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 A higher resolution version of the Graphical abstract is available as Supplementary information