Transpl Int, 20 May 2022

Evolution of the Definition of Rejection in Kidney Transplantation and Its Use as an Endpoint in Clinical Trials

  • 1Institute of Pathology, University Hospital Cologne, Cologne, Germany
  • 2Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
  • 3Department of Pathology, Hôpital Necker–Enfants Malades, Paris, France
  • 4Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
  • 5Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

This article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT’s opinion, the use of “biopsy-proven acute rejection” as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build.


The approved histopathological endpoint for clinical trials of kidney transplantation is the presence or absence of biopsy-proven acute rejection (BPAR) (1). This endpoint has not changed for decades, despite many improvements in diagnostic assessment, immunosuppression, and monitoring protocols for kidney transplant recipients, as well as developments in our understanding of the epidemiology and pathophysiology of rejection (2).

Over time, the spectrum of rejection has broadened, with distinctions made between two major subtypes: T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR) (3). Deeper distinctions have also been made between acute (or active) and chronic phenotypes of TCMR and AMR, as defined in the Banff Classification (2), and subtypes within these phenotypes. In addition, evidence has emerged to indicate that non-specific acute rejection, or early TCMR, is becoming less relevant as the primary endpoint in kidney transplantation (4) because it is no longer considered a strong predictor of graft loss. Ongoing use of outdated terminology and definitions of histopathological endpoints such as BPAR in clinical trials has therefore become a potential barrier to research, particularly for drug development programs that aim specifically at treating only one main rejection subtype.

Furthermore, the strategy of performing protocol biopsies in the early years following transplantation has been adopted by several European centers, to detect subclinical rejection and guide ongoing patient management (5). It has become important, therefore, to consider whether endpoints defined for indication biopsies are also valid for protocol biopsies.

Rejection Phenotypes

The classification of allograft rejection has often been modified over the years, such that six histological rejection phenotypes are widely described (2, 6):

• Suspicious (borderline) for acute TCMR (henceforth simplified to “borderline changes”)

• Acute TCMR (aTCMR; classified as IA, IB, IIA, IIB, III)

• Chronic active TCMR (caTCMR)

• Acute/active antibody-mediated rejection (aAMR)

• Chronic antibody-mediated rejection (cAMR)

• Chronic active antibody-mediated rejection (caAMR).

Borderline changes represent less severe inflammation scores than aTCMR. The threshold of inflammation used for diagnosis of borderline changes (interstitial inflammation [i]0, <10% of the non-fibrotic cortex; or i1, 10%–25% of the non-fibrotic cortex) varies among centers, because between 2005 and 2017 the Banff Classification stated that retaining the i1 threshold for borderline changes with tubulitis (t) > 0 was permitted (7). However, in 2019 the minimal threshold changed to i1t1, given that several studies indicated that isolated tubulitis in the absence of interstitial inflammation (i0) did not associate with impaired graft outcome—a finding supported by most of those involved in ratifying the Banff 2019 update (7-11). In addition, decreased heterogeneity in center practice is anticipated (11). Banff 2019 also emphasized that “borderline changes” should be known as “borderline (suspicious) for acute TCMR,” to make a clear reference to rejection and treatment (11).

In the 1990s, a diagnosis of aTCMR was based on a clinical definition (i.e., an acute rise of serum creatinine that responded to antirejection therapy) and/or a clinicopathological definition (i.e., acute rejection, being aTCMR or borderline changes in an indication biopsy) (12, 13). The criteria for aTCMR have not changed since the original 1997 Banff Classification and the scores remain based on the presence of interstitial inflammation (i), tubulitis (t), and arteritis (v). However, tubulitis is now considered in all but severely atrophic cortical tubules as either Banff lesion score t or t-IFTA (defined below), whereas previously it was only considered in mildly atrophic or non-atrophic tubules (11).

The impact of inflammation in atrophic areas (i-IFTA) on graft outcomes has been widely demonstrated (8, 1416), and the effect of i-IFTA on graft survival was not significantly affected by treatment for concomitant aTCMR (15); i-IFTA has also been shown to be related to under-immunosuppression and is more commonly preceded by aTCMR than biopsies without i-IFTA (16, 17), although in some reports the majority of cases with i-IFTA did not have a previous biopsy with rejection (18). These findings suggest that i-IFTA could partly reflect alloimmunity, although further research is warranted. The same applies for tubulitis in moderately atrophic tubules captured as Banff lesion Score t-IFTA (16).

The Banff 2015 meeting noted for the first time that caTCMR could manifest in tubulointerstitial and vascular compartments, and at the 2017 meeting the proposal to include inflammation in areas of fibrosis was incorporated into the consensus classification as caTCMR (2). This classification requires interstitial inflammation involving >25% of the total cortex (ti score 2 or 3) and >25% of the sclerotic cortical parenchyma (i-IFTA score 2 or 3) with moderate tubulitis (t2) involving one or more tubules, not including severely atrophic tubules, while other known causes of i-IFTA are ruled out. Excluding other causes of inflammation in fibrosed areas is important, as i-IFTA is not a specific lesion and can be seen in cases of polyomavirus infection, pyelonephritis, AMR, recurrent glomerulonephritis, and obstruction. Inflammation might instead be an indication of very recent nephron loss as consequence (rather than the cause) of the injury per se. The response of caTCMR to increased doses of immunosuppressive therapy has not been studied (2).

In 2001, specific criteria for AMR were introduced (3), linking histopathological changes, presence of C4d, and presence of donor-specific antibodies (DSA). These were revised in 2007 (19) with the introduction of peritubular capillary (PTC) and C4d scores, and cAMR. In 2013, C4d-negative AMR was recognized, and C4d was replaced by a sign of interaction between the DSA and the endothelium (positive C4d or microcirculation inflammation, glomerulitis and peritubular capillaritis [g + PTC] ≥2, or molecular markers) (20). Finally, and importantly, in 2017 the classification for AMR was revised a second time, with acceptance of positive C4d staining as substitute for DSA in the serological criterion for DSA-negative cases and elimination of the suspicious for AMR category (not fulfilling all three criteria). Criteria for AMR were unchanged in 2019.

In addition, rejection phenotypes of kidney transplants are distinguished according to their association with graft (dys)function. Protocol (surveillance) biopsies are performed, per definition, at the time of stable graft function to detect subclinical inflammation (subclinical aTCMR and AMR) (5). Indication (for-cause) biopsies are performed at the time of graft dysfunction.

Finally, although molecular diagnostics of kidney transplant rejection has been validated prospectively in a multicentric fashion (21) and is currently applied for secondary endpoints in clinical trials, we do not consider mRNA expression patterns a valid primary endpoint at this time. Banff has not formally recognized this particular assay and is moving towards an entirely different technological platform (22) which will also need rigorous validation for diagnostic or theranostics use, before being proposed as primary endpoint for clinical trials.


ESOT has come to the following conclusions:

• The use of BPAR as an endpoint for clinical trials in kidney transplantation is no longer accurate.

○ Using outdated and/or non-specific definitions, such as BPAR, compromises the future of high-quality clinical research, especially for interventions that are targeted at one rejection subtype.

• Kidney transplant rejection should be classified by its phenotypes—borderline changes, TCMR, and AMR (the two latter having subtypes), and in relation to the nature of graft (dys)function (i.e., indication [for-cause] vs. protocol [surveillance] biopsies).

Scientific Advice From the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) About These Conclusions

• The CHMP acknowledged that histological subclassifications of rejection have evolved during the last decade.

• The CHMP agreed that the histological subtype of rejection is a useful specification and noted that this detailing might be very informative in profiling efficacy of immunosuppression.

• The CHMP commented that the reason for undertaking a protocol or indication biopsy should be taken into consideration when defining endpoints for clinical trials.

Author Contributions

This article is one of several papers developed from the Broad Scientific Advice request, submitted to the EMA/CHMP by ESOT in 2020: interactions between the EMA and ESOT regarding this request began in 2016. For the present article, working groups on histological and functional endpoints in kidney transplantation developed the ESOT position on the core question “Does CHMP agree with the updated definitions of rejection and their potential use as primary endpoints in studies of kidney transplantation?”. The Centre for Evidence in Transplantation provided support with specific data extractions: these literature searches formed the basis of evidence used in the advice request and present article. Input into the working groups was provided from all ESOT members involved in the advice request process. The present article was adapted by MN from the Broad Scientific Advice request submission documents and minutes of the meeting between ESOT and the CHMP Scientific Advice Working Party (SAWP), and the final response from the SAWP (December 2020). The article was revised by JUB and DS, and circulated to MR, CR, and MN for e-mail review. The article was finalized and approved by all co-authors before submission.


This initiative was supported by the European Society for Organ Transplantation.

Conflict of Interest

JUB consults for Sanofi. MR has received lecture fees from Astellas and Chiesi; and research grant support (paid to institution) from Astellas and Chiesi for investigator-initiated studies.

The remaining authors declare that the work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The authors thank the experts involved with the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) who participated in the Broad Scientific Advice request. The published information is based on EMA feedback received during the Broad Scientific Advice request. EMA/CHMP have not been involved in the drafting or review of the manuscript to be published. This publication does not constitute a formal EMA/CHMP endorsement of the manuscript. Literature searches were undertaken by Liset Pengel, Centre for Evidence in Transplantation, Oxford, United Kingdom. Medical writing support was provided by Linda Edmondson, independent medical writer, funded by ESOT.


1.European Medicines Agency. Clinical Investigation of Immunosuppressants for Solid Organ Transplantation (2008). CHMP/EWP/263148/06.

Google Scholar

2. Haas, M, Loupy, A, Lefaucheur, C, Roufosse, C, Glotz, D, Seron, D, et al. The Banff 2017 Kidney Meeting Report: Revised Diagnostic Criteria for Chronic Active T Cell-Mediated Rejection, Antibody-Mediated Rejection, and Prospects for Integrative Endpoints for Next-Generation Clinical Trials. Am J Transplant (2018) 18(2):293–307. doi:10.1111/ajt.14625

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Racusen, LC, Colvin, RB, Solez, K, Mihatsch, MJ, Halloran, PF, Campbell, PM, et al. Antibody-Mediated Rejection Criteria - an Addition to the Banff ′97 Classification of Renal Allograft Rejection. Am J Transplant (2003) 3:708–14. doi:10.1034/j.1600-6143.2003.00072.x

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Klintmalm, GB, Vincenti, F, and Kirk, A Steroid-Responsive Acute Rejection Should Not Be the End Point for Immunosuppressive Trials. Am J Transplant (2016) 16:3077–8. doi:10.1111/ajt.13889

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Chapman, JR Do protocol Transplant Biopsies Improve Kidney Transplant Outcomes? Curr Opin Nephrol Hypertens (2012) 21:580–6. doi:10.1097/mnh.0b013e32835903f4

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Roufosse, C, Simmonds, N, Groningen, MC, Haas, M, Henriksen, KJ, Horsfield, C, et al. Reference Guide to the Banff Classification of Renal Allograft Pathology. Transplantation (2018) 102:1795–814. doi:10.1097/TP.0000000000002366

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Becker, JU, Chang, A, Nickeleit, V, Randhawa, P, and Roufosse, C. Banff Borderline Changes Suspicious for Acute T-Cell Mediated Rejection: where Do We Stand? Am J Transplant (2016) 16(9):2654–60. doi:10.1111/ajt.13784

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Nankivell, BJ, P'Ng, CH, and Chapman, JR. Does Tubulitis without Interstitial Inflammation Represent Borderline Acute T Cell Mediated Rejection? Am J Transplant (2019) 19(1):132–44. doi:10.1111/ajt.14888

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Wiebe, C, Rush, DN, Gibson, IW, Pochinco, D, Birk, PE, Goldberg, A, et al. Evidence for the Alloimmune Basis and Prognostic Significance of Borderline T Cell-Mediated Rejection. Am J Transplant (2020) 20:2499–508. doi:10.1111/ajt.15860

PubMed Abstract | CrossRef Full Text | Google Scholar

10. McRae, M, Bouchard-Boivin, F, Béland, S, Noël, R, Côté, I, Lapointe, I, et al. 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. Transplantation (2018) 102:2120–5. doi:10.1097/tp.0000000000002327

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Loupy, A, Haas, M, Roufosse, C, Maarten, N, Benjamin, A, Marjan, A, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and Clarification of Criteria for T Cell- and Antibody-Mediated Rejection. Am J Transplant (2020) 20:2318–31. doi:10.1111/ajt.15898

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Meier-Kriesche, H-U, Ojo, AO, Hanson, JA, Cibrik, DM, Punch, JD, Leichtman, AB, et al. Increased Impact of Acute Rejection on Chronic Allograft Failure in Recent Era. Transplantation (2000) 70:1098–100. doi:10.1097/00007890-200010150-00018

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Serón, D, Arias, M, Campistol, JM, and Morales, JM. Late Renal Allograft Failure between 1990 and 1998 in Spain: a Changing Scenario. Transplantation (2003) 76:1588–94. doi:10.1097/01.TP.0000092495.07385.3C

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Mengel, M, Reeve, J, Bunnag, S, Einecke, G, Jhangri, GS, Sis, B, et al. Scoring Total Inflammation Is superior to the Current Banff Inflammation Score in Predicting Outcome and the Degree of Molecular Disturbance in Renal Allografts. Am J Transplant (2009) 9:1859–67. doi:10.1111/j.1600-6143.2009.02727.x

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Mannon, RB, Matas, AJ, Grande, J, Leduc, R, Connett, J, Kasiske, B, et al. Inflammation in Areas of Tubular Atrophy in Kidney Allograft Biopsies: a Potent Predictor of Allograft Failure. Am J Transplant (2010) 10:2066–73. doi:10.1111/j.1600-6143.2010.03240.x

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Lefaucheur, C, Gosset, C, Rabant, M, Viglietti, D, Verine, J, Aubert, O, et al. T Cell-Mediated Rejection Is a Major Determinant of Inflammation in Scarred Areas in Kidney Allografts. Am J Transplant (2018) 18:377–90. doi:10.1111/ajt.14565

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Nankivell, BJ, Shingde, M, Keung, KL, Fung, CLS, Borrows, RJ, O'Connell, PJ, et al. The Causes, Significance and Consequences of Inflammatory Fibrosis in Kidney Transplantation: The Banff i‐IFTA Lesion. Am J Transplant (2018) 18:364–76. doi:10.1111/ajt.14609

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Helgeson, ES, Mannon, R, Grande, J, Gaston, RS, Cecka, MJ, Kasiske, BL, et al. I‐IFTA and Chronic Active T Cell-Mediated Rejection: A Tale of 2 (DeKAF) Cohorts. Am J Transplant (2021) 21:1866–77. doi:10.1111/ajt.16352

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Solez, K, Colvin, RB, Racusen, LC, Haas, M, Sis, B, Mengel, M, et al. Banff 07 Classification of Renal Allograft Pathology: Updates and Future Directions. Am J Transplant (2008) 8:753–60. doi:10.1111/j.1600-6143.2008.02159.x

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Haas, M, Sis, B, Racusen, LC, Solez, K, Glotz, D, Colvin, RB, et al. Banff 2013 Meeting Report: Inclusion of C4d-Negative Antibody-Mediated Rejection and Antibody-Associated Arterial Lesions. Am J Transplant (2014) 14:272–83. doi:10.1111/ajt.12590

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Halloran, PF, Reeve, J, Akalin, E, Aubert, O, Bohmig, GA, Brennan, D, et al. Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study. Am J Transplant (2017) 17(11):2851–62. doi:10.1111/ajt.14329

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Mengel, M, Loupy, A, Haas, M, Candice, R, Maarten, N, Enver, A, et al. Banff 2019 Meeting Report: Molecular Diagnostics in Solid Organ Transplantation - Consensus for the Banff Human Organ Transplant (B-HOT) Gene Panel and Open Source Multicenter Validation. Am J Transplant (2020) 20(9):2305–17. doi:10.1111/ajt.16059

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: biopsy, subclinical rejection, antibody-mediated rejection, T cell-mediated rejection, borderline changes, kidney transplantation outcome

Citation: Becker JU, Seron D, Rabant M, Roufosse C and Naesens M (2022) Evolution of the Definition of Rejection in Kidney Transplantation and Its Use as an Endpoint in Clinical Trials. Transpl Int 35:10141. doi: 10.3389/ti.2022.10141

Received: 21 October 2021; Accepted: 11 January 2022;
Published: 20 May 2022.

Copyright © 2022 Becker, Seron, Rabant, Roufosse and Naesens. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Maarten Naesens,

These authors have contributed equally to this work