Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy

Transplantation. 2003 Apr 27;75(8):1147-53. doi: 10.1097/01.TP.0000062836.93496.CE.


Background: Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation, and currently there is no treatment available for it. Platelet-derived growth factor (PDGF) is suggested to be a major mitogen mediating mesenchymal cell proliferation in CAN. It has been shown that PDGF is already induced at acute renal allograft rejection, indicating a link between acute rejection and subsequent development of CAN. However, the definite effect of PDGF on the pathogenesis of CAN is still unknown. We investigated the role of PDGF in CAN by inhibiting PDGF by imatinib (STI571), a selective PDGF receptor tyrosine kinase inhibitor.

Methods: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth rats, and syngenic control transplantations were performed from DA to DA rats. All allograft recipients were immunosuppressed with cyclosporine A (1.5 mg/kg/day subcutaneously). One group of the animals was also treated with imatinib (10 mg/kg/day orally). Serum creatinine levels and cyclosporine A concentrations were measured once per week until the animals were killed. Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry.

Results: Only very few histologic chronic changes, similar to syngenic grafts, were seen in imatinib-treated allografts compared with control allografts. Creatinine values of imatinib-treated allograft recipients and infiltration of inflammatory cells, PDGF ligand, and receptor induction were also at the same level as in syngenic grafts.

Conclusions: Our results demonstrate that imatinib prevents CAN almost completely, indicating that PDGF plays an important role in its pathogenesis. On the basis of our findings, imatinib could be a potential intervention in preventing CAN in clinical kidney transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides
  • Chronic Disease
  • Cyclosporine / therapeutic use
  • Enzyme Inhibitors / therapeutic use*
  • Graft Rejection / drug therapy
  • Graft Rejection / pathology
  • Imatinib Mesylate
  • Immunosuppressive Agents / therapeutic use
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Diseases / prevention & control*
  • Kidney Transplantation*
  • Male
  • Piperazines / therapeutic use*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrimidines / therapeutic use*
  • Rats
  • Rats, Inbred Strains
  • Rats, Inbred WF
  • Receptors, Platelet-Derived Growth Factor / antagonists & inhibitors*
  • Transplantation, Homologous
  • Transplantation, Isogeneic


  • Benzamides
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Piperazines
  • Pyrimidines
  • Cyclosporine
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Receptors, Platelet-Derived Growth Factor