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.     

Acute septal myocardial infarction diagnosed by endomyocardial biopsy in a heart transplant recipient.

We describe an unusual case of acute septal myocardial infarction in a heart transplant recipient. The clinical presentation was most suggestive of acute rejection; the correct diagnosis was first made by endomyocardial biopsy and was then verified by coronary angiography. Acute myocardial infarction should be included in the differential diagnosis of acute rejection after heart transplantation and included among the possible diagnoses made by endomyocardial biopsy in these patients.     

Hemodynamics versus biopsy findings during cardiac transplant rejection

Before the use of cyclosporine as the major component for immunosuppression after cardiac transplantation, rejection was accompanied by catastrophic hemodynamic decompensation. However, the hemodynamic changes that occur during rejection after cardiac transplantation in patients treated with cyclosporine have not been clearly described. Between July 1986 and October 1989, 89 adults underwent orthotopic heart transplantation at the University of Michigan Medical Center. All patients received triple-drug therapy immunosuppression consisting of steroids, cyclosporine, and azathioprine. Cardiac hemodynamics were measured and correlated with the histologic assessment of rejection. There have been ten deaths among these 89 patients for an overall survival of 89%. There were no deaths from rejection. One hundred fifty-three of the biopsy specimens were read as grade 0, 31 were grade 1, 75 were grade 2, 103 were grade 3, and 9 patients had grade 4 biopsy specimens. No hemodynamic differences were noted in patients with increasing grade of rejection. Five patients (5/9, 55%) with severe rejection (grade 4) had symptoms of congestive heart failure at the time of biopsy. These symptomatic grade 4 patients differed from asymptomatic grade 4 patients only in cardiac output (2.9 versus 5.2 L/min). Overall hemodynamic decompensation was not evident as rejection grade increased. Routine serial endomyocardial biopsies remain the procedure of choice in the diagnosis of rejection in the asymptomatic patient after cardiac transplantation as hemodynamics do not predict degree of rejection.     

心脏移植术后急性排斥反应1例临床监测经验总结

目的 总结心脏移植术后急性排斥反应的临床监测体会.方法 回顾性分析1例心脏移植术后死于急性排斥反应患者的临床资料,分析术后排斥反应监测情况.结果 患者术后半年随访行心内膜心肌活组织检查(活检),结果为Ⅱ级急性排斥反应,经治疗好转出院.术后3年因上呼吸道感染出现气促再次入院,心内膜心肌活检结果为0~ⅠA级改变,病情恶化,...     

Elevated levels of serum interleukin-6 are associated with low grade cellular rejection in patients with heart transplantation

Endomyocardial biopsy is the gold-standard procedure to diagnose acute cellular rejection after heart transplantation. This study assessed whether the blood levels of cytokines involved in inflammation and immune activation are useful to detect the presence of acute cellular rejection.MethodsBlood specimens collected before 275 endomyocardial biopsies in 66 patients were assayed for levels of TNFα, IL6, IL1β, and IL2 receptor. The biopsies were grouped according to the presence (n = 41) or absence (n = 234) of acute cellular rejection grade ≥3A of the International Society for Heart and Lung Transplantation. We compared the levels of cytokines in the two groups.ResultsCirculating IL6 levels were significantly higher when there was a low grade (0–2) cellular rejection in the biopsy versus the group of biopsies grade ≥3A (19.8 ± 27 versus 12.9 ± 10 pg/mL; P = .001). An IL6 level higher than 30 pg/mL showed a negative predictive value of 95% for the presence of acute rejection grade ≥ 3A.ConclusionIn heart transplant patients, high levels of serum IL6 were associated with low grade cellular rejection. Determination of IL6 levels may be useful to reduce the number of endomyocardial biopsies during follow-up in these patients.     

Interpretation of endomyocardial biopsy after heart transplantation. Potentially confusing factors

Histological examination of the myocardium by endomyocardial biopsy is a standard method of monitoring the presence of acute rejection in the transplanted heart. The histopathological consequences of the biopsy procedure itself have been investigated in non-transplanted hearts in the baboon. Organization of thrombus, necrosis of myocytes adjacent to the biopsy site, and mononuclear cells (including T lymphocytes) surrounding the biopsy site appear after biopsy; should a subsequent biopsy be taken from this area, these appearances may be confused with the appearances associated with acute or resolving cardiac rejection. This problem has been encountered in the clinical transplant programme. Observations on the myocardial histopathological changes resulting from brain death and from parasitic infestation, both of which may also lead to confusion in the interpretation of endomyocardial biopsies, are also presented. Awareness of these factors in patients with heart transplants should lead to caution in the interpretation of the histopathological features and may avoid unnecessary extra immunosuppression early after transplantation. Observations indicate that endomyocardial biopsy should not be the sole method of monitoring for the development of acute rejection.     

Survival and incidence of acute rejection in heart transplant recipients undergoing successful withdrawal from steroid therapy.

BACKGROUND: Steroid-free immunosuppression is feasible in selected patients after heart transplantation. Survival and incidence of acute rejection are important parameters to evaluate when weighing risks and benefits of steroid withdrawal. METHODS: One hundred thirty-seven patients were retrospectively reviewed who underwent heart transplant at Emory University between January 1988 and April 1994 and survived >1 year. Standard immunosuppression (cyclosporine, azathioprine and prednisone) without induction therapy was used. Weaning from steroids was attempted in all patients. Scheduled endomyocardial biopsy was used for long-term surveillance screening. RESULTS: Seventy-two patients (52.5%) underwent successful prednisone withdrawal (Group P0) at an average of 13 months after heart transplant, whereas 65 patients (47.5%) did not achieve steroid-free immunosuppression (Group P1). Group P0 had a mean of 1.3 treated rejection episodes (ISHLT Grade > or = 1b) during the first post-transplant year and Group P1 a mean of 2.3 (p <0.0001). In Group P0, 40 patients (55.6%) suffered a subsequent acute rejection with an ISHLT Grade > or = 1b, resulting in treatment. Of these, 15% were ISHLT Grade 1b, 47.5% Grade 2, 35% Grade 3a and 2.5% Grade 3b. The estimated risk of suffering from acute rejection of at least Grade 1b after achieving steroid-free immunosuppression was 50% at 21 months. Estimated survival at 5 years after heart transplant was 92.9% in Group P0 and 72.3% in Group P1 (p <0.01). Cox proportional hazard modeling revealed black recipient race as effect modifier of group status with decreased survival time in both groups. CONCLUSION: Steroid-free immunosuppression in white heart transplant recipients is associated with improved survival. A low acute rejection score during the first year predicts successful steroid withdrawal. Black recipient race appears to be negatively associated with survival and deserves further detailed study. Long-term surveillance screening using endomyocardial biopsy is recommended.     

Futility of yearly heart biopsies in patients undergoing heart transplantation.

Three hundred thirty-eight endomyocardial biopsies, performed as part of the routine annual evaluation at 1 or more years after transplantation in 211 patients, were reviewed. In only two instances (0.6%) were the histologic findings suggestive, but not pathognomonic, of acute rejection. Both patients were treated for rejection and are doing well at 4 and 6 years postoperatively. On the basis of the results of this study, we believe that routine yearly heart biopsies in asymptomatic patients are not necessary for long-term care of patients after heart transplantation, and we believe they should be performed only if there is clinical suspicion of rejection or as part of a research protocol.     

Complement activation products in plasma after heart transplantation in humans

BACKGROUND: Complement activation has recently been implicated as a contributing factor to early and late allograft dysfunction in cardiac transplantation. The current study was designed to determine whether measurement of plasma complement fragments C4d and SC5b-9 would be useful in detecting acute rejection or accelerated graft atherosclerosis (AGA) in cardiac allograft recipients. METHODS: We measured complement activation products, C4d (classical pathway) and SC5b-9 (terminal pathway), at the time of routine endomyocardial biopsy in heart transplant recipients. Ten patients in the immediate posttransplantation period (0-100 days) and 19 patients more than 6 months after transplantation were studied. RESULTS: No correlation was found between plasma levels of complement activation fragments and the presence of biopsy-proven acute allograft rejection or AGA (assessed by coronary angiography). However, plasma C4d and SC5b-9 were significantly elevated in 9 of 10 and 7 of 10 patients, respectively, in the immediate posttransplantation period. This was followed by progressive decrease in the levels of C4d and SC5b-9 fragments during the first 4-6 weeks after transplantation. CONCLUSION: We conclude that measuring plasma levels of fragments C4d and SC5b-9 is not a useful noninvasive method for detecting acute rejection or AGA after heart transplantation. However, this study provides further evidence that early complement activation after heart transplantation may play a pathogenic role in allograft injury.     

Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection

BACKGROUND: When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation. METHODS: Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart. RESULTS: There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose. CONCLUSION: There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.     

Repeated endomyocardial biopsy without complication in an infant after heart transplantation

Endomyocardial biopsy is necessary for accurate diagnosis of rejection after heart transplantation. This case illustrates the safe use of repeated endomyocardial biopsies in an infant after heart transplantation.     

Brain natriuretic peptide levels do not correlate with acute cellular rejection in De Novo orthotopic heart transplant recipients.

BACKGROUND: The changes in brain natriuretic peptide (BNP) levels after orthotopic heart transplantation have not been previously described. The use of brain natriuretic peptide levels as a surrogate marker for cellular rejection remains controversial, with conflicting data. METHODS: We prospectively evaluated the potential utility of BNP levels in the first 6 months after transplantation and sought correlation with histologic grade of rejection and hemodynamic status. RESULTS: Thirty-five patients and 265 biopsy samples were included in the study. BNP levels did not correlate with histologic grade of rejection. They showed good correlation with central venous pressure and pulmonary capillary wedge pressure. BNP levels were elevated after transplant and showed a steep time-dependent decline. BNP levels correlated with echocardiographically derived indices of diastolic dysfunction. CONCLUSIONS: BNP levels are not a surrogate marker for rejection in the first 2 months after orthotopic heart transplantation and do not obviate the necessity for endomyocardial biopsy. Whether BNP levels have long-term prognostic significance is unclear and remains the subject of ongoing prospective study.     

Percutaneous transvenous endomyocardial biopsy in human heart recipients. Experience with a new technique

Sixty-seven cardiac biopsy procedures have been performed in 17 cardiac transplant recipients at Stanford University Medical Center. Six other patients were biopsied as part of their assessment prior to transplantation. Biopsies were performed percutaneously through a sheath inserted into the right internal jugular vein. Two instruments were used, a Konno-Sakakibara bioptome and a new catheter biopsy forceps of our own design. Biopsies of the endomyocardium sufficient for examination by light and electron microscopy were obtained on all but one occasion. There were no deaths and no serious complications.Serial biopsies performed in the first two months after transplantation were used to diagnose and aid the management of acute rejection episodes. Biopsies on long-term survivors permitted the recognition of late acute rejection episodes and provided a new assessment of the myocardium following cardiac transplantation.Percutaneous transvenous endomyocardial biopsy is simple and safe to perform and is an important new aid in the management of patients following cardiac transplantation.     

Noninvasive assessment of cardiac transplant rejection. A critical look at the approach to acute rejection.

The diagnosis of acute rejection remains a key issue in the management of the heart transplant recipient. Myocardial biopsy for tissue examination is the basic step for screening and diagnosis of acute rejection. Although endomyocardial biopsy is reliable, it is an inefficient approach to screening after transplantation and yielded only a 14% rate of positive results in the author's experience, from 1983 to 1990, of 568 biopsies. A reliable noninvasive method for screening acute rejection is therefore needed. Numerous noninvasive methods have been studied to monitor the systemic immune process against the allograft or to evaluate the effect of rejection on graft function and status. For 13 methods of evaluating immune process against the allograft the sensitivity and specificity ranged from 13% to 95% and 19% to 94% respectively. For nine methods of evaluating allograft function, sensitivity and specificity ranged from 60% to 93% and 65% to 97% respectively. Overall, methods monitoring allograft function and status have better results in predicting acute rejection. Nevertheless, the author estimated that 15 episodes of acute rejection would have been missed by these monitoring methods in his group of patients.     

Inducible NO synthase expression in endomyocardial biopsies after heart transplantation in relation to the postoperative course.

OBJECTIVE: Ischemia and reperfusion during heart transplantation cause damage to cardiomyocytes and endothelial cells and may initiate later acute rejection. Free oxygen radicals generated by iNOS are widely accepted to be responsible for ischemic injury. Increased iNOS expression on cardiac tissue may represent a more intensive tissue injury during ischemia and reperfusion in heart transplantation. The aim of this study was, therefore, to test the hypothesis that increased iNOS expression in early postoperative endomyocardial biopsies correlates with rejection or infection episodes in the later postoperative course. PATIENTS AND METHODS: Right ventricular endomyocardial biopsies were obtained from heart transplantation recipients at transplantation and during the first 2 weeks postoperatively. The recipients were divided into three groups depending on the postoperative course during the first year after transplantation: patients in group 1 had an uncomplicated postoperative course, patients in group 2 developed significant signs of postoperative infection, while patients in group 3 presented with acute rejection (< or =grade 2R ISHLT). The expression was analyzed in a semi-quantitative score. RESULTS: iNOS expression was found in cardiomyocytes, endothelial cells, infiltrating cells, and vascular smooth muscle cells. At the time of heart transplantation, the expression was significantly increased in the rejection group compared to the other groups. This increase was even more pronounced in week 2. CONCLUSIONS: The present study shows that an increased iNOS expression at the time of heart transplantation could precede an acute rejection in the later postoperative course. Thus, measurements of iNOS expression may be of predictive value for an increased rejection risk and therefore offer the possibility of earlier therapeutic intervention.     

Anti-Hla donor-specific antibody monitoring in pancreas transplantation: Role of protocol biopsies

In kidney transplantation, de novo donor-specific antibodies (DSA) correlate with poor graft survival, and Consensus Guidelines recommend a protocol biopsy. In pancreas transplantation, DSA are also associated with poor graft outcomes; however, there are no recommendations on protocol biopsies. We started an antibody screening protocol on pancreas transplant patients at 0, 3, 6, 12 months, and yearly. Patients with DSA or high MFI non-DSA were considered for protocol biopsies of both organs. Results: 143 pancreas recipients were screened. 84 patients had negative antibodies throughout the study, 11 patients were found to have antibodies at graft dysfunction, and 48 patients had positive antibodies at screening without acute organ dysfunction (study group). Among the 30 non-DSA patients, 9 had protocol simultaneous pancreas and kidney biopsies performed with negative results in all of them. In contrast, among the 18 DSA patients, 15 had these biopsies performed, and 47% presented with subclinical rejection of the kidney, the pancreas, or both. In addition, some of the DSA patients without a protocol biopsy presented with rejection during the first 15 months of follow-up. Conclusion: We conclude that protocol biopsies of both grafts may play a role in the follow-up of pancreas transplant patients with de novo DSA appearance.     

An analysis of early renal transplant protocol biopsies--the high incidence of subclinical tubulitis.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2+/-2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.     

Endomyocardial biopsy in heart transplantation: schedule or event?

Background

Endomyocardial biopsy is the gold standard to identify rejection after heart transplantation. Due to its invasiveness, discomfort, and difficult vascular access, some patients are not willing to accept routine scheduled biopsies years after heart transplantation. The purpose of this study was to identify whether there was a difference in outcomes among the scheduled versus event biopsy groups.

Methods

We studied 411 patients who underwent heart transplantation from 1987 to 2011, reviewing biopsy results and pathology reports. There were 363 patients who followed the scheduled biopsy protocol, and 48 patients who were assigned to the event biopsy group. We extracted data on biopsy results, rejection episodes, rejection types, and survival time.

Results

The 2481 reviewed biopsies over 24 years, showed most rejection episodes (86.4%) to occur within 2 years after heart transplantation. The rejection incidence was low (2.1%) at 3 years after transplantation. The major reason for an event biopsy was poor vascular access, such as tiny central vein or congenital disease without a suitable central vein. Event biopsy group patients were younger than schedule biopsy patients (19.7 years old vs 47.6 years old; P < .05). The 10-year survival rates were 64% among the event versus 53% among the scheduled biopsy group (P = .029). The 10-year rates of freedom from rejection were similar.

Conclusions

The rejection rate was low after 3 years; episodes occurred within 2 years. Although the long-term survival in the event group was better, they had a younger man age. The rejection and freedom from rejection rates were similar. As the rejection rate was low at 3 years after transplantation, we suggest that the event principle could be applied for biopsy at 3 years after heart transplantation.     

Prediction of acute cardiac rejection using radionuclide techniques

Radionuclide scanning of the donor left ventricle using technetium-99m-labelled red cells was used to monitor acute rejection after heterotopic heart transplantation and compared with histopathological evidence of rejection obtained at examination of an endomyocardial biopsy specimen. The ejection fraction and end-diastolic, end-systolic and stroke volumes were calculated at each examination; an equation was derived from these data to predict the degree of acute rejection, using histopathological examination of endomyocardial biopsy specimens as criteria of the presence and severity of rejection. A highly significant multiple correlation between radionuclide scanning parameters and endomyocardial biopsy was found. The advantages of non-invasive radionuclide scanning over the invasive procedure of endomyocardial biopsy are discussed.     

Antibody-Mediated Rejection in Human Cardiac Allografts: Evaluation of Immunoglobulins and Complement Activation Products C4d and C3d as Markers

Antibody-mediated rejection (AMR) in human heart transplantation is an immunopathologic process in which injury to the graft is in part the result of activation of complement and it is poorly responsive to conventional therapy. We evaluated by immunofluorescence (IF), 665 consecutive endomyocardial biopsies from 165 patients for deposits of immunoglobulins and complement. Diffuse IF deposits in a linear capillary pattern greater than 2+ were considered significant. Clinical evidence of graft dysfunction was correlated with complement deposits. IF 2+ or higher was positive for IgG, 66%; IgM, 12%; IgA, 0.6%; C1q, 1.8%; C4d, 9% and C3d, 10%. In 3% of patients, concomitant C4d and C3d correlated with graft dysfunction or heart failure. In these 5 patients AMR occurred 56-163 months after transplantation, and they responded well to therapy for AMR but not to treatment with steroids. Systematic evaluation of endomyocardial biopsies is not improved by the use of antibodies for immunoglobulins or C1q. Concomitant use of C4d and C3d is very useful to diagnose AMR, when correlated with clinical parameters of graft function. AMR in heart transplant patients can occur many months or years after transplant.