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

Influence of Intrauterine Inflammation, Delivery, and Postnatal Feeding on the Temporal Changes of Serum Alpha 1 Acid Glycoprotein Levels in Extremely-Low-Birth-Weight Infants.

Infection remains the primary cause of death in extremely-low-birth-weight infants (ELBWIs). Alpha 1 acid glycoprotein (α1AG), an acute-phase protein, has been shown to be elevated in sporadic cases of septic ELBWIs prior to abnormal clinical signs. To delineate the roles of inflammation, delivery, and feeding in postnatal α1AG changes in ELBWIs, 75 ELBWIs of 26.5 ± 2.2 weeks of gestation born between May 2011 and August 2017 were retrospectively studied. The dependence of α1AG levels obtained on days 0−5 on the clinical variables was examined by incorporating interactions with age, followed by estimations of regression coefficients between clinical variables and α1AG levels at the early and late postnatal ages, defined by their standard deviation. Chorioamnionitis (p < 0.001), funisitis (p = 0.045), vaginal delivery (p = 0.025), enteral feeding (p = 0.022), and probiotics (p = 0.005) were associated with early α1AG elevations. Hypertensive disorder of pregnancy (p < 0.001) and gestational age (p = 0.001) were associated with late α1AG elevation; premature rupture of membranes (p < 0.001), funisitis (p = 0.021), body weight z-scores (p < 0.001), and enteral feeding (p = 0.045) were associated with late α1AG reduction. Postnatal α1AG changes in ELBWIs were associated with variables representative of age, growth, delivery, inflammation, and enteral feeding, potentially reflecting the process of sensitization to extrinsic microbes in utero, at birth, and thereafter.