Continuous indices to assess the phenotypic spectrum of kidney transplant rejection

Abstract

The Banff classification for kidney transplant pathology dichotomizes the rejection continuum into distinct diagnostic categories, introducing artificial cutoff points and threshold effects. To better reflect the underlying disease spectrum, in this cohort study of 19,500 biopsies from 8873 patients across 10 centers worldwide, we developed two indices for quantifying antibody-mediated rejection/microvascular inflammation and T-cell-mediated rejection/tubulointerstitial inflammation from histological lesion scores and calculated indices for overall activity and chronicity. These indices demonstrate excellent discrimination for the main diagnostic categories of rejection (AUCs from 0.95 to 0.99), with consistent performance across derivation and validation datasets. These indices strictly confine intermediate phenotypes to low index values and are associated to graft failure even within the diagnostic categories, thus reflecting the underlying rejection continuum. In this work, we demonstrate that four continuous indices provide implementable and interpretable global evaluation of kidney transplant histology that align with the continuous nature of the rejection process regardless of the underlying disease cause.

Fig. 1. Distribution of the indices among the main Banff diagnoses in the derivation cohort (N = 6272 biopsies).

Antibody-mediated rejection/microvascular inflammation (AMR/MVI) and T-cell-mediated rejection/tubulointerstitial inflammation (TCMR/TI), activity and chronicity indices, ordered by the mean activity index per category (gray vertical line). Both the AMR/MVI and TCMR/TI indices demonstrated logical and hierarchical ordering between No rejection, intermediate (Probable AMR, Borderline TCMR, isolated v) and complete rejection histology, with, in some cases, significant overlap. The activity index demonstrated similar gradual and hierarchical ordering between No rejection biopsies and fully inflamed categories, with intermediate categories (Borderline TCMR, Probable AMR and isolated v) in between. The chronicity index demonstrated low variability among the main diagnostic categories.

Fig. 2. Comparison of the continuous rejection indices to Banff diagnostic categories in all classifiable biopsies, N = 18,778.

Distribution of the individual biopsies per diagnostic category (in red) on the basis of the antibody-mediated rejection/microvascular inflammation (AMR/MVI) (y axis) and T-cell-mediated rejection/tubulointerstitial inflammation (TCMR/TI) indices (x axis). For visualization purposes, only the ‘pure’ phenotypes with no other concomitant diagnoses are displayed. No rejection biopsies are strictly characterized by both low AMR/MVI and low TCMR/TI indices, whereas Mixed rejection cases have both high AMR/MVI and TCMR/TI indices. High heterogeneity in Mixed rejection cases is, however, observed, resulting from the combination of various levels of intensity of the AMR and TCMR phenotypes within this diagnostic category. TCMR and Borderline TCMR cases are contained within clear boundaries of the TCMR/TI index. Probable AMR cases are restricted by a low AMR/MVI index. We note a significant overlap of the MVI_DSA-/C4d- cases with the AMR cases in terms of the AMR/MVI index, although high values of the AMR/MVI index are affected only by biopsies.

Fig. 3. Comparison of the discriminative performance of individual Banff lesions and continuous indices across relevant Banff diagnostic categories.

Panel A shows ROC curves for individual acute Banff lesions, panel B for chronic lesions, and panel C for the derived continuous indices. ROC curves from individual Banff lesions appear stepwise due to the ordinal scoring system (four discrete levels), which limits granularity. In contrast, continuous indices produce smoother and more discriminative curves. Across all diagnostic comparisons, the three acute indices—AMR/MVI, TCMR/TI, and the activity index—consistently outperformed individual lesion scores. As expected, the chronicity index did not discriminate among rejection phenotypes. The lesions selected for each index typically had the highest AUCs within their diagnostic category, supporting their biological and diagnostic relevance.

Fig. 4. Associations between continuous indices and graft failure across Banff categories and cohorts.

Associations with graft failure are shown for the activity (A), chronicity (B), AMR/MVI (C) and TCMR/TI (D) indices. Dots represent hazard ratios (HR) as the measure of centre, and error bars indicate the 95% confidence intervals (CIs). HR are adjusted for time posttransplantation, donor age, recipient age and recipient sex in the three cohorts. HR refers to a one-unit increase in the indices. The corresponding numbers, as well as the subsets sample sizes are reported in Table S14-S15.

Fig. 5. Risk of graft failure across diagnostic categories and index-based stratifications and functional form of index associations.

Kaplan-Meier curves of the AMR-related (A) and TCMR-related (C) Banff diagnostic categories and stratification of the AMR/MVI (B) and TCMR/TI (D) indices in three strata based on arbitrary cut-offs (all cohorts, N = 19,500). No AMR refers to all biopsies that are not AMR, Probable AMR or MVI_DSA-/C4d-. Similarly, No TCMR refers to all biopsies that are not TCMR, Borderline TCMR or isolated v. Note that beyond those non-overlapping categories, concomitant diagnoses are possible (e.g. AMR cases can co-exist with TCMR and Borderline). Due to the negative exponential aspect of the index distributions, the discretization into low, medium and high index, was based on the index value at the 75th and 95th percentiles, corresponding to the following pairs of thresholds: 0.9 and 4.6 and; 1.6 and 4.5, and for the ARM/MVI index and TCMR/TI index, respectively. All Kaplan-Meier curves use the last biopsy per individual. P-values refer to log-rank tests. Shaded areas in panels B and D represent the 95% confidence interval for the Kaplan–Meier survival estimates. E Association of the four indices with the hazard of graft failure. Shaded areas represent the 95% confidence intervals around the model fit. The activity, chronicity and TCMR/TI indices linearly associate with graft outcome (p-value from Wald test for non-linear effect with restricted cubic splines with 3 knots: 0.86, 0.83 and 0.45, respectively). The AMR/MVI index demonstrated slight departures from a strict linear association (p = 0.004). Models based on a random biopsy per patient, all cohorts (N = 19,500).