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

Abstract

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials.

Keywords: classification systems: Banff classification; kidney transplantation/nephrology; molecular biology; pathology/histopathology; rejection; translational research/science.

Figure 1

Representative cases of chronic active T cell–mediated rejection, grades 1A (A, B) and 1B (C, D). Each biopsy specimen shows widespread interstitial inflammation (mainly lymphocytes in A and B; lymphocytes with plasma cells in C and D) with accompanying interstitial edema in areas of the cortex with interstitial fibrosis and tubular atrophy (i‐IFTA score 3). Both biopsy specimens also show tubulitis involving tubules with mild to moderate atrophic changes; this tubulitis is moderate (t2) in A and B and severe (t3) in C and D. There was also mild tubulitis (t1) in nonatrophic tubules in both biopsy specimens, and each specimen also had a total inflammation (ti) score of 2, although this cannot be determined from the photomicrographs. While both biopsy specimens show considerable edema associated with the inflammation, there is also interstitial fibrosis in these areas as is most evident from the darker staining areas of the interstitium in B and D. The yellow arrows indicate tubules with tubulitis; the tubules so indicated are the same tubules in the low‐power and corresponding high‐power photomicrographs (A, B; C, D). Jones methenamine silver stain; original magnification 100× (A, C) or 400× (B, D; scale bars in A and C indicate 50 µm)

Figure 2

Three renal allograft biopsies specimens showing inflammation in areas of interstitial fibrosis and tubular atrophy (i‐IFTA) with varying densities of interstitial fibrosis and degrees of interstitial inflammation, edema, and tubulitis, using 3 different histologic stains. The biopsy specimen in A‐C shows dense interstitial fibrosis but also widespread and focally heavy inflammation in the sclerotic interstitium (i‐IFTA 3) with tubulitis involving several mildly to moderately atrophic tubules, up to score t3 (arrow, B). The biopsy specimen in D‐F also shows dense interstitial fibrosis, but milder inflammation. Although the inflammation in D‐F is fairly diffuse, this was not true in other areas of cortex with fibrosis, and the i‐IFTA score on this biopsy was 2. In addition, there is only mild tubulitis (t1), and as such, this biopsy specimen did not meet criteria for chronic active T cell–mediated rejection. In the biopsy specimen in G‐I, the interstitial fibrosis is focally dense and focally less so with interstitial edema, as is most evident on the trichrome stain in I. There is more variable inflammation (overall i‐IFTA score was 2), although t2 tubulitis is evident in a mildly atrophic tubule (arrow, G). Hematoxylin and eosin (H&E; A, D, G), periodic acid–Schiff (PAS; B, E, H), and Masson trichrome (C, F, I) stains; original magnification 200× (all panels). The scale bar at the bottom right of each panel indicates 50 µm