Role of macrophages and lymphocytes in the induction of neovascularization in renal allograft rejection.

The aim of this study was to clarify the relationship between angiogenesis and mononuclear cell infiltration in renal allografts. Kidney biopsies from 70 renal transplant recipients were evaluated. The density of CD68, CD3, and HLA-DR-positive infiltrating cells were semiquantitatively assessed by immunohistochemistry. Microvessels were highlighted by immunostaining endothelial cells for factor VIII-RA. Of the 70 patients, 38 showed acute rejection (AR), and 32 showed chronic rejection (CR). The mean microvessel density (MVD) in the AR cases was 931.6 +/- 82 and 481.6 +/- 43.6 in the CR cases. MVD in the controls was 210.4 +/- 21.7. A significant difference was found between the 3 groups (P < 0.001). There were significant positive correlations between MVD and the proportions of the various types of mononuclear cells in the interstitial tissue in both the AR (P < 0.001) and CR (P < 0.001) groups. In the CR group, mean MVD increased in parallel with increasing interstitial fibrosis (P < 0.001). In follow-up biopsies, 23 of 38 patients with AR showed variable degrees of interstitial fibrosis. The mean MVD in the initial biopsy was 537.2 +/- 46.8 in cases that showed no fibrosis in follow-up biopsies, whereas mean MVD in the initial biopsy was 1,196 +/- 98.7 in 23 patients who showed interstitial fibrosis in follow-up biopsies. The difference between these values was significant (P < 0.001). Patients with AR whose initial biopsies showed high MVD developed interstitial fibrosis earlier and had poorer graft outcome than those whose initial biopsies showed low MVD. The results suggest that advanced tubulointerstitial injury and mononuclear cell infiltration may play an important role in the induction of angiogenesis. Mononuclear cells may potentiate interstitial fibrosis in vivo by stimulating neovascularization, which leads to early fibrotic changes and poor outcome.