Early short-term platelet-derived growth factor inhibition prevents the development of chronic allograft nephropathy in experimental rat kidney transplantation.
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.
Savikko
J
J
Transplantation Laboratory, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland. johanna.savikko@helsinki.fi
Rintala
J
J
von Willebrand
Eva
E
D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D023421:Models, Animal; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D016572:Cyclosporine