The Role of Complement in Microangiopathic Lesions of IgA Nephropathy

INTRODUCTION: Arteriolar microangiopathic (MA) lesions are independent risk factors for IgA nephropathy (IgAN) patient prognosis, and the underlying mechanism remains to be elucidated. The complement plays an important role in IgAN and thrombotic microangiopathy; however, its role in MA lesions in IgAN remains unclear. METHODS: Immunohistochemistry was performed to detect arteriolar complement deposition. Enzyme-linked immunosorbent assay (ELISA) and whole-exome sequencing were performed to explore possible mechanism. RESULTS: In this study, we found that patients with IgAN with MA lesions have more complement deposition, especially C4d, on renal arterioles than those in patients with arteriolosclerosis (AS) and patients with no vascular lesions (100% vs. 53% vs. 14%, P < 0.05). Furthermore, our large prospective cohort demonstrated that patients with IgAN with MA lesions had higher levels of Gd-IgA1 (median: 326.98 U/ml, interquartile range 303.46–370.5 vs. 319.22, 292.01–347.3 vs. 321.95, 291.68–350.68, P = 0.014) and C3a (122.57 ± 42.07 vs. 93.79 ± 29.49 vs. 93.51 ± 45.87 ng/ml, P = 0.01) than those in patients with AS and those with no vascular lesions. However, serum IgA1 and C3 levels were not significantly different. Finally, through whole-exome sequencing, we found that nearly half of the patients with MA lesions had rare genetic variations in complement-related genes. CONCLUSION: Our results indicate that the complement is involved in the development of MA lesions in IgAN, which might be associated with the circulating complex containing Gd-IgA1.