Treatment of chronic renal allograft rejection in rats with a low-molecular-weight heparin (reviparin).
BACKGROUND
Low-molecular-weight heparin (LMWH) has been shown to prolong survival of rat cardiac allografts independently from immunosuppressive treatment. Furthermore, long-term treatment reduces the development of chronic graft vascular disease after experimental heart transplantation. The aim of the present study was to determine whether treatment with the LMWH reviparin has a beneficial effect on chronic rejection in a rat renal allograft model.


METHODS
Kidneys of Fisher (F344) rats were transplanted into unilaterally nephrectomized Lewis (LEW) recipients. LEW-->LEW isografts served as controls. Animals were treated with cyclosporine (5 mg/kg/d) for the first 10 days. Nephrectomy of the remaining kidney was performed after 10 days. Allografted animals were treated either with reviparin (2 mg/kg/d subcutaneously) for 24 weeks (Allo-24), from week 12 to 24 (Allo-12), or with vehicle for 24 weeks. Proteinuria was determined at regular intervals. Kidneys were harvested after 24 weeks for histomorphological and immunohistochemical evaluation.


RESULTS
No major bleeding complications were observed in reviparin-treated animals. Proteinuria was significantly reduced in allografted animals both by early as well as by late-onset treatment with reviparin. Transplant glomerulopathy was diminished in Allo-24 and in Allo-12 groups compared to vehicle-treated animals, whereas tubulointerstitial inflammation was influenced only in animals immediately treated with reviparin. Immunohistochemical studies demonstrated a marked reduction of renal monocyte and T-cell infiltration as well as expression of MHC II by treatment with reviparin.


CONCLUSIONS
Treatment with the LMWH reviparin significantly improved chronic renal allograft rejection in the F344-to-LEW rat model, both after early and late start of therapy. Although the exact mechanisms of this beneficial effect remain unclear, our data offer a potential new therapeutical approach for prevention of chronic allograft nephropathy.
Braun
C
C
V. Department of Medicine (Nephrology/Endocrinology), University Hospital Mannheim, University of Heidelberg, Germany.
Schultz
M
M
Fang
L
L
Schaub
M
M
Back
W E
WE
Herr
D
D
Laux
V
V
Rohmeiss
P
P
Schnuelle
P
P
van der Woude
F J
FJ
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology / Q000502:physiology; D008297:Male; D011507:Proteinuria; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013599:Systole / Q000187:drug effects; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D000949:Histocompatibility Antigens Class II; C094240:reviparin; D016572:Cyclosporine