TY - JOUR
T1 - Adverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients
AU - Hricik, Donald E.
AU - Formica, Richard N.
AU - Nickerson, Peter
AU - Rush, David
AU - Fairchild, Robert L.
AU - Poggio, Emilio D.
AU - Gibson, Ian W.
AU - Wiebe, Chris
AU - Tinckam, Kathryn
AU - Bunnapradist, Suphamai
AU - Samaniego-Picota, Milagros
AU - Brennan, Daniel C.
AU - Schröppel, Bernd
AU - Gaber, Osama
AU - Armstrong, Brian
AU - Ikle, David
AU - Diop, Helena
AU - Bridges, Nancy D.
AU - Heeger, Peter S.
N1 - Funding Information:
Participating centers, investigators, and staff for the Clinical Trials in OrganTransplantation-09Consortium: ClevelandClinic:R.L.F.,Richard Fatica, Stuart Flechner, David Goldfarb, Karen Keslar, Venkatesh Krishnamurthi, Saul Nurko, E.D.P., and Brian Stephany; Houston MethodistHospital: SarahJ.BrannandO.G.; IcahnSchoolofMedicine at Mount Sinai: Scott Ames, Sander Florman, Rajani Dinavahi, Michael Goldstein, P.S.H., Susan Lerner, Barbara Murphy, Vinay Nair, Denise Peace, Anja Richter, Juan Rocca, B.S., and Vinita Seghal; Transplantation Branch, National Institutes of Allergy and Infectious Disease, National Institutes ofHealth: N.D.B.,H.D., and YvonneMorrison; Rho: B.A. and D.I.; University of California, Los Angeles: S.B. and Marcelo Sampaio; University Health Network, University of Toronto: Segun Famure, Heather Ford, Nicholas Phan, and K.T.; University Hospitals Case Medical Center: Joshua Augustine, D.E.H., Aparna Padiyar, Edmund Sanchez, JamesSchulak, andKennethWoodside;UniversityofManitoba: I.W.G.,P.N.,D.R., and C.W.;UniversityofMichigan:M.S.-P. andRandall Sung; Washington University: D.C.B.; and Yale University School of Medicine: R.N.F., Danielle Jacques, and Ricarda Tomlin.
Publisher Copyright:
Copyright © 2015 by the American Society of Nephrology.
PY - 2015/12
Y1 - 2015/12
N2 - 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,mycophenolatemofetil, and prednisone. Sixmonths 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 HLADQepitopemismatches and pretransplant, peripheral blood, donor-reactive IFN-g 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.
AB - 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,mycophenolatemofetil, and prednisone. Sixmonths 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 HLADQepitopemismatches and pretransplant, peripheral blood, donor-reactive IFN-g 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.
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U2 - 10.1681/ASN.2014121234
DO - 10.1681/ASN.2014121234
M3 - Article
C2 - 25925687
AN - SCOPUS:84944092747
SN - 1046-6673
VL - 26
SP - 3114
EP - 3122
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 12
ER -