Background. The safety, tolerability, and pharmacokinetics of conventional cyclosporine (ConCsA) and cyclosporine microemulsion (MeCsA) were compared under conditions of normal clinical practice in a prospective, randomized, concentration-controlled, pharmacoepidemiologic study. Methods. Between September 1994 and March 1995, 1097 stable renal transplant recipients in 14 Canadian centers were randomized 2:1 to treatment with MeCsA or ConCsA. Patients were commenced on each study drug at a dose equal to their previous therapy with ConCsA, and the dose was adjusted to maintain predose whole blood cyclosporine concentrations within the therapeutic range established for each center. Prednisone and azathioprine were continued unless dose adjustment was required for clinical reasons. Results. The mean cyclosporine concentration was comparable in both treatment groups at all time points throughout the 6 months of follow-up. The mean dose of cyclosporine was 3.6 mg/kg/day in both treatment groups at entry to the study, and declined by 0.3% and by 2.8% in patients receiving ConCsA and MeCsA, respectively. The nature and severity of adverse events were similar in both treatment groups, but there was a transient increase in neurological and gastrointestinal complications in the group receiving MeCsA within the first month after conversion (P<0.05). Serum creatinine and creatinine clearance did not change in either treatment group throughout the study. Biopsy-proven acute rejection occurred in three patients (0.8%) receiving ConCsA and in seven patients (0.9%) receiving MeCsA, with non-histologically proven acute rejection in an additional three patients(0.8%) receiving ConCsA and five patients (0.6%) receiving MeCsA(P=NS). Serum creatinine rose transiently in 35 patients(9.8%) receiving ConCsA and 138 patients (18.7%) receiving MeCsA(P<0.05) and resolved either spontaneously or after a reduction in the cyclosporine dose. One graft was lost in the MeCsA group due to irreversible rejection, and seven patients died, three in the group receiving ConCsA and four of those receiving MeCsA(P=NS). Absorption of cyclosporine was more rapid and complete from MeCsA than from ConCsA during the first 4 hr of the dosing interval, resulting in almost 40% greater exposure to the drug(P<0.001). There was close correlation between area under the time-concentration curve (AUC) over the first 4 hr of the 12-hr dosage interval and AUC over the entire 12-hr dosage interval for both formulations, making AUC over the first 4 hr a good predictor of total cyclosporine exposure. Using this parameter, patients with low absorption randomized to receive MeCsA showed a marked increase in drug exposure by months 3 and 6, whereas there was no change in those who continued on ConCsA. A limited sampling strategy utilizing samples at the predose and postdose trough levels provided an excellent correlation with drug exposure, particularly for patients receiving MeCsA (r2=0.94 MeCsA vs. r2=0.89 ConCsA). Conclusions. MeCsA appears to be a safe and effective therapy in stable renal transplant patients and provides superior and more consistent absorption of cyclosporine when compared with ConCsA. Transient toxicity after conversion to MeCsA occurs in some patients, and may reflect the increased exposure to cyclosporine. Use of a limited sampling approach combining trough and 2-hr postdose concentrations may provide an effective way to monitor this exposure.

Tolerability

Single Center

Ciclosporin

10.1097/00007890-199612270-00009

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Citations (210)

Immunosuppressive Agents Used in Transplantation

Elsevier eBooks (2007)

Gunilla Einecke Anette Melk Philip F. Halloran

10.1016/b978-0-323-04602-2.50093-x

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Continuous indices to assess the phenotypic spectrum of kidney transplant rejection

medRxiv (Cold Spring Harbor Laboratory) (2024)

Thibaut Vaulet Priyanka Joseph Koshi Karolien Wellekens Olivier Aubert Cecilia Bottomley

The international Banff classification for kidney transplant pathology discretizes the rejection continuum into distinct diagnostic categories, introducing artificial dichotomization and threshold effects. To better reflect the underlying disease spectrum, we developed, in this cohort study, two novel indices for quantifying antibody-mediated (AMR) and T-cell mediated rejection (TCMR) from histological lesion scores, and calculated indices for overall activity and chronicity. These indices were evaluated in one derivation cohort and two independent validation cohorts, totaling 19,500 biopsies from 8,873 kidney transplant patients across 10 centers worldwide. The AMR, TCMR, and activity indices demonstrated hierarchical ordering between No rejection, intermediate and complete rejection histology. The chronicity index showed limited association with the major diagnostic categories. In the derivation cohort, the AMR and TCMR indices discriminated AMR from absence of AMR, and TCMR from absence of TCMR, with an AUC of 0.98 (95% confidence interval 0.97 to 0.98) and 0.99 (0.99 to 1.00) respectively). This excellent discrimination was confirmed in the validation cohorts. Those indices strictly confined intermediate phenotypes to a range of low index values and related to graft failure rates even within the diagnostic categories, thus reflecting the underlying rejection continuum. The four continuous indices offer an implementable and interpretable global evaluation of kidney transplant biopsy histology while eliminating the need for intermediate diagnostic categories and enable more probabilistic reasoning in the diagnostic approach to the spectrum of kidney transplant rejection.

10.1101/2024.12.10.24318058

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Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR)

American Journal of Transplantation (2018)

Antoine Roux Deborah J. Levine Adriana Zeevi Ramsey R. Hachem K. Halloran

The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejection (AMR) in lung transplantation. Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research. The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report. The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regarding pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

10.1111/ajt.14990

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The Nature of Biopsies with “Borderline Rejection” and Prospects for Eliminating This Category

American Journal of Transplantation (2011)

D.G. de Freitas Jacobo Sellarés Michael Mengel J. Chang Luis Hidalgo

Histopathology

10.1111/j.1600-6143.2011.03784.x

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Citations (102)

RANDOMIZED TRIAL OF TACROLIMUS (PROGRAF) IN COMBINATION WITH AZATHIOPRINE OR MYCHOPHENOLATE MOFETIL VERSUS CYCLOSPORINE (NEORAL) WITH MYCOPHENOLATE MOFETIL AFTER CADAVERIC KIDNEY TRANSPLANTATION1, 2

Transplantation (2000)

Christopher P. Johnson Nasimul Ahsan Thomas A. Gonwa Philip F. Halloran Mark D. Stegall

Background. Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. Methods. A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. Results. There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. Conclusions. All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

Regimen

Ciclosporin

10.1097/00007890-200003150-00028

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Citations (292)

Commemorating the 10th anniversary of the launch of the AJT project

American Journal of Transplantation (2010)

Philip F. Halloran

This issue celebrates the 10th year of the American Journal of Transplantation. The project was formally launched in the spring of 2000, with a call for papers in September 2000 and the first issue publishing in May 2001. The editors decided to commemorate our 10th anniversary with some special articles. These include the following: Evolving paradigms that determine the fate of an allograft (Bromberg et al.). T-cell-mediated rejection of kidney transplants: A personal viewpoint (Halloran). Phenotypic expression of recurrent disease after liver transplantation (O’Grady). Donor intervention and organ preservation: Where is the science and what are the obstacles (Feng). The elephant in the room: Failings of current clinical endpoints in kidney transplantation (Kaplan & Schold). Recent progress and new perspectives in studying T cell responses to allografts (Fairchild et al.). Antibody mediated rejection: Emergence of animal models to answer clinical questions (Fairchild et al.). Moreover, it gives us an opportunity to reflect on the AJT project. The proposal was to establish a new journal as a forum for publishing significant advances in transplantation and encouraging dialog on the issues. The concept was that the American Society of Transplantation and the American Society of Transplant Surgeons should, like any professional societies, publish a journal that would advance their field and also generate revenues for their good works. The societies asked me to undertake this for the first term and later, to continue for a second term. I chose a three-level editorial board: Editor-in-Chief, deputy editors and associate editors. These people have created AJT. The three levels reflect the diversity of activity in the field of transplantation—organs, sciences, disciplines—which is greater than in most fields of medicine. From the outset, the AJT was committed to being an international journal with editorial representation from major centers around the world. With these editors AJT has achieved a number of milestones. For example, we were recognized in 2005 in ISI Essential Science Indicators Web product as achieving the highest percentage increase in total citations in the field of Clinical Medicine for the selected period. AJT receives over 1600 new submissions per year, making the editorial processes challenging. We have maintained short decision times and kept our average decision turnaround to approximately 20 days. In addition, we have set our goals at an acceptance rate in the range of approximately 25%, not letting the acceptance rate fall too low. This is because we want submitting authors to have a reasonable chance of success and to publish material that has some risk and novelty. We feel these parameters give us the best opportunity to represent the creative efforts of our transplant community, on behalf of the patients whom we serve. The mandate of AJT is unfinished—a work in progress. The new stewardship of Dr Allan Kirk as Editor-in-Chief in the fall of 2010 offers exciting new possibilities. We have been fortunate in securing a clinician-scientist of Allan's stature, as well as the ongoing commitment of the American societies to the AJT vision. We hope that the AJT will continue to serve our readers, help them serve their patients and advance the field to which we are committed. If so, this celebration of the 10th volume of AJT is just the beginning.

Publication

10.1111/j.1600-6143.2010.03121.x

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Citations (3)

Microarray Analysis of Transbronchial Biopsies in Lung Transplant Recipients Detects Molecular Changes of T-cell Mediated Inflammation

The Journal of Heart and Lung Transplantation (2016)

K. Halloran Jui-Chih Chang V. Ramassar A. Kapasi J. Weinkauf

Histology

10.1016/j.healun.2016.01.666

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Citations (1)