Adverse Outcomes of Tacrolimus Withdrawal in Immune–Quiescent Kidney Transplant Recipients

Abstract

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-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.

Early Low Urinary CXCL9 and CXCL10 Might Predict Immunological Quiescence in Clinically and Histologically Stable Kidney Recipients

“…The recently published results of the CTOT-09 study suggested that urinary CXCL9 levels might predict subsequent AR after tacrolimus withdrawal. However, it also showed that a large proportion of patients deemed to be clinically "low risk" and with baseline negative values for CXCL9 and CXCL10 developed subclinical rejection or new DSAs shortly after withdrawal of tacrolimus (21). Whether urinary chemokine levels can be used for individualized adjustment of immunosuppressive regimens, allowing immunosuppression reduction in immunologically quiescent patients and similar increased immunosuppression in patients with increased chemokine levels, will require careful evaluation in interventional trials.…”

Biomarkers in Transplantation—Proteomics and Metabolomics

“…The results showed that low urinary CXCL-9 protein concentrations collected 6 months after transplantation from stable allograft recipients classified individuals least likely to develop acute rejection or a reduction in estimated glomerular filtration rate between 6 and 24 months. In a prospective study of non-sensitized stable living donor kidney transplant patients randomized to stay on or to be withdrawn from tacrolimus, high urinary CXCL-9 levels predated clinical detection of acute rejection by a median of 15 days 41 . It was also found that the combination of urinary CXCL-10 levels normalized to urine creatinine with donor-specific antibody monitoring significantly improved the non-invasive diagnosis of antibody-mediated rejection and may allow for the stratification of patients at high risk for graft loss 42 .…”

B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function

“…Consequently, changes in immunosuppression for individuals are often based upon patient demographics, clinical variables, or physician experience. Two recent studies attempting to withdrawal CNI from carefully selected recipients were both halted prematurely due to high rates of acute rejection and the de novo formation of DSA (8, 10). These experiences highlight the need to develop biomarkers capable of better identifying those individuals in whom immunosuppressive minimization or even withdrawal is safe.…”