Immunofluorescence Patterns in IgAN are Associated With Active, Necrotizing Lesions

IgA nephropathy (IgAN) is characterized by profound heterogeneity, yet therapeutic decisions often rely on a "1-size-fits-all" strategy. As the therapeutic landscape expands to include B-cell and complement-targeting agents, a better understanding of underlying disease mechanisms is increasingly important. This study aimed to identify distinct immunological endotypes and determine their associations with severe, active histological lesions - particularly glomerular necrosis - to guide precision medicine.

We performed a comprehensive retrospective analysis of 284 patients with biopsy-proven IgAN from the Magdeburg Biopsy Registry (2010-2023). Patients with secondary forms of IgAN, including lupus nephritis and infection-associated glomerulonephritis, were strictly excluded. The cohort was characterized by a high burden of advanced disease, reflected by reduced estimated glomerular filtration rate (eGFR) at the time of diagnosis and a high prevalence of chronic histopathological changes on kidney biopsy. Beyond standard mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, and crescents (MEST-C) scoring, we stratified patients into 3 immunofluorescence endotypes as follows: (i) "classic" (IgA, IgM, C3, C1q); (ii) "full-house" (classic + IgG); and (iii) "complement" (IgA + C3/C1q, negative for IgG/IgM). Multivariable logistic regression was used to isolate factors associated with glomerular necrosis.

The "full-house" pattern (26.1%) emerged as a highly aggressive phenotype, showing a 30.1% prevalence of glomerular necrosis - 5 times higher than the "classic" pattern. In multivariable analysis, the "full-house" pattern was the most powerful independent factor associated with necrosis (odds ratio [OR]: 11.32; 95% confidence interval [CI]: 4.17-30.72; P < 0.001). In contrast, the isolated "complement" pattern (9.2%) identified a distinct phenotype of severe functional decline, associated with the worst baseline renal function (median eGFR 20 ml/min per 1.73 m²; P = 0.003).

Immunohistological subtyping unmasks critical endotypes in IgAN that MEST-C scores alone may miss. The "full-house" pattern is a robust marker for necrotizing lesions, potentially driven by IgG-mediated classical pathway activation, whereas the "complement" pattern signals advanced functional loss. These findings improve the biological characterization of IgAN and identify distinct immunopathological subgroups associated with disease severity. Their potential relevance for treatment stratification remains hypothesis-generating and requires validation in prospective studies.