Impact of the Current versus the Previous Diagnostic Threshold on the Outcome of Patients with Borderline Changes Suspicious for T-cell-mediated Rejection Diagnosed on Indication Biopsies

Background Since the borderline changes suspicious for acute T-cell-mediated rejection (BL) category was broadened, there has been a debate regarding the right threshold for tubulitis (t) and interstitial inflammation (i) scores. Methods We studied a first cohort of 111 patients with BL found on an indication biopsy between 2006 and 2016 and compared those with scores of t1i0 (BLt1i0) to those with higher scores (BL≥t1i1). A second cohort of 56 patients with BL was used for external validation. We used a composite endpoint of death-censored graft failure or doubling of the serum creatinine level postbiopsy. Results In the first cohort, sixty-eight percent (75/111) of the BL cases fell in the BLt1i0 group. The occurrence of the composite endpoint was 5% and 14% for BLt1i0 and BL≥t1i1, respectively. In contrast, the endpoint occurred in 5% of nonrejectors and 21% of patients with T-cell-mediated rejection (TCMR). In the validation cohort, 8% versus 36% of BLt1i0 and BL≥t1i1 reached the endpoint, respectively. Multivariable Cox modeling revealed that BLt1i0 patients had a prognosis similar to that of nonrejectors (adjusted hazard ratio, HR 0.6, 95% confidence interval 0.1 to 2.2, P = 0.40) but better than that of patients with BL≥t1i1 (HR 3.8, 95% confidence interval 1.3 to 11.5, P = 0.02). Sensitivity analyses restricted to death-censored graft loss or using time post transplant as the time of reference provided similar results. Conclusions In summary, patients with BLt1i0 have a different prognosis to that of BL≥t1i1 patients, which brings into question the current diagnostic thresholds. *These authors contributed equally to this work and should be regarded as co-first authors §These authors supervised this work and should be regarded as co-senior authors Correspondence information: Sacha A. De Serres, MD SM FRCPC, Transplantation Unit, Renal Division, Department of Medicine, University Health Center of Quebec, Faculty of Medicine, Laval University, 11 Côte du Palais, Quebec, QC, Canada G1R 2J6. Tel: 418-691-5464. Fax: 418-691-5757. sacha.deserres@crchuq.ulaval.ca AUTHORSHIP M.M., F.B.B. and S.A.D.S. participated in research design, performance of the research, data analysis and writing of the paper. O.D., S.B., E.L., J.R., D.S., S.A.H. and I.B. participated in data analysis and writing of the paper. I.H., R.N., I.C., I.L. AND J.L. participated in research design and in the writing of the paper. DISCLOSURE The authors declare no conflicts of interest. FUNDING This work received support from Canadian Institutes of Health Research through Operating Grant 201309 PCL-134068 and Canada Foundation for Innovation Grant 31981. S.A.D.S. was supported by a scholarship from the Fonds de Recherche Québec Santé (FRQS) Grant 24676. S.B. is the recipient of a scholarship from CIHR and FRQS. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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