Cyclosporine withdrawal and mycophenolate mofetil treatment effects on the progression of chronic cyclosporine nephrotoxicity

Woo Yang Chul; Jong Ahn Hee; Young Kim Wan; Can Li; Wook Kim Hyung; Soon Choi Bum; Ho Cha Jung; Soo Kim Yong; Jin Kim; Kee Bang Byung

doi:10.1046/j.1523-1755.2002.00400.x

Cyclosporine withdrawal and mycophenolate mofetil treatment effects on the progression of chronic cyclosporine nephrotoxicity

Woo Yang Chul
, Jong Ahn Hee
, Young Kim Wan
, Can Li
, Wook Kim Hyung
, Soon Choi Bum
, Ho Cha Jung
, Soo Kim Yong
, Jin Kim
, Kee Bang Byung

Catholic Univ. of Korea Coll. Med.

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

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 In the second experiment, rats were treated with CsA for five weeks, and CsA was then withdrawn for five weeks with or without MMF treatment.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-l-positive cells, renin-positive glomeruli, TUNEL-positive cells) and the expression of osteopontin and transforming growth factor (TGF)-β1 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-β1 (TGF-β1) 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. Conclusion. 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.

Original language	English
Pages (from-to)	20-30
Number of pages	11
Journal	Kidney International
Volume	62
Issue number	1
DOIs	https://doi.org/10.1046/j.1523-1755.2002.00400.x
State	Published - 2002

Bibliographical note

Funding Information:
The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation extended in 1999, and the Korean Society of Nephrology. A part of this study was presented at the meeting of the American Society of Nephrology in 2001 and the Third Roche Asian Transplant Forum in Taiwan, 2001.

Keywords

Chronic allograft nephropathy
Immunosuppression
Nephrotoxicity
Progressive renal failure
Transplantation

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10.1046/j.1523-1755.2002.00400.x

Cite this

@article{8353b377214b4cef9e10e050e7fd88cd,

title = "Cyclosporine withdrawal and mycophenolate mofetil treatment effects on the progression of chronic cyclosporine nephrotoxicity",

abstract = "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-l-positive cells, renin-positive glomeruli, TUNEL-positive cells) and the expression of osteopontin and transforming growth factor (TGF)-β1 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-β1 (TGF-β1) 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. Conclusion. 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.",

keywords = "Chronic allograft nephropathy, Immunosuppression, Nephrotoxicity, Progressive renal failure, Transplantation",

author = "Chul, \{Woo Yang\} and Hee, \{Jong Ahn\} and Wan, \{Young Kim\} and Can Li and Hyung, \{Wook Kim\} and Bum, \{Soon Choi\} and Jung, \{Ho Cha\} and Yong, \{Soo Kim\} and Jin Kim and Byung, \{Kee Bang\}",

note = "Funding Information: The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation extended in 1999, and the Korean Society of Nephrology. A part of this study was presented at the meeting of the American Society of Nephrology in 2001 and the Third Roche Asian Transplant Forum in Taiwan, 2001.",

year = "2002",

doi = "10.1046/j.1523-1755.2002.00400.x",

language = "English",

volume = "62",

pages = "20--30",

journal = "Kidney International",

issn = "0085-2538",

publisher = "Elsevier B.V.",

number = "1",

}

TY - JOUR

T1 - Cyclosporine withdrawal and mycophenolate mofetil treatment effects on the progression of chronic cyclosporine nephrotoxicity

AU - Chul, Woo Yang

AU - Hee, Jong Ahn

AU - Wan, Young Kim

AU - Li, Can

AU - Hyung, Wook Kim

AU - Bum, Soon Choi

AU - Jung, Ho Cha

AU - Yong, Soo Kim

AU - Kim, Jin

AU - Byung, Kee Bang

N1 - Funding Information: The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation extended in 1999, and the Korean Society of Nephrology. A part of this study was presented at the meeting of the American Society of Nephrology in 2001 and the Third Roche Asian Transplant Forum in Taiwan, 2001.

PY - 2002

Y1 - 2002

N2 - 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-l-positive cells, renin-positive glomeruli, TUNEL-positive cells) and the expression of osteopontin and transforming growth factor (TGF)-β1 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-β1 (TGF-β1) 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. Conclusion. 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.

AB - 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-l-positive cells, renin-positive glomeruli, TUNEL-positive cells) and the expression of osteopontin and transforming growth factor (TGF)-β1 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-β1 (TGF-β1) 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. Conclusion. 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.

KW - Chronic allograft nephropathy

KW - Immunosuppression

KW - Nephrotoxicity

KW - Progressive renal failure

KW - Transplantation

UR - https://www.scopus.com/pages/publications/0036315487

U2 - 10.1046/j.1523-1755.2002.00400.x

DO - 10.1046/j.1523-1755.2002.00400.x

M3 - Article

C2 - 12081560

AN - SCOPUS:0036315487

SN - 0085-2538

VL - 62

SP - 20

EP - 30

JO - Kidney International

JF - Kidney International

IS - 1

ER -

Cyclosporine withdrawal and mycophenolate mofetil treatment effects on the progression of chronic cyclosporine nephrotoxicity

Abstract

Bibliographical note

Keywords

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