TRANSFORMING GROWTH FACTOR-?? LEVELS IN HUMAN ALLOGRAFT CHRONIC FIBROSIS CORRELATE WITH RATE OF DECLINE IN RENAL FUNCTION1

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Abstract
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 β (TGFβ). Previously, we demonstrated that, in human transplant biopsies, acute CsA toxicity but not acute tubular necrosis is associated with elevated levels of renal TGFβ protein. We now examine whether long-term CsA treatment (>1 year) is associated with elevated levels of intra-allograft TGFβ and whether heightened expression of TGFβ is clinically significant. Using immunohistochemical techniques, we determined the relative level of expression of intrarenal TGFβ 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 TGFβ. Seventy-two percent of patients expressed high levels of intra-allograft TGFβ. 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 TGFβ expression experienced a decline of only −6.2±4.1 ml/min/year (P=0.01). These results suggest that the majority of CsA-treated patients with biopsy proven chronic fibrosis have elevated levels of intra-graft TGFβ that correlates with an increased rate of decline in renal function.