Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Chronic allograft nephropathy Behzad Najafian a and Bertram L. Kasiske b Introduction Kidney transplantation improves the quality of life and the survival of patients with end-stage renal disease [1]. Since the early 1980s there has been a dramatic improve- ment in 1-year allograft survival rates [2,3]. Nevertheless, long-term outcomes have changed little [4]. Death with a functioning graft and chronic allograft nephropathy (CAN) are the major causes of late graft loss [2,5–7]. The prevalence of CAN is as high as 60 – 70% on protocol biopsies after the first year [8–10]. However, CAN – defined by interstitial fibrosis and tubular atrophy – is probably the result of several different immunologic and nonimmunologic processes. Studies of the natural history of CAN have suggested that it may result from immu- nologic causes during the first year and nonimmunologic causes, particularly calcineurin inhibitor (CNI) toxicity, thereafter [10]. There is a growing need to discriminate among the different causes of CAN and to elucidate the pathogenesis of CAN [11]. The rise and fall of ‘chronic allograft nephropathy’ Initial efforts to classify renal transplantation biopsy findings in the early 1990s in Banff, Canada, were focused on acute rejection [12–15]. The term ‘CAN’ first emerged in the Banff schema in 1991 and was used interchangeably with ‘chronic rejection’. The Banff 97 classification, however, proposed that the term CAN be used when it is impossible to precisely define the etiology of chronic allograft damage, and to avoid use of the term chronic rejection except when features of allogenic injury are present [15]. This led to the misconception that CAN is a specific disease, ignoring the fact that it was only meant to describe nonspecific renal cortical scarring. Efforts to discriminate among the causes of CAN [16] eventually led to the elimination of this term from the Banff classification at the eighth Banff conference [11]. The Banff ’05 Meeting Report [11] classifies what would have previously been called CAN into the following: chronic allograft rejection, including chronic active anti- body or T-cell-mediated rejection; nonrejection causes, including (but not limited to) chronic hypertension, CNI toxicity, chronic obstruction, bacterial pyelonephritis, and viral infections; and cases for which no specific etiologic features can be identified. Chronic active alloimmune rejection/injury The term ‘chronic active alloimmune rejection’ implies slowly progressive cortical scarring due to alloimmune processes [17]. Similar to acute rejection, chronic active rejection may be antibody [18,19] or T cell mediated. a Department of Laboratory Medicine and Pathology, University of Minnesota, USA and b Department of Medicine, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota, USA Correspondence to Bertram L. Kasiske, MD, Department of Medicine, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415, USA Tel: +1 612 347 5871; fax: +1 612 347 2003; e-mail: kasis001@umn.edu Current Opinion in Nephrology and Hypertension 2008, 17:149–155 Purpose of review 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 findings 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. Summary 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. Keywords C4d, calcineurin inhibitor toxicity, chronic rejection, transplant glomerulopathy Curr Opin Nephrol Hypertens 17:149–155 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1062-4821 1062-4821 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins