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.     

Risk factors for high blood lead levels among the general population in Taiwan

BACKGROUND: Tacrolimus (FK506) may represent a major advance in the management of allograft rejection after solid organ transplantation. In August 1994 a European heart transplantation pilot study was initiated to assess the efficacy and safety of tacrolimus when administered exclusively through an oral route. METHODS: Eighty-two heart transplant recipients were randomized to treatment (2:1 ratio) with either tacrolimus- (n=54) or cyclosporine-based therapy (n=28). RESULTS: No significant differences were evident between the two treatment groups in either rejection or survival rates at 1 year. Kaplan-Meier estimates of the freedom from rejection were 26.3% and 18.5%, respectively, for the tacrolimus and cyclosporine treatment groups (p=.444). Survival rates were 79.6% and 92.9% (p=.125). At 3 of the 5 centers, patients received antithymocyte globulin during the immediate postoperative period and fared better than those who did not (with acute rejection-free rates of 49.2% and 26.7% for tacrolimus and cyclosporine, respectively [p=.080], as opposed to 7.1% and 8.3% [p=.965]; patient survival rates of 84.6% and 93.3% [p=.382] vs 75.0% and 92.3% [p=.243]). The overall rates of infection, impaired renal function (31.5% vs 21.4%), and glucose intolerance (7.0% vs 4.3%) did not differ significantly between the tacrolimus and cyclosporine treatment groups. Tacrolimus seemed to possess an advantage with regard to a reduced requirement for antihypertensive therapy (59.5% vs 87.5%, p=.025). CONCLUSIONS: Immunosuppression with oral tacrolimus provides a viable alternative to treatment with cyclosporine, particularly when administered in conjunction with antibody therapy. Further studies are warranted to optimize the administration of tacrolimus in this indication.     

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.     

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.     

A semiquantitative approach to the evaluation of acute cardiac allograft rejection at endomyocardial biopsy

BACKGROUND: Histopathologic criteria for grading of acute cardiac allograft rejection are focused on the most severe lesion that is recognized among the myocardial fragments provided by each endomyocardial biopsy specimen. Considering the distribution of rejection lesions among all the fragments improved the accuracy in characterizing the severity of rejection in pathologic studies. This study was undertaken to verify the usefulness of a semiquantitative evaluation of endomyocardial biopsy specimens, consisting of the calculation of the proportion of fragments showing rejection in the clinical setting. METHODS: Of the 2386 biopsy specimens obtained during the first posttransplantation year in 168 consecutive cardiac allograft recipients, 290 biopsy specimens constituted by > or = 3 adequate fragments and showing rejection not followed by treatment (n = 159) or being the first biopsy specimen prompting treatment with augmented immunosuppression for that rejection episode (n = 131) were selected. These biopsy specimens (index biopsy specimens) were grouped according to whether rejection was present in < or = 33%, > 33% to < or = 67%, and > 67% of the fragments. The rejection grade (according to the standardized grading system) and the proportion of fragments positive for rejection were correlated with the occurrence of clinical symptoms and signs of rejection at index biopsy and with the results of the next biopsy. RESULTS: Rejections graded > or = 3A were more frequently symptomatic (36% vs 9% for those graded < 3, p < 0.0001), as were those involving increasing proportions of fragments (< or = 33%: 5 of 124, 4%; > 33 to < or = 67%: 13 of 99, 13%; > 67%: 19 of 67, 28% [p < 0.0001]). Spontaneous resolution after untreated biopsies was more frequent in focal (grade 1A and 2) than in diffuse mild (1B) rejections (68% vs 38% [p < 0.04]), whereas progression to grade 3A or greater was less frequent (4% vs 27% [p < 0.01]). Increasing proportions of positive fragments were associated with lower frequencies of spontaneous resolution (p < 0.05) and higher frequencies of worsening (9%, 22%, 43% [p < 0.009]) or progression to grade 3A or greater (2%, 6%, 28% [p < 0.005]). Complete resolution after treatment was less frequent for increasing proportions of positive fragments at index biopsy (80%, 66%, 49% [p < 0.05]). CONCLUSIONS: Diffuse versus focal rejection pattern and the proportion of positive fragments seem to be clinically relevant in terms of occurrence of symptoms, spontaneous evolution, and response to treatment.     

Clinical and histopathologic examination of renal allografts treated with tacrolimus (FK506) for at least one year

BACKGROUND: We clinically and pathologically analyzed renal allografts from 1 9 renal transplant patients treated with tacrolimus (FK506) for more than 1 year. METHODS: Twenty-six renal allograft biopsy specimens from 1 9 renal transplant patients who underwent transplantations between 1991 and 1993 were evaluated. Thirteen biopsies were performed from stable functioning renal allografts with informed consent (nonepisode biopsy) and the other 13 were from dysfunctional renal allografts with a clinical indication for biopsy (episode biopsy). RESULTS: The main pathologic diagnoses (some overlap) were acute rejection (AR; n = 4), chronic rejection (CR; n=5), AR+CR (n =4), recurrent IgA nephropathy (n =5), normal findings (n =2), minimal-type chronic FK506 nephropathy (n = 9), and mild-type FK506 nephropathy (n = 11). Of the nonepisode biopsies, 7 and 4 biopsies showed minimal-type and mild-type chronic FK506 nephropathy, respectively. Chronic FK506 nephropathy consisted of rough and foamy tubular vacuolization (5 biopsies), arteriolopathy (angiodegeneration of the arteriolar wall; 20 biopsies), focal segmental glomerulosclerosis (4 biopsies) and the striped form of interstitial fibrosis (11 biopsies). The serum creatinine levels of patients in the mild-type chronic FK506 nephropathy group, which included 7 episode biopsies, were statistically higher than those in the minimum-type chronic FK506-nephropathy group (P< 0.001). CONCLUSIONS: This study demonstrates that chronic FK506 nephropathy consists primarily of arteriolopathy manifesting as insudative hyalinosis of the arteriolar wall, and suggests that mild-type chronic FK506 nephropathy is a condition which may lead to deterioration of renal allograft function.     

Identification of patients not requiring endomyocardial biopsies late after cardiac transplantation

BACKGROUND: The risk for rejection is highest early, but graft rejection requiring intensified immunosuppression may be present even late after transplantation. Nonetheless, a considerable number of patients are absolutely free of rejection requiring intensified immunosuppression (Rej) late after transplantation. Therefore, we tried to identify patients who do not need endomyocardial biopsies > or = 2 years after transplantation and those who may benefit from long-term follow-up with routine endomyocardial biopsies. METHODS: A total of 112 patients (age 45+/-12 years) had a follow-up with regular endomyocardial biopsies of > or = 3 years. A total of 4194 endomyocardial biopsies were performed (1364 > or = 2 years after transplantation). They were divided into three categories: rejection score=0, Texas 0-2 or International Society for Heart and Lung Transplantation (ISHLT) 0 or 1A; rejection score=1, Texas 3-4 or ISHLT 1B or 2; rejection score=2, Texas > or = 5 or ISHLT > or = 3A. RESULTS: During the third and subsequent posttransplantation years, 31 of 112 (28%) patients had < or = 1 further Rej (total 51). Independent predictors identifying patients with Rej in multivariate analysis were age [odds ratio (OR)=0.96 per year, P<0.05], the sum of rejection score (OR=1.07 per score point, P<0.005) and the mean cyclosporine level in the first 2 years (OR=1.07 per % of upper therapeutic range, P<0.01). Fifty-eight (52%) patients with age >25 years, sum of rejection score < or = 17, and mean cyclosporine level <90th percentile during the first 2 years would not have needed biopsies in the third and subsequent years, whereas the other 48% had a risk of 54% to develop further Rej. In addition to predictors identifying patients with rejection, time after transplantation (OR=0.73 per year, P<0.005), cyclosporine level below therapeutic range (OR=2.15, P<0.05), and reduction of prednisone (OR=2.64, P<0.05) were independent predictors at each endomyocardial biopsy. CONCLUSIONS: Risk of Rej remained considerably high in approximately one third of our patients late after transplantation. In these, further surveillance biopsies appear justified, whereas half of the patients had no risk of Rej as long as immunosuppressive therapy was sufficient.     

Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection

BACKGROUND: To compare the efficacy and safety of tacrolimus and cyclosporine in heart transplantation, this single-center, prospective, randomized, open-label clinical trial was undertaken. METHODS: Seventy-three adult patients were randomly assigned at the time of transplantation to receive either tacrolimus (n=43) or cyclosporine (n=30) as the primary immunosuppressant. Ten of the 43 patients in the tacrolimus group received the drug intravenously in the perioperative period; all other patients received only oral tacrolimus. RESULTS: With a mean follow-up of 27 months, patient survival rates (tacrolimus 83%, cyclosporine 81%) were similar. Fewer patients experienced acute rejection in the tacrolimus group (79%) than in the cyclosporine group (100%), but the difference was not statistically significant. The number of infections and dialysis and insulin requirements were similar for the 2 treatment groups, but the proportion of patients requiring multidrug antihypertensive regimens was lower in the tacrolimus group (12.5% vs 50.0% at month 6; p=.025). The interpatient variance in pharmacokinetic parameters in a subset of 10 patients was much higher after the first oral dose of tacrolimus than at steady-state (eg, first-dose time at which maximal concentration is reached (t(max)): 3.5+/-2.5h, steady-state t(max): 2.0+/-0.7h), and patients treated with intravenous tacrolimus (n=13) rather than oral tacrolimus (n=30) reached target concentrations faster and with less interpatient variability (eg, at day 0: 9.72+/-10.9 ng/mL intravenously vs 3.31+/-8.1 orally). CONCLUSIONS: Tacrolimus was associated with similar efficacy and safety profiles compared with cyclosporine. The higher interpatient variance in absorption associated with oral tacrolimus during the first few days after transplantation would suggest that intravenous tacrolimus should be used during the perioperative period.     

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.     

Adhesion molecules (E-selectin and ICAM-1) in pulmonary allograft rejection

Vascular endothelial cells act as antigen-presenting cells in the lung allograft and stimulate alloreactive host lymphocytes. Activated lymphocytes and cytokines can induce expression of leukocyte-endothelial adhesion molecules that facilitate invasion of the allograft by circulating leukocytes. To define the role of endothelial HLA class II antigen and adhesion molecule expression in lung allograft rejection, we prospectively analyzed endothelial expression of HLA class II, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) antigens in 52 transbronchial biopsy specimens from 24 lung allograft recipients as compared to normal control subjects. Thirty-one of 52 specimens showed histologic rejection and 8 of 24 patients developed histologic obliterative bronchiolitis (OB) by the end of the study period. Increased expression of HLA class II antigen was seen in 32 of 52 (62%) lung allograft specimens, but increased expression did not correlate with acute rejection or OB. In contrast, E-selectin expression was seen in 30 of 52 (58%) biopsy specimens and was associated with acute rejection (p < 0.005) and with the development of OB (p < 0.05). Increased expression of ICAM-1 was seen in only 18 of 52 (35%) biopsy specimens and did not correlate with acute rejection or OB. These data suggest that E-selectin expression may be a tissue marker of acute and chronic lung rejection possibly by promoting leukocyte adhesion to the allograft endothelium. The high levels of endothelial HLA class II expression may reflect long-term antigenic stimulation of the allograft even in the absence of rejection.     

The United Kingdom Prospective Diabetes Study (UKPDS) implications for the pharmacotherapy of type 2 diabetes mellitus

Tacrolimus has already gained a high reputation as an induction-maintenance immunosuppressive therapy after kidney transplantation. Recently, it is being used as rescue therapy against rejection, and its effectiveness also appears to have been established to some extent. In this study, we evaluated the efficacy of Tacrolimus rescue therapy at 4 institutions in the Kinki District. The subjects were 19 patients treated with Tacrolimus against rejection observed during immunosuppressive therapy using cyclosporin. Evaluation was made by classifying the patients into 6 with acute rejection that occurred within 3 months after transplantation (AR), 4 with late onset acute rejection that developed more than 3 months after operation (LAR), and 9 patients with chronic rejection (CR). In the AR group, many patients received combination therapy at the introduction of Tacrolimus, and the long-term outcome was satisfactory. Tacrolimus was effective in 2 (50%) of the 4 patients in the LAR group. The trough levels of Tacrolimus at its introduction were 10-15 ng/ml in the AR and LAR groups. Deterioration of the transplanted kidney function was prevented in 3 (50%) out of 6 patients in the CR group observed for less than 1 year, but it deteriorated in all 3 patients observed for 1 year or longer. The trough levels of tacrolimus at its introduction were 5-10 ng/ml in many patients in the CR group. The rescue therapy using Tacrolimus was effective against acute rejection but further follow-up is considered to be needed to evaluate its efficacy against chronic rejection.     

RANTES chemokine expression is related to acute cardiac cellular rejection and infiltration by CD45RO T-lymphocytes and macrophages

BACKGROUND: Despite the advances made in immunosuppression therapy, episodes of acute cellular rejection may affect graft function and survival. We investigated the role of RANTES in cellular recruitment and in cardiac allograft rejection. METHODS: Endomyocardial biopsies (n = 65) from 30 patients were taken at various times after transplantation. In 4 subjects who died of acute cellular rejection, the profile of RANTES expression was monitored in all biopsy specimens and in postmortem tissue. Myocardial tissue from 10 other transplants was also analyzed. Sections were stained with an anti-human RANTES antibody with the streptavidin-biotin technique. RANTES-positive cells were related to macrophage, CD45RO "memory" T-cell, and eosinophil infiltration. RESULTS: RANTES-positive cells were identified within the cellular infiltrate in 95% of biopsies with moderate/severe rejection and 28% with mild rejection. RANTES-positive, CD45RO-positive, and macrophage cell numbers were higher in subjects who died of acute cellular rejection than of other causes. A highly significant difference in RANTES-positive cell number was observed between moderate/severe, mild, and nonrejection groups (p = .0001) and correlated significantly with macrophage number in both right and left ventricles (r = .693, p < .01; r = .599, p < .05, respectively) and with the number of "memory" T cells (r = .829, p < .001; r = .779, p < .01, respectively). CONCLUSIONS: These findings suggest that local release of RANTES is important in the recruitment of both macrophages and CD45RO T cells in cardiac allograft rejection. RANTES may be an important chemokine to target for therapeutic intervention in heart rejection.     

Measurement of tacrolimus (FK506) and its metabolites: a review of assay development and application in therapeutic drug monitoring and pharmacokinetic studies

Tacrolimus (FK506, Prograf) is a macrolide immunosuppressant used for the prevention of organ rejection after transplantation. Tacrolimus demonstrates considerable interindividual variation in its pharmacokinetic profile. This has caused difficulty in defining the optimum regimen and has highlighted the need for therapeutic drug monitoring. Several assay methods for the measurements of tacrolimus in biological specimens have been developed. These assay methods were used for therapeutic drug monitoring and/or pharmacokinetic studies. Two commercially available immunoassays, based on the same monoclonal antibody to tacrolimus, have been used for therapeutic drug monitoring of tacrolimus in whole blood. For pharmacokinetic studies, the assay methods were used to measure tacrolimus and its metabolites in very low concentrations in selected biological matrixes to determine the metabolic and pharmacokinetic profiles of this drug.     

Determinants of late allograft nephrectomy

When loss of graft function occurs more than six months after transplantation, allograft nephrectomy is not routinely performed at the time of graft failure. It is usually performed only on those patients who subsequently develop specific complications. However, little is known about the characteristics that make patients more likely to require allograft nephrectomy. The purpose of our study was to identify risk factors for the subsequent need for allograft nephrectomy in patients with graft failure occurring more than 6 months after transplantation. Forty-one patients were studied. Inclusion criteria were: loss of graft function > or = 6 months after transplantation, resumption of dialysis and initiation of weaning from immunosuppression. Thirty patients were treated with cyclosporine + prednisone +/- azathioprine and 11 with azathioprine + prednisone. Mean follow-up time was 17.8 months, ranging from 6 months to 6.1 years. Recipient age, sex and race, original renal disease, donor, donor source (cadaveric vs living related), HLA compatibility, levels of panel reactive antibodies, occurrence of initial delayed graft function, causes of graft failure and tapering of immunosuppression were similar in patients with and without allograft nephrectomy. Using univariate analysis, allograft nephrectomy was found to be significantly more frequent in patients with a history of 2 or more episodes of acute rejection than in patients with no rejection episode: 83% vs 30% (p = 0.03). In addition, allograft nephrectomy was found to be significantly more frequent if the immunosuppressive regimen included cyclosporine (62% vs 27.3%; p = 0.04). Using multivariate analysis however, the number of previous episodes of rejection was found to be the only significant predictor for allograft nephrectomy. None of the other variables considered in the multivariate analysis, including the type of immunosuppressive therapy, was identified as a significant predictor for the need to perform allograft nephrectomy. In summary, the need for late allograft nephrectomy was correlated with the number of previous episodes of acute rejection. Patients with a history of numerous rejection episodes should thus be considered more likely to require allograft nephrectomy once immunosuppression is withdrawn. Possible interventions to reduce or prevent the need for nephrectomy include more gradual tapering of immunosuppression at the time of graft failure or indefinite low-dose immunosuppressive therapy.     

Myocardial acoustics in pediatric allograft rejection

BACKGROUND: Ultrasonographic tissue characterization is the assessment of physical properties of biologic tissue on the basis of quantitative analysis of its acoustic characteristics. Abnormalities in microscopic structure that occur with cardiac allograft rejection may result in characteristic alterations in myocardial acoustics. Ultrasonographic tissue characterization may allow noninvasive detection of rejection. METHODS: Findings in 22 pediatric heart transplant patients undergoing routine surveillance for rejection by endomyocardial biopsy were prospectively evaluated. Off-line ultrasonographic tissue characterization analysis was done on transthoracic echocardiograms obtained at each biopsy. Within patients, tissue characterization texture measures derived from the ultrasonographic image data were compared with histologic findings. Univariate multiple regression analysis was used to identify texture measures associated with acute allograft rejection in a subgroup (n = 8) with at least one biopsy-proven episode of moderate rejection. RESULTS: Measures of homogeneity (co-occurrence matrix correlation and heterogeneity (run-length nonuniformity) decreased with moderate rejection (p < 0.03). Homogeneity measures decreased if the patient had a previous episode of rejection. Several measures of heterogeneity (gray level difference and run-length statistics) were affected by the presence of edema. Run-length nonuniformity was the only measure that differentiated moderate rejection from edema. Discriminant analysis on all 22 patients correctly identified 96% of first rejection episodes (sensitivity 80%, specificity 64%), 93% of moderate and severe rejection episodes (sensitivity 71%; specificity 62%), and 69% of all rejection episodes (sensitivity 51%, specificity 91%). CONCLUSIONS: Histologic changes associated with moderate and severe pediatric allograft rejection as reflected by characteristic alterations in myocardial acoustics can be assessed with ultrasonographic tissue characterization. Histologic changes associated with transplantation itself (resolution of rejection and edema) also affect myocardial acoustics and must be taken into account in rejection surveillance.     

Echocardiographic analysis of rejection in the infant heart transplant recipient

Eleven children who received transplants at less than 2 years of age underwent 59 echocardiograms at the time of endomyocardial biopsy for the assessment of the ability of echocardiography to predict acute rejection in the infant heart transplant recipient. Two patients died of acute rejection and autopsy findings were compared with premortum echocardiograms. Biopsy specimens were graded as no rejection (n = 46), mild rejection (cellular infiltrate, n = 5), or moderate-severe rejection (myocyte necrosis/edema, n = 8). Echocardiographic indexes measured included the following: left ventricular mass, left ventricular volume, ejection fraction, heart rate, and peak rate of posterior wall thinning. Compared with controls, patients during mild rejection had slower posterior wall diastolic thinning (p < 0.01). No significant change was noted in left ventricular mass until endomyocardial biopsy specimens showed severe rejection. No significant changes were noted in heart rate or ejection fraction in any of the groups. In conclusion, decrease in the peak rate of posterior wall diastolic thinning may be a sensitive indicator of acute rejection in the infant heart transplant recipient.     

Emergency medicine: the Italian experience

BACKGROUND: Studies using tacrolimus and corticosteroids or the combination of cyclosporine, mycophenolate mofetil, and corticosteroids have been shown to reduce the incidence of biopsy-proven acute rejection episodes in cadaveric kidney recipients compared with cyclosporine-based immunosuppression. The current study is a retrospective analysis of our experience with tacrolimus combined with mycophenolate mofetil and steroids as primary immunosuppression for kidney transplant recipients. METHODS: In a retrospective analysis, 72 patients who received primary therapy with tacrolimus, mycophenolate mofetil, and corticosteroids (triple therapy) were compared with a control group of 98 kidney recipients who received tacrolimus and corticosteroids (double therapy). RESULTS: There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the triple therapy group (8.2%) compared with the double therapy group (21%; P=0.003). One-year patient and graft survival did not differ between groups. The incidence of posttransplant diabetes mellitus was 18% and 21% in the triple and double therapy groups, respectively. Leukopenia and gastrointestinal side effects were the most common cause for discontinuation of mycophenolate mofetil. CONCLUSIONS: The combination of tacrolimus with mycophenolate mofetil and corticosteroids is more effective at preventing early acute rejection than tacrolimus and corticosteroids alone. The use of mycophenolate mofetil was associated with a higher incidence of leukopenia and diarrhea, often leading to discontinuation of the drug.     

Myocardial lactate dehydrogenase subunit ratio in cardiac allograft recipients

BACKGROUND: Allograft coronary artery disease (CAD) is a major long-term complication in heart transplanted patients. However, the metabolic basis of allograft CAD remains to be fully elucidated. We analyzed the lactate dehydrogenase heart (H) and muscle (M) isoenzyme pattern in endomyocardial biopsy specimens and the evolution of the H/M ratio to test whether changes in this ratio could be the earliest manifestation of allograft CAD. METHODS: Twenty-four heart transplant recipients were followed up for 12 months. Endomyocardial biopsy was performed at 1, 2, 3, 6, and 12 months after transplantation. Lactate dehydrogenase 1 through 5 isoenzymes were separated by electrophoresis, and the H/M ratio was calculated. Two groups of patients were identified: group 1 (n = 20), patients without allograft CAD; and group 2 (n = 4), patients with poor outcome (three deaths, 1 case of low cardiac output) and angiographic and histologic evidence of allograft CAD. RESULTS: Both groups had similar H/M baseline values. The H/M ratio was higher (p = 0.01) in group 1 at 6 months (3.48 +/- 0.64 versus 2.17 +/- 0.43) and 12 months (3.76 +/- 0.92 versus 2.18 +/- 0.45) when compared with group 2. The H/M ratio increased from 2.78 +/- 0.89 at 1 month to 3.76 +/- 0.92 at 12 months (p = 0.02) in group 1 and decreased in group 2 (2.86 +/- 0.49 versus 2.18 +/- 0.45; not significant). CONCLUSIONS: Changes in H/M ratio reflect an anaerobic shift in the lactate dehydrogenase isoenzyme composition and can be taken as an early indicator of allograft CAD.