Transforming growth factor-beta levels in human allograft chronic fibrosiscorrelate with rate of decline in renal function

Background.Long-term renal transplant function is limited primarily by a pr ogressive scarring process loosely termed "chronic rejection, chronic allog raft nephropathy, or allograft fibrosis," Although the etiology of transpla nt fibrosis is uncertain, several possible factors including chronic cyclos porin A (CsA) exposure may contribute to its pathogenesis. CsA stimulates r enal fibrosis perhaps through the induction of the potent pro-sclerotic gro wth factor, transforming growth factor beta (TGF beta), previously, we demo nstrated that, in human transplant biopsies, acute CsA toxicity but not acu te tubular necrosis is associated with elevated levels of renal TGF beta pr otein. We now examine whether long-term CsA treatment (>1 year) is associat ed with elevated levels of intra-allograft TGF beta and whether heightened expression of TGF beta is clinically significant. Methods, Using immunohistochemical. techniques, we determined the relative level of expression of intrarenal TGF beta protein in transplant biopsies. We studied biopsies obtained from 40 CsA-treated patients that were diagnos ed as having chronic allograft fibrosis. Biopsies were scored as having min imal or high levels of TGF beta. Results. Seventy-two percent of patients expressed high levels of intra-all ograft TGF beta. This group of patients lost renal function at an average r ate of -19.5+/-17.3 ml/min/year. In contrast, patients with minimal or no T GF beta expression experienced a decline of only -6.2+/- 4.1 ml/min/year (P =0.01). Conclusions. These results suggest that the majority of CsA-treated patient s with biopsy proven chronic fibrosis have elevated levels of intra-graft T GF beta that correlates with an increased rate of decline in renal function .