The effect of FK778 on the progression of chronic allograft nephropathy in a rat model.
BACKGROUND
Chronic allograft nephropathy (CAN) still belongs to the leading causes of graft loss over the long term. The leflunomide derivative FK778 is a novel immunosuppressant with improved pharmacokinetic properties that effectively prolonged graft survival in several transplantation models. In the present study, we investigated the effects of FK778 at different phases after transplantation on the progression of CAN.


METHODS
Fisher 344 kidneys were orthotopically transplanted into Lewis recipients. Recipients were treated with FK778 (5 mg/kg/day) over different time periods (early: days 0-10 only, continuous: day 0 to week 24, or late: weeks 16-24 only posttransplantation). Proteinuria was measured every 4 weeks, whereas grafts were harvested at 24 weeks posttransplantation for morphological and immunohistochemical analysis as well as transforming growth factor-beta and platelet derived growth factor-B chain expression.


RESULTS
Continuous treatment with FK778 ameliorated the progression of CAN, whereas late treatment reduced proteinuria and resulted in a similar grade of CAN as compared to animals with continuous treatment. In contrast, FK778 given only during the early phase after transplantation had no effect on the progression of CAN as compared to controls.


CONCLUSIONS
In summary, FK778 is a potent immunosuppressive drug that can delay the progression of CAN, even when given at later stages after transplantation.
Lutz
Jens
J
Department of Nephrology, Klinikum rechts der Isar, Munich, Germany.
Huang
Hai
H
Deng
Meihong
M
Wagner
Bettina
B
Roos
Marcel
M
Schmaderer
Christoph
C
Strobl
Matthias
M
Heemann
Uwe
U
D000480:Alkynes / Q000627:therapeutic use*; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007555:Isoxazoles / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D016030:Kidney Transplantation / Q000473:pathology*; D008297:Male; D009570:Nitriles / Q000627:therapeutic use*; D011507:Proteinuria / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous / Q000473:pathology
D000480:Alkynes; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D003404:Creatinine