Cyclosporine withdrawal and mycophenolate mofetil treatment effects on the progression of chronic cyclosporine nephrotoxicity.
BACKGROUND
Recent clinical trials of mycophenolate mofetil (MMF) in chronic allograft nephropathy (CAN) demonstrated that the dose of cyclosporine A (CsA) is one of the critical factors in determining graft function in CAN, but the effect of MMF on chronic CsA nephropathy is undetermined. We undertook this study to evaluate the effect of MMF on CsA-induced nephrotoxicity in an animal model of chronic CsA nephropathy.


METHODS
In the first experiment, Sprague-Dawley rats on a low-salt diet were treated with CsA (7.5 mg/kg per day) for 10 weeks, or were treated with CsA for five weeks and then MMF (20 mg/kg per day) was administered five weeks later. In the second experiment, rats were treated with CsA for five weeks, and CsA was then withdrawn for five weeks with or without MMF treatment. Renal function, histologic parameters (tubulointerstitial fibrosis, arteriolopathy, ED-1-positive cells, renin-positive glomeruli, TUNEL-positive cells) and the expression of osteopontin and transforming growth factor (TGF)-beta1 mRNA expressions were compared for different treatment groups.


RESULTS
CsA-treated rats showed decreased renal function and increased histologic parameters compared with the vehicle (VH)-treated rats. The addition of MMF did not improve these parameters compared with the CsA-treated rats. With CsA withdrawal, renal function and histologic parameters were significantly improved compared with the CsA-treated rats, and MMF treatment after CsA withdrawal further improved the histologic parameters. At the molecular level, the addition of MMF did not decrease the expression of osteopontin and transforming growth factor-beta1 (TGF-beta1) mRNAs, which were increased in the CsA-treated rat kidney. With CsA withdrawal, the expression of both mRNAs was significantly decreased compared with the CsA group, and a further decrease was observed with MMF treatment after CsA was withdrawn.


CONCLUSIONS
The combined treatment of CsA and MMF does not prevent the development of chronic CsA nephrotoxicity, but MMF treatment after CsA withdrawal does improve chronic CsA nephrotoxicity. This finding provides a rationale for MMF treatment in chronic CsA nephrotoxicity.
Yang
Chul Woo
CW
Division of Nephrology, Department of Internal Medicine, Kangnam St. Mary's Hospital, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku, Seoul 137-040, Korea. yangch@cmc.cuk.ac.kr
Ahn
Hee Jong
HJ
Kim
Wan Young
WY
Li
Can
C
Kim
Hyung Wook
HW
Choi
Bum Soon
BS
Cha
Jung Ho
JH
Kim
Yong Soo
YS
Kim
Jin
J
Bang
Byung Kee
BK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D016572:Cyclosporine; D012083:Renin; D009173:Mycophenolic Acid