Expression of fibrosis-associated molecules in IgA nephropathy treated with cyclosporine

Cyclosporine (CsA) treatment in immunoglobulin A nephropathy (IgAN) is controversial and has not been widely studied. The aim of this study was to investigate the effects of CsA on renal histology and the expression of interstitial fibrosis-associated molecules in childhood IgAN. The subjects were 18 children (age 4.2-13.9 years; male:female 13:5) who had been treated with CsA for 8 or 12 months and who had renal biopsies before and after treatment. Renal biopsies were assessed by routine histology and immunohistochemistry against osteopontin (OPN), transforming growth factor-beta (TGF-beta), CD68, and CD34. The degree of proteinuria and mesangial IgA deposits decreased or disappeared after treatment in all cases, and the percentage of patients with diffuse mesangial proliferation decreased from 44.4 to 22.2%. However, interstitial fibrosis developed or was aggravated in nine patients (50%) after treatment and was associated with an increased degree of interstitial inflammation in five patients. Tubular OPN expression (45.3 +/- 23.4 vs. 37.6 +/- 19.3%) and the degree of CD68-positive macrophage infiltration (136.1 +/- 88.2 vs. 132 +/- 86.0/mm(2)) were not increased after CsA treatment, but TGF-beta expression was significantly increased (6.4 +/- 4.2 vs. 13.3 +/- 9.9%; p = 0.025). Microvascular density was increased and peritubular capillaries were of small caliber in inflamed areas. We conclude that increased levels of TGF-beta and the development of interstitial fibrosis limit the long-term use of CsA in IgAN patients. Osteopontin and macrophages may be indirectly involved in renal fibrosis by prolonging interstitial inflammation rather than by directly increasing TGF-beta expression.