Multiomic profiling of transplant glomerulopathy reveals a novel T-cell dominant subclass

Abstract

Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype. Kidney transplant (KTx) biopsies showing transplant glomerulopathy (TG) (glomerular basement membrane double contours (cg) > 0) and microvascular inflammation (MVI) in the absence of C4d staining and donor-specific antibodies (DSAs) do not fulfill the criteria for chronic active antibody–mediated rejection (CA-AMR) diagnosis and do not fit into any other Banff category. To investigate this, we initiated a multicenter intercontinental study encompassing 36 cases, comparing the immunomic and transcriptomic profiles of 14 KTx biopsies classified as cg+MVI DSA-/C4d- with 22 classified as CA-AMR DSA+/C4d+ through novel transcriptomic analysis using the NanoString Banff-Human Organ Transplant (B-HOT) panel and subsequent orthogonal subset analysis using two innovative 5-marker multiplex immunofluorescent panels. Nineteen genes were differentially expressed between the two study groups. Samples diagnosed with CA-AMR DSA+/C4d+ showed a higher glomerular abundance of natural killer cells and higher transcriptomic cell type scores for macrophages in an environment characterized by increased expression of complement-related genes (i.e., C5AR1) and higher activity of angiogenesis, interstitial fibrosis tubular atrophy, CA-AMR, and DSA-related pathways when compared to samples diagnosed with cg+MVI DSA-/C4d-. Samples diagnosed with cg+MVI DSA-/C4d- displayed a higher glomerular abundance and activity of T cells (CD3+, CD3+CD8+, and CD3+CD8-). Thus, we show that using novel multiomic techniques, KTx biopsies with cg+MVI DSA-/C4d- have a prominent T-cell presence and activity, putting forward the possibility that these represent a more T-cell dominant phenotype. Lay SummaryIn this study, we compared 2 kidney transplant biopsy rejection diagnoses: one with a rejection type called “chronic-active antibody-mediated rejection” and another that under the microscope looks the same but does not have all the criteria for that diagnosis. Using new and state-of-the-art techniques, we found distinct differences in the biological characteristics between the 2 groups, suggesting that the second group is a different type of rejection with a high presence of T cells. The study will help improve how to diagnose and treat kidney transplant patients with this type of chronic rejection. In this study, we compared 2 kidney transplant biopsy rejection diagnoses: one with a rejection type called “chronic-active antibody-mediated rejection” and another that under the microscope looks the same but does not have all the criteria for that diagnosis. Using new and state-of-the-art techniques, we found distinct differences in the biological characteristics between the 2 groups, suggesting that the second group is a different type of rejection with a high presence of T cells. The study will help improve how to diagnose and treat kidney transplant patients with this type of chronic rejection. The development of chronic-active antibody-mediated rejection (CA-AMR) in kidney transplants (KTxs) represents an intermediate stage in the progression of morphologic lesions from active to chronic AMR and has a large impact on long-term transplant outcome.1Sellarés 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: 388-399Abstract Full Text Full Text PDF PubMed Scopus (1203) Google Scholar, 2Naesens M. Kuypers D.R.J. De Vusser K. et al.The histology of kidney transplant failure: a long-term follow-up study.Transplantation. 2014; 98: 427-435Crossref PubMed Scopus (117) Google Scholar, 3Pouliquen E. Koenig A. Chen C.C. et al.Recent advances in renal transplantation: antibody-mediated rejection takes center stage.F1000Prime Rep. 2015; 7: 51Crossref PubMed Scopus (42) Google Scholar, 4Valenzuela N.M. Reed E.F. Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies.J Clin Invest. 2017; 127: 2492-2504Crossref PubMed Scopus (150) Google Scholar According to the Banff Classification of Allograft Pathology 2019 update,5Loupy 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: 2318-2331Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar CA-AMR can be diagnosed when 3 diagnostic criteria are met: (i) the presence of morphologic evidence of chronic tissue injury, for example, transplant glomerulopathy (TG, cg >0); (ii) evidence of current/recent antibody interaction with vascular endothelium, for example, microvascular inflammation (MVI); and (iii) serologic evidence of circulating donor-specific antibodies (DSAs to human leukocyte antigen [HLA] or other antigens) that can be substituted by C4d staining of peritubular capillaries (ptcs) (also diagnostic criterion 2) or the presence of validated gene transcripts/classifiers. Diagnosing CA-AMR remains difficult for several reasons. First, the absence of DSAs at the time of for-cause KTx biopsies does not exclude the presence of CA-AMR. Current antibody testing methods focus on circulating anti-HLA antibodies, thereby missing non-HLA antibodies and possibly leading to false negatives.6Haas M. The revised (2013) Banff classification for antibody-mediated rejection of renal allografts: update, difficulties, and future considerations.Am J Transplant. 2016; 16: 1352-1357Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 7Lucia M. Luque S. Crespo E. et al.Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation.Kidney Int. 2015; 88: 874-887Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 8Snanoudj R. Claas F.H. Heidt S. et al.Restricted specificity of peripheral alloreactive memory B cells in HLA-sensitized patients awaiting a kidney transplant.Kidney Int. 2015; 87: 1230-1240Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 9Michielsen L.A. van Zuilen A.D. Krebber M.M. et al.Clinical value of non-HLA antibodies in kidney transplantation: still an enigma?.Transplant Rev (Orlando). 2016; 30: 195-202Crossref PubMed Scopus (36) Google Scholar, 10Dragun D. Catar R. Philippe A. Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity.Kidney Int. 2016; 90: 280-288Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 11Sigdel T.K. Li L. Tran T.Q. et al.Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft injury.J Am Soc Nephrol. 2012; 23: 750-763Crossref PubMed Scopus (75) Google Scholar, 12Pineda S. Sigdel T.K. Chen J. et al.Corrigendum: novel non-histocompatibility antigen mismatched variants improve the ability to predict antibody-mediated rejection risk in kidney transplant.Front Immunol. 2018; 9: 107Crossref PubMed Scopus (3) Google Scholar Even when using highly sensitive antibody-detection techniques, in approximately 40% of patients with AMR, no DSAs are detected.13Akalin E. Dinavahi R. Dikman S. et al.Transplant glomerulopathy may occur in the absence of donor-specific antibody and C4d staining.Clin J Am Soc Nephrol. 2007; 2: 1261-1267Crossref PubMed Scopus (56) Google Scholar Second, C4d scoring is affected by subjectivity,14Cohen D. Colvin R.B. Daha M.R. et al.Pros and cons for C4d as a biomarker.Kidney Int. 2012; 81: 628-639Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar and lack of C4d staining of ptcs is also relatively common in CA-AMR,15Gloor J.M. Sethi S. Stegall M.D. et al.Transplant glomerulopathy: subclinical incidence and association with alloantibody.Am J Transplant. 2007; 7: 2124-2132Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar,16Becker L.E. Morath C. Suesal C. Immune mechanisms of acute and chronic rejection.Clin Biochem. 2016; 49: 320-323Crossref PubMed Scopus (33) Google Scholar suggesting that TG could occur in the absence of complement activation. Lastly, although promising developments are made in transcriptomic analysis of for-cause kidney biopsies with DSA-selective transcripts,17Hidalgo L.G. Sis B. Sellares J. et al.NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection.Am J Transplant. 2010; 10: 1812-1822Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar it is not commonly used in clinical practice. Therefore, clinicians identify patients fulfilling only the first 2 diagnostic criteria for the CA-AMR diagnosis showing TG and MVI, testing negative for circulating DSAs with no C4d staining of ptcs, but lacking the opportunity of performing transcript analysis. Hence, there is an unmet need to correctly classify those cases with cg+MVI that do not have C4d positivity and DSAs. To improve classification and therapeutic management, comparison of cg+MVI DSA−/C4d− samples with CA-AMR DSA+/C4d+ samples is needed. Clinical centers encountering cg+MVI DSA−/C4d− patients are usually not able to perform and classify patients one of the Banff cases are as to the same therapeutic as cases fulfilling Banff CA-AMR. the Banff in have the need to not classify those cases as AMR do not all M. Roufosse C. Colvin R.B. et al.The Banff Kidney Meeting of microvascular inflammation and the role of transcript J Transplant. Full Text Full Text PDF Scopus Google Scholar cg+MVI DSA−/C4d− samples be diagnosed as has that active AMR cases displayed gene expression profiles to cases only the first 2 diagnostic criteria for the AMR diagnosis (MVI) in the absence of J. E. de et in kidney with histology of antibody-mediated rejection anti-HLA donor-specific Am Soc Nephrol. 2020; PubMed Scopus Google Scholar comparing cg+MVI DSA−/C4d− with CA-AMR DSA+/C4d+ cases could a of these chronic to improve the classification and the therapeutic In this multicenter intercontinental study, we compared the profiles of for-cause KTx biopsies classified as CA-AMR DSA+/C4d+ with those classified as cg+MVI DSA−/C4d− using the Banff Organ Transplant panel with the innovative NanoString we on a subset of the through orthogonal a state-of-the-art multiplex analysis using 2 on the cell by gene expression analysis. of and is in the multicenter intercontinental study a highly of KTx KTx biopsy samples were from the of the of the cases, and the of cases, with the of this study, samples were for diagnosed with the of and for analysis. transplant the first 2 diagnostic criteria for CA-AMR were in this study patients were classified as CA-AMR as C4d staining of ptcs C4d and showed circulating DSAs. The 14 patients were classified as cg+MVI DSA−/C4d− as not show staining of ptcs C4d 0) and no circulating DSAs. with the TG and were M. Transplant glomerulopathy: not chronic Int. Full Text Full Text PDF PubMed Scopus Google S. M. et pathways to transplant glomerulopathy: chronic humoral and Int. Full Text Full Text PDF PubMed Scopus Google Scholar through the of clinical and The of the cases are in a K. et human organ transplant transcripts with renal allograft and of and Am Soc Nephrol. PubMed Scopus Google Scholar were using the 2019 Banff Classification of Allograft Pathology by 2 and to the study group the cases donor-specific anti-HLA with the using in with a of more were using The between the diagnosis group and the of through for were for the therapeutic of these cases were in the analysis. and were through the of and analysis for expression profiles of KTx biopsies CA-AMR DSA+/C4d+ and 14 cg+MVI were compared one not of for analysis. The Banff Organ Transplant panel using NanoString used to the genes with transplant M. A. Haas M. et 2019 Meeting in solid organ for the Banff Organ Transplant (B-HOT) gene panel and multicenter J Transplant. 2020; 20: Full Text Full Text PDF PubMed Scopus Google Scholar The of the and gene expression analysis of the cases were in a K. et human organ transplant transcripts with renal allograft and of and Am Soc Nephrol. 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In CA-AMR, the of complement is by DSAs to on the endothelial cells of the E. M. J.M. The complement and antibody-mediated transplant Immunol. 2015; PubMed Scopus Google Scholar this the expression of complement-related genes as in the CA-AMR DSA+/C4d+ group can be by the of a more antibody-mediated compared with cg+MVI In a study by Li et et of renal allograft Am Soc Nephrol. 2010; PubMed Scopus Google Scholar to be for a and to KTx rejection. In expression increased in human with acute rejection compared with kidney and long-term allograft and of macrophages were in KTx with or of S. et renal allograft Am Soc Nephrol. PubMed Scopus Google Scholar that KTx biopsies with cg+MVI DSA−/C4d− have expression of and presence and activity compared with KTx biopsies with CA-AMR DSA+/C4d+ is with diagnosed as CA-AMR DSA+/C4d+ have an environment characterized by a of that the of endothelial cells with antibodies can to the of as and N.M. Reed E.F. antibody-mediated endothelial and cell Organ Transplant. 2012; PubMed Scopus Google S. M. et al.The involvement of mechanisms in antibody-mediated 2007; PubMed Scopus Google Scholar through complement could the same cell M. J.M. The role of complement in organ Immunol. 10: PubMed Scopus Google Scholar through a higher of and killer cells in the of samples diagnosed as CA-AMR DSA+/C4d+ compared with samples diagnosed with cg+MVI the increased cell type and expression of the and found in cases with CA-AMR and fibrosis are of in chronic as chronic allograft rejection. The presence of and the dominant cell CA-AMR DSA+/C4d+ samples could these how the expression of from macrophages and cells could in the and endothelial cell in renal and allograft Am Soc Nephrol. PubMed Scopus Google Scholar, and allograft Scopus Google Scholar, M. M. between macrophages and a in Immunol. 10: PubMed Scopus Google Scholar, of the in of Scopus Google Scholar in with J.M. et high risk and risk of kidney transplantation: a study of J Transplant. 2007; 7: Full Text Full Text PDF PubMed Scopus Google Scholar could be a of allograft C. D. M. et donor-specific anti-HLA antibodies are a in and allograft Int. 2017; Full Text Full Text PDF PubMed Scopus (42) Google Scholar The angiogenesis, endothelium, endothelial DSA-selective and interstitial fibrosis and tubular scores in cases with CA-AMR in to the cell type scores and and the increased expression of are in with and of fibrosis not between the 2 study groups. is although with showing how the Banff also not different between study groups, is not with the incidence and of interstitial also that a more and chronic patients diagnosed with CA-AMR DSA+/C4d+ in comparison with those diagnosed with cg+MVI but is to the between these and the the Banff in in on how not all could be to an antibody-mediated In study, samples diagnosed with cg+MVI DSA−/C4d− showed a higher abundance of glomerular cells T cells T and cells T the higher T cells cell type and higher expression of the T gene is in with showing higher T-cell presence in DSA−/C4d− samples when compared with samples diagnosed with AMR A. L. J. et inflammation in the absence of human leukocyte antibody and an in Banff classification with T and natural killer cell J Transplant. 23: Full Text Full Text PDF PubMed Scopus Google Scholar in T cells is not with the of as by the Banff as that between the 2 groups. a role of T activity in the development of transplant subsequent in in the absence of A. E. E. et and of transplant glomerulopathy in the absence of donor-specific Int. Full Text Full Text PDF PubMed Scopus Google M. A. E. et al.The evolution of of antibody-mediated injury, in the presence and absence of donor-specific anti-HLA Int. PubMed Scopus Google Scholar The same activity could to chronic endothelial cell as in the of patients diagnosed with T in chronic Thus, samples fulfilling the criteria for the CA-AMR diagnosis but lacking circulating DSAs and C4d staining of ptcs to be characterized by T-cell activity, a that from samples diagnosed with CA-AMR. on the of cg+MVI DSA−/C4d− with the Banff diagnostic of CA-AMR, with therapeutic with DSA+/C4d+ were characterized by different and that could when compared with cases with cg+MVI as this is also with for characterized by increased interstitial fibrosis and tubular and R.B. J. et in of tubular in kidney allograft a of allograft J Transplant. 2010; 10: Full Text Full Text PDF PubMed Scopus Google Scholar, M. C. et fibrosis and inflammation by an Am Soc Nephrol. 2016; PubMed Scopus Google Scholar, et expression in biopsies of acute rejection and interstitial highly mechanisms that with long-term J Transplant. 2016; 16: Full Text Full Text PDF PubMed Scopus Google Scholar could have a role in the of cases with cg+MVI as all cases of and et with and may of renal in chronic-active antibody-mediated Nephrol. 20: PubMed Scopus Google Scholar have forward a more T this does not exclude the possibility that these 2 could represent 2 different of activity of is to to the of these the new Banff and will help in M. Roufosse C. Colvin R.B. et al.The Banff Kidney Meeting of microvascular inflammation and the role of transcript J Transplant. Full Text Full Text PDF Scopus Google Scholar study has several the of and the the of this study and the high and that we the of samples more the and the 36 samples were to orthogonal analysis the of gene expression analysis on a different the of 2 chronic-active transplant rejection Banff 2 CA-AMR DSA+/C4d+ and the cg+MVI characterized by higher abundance of T cells and complement and more could for a more therapeutic to transplant and of the higher T-cell abundance and activity in cases with cg+MVI In cg+MVI DSA−/C4d− is not as a diagnosis in the Banff Classification of Allograft the presence of a more T-cell dominant in cases with cg+MVI DSA−/C4d− compared with CA-AMR putting forward the possibility that these are not a of AMR and a different is to and to the of these 2 of chronic-active transplant rejection and to differences in and subsequent transplant The no to this The and as has from and and is a for and by has and from and and from and to does not have or at any of these does have or from to other no The gene expression the of this study are in the with The used in the is on at with with of the multiplex staining panels. to the Banff Classification 2019 scoring analysis analysis Full gene expression analysis

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