Savikko J, Rintala J, von Willebrand Eva
Transplantation Laboratory, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
Transplant Proc. 2006 Dec;38(10):3231-2. doi: 10.1016/j.transproceed.2006.10.083.
Chronic allograft nephropathy (CAN) remains the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CAN. When administered continuously the PDGF receptor tyrosine kinase inhibitor imatinib prevents the development of CAN and restores kidney function in experimental kidney transplantation. Herein we investigated whether early short-term imatinib treatment prevented CAN. Kidney transplantations were performed from DA to WF rats and syngenic controls were done between DA rats. Allograft recipients were immunosuppressed with cyclosporine (CsA; 1.5 mg/kg/d sc). One group of allografts was also treated with imatinib (10 mg/kg/d po). Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry (PDGF-AA, -BB, PDGFR-alpha, -beta). Histological changes were scored according to the Chronic Allograft Damage Index (CADI). Among syngenic grafts, no signs of CAN were observed, namely, CADI 0.3 +/- 0.2 (mean +/- SEM). Control allografts showed moderate to intense chronic changes, CADI 6.5 +/- 1.3. Early short-term imatinib treatment significantly prevented the development of CAN compared with control allografts. Only a few histological changes were seen, namely, CADI 3.3 +/- 1.4. Compared with control allografts PDGF ligand and receptor induction was significantly inhibited by imatinib to nearly the same level as in syngenic grafts. Creatinine values of imatinib-treated allografts were also lower than control allografts. Our results demonstrated that early short-term imatinib treatment significantly prevented CAN. This indicated that early PDGF induction has an important role in the pathogenesis of CAN.
慢性移植肾肾病（CAN）仍然是肾移植中移植肾晚期丢失的主要原因。血小板衍生生长因子（PDGF）是介导CAN中间质细胞增殖的主要促有丝分裂原。在实验性肾移植中，持续给予PDGF受体酪氨酸激酶抑制剂伊马替尼可预防CAN的发生并恢复肾功能。在此，我们研究了早期短期伊马替尼治疗是否能预防CAN。将DA大鼠的肾脏移植到WF大鼠体内，并在DA大鼠之间进行同基因对照移植。移植肾受体用环孢素（CsA；1.5mg/kg/d皮下注射）进行免疫抑制。一组移植肾还用伊马替尼（10mg/kg/d口服）进行治疗。每周测量一次血清肌酐水平。移植90天后取出移植肾进行组织学和免疫组织化学检查（PDGF-AA、-BB、PDGFR-α、-β）。根据慢性移植肾损伤指数（CADI）对组织学变化进行评分。在同基因移植肾中，未观察到CAN的迹象，即CADI为0.3±0.2（平均值±标准误）。对照移植肾显示出中度至重度的慢性变化，CADI为6.5±1.3。与对照移植肾相比，早期短期伊马替尼治疗显著预防了CAN的发生。仅观察到少数组织学变化，即CADI为3.3±1.4。与对照移植肾相比，伊马替尼显著抑制了PDGF配体和受体的诱导，使其水平与同基因移植肾几乎相同。伊马替尼治疗的移植肾的肌酐值也低于对照移植肾。我们的结果表明，早期短期伊马替尼治疗可显著预防CAN。这表明早期PDGF诱导在CAN的发病机制中起重要作用。
