome after late rejection. METHODS: We analyzed data from 685 pediatric recipients (<18 years at transplantation) who underwent transplantation between January 1, 1993, and December 31, 1997, at 18 centers in the Pediatric Heart Transplant Study (PHTS). Probability of freedom from late rejection was determined and risk factors for late rejection and for death after late rejection were sought using univariate and multivariate analyses. RESULTS: We followed 431 patients for >1 year (median follow-up, 32.9 months) of whom 106 (24.6%) experienced 1 or more late rejection episodes (total of 178 episodes, 27 with severe hemodynamic compromise). Probability of freedom from first late rejection was 73% at 3 years and 66% at 4 years after transplantation. Risk factors (multivariate analysis) for first late rejection were >1 episode of rejection in the first year (p = 0.009), recipient black race (p = 0.0002), and older age at transplantation (p = 0.0003). Only 4 of 325 (1.2%) children who survived beyond 1 year without late rejection died compared with 26 of 106 (24.6%) with late rejection (p < 0.0001). Nine of these 26 died within 1 month of the first late rejection episode, and 17 died subsequently: 5 of acute rejection, 3 of sudden unexplained deaths, 3 of documented coronary artery disease, and 6 of other causes. Severe hemodynamic compromise with late rejection was identified as a risk factor for death among children with 1 or more episodes of late rejection. CONCLUSIONS: Approximately 25% of pediatric recipients in the PHTS who survived beyond 1 year experienced late rejection episodes. Late rejection is associated with poor survival, especially when associated with hemodynamic compromise. Absence of late rejection episodes is associated with very low risk of death during medium-term follow-up after pediatric heart transplantation. Determining the risk factors for late rejection will help to identify a cohort of patients who may benefit from enhanced rejection surveillance and treatment.     

Late pacemaker requirement after pediatric orthotopic heart transplantation may predict the presence of transplant coronary artery disease.

BACKGROUND: Few data are available regarding pacemaker implantation after pediatric orthotopic heart transplantation. The purpose of this study was to assess the incidence, indications and associations with regard to pacemaker placement in children who have undergone orthotopic heart transplantation. METHODS: We performed a retrospective study of all patients undergoing orthotopic heart transplantation at our institution from October 1984 to March 2001. Data obtained included demographics, indications for pacemaker, presence of transplant coronary artery disease and long-term follow-up. Patients were divided into: Group 1, patients requiring a pacemaker within 3 months of transplantation; and Group 2, patients requiring a pacemaker beyond 3 months. RESULTS: Pacemakers were required in 7 of 106 (6.6%) transplant recipients. Pacing indications for patients in Group 1 (n = 2) were persistent bradycardia with pause-related ventricular arrhythmia and atrial flutter with resultant sinus pauses of up to 4 seconds. In Group 2 patients (n = 5), indications for pacing were high-grade atrioventricular (AV) block in 1 patient and episodic sinus pauses up to 3.3 seconds associated with syncope/dizziness in the remaining 4 patients. All patients in Group 2 had transplant coronary disease diagnosed within 1 year of pacemaker implantation. All had resolution of symptoms and no complications after implantation. CONCLUSIONS: Pacemakers are infrequently required after cardiac transplantation in children. Despite not meeting classic symptomatic sinus bradycardia criteria, pacemaker placement should be considered post-transplantation in patients with episodic sinus pauses and dizziness or syncope. Patients who present with the aforementioned symptoms or high-grade AV block should be evaluated closely for the presence or development of transplant coronary artery disease, as it may be their first symptom.