Treatment of chronic allograft nephropathy at late stages using everolimus or FTY720 in combination with cyclosporine.
OBJECTIVE
In this study, we used combined treatment with cyclosporine (CsA)/everolimus (EVR) or CsA/FTY720 to affect ongoing chronic allograft nephropathy (CAN) compared with monotherapy with EVR or FTY720.


BACKGROUND
CAN is an important cause of renal allograft loss. Immunosuppressive therapy is based on calcineurin inhibitors, which are associated with nephrotoxicity and decreasing graft function. Thus, alternative treatment regimens, including new immunosuppressants, such as EVR or FTY720, are of interest. We asked whether the combination of CsA with EVR or FTY720 ameliorated the development of CAN more effectively than monotherapy with EVR and/or FTY720 during the later stages of CAN.


METHODS
Kidneys from Fisher rats were orthotopically transplanted into Lewis rats. Animals received CsA (1.5 mg/kg/d) for the first 10 days after transplantation. Animals were assigned to 6 groups: EVR (0.5 mg/kg/d), FTY720 (0.5 mg/kg/d), CsA (1.5 mg/kg/d), CsA+EVR (1.5 + 0.5 mg/kg/d), CsA+FTY720 (1.5 + 0.5 mg/kg/d), and vehicle (VEH). Treatment started at week 20. The observation period ended after 28 weeks.


RESULTS
Treatment with EVR and FTY720 reduced proteinuria and glomerulosclerosis, suppressed lymphocyte and macrophage infiltration, and resulted in a greater number of apoptotic tubular and interstitial cells compared with the combined treatment groups and controls.


CONCLUSIONS
Although EVR and FTY720 monotherapy delayed the progression of CAN, their combination with CsA had no beneficial effect.
Roos
M
M
Department of Nephrology, Klinikum rechts der Isar, Munich, Germany.
Liu
S
S
Strobl
M
M
Schmaderer
C
C
Baumann
M
M
Heemann
U
U
Lutz
J
J
D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000276:immunology
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus