Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis. Methods. We investigated the involvement of tTg and its crosslink product, ε-(γ-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques. Results. From implantation, tTg (+266%) and ε-(γ-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P<0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P<0.001) and ε-(γ-glutamyl) lysine bonds (+465%, P<0.01) that correlated with interstitial fibrosis (r=0.843, P=0.009 and r=0.622, P=0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and ε-(γ-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P=0.04). Conclusions. tTg and ε-(γ-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target.
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