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.     

Studies towards a disposable screen-printed amperometric biosensor for progesterone

BACKGROUND: Little is known about the causes of death of heart transplant recipients who survive long-term. METHODS: The pathologic and clinical records of 97 patients who underwent heart transplantation in Italy from 1985 to 1995 and died (85 of 97) or underwent retransplantation (12 of 97) at least 2 years after transplantation were surveyed. Graft failures were classified as late (occurring between 2 and 5 years after transplantation) and belated (more than 5 years). RESULTS: Graft vasculopathy was the single most common cause of death (40.0%) and the only cause of late retransplantation. Tumors ranked second (23.5% of deaths), but the expected non-Hodgkin's lymphomas and Kaposi's sarcoma were accompanied by a high number of lung cancers (especially metastasizing adenocarcinomas). They were followed by the emergence or recurrence of pretransplantation diseases (9.4%), fatal infections (exclusively bacterial) (4.7%), the development of transmissible diseases (viral hepatitis and acquired immunodeficiency syndrome, 4.7%), and late acute rejection (2.3%). The distribution of failures differed in the late and belated periods: death and organ loss proportions for graft vasculopathy, respectively, fell and rose from the late to the belated period; some types of malignancy and fatal acute rejection were never observed in the belated period, whereas the emergence of pretransplantation diseases prevailed in the belated period. Graft vasculopathy was more frequent and tumors were less frequent among patients undergoing transplantation for ischemic heart disease. CONCLUSIONS: The reasons why heart transplant recipients die or undergo retransplantation, respectively, in the late and belated periods slightly differ from one another and are widely different than in short-term survivors.     

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.     

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.     

Measuring bioelectric myocardial impedance as a noninvasive method for diagnosis of graft rejection after heart transplantation

12 beagle dogs underwent neck-heart transplantation and were immunosuppressed with cyclosporine and methylprednisolone. Intramyocardial impedance was determined twice daily with four screw-in electrodes in the right and left ventricle. Transmyocardial biopsies and the intra-myocardial electrogram (IMEG) were performed as reference methods. 19 rejection episodes were induced. When acute rejection was seen in histology the animals were treated with pulsed 125 mg methylprednisolone over 5 consecutive days and immunosuppression was raised to sufficient levels. Successful treatment of rejection was controlled by biopsy. All hearts showed a uniform decrease of impedance of about 28.3% +/- 5.5% immediately after implantation, then reaching a stable plateau after 7 to 8 days. Impedance values then remained unchanged as long as rejection was absent. Biopsy findings of grade 1A to 1B (ISHLT) were accompanied by a statistically significant increase of impedance of 12.2% +/- 2.5%, of grade 2 to 3A of 19.2% +/- 3.2%, and of grade 3B to 4 of 27.0% +/- 2.9%. Sensitivity was 95%, specificity 91%. Successful treatment of rejection led to a uniform decrease of impedance to intramyocardial impedance for high frequencies can reliably indicate alterations of the cell membrane and the intracellular space during acute cardiac allograft rejection. The amount of increase of impedance is a reliable noninvasive parameter to graduate acute cardiac allograft rejection. The success of treatment of rejection can also be monitored by impedance. This noninvasive method is applicable for telemetric rejection monitoring via an implantable device, which would allow continuous rejection surveillance of a patient at home without hospital admission.     

Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

Reversal of early acute rejection with increased doses of tacrolimus in liver transplantation: a pilot study

BACKGROUND: In this pilot study, we present the results of treatment of early (3 months after liver transplantation) acute rejection episodes by increasing only the tacrolimus doses. METHODS: Ten patients who received tacrolimus as primary treatment experienced acute mild (one case), moderate (four cases), or severe (five cases) rejection episodes. Tacrolimus dosing was increased 1-2 mg every 1 or 2 days until hepatic enzymes started to improve. Steroid basic daily doses were kept unchanged. RESULTS: With the daily dose of tacrolimus increased by a median 1.89-fold (range: 1.2-5), alanine aminotransferase, bilirubin, and gamma-glutamyltranspeptidase levels rapidly reached normal values within the first month. During a median follow-up time of 19.5 months (range: 14-24), none of the 10 patients died or lost their graft. Control liver biopsies were done 13.5 months (range: 7-19) after rejection episode in all patients, and none demonstrated evidence of rejection or sequela. CONCLUSION: This pilot study suggests that increasing tacrolimus dosage could be considered as treatment against early acute rejection episodes including the severe grade.     

Donor cardiac troponin T: a marker to predict heart transplant rejection

BACKGROUND: Noninvasive methodologies have shown poor sensitivity in predicting rejection when compared to serial endomyocardial biopsies. We studied the potential role of donor blood troponin T (Tn-T) as a marker for predicting heart transplant rejection. METHODS: Blood cardiac Tn-T was measured from 16 heart donors. Transplant rejection and cardiac function in the recipients were monitored for 1 year. RESULTS: When data were analyzed based on donor blood Tn-T levels, 6 patients who received hearts from donors with low Tn-T (<0.45+/-0.1 ng/mL) showed no rejection, and patients whose hearts came from donors with higher Tn-T (6.01+/-0.81 ng/mL) developed episodes of high-grade rejection (3A) within 38.5+/-2.1 days after transplantation. Eight patients who received hearts from donors with intermediate levels of Tn-T (3.57+/-0.55 ng/mL) showed mild rejection (grade 1). All recipients had qualitatively normal left ventricular systolic function by serial echocardiography. The mean donor ischemic time was 169+/-47 minutes. CONCLUSIONS: The quality of the donor heart is an important prognostic factor in heart transplantation. It may be possible to identify severely damaged donor organs before transplantation and avoid their use or to develop more aggressive strategies for reducing recurrent acute rejection episodes in high-risk patients.     

Cell-mediated cytotoxicity: a predictor of chronic rejection in pediatric HLA haploidentical renal transplants

BACKGROUND: Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. METHODS: Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. RESULTS: Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P<0.01) but not acute rejection (P=0.11). It was estimated that every 1-unit increase in CML level raises the monthly risk of chronic rejection by 7%. Ten children received HLA-identical kidneys from their siblings. There were no episodes of chronic rejection after 5 years. Two patients with high CML levels had episodes of acute rejection; both patients responded to treatment. CONCLUSION: Our data demonstrate an association between pretransplant cell-mediated cytotoxicity and the occurrence of chronic rejection in living related one-haploidentical renal transplants in pediatric patients.     

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.     

Study of the beta -delayed neutron decay of 18N

The shortage of suitable liver donors for children has motivated the use of ABO-incompatible (ABO-I) grafts for transplantation in urgent situations. However, survival after ABO-I liver grafts has been reported at about 30% as compared with 80% in cases of ABO-identical or -compatible liver grafts. This difference has been attributed to antibody-mediated, hyperacute or chronic liver rejection, due to preformed ABO antibodies (alloantibodies). In this study, we report our results with ABO-I livers in children without alloantibodies at the time of transplantation. From January 1988 to June 1993, 143 OLT were performed in 122 children. Eight children received 8 ABO-I liver grafts. Of these, 7 patients were included in the study. All 7 were alloantibody free before OLT. Five children were spontaneously alloantibody free, while in 2 children, the plasma alloantibodies were eliminated before and after transplantation using intravenous infusion of specific blood group antigens of the donor blood group (soluble antigens). Immunosuppression consisted of a triple-drug treatment combining CsA, AZA, and steroids. The follow-up period was between 10 and 48 months. One child died from a surgical complication. Six children survived, but 1 died 10 months later from intestinal obstruction. There were no graft losses and no episodes of hyperacute or chronic rejection. The graft and patient survival rate was 71%. There was a 28% incidence of rejection, but all were mild (requiring steroid boluses only). Our results suggest that the absence of ABO alloantibodies at the time of and after transplantation can protect ABO-I liver grafts against antibody-mediated rejection, whether hyperacute or chronic, and that soluble antigens are effective in eliminating alloantibodies in children.     

Validation of an in-office dental unit water monitoring technique

OBJECTIVE: Intestinal transplantation has become an option as a treatment for permanent intestinal failure. Endoscopy is an essential tool in assessing the intestinal allograft after intestinal transplantation. The aim of this study was to analyze our experience using endoscopy in intestinal transplant recipients. METHODS: This was a retrospective review of endoscopic and histological reports in 41 children who received an intestinal transplant between 1990 and 1995 at Children's Hospital of Pittsburgh. RESULTS: A total of 1273 endoscopies was performed of which 760 were ileoscopies via allograft ileostomy, 273 were upper endoscopies, and 240 were colonoscopies. One hundred four rejection episodes were documented histologically in 32 patients, 6 days to >4 yr after transplantation. Most episodes were mild and easily treated with increased immunosuppression; however, severe rejection with mucosal exfoliation was seen in nine patients. Rejection sometimes involved only part of the allograft. Endoscopic appearance alone without biopsies was sensitive enough to diagnose only 63% of the rejection episodes. Epstein-Barr and cytomegalovirus infections occurred in 11 and eight patients, respectively, and involved both native bowel and allograft in some. Complications of endoscopy were few: one perforation, three episodes of bleeding, and three episodes of transient respiratory compromise. CONCLUSIONS: Endoscopy is an essential tool in the postoperative assessment of intestinal transplant recipients. Frequent surveillance ileoscopies with biopsies should be performed after transplantation. If patients clinically deteriorate with fever, diarrhea, bacteremia, or gastrointestinal bleeding and a clear cause is not elucidated by ileoscopy, an upper endoscopy with biopsies is indicated.     

Pediatric lung transplantation. Indications, techniques, and early results

From July 1990 to April 1993, 36 lung transplantations in 33 patients were performed in our pediatric transplant program (0.25 to 23 years, mean age 10.3 years). Eight children had been continuously supported with a ventilator for 3 days to 4.5 years before transplantation and three were supported by extracorporeal membrane oxygenation. Indications for lung transplantation in this pediatric population included the following: cystic fibrosis (n = 13), pulmonary hypertension, and associated congenital heart disease (n = 10), pulmonary atresia, ventricular septal defect and nonconfluent pulmonary arteries (n = 3), pulmonary fibrosis (n = 6), and acute respiratory distress syndrome (n = 1). Three children underwent retransplantation for acute graft failure (n = 2) or chronic rejection (n = 1). Pulmonary fibrosis was related to complications of treatment of acute of myelogenous leukemia with bone marrow transplantation in two children and to bronchiolitis obliterans, bronchopulmonary dysplasia, interstitial pneumonitis, and Langerhans cell histiocytosis in four others. Thirteen children underwent lung transplantation and concomitant cardiac repair. Bilateral lung transplantation, ventricular septal defect closure and pulmonary homograft reconstruction of the right ventricular outflow tract to the transplanted lungs was performed in three children by means of a new technique that avoids the need for combined heart-lung transplantation. Two patients had ventricular septal defect closure and single lung transplant for Eisenmenger's syndrome, two had ligation of a patent ductus arteriosus and transplantation, three additional children underwent atrial septal defect closure and lung transplantation, and two underwent lung transplantation for congenital pulmonary vein stenosis. Eight early deaths and three late deaths occurred (actuarial 1-year survival 62%). Lung transplantation in children has been associated with acceptable early results, although modification of the adult implantation technique has been necessary. Lung transplantation and repair of complex congenital heart defects is possible; heart-lung transplantation may only be required for patients with severe left heart dysfunction and associated pulmonary vascular disease. Bronchiolitis obliterans remains a major concern for long-term graft function in pediatric lung transplant recipients.     

46-year-old patient with hemorrhagic diathesis and renal artery aneurysms. Type IV Ehlers-Danlos syndrome

To establish the medium-term results of our transplant population, we retrospectively reviewed the charts of 51 consecutive patients who underwent orthotopic heart transplantation between July 1988 and April 1995. These patients comprised two groups: group A consists of 26 patients (age 6 days to 16.4 years, median 1.4 years) with no previous heart surgery, and group B consists of 25 patients (ages 0.1 to 14.3 years, median 8.3 years), all of whom had heart surgery before undergoing transplantation. There was no difference between these groups in early or late survival rates, and neither age at transplantation nor sex was an indicator of survival. There have been 14 deaths, six early (before hospital discharge) and eight late. Early deaths have predominantly been attributed to long-term ventilation and hemodynamic instability before transplantation, and late deaths to graft coronary artery disease (n = 4), acute coronary vasculitis (n = 3), and acute cellular rejection (n = 1). Although infection has resulted in significant morbidity (57 hospital admissions), there have been no late deaths resulting from infection. Sepsis accounts for four early deaths in chronically ill patients. Orthotopic heart transplantation in the pediatric patient with and without previous heart surgery is a viable option for those with end-stage heart disease and those in whom other surgical options carry a prohibitively high mortality rate.     

Follicular fluid immunoreactive-inhibin concentrations in relation to follicular diameter and estradiol-17 beta, progesterone and testosterone concentrations in individual ovarian follicles in buffalo, Bubalus bubalis

BACKGROUND: Mycophenolate mofetil reduces episodes of biopsy-proven acute cellular rejection or treatment failure in the first year after kidney transplantation; however, limited data exist regarding the efficacy after lung transplantation. METHODS: In a 2-center, nonrandomized concurrent cohort study (level III evidence), we analyzed the incidence of biopsy-proven acute cellular rejection (International Society for Heart and Lung Transplantation grade > or=A2) and decrement in pulmonary function during the first 12 months after successful lung transplantation. All patients received induction immunosuppression with antithymocyte globulin (< or=5 days' duration), cyclosporine and prednisone, in addition to either mycophenolate mofetil (2.0 g/d) [n=11] or azathioprine (1 to 2 mg/kg per day) [n=11]. RESULTS: During the first 12 months after lung transplantation, the mycophenolate mofetil group experienced significantly fewer episodes of acute cellular rejection than the azathioprine group (0.26+/-0.34 vs 0.72+/-0.43 episodes/100 patient-days [mean+/-SD], p < 0.01; 95% CI for the difference=0.126 to 0.813). The change in forced expiratory volume -1 second [deltaFEV1] (liters) between the 3rd and 12th months after lung transplantation was analyzed for the two treatment groups. For this interval, deltaFEV1 for the mycophenolate mofetil group was +0.158+/-0.497 L vs -0.281+/-0.406 L for the azathioprine group (p < 0.05; 95% CI for difference=+0.0356 to 0.843). During the first year, there was 1 death in each group attributed to bronchiolitis obliterans syndrome with concurrent pneumonia. There were no differences in incidence of cytomegalovirus or bacterial infections between the treatment groups; however, a higher prevalence of aspergillus sp airway colonization in bronchoalveolar lavage fluid was observed for the mycophenolate mofetil group (p < .05). The prevalence of bronchiolitis obliterans syndrome at 12 months was 36% for the azathioprine group vs 18% for the mycophenolate mofetil group (p=NS). CONCLUSIONS: Our preliminary experience with mycophenolate mofetil after lung transplantation suggests a decreased incidence of biopsy-proven acute cellular rejection. Furthermore, less decline in FEV1 after 12 months may suggest a reduced incidence or delayed onset for development of bronchiolitis obliterans syndrome. Prospective randomized trials with low beta error (level I evidence) should be performed to assess the efficacy of mycophenolate mofetil vis-à-vis acute allograft rejection and bronchiolitis obliterans syndrome.     

Metabolic factors have a major impact on kidney allograft survival

BACKGROUND: At the present time, late graft loss is the major cause of kidney failure after transplantation. However, the influence of metabolic factors on this process is ill-defined. METHODS: To identify the impact of lipid metabolism, glucose metabolism, and blood pressure and their prognostic value for graft survival, data for all recipients of a kidney allograft with a potential graft survival of >15 years and a minimum graft survival of 1 month were analyzed retrospectively. Recipients of kidney grafts functioning more than 15 years (n=32) were compared with those with a graft function of less than 10 years (n=152, controls) and evaluated in a multivariate analysis. RESULTS: Low levels of serum cholesterol, triglycerides, and glucose, before and after transplantation, were accompanied by a prolonged graft survival. Prognostic factors for early graft failure included serum triglycerides >300 mg/dl, cholesterol >250 mg/dl before transplantation, serum creatinine >4.0 mg/dl 1 month after transplantation, and donor age above 45 or less than 10 years. Additionally, systolic and, particularly, diastolic blood pressure was lower in the group with a prolonged graft function as compared with controls immediately before and after transplantation. In addition, the incidence of primary graft function was lower and the incidence of acute rejection episodes higher in controls. Cold and warm ischemic time, body mass index, recipient age, and gender did not differ significantly. CONCLUSIONS: Our data suggest that metabolic parameters play an important role in the process of late graft loss after kidney transplantation.     

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.     

Preliminary experience with mycophenolate mofetil used after lung transplantation

This study reports our preliminary experience with mycophenolate mofetil (MMF)-based immune suppression after lung transplantation. Thirteen patients (group 1) received MMF as primary therapy immediately after transplantation. Use of MMF was associated with a linearized rate of 0.85 episodes of acute rejection per 100 patient days during the first 3 months after transplantation, as compared with rates of 1.49 and 1.38, observed in two groups of historical control subjects (p = .094 and p = .053, respectively). Rejection rates after the first 3 months were not lower than in historical control subjects. Nine additional patients were switched from azathioprine to MMF because of recurrent episodes of high-grade acute rejection (group 2). In this group, the linearized rate of acute rejection episodes declined significantly (p = .004) after initiation of MMF therapy. These data suggest a potential role for MMF in reducing the rate of acute rejection episodes after lung transplantation.     

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.