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T J Schroeder

Publications and source records attributed to T J Schroeder.

At least 19 recordsLinked to original sources
PubMed1998

Results of the double-blind, randomized, multicenter, phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.

BACKGROUND: Thymoglobulin, a rabbit anti-human thymocyte globulin, was compared with Atgam, a horse anti-human thymocyte globulin for the treatment of acute rejection after renal transplantation. METHODS: A multicenter, double-blind, randomized trial with enrollment stratification based on standardized histology (Banff grading) was conducted. Subjects received 7-14 days of Thymoglobulin (1.5 mg/kg/ day) or Atgam (15 mg/kg/day). The primary end point was rejection reversal (return of serum creatinine level to or below the day 0 baseline value). RESULTS: A total of 163 patients were enrolled at 25 transplant centers in the United States. No differences in demographics or transplant characteristics were noted. Intent-to-treat analysis demonstrated that Thymoglobulin had a higher rejection reversal rate than Atgam (88% versus 76%, P=0.027, primary end point). Day 30 graft survival rates (Thymoglobulin 94% and Atgam 90%, P=0.17), day 30 serum creatinine levels as a percentage of baseline (Thymoglobulin 72% and Atgam 80%; P=0.43), and improvement in posttreatment biopsy results (Thymoglobulin 65% and Atgam 50%; P=0.15) were not statistically different. T-cell depletion was maintained more effectively with Thymoglobulin than Atgam both at the end of therapy (P=0.001) and at day 30 (P=0.016). Recurrent rejection, at 90 days after therapy, occurred less frequently with Thymoglobulin (17%) versus Atgam (36%) (P=0.011). A similar incidence of adverse events, post-therapy infections, and 1-year patient and graft survival rates were observed with both treatments. CONCLUSIONS: Thymoglobulin was found to be superior to Atgam in reversing acute rejection and preventing recurrent rejection after therapy in renal transplant recipients.

Acute Disease↗
PubMed1998

Utility of standardized histological classification in the management of acute rejection. 1995 Efficacy Endpoints Conference.

BACKGROUND: Standardized histological grading of transplant kidney biopsies has become a primary criterion for diagnosis of rejection in immunosuppression clinical trials. METHODS: A consortium of 19 transplant centers from North America, Europe, and Australia convened in 1995 to examine kidney transplant rejection. Data from the 1995 Efficacy Endpoints Conference were examined for frequency of adoption of Banff schema. Biopsy grading was correlated with clinical parameters of rejection and therapy response. RESULTS: Histological confirmation of rejection episodes occurred in 73% of 953 cases, with Banff criteria adoption increasing in frequency between 1992 and 1995. Banff grading significantly correlated with clinical rejection severity (rejection creatinine: grade I, 2.8+/-0.2 mg/dl; grade II, 3.5+/-0.2 mg/dl; grade III, 4.1+/-0.3 mg/dl; P < 0.001), although nadir creatinines were similar. Response rates of Banff grades I and II to steroid therapy were not different, but only 42% of grade III rejections responded to steroids (P < 0.003. Banff grading also correlated with postrejection creatinine, day 15: grade I, 2.2+/-0.2 mg/dl; grade II, 3.0+/-0.2 mg/dl; grade III, 3.8+/-0.4 mg/dl (P < 0.001), and day 30: grade I, 2.1+/-0.1 mg/dl; grade II, 2.2+/-0.2 mg/dl; grade III, 2.7+/-0.2 mg/dl (P < 0.06). Banff grade III correlated with reduced graft survival at 1 year: grade I, 86%; grade II, 88%; grade III, 70% (P < 0.01). CONCLUSIONS: This multicenter review of rejection severity confirms that standardized histologic classifications such as the Banff schema provide a reliable means for stratifying patient risk of treatment success or failure. These data support the use of Banff criteria in clinical trial design.

Acute Disease↗
PubMed1998

Efficacy Endpoints Conference on Acute Rejection in Kidney Transplantation: summary report of the database.

An international database of rejection episodes and their characteristics with regard to definition and follow-up parameters was developed to improve the approach to protocol development for clinical trials. Nineteen North American, European, and Australian centers uniformly reported on 50 consecutive transplant rejection episodes. Data collected included patient demographic parameters, induction and maintenance immunosuppression therapies, rejection agents (drug, dose, duration), clinical signs (50% decrease in urine, fever), serum creatinine (nadir, at rejection, daily during antirejection therapy to 15 days, and days 30, 90, 180, and 365 after rejection date), histopathological findings, morbidity, recurrence of rejection, and function at 1 year. The centers contributed a total of 953 presumed rejection episodes, of which 842 were confirmed as acute rejection episodes. The majority of cases were first rejections (81%), and rejection occurred 119 +/- 345 days following transplantation. The Banff Schema of histological grading was used in 38% of biopsy-proven rejection episodes (2% Borderline, 42% Grade I, 38% Grade II, 18% Grade III). Only 30% of all rejections showed clinical signs that were most likely to occur in Grade III rejection episodes (P < 0.006). The serum creatinine response was well below the rejection creatinine level by day 15 following initiation of antirejection therapy in the majority of cases. A significant number of the cases (34%) reported in this database experienced a recurrent rejection approximately 85 days following the first rejection. Graft survival 1 year following the rejection episode was good (83%). These findings will facilitate development of clinical trial design and beneficially impact approaches to antirejection therapies for kidney allograft recipients.

Acute Disease↗
PubMed1998

Proposed consensus for definitions and endpoints for clinical trials of acute kidney transplant rejection.

Progress in transplantation therapeutics requires validation from multicenter trials in which enrollment criteria and endpoint definitions have been standardized. A database of acute rejection was established from 19 North American, European, and Australian transplant centers and included parameters on rejection diagnosis and treatment of 50 consecutive rejection episodes from each center. Patient demographics, induction and maintenance immunosuppressive therapies, antirejection agents (drug, dose, duration), clinical signs (decrease in urine volume, presence of fever of > or =38.5 degrees C), serum creatinine concentration (nadir, at rejection, daily during antirejection therapy to 15 days, and days 30, 90, 180, and 365 after rejection date), rejection biopsy findings, morbidity, recurrence of rejection, and renal function at 1 year were recorded for 953 rejection episodes. From these data, three definitions were proposed. Acute rejection was defined as an immunologic process resulting in a serum creatinine increase of > or =0.4 mg/dL, with or without clinical signs, and should include a biopsy confirmation that has been standardized to the Banff criteria. Corticosteroid-resistant rejection was defined as a rejection episode in which a minimum of 250 to 1000 mg of methylprednisolone administered as initial therapy fails to result in stabilization or reduction of the serum creatinine after 3 days of corticosteroid treatment. Successful response to therapy was defined as a serum creatinine level < or =110% of the serum creatinine on the day of the rejection diagnosis and a return of the serum creatinine to or below the rejection creatinine level by 5 days of therapy with maintenance of this response for a minimum of 30 days. The work represented in the Efficacy Endpoints Database provides a step toward improving definitions in clinical trials. Continuity in clinical trial design should lead to improvements in evaluation of outcomes and, thereby have an effect on clinical practice.

Acute Disease↗
PubMed1998

Observations on recovery of renal function following treatment for acute rejection.

The characteristics of rejection and rejection response have not been systematically described in renal transplant recipients. The Efficacy Endpoints Conference Database contains characteristics from 953 episodes of rejection occurring at 19 North American, European, and Australian transplant centers. This database was used to profile renal transplant rejection episodes treated with primary steroid therapy, primary antilymphocyte antibody therapy, and rescue antilymphocyte antibody therapy. Primary steroid therapy was used in 88% of the rejection episodes. A successful response was more common in recipients without fever (72% v 61%; P < 0.004), in recipients experiencing less than a Banff Grade III rejection (92% v 75%; P = 0.009), and was more likely associated with graft function at 1 year following the rejection than rejection episodes that failed steroid therapy (89% v 82%; P = 0.013). Steroid success was statistically identifiable by day 2 of therapy and clinically useful by day 3; serum creatinine on these days of therapy is shown as a ratio of the rejection creatinine (102% v 112% day 1, success v failure, P< 0.002; 104% v122% day 2, success v failure, P < 0.0001; 105% v125% day 3, success vfailure, P < 0.0001). Response to primary antilymphocyte antibody therapy reached significance at day 5 of therapy when serum creatinine decreased below the rejection creatinine level in antilymphocyte successes but remained at or above the rejection creatinine in those who failed the therapy (90% v 135%; P < 0.01). For rescue antilymphocyte antibody therapy, a response was evident after 5 days of therapy (approximately day 9 to 10 of rejection) when serum creatinine began to decline and continued lower throughout the 10-day course of antilymphocyte antibody therapy (day 14 to 15 of rejection; serum creatinine 3.0 mg/dL v 4.4 mg/dL for success v failure; P < 0.004). Serum creatinine was lower throughout the first year following therapy in each success group (steroids, antilymphocyte antibody therapy as primary or as rescue), and a greater percentage of failures of any of the three therapies resulted in graft loss. Interestingly, 1-year graft survival was not different in the patients who were treated with antilymphocyte antibody therapy as primary than those who received these antirejection agents as rescue therapy (81% and 84%, respectively). The Efficacy Endpoints Conference Database provides an essential tool for profiling acute rejection in renal transplantation and should lead to improved evaluation of rejection therapies.

Acute Disease↗
PubMed1997

Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection.

BACKGROUND: OKT3 is often used as primary treatment for acute renal allograft rejection. In a retrospective study, we sought to determine the efficacy of OKT3 as a first-line agent in reversing histologically confirmed acute renal allograft rejection. METHODS: Patients with mild to moderate, moderate, or severe acute cellular and acute vascular rejection who had not received any other anti-rejection treatment were included in this analysis. A total of 88 patients, who received OKT3 between 1987 and 1995, fulfilled these criteria. RESULT: Seventy of these patients were renal transplant recipients, and 18 were combined kidney and pancreas transplant recipients. The median time to the diagnosis of rejection from transplantation was 32 days (range, 6 days to 13 years). On histology, 6 were graded as mild to moderate, 36 as moderate, 29 as moderate to severe, and 17 as severe rejection. The mean baseline serum creatinine was 1.62 mg/dl (range, 0.7-10.1 mg/dl), and the mean serum creatinine at the time of diagnosis of rejection was 2.60 mg/dl (range, 1.4-12.7 mg/dl) (P=<0.0001). The mean duration of OKT3 treatment was 11.2 days (range, 8-18 days). The mean serum creatinine at the end of OKT3 treatment was 1.73 mg/dl (range, 0.6-5.0 mg/dl; P=0.24 compared with baseline serum creatinine). Rejection was reversed in 86 (98%) patients. Graft survival at 1 year after OKT3 therapy was 87.5% (77 of 88). At a mean follow-up of 38 months, 8 patients had died and 26 grafts were lost. The mean serum creatinine level in the 64 patients with a functioning graft was 1.76 mg/dl (range, 0.8-4.0 mg/dl) at the last follow-up. CONCLUSION: OKT3 when utilized as first-line therapy reversed 98% of the acute rejection episodes, with a 1-year post-OKT3 graft survival of 87.5%.

Acute Disease↗
PubMed1997

Are surveillance endomyocardial biopsies necessary during OKT3 induction therapy?

BACKGROUND: To determine the utility of surveillance endomyocardial biopsies (EMBs) during a 14-day OKT3 induction course after cardiac transplantation, histologic results of the first two EMBs were retrospectively reviewed. METHODS: Seventy-three consecutive cardiac transplant recipients who received an OKT3-based quadruple sequential immunosuppressive protocol were analyzed. Patients were predominantly white (85%) and male (72%), with ischemic cardiomyopathy (54%) and a pretransplant panel-reactive antibody level of <10% (93%). RESULTS: The first EMB in 73 patients demonstrated no rejection in 70 patients (96%) and grade 1A rejection in 3 patients (4%). The second EMB showed no rejection in 64 patients (88%), grade 1A or 1B rejection in 8 patients (11%), and grade 3A rejection without hemodynamic compromise in only 1 patient (1%). Absolute CD3+ cells remained below 25 lymphocytes/mm3, and mean trough OKT3 serum levels exceeded 500 ng/ml throughout the 14 days of therapy, demonstrating the immunosuppressive efficacy of OKT3. Posttransplant echocardiograms showed normal left ventricular systolic function. CONCLUSIONS: Since 145 of 146 EMBs (99%) demonstrated no or minimal allograft rejection, a large cost savings could be realized if EMBs were performed only when clinically indicated during the 14-day OKT3 induction course in cardiac transplant recipients. Appropriate immunologic monitoring and echocardiographic testing may obviate the need for performing costly EMBs during OKT3 induction without an adverse clinical outcome.

Adolescent↗
PubMed1997

Characterization of anti-thymoglobulin, anti-Atgam and anti-OKT3 IgG antibodies in human serum with an 11-min ELISA.

Patients treated with OKT3 may become resistant to OKT3 therapy following induction of anti-idiotypic antibodies. Antirabbit or antihorse antibodies following Thymoglobulin (rabbit antithymocyte globulin (ATG) or Atgam (horse ATG) therapy may not similarly inhibit drug efficacy due to an insufficient anti-idiotypic response against the multiple idiotypic specificities of the polyclonal anti-T cell preparations. However, no standardized assay had been developed to monitor antihorse and antirabbit antibodies. To address this issue, we developed three rapid (11-min) and standardized semiquantitative plate enzyme-linked immunoassays (ELISAs) to monitor human serum immunoglobulin-G (IgG) antibodies to Orthoclone OKT3 IgG2a, Atgam and Thymoglobulin. The format was identical for the three assays, with the exception of the immunoglobulin antigen coated on the ELISA plates. As OKT3 is a monoclonal antibody, OKT3 itself is used as the capture antigen. However, for antibody responses against the polyclonal antibody preparations Atgam and Thymoglobulin, it was found that horse IgG and rabbit IgG respectively were equivalent to Atgam and Thymoglobulin as capture antigens. Excellent correlation with a 3.5-h format was demonstrated (r values between 0.986 and 0.845). Specificity was demonstrated by inhibition experiments. Correlations between endpoint titres calculated from serial dilutions and 1:50 dilution OD values were 0.821, 0.983 and 0.937 respectively for the mouse, horse and rabbit assay. High titre sera were selected to assess their ability to block in vitro the binding of OKT3, Thymoglobulin and Atgam to T cells, using flow cytometry. None of the sera containing antihorse (n = 9) or antirabbit (n = 8) antibodies blocked T cell binding of Atgam or Thymoglobulin. In contrast, OKT3 binding was blocked by the four highest titre sera of the 13 anti-OKT3 sera tested. Consequently, prospective monitoring of treated patients using standardized 11-min assays may allow a better assessment of the effect of presensitization to OKT3, Atgam or Thymoglobulin.

Animals↗
PubMed1997

Impact of ganciclovir prophylaxis on cytomegalovirus infection in recipients of cadaveric renal allografts.

Cytomegalovirus (CMV) infection is a major cause of morbidity and occasionally of mortality in immunosuppressed allograft recipients. At the University of Cincinnati Medical Center, ganciclovir has been administered for the prevention of CMV infection since July 1992. Forty-six recipients of cadaveric renal allografts (Group I) received ganciclovir at a dose of 2.5 or 5 mg/kg/day (adjusted for renal function) for 14-21 days, during induction treatment and during antirejection treatment with monoclonal or polyclonal antilymphocyte preparations. In this retrospective study, these 46 patients were compared with 77 recipients of cadaveric renal allografts transplanted prior to July 1992 (Group II) for the prevalence, severity and time of CMV occurrence after transplantation. CMV diagnosis was based on clinical evaluation and was confirmed by blood cultures, CMV antigen immunofluorescence assay and/or histology. Patients were stratified according to CMV serology (+) or (-) in donor and recipient. CMV infection developed in 16 of 46 (35%) patients in Group I vs. 27 of 77 (35%) patients in Group II (p = 0.97). A total of 25 episodes of CMV infection occurred in Group I compared to 44 in Group II (p = 0.76). CMV infection was diagnosed an average of 97.4 days after transplant in Group I compared to 48.3 days in Group II (p = 0.0003). Tissue-invasive CMV infection occurred in 3 patients in Group I (19%) vs. 12 in Group II (44%) (p = 0.5). In conclusion, ganciclovir prophylaxis resulted in a delayed onset of clinical CMV infection with a trend towards less severe infection in patients treated with antilymphocyte antibody preparations.

Adult↗
PubMed1997

Causes of renal allograft loss in black vs. white transplant recipients in the cyclosporine era.

Black renal transplant recipients have a higher rate of allograft loss than white recipients. From 1 January 1984 to 1 January 1995, 463 transplants were performed at a single center and followed for a mean duration of 71 months. The causes of graft loss for white and black recipients, their age, gender, retransplantation rate, organ source, and HLA matching were compared. In the 150 black and 313 white recipients, graft loss rates in the first year were 20% in both groups, while after 1 yr there were 42 (28%) graft losses in blacks vs. 62 (20%) in whites (log-rank test p = 0.04). All diagnoses deemed causative of allograft loss were confirmed by biopsy. Chronic rejection resulting in graft loss occurred in 15% (n = 23) of black recipients compared to only 7% (n = 22) of white recipients (p = 0.002). There were no significant differences in the rate of death with a functioning kidney or other causes of graft loss between the two groups. A significant increase in HLA mismatches was noted in black recipients of cadaveric grafts compared to whites, but there was no difference between races in the rate of graft loss due to acute rejection. While the rate of graft survival remains lower in black recipients in the cyclosporine era, this is due entirely to late graft loss after 1-yr post-transplant due to chronic rejection.

Acute Disease↗