Tubuloreticular Inclusions in Kidney Tissues of Patients with Lupus Nephritis: An Ultrastructural Biomarker of Type I Interferon-Driven Disease Activity.

BACKGROUND

Tubuloreticular inclusions (TRIs) in kidney tissues associate with type I interferon (IFN-I) pathway activation, but their clinical and pathological significance in lupus nephritis (LN) remains incompletely defined.

METHODS

We conducted a retrospective cohort study of 327 patients with biopsy-confirmed LN at the National Clinical Research Center for Kidney Diseases from January 2023 to December 2025. TRIs were identified in kidney tissues by transmission electron microscopy in both glomerular endothelial cells (GEC) and peritubular capillary (PTC) endothelial cells. For semi-quantitative assessment, 10 capillary loops per glomerulus and 10 peritubular capillaries per case were examined; in cases with more than one glomerulus, loops were randomly selected from each glomerulus and the maximum score across all glomeruli was recorded as the GEC-TRI grade. The final TRI grade for each case was defined as the higher of the GEC-TRI and PTC-TRI grades, classified as grade 0 (no TRIs), grade 1 (TRIs in 1 of 10 capillary profiles) or grade 2 (TRIs in ≥2 of 10 capillary profiles), with patients subsequently grouped as TRI-negative (grade 0) or TRI-positive (grade 1 or 2). Clinical, pathological, immunofluorescence and extrarenal manifestations were compared between groups. In a subset, peripheral blood RNA sequencing was performed to calculate IFN I scores and assess pathway activation.

RESULTS

TRIs were observed in 207 of 327 patients (63.3%). Pathologically, TRI-positive patients exhibited lower chronicity index, higher frequency of segmental loop necrosis, along with reduced rates of vascular lesions, interstitial fibrosis and tubular atrophy (all P < 0.05). On immunofluorescence, increased deposition of IgM and C1q and a higher prevalence of full-house pattern were observed in TRI-positive patients (all P < 0.05); C3 deposition showed a significant stepwise increase across TRI grades (P = 0.03), though the dichotomized comparison was not significant (P = 0.06). Clinically, they had higher SLE Disease Activity Index scores, increased urinary red blood cell counts and elevated proteinuria (all P < 0.05). They also demonstrated lower serum complement levels, increased immunoglobulin levels (e.g., IgA) and higher prevalence of multiple autoantibodies (e.g., anti-dsDNA; all P < 0.05). TRI-positive patients also showed heightened IFN-I signatures and higher prevalence of extrarenal manifestations, including mucocutaneous, musculoskeletal, hematological, pulmonary involvement, serositis and organic brain syndrome (all P < 0.05).

CONCLUSION

TRIs are highly prevalent in kidney tissues of patients with LN. They identify a distinct IFN-I-driven disease subset, offering a practical histopathological marker of heightened activity and potential target for therapeutic stratification.