NDT Advance Access originally published online on June 16, 2008
Nephrology Dialysis Transplantation 2008 23(11):3446-3455; doi:10.1093/ndt/gfn340
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FK778 ameliorates post-transplant expression of fibrogenic growth factors and development of chronic rejection changes in rat kidney allografts*
1 Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki 2 Department of Surgery, Päijät-Häme Central Hospital, Lahti, Finland
Correspondence and offprint requests to: Jukka M. Rintala, Transplantation Laboratory, University of Helsinki, PO Box 21 (Haartmaninkatu 3), FIN-00014, Finland. Tel: +358-9-19126596; Fax: +358-9-2411227; E-mail: jukka.m.rintala{at}helsinki.fi
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Abstract |
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Background. Acute rejection is the major risk factor for the development of subsequent chronic allograft nephropathy (CAN), which is the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) are the main mitogens mediating mesenchymal cell proliferation. Their early post-transplant induction may start cascades leading to the development of CAN. An immunosuppressive drug, FK778, inhibits de novo pyrimidine biosynthesis and several receptor tyrosine kinases (RTKs). Here we investigated its effects on acute and chronic rejection as well as post-transplant PDGF and TGF-β expression in combination therapy with calcineurin inhibitors (CNIs).
Methods. Kidney transplantations were performed from DA to WF rats. Syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed with a combination of FK778 (10 mg/kg/day p.o.) and CsA (1.5 mg/kg/day s.c.) or tacrolimus (Tac) (1.5 mg/kg/day p.o.). Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry (PDGF-A, PDGF-B, PDGFR-
, PDGFR-β, TGF-β, TGF-βR). The dose response of FK778 on acute rejection was studied with monotherapy of 5, 10 and 20 mg/kg/day. Chronic changes were scored according to the Chronic Allograft Damage Index (CADI).
Results. FK778 ameliorated the early post-transplant inflammatory response dose dependently. Additive effects were seen with FK778 and CNIs. Significantly lower CADI scores were seen in combination therapy of FK778 and CNIs compared with CNI monotherapies. FK778 also significantly reduced both early and late PDGF and TGF-β expression when combined with CNIs.
Conclusions. These results indicate that FK778 could prevent the development of CAN and be a promising therapy also in clinical kidney transplantation.
Keywords: acute rejection; chronic allograft nephropathy; FK778; PDGF; TGF-β
* Contribution of individual authors: Jukka M Rintala (designing, drafting the article, providing intellectual content, final approval of the version to be published), Johanna Savikko (designing, drafting the article, providing intellectual content, final approval of the version to be published), Sini E Rintala (drafting the article, providing intellectual content, final approval of the version to be published), Eva von Willebrand (designing, providing intellectual content, final approval of the version to be published).
Received for publication: 9.12.07
Accepted in revised form: 22. 5.08