The new chimaera: the industrialization of organ transplantation. International Forum for Transplant Ethics.

Clinical organ transplantation has evolved through advances in patient care in parallel with investigations in associated biologies. It has developed from a cottage industry to an important medical specialty driven increasingly by the availability of newer and more effective immunosuppressive drugs, and dependent on consistently close collaborations between university-based clinical scientists and the pharmaceutical industry. Particularly during the past decade, however, this industry has undergone striking changes, consolidating into huge multi-national corporations, each competing for patients, their doctors, and for support of the allied hospitals. Because of the growth of "Big Pharma," the relationship between academia and industry has changed. There have been many advantages to such mutually dependent interactions. A combination of university-based expertise and the specialized knowledge and resources of industry have produced important scientific gains in drug development. Commercial sponsorship of applied research has been crucial. The orchestration of multicenter controlled clinical drug trials has provided invaluable information about the effectiveness of newer agents. But there are also disadvantages of increasing concern. Indeed, the power of "Big Pharma" in many medical fields including transplantation is such that presentation of data can be delayed, adverse results withheld, and individual investigations hampered. Clinical trials may be protracted to stifle competition. Monetary considerations may transcend common sense. Several measures to enhance the clinical relationship between the pharmaceutical industry and those involved with organ transplantation are suggested, particularly the use of third party advisors in the production of clinical trials, support for more basic research and in the dissemination of results. In this way, the increasingly problematic phenomenon of commercialization of the field of transplantation can be tempered and controlled.

Definitions of acute rejection and controlled clinical trials in the medical literature.

Definitions of acute rejection for clinical trial use would allow for standardized comparison of outcomes. The medical literature reporting trial results was searched to record definitions used in controlled trials. Over 6,000 refereed transplantation articles were searched for the following keywords: randomized controlled trials, multicenter studies, clinical trials, phase III, and immunosuppressive agents. Only three references resulted. Another pass through the literature resulted in 11 prospective studies on induction therapy and two prospective antirejection therapy studies that met the criteria for the search. Retrospective studies appearing in the literature search were two induction citations and seven antirejection therapy reports. Rejection criteria ranged from having been given no definition in both outcomes of induction trials as well as reports on antirejection therapy to having a large-scale list of criteria not all of which had to be met by every rejection case in a given study to be termed rejection. The transplant literature that was reviewed frequently provided only vague descriptions of the methodologies used to diagnose rejection and rejection reversal. The Efficacy Endpoints Conference on Kidney Transplant Rejection was formulated to review kidney transplant rejection using a database of consecutive rejection episodes. An attempt to derive definitions for clinical trial endpoints in kidney transplant rejections was planned for the conference because of a lack of continuity in the transplant literature.

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.

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.

Pharmacokinetics, foreign protein immune response, cytokine release, and lymphocyte subsets in patients receiving thymoglobuline and immunosuppression.

The pharmacokinetics and immune response to the rabbit IgG of rabbit antihuman thymocyte globulin, Thymoglobuline has been characterized. A cytokine release pattern of TNF alpha and IL-6 but not IL-1 beta and IFN chi has been demonstrated with the first and not subsequent doses. An effect on lymphocyte depletion of peripheral blood with major subset suppression has been shown to last more than the 3-month observation period in patients on a regimen of quadruple sequential immunosuppression.

Sequential biological immunosuppression. Induction therapy with rabbit antithymocyte globulin.

This paper describes 108 consecutively treated patients receiving 109 cadaveric (CD) and living donor (LD) renal allografts using a protocol of quadruple sequential immunosuppression with a rabbit anti-human thymocyte IgG (Thymoglobuline), azathioprine, tapering corticosteroids, and delayed introduction of cyclosporine A. The average length of induction was 6.1 d with an average Thymoglobuline dose of 2.0 mg/kg/d. The mean serum creatinine pre-transplant of the cohort was 877 +/- 263 (sd) mumol/L, 146 +/- 44 mumol/L by 3 months post-transplant, and 136 +/- 40 mumol/L at 1 yr. The overall 4-yr actuarial patient survival was 96.6%, and allograft survival was 88.6% at 2 yr and 83.6% at 4 yr. The incidence of acute rejection episodes defined by intention to treat was 32%. Additionally, eight patients in this series received retreatment with Thymoglobuline for a first acute rejection, and only one of these had a second rejection. This was in contrast to 5/11 recurrent rejections following steroid treatment only, and 5/13 recurrences following OKT3 treatment for the first rejection episode. The side-effect profile of Thymoglobuline was largely benign, and the biological agent was well tolerated with initial fever in 75%, chills in 27%, and leucopenia in 22% of the patients. All other drug-related adverse events had a prevalence of less than 3%, and clinical signs of meningismus were seen in only one patient. There were five associated episodes of CMV. We conclude that Thymoglobuline as part of a quadruple sequential immunosuppressive regimen for renal transplantation is well tolerated and can be associated with a good short- and long-term outcome of renal transplantation.

The pathophysiology of chronic rejection.

The understanding of chronic rejection has been greatly enhanced by the use of genetically controlled experimental models using inbred rats. Models that express all lesions encountered in human transplants are described. Findings of chronic rejection depend on genetic disparity, strength of the immunologic reaction, response to injury, and perpetuation of an ischemic state. Lesions of vasculopathy and parenchymal cell damage may proceed at different rates, but the vasculopathy seems reversible until healing occurs. The experimental models that have led us to significant understanding are described herein.

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.

Irreversible chronic vascular rejection occurs only after development of advanced allograft vasculopathy: a comparative study of a rat cardiac allograft model using a retransplantation protocol.

Indefinitely surviving WF.1L (RT1(1)) cardiac allografts transplanted to LEW (RT1(1)) recipients provide an ideal model for controlled comparative studies of chronic vascular rejection (CVR). To determine the stage of development at which the progressive CVR can be reversed when deprived of an ongoing recipient alloimmune response, WF.1L-LEW cardiac allografts were retransplanted back into syngeneic donor strain WF.1L recipients at specific time periods after initial allogeneic engraftment and were maintained in WF.1L syngeneic hosts for a further 40 days. The vascular changes in the retransplanted allografts were compared with those of nonretransplanted allografts and with nonretransplanted and retransplanted LEW-LEW isografts examined at similar time periods. The early vasculopathic inflammatory changes were consistently reversed by retransplantation of the cardiac allografts back into syngeneic recipients after 20 days and 40 days of allotransplantation. Syngeneic retransplantation of the cardiac allografts at 60 days after allotransplantation did not reverse the essentially nonvasculitic occlusive vasculopathy invariably present in WF.1L-LEW cardiac allografts at this time period. Thus, the vasculitic and minimal subocclusive myointimal changes associated with early CVR in this model are alloantigen dependent and reversible. Irreversible CVR occurs only after advanced proliferative vasculopathy has been established in the allogeneic host.