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.     

Positive selection driving the evolution of a gene of male reproduction, Acp26Aa, of Drosophila: II. Divergence versus polymorphism

BACKGROUND: Sirolimus, a novel immunosuppressant that inhibits cytokine-driven cell proliferation and maturation, prolongs allograft survival in animal models. After a phase I trial in stable renal transplant recipients documented that cyclosporine and sirolimus have few overlapping toxicities, we conducted an open-label, single-center, phase I/II dose-escalation trial to examine the safety and efficacy of this drug combination. METHODS: Forty mismatched living-donor renal transplant recipients were sequentially assigned to receive escalating initial doses of sirolimus (0.5-7.0 mg/m2/day), in addition to courses of prednisone and a concentration-controlled regimen of cyclosporine. We conducted surveillance for drug-induced side effects among sirolimus-treated patients and compared their incidence of acute rejection episodes as well as mean laboratory values with those of a historical cohort of 65 consecutive, immediately precedent, demographically similar recipients treated with the same concentration-controlled regimen of cyclosporine and tapering doses of prednisone. RESULTS: The addition of sirolimus reduced the overall incidence of acute allograft rejection episodes to 7.5% from 32% in the immediately precedent cyclosporine/prednisone-treated patients. At 18- to 47-month follow-up periods, both treatment groups displayed similar rates of patient and graft survival, as well as morbid complications. Although sirolimus-treated patients displayed comparatively lower platelet and white blood cell counts and higher levels of serum cholesterol and triglycerides, sirolimus did not augment the nephrotoxic or hypertensive proclivities of cyclosporine. The degree of change in the laboratory values was more directly associated with whole blood trough drug concentrations than with doses of sirolimus. CONCLUSIONS: Sirolimus potentiates the immunosuppressive effects of a cyclosporine-based regimen by reducing the rate of acute rejection episodes.     

Survival after heart transplantation without regular immunosuppression

Seventy renal allograft biopsies were done in 31 patients, routinely at 1, 2, and 3 months posttransplant, and as clinically indicated, using an automated biopsy "gun." The histological diagnosis was made according to the Banff schema, which emphasizes tubulitis and vascular inflammation over mononuclear cell infiltration. Fifty-three biopsies satisfied histological inclusion criteria. Twenty-nine biopsies were obtained from stable patients, defined as those in whom serum creatinine had changed < 10% in 2 weeks, and in whom immunosuppression (cyclosporine, azathioprine, and prednisone) had not been increased in that interval. Of these biopsies, 30% (9/29) showed rejection, which could not have been predicted from pretransplant (HLA mismatch, panel-reactive antibody titer) or posttransplant (cyclosporine and serum interleukin 2 receptor levels) variables. The significance of these early subclinical rejection episodes is unknown, and their effects on long-term graft histology and function are being examined in a controlled study.     

Surgical wound infection in renal transplantation: outcome data in 102 consecutive patients without perioperative systemic antibiotic coverage

BACKGROUND: The incidence of surgical wound infection in the presence of immunosuppression has been reported in the literature to approach 7%. Perioperative systemic antibiotic therapy is routinely used to reduce the occurrence of wound infections. This therapy is not without complications, including adverse effects and development of resistant strains. DESIGN: Surgical wound infection rates during the first 100 days after renal transplantation were studied in 102 consecutive patients. Eighty-one patients underwent cadaveric transplantation and 21 patients underwent living-related donor transplantation from February 1, 1991, to January 1, 1992. No systemic perioperative antibiotic coverage was used, but local antibiotic irrigation was part of the perioperative protocol. SETTING: Hahnemann University Hospital, Philadelphia, Pa, is a large, tertiary care center. Patients were initially hospitalized and were discharged during the 100-day follow-up period based on clinical status and improvement in renal function. PATIENTS: Twenty-seven (25%) of 102 patients had diabetes mellitus. INTERVENTIONS: Induction immunosuppression consisted of azathioprine, prednisone, and anitlymphocyte globulin, while maintenance immunosuppression consisted of azathioprine, prednisone, and cyclosporine. Acute allograft rejection episodes were treated with steroids and/or OKT3 (Ortho Pharmaceutical Group, Raritan, NJ). RESULTS: Two surgical wound infections (2%) occurred. In both, infection was superficial, resolving with wound drainage and intravenous antibiotics. The surgical wound infection rate was not significantly affected by age, sex, allograft source, or presence of diabetes mellitus. CONCLUSIONS: Despite immunosuppression, the incidence of surgical wound infection was minimal, comparing favorably to rates reported for renal transplantation with the use of systemic antibiotics. Possible explanations for the low incidence of surgical wound infections include local wound irrigation, meticulous hemostasis, improved organ procurement techniques, and continuity in perioperative care.     

A study comparing mycophenolate mofetil to azathioprine in simultaneous pancreas-kidney transplantation

BACKGROUND: Mycophenolate mofetil (MMF; Cell-Cept) is a potent and selective inhibitor of B and T lymphocyte proliferation that has proven effective in reducing the incidence of acute rejection in cadaveric kidney transplant recipients in several randomized, blinded clinical studies. Because the frequency and characteristics of rejection episodes may be different and more severe after combined pancreas-kidney transplantation, we hypothesized that MMF would have a significant impact on pancreas-kidney rejection and graft outcome. Therefore, we compared the efficacy of MMF versus azathioprine (AZA) in cyclosporine-treated simultaneous pancreas-kidney transplantations. METHODS: A retrospective comparison of 358 consecutive primary SPK transplantations performed from 1990 to 1997 was conducted. Patients received either MMF (n=109, 3 g/day) or AZA (n=249, 2 mg/kg q.d.) in combination with cyclosporine-based immunosuppression. All patients received a quadruple-drug sequential induction protocol with either OKT3 or Atgam. Several outcome parameters, including patient and graft survival rates and frequency of rejection, were analyzed. RESULTS: MMF-treated patients demonstrated a markedly reduced rate of biopsy-proven kidney rejection (31 vs. 75% AZA, P=0.0001), clinically significant pancreas rejection (7 vs. 24% AZA; P=0.003), and steroid-refractory rejection (15 vs. 52% AZA; P=0.01). As a result, kidney and pancreas allograft survival was significantly better in MMF patients compared with AZA patients (2-year survival rates: kidney, 95 vs. 86%; and pancreas, 95 vs. 83%). Although surgical infections after transplantation were more frequent in MMF patients, MMF patients were more likely to have undergone enteric drainage. Importantly, we did not observe an increased incidence of any of the bacterial, fungal, or viral infections that typically plague immunosuppressed transplant recipients. CONCLUSIONS: This retrospective study demonstrates that MMF is a highly effective immunosuppressant in SPK transplantation. It is not associated with an increased risk of opportunistic infections when a balanced immunosuppressive management approach is used. MMF strikingly reduces the frequency of acute cellular and steroid-resistant rejection. As a result of this combined experience, it is not unexpected then that we observe significantly improved graft survival rates in MMF-treated SPK patients compared with patients receiving a more traditional immunosuppressive regimen.     

A new rat infection-heart transplant model: effect of infection on graft survival studies

Considerable progress has been made in survival rates of heart transplant recipients; however, infections continue to be a major cause of death after transplantation. Although infection itself appears to cause immunologic suppression in some nontransplantation studies, the lack of an infection-transplant animal model has limited further investigation of this observation. We evaluated the utility of a heterotopic rat infection heart-transplant model by studying the effect of infection and limited administration of two immunosuppressive agents, cyclosporine and FK506, on allograft rejection and survival. Lewis rats received ACI heart allografts, and intraperitoneal infection was induced by cecal ligation. Infection was confirmed by blood and ascitic fluid cultures. Results showed that graft survival was slightly, but significantly, higher (p < 0.05) in group II (transplantation with infection) when compared to the control group I (transplantation only). Histologic rejection scores were less (p < 0.05) in group II 6 days after transplantation. The second phase of the study compared the effect of infection after transplantation in rats given a 1-week course of cyclosporine or FK506, which were discontinued after the induction of infection. Although the cyclosporine group had prolonged survival when compared to the FK506 group (p < 0.05), the respective infection groups receiving immunosuppression revealed no significant difference in allograft survival or histologic rejection scores when compared to the control groups. In this preliminary study, infection without immunosuppression resulted in a slight, but statistically significant, increase in allograft survival and reduced acute cellular rejection. In those groups receiving immunosuppressive agents, no additive immunosuppressive effect was attributable to bacterial infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Withdrawal of immunosuppression: implications for composite tissue allograft transplantation

Complete or partial withdrawal of immunosuppression is a desirable goal for physicians managing solid organ transplant recipients and has particular appeal for the management of composite tissue allograft recipients. Experience to date with steroid withdrawal or cyclosporine withdrawal in organ transplant recipients suggests that the risks of acute rejection are minimized with slow tapering of the drugs and when drug withdrawal is attempted many months or years after transplantation. Unfortunately, the full benefits of withdrawing any component of a multidrug immunosuppression regimen can probably be achieved only when the drug is withdrawn relatively early after transplantation. Thus, there is a need for improved immunologic monitoring to facilitate withdrawal of immunosuppression in any setting. Because steroid withdrawal might be particularly advantageous to the recipient of a composite tissue allograft, further experience is needed to determine the safety of steroid withdrawal with newer immunosuppressants such as tacrolimus, mycophenolate mofetil, and sirolimus.     

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.     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

BACKGROUND: In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. METHODS: Patients with preformed reactive antibodies < 500% receiving a first graft from a suboptimal donor (age > or = 40 years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time > or = 24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. RESULTS: delayed graft function occurred in two cases (12%). Four of 17 patients (24%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159+/-59 micromol/1. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. CONCLUSIONS: These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

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.     

Mycophenolic acid: a welcome adjunct immunosuppressant after organ transplants

Three major double-blind trials in kidney transplantation patients have shown that mycophenolic acid (mycophenolate mofetil), added to an immunosuppressive regimen consisting of cyclosporine and prednisone, reduces the incidence of acute rejection after kidney transplantation by 50%, during the first six months. This statistically significant reduction is achieved equally with daily doses of 2 or of 3 g. In view of the fact that the side effects (diarrhoea, abdominal cramps, leukopenia) are more frequently found in the patients treated with 3 g, it is advised to prescribe 2 g mycophenolic acid. As acute rejection is a risk factor for the development of chronic rejection and because a beneficial effect of mycophenolic acid on chronic rejection in animal models has been observed, there may also be an effect on late graft loss due to chronic rejection after kidney transplantation in man.     

A comparative study of the outcome of renal transplantation in peritoneal dialysis and hemodialysis patients

Fifty-four cases of renal transplantation performed in peritoneal dialysis (PD) patients were compared with 48 cases in hemodialysis (HD) patients. Three immunosuppressive treatments were used: prednisolone, azathioprine and cyclosporine. Methylprednisolone was used to treat rejection, and polyclonal Atgem or monoclonal OKT3 antibodies were used if there was no response. There was no difference in sex, age, donor source, immunosuppressive regime, duration of dialysis before transplantation, or duration of follow-up between the two groups. Following transplantation, there was no significant difference in patient mortality and survival or graft survival between the groups. The incidences of infections were also similar in the two groups. PD is commonly used in developing countries as an alternative to hemodialysis for the treatment of chronic renal failure. This study has shown that renal transplantation can be successfully performed in patients treated by this method.     

Prevalence of asthma and wheeze in primary school children in northern Jordan

While the existence of chimeric cells in host tissue following organ transplantation is well documented, its distribution, temporal evolution and relationship to allograft survival is less clear. To explore this phenomenon, Lewis recipients of ACI cardiac allografts representing a wide range of immunosuppressive protocols and graft survival times were examined for the presence of chimerism using a sensitive polymerase chain reaction assay. Four groups of animals were examined: untransplanted animals receiving donor specific transfusion (DST)/cyclosporine A (CsA); allograft recipients with no treatment; recipients treated with DST/CsA/supplementary immunosuppression with rejection at 21-183 days; and recipients sacrificed with functioning allografts, treated with DST/CsA/supplementary immunosuppression and surviving > 200 days. To elucidate variations in the tissue distribution of chimeric cells, bone marrow, skin, liver, spleen, and thymus were examined in each animal. Untransplanted animals receiving DST/CsA displayed no evidence of chimerism. In animals receiving a cardiac allograft but no treatment, there was extensive evidence of chimerism in four of five animals. Chimerism was also detected in seven of nine animals with intermediate graft survival at the time of rejection. In animals with long-term graft survival, only four of eight displayed chimerism. These results suggest that, without immunosuppression, early chimerism does not lead to prolonged graft survival and that, even when graft survival is moderately prolonged, these cells are not sufficient to prevent rejection. In conclusion, chimerism appears to be a common phenomenon following transplantation, is not a result of DST, and may not be necessary for maintenance of long-term graft survival.     

Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group

BACKGROUND: Photopheresis is an immunoregulatory technique in which lymphocytes are reinfused after exposure to a photoactive compound (methoxsalen) and ultraviolet A light. We performed a preliminary study to assess the safety and efficacy of photopheresis in the prevention of acute rejection of cardiac allografts. METHODS: A total of 60 consecutive eligible recipients of primary cardiac transplants were randomly assigned to standard triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone) alone or in conjunction with photopheresis. The photopheresis group received a total of 24 photopheresis treatments, each pair of treatments given on two consecutive days, during the first six months after transplantation. The regimen for maintenance immunosuppression, the definition and treatment of rejection episodes, the use of prophylactic antibiotics, and the schedule for cardiac biopsies were standardized among all 12 study centers. All the cardiac-biopsy samples were graded in a blinded manner at a central pathology laboratory. Plasma from the subgroup of 34 patients (57 percent) who were enrolled at the nine U.S. centers was analyzed by polymerase-chain-reaction amplification for cytomegalovirus DNA. RESULTS: After six months of follow-up, the mean (+/-SD) number of episodes of acute rejection per patient was 1.44+/-1.0 in the standard-therapy group, as compared with 0.91+/-1.0 in the photopheresis group (P=0.04). Significantly more patients in the photopheresis group had one rejection episode or none (27 of 33) than in the standard-therapy group (14 of 27), and significantly fewer patients in the photopheresis group had two or more rejection episodes (6 of 33) than in the standard-therapy group (13 of 27, P=0.02). There was no significant difference in the time to a first episode of rejection, the incidence of rejection associated with hemodynamic compromise, or survival at 6 and 12 months. Although there were no significant differences in the rates or types of infection, cytomegalovirus DNA was detected significantly less frequently in the photopheresis group than in the standard-therapy group (P=0.04). CONCLUSIONS: In this pilot study, the addition of photopheresis to triple-drug immunosuppressive therapy significantly decreased the risk of cardiac rejection without increasing the incidence of infection.     

Adult heart transplantation under tacrolimus (FK506) immunosuppression: histopathologic observations and comparison to a cyclosporine-based regimen with lympholytic (ATG) induction

BACKGROUND: Tacrolimus (FK506) is an effective immunosuppressant for human heart transplantation, but information about its effects on cardiac allograft and nonallograft kidney and liver histopathologic study is limited. METHODS: We therefore reviewed 1145 endomyocardial biopsy specimens and eight autopsy results from 80 heart transplant recipients who received tacrolimus as baseline immunosuppression. These were compared with 619 endomyocardial biopsy specimens and four autopsy results from 51 patients treated with cyclosporine-based immunosuppression with lympholytic induction (CLI) by use of rabbit anti-thymocyte globulin. Twenty-one histologic features including the International Society for Heart and Lung Transplantation histopathologic grade were retrospectively assessed without knowledge of the treatment regimen. The lymphocyte growth index on biopsy specimens obtained from these patients was also compared. RESULTS: In general, there were no qualitative differences in the histopathologic appearance of various allograft syndromes between tacrolimus- and CLI-treated patients. Thus histopathologic criteria used to diagnose various graft syndromes are applicable under tacrolimus immunosuppression. However, early (between 10 and 30 days) after transplantation, biopsy specimens from patients treated with tacrolimus showed a significantly higher percentage of inflamed fragments (p = 0.02), the inflammation tended to be more severe (p = 0.09), and the rejection grade tended to be slightly higher (p = 0.08). In contrast, during the late transplantation period (275 to 548 days), biopsy specimens from patients treated with CLI showed a significantly higher percentage of inflamed fragments (p = 0.03), more severe inflammation (p = 0.03), higher rejection grades (p = 0.01), and a higher frequency of Quilty lesions (p = 0.05). Although overall freedom from any grade 3A or higher rejection was greater in the CLI-treated arm, tacrolimus was successfully used to treat refractory rejection in three patients from the CLI-treated arm. Concern has been raised in the literature about the possibility of tacrolimus being a direct hepatotoxin and an accelerant of allograft obliterative arteriopathy. However, no evidence to support either of these contentions was detected in this patient population. In contrast, tacrolimus is clearly nephrotoxic, although similar to cyclosporine in this regard. CONCLUSIONS: Tacrolimus is an effective immunosuppressive drug for heart transplantation. The cardiac allograft histopathologic study of patients treated with tacrolimus immunosuppression does not significantly differ from those given conventional, cyclosporine-based triple therapy with lympholytic induction.     

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.     

Nomenclature and classification of the rheumatic diseases

BACKGROUND: A pilot study was performed to prospectively evaluate the safety and efficacy of "low-dose" OKT3 induction after liver transplantation. METHODS: Sixteen patients received a 5- to 10-day course of OKT3 (2.5 mg i.v. daily) along with azathioprine, prednisone, and the delayed introduction of cyclosporine (Neoral). RESULTS: Patient and graft survival rates at 1 year were 88% and 82%. Five patients (31%) had biopsy-proven rejection; all five were treated successfully with steroids. There were 15 infections in 12 patients, including 5 cytomegalovirus infections. Adverse events attributed to OKT3 consisted of low-grade fever (five patients), transient hypoxemia (three patients), and transient hypotension (two patients). Pharmacy acquisition costs for OKT3 averaged $2,139 less as compared to a group of historical controls receiving full-dose therapy. CONCLUSIONS: Low-dose OKT3 induction appears to be a safe and useful method of postoperative immunosuppression after liver transplantation. Its ultimate clinical, immunologic, and economic efficacy awaits determination by randomized trial.     

Heart transplantation in patients with treated breast carcinoma

Since 1987, five women with end-stage cardiomyopathy and a history of treated breast carcinoma have undergone transplantation at our institution. All patients underwent extensive multidisciplinary pretransplantation evaluation to rule out metastatic disease. Disease-free interval before heart transplantation ranged from 5 to 11 years (mean, 7.6 years). All patients received immunosuppression in accordance with a standard protocol of rabbit antithymocyte globulin, cyclosporine, prednisone, and azathioprine. Mean postoperative follow-up is 49 months. All patients are alive and have no symptoms 18 to 73 months after transplantation. In carefully selected patients with a history of breast carcinoma, heart transplantation can be performed with good functional results and satisfactory late survival.     

Low level of interleukin 10 synthesis during liver allograft rejection

Interleukin 10 (IL-10) is a macrophage and T-cell-derived cytokine with potent immunosuppressive properties. To assess its role in liver allograft rejection, we evaluated the plasma level and in situ production of IL-10 after liver transplantation and designed in vitro studies to asses the effects of IL-10 on the allogeneic response. Normal controls and liver transplant recipients with acute rejection, chronic rejection, other complications (recurrent hepatitis C, biliary complications), or no complications were evaluated. The plasma IL-10 level was measured by an immunoenzymatic technique. IL-10 expression in the liver was detected on frozen liver biopsies by in situ hybridization and immunohistochemistry. Plasma IL-10 levels were not elevated during acute or chronic rejection, when compared with liver recipients with uncomplicated transplants. IL-10 mRNA and protein expressions in the liver graft were restricted to rare scattered sinusoidal cells of transplant recipients with acute or chronic rejection, as well as in those with no complications. In mixed lymphocyte cultures performed with peripheral blood mononuclear cells (PBMC) from normal subjects, IL-10 decreased the cell proliferation in a dose-dependent manner, and this immunosuppression was synergistic with that of cyclosporine or FK506. These findings indicate that IL-10 production is low during allograft rejection. Thus, IL-10 therapy in association with cyclosporine or FK506 might be proposed after liver transplantation.     

Heart transplantation in children and young adults: early and intermediate-term results

The purpose of this article is to report our short- and intermediate-term follow-up of cardiac transplantation for congenital heart disease and cardiomyopathy in children (age greater than 6 months), adolescents, and young adults. Thirty patients (ages 8 months to 24 years) with end-stage heart failure have undergone cardiac transplantation in our program: 12 (40%) for postoperative end-stage heart failure, 9 (30%) as primary treatment for congenital heart disease, 5 (17%) for dilated cardiomyopathy, and 4 (13%) for restrictive/hypertrophic cardiomyopathy. Nineteen patients (63%) had undergone prior operations; 4 patients received transplants for failed Fontan procedures. Induction therapy with antithymocyte therapy was used routinely, and long-term immunosuppression was by cyclosporine and azathioprine alone. Rejection surveillance/diagnosis was based on echocardiographic criteria. Posttransplantation follow-up ranges from 3 to 78 months. Operative mortality was 3.3% (1/30). No patients have been diagnosed with either accelerated allograft atherosclerosis or posttransplantation lymphoproliferative disease. We conclude that cardiac transplantation may be performed with excellent early and intermediate-term results.