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      Sirolimus therapy following early cyclosporine withdrawal in transplant patients: mechanisms of action and clinical results

      International Journal of Nanomedicine

      Dove Medical Press

      cyclosporine, sirolimus, transplantation, nephrotoxicity, withdrawal

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          Abstract

          Cyclosporine (CsA), a member of the family of calcineurin inhibitors, is a cornerstone of the immunosuppressive treatments used after organ transplantation. However, it exhibits significant toxicity, including nephrotoxicity and increased cardiovascular risk factors. CsA withdrawal has been used as a strategy to improve renal allograft function and other CsA-related toxicities. In order to maintain adequate immunosuppression levels, sirolimus may be used in association with CsA withdrawal. Sirolimus is a member of the mammalian target of rapamycin (mTOR) family. It presents a good immunosuppressive efficacy associated with antiproliferative actions. Early withdrawal of CsA with sirolimus is associated with a significant improvement of renal function. Despite numerically a higher incidence of acute rejection episodes, this maneuver seems also to be associated with a better allograft survival in the long-term, and improvement of renal histology and blood pressure. However, CsA withdrawal is only feasible in a selected population. Furthermore, the use of sirolimus is associated with other side-effects including lipid abnormalities, abnormal liver tests, and thrombocytopenia. Other studies are mandatory to define the population who can benefit from this maneuver. Finally, complete CsA avoidance has been already reported and is currently under clinical investigation.

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          The Banff 97 working classification of renal allograft pathology.

          Standardization of renal allograft biopsy interpretation is necessary to guide therapy and to establish an objective end point for clinical trials. This manuscript describes a classification, Banff 97, developed by investigators using the Banff Schema and the Collaborative Clinical Trials in Transplantation (CCTT) modification for diagnosis of renal allograft pathology. Banff 97 grew from an international consensus discussion begun at Banff and continued via the Internet. This schema developed from (a) analysis of data using the Banff classification, (b) publication of and experience with the CCTT modification, (c) international conferences, and (d) data from recent studies on impact of vasculitis on transplant outcome. Semiquantitative lesion scoring continues to focus on tubulitis and arteritis but includes a minimum threshold for interstitial inflammation. Banff 97 defines "types" of acute/active rejection. Type I is tubulointerstitial rejection without arteritis. Type II is vascular rejection with intimal arteritis, and type III is severe rejection with transmural arterial changes. Biopsies with only mild inflammation are graded as "borderline/suspicious for rejection." Chronic/sclerosing allograft changes are graded based on severity of tubular atrophy and interstitial fibrosis. Antibody-mediated rejection, hyperacute or accelerated acute in presentation, is also categorized, as are other significant allograft findings. The Banff 97 working classification refines earlier schemas and represents input from two classifications most widely used in clinical rejection trials and in clinical practice worldwide. 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. Criteria for specimen adequacy have also been modified. Banff 97 represents a significant refinement of allograft assessment, developed via international consensus discussions.
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            The natural history of chronic allograft nephropathy.

            With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure. We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter. Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in declining renal function and graft failure. Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes. Copyright 2003 Massachusetts Medical Society
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              The TOR pathway: a target for cancer therapy.

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                Author and article information

                Journal
                Int J Nanomedicine
                International Journal of Nanomedicine
                International Journal of Nanomedicine
                Dove Medical Press
                1176-9114
                1178-2013
                September 2006
                : 1
                : 3
                : 269-281
                Affiliations
                simpleService de Transplantation Rénale, Hôpital Necker Paris, France
                Author notes
                Correspondence: Eric Thervet Service de Transplantation Rénale, Hôpital Necker, 149 rue de Sèvres, 75015 Paris, France Tel +33 144 495 432 Fax +33 144 495 430 Email eric.thervet@ 123456nck.aphp.fr
                Article
                2426801
                17717968
                © 2006 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Molecular medicine

                transplantation, nephrotoxicity, cyclosporine, sirolimus, withdrawal

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