Chronic allograft nephropathy

Department of Laboratory Medicine and Pathology, University of Minnesota, USA.
Current Opinion in Nephrology and Hypertension (Impact Factor: 3.86). 04/2008; 17(2):149-55. DOI: 10.1097/MNH.0b013e3282f4e514
Source: PubMed


Despite dramatic declines in acute rejection and early graft failure, long-term outcomes after kidney transplantation have improved little during the past 25 years. Most late allograft failure is attributed to chronic allograft nephropathy, but this is a clinicopathological description and not a diagnosis, and its pathogenesis and treatment are largely unknown.
Recent studies suggest that acute rejection during the first few months, and calcineurin inhibitor toxicity thereafter, may both contribute to chronic allograft nephropathy. There is also accumulating evidence that injury from antibody-mediated rejection may play an important pathogenic role in at least some patients with chronic allograft nephropathy, particularly those with transplant glomerulopathy. Therapeutic measures, including protocols to reduce calcineurin inhibitor exposure, remain largely unproven.
Understanding why so many kidney allografts fail, despite effective preventive measures for early acute rejection, is one of the most important areas of research in kidney transplantation today.

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Available from: Behzad Najafian
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    • "During the last decades, kidney transplantation has been recognized as the best therapeutic strategy for patients with end-stage renal disease (Wolfe et al., 1999). In spite of the progress in surgical techniques, the development of improved immunosuppressive agents, and a better understanding of immunologic phenomena, acute rejection remains a serious complication of kidney transplantation (Najafian and Kasiske, 2008). Both cellular and humoral immune responses and many different types of immune cells and cytokines are involved in acute rejection, although the underlying pathophysiologic mechanisms have not been fully elucidated. "
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    ABSTRACT: The Rho kinase pathway plays an important role in epithelial dedifferentiation and inflammatory cell infiltration. Recent studies suggest that inflammation promotes lymphangiogenesis, which has been associated with renal allograft rejection. We investigated whether targeted inhibition of the Rho kinase pathway in proximal tubular cells reduces inflammation and lymphangiogenesis in acute renal allograft rejection. The Rho kinase inhibitor Y27632 was coupled to lysozyme (Y27632-lysozyme), providing a kidney-specific conjugate that can release its drug in proximal tubular cells. Isogenic (Fisher-Fisher, n=18), or allogenic (Fisher-Lewis, n=24) kidney transplantations were performed, with the contralateral kidney remaining in situ. To elicit acute rejection, no immunosuppressive treatment was given. Animals were treated daily with Y27632-lysozyme (10mg/kg/day i.v.) or vehicle (saline i.v.) until sacrifice (1 or 4 days post-transplantation). After allogenic transplantation, interstitial macrophage accumulation was strongly reduced by Y27632-lysozyme at day 4 after transplantation. Interstitial lymphangiogenesis, which was induced in allografts as compared to control kidney, was also reduced by renal Rho kinase inhibition at day 4 after transplantation. The increase of vimentin and procollagen-1alpha1 gene expression in renal allografts from day 1 to day 4 after transplantation was significantly reduced by Y27632-lysozyme. Y27632-lysozyme did not affect systolic blood pressure in isogenic or allogenic transplantation groups. In cultured tubular epithelial cells (NRK-52E), Rho kinase inhibition dose-dependently reduced IL-1β-induced MCP-1 gene expression. Renal inhibition of Rho kinase causes a marked reduction in renal inflammation and renal lymphangiogenesis during acute transplant rejection, suggesting that this treatment regimen is a valuable future treatment in renal transplantation.
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    ABSTRACT: Fibrozyten sind Kollagen Typ I produzierende Zellen, die sich unter bestimmten Bedingungen aus hämatopoietischen Vorläuferzellen entwickeln. Im Mausmodell wurde untersucht, welche Leukozytensubpopulationen für die Entwicklung von Fibrozyten notwendig sind. Es konnte gezeigt werden, dass sich murine Fibrozyten aus einer Subpopulation von CD11b+ CD115+ Gr1+ Monozyten unter der Kontrolle von CD4+ T-Zellen differenzieren. In Abwesenheit von CD4+ T-Zellen war die Entwicklung von Fibrozyten in vitro wie in vivo deutlich vermindert. In Anwesenheit von CD4+ T-Zellen waren die Bedingungen der T-Zellaktivierung entscheidend für die Entwicklung der Fibrozyten. Eine polyklonale Aktivierung von CD4+ T-Zellen induzierte die Freisetzung von löslichen Faktoren, die das Auswachsen von Fibrozyten vollständig hemmte. Die Zytokine IL-2, TNF-alpha, IFN-gamma und IL-4 konnten als verantwortliche Faktoren identifiziert werden. Die Behandlung mit IL-2 und TNF-alpha führte zu einem deutlich verringerten Auftreten von Fibrozyten und einer Verminderung des Gesamtfibrosegrades im Modell der einseitigen Ureterligatur. Im Gegensatz dazu führte die Aktivierung von CD4+ T-Zellen in Anwesenheit von Calcineurininhibitoren, nicht aber von mTOR-Inhibitoren zu einem deutlich verstärkten Auswachsen von Fibrozyten und einer vermehrten Kollagenablagerung in der Niere. Daraus lässt sich schließen, dass die Differenzierung von Fibrozyten von CD4+ T-Zellen abhängig ist und die Konditionen der T-Zellaktivierung dafür entscheidend sind, ob die Fibrozytendifferenzierung gesteigert oder gehemmt wird. Diese Daten stellen dabei möglicherweise Ansatzpunkte für die Vorbeugung von Organfibrosen bei Autoimmunerkrankungen und der Transplantatabstoßung dar.
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