The podocyte contactome in lupus nephritis: Current evidence and a framework for disease progression.

Lupus nephritis (LN) is initiated by immune-complex deposition, complement activation, and inflammation, but these mechanisms do not fully explain why some glomerular lesions resolve whereas others progress to podocyte depletion, glomerulosclerosis, and fibrosis. We present a conceptual spatial framework in which graded disruption of the podocyte organelle-contact network may contribute to this transition. The framework does not assume that contact-site abundance is uniformly protective or injurious. Contactome remodeling denotes an axis-specific change in contact distance, length, frequency, molecular composition, or organelle positioning, whereas contactome collapse is reserved for a composite state in which abnormalities across multiple contact axes are accompanied by concordant calcium, bioenergetic, redox, degradative, or cytoskeletal failure. Mitochondrial fragmentation, lysosomal redistribution, or urinary mitochondrial and podocyte-derived markers alone do not establish contactome collapse. Direct population-level three-dimensional mapping of podocyte contact sites in human LN biopsies is not yet available; therefore, the model remains a proposed organizing framework rather than an established human disease mechanism. The framework predicts that integrated contact-site metrics should provide information beyond isolated mitochondrial, autophagy, or cytoskeletal markers, precede established podocyte detachment, and improve risk prediction only after adjustment for histologic class, activity and chronicity, proteinuria, kidney function, treatment exposure, and competing kidney injury. These predictions can be tested and refuted through standardized human-biopsy morphometry, longitudinal LN models, perturbation-rescue experiments, and biopsy-linked biomarker cohorts.