SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts.
BACKGROUND
Chronic rejection remains the most frequent cause of renal graft loss over the long term. However, effective treatment of this process is not yet available. SDZ-RAD (40-O-[2-hydroxyethyl]-rapamycin) is a new, orally active rapamycin derivative with potent immunosuppressive activity. We have examined the effects of SDZ-RAD in a well-established model of chronic renal allograft rejection in rats.


METHODS
Kidneys of Fisher (F334) rats were orthotopically transplanted into bilaterally nephrectomized Lewis recipients. To suppress an initial episode of acute rejection, rats were briefly treated with low doses of cyclosporine for the first 10 days. Thereafter they received either SDZ-RAD (0.5 mg/kg(day) or vehicle. At 24 weeks, functional evaluations were performed, kidneys were harvested, and histological, immunohistological, and reverse transcription-polymerase chain reaction evaluations were performed.


RESULTS
Animals treated with SDZ-RAD developed lower proteinuria and less glomerulosclerosis as compared with controls. Additionally SDZ-RAD reduced the infiltration of macrophages and lymphocytes and the expression of intercellular adhesion molecule-1, laminin, and fibronectin. Furthermore, we observed a reduced expression of growth factor mRNA (transforming growth factor-beta and platelet-derived growth factor-AA) in these animals.


CONCLUSIONS
Our results demonstrated that SDZ-RAD effectively ameliorates chronic renal allograft rejection in rats, probably mediated by suppression of growth factors.
Viklický
O
O
Department of Nephrology, University Hospital, Essen, Germany.
Zou
H
H
Müller
V
V
Lacha
J
J
Szabó
A
A
Heemann
U
U
D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D000068338:Everolimus; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology; D006084:Graft Rejection / Q000517:prevention & control; D006133:Growth Substances / Q000235:genetics; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007668:Kidney / Q000737:chemistry; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000276:immunology
D006133:Growth Substances; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus