Low-density granulocyte-driven NET formation is associated with poor prognosis in IgA nephropathy with thrombotic microangiopathy.

Introduction

Thrombotic microangiopathy (TMA) is a common pathological phenotype of immunoglobulin A nephropathy (IgAN). Low-density granulocytes (LDGs) exhibit potent pro-inflammatory properties and promote neutrophil extracellular trap (NET) formation, playing a pivotal role in thrombus development. This study aims to investigate the long-term prognosis of IgAN-TMA and explore the role of LDGs in its pathogenesis.

Methods

Sixty patients with IgAN-TMA and 249 high-risk IgAN controls were included. LDGs (CD14^lowCD15^high) were quantified via flow cytometry among 15 IgAN-TMA patients, 20 IgAN patients, and 15 healthy controls. Serum dsDNA and MPO-DNA complex levels were quantified via PicoGreen and ELISA, respectively. Serum-induced NET formation was assessed with fluorescence microscopy.

Results

Compared with controls, IgAN-TMA patients showed more adverse clinico-pathological profiles. TMA was identified as independently associated with adverse renal outcomes and poor renal prognosis in IgAN. Additionally, IgAN-TMA patients had a significantly higher proportion of circulating LDGs, correlating with disease severity. Furthermore, IgAN-TMA patients exhibited increased levels of circulating dsDNA and MPO-DNA complexes, serum from these patients significantly induced NET formation.

Conclusions

IgAN-TMA prognosis is worse than that of high-risk IgAN. LDGs are significantly elevated and correlate with the severity of the pathogenic process in IgAN-TMA, warranting further extensive investigation.