Mizoribine halts kidney fibrosis in childhood IgA nephropathy: association with modulation of M2-type macrophages

Background: The immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163⁺ M2-type macrophages which are associated with kidney fibrosis in childhood IgAN. Methods: A retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group; n = 42) or PSL plus Miz (PM group; n = 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray. Results: Clinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163⁺ macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression of CD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163⁺ macrophages was evident in the P group, which was reduced by Miz treatment. Conclusion: Miz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163⁺ and CD163⁺CD300e⁺ macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules. Graphical abstract: [Figure not available: see fulltext.].