Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.
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.
Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio;
Donald E
DE
Hricik
Departments of Medicine and Surgery, Yale University School of Medicine, New Haven, Connecticut;
Richard N
RN
Formica
College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
Peter
P
Nickerson
College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
David
D
Rush
Department of Immunology and Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio;
Robert L
RL
Fairchild
Department of Immunology and Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio;
Emilio D
ED
Poggio
College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
Ian W
IW
Gibson
College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada;
Chris
C
Wiebe
Department of Medicine, University of Toronto, Toronto, Ontario, Canada;
Kathryn
K
Tinckam
Department of Medicine, University of California at Los Angeles Medical Center, Los Angeles, California;
Suphamai
S
Bunnapradist
Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
Milagros
M
Samaniego-Picota
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri;
Daniel C
DC
Brennan
Department of Medicine and Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York;
Bernd
B
Schröppel
Department of Surgery, Houston Methodist Hospital, Houston, Texas; Weil Cornell Medical College, New York, New York;
Osama
O
Gaber
Rho, Chapel Hill, North Carolina; and.
Brian
B
Armstrong
Rho, Chapel Hill, North Carolina; and.
David
D
Ikle
Transplantation Branch, National Institute Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Helena
H
Diop
Transplantation Branch, National Institute Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Nancy D
ND
Bridges
Department of Medicine and Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York; peter.heeger@mssm.edu.
Peter S
PS
Heeger
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D001284:Atrophy; D065095:Calcineurin Inhibitors / Q000008:administration & dosage*; D054370:Chemokine CXCL9 / Q000652:urine; D057239:Early Termination of Clinical Trials; D005260:Female; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control* / Q000652:urine; D006683:HLA-DQ Antigens / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007371:Interferon-gamma / Q000097:blood; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009393:Nephritis / Q000473:pathology; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D028761:Withholding Treatment; D055815:Young Adult
D000906:Antibodies; C080810:CXCL9 protein, human; D065095:Calcineurin Inhibitors; D054370:Chemokine CXCL9; D006683:HLA-DQ Antigens; D007371:Interferon-gamma; D016559:Tacrolimus
immunosuppression; rejection; renal transplantation