Transforming growth factor-β levels in human allograft chronic fibrosis correlate with rate of decline in renal function

Background.Long-term renal transplant function is limited primarily by a progressive scarring process loosely termed "chronic rejection, chronic allograft nephropathy, or allograft fibrosis," Although the etiology of transplant fibrosis is uncertain, several possible factors including chronic cyclosporin A (CsA) exposure may contribute to its pathogenesis. CsA stimulates renal fibrosis perhaps through the induction of the potent pro-sclerotic growth factor, transforming growth factor beta (TGF beta), previously, we demonstrated that, in human transplant biopsies, acute CsA toxicity but not acute tubular necrosis is associated with elevated levels of renal TGF beta protein. We now examine whether long-term CsA treatment (>1 year) is associated 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 diagnosed as having chronic allograft fibrosis. Biopsies were scored as having minimal or high levels of TGF beta. Results. Seventy-two percent of patients expressed high levels of intra-allograft TGF beta. This group of patients lost renal function at an average rate of -19.5+/-17.3 ml/min/year. In contrast, patients with minimal or no TGF 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 patients with biopsy proven chronic fibrosis have elevated levels of intra-graft TGF beta that correlates with an increased rate of decline in renal function.