Letter to AJT editor re: Nankivell et al

To the Editor: We read with interest the analysis of inflammation in areas of atrophy scarring (i-IFTA) in renal transplant biopsies by Nankivell et al1Nankivell BJ, Shingde M, Keung KL, et al. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: the Banff i-IFTA lesion [published online ahead of print 2017]. Am J Transplant. https://doi.org/10.1111/ajt.14609.Google Scholar concluding that this represents chronic active T cell–mediated rejection (TCMR). This theme is also advocated by another recent publication2Lefaucheur C, Gosset C, Rambant M, et al. T cell-mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts [published online ahead of print 2017]. Am J Transplant. https://doi.org/10.1111/ajt.14565.Google Scholar and by the forthcoming Banff report,3Haas 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 [published online ahead of print 2017]. Am J Transplant. https://doi.org/10.1111/ajt.14625.Google Scholar contradicting the previous Banff consensus opinion that i-IFTA lesions are a reflection of injury and a risk for progression but not a sign of active TCMR. We write because molecular analyses do not support the conclusion that i-IFTA indicates chronic active TCMR. Inflammation is a well-known feature of recent or active nephron injury and is seen in many primary renal diseases in native kidneys.4Marcussen N Lai R Olsen TS Solez K Morphometric and immunohistochemical investigation of renal biopsies from patients with transplant ATN, native ATN, or acute graft rejection.Transplant Proc. 1996; 28: 470-476PubMed Google Scholar, 5Yu F Wu LH Tan Y et al.Tubulointerstitial lesions of patients with lupus nephritis classified by the 2003 International Society of Nephrology and Renal Pathology Society system.Kidney Int. 2010; 77: 820-829Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 6Berden AE Jones RB Erasmus DD et al.Tubular lesions predict renal outcome in antineutrophil cytoplasmic antibody-associated glomerulonephritis after rituximab therapy.J Am Soc Nephrol. 2012; 23: 313-321Crossref PubMed Scopus (93) Google Scholar, 7Ferrario F Vanzati A Pagni F Pathology of ANCA-associated vasculitis.Clin Exp Nephrol. 2013; 17: 652-658Crossref PubMed Scopus (12) Google Scholar In renal transplants, this will be associated with progression when compared to controls that have atrophy scarring, with no inflammation because inflammation in areas of atrophy scarring indicates a more active or recent injury process than atrophy fibrosis with no inflammation, reflecting recent or ongoing stress. In some cases, this will follow severe treated TCMR, often due to nonadherence, but this does not justify the conclusion that the cognate TCMR process is still active. Successful treatment of TCMR will usually sterilize the cognate process, leaving nephron injury that resolves with atrophy fibrosis that will initially be inflamed (ie, i-IFTA). Active TCMR is best diagnosed by molecular classifiers, which correlate with the current histology definition of TCMR. We analyzed 234 indication biopsies scored for histologic i-IFTA by one pathologist who was blinded to molecular results (Table 1). Frequency of graft failures was high after i-IFTA>0 biopsies, as expected. However, by histology most biopsies with i-IFTA>0 are classified as having no rejection or having antibody-mediated rejection (ABMR), but not TCMR. Although one might argue that i-IFTA cannot be diagnosed as TCMR because the existing Banff criteria are wrong, Molecular microscope (MMDx)8Reeve J Bohmig GA Eskandary F et al.Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes.JCI Insight. 2017; 2 (pii:): 94197Crossref PubMed Google Scholar analysis also showed no increase in molecular TCMR in i-IFTA versus other biopsies, although there was an increase in molecular ABMR. (In i-IFTA biopsies, more graft losses followed molecular diagnosis of ABMR [48%] than TCMR [8%].) In terms of molecular scores, the dominant features of the i-IFTA>0 group was higher acute kidney injury (AKI) scores and higher ABMR scores but not higher TCMR scores. Nevertheless i-IFTA showed increased expression of T cell transcripts (quantitative effector T cell transcripts; QCATs), reflecting the observed nonspecific T cell infiltrate, but not of TCMR.TABLE 1Histologic and molecular rejection in 234 biopsies with known i-IFTA status: most i-IFTA biopsies have no TCMR but often have ABMRPhenotypes comparedAll i-IFTA = 0 (n=126)ci>0, i-IFTA>0 (n=108)Graft failuresNumber of failures21 (17%)50 (46%)**P<.0001 by Fisher exact test comparing i-IFTA>0 vs i-IFTA=0.Histologic diagnosisABMR/TG13 (10%)33**P<.0001 by Fisher exact test comparing i-IFTA>0 vs i-IFTA=0. (31%)bPercentage of total number of biopsies in the group.Mixed69TCMR11 (9%)9 NS (8%)No rejection96 (76%)57 (53%)Molecular (MMDx) diagnosis*MMDx diagnoses were assigned by the highest archetype score.ABMR17 (13%)40**P<.0001 by Fisher exact test comparing i-IFTA>0 vs i-IFTA=0. (37%)Mixed53TCMR4 (3%)7 NS (6%)No rejectionaHistologic no rejection diagnoses contained AKI, BK virus, borderline, glomerulonephritis, IFTA, and other.100 (79%)58 (54%)Mean molecular scoresAKI scorecMean TCMR classifier scores are below the positivity cut off.0.260.52***P<.0001 by Mann-Whitney test comparing i-IFTA>0 vs i-IFTA=0.QCAT scorecMean TCMR classifier scores are below the positivity cut off.0.721.16***P<.0001 by Mann-Whitney test comparing i-IFTA>0 vs i-IFTA=0.ABMR classifier score0.140.31***P<.0001 by Mann-Whitney test comparing i-IFTA>0 vs i-IFTA=0.TCMR classifier score0.06aHistologic no rejection diagnoses contained AKI, BK virus, borderline, glomerulonephritis, IFTA, and other.0.09NS, cMean TCMR classifier scores are below the positivity cut off.AKI, acute kidney injury transcripts; QCAT, quantitative effector T cell transcripts; NS, not significant.a Histologic no rejection diagnoses contained AKI, BK virus, borderline, glomerulonephritis, IFTA, and other.b Percentage of total number of biopsies in the group.c Mean TCMR classifier scores are below the positivity cut off.* MMDx diagnoses were assigned by the highest archetype score.** P<.0001 by Fisher exact test comparing i-IFTA>0 vs i-IFTA=0.*** P<.0001 by Mann-Whitney test comparing i-IFTA>0 vs i-IFTA=0. Open table in a new tab AKI, acute kidney injury transcripts; QCAT, quantitative effector T cell transcripts; NS, not significant. Thus, the strongest molecular correlate of i-IFTA is actually the expression of renal injury-repair transcripts (AKI score),9Famulski KS Reeve J de Freitas DG Kreepala C Chang J Halloran PF Kidney transplants with progressing chronic kidney diseases express high levels of acute kidney injury transcripts.Am J Transplant. 2013; 13: 634-644Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar not molecular TCMR scores, and biopsies with i–IFTA often have AKI scores but no rejection.9Famulski KS Reeve J de Freitas DG Kreepala C Chang J Halloran PF Kidney transplants with progressing chronic kidney diseases express high levels of acute kidney injury transcripts.Am J Transplant. 2013; 13: 634-644Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The source of injury was often ABMR, and in some cases recurrent glomerulonephritis or previously treated TCMR. In general, TCMR scores are not a strong predictor of graft loss,10Halloran PF Chang J Famulski K et al.Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients.JASN. 2015; 26: 1711-1720Crossref Scopus (129) Google Scholar and TCMR is rare after 10 years, whereas i-IFTA can be found at any time.10Halloran PF Chang J Famulski K et al.Disappearance of T cell-mediated rejection despite continued antibody-mediated rejection in late kidney transplant recipients.JASN. 2015; 26: 1711-1720Crossref Scopus (129) Google Scholar We conclude that i-IFTA lesions should not be taken as chronic active TCMR unless new evidence is presented.1Nankivell BJ, Shingde M, Keung KL, et al. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: the Banff i-IFTA lesion [published online ahead of print 2017]. Am J Transplant. https://doi.org/10.1111/ajt.14609.Google Scholar It is a serious error to mistake nonspecific T cell infiltrates in damaged tissue for active TCMR, subjecting patients to potential harm without benefit. P F Halloran holds shares in Transcriptome Sciences Inc., a company with an interest in molecular diagnostics. K S Famulski has no competing financial interests.

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