Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting

BACKGROUND: Graft coronary artery disease (CAD) is an increasingly important problem during long-term survival after heart transplantation, but the importance of cellular rejection, in particular late after transplantation, remains undetermined. METHODS and RESULTS: We analyzed 492 coronary angiographies (967+/-705 days after transplantation; range, 49 days to 9.4 years) and 5201 endomyocardial biopsies (518+/-648 days after transplantation) from 156 patients (age, 47+/-11 years). Patients with angiographically detectable graft CAD had significantly more episodes of rejection requiring augmentation of immunosuppressive therapy (i.e., International Society of Heart and Lung Transplantation score > or = 3A) than those without graft CAD during the first (3.7+/-2.6 vs. 2.2+/-2.0, P<0.001) as well as subsequent years after transplantation (1.2+/-1.9 vs. 0.4+/-0.9, P<0.01). Multivariate logistic regression analysis including established risk factors for CAD, ischemic time, gender and age of donors and recipients, number of mismatches, cytomegalovirus infection, and drug therapy showed that the number of rejections during the first [odds ratio (OR)=1.39, P<0.005] as well as subsequent years (OR=1.49, P<0.05), previous cytomegalovirus infection (OR=3.21, P<0.05), donor age >40 years (OR=2.97, P<0.05), and current or former smoker status (OR=2.76, P<0.05) were independent predictors of graft CAD. In patients without angiographically detectable graft CAD 1 year after transplantation, the number of rejections after the first year was even more strongly related to graft coronary artery disease than in the total patient population, underlining the importance of late cellular rejection (OR=1.74, P<0.005). CONCLUSION: Rejection requiring augmentation of immunosuppression early and late after transplantation is an independent risk factor for the development of angiographically detectable graft CAD. Hence, the search for and treatment of moderate or severe rejection seems to be prudent even late after transplantation.     

Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tarolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group

BACKGROUND: This paper reports the histopathologic results of 2-year protocol biopsies from patients who were enrolled in the U.S. FK506 kidney transplant study . METHODS: Recipients of cadaveric kidney transplants were randomized to tacrolimus or cyclosporine therapy. Patients active in the trial at 2 years after transplantation were approached for a protocol biopsy. Biopsies were scored by the Banff classification in a blinded fashion by one pathologist. RESULTS: A total of 144 patients (41.3% of those active at 2 years) had a 2-year protocol biopsy performed; 79 patients were treated with tacrolimus and 65 patients were treated with cyclosporine. Evidence of acute rejection was found in seven (8.9%) of the 2-year biopsies in tacrolimus-treated patients and six (9.2%) cyclosporine-treated patients. Chronic allograft nephropathy was found in 49 (62.0%) tacrolimus biopsies and 47 (72.3%) cyclosporine biopsies (P=0.155). There were no apparent histopathologic differences between the tacrolimus and cyclosporine biopsies. The occurrence of chronic allograft nephropathy was significantly higher in patients who received a graft from an older donor (P<0.01), who experienced presumed cyclosporine or tacrolimus nephrotoxicity (P<0.001), who developed a cytomegalovirus infection (P=0.038), or who experienced acute rejection in the first year after transplantation (P=0.045). A multivariate analysis showed that nephrotoxicity and acute rejection were the most significant predictors for chronic allograft nephropathy. CONCLUSIONS: The occurrence of histologic acute rejection was rare at 2 years, confirming the absence of subclinical acute rejection in these late biopsies. A majority of the biopsies showed features consistent with chronic allograft nephropathy that was associated with acute rejection (particularly in cyclosporine-treated patients), nephrotoxicity, and cytomegalovirus infection in the first year. This suggests that nonimmunologic factors, such as drug-induced toxicity, may play an important role in chronic allograft nephropathy.     

Long-term follow-up of anatomic heart transplantation. Apropos of 60 patients with a mean follow-up of 36 months

The aim of this study was to collect different problems seen in long-term evolution of patients who had anatomical cardiac transplantation and to compare with those seen in patients with standard transplantation. During the mean follow-up of 36 months, we analysed different data of 60 patients mean aged 51, who underwent anatomical cardiac transplantation. Six patients (10%) died within the 30 days after surgery. No patient needed the use of permanent pacemaker. Echocardiographic examination found normal atrial shape. One month after surgery, echocardiography described 16 tricuspid regurgitations (22.66%) and 8 mitral regurgitations (13.33%), 1 year later, there was respectively 13.33 and 6.66% tricuspid and mitral regurgitation. We had 8 late deaths: 1 sudden death, 2 chronic rejections, 1 pancreatitis and 4 cancers. The survival analysis pointed out 84% at 1 year, 80 at 2 years, 78 at 3 years and 73 at 5 years. Six months after surgery, 80% of patients were treated for high blood pressure; 85% had serum creatinine level equal or superior to 13 mg/L, with mean serum ciclosporin at 130 ng/mL. At the 3rd month, 6 endomyocardial biopsies were equal or superior to grade 2 rejection (International Society for Heart Transplantation). Between the 3rd and 12th month, 3 endomyocardial biopsies were equal or superior to grade 2 rejection, and the same between the 12th and 24th month. The infections rate was 0.8 episode per patient. Long term follow-up of anatomical cardiac transplantation faces the same problems as in standard cardiac transplantation. It is better to perform anatomical cardiac transplantation because of its early postsurgical advantages. Long term care is the same as in standard cardiac transplantation.     

Prospective study of the value of transbronchial lung biopsy after lung transplantation

Transbronchial lung biopsy (TBB) has become the gold standard for the diagnosis of acute rejection and cytomegalovirus (CMV) pneumonia in lung transplant recipients. The aim of this study was to assess the value of regular surveillance TBB in stable asymptomatic patients and to establish the role of TBB as a follow-up procedure 1 month after a previous pathological biopsy result. We prospectively evaluated 76 TBBs performed in 17 lung transplant recipients. A definite pathological results was found in 14 of 15 TBBs performed for clinical indications: CMV pneumonia (5), acute rejection grade > or = A2 according to the criteria of the International Society for Heart and Lung Transplantation (ISHLT) (4), bronchiolitis obliterans (3), and desquamative interstitial pneumonitis (2). Fifteen of 45 surveillance TBBs performed in asymptomatic patients revealed significant abnormalities. Ten episodes of acute rejection ISHLT grade > or = A2 and three episodes of CMV pneumonia detected by TBB had direct therapeutic consequences. Nine of 16 follow-up TBBs performed 1 month after a pathological biopsy result again showed relevant pathological findings. With the exception of one severe haemorrhage, no life-threatening complications occurred. Our results suggest that transbronchial lung biopsies performed on a regular basis after lung transplantation are important for the detection of asymptomatic and/or persistent acute rejection or injection. In the long-term, this strategy might be the most effective tool in reducing the incidence of bronchiolitis obliterans, which is still the main obstacle for further improvement of long-term survival after lung transplantation.     

Evaluation of biopsy classification for rejection: relation to detection of myocardial damage by monoclonal antimyosin antibody imaging

OBJECTIVES: This study sought to compare the histologic grades of rejection in endomyocardial biopsy specimens with the global estimate of myocardial transplant-related cardiac damage detected by myocardial uptake of monoclonal antimyosin antibodies. BACKGROUND: The diagnosis and treatment of acute cardiac allograft rejection is based on the interpretation of endomyocardial biopsies. Because allograft rejection is a multifocal process and biopsy is obtained from a small area of the right ventricle, sampling error may occur. Global assessment of myocardial damage associated with graft rejection is now possible with the use of antimyosin scintigraphy. The present study was undertaken to compare the histologic grades of rejection in endomyocardial biopsy specimens with the global assessment of transplant-related myocardial damage detected by antimyosin scintigraphy. METHODS: Biopsies (n=395) from 112 patients were independently interpreted by three pathologists in a blinded manner according to the original Stanford four-grade (normal, mild, moderate and severe) and the current International Society of Heart and Lung Transplantation (ISHLT) seven-grade (0, 1A, 1B, 2, 3A, 3B and 4) classifications. The results were correlated with 395 antimyosin studies performed at the time of the biopsies. The heart/lung ratio of antimyosin antibody uptake was used to assess the severity of myocardial damage. RESULTS: In the Stanford biopsy grade classification, significantly higher antimyosin uptake, indicating increasing degrees of myocardial damage, were associated with normal (1.78+/-0.26), mild (1.88+/-0.31) and moderate (1.95+/-0.38) biopsy classifications for rejection (p < 0.01). In the ISHLT classification, significant differences were detected only for antimyosin uptake associated with grades 0 (1.77+/-0.26) and 3A (1.98+/-0.39) but not for intermediate scores (1A, 1B and 2). In view of the similar intensity of antibody uptake among the various grades, ISHLT biopsy scores were regrouped: normal biopsies in grade A; 1A and 1B as grade B; and 2 and 3A as grade C. Antimyosin uptake in grades A, B and C was 1.78+/-0.26, 1.88+/-0.31, 1.95+/-0.38, respectively (p < 0.01). CONCLUSIONS: The current ISHLT seven-grade scoring system does not reflect the progressive severity of myocardial damage associated with heart transplant rejection. Because myocardial damage constitutes the basis of treatment for allograft rejection, there is a need to reevaluate the ISHLT grading system, given its importance for multicenter trials.     

Daily noninvasive rejection monitoring improves long-term survival in pediatric heart transplantation

BACKGROUND: Acute rejection episodes and transplant vasculopathy (TVP) account for most of the late deaths after heart transplantation in both adults and children. Accumulating evidence indicates that fatal acute rejection and TVP are related to unrecognized and untreated early and ongoing acute rejection. Day-by-day surveillance of the heart and prompt treatment of any rejection may yield improved long-term survival. METHODS: In almost all patients having transplantation at our institution (978 patients since 1986), the intramyocardial electrogram (IMEG) was recorded routinely every day through a telemetry pacemaker and transmitted to our center by telephone modem. Earlier studies showed a substantial voltage drop in the IMEG QRS complex is highly indicative of acute rejection, including humoral rejection. In this study, we reviewed the data from 69 pediatric patients up to 16 years old for the incidence of acute rejection, TVP, and long-term outcome. Diagnostic endomyocardial biopsies were performed in only 10 patients, and recent coronary angiograms from 29 children were reviewed. RESULTS: In 50 children discharged after heart transplantation, IMEG surveillance data for a mean of 2.9 years indicated 72 acute rejection episodes. During follow-up of 1 month to 10.5 years (mean follow-up, 4.4 years), 2 patients died late of causes unrelated to either rejection or TVP. Another patient died of rejection during unrecognized underimmunosuppression nearly 8 years after transplantation and nearly 31/2 years after discontinuing IMEG recordings. Two patients without IMEG recording died of acute rejection or late TVP. In 1 patient, moderate TVP was seen on an angiogram after 41/2 years (incidence, 2.0%; 5-year incidence, 5.6%). CONCLUSIONS: Daily recording of the IMEG can reliably detect early stages of acute rejection episodes, and immediate rejection treatment seems to keep the incidence of TVP low. The IMEG appears better than all the other rejection monitoring protocols currently in use.     

Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients

BACKGROUND: Although noncompliance with immunosuppressive medication is recognized as a critical behavioral risk factor for late acute rejection episodes and graft loss after transplantation, little is known about the degree of subclinical cyclosporine noncompliance, its associated risk for acute late rejection episodes (>1 year after transplantation), and its determinants in heart transplant recipients. METHODS: The convenience sample of this longitudinal study included 101 European heart transplant recipients (87 men and 14 women), with a median age of 56 (Q1 = 50, Q3 = 61) and a median posttransplantation status of 3 (range 1 to 6) years. Subclinical cyclosporine noncompliance was measured during a 3-month period with electronic event monitoring. Selected sociodemographic, behavioral, cognitive, emotional, health, and treatment-related determinants of medication noncompliance were measured by using instruments with established psychometric properties or by patient interviews. With the use of iterative partitioning methods of cluster analysis, including nonstandardized electronic event monitoring compliance parameters, patients were categorized by degree of subclinical cyclosporine noncompliance into a 3-cluster solution. RESULTS: Overall compliance was high, with a median medication taking compliance of 99.4%. The 3 derived clusters, that is, excellent compliers (84%), minor subclinical noncompliers (7%), and moderate subclinical noncompliers (9%), differed significantly by degree of subclinical noncompliance (p < .0001) and showed a 1.19%, 14.28%, and 22.22% incidence of late acute rejections (p = .01), respectively. The 3 groups also differed in terms of former medication noncompliance (p = .02), appointment noncompliance (p = .03), and perceived self-efficacy with medication taking (p = .04). CONCLUSIONS: Although in absolute numbers cyclosporine compliance in this sample was high, minor deviations from dosing schedule were associated with an increased risk for acute late rejection episodes. This suggests a pivotal role of patient compliance in successful long-term outcome after transplantation.     

Relationship between myocardial collagen and echo amplitude in non-fibrotic hearts

The aim of the study was to investigate the relationship between myocardial collagen and regional echo amplitude in humans with non-fibrotic myocardium. The ratio of myocardial collagen to total myocardial protein was determined as the hydroxyproline/leucine ratio in endomyocardial biopsies obtained from the right ventricular side of the interventricular septum in orthotopically transplanted hearts. Regional echo amplitude was measured in the interventricular septum. Patients were studied prospectively. Twenty-five patients (five female, 20 male) who had undergone orthotopic cardiac transplantation were studied 355 to 2939 days (1009 +/- 718, mean +/- SD) post-transplantation at the time of annual cardiac catheterization and endomyocardial biopsy. Patient ages varied from 22 to 62 years (46 +/- 11). Donor ages were 14 to 47 years (25 +/- 8) and the ischaemic time, 90 to 245 min (151 +/- 42). Cardiac transplantation was performed for end-stage cardiac failure in all patients. The aetiology of cardiac failure was valvular heart disease in three, dilated cardiomyopathy in eight and ischaemic heart disease in the remainder. Echo amplitude studies were performed within 24 h of endomyocardial biopsy. All but one patient were on an immunosuppressive regime consisting of cyclosporine A and azathioprine with additional steroids in three. The remaining patient, who was the longest surviving patient in the study group, had never been treated with cyclosporine. This patient was maintained on steroids and azathioprine alone. No patient had clinical or histological evidence for acute cardiac rejection and all were clinically well. Five patients had angiographic evidence of coronary artery disease. All subject studies were performed at Harefield Hospital.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety of influenza vaccine in heart transplant recipients

BACKGROUND: Influenza vaccine is recommended for heart transplant recipients, but its administration is often deferred because of anecdotal reports of rejection associated with the vaccine. We evaluated the safety of influenza vaccine in a group of stable heart transplant recipients over a 2-year period. METHODS: During the 1993 to 1994 influenza season, stable heart transplant recipients who had undergone transplantation a minimum of 1 year before study entry were randomized to vaccination with a single dose of influenza vaccine versus no vaccination. Routine endomyocardial biopsies and postvaccination influenza serologic studies were performed between 2 and 6 weeks after enrollment/immunization. During the 1994 to 1995 season, patients were given 2 doses of influenza vaccine, separated by 3 weeks; endomyocardial biopsies and serologic studies were performed between 2 and 6 weeks after the second immunization or enrollment (if control subject). Biopsy results were evaluated with respect to vaccine response, immunosuppressive regimens, and patient demographics. RESULTS: Eighteen patients were enrolled in the single vaccine trial and 10 in the booster vaccine trial. Four of 14 vaccine recipients had biopsy specimens consistent with International Society for Heart and Lung Transplantation grades 2 to 3A as compared with 1 of 14 control subjects (grade 2) (p = .326). All episodes of rejection in the vaccine recipients were asymptomatic and responded to a single course of treatment. Rejection was unrelated to the time from transplantation, doses of immunosuppression, age, or number of doses of or response to vaccine. CONCLUSIONS: Influenza vaccine can be safely administered to most heart transplant recipients but may be associated with low-level histologic rejection.     

Routine surveillance endomyocardial biopsy: late rejection after heart transplantation

BACKGROUND: Transplant programs use routine surveillance endomyocardial biopsies (RSEMB), which are performed at preset intervals to diagnose cardiac rejection. This retrospective study determined the incidence of graft rejection detected by RSEMB. METHODS: The records of 95 patients who underwent heart transplantation between 1987 and 1995 were reviewed. Rejection incidence was recorded for 80 patients who survived at least 30 days, with a mean follow-up of 35 months. RESULTS: One thousand five hundred sixteen total biopsies were performed; 1,170 were RSEMB. Four hundred seventy-five total rejection episodes occurred and 269 (56%) were diagnosed by RSEMB. Two distinct patient groups were identified. The majority (70 patients), had a decline in the incidence of rejection and no rejection episodes were identified by RSEMB after 36 months. In contrast, the high rejection group (10 patients) had a significantly higher ongoing rejection rate (p < or = 0.04 to p < or = 0.001) throughout their postoperative course up to 72 months. CONCLUSIONS: The majority of our transplant patients demonstrate a decrease in rejection with time and do not require RSEMB beyond 30 months. We identified a group of patients who exhibited a higher rate of rejection and need continued RSEMB.     

Renal transplantation for patients 60 years of older. A single-institution experience

OBJECTIVE: The authors reviewed renal transplant outcomes in recipients 60 years of age or older. BACKGROUND: Before cyclosporine, patients older than 45 years of age were considered to be at high risk for transplantation. With cyclosporine, the age limits for transplantation have expanded. METHODS: The authors compared patient and graft survival, hospital stay, the incidence of rejection and rehospitalization, and the cause of graft loss for primary kidney recipients 60 years of age or older versus those 18 to 59 years of age. For those patients > or = 60 years transplanted since 1985, the authors analyzed pretransplant extrarenal disease and its impact on post-transplant outcome. In addition, all surviving recipients > or = 60 years completed a medical outcome survey (SF-36). RESULTS: Patient and graft survival for those > or = 60 years of age versus those 18 to 59 years of age were similar 3 years after transplant. Subsequently, mortality increased for the older recipients. Death-censored graft survival was identical in the two groups. There were no differences in the cause of graft loss. Those 60 years of age or older had a longer initial hospitalization, but had fewer rejection episodes and fewer rehospitalizations. Quality of life for recipients 60 years of age or older was similar to the age-matched U.S. population. CONCLUSION: Renal transplantation is successful for recipients 60 years of age or older. Most of them had extrarenal disease at the time of transplantation; however, extrarenal disease was not an important predictor of outcome and should not be used as an exclusion criterion. Post-transplant quality of life is excellent.     

Histological and clinical outcome after liver transplantation for hepatitis C

Hepatitis frequently recurs after liver transplantation for hepatitis C. However, the histological progression of disease, predictors of recurrence and disease severity, and patient survival remain uncertain. Fifty-five patients with cirrhosis caused by chronic hepatitis C underwent liver transplantation between January 1990 and December 1993. Hepatitis C genotype was determined, and liver biopsies were performed at frequent intervals posttransplantation. The median follow-up time was 40.4 months. The cumulative rate of survival was no different in liver transplant recipients for hepatitis C than in liver transplant recipients for other chronic liver diseases (P = .62). Histological recurrent hepatitis C developed in 33 of 50 patients assessable for disease recurrence; the median recurrence-free survival time was 13.4 months. Histological activity and stage were mild in most cases. Only 2 patients developed cirrhosis, and no patient required a second transplantation for recurrent disease. Patients with acute cellular rejection had a shorter recurrence-free survival (P = .0141). In patients with recurrent hepatitis, rejection also was correlated with increased histological grade 2 years after transplantation (P = .0061). Recurrence-free survival was decreased in patients infected with genotype 1 (1a and 1b combined) compared with genotypes 2 and 3 combined (P = .02), whereas there was no difference between genotypes 1a and 1b (P > .80). Only patients infected with genotype 1a or 1b developed bridging fibrosis or cirrhosis. In addition, patients who had an early recurrence had a greater risk of progressing to bridging fibrosis or cirrhosis (hazard ratio, 5.1; P = .0473). In our experience, recurrent hepatitiS C after liver transplantation in most cases is mild and survival is unaffected. Both acute cellular rejection and infection with genotype 1 are independent risk factors for reduced recurrence-free survival, and early recurrence is associated with a higher risk of disease progression.     

Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid leukemia

BACKGROUND: One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression. METHODS: Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years). RESULTS: Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07). CONCLUSIONS: Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.     

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. METHODS: A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. RESULTS: One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.     

Can solid state Holter monitoring replace endomyocardial biopsy in patients with heart transplantation?]

Acute cardiac graft rejection after transplantation, the diagnosis of which is based on the findings of endomyocardial biopsy, is associated with a reduction in coronary reserve due to abnormalities of the microcirculation. But this reduction in coronary reserve cause silent myocardial ischaemia (SMI)? In order to assess the frequency of SMI and ventricular arrhythmias during rejection, 53 consecutive Holter recordings were performed in 32 patients (28 men, 4 women, average age 47 +/- 11 years) 11 months after transplantation and within 24 hours of endomyocardial biopsy. The recorder which was used (Monitor One TC) analysed the ST segment in 2 leads in real time: ST segment depression of more than 1 mm lasting over 40 ms, 0.08 s after the J point were considered to be diagnostic of myocardial ischaemia. Although the frequency of SMI is low and not specific for cardiac rejection, its duration was twice as long (80 mn vs 38 mn) in this condition. On the other hand, ventricular arrhythmias are common in cardiac rejection and correlated with its severity according to Billingham's classification (VES p = 0.045; doublets p = 0.035; non-sustained VT p = 0.006).     

Biopsy-induced tricuspid regurgitation after cardiac transplantation

Transvenous endomyocardial biopsy is now well-established as the gold standard for evaluation of possible rejection episodes after cardiac transplantation. From 1985 to August 1992, 1990 patients have undergone 193 cardiac transplantations at Barnes Hospital. One hundred eighty-three patients survived their initial hospitalization and serve as the study group. Their records were reviewed for the purposes of identifying those with tricuspid regurgitation as a complication of right ventricular endomyocardial biopsy. These patients have undergone a total of 2,960 biopsies for an average of 16.2 biopsies per patient. Over a mean follow-up period of 4.22 years, all patients have been evaluated with standard two-dimensional echocardiograms. Mild to moderate tricuspid regurgitation was very common, but was thought to be biopsy-induced only if severe and accompanied by flail components of the tricuspid valve. Twelve patients were identified with this entity at our institution. Of these, 5 had no symptoms and were receiving no diuretics, 3 had mild symptoms consisting of lower extremity edema and continued to receive diuretics, 2 had moderate symptoms, and 2 had right heart failure and anasarca refractory to medical therapy. Both of the severely affected patients subsequently required tricuspid valve replacement. We conclude that the tricuspid valve apparatus is at significant risk of injury during endomyocardial biopsy, that most patients will be minimally symptomatic due to tricuspid regurgitation when this injury occurs, and that when the injury is accompanied by severe symptoms, the likelihood of improvement with medical therapy is small.     

Nicardipine as antihypertensive therapy in liver transplant recipients: results of long-term use

Arterial hypertension is frequent in liver transplant recipients on cyclosporine A (CsA). Nicardipine is a calcium channel blocker (CCB) that has been shown to be efficient in controlling postoperative hypertension. However, its use has been limited in organ recipients because of its reported interaction with CsA metabolism. In this report, we studied the results of the long-term use of nicardipine after liver transplantation. Forty-nine consecutive liver transplant recipients with a follow-up longer than 2 years were studied. Immunosuppressive regimen was based on CsA and prednisone. Patients with immediate postoperative hypertension received intravenous nicardipine, secondarily switched to oral nicardipine (group 1, n = 27). Patients with delayed hypertension (i.e., >2 weeks posttransplant) received other antihypertensive drugs which did not interact with CsA metabolism. These patients and those without hypertension formed group 2 (n = 22). The two groups were similar for age, sex, body weight, and transplantation indications. Interaction of nicardipine with CsA metabolism was confirmed. Whereas cyclosporine blood levels were similar in both groups at any time during the study, the mean cyclosporine daily dose required to achieve such levels was 30% lower in group 1 compared with group 2 (P < .01). This resulted in a significant cost-containment. The use of nicardipine was not associated with an increased incidence of graft rejection or CsA toxicity episodes. The results in liver transplant recipients showed that nicardipine interacts with CsA metabolism, leading to a 30% reduction in CsA dose and does not increase the risk of CsA toxicity or graft rejection. Nicardipine can be used safely for the treatment of arterial hypertension after liver transplantation with a potential cost-containment.     

Early cyclosporine monotherapy in liver transplantation: a 5-year follow-up of a prospective, randomized trial

Maintenance of adequate immunosuppression and avoidance of side-effects are the goals of long-term management of all organ-transplanted patients. We here report the final results of a prospective, randomized trial comparing early cyclosporine monotherapy versus double-drug therapy (cyclosporine and steroids) in adult liver transplantation patients. One hundred four patients were randomized 3 months after transplantation either to continue (Group I = 50 patients) or to stop steroids (Group II = 54 patients). Patients on a double-drug regimen were maintained long term on methylprednisolone at a dose of 0.1 mg/kg/d. Target cyclosporine trough levels were between 150 and 250 ng/mL in both groups. Our main points of interest were the prevalence of acute and chronic rejections and steroid-related side-effects in the two groups of patients. Mean follow-up was 41 +/- 16 months (range, 4-68 months). Patient actuarial survival 2 and 5 years after randomization was similar in the two groups (82% vs. 83% and 82% vs. 77%). The prevalence of acute rejections after randomization was, respectively, 8% and 4%. A single episode of chronic rejection was observed only in a patient on long-term steroid therapy. Side-effects of steroid therapy were less frequent in patients weaned off steroids, and when considering hypertension and diabetes, the differences between the two groups were statistically significant. Early cyclosporine monotherapy is a safe undertaking in liver transplantation because it allows a significant reduction of steroid-related side-effects without increasing the risk of acute and chronic rejection. After 5 years, patient survival was similar in patients with or without steroids.     

De novo expression of MHC class I and class II antigens on endomyocardial biopsies from patients with inflammatory heart disease and rejection following heart transplantation

Inflammation of the heart muscle is caused either by infection (i.e. coxsackie virus) resulting in myocarditis or by rejection following heart transplantation. These processes induce activation of the immune system. We examined endomyocardial biopsies from patients with myocarditis, perimyocarditis and rejection following heart transplantation and compared these to biopsies from patients with coronary artery disease. The biopsies were examined immunohistologically with specific monoclonal antibodies against class I and class II molecules of the major histocompatibility complex (MHC). MHC class I antigens on the normally negative myocytes were evident in myocarditis (38%) and in rejection after heart transplantation (68%). In the interstitium there was an increase of both MHC class I and class II antigens. MHC class II antigens, however, were never seen on myocytes. MHC class I antigens are required for the action of CD 8 positive cytotoxic T cells. Therefore myocytes which express MHC class I antigens are susceptible to cytotoxic effects of the immune system. MHC class II antigens are essential to T helper cells. By cytokine release, activated T helper cells play a central role in the initiation, regulation and mediation of an immune response in myocarditis and rejection following heart transplantation.