Journal ArticleDOI
Calcineurin Inhibitor Nephrotoxicity: Longitudinal Assessment by Protocol Histology
Brian J. Nankivell,Richard Borrows,Caroline L.-S. Fung,Philip J. O'Connell,Jeremy R. Chapman,Richard D. M. Allen +5 more
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TLDR
CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation and strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.Abstract:
BACKGROUND The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented. METHODS The authors evaluated 888 prospective protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity. RESULTS The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity. Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis (both P < 0.05). The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis, striped fibrosis, and tubular microcalcification was 100%, 88.0%, and 79.2% of kidneys, respectively. Beyond 1 year, 53.9% had two or more lesions of CsA nephrotoxicity. Structural CsA nephrotoxicity occurred in two phases, with different clinical and histologic characteristics. The acute phase occurred with a median onset 6 months after transplantation, was usually reversible, and was associated with functional CsA nephrotoxicity (P < 0.05), high CsA levels (P < 0.05), and mild arteriolar hyalinosis (P < 0.001). The chronic phase of CsA nephrotoxicity persisted over several biopsies, occurred at a median onset of 3 years, and was associated with lower CsA doses and trough levels (both P < 0.05). It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis (both P < 0.001). A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology. CONCLUSIONS Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.read more
Citations
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Journal ArticleDOI
Reduced exposure to calcineurin inhibitors in renal transplantation.
Henrik Ekberg,Helio Tedesco-Silva,Alper Demirbas,Stefan Vitko,Björn Nashan,A. Gurkan,Raimund Margreiter,Christian Hugo,Josep M. Grinyó,Ulrich Frei,Yves Vanrenterghem,Pierre Daloze,Philip F. Halloran +12 more
TL;DR: In this paper, the authors evaluated the efficacy and relative toxic effects of four immunosuppressive regimens: cyclosporine, mycophenolate mofetil, and corticosteroids.
Journal ArticleDOI
Calcineurin Inhibitor Nephrotoxicity
TL;DR: The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cycloporine or tacolimus could be more important than systemic exposure.
Journal Article
Reduced exposure to calcineurin inhibitors in renal transplantation.
Henrik Ekberg,Philip F. Halloran +1 more
TL;DR: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing dacluzumab induction plus either low- doses of cyclosporine or low- dose sirolimus or with standard-dose cyclosporaine without induction.
Journal ArticleDOI
Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data
TL;DR: Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes.
Journal ArticleDOI
Chronic Renal Allograft Dysfunction
TL;DR: There have been a number of approaches to treatment aimed at reducing the impact of CAN, mostly centered around avoidance of calcineurin inhibitors through their elimination in all, or just selected, patients.
References
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Journal ArticleDOI
The Banff 97 working classification of renal allograft pathology
Lorraine C. Racusen,Kim Solez,Robert B. Colvin,Stephen M. Bonsib,Maria Castro,Tito Cavallo,Byron P. Croker,A. Jake Demetris,Cynthia B. Drachenberg,Agnes B. Fogo,Peter N. Furness,Lillian W. Gaber,Ian W. Gibson,Dennis Glotz,J. Goldberg,Joseph P. Grande,Philip F. Halloran,H.E. Hansen,Barry Hartley,Pekka Hayry,Claire M. Hill,Ernesto O. Hoffman,Lawrence G. Hunsicker,Anne S. Lindblad,Niels Marcussen,M. J. Mihatsch,Tibor Nadasdy,Peter Nickerson,T. Steen Olsen,John C. Papadimitriou,Parmjeet Randhawa,David C. Rayner,Ian S.D. Roberts,Stephen Rose,D. Rush,Luis Salinas-Madrigal,Daniel R. Salomon,Stale Sund,Eero Taskinen,Kiril Trpkov,Yutaka Yamaguchi +40 more
TL;DR: Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures.
Journal ArticleDOI
Chronic renal failure after transplantation of a nonrenal organ.
Akinlolu O. Ojo,Philip J. Held,Friedrich K. Port,Robert A. Wolfe,Alan B. Leichtman,Eric W. Young,J.A Arndorfer,Laura L. Christensen,Robert M. Merion +8 more
TL;DR: The five-year risk of chronic renal failure after transplantation of a nonrenal organ ranges from 7 to 21 percent, depending on the type of organ transplanted, and is associated with an increase by a factor of more than four in the risk of death.
Journal ArticleDOI
The natural history of chronic allograft nephropathy.
Brian J. Nankivell,Richard Borrows,Caroline L.-S. Fung,Philip J. O'Connell,Richard D. M. Allen,Jeremy R. Chapman +5 more
TL;DR: Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes, and was irreversible, resulting in declining renal function and graft failure.
Journal ArticleDOI
Improved Graft Survival after Renal Transplantation in the United States, 1988 to 1996
Sundaram Hariharan,Christopher P. Johnson,Barbara A. Bresnahan,S. Taranto,Matthew McIntosh,Donald Stablein +5 more
TL;DR: There has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors since 1988.
Journal ArticleDOI
International standardization of criteria for the histologic diagnosis of renal allograft rejection : the Banff working classification of kidney transplant pathology
Kim Solez,Roy A. Axelsen,Hallgrimur Benediktsson,James F. Burdick,Arthur H. Cohen,Robert B. Colvin,Byron P. Croker,Dominique Droz,Michael S. Dunnill,Philip F. Halloran,Pekka Häyry,J. Charles Jennette,Paul Keown,Niels Marcussen,Michael J. Mihatsch,Kunio Morozumi,Bryan D. Myers,Cynthia C. Nast,Steen Olsen,Lorraine C. Racusen,E L Ramos,Seymour Rosen,David H. Sachs,Daniel R. Salomon,Fred Sanfilippo,Regina R. Verani,Eeva von Willebrand,Yutaka Yamaguchi +27 more
TL;DR: A schema for international standardization of nomenclature and criteria for the histologic diagnosis of renal allograft rejection was developed in Banff, Canada on August 2-4, 1991 and validated by the circulation of sets of slides for scoring by participant pathologists.
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The Banff 97 working classification of renal allograft pathology
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