IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder with frequent renal involvement, but its diagnosis remains challenging due to multi-organ involvement and marked heterogeneity across serological, imaging, and pathological findings. In this dual-center cohort study, we characterized the clinicopathological features of IgG4-related kidney disease (IgG4-RKD) and evaluated the diagnostic value of phospholipase A2 receptor (PLA2R) expression and antineutrophil cytoplasmic antibody (ANCA) seropositivity.

The retrospective study was conducted on 183 patients with suspected IgG4-related disease (IgG4-RD) who received treated at the First Affiliated Hospital of Wenzhou Medical University and the University of Hong Kong–Shenzhen Hospital between April 2014 and December 2025. The diagnosis of IgG4-RD was established according to the 2020 revised comprehensive diagnostic criteria (RCD). 

Renal involvement was observed in 51 of 183 patients with IgG4-RD, of whom 24 underwent renal biopsy. All biopsied cases demonstrated the characteristic pathological features of IgG4-related tubulointerstitial nephritis (IgG4-TIN), including dense lymphoplasmacytic infiltration and storiform fibrosis. Beyond these typical findings, a subset of patients exhibited concurrent immune-mediated or metabolic renal conditions. Among the 24 biopsied patients, 3 (12.5%) had IgG4-related membranous nephropathy (IgG4-MN), 3 (12.5%) showed PLA2R positivity, and 5 (20.8%) were ANCA-positive. In addition, three patients had coexisting metabolic or hypertensive kidney diseases, including diabetic nephropathy, hypertensive nephrosclerosis, and combined hypertensive nephrosclerosis with diabetic nephropathy. These overlapping pathological patterns highlight the diagnostic complexity of IgG4-related kidney disease (IgG4-RKD) in clinical practice.

IgG4-related kidney disease represents a heterogeneous spectrum predominantly characterized by IgG4-related tubulointerstitial nephritis, which can affect multiple renal structures and incidental co-occurrence with other immune-mediated processes.  Importantly, this study challenges rigid diagnostic paradigms by demonstrating that PLA2R positivity or ANCA seropositivity can co-exist with biopsy-proven IgG4-RKD in a subset of patients. These findings suggest that strict application of the 2019 ACR/EULAR classification criteria as diagnostic exclusion tools may lead to underdiagnosis of clinically complex cases. An integrated assessment incorporating renal histopathology and the full clinical context is essential for accurate recognition of IgG4-RKD in real-world practice.