Pathogenesis of Chronic Cyclosporine Nephropathy in Childhood Nephrotic Syndrome

Abstract

  Although the pivotal role of intrarenal renin-angiotensin system (RAS) activation has been demonstrated in the rat model of chronic Cyclosporine (CyA) nephropathy, it is still unclear whether intrarenal RAS activation is responsible for chronic CyA nephropathy in humans. Therefore, the renin distribution of formalin-fixed paraffin embedded renal biopsy specimens obtained from 26 children with idiopathic nephrotic syndrome (NS) treated with long-term moderate dose CyA was examined by immunohistochemistry using rabbit polyclonal anti-human renin antibody. Nineteen patients were steroid-dependent NS and 7 were steroid-resistant NS. However, CyA treatment led all the latter patients into complete remission. All the patients underwent renal biopsies at the start and the end of CyA treatment. Immunoreactivity to renin was mainly detected in the part of arterioles within anatomically well-defined juxtaglomerular apparatus (JGA) in pre-CyA specimells. However, it was also detected in the parts of vessels upstream from JGA in post-CyA specimens. Moreover, the number of renin-positive cells per glomeruli (R-pos-C/G) was significantly increased by long-term CyA treatment (1.26±0.24 vs. 4.30±0.40, p<0.0001). In post-CyA specimens, 11 showed mild or moderate CyA-associated arteriolopathy (CAA), whereas 15 showed no CAA. R-pos-C/G was significantly higher in the specimens with CAA than those without (5.16±0.59 vs. 3.67±0.48, p=0.031). Seven CAA positive patients underwent repeat biopsies 6-12 months after discontinuation of CyA. The specimens after CyA discontinuation showed the improvement of CAA and significantly lower R-pos-C/G compared with the post-CyA specimens (4.18±0.69 vs. 2.10±0.25, p=0,018). In post-CyA specimens, 11 showed mild to moderate interstitial fibrosis, whereas 15 showed no fibrosis. There was no significant difference in immunoreactivity to renin between the specimens with interstitial fibrosis and those without. However, patients having interstitial fibrosis showed significantly longer period of heavy proteinuria during CyA therapy due to steroid-resistant NS or frequent relapses of NS (83±18 vs. 35±12 days, p=0.030). These findings indicate that long-term CyA treatment for idiopathic NS in children may stimulate renin production in arterioles, and suggest that CyA-stimulated intrarenal RAS activation may be responsible for the development of CAA and that CyA-induced interstitial fibrosis may be potentiated by long-term heavy proteinuria, at least in part, independently from CyA-stimulated intrarenal RAS activation.