The relationship between pathologic lesions of active and chronic antibody-mediated rejection in renal allografts

Abstract

The Banff classification of renal allograft pathology defines specific morphologic lesions that are used in the diagnosis of active (glomerulitis, peritubular capillaritis, endarteritis) and chronic (transplant glomerulopathy, peritubular capillary basement membrane multilayering, transplant arteriopathy) antibody-mediated rejection (ABMR). However, none of these individual lesions are specific for ABMR, and for this reason Banff requires 1 or more additional findings, including C4d deposition in peritubular capillaries, presence of circulating donor-specific antibodies (DSAs), and/or expression in the tissue of transcripts strongly associated with ABMR, for a definitive diagnosis of ABMR to be made. In addition, while animal studies examining serial biopsies have established the progression of morphologic lesions of active to chronic ABMR as well as intermediate forms (chronic active ABMR) exhibiting features of both, clear documentation that lesions of chronic ABMR require the earlier presence of corresponding active and intermediate lesions is less well established in human renal allografts. This review examines temporal relationships between key morphologic lesions of active and chronic ABMR in biopsies of human grafts, likely intermediate forms, and findings for and possibly against direct and potentially interruptible progression from active to chronic lesions.

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection

“…Since the introduction of ABMR into the Banff classification in 2003, 14 the criteria for diagnosis of ABMR have become more complex, with major modifications in 2013 15 and 2017, 5 which have improved diagnostic sensitivity and predictive value for graft outcomes 16 . A major residual issue within the classification is that it still subclassifies ABMR into active or chronic active and chronic inactive (ie, transplant glomerulopathy without MVI and with current or historic DSA; Table 4) subtypes as opposed to representing the diverse morphologic and molecular lesions at different posttransplant time points in antibody‐mediated tissue injury 17,18 . In particular, the category of CA ABMR encompasses lesions with severe activity and mild chronicity (eg, g3 ptc3 cg1 ci0 ct0 C4d3), those with mild activity and severe chronicity (eg, g1 ptc1 cg3 ci3 ct3 C4d0), and intermediate cases.…”

The therapeutic challenge of late antibody‐mediated kidney allograft rejection

“…Another (invasive) surrogate endpoint may be the read‐out of systematic follow‐up biopsies. Lesions reflecting microcirculation inflammation are well‐known to be associated with the development of chronic lesions, such as transplant glomerulopathy or basement membrane multilayering in peritubular capillaries , and chronic microcirculation injury has shown to be a strong predictor of graft survival . In addition, one may argue that detecting patterns of transcript expression that specifically reflect the extent of rejection and injury may help to dissect treatment responsiveness (or nonresponsiveness) early after initiation of a given intervention.…”

Outstanding questions in transplantation: B cells, alloantibodies, and humoral rejection

“…In addition to IgG binding to the graft endothelium, other upstream triggers may result in C4d deposition, including mannose residues and bacterial toxins that activate the lectin and alternative complement activation pathways, respectively. Finally, despite the stability of C4d, there are many instances in which evaluation of the biopsy specimen shows signs of chronic antibody‐mediated rejection but lacks C4d deposition . This scenario has led to the development of complementary techniques, such as the microarray‐based molecular characterization of biopsies for AMR, which are less dependent on contemporaneous C4d deposition, and more dependent on gene expression profiles thought to be consistent with antibody‐mediated pathology .…”

“…Finally, the entire paradigm of chronic AMR was challenged by Fadi Lakkis, who pointed out that Koch's postulates have not been fulfilled and noted that “it is difficult to prove a pathogenic role for antibodies unless they are present in high titers” and that “the pathologic criteria are not pathognomonic of antibody‐mediated tissue injury and could be caused by other mediators.” He raised the provocative question of whether DSA was pathogenic and driving rejection, or simply a marker of a mature immune response where other cells are actually mediating graft rejection. Indeed, many of the histologic features of chronic rejection including transplant glomerulopathy and transplant arteriopathy can be seen in conditions other than antibody‐mediated injury . Although, studies investigating transplant recipients with positive crossmatches at the time of transplant and protocol biopsies do indicate a progressive evolution from glomerulitis to transplant glomerulopathy, a causal relationship of antibodies per se and the contribution of other immune cells cannot be established in such studies .…”