Intensity of Macrophage Infiltration in Glomeruli Predicts Response to Immunosuppressive Therapy in Patients with IgA Nephropathy

Significance Statement The lack of a tool for predicting the response to immunosuppressive therapy in IgA nephropathy (IgAN) limits patient-specific risk stratification and early treatment decisions. To derive and validate the models for predicting response to immunosuppressive therapy in IgAN that can be applied at the time of kidney biopsy, the authors conducted a prospective cohort study of 621 Chinese patients with IgAN. Patients had persistent proteinuria of ?1 g/d, despite 3 months of optimized supportive care with renin-angiotensin system inhibitors, and received immunosuppressive therapy. The authors used immunohistochemistry to identify cellular infiltrates in biopsy specimens and digital image analysis to quantify them. The intensity of glomerular macrophage infiltration, alone or combined with clinical and histologic data, accurately predicted the response to immunosuppression and, thus, may help physicians identify patients with IgAN who will benefit from immunosuppression. Background The lack of a tool for predicting the response to immunosuppressive therapy in IgA nephropathy (IgAN) limits patient-specific risk stratification and early treatment decision making. Models for predicting response to immunosuppression in IgAN that can be applied at the time of kidney biopsy are needed. Methods This prospective cohort study involved 621 Chinese patients with IgAN who were at high risk for disease progression and had persistent proteinuria ?1 g/d, despite 3 months of optimized supportive care with renin-angiotensin system inhibitors. Participants received immunosuppressive therapy for a median of 18 months. We used immunochemistry to identify macrophage and lymphocyte infiltrates in biopsy specimens and digital image analysis to quantify them. The outcome was response to immunosuppression, defined as complete or partial remission within 12 months of immunosuppression. Results Kidney infiltration of CD68(+) and CD206(+) macrophages increased in patients with IgAN. Having higher levels of glomerular CD206(+) macrophage infiltration was associated with a 40-fold increased probability of response to immunosuppression in adjusted analysis compared with having lower levels. Patients with a higher intensity of glomerular CD68(+) infiltrates had a 13-fold increase in probability of responding to immunosuppression. Intensity of glomerular CD206(+) and CD68(+) macrophage infiltration predicted the response to immunosuppression (area under the curve [AUC], 0.84; 95% CI, 0.81 to 0.88). The AUC increased to 0.87 (95% CI, 0.84 to 0.91) in a model combining the infiltration score of CD206(+) and CD68(+) infiltrates with the MEST-C score and clinical data at biopsy. Conclusions Intensity of glomerular macrophage infiltration predicted response to immunosuppressive therapy in patients with IgAN who were at high risk of progression, and may help physicians identify patients who will benefit from such treatment.

Automated summary

The study found that higher levels of glomerular CD206(+) macrophage infiltration in IgAN patients were associated with a 40-fold increased probability of response to immunosuppression, while those with higher intensity of glomerular CD68(+) infiltrates had a 13-fold increase in probability of responding to immunosuppression. The intensity of glomerular CD206(+) and CD68(+) macrophage infiltration accurately predicted the response to immunosuppression, and combining these with the MEST-C score and clinical data at biopsy further improved the predictive ability.