Allorecognition and the spectrum of kidney transplant rejection

Detection of mismatched human leukocyte antigens by adaptive immune cells is considered as the main cause of transplant rejection, leading to either T-cell mediated rejection or antibody-mediated rejection. This canonical view guided the successful development of immunosuppressive therapies and shaped the diagnostic Banff classification for kidney transplant rejection that is used in clinics worldwide.However, several observations have recently emerged that question this dichotomization between T-cell mediated rejection and antibody-mediated rejection, related to heterogeneity in the serology, histology, and prognosis of the rejection phenotypes. In parallel, novel insights were obtained concerning the dynamics of donor-specific anti–human leukocyte antigen antibodies, the immunogenicity of donor-recipient non–human leukocyte antigen mismatches, and the autoreactivity against self-antigens. Moreover, the potential of innate allorecognition was uncovered, as exemplified by natural killer cell–mediated microvascular inflammation through missing self, and by the emerging evidence on monocyte-driven allorecognition. In this review, we highlight the gaps in the current classification of rejection, provide an overview of the expanding insights into the mechanisms of allorecognition, and critically appraise how these could improve our understanding and clinical approach to kidney transplant rejection. We argue that consideration of the complex interplay of various allorecognition mechanisms can foster a more integrated view of kidney transplant rejection and can lead to improved risk stratification, targeted therapies, and better outcome after kidney transplantation. Detection of mismatched human leukocyte antigens by adaptive immune cells is considered as the main cause of transplant rejection, leading to either T-cell mediated rejection or antibody-mediated rejection. This canonical view guided the successful development of immunosuppressive therapies and shaped the diagnostic Banff classification for kidney transplant rejection that is used in clinics worldwide. However, several observations have recently emerged that question this dichotomization between T-cell mediated rejection and antibody-mediated rejection, related to heterogeneity in the serology, histology, and prognosis of the rejection phenotypes. In parallel, novel insights were obtained concerning the dynamics of donor-specific anti–human leukocyte antigen antibodies, the immunogenicity of donor-recipient non–human leukocyte antigen mismatches, and the autoreactivity against self-antigens. Moreover, the potential of innate allorecognition was uncovered, as exemplified by natural killer cell–mediated microvascular inflammation through missing self, and by the emerging evidence on monocyte-driven allorecognition. In this review, we highlight the gaps in the current classification of rejection, provide an overview of the expanding insights into the mechanisms of allorecognition, and critically appraise how these could improve our understanding and clinical approach to kidney transplant rejection. We argue that consideration of the complex interplay of various allorecognition mechanisms can foster a more integrated view of kidney transplant rejection and can lead to improved risk stratification, targeted therapies, and better outcome after kidney transplantation. The Banff classification is internationally adopted for the interpretation of kidney transplant pathology. Biopsies obtain a binary diagnostic label based on an ensemble of individual histologic lesions, scored according to their severity or extent.1Roufosse C. Simmonds N. Clahsen-Van Groningen M. et al.2018 reference guide to the Banff Classification of Renal Allograft Pathology.Transplantation. 2018; 102: 1795-1814Google Scholar Large cohort studies showed that acute inflammatory lesions form specific clusters, including microvascular inflammation (i.e., the combination of glomerulitis and peritubular capillaritis) and tubulointerstitial inflammation (i.e., the combination of tubulitis and interstitial inflammation).2Sis B. Einecke G. Chang J. et al.Cluster analysis of lesions in nonselected kidney transplant biopsies: microcirculation changes, tubulointerstitial inflammation and scarring.Am J Transplant. 2010; 10: 421-430Google Scholar, 3Matas A.J. Leduc R. Rush D. et al.Histopathologic clusters differentiate subgroups within the nonspecific diagnoses of CAN or CR: preliminary data from the DeKAF study.Am J Transplant. 2010; 10: 315-323Google Scholar, 4Lefaucheur C. Loupy A. Vernerey D. et al.Antibody-mediated vascular rejection of kidney allografts: a population-based study.Lancet. 2013; 381: 313-319Google Scholar, 5Vaulet T. Divard G. Thaunat O. et al.Data-driven derivation and validation of novel phenotypes for acute kidney transplant rejection using semi-supervised clustering.J Am Soc Nephrol. 2021; 32: 1084-1096Google Scholar Currently, kidney transplant rejection is categorized in 2 main groups: T-cell mediated rejection (TCMR), referring to tubulointerstitial inflammation following T-lymphocyte activation and migration to the allograft; and antibody-mediated rejection (ABMR), referring to microvascular inflammation following B-cell activation, plasma cell differentiation, and production of antibodies targeting the donor endothelium.6Loupy A. Haas M. Roufosse C. 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: 2305-2317Google Scholar,7Chen C.C. Pouliquen E. Broisat A. et al.Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection.J Clin Invest. 2018; 128: 219-232Google Scholar However, recent fundamental, translational, and clinical observations call this dichotomized view of rejection into question. Herein, we highlight the heterogeneity that pervades the current classification, and discuss how the (re)discovery of other allorecognition mechanisms could improve our understanding of kidney transplant rejection. The dichotomized view of kidney transplant rejection is challenged by the nonspecificity of the histologic lesions. Lesions of ABMR (ABMR histology) are also observed with other disease entities, such as glomerulonephritis (for glomerulitis) or T-cell mediated rejection (for intimal arteritis). Therefore, in addition to histologic lesions, the diagnosis of ABMR requires additional evidence of a humoral factor underlying the histologic picture. As attempts to visualize presence of IgG or IgM in renal allografts with suspected ABMR proved unreliable,8Feucht H.E. Felber E. Gokel M.J. et al.Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection.Clin Exp Immunol. 1991; 86: 464-470Google Scholar,9Halloran P.F. Wadgymar A. Ritchie S. et al.The significance of anti-class I antibody response.Transplantation. 1990; 49: 85-91Google Scholar alternative criteria, such as detection of circulating anti–human leukocyte antigen donor-specific antibodies (HLA-DSA) and linear C4d deposition in peritubular capillaries (C4dptc) are considered to reflect humoral etiology.10Feucht H.E. Schneeberger H. Hillebrand G. et al.Capillary deposition of C4d complement fragment and early renal graft loss.Kidney Int. 1993; 43: 1333-1338Google Scholar,11Racusen L. Colvin R. Solez K. et al.Antibody-mediated rejection criteria: an addition to the Banff '97 classification of renal allograft rejection.Am J Transplant. 2003; 3: 708-714Google Scholar However, the current Banff definition of ABMR, combining histologic lesions with information on HLA-DSA, is not able to classify all cases. Multiple independent studies have shown that circulating HLA-DSA are often absent in recipients with microvascular inflammation,12Senev A. Coemans M. Lerut E. et al.Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: clinical presentation and implications for outcome.Am J Transplant. 2019; 19: 763-780Google Scholar, 13Bestard O. Grinyó J. Refinement of humoral rejection effector mechanisms to identify specific pathogenic histological lesions with different graft outcomes.Am J Transplant. 2019; 19: 952-953Google Scholar, 14Amico P. Hönger G. Bielmann D. et al.Incidence and prediction of early antibody-mediated rejection due to non-human leukocyte antigen-antibodies.Transplantation. 2008; 85: 1557-1563Google Scholar, 15Lee J. Park Y. Kim B.S. et al.Clinical implications of angiotensin II type 1 receptor antibodies in antibody-mediated rejection without detectable donor-specific HLA antibodies after renal transplantation.Transplant Proc. 2015; 47: 649-652Google Scholar, 16Koenig A. Chen C.C.-C. Marçais A. et al.Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants.Nat Commun. 2019; 10: 5350Google Scholar, 17Callemeyn J. Lerut E. de Loor H. et al.Transcriptional changes in kidney allografts with histology of antibody-mediated rejection without anti-HLA donor-specific antibodies.J Am Soc Nephrol. 2020; 31: 2168-2183Google Scholar, 18Sablik K.A. Clahsen-van Groningen M.C. Looman C.W.N. et al.Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome: a retrospective study.Transpl Int. 2018; 31: 900-908Google Scholar, 19Parajuli S. Redfield R.R. Garg N. et al.Clinical significance of microvascular inflammation in the absence of anti-HLA DSA in kidney transplantation.Transplantation. 2019; 103: 1468-1476Google Scholar, 20Lefaucheur C. Viglietti D. Bouatou Y. et al.Non-HLA agonistic anti-angiotensin II type 1 receptor antibodies induce a distinctive phenotype of antibody-mediated rejection in kidney transplant recipients.Kidney Int. 2019; 96: 189-201Google Scholar, 21Delville M. Lamarthée B. Pagie S. et al.Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens.J Am Soc Nephrol. 2019; 30: 692-709Google Scholar, 22Lubetzky M. Hayde N. Ó Broin P. et al.Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody.Clin Transplant. 2019; 33: e13469Google Scholar, 23Van Loon E. Lerut E. de Loor H. et al.Antibody-mediated rejection with and without donor-specific anti-human leucocyte antigen antibodies: performance of the peripheral blood 8-gene expression assay.Nephrol Dial Transplant. 2020; 35: 1328-1337Google Scholar despite the development of single-antigen bead (SAB) assays with increased specificity and sensitivity for HLA-DSA. All these studies identified a substantial portion of HLA-DSA–negative cases, ranging from 17% to 66% (Supplementary Table S1), despite variations in study design, antibody detection method, donor HLA genotype resolution, applied mean fluorescence index (MFI) cutoff values, and definitions of microvascular inflammation or HLA-DSA negativity. The clinical presentation of HLA-DSA–negative ABMR histology appears distinct from HLA-DSA–positive ABMR. In a cohort study of 935 transplantations, we found that HLA-DSA–negative ABMR histology associated with less histologic persistence at follow-up.12Senev A. Coemans M. Lerut E. et al.Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: clinical presentation and implications for outcome.Am J Transplant. 2019; 19: 763-780Google Scholar In addition, improved long-term allograft outcome was reported after HLA-DSA–negative ABMR histology in comparison to HLA-DSA–positive ABMR,12Senev A. Coemans M. Lerut E. et al.Histological picture of antibody-mediated rejection without donor-specific anti-HLA antibodies: clinical presentation and implications for outcome.Am J Transplant. 2019; 19: 763-780Google Scholar,13Bestard O. Grinyó J. Refinement of humoral rejection effector mechanisms to identify specific pathogenic histological lesions with different graft outcomes.Am J Transplant. 2019; 19: 952-953Google Scholar,17Callemeyn J. Lerut E. de Loor H. et al.Transcriptional changes in kidney allografts with histology of antibody-mediated rejection without anti-HLA donor-specific antibodies.J Am Soc Nephrol. 2020; 31: 2168-2183Google Scholar although similar outcomes were reported by others.18Sablik K.A. Clahsen-van Groningen M.C. Looman C.W.N. et al.Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome: a retrospective study.Transpl Int. 2018; 31: 900-908Google Scholar,19Parajuli S. Redfield R.R. Garg N. et al.Clinical significance of microvascular inflammation in the absence of anti-HLA DSA in kidney transplantation.Transplantation. 2019; 103: 1468-1476Google Scholar,22Lubetzky M. Hayde N. Ó Broin P. et al.Molecular signatures and clinical outcomes of transplant glomerulopathy stratified by microvascular inflammation and donor-specific antibody.Clin Transplant. 2019; 33: e13469Google Scholar The Banff community tried to solve this lack of detection of HLA-DSA in many cases of microvascular inflammation by introducing C4dptc as a surrogate criterion for HLA-DSA in Banff'17. C4dptc is thought to reflect complement activation upon antibody-endothelium interaction, leading to a covalent binding of the split product C4d and the endothelium.24Haas M. Loupy A. Lefaucheur C. 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: 293-307Google Scholar However, there are several issues with the suggestion that C4dptc reflects HLA-DSA positivity and "true" ABMR, in cases when no HLA-DSA are detected. The sensitivity of C4dptc for presence of HLA-DSA is poor, attributed to the fact that (i) circulating HLA-DSA do not always interact with the endothelium or that (ii) the endothelial interaction of certain HLA-DSA does not always trigger complement activation. Indeed, not all anti-HLA antibodies display in vitro complement activation, as evaluated by C1q- and C3d-binding assays, which identify antibodies with increased risk of graft failure.25Loupy A. Lefaucheur C. Vernerey D. et al.Complement-binding anti-HLA antibodies and kidney-allograft survival.N Engl J Med. 2013; 369: 1215-1226Google Scholar, 26Sicard A. Ducreux S. Rabeyrin M. et al.Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss.J Am Soc Nephrol. 2015; 26: 457-467Google Scholar, 27Bouquegneau A. Loheac C. Aubert O. et al.HLA antibodies and solid organ transplant survival: a systematic review and meta-analysis.PLoS Med. 2018; 15e1002572Google Scholar However, neither C1q- nor C3d-binding properties completely overlapped with C4dptc, suggesting that C4dptc is less specific than previously thought. In addition, conflicting results have been reported on the prognostic value of C4dptc in ABMR, with most studies reporting no association with graft failure.26Sicard A. Ducreux S. Rabeyrin M. et al.Detection of C3d-binding donor-specific anti-HLA antibodies at diagnosis of humoral rejection predicts renal graft loss.J Am Soc Nephrol. 2015; 26: 457-467Google Scholar,28Loupy A. Hill G.S. Suberbielle C. et al.Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA).Am J Transplant. 2011; 11: 56-65Google Scholar, 29Sapir-pichhadze R. Curran S.P. John R. et al.A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection.Kidney Int. 2015; 87: 182-194Google Scholar, 30Malheiro J. Santos S. Tafulo S. et al.Antibodies, not IgG-antibody strength nor C4d status, at antibody-mediated rejection diagnosis is an independent predictor of kidney graft failure.Transplantation. 2018; 102: 1943-1954Google Scholar, 31Callemeyn J. Ameye H. Lerut E. et al.Revisiting the changes in the Banff Classification for antibody-mediated rejection after kidney transplantation.Am J Transplant. 2021; 21: 2413-2423Google Scholar, 32Gaston R.S. Cecka J.M. Kasiske B.L. et al.Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure.Transplantation. 2010; 90: 68-74Google Scholar The observed heterogeneity between studies is likely a result of unstandardized C4d staining techniques, varying time after transplantation, treatment strategies, and pathologist experience. Finally, isolated C4dptc can be found in the absence of microvascular lesions. Not only is this observed in most biopsies of ABO incompatible transplants, where it may represent accommodation,33Haas M. Rahman M.H. Racusen L.C. C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings.Am J Transplant. 2006; 6: 1829-1840Google Scholar but also after ABO compatible transplantation, the molecular landscape of C4dptc is akin to that of biopsies without ABMR or C4dptc.34Dominy K.M. Willicombe M. Johani T Al et al.Molecular assessment of C4d-positive renal transplant biopsies without evidence of rejection.Kidney Int Rep. 2019; 4: 148-158Google Scholar Taken together, these results suggest that C4dptc offers less etiological evidence than HLA-DSA toward an underlying humoral cause in patients with microvascular inflammation. Next to the observation that not all microvascular inflammation cases are explained by HLA-DSA, another issue of the dichotomized model of rejection concerns the molecular heterogeneity of ABMR and TCMR. Molecular studies revealed distinct transcriptional changes in ABMR and TCMR that not only provided new mechanistic insights, but could also be applied to refine the histologic diagnosis of rejection.35Sellarés J. Reeve J. Loupy A. et al.Molecular diagnosis of antibody-mediated rejection in human kidney transplants.Am J Transplant. 2013; 13: 971-983Google Scholar,36Reeve J. Sellarés J. Mengel M. et al.Molecular diagnosis of T cell-mediated rejection in human kidney transplant biopsies.Am J Transplant. 2013; 13: 645-655Google Scholar The use of molecular markers was introduced in the Banff 2013 classification for ABMR,37Cendales L.C. Glotz D. Liapis H. et al.Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant. 2014; 14: 272-283Google Scholar and further expanded in 2017 as a surrogate for serologic evidence in patients without detectable HLA-DSA.24Haas M. Loupy A. Lefaucheur C. 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: 293-307Google Scholar In Banff 2019, a 758 gene set (B-HOT panel) was proposed that could be assessed for on formalin-fixed, paraffin-embedded tissue using Nanostring technology, allowing for integrated molecular and histologic diagnostics.38Mengel M. Loupy A. Haas M. 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: 2305-2317Google Scholar Despite the clear association between ABMR, TCMR, and specific transcripts, important discrepancies between molecular and histologic diagnoses were noted by the Edmonton group,39Halloran P.F. Pereira A.B. Chang J. et al.Microarray diagnosis of antibody-mediated rejection in kidney transplant biopsies: an international prospective study (INTERCOM).Am J Transplant. 2013; 13: 2865-2874Google Scholar,40Halloran P.F. Pereira A.B. Chang J. et al.Potential impact of microarray diagnosis of T cell-mediated rejection in kidney transplants: the INTERCOM study.Am J Transplant. 2013; 13: 2352-2363Google Scholar leading to the development of an automated molecular diagnostic platform (Molecular Microscope MMDx),41Halloran P.F. Reeve J. Akalin E. Real time central assessment of kidney transplant indication biopsies by microarrays: the INTERCOMEX study.Am J Transplant. 2017; 17: 2851-2862Google Scholar and the proposition of novel molecular rejection archetypes.42Reeve J. Bohmig G.A. Eskandary F. et al.Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes.JCI Insight. 2017; 2e94197Google Scholar Likewise, other groups have reported molecular heterogeneity in biopsies with similar microscopic appearances,17Callemeyn J. Lerut E. de Loor H. et al.Transcriptional changes in kidney allografts with histology of antibody-mediated rejection without anti-HLA donor-specific antibodies.J Am Soc Nephrol. 2020; 31: 2168-2183Google Scholar,43Sarwal M. Chua M.-S. Kambham N. et al.Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling.N Engl J Med. 2003; 349: 125-138Google Scholar, 44Buscher K. Heitplatz B. Van Marck V. et al.Data driven kidney transplant phenotyping as a histology-independent framework for biomarker discovery.J Am Soc Nephrol. 2021; 32: 1933-1945Google Scholar, 45Rychkov D. Sur S. Sirota M. et al.Molecular diversity of clinically stable human kidney allografts.JAMA Netw Open. 2021; 4e2035048Google Scholar A recent unsupervised clustering analysis based on cellular deconvolution and gene networks revealed distinct molecular phenotypes that did not match with the histologic diagnoses of ABMR and TCMR.44Buscher K. Heitplatz B. Van Marck V. et al.Data driven kidney transplant phenotyping as a histology-independent framework for biomarker discovery.J Am Soc Nephrol. 2021; 32: 1933-1945Google Scholar This molecular heterogeneity suggests that different immune-related pathways can lead to similar spatial patterns of graft injury. Rejection involves leukocyte invasion or accumulation in vascular, epithelial, and stromal allograft compartments.1Roufosse C. Simmonds N. Clahsen-Van Groningen M. et al.2018 reference guide to the Banff Classification of Renal Allograft Pathology.Transplantation. 2018; 102: 1795-1814Google Scholar The Banff classification categorizes acute rejection phenotypes based on the spatial organization of the inflammatory burden within the allograft, but does not consider the constitution of the inflammatory infiltrate, although this could be of relevance. Indeed, recent studies demonstrated that the immune cell infiltrate in transplant biopsies is highly heterogeneous, even within the same Banff rejection category. Using multiplex immunofluorescence with quantification of CD3-, CD163-, and NKp46-positive cells, remarkable variability in the relative fraction of immune cells was reported: although the inflammation in some ABMR biopsies largely consisted of macrophages, other biopsies were predominantly hallmarked by T-cell infiltration, and similar distributions were seen in TCMR biopsies.46Calvani J. Terada M. Lesaffre C. et al.In situ multiplex immunofluorescence analysis of the inflammatory burden in kidney allograft rejection: a new tool to characterize the alloimmune response.Am J Transplant. 2020; 20: 942-953Google Scholar Two other multiplex studies found similar results in acute and chronic ABMR, and in addition highlighted heterogeneity in B-cell infiltration.47Aguado-domínguez E. Cabrera-pérez R. Suarez-benjumea A. Computer-assisted definition of the inflammatory infiltrates in patients with different categories of Banff kidney allograft rejection.Front Immunol. 2019; 10: 2605Google Scholar,48Sablik K.A. Jordanova E.S. Pocorni N. et al.Immune cell infiltrate in chronic-active antibody-mediated rejection.Front Immunol. 2020; 10: 3106Google Scholar Finally, plasma cell–rich infiltrates have been reported across ABMR and TCMR, where they confer markedly worse allograft survival.49Hasegawa J. Honda K. Omoto K. et al.Clinical and pathological features of plasma cell-rich acute rejection after kidney transplantation.Transplantation. 2018; 102: 853-859Google Scholar Taken together, although cell type abundance in rejection does not necessarily correlate with the initial trigger, these interindividual differences indicate that reducing tubulointerstitial inflammation and microvascular inflammation to either "T-cell mediated" or "antibody mediated" does not represent the complexity of ongoing immune processes. A fourth issue with the dichotomized model of rejection is the inconsistent response to treatment of ABMR and TCMR. Currently, there is no standardized approach for the prevention of ABMR in patients with HLA-DSA. Although specific therapies, such as antibody removal, complement inhibition, B-cell depletion, and plasma cell inhibition, have been shown to improve short-term outcomes, no treatment option has consistently shown beneficial long-term results after development of ABMR.50Schinstock C.A. Mannon R.B. Budde K. et al.Recommended treatment for antibody-mediated rejection after kidney transplantation: the 2019 expert consensus from the Transplantion Society working group.Transplantation. 2020; 104: 911-922Google Scholar In part, this might be attributed to important heterogeneity between trials in terms of treatment dosing, combination, and duration, but also relate to varying inclusion criteria, changing Banff criteria and small study populations. However, even within trial populations, the results may differ. For example, Viglietti et al. found large interpatient variability in long-term outcomes after ABMR treatment, related to persisting peritubular capillaritis, C4d deposition, and HLA-DSA MFI titers.51Viglietti D. Loupy A. Aubert O. et al.Dynamic prognostic score to predict kidney allograft survival in patients with antibody-mediated rejection.J Am Soc Nephrol. 2018; 29: 606-619Google Scholar In a cohort of sensitized patients, eculizumab at the time of transplantation reduced the incidence of ABMR compared with plasmapheresis and intravenous immunoglobulins, but only in patients with complement-binding HLA-DSA.52Lefaucheur C. Viglietti D. Hidalgo L.G. et al.Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment.J Am Soc Nephrol. 2018; 29: 620-635Google Scholar This inconsistency in therapeutic responses should encourage future research efforts to identify predictive biomarkers for guiding therapy,53Naesens M. Anglicheau D. Precision transplant medicine: biomarkers to the rescue.J Am Soc Nephrol. 2018; 29: 24-34Google Scholar and to better understand ABMR that does not respond to conventional treatment. The options for TCMR are better understood, given that the currently used induction protocols and maintenance immunosuppressive regimens were primarily developed to prevent cellular rejection. These T-cell targeted therapies resulted in a decreased TCMR incidence and improved short-term allograft survival, although long-term survival has stagnated.54Meier-Kriesche H.U. Schold J.D. Srinivas T.R. et al.Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era.Am J Transplant. 2004; 4: 378-383Google Scholar, 55Famulski K.S. Einecke G. Sis B. et al.Defining the canonical form of T-cell-mediated rejection in human kidney transplants.Am J Transplant. 2010; 10: 810-820Google Scholar, 56Sellarés J. De Freitas D.G. Mengel M. et al.Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.Am J Transplant. 2012; 12: 388-399Google Scholar, 57Halloran P.F. Chang J. Famulski K. et al.Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients.J Am Soc Nephrol. 2015; 26: 1711-1720Google Scholar, 58Coemans M. Süsal C. Döhler B. et al.Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015.Kidney Int. 2018; 94: 964-973Google Scholar The causes of death-censored graft failure are complex and often multifactorial, but preceding TCMR remains reported in 33% to 56% of cases in contemporary cohorts,59Van Loon E. Senev A. Lerut E. et al.Assessing the complex causes of kidney allograft loss.Transplantation. 2020; 104: 2557-2566Google Scholar,60Mayrdorfer M. Liefeldt L. Wu K. et al.Exploring the complexity of death-censored kidney allograft failure.J Am Soc Nephrol. 2021; 32: 1513-1526Google Scholar suggesting that TCMR is less trivial than sometimes considered. In addition, heterogeneity in response to treatment of pure TCMR with corticosteroids and/or lymphocyte depletion was noted, highlighting the negative prognostic impact of unresolved tubulointerstitial inflammation, development of chronic injury, de novo HLA-DSA, and concomitant ABMR after TCMR diagnosis.61Bouatou Y. Viglietti D. Pievani D. et al.Response to treatment and long-term outcomes in kidney transplant recipients with acute T cell–mediated rejection.Am J Transplant. 2019; 19: 1972-1988Google Scholar,62Clayton P.A. Mcdonald S.P. Russ G.R. et al.Long-term outcomes after acute rejection in kidney transplant recipients: an ANZDATA analysis.J Am Soc Nephrol. 2019; 30: 1697-1707Google Scholar Finally, a last challenge to the dichotomization of kidney transplant rejection relates to the fact that microvascular inflammation and tubulointerstitial inflammation frequently coincide, often referred to as "mixed rejection."63Nickeleit V. Andreoni K. The classification and treatment of antibody-mediated renal allograft injury: where do we stand?.Kidney Int. 2007; 71: 7-10Google Scholar Although not recognized as a separate diagnostic category by the Banff classification, mi