Corticosteroids augment cyclosporine nephrotoxicity in pediatric nephrotic syndrome: potential role of alternatively activated macrophages

Background: Cyclosporine A (CsA) is an effective steroid-sparing agent for steroid-dependent nephrotic syndrome (SDNS); however, long-term use can cause chronic kidney injury (CsA nephropathy). We previously reported that alternatively activated macrophages (M2-type) are linked to interstitial fibrosis in progressive kidney disease. This study aimed to investigate the potential involvement of M2-type macrophages in CsA nephropathy in SDNS. Methods: Thirty-three children with SDNS treated with CsA for more than 2 years were investigated. Fourteen age-matched SDNS children without CsA served as controls. Kidney fibrosis was assessed by Masson staining. Sections were immunostained for α-SMA, type I collagen, CD68, CD163, and CCL2. Urine levels of CCL2 were measured using a cytometric bead array kit. Results: The CsA-treated group showed greater interstitial fibrosis (12.2 ± 7.3 vs.7.6 ± 2.1%, p < 0.001) and increased CD163⁺CD68⁺ macrophages (10.8 vs.7.9/HPF; p < 0.001). Multivariate analysis identified CD163⁺ infiltration (β = 0.632, p < 0.0001), cumulative prednisolone (PSL) dose during CsA therapy (β = 0.015, p = 0.0031), and cumulative PSL dose from onset to biopsy (β = − 0.005, p = 0.030) as independent predictors of fibrosis. CCN2 and CCL2 co-localized with CD163⁺ macrophages in CsA biopsies. Urinary CCL2/creatinine ratio was higher in the CsA group than controls at relapse (1012 ± 641.2 vs. 239.9 ± 226.9 pg/mg; p = 0.02) and at remission (202.0 ± 178.4 vs. 77.7 ± 127.3 pg/mg; p = 0.04). Conclusion: CD163⁺ M2-type macrophages may contribute to CsA-induced interstitial fibrosis. Steroid treatment during CsA treatment appears to augment CsA nephrotoxicity via pro-fibrotic pathways.