GloPath: An Entity-Centric Foundation Model for Glomerular Lesion Assessment and Clinicopathological Insights

Fine-grained glomerular subtyping is essential for kidney biopsy interpretation, yet it presents a harder setting than the broad organ- or disease-level recognition tasks commonly used in vision-language model (VLM) evaluation. In this task, all categories arise within the same renal microanatomic unit, and clinically meaningful subtypes often differ by subtle, overlapping, and continuum-like morphological cues. Clinically valuable labels are also scarce, making fully supervised image-only paradigms difficult to translate to practice. Although VLMs are promising for data-efficient pathology learning, it remains unclear how their cross-modal representations should be adapted and evaluated for such within-structure discrimination under realistic few-shot constraints. To our knowledge, this study establishes the first fine-grained renal pathology benchmark for few-shot VLM adaptation and systematically examines how supervision level, model design, and adaptation strategy shape both classification performance and multimodal representation structure. Beyond accuracy, AUC, and F1, we assess image-text alignment, positive-negative similarity separation, embedding geometry, and calibration (ECE), asking when performance gains reflect more reliable cross-modal understanding. Across renal pathology cohorts, additional supervision consistently improves discrimination, but reliable adaptation is not explained by alignment alone; stronger performance is associated with larger class separation, more coherent embedding organization, and better awareness of confidence-related failure modes under domain variation. Within this retrospective two-cohort evaluation, these findings move assessment beyond coarse classification and accuracy alone and provide comparative evidence to inform model selection and future translational validation. Code: https://github.com/ddrrnn123/glo-vlms

Stain variability is a pervasive source of distribution shift and potential shortcut learning in renal pathology AI. We ask whether lupus nephritis glomerular lesion classifiers exploit stain as a shortcut, and how to mitigate such bias without stain or site labels. We curate a multi-center, multi-stain dataset of 9,674 glomerular patches (224$\times$224) from 365 WSIs across three centers and four stains (PAS, H&E, Jones, Trichrome), labeled as proliferative vs. non-proliferative. We evaluate Bayesian CNN and ViT backbones with Monte Carlo dropout in three settings: (1) stain-only classification; (2) a dual-head model jointly predicting lesion and stain with supervised stain loss; and (3) a dual-head model with label-free stain regularization via entropy maximization on the stain head. In (1), stain identity is trivially learnable, confirming a strong candidate shortcut. In (2), varying the strength and sign of stain supervision strongly modulates stain performance but leaves lesion metrics essentially unchanged, indicating no measurable stain-driven shortcut learning on this multi-stain, multi-center dataset, while overly adversarial stain penalties inflate predictive uncertainty. In (3), entropy-based regularization holds stain predictions near chance without degrading lesion accuracy or calibration. Overall, a carefully curated multi-stain dataset can be inherently robust to stain shortcuts, and a Bayesian dual-head architecture with label-free entropy regularization offers a simple, deployment-friendly safeguard against potential stain-related drift in glomerular AI.

Fine-grained evaluation of glomerular pathology must distinguish normal glomeruli from abnormalities such as global and segmental glomerulosclerosis, obsolescent, ischemic, solidified, disappearing, and atubular glomeruli. Supervised classification requires labeled examples of every category, which is impractical when subtypes are rare or absent from the training cohort. One-class anomaly detection offers an alternative by modeling normal data and scoring deviations, allowing previously unseen abnormalities to be detected. We use the frozen residual U-Net backbone of Omni-Seg, pretrained to segment structurally normal renal primitives without abnormal-subtype labels. We propose NoRDeC (Normal-Reference Detection and Characterization), a framework combining Mahalanobis normal-reference scoring with layer-wise representation analysis to determine whether and where glomerular pathology is encoded, how spatial aggregation affects detection, and whether abnormalities alter inter-layer relationships differently. Using glomerular images from two institutions, we evaluate backbone layers and aggregation strategies, compare NoRDeC with PaDiM and PatchCore, and analyze representations using centered kernel alignment (CKA). Layer 4 with Center-70 aggregation achieved a pooled AUROC of $0.926\pm0.013$. NoRDeC achieved the highest AUROC in six of seven abnormality categories and in the pooled analysis, while CKA suggested subtype-dependent changes in inter-layer relationships not captured by anomaly scores alone. The normal-reference model is fitted using only normal glomeruli; abnormality labels are used for configuration selection, evaluation, and grouping in the representation analysis. These results show that a frozen renal feature extractor can support both detection and representation-level characterization of glomerular abnormalities without using abnormal examples to fit the detector.