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J Am Soc Nephrol. 2015 Dec;26(12):3114-22. doi: 10.1681/ASN.2014121234. Epub 2015 Apr 29.

Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

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Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio;
Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, Connecticut;
College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
Department of Immunology and Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio;
Department of Medicine, University of Toronto, Toronto, Ontario, Canada;
Department of Medicine, University of California at Los Angeles Medical Center, Los Angeles, California;
Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri;
Department of Medicine and Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York;
Department of Surgery, Houston Methodist Hospital, Houston, Texas; Weil Cornell Medical College, New York, New York;
Rho, Chapel Hill, North Carolina; and.
Transplantation Branch, National Institute Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Department of Medicine and Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York;


Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.


immunosuppression; rejection; renal transplantation

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