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.

Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients’ access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations. To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55–3.74, P = 0.001; I² = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05–6.87, P = 0.001; I² = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection. In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification. National Clinical Trial protocol ID: NCT03438058.

The recent recognition of complex and chronic phenotypes of T cell‐mediated rejection (TCMR) has fostered the need to better evaluate the response of acute TCMR − a condition previously considered to lack relevant consequences for allograft survival − to the standard of care. In a prospective cohort of kidney recipients (n=256) with biopsy‐proven acute TCMR receiving corticosteroids, we investigated clinical, histological and immunological phenotypes at the time of acute TCMR diagnosis and 3 months posttreatment. Independent posttreatment determinants of allograft loss included the glomerular filtration rate (GFR) (HR=0.94; 95%CI=0.92‐0.96; p<0.001), proteinuria (HR=1.40; 95%CI=1.10‐1.79; p=0.007), time since transplantation (HR=1.02; 95%CI=1.00‐1.03; p=0.016), peritubular capillaritis (HR=2.27; 95%CI=1.13‐4.55; p=0.022), interstitial inflammation in sclerotic cortical parenchyma (i‐IF/TA) (HR=1.87; 95%CI=1.08‐3.25; p=0.025) and donor‐specific anti‐HLA antibodies (DSAs) (HR=2.67; 95%CI=1.46‐4.88; p=0.001). Prognostic value was improved using a composite evaluation of response to treatment vs clinical parameters only (cNRI=0.68; 95%CI=0.41‐0.95; p<0.001). A classification tree for allograft loss identified five patterns of response to treatment based on the posttreatment GFR, i‐IF/TA and anti‐HLA DSAs (cross‐validated accuracy=0.80). Compared with responders (n=155, 60.5%), nonresponders (n=101, 39.5%) had a higher incidence of de novo DSAs, antibody‐mediated rejection and allograft loss at ten years (p<0.001 for all comparisons). Thus, clinical, histological and immunological assessment of response to treatment of acute TCMR revealed different profiles of the response to treatment with distinct outcomes.

Significance Statement: Differential diagnosis of transplant glomerulopathy, a common lesion observed after kidney transplant that is associated with poor prognosis, remains challenging because its morphologic pattern (double contour of the glomerular basement membrane) is found in several disease processes. The authors used archetype analysis, a probabilistic data-driven unsupervised statistical approach, to identify distinct groups of patients (archetypes) with this condition. By applying this approach to a large, comprehensively phenotyped multicenter cohort from patients diagnosed with transplant glomerulopathy on the basis of post-transplant biopsies, the authors identified five archetypes with distinct clinical, histologic, and immunologic features, as well as different outcomes (kidney allograft survival rates). The findings suggest that an archetype-based characterization of this condition may improve risk stratification for individual patients undergoing kidney transplant and those included in clinical trials. Background: Transplant glomerulopathy, a common glomerular lesion observed after kidney transplant that is associated with poor prognosis, is not a specific entity but rather the end stage of overlapping disease pathways. Its heterogeneity has not been precisely characterized to date. Methods: Our study included consecutive kidney transplant recipients from three centers in France and one in Canada who presented with a diagnosis of transplant glomerulopathy (Banff cg score ≥1 by light microscopy), on the basis of biopsies performed from January of 2004 through December of 2014. We used an unsupervised archetype analysis of comprehensive pathology findings and clinical, immunologic, and outcome data to identify distinct groups of patients. Results: Among the 8207 post-transplant allograft biopsies performed during the inclusion period, we identified 552 biopsy samples (from 385 patients) with transplant glomerulopathy (incidence of 6.7%). The median time from transplant to transplant glomerulopathy diagnosis was 33.18 months. Kidney allograft survival rates at 3, 5, 7, and 10 years after diagnosis were 69.4%, 57.1%, 43.3%, and 25.5%, respectively. An unsupervised learning method integrating clinical, functional, immunologic, and histologic parameters revealed five transplant glomerulopathy archetypes characterized by distinct functional, immunologic, and histologic features and associated causes and distinct allograft survival profiles. These archetypes showed significant differences in allograft outcomes, with allograft survival rates 5 years after diagnosis ranging from 88% to 22%. Based on those results, we built an online application, which can be used in clinical practice on the basis of real patients. Conclusions: A probabilistic data-driven archetype analysis approach applied in a large, well defined multicenter cohort refines the diagnostic and prognostic features associated with cases of transplant glomerulopathy. Reducing heterogeneity among such cases can improve disease characterization, enable patient-specific risk stratification, and open new avenues for archetype-based treatment strategies and clinical trials optimization.