Microangiopathic lesions associated with poor immunosuppressive therapy response in IgA nephropathy

Abstract Background and Hypothesis Renal arteriolar microangiopathic lesions are frequently observed in immunoglobulin A nephropathy (IgAN). However, their impact on the response to immunosuppressive therapy remains unclear. This study aimed to evaluate the association between these lesions and treatment response in patients with IgAN. Methods In this prospective cohort study, we included 620 patients with biopsy-proven primary IgAN who had persistent proteinuria ≥1 g/d despite at least 3 months of optimized supportive care with renin-angiotensin system inhibitors (RASi) and subsequently received immunosuppressive therapy for >6 months. Renal arteriolar microangiopathic lesions were independently reviewed by two pathologists. The primary outcome was treatment response, defined as a ≥50% reduction in proteinuria from baseline to <1 g/day, combined with an estimated glomerular filtration rate (eGFR) decline of <25%. Logistic regression, propensity score matching (PSM), and subgroup analyses were used to assess the association between microangiopathic lesions and treatment response. Results Among the 620 enrolled patients, 154 (24.8%) had renal arteriolar microangiopathic lesions. Compared to patients without microangiopathic lesions, those with microangiopathic lesions had higher blood pressure, more severe proteinuria, and lower eGFR. The non-response rate to immunosuppressive therapy was significantly higher in patients with microangiopathic lesions than in those without (61.0% vs. 26.2%). Multivariable logistic regression indicated that the presence of microangiopathic lesions was independently associated with an increased risk of non-response (odds ratio 4.04, 95% confidence interval 2.61-6.25). This association remained consistent after PSM and across all prespecified subgroups. Conclusion Renal arteriolar microangiopathic lesions are relatively common in IgAN and are associated with worse clinical outcomes and poorer response to immunosuppressive therapy. These findings suggest that conventional immunosuppression may be less effective for this high-risk subgroup, necessitating further research into targeted therapeutic strategies.