OVERVIEW The Decade of Polyomavirus BK-Associated Nephropathy: State of Affairs Emilio Ramos, 1,5 Cinthia B. Drachenberg, 2 Ravinder Wali, 1 and Hans H. Hirsch 3,4 In the last 10 years, better immunosuppression drugs have decreased the rates of acute rejection in kidney transplan- tation but have also led to the emergence of polyomavirus-associated nephropathy (PVAN). This occurs in 1% to 10% of patients with kidney transplantion and is caused by BK virus in more than 95% of cases. Less than 5% of cases are attributed to the JC virus. Initially, lack of recognition or late diagnosis of PVAN resulted in rapid loss of graft function in more than 50% of patients. In recent years, it has become clear that early diagnosis and timely reduction in immunosuppression is the only proven measure, which significantly affects the outcome of PVAN. Diverse interven- tions have been explored including the adjunctive use of cidofovir, leflunomide, fluoroquinolones, and intravenous immunoglobulins. Allograft histology is needed to definitively establish the diagnosis of PVAN, but is of limited sensitivity in the early stage of disease. Well-established techniques and protocols for systematic screening by urine cytology and quantitative molecular-genetic techniques allow now for timely intervention before irreversible paren- chymal changes occur. Moreover, preemptive reduction in immunosuppression is most effective in presumptive PVAN as defined by surrogate markers (i.e., high BK virus viremia). In this setting, preservation of graft function can be considered the rule. Nevertheless, the recovery of BK virus-specific T-cell immunity may require prolonged periods during which cytopathic damage may continue to accumulate. Despite remarkable progress in the field, important challenges remain, such as the rare patient with PVAN refractory to any intervention and the newly recognized association of PVAN with urogenital tumors. Keywords: Renal biopsy, JC, Viremia, Viruria, Viral loads, Histologic patterns, Early diagnosis, Nephritis, Renal transplant, SV40, Graft loss. (Transplantation 2009;87: 621–630) I n the last 50 years, solid organ transplantation (SOT) has been established as not only a key life saving procedure of terminal organ failure (1), but also as the treatment of choice with respect to patients’ quality of life (2, 3). In addition to better procurement and surgical procedures, much of the success of SOT stems from improving the control of acute immune reactions across human leukocyte antigen (HLA)- mismatches through new immunosuppressive protocols, which have efficiently reduced immune injury and acute and chronic loss of function (4). In the most recent decade, how- ever, the declining rates of rejection episodes after kidney transplantation has no longer been translated into similarly improved rates of graft survival (5). Moreover, an increased vulnerability to known and newly emerging infections has been noted in both pediatric and adult transplant patients (6–8). The emergence of polyomavirus BK-associated ne- phropathy (PVAN) in the last decade is an example of this recent development (9 –11). Although sporadic cases of PVAN had been described as early as 1978 (12), the appreciation of BK virus (BKV) as a serious threat to kidney transplantation became evident in the late 1990s when several centers reported a rise in PVAN cases (13–18). Premature functional decline of renal allo- grafts in 60% to 90% of cases and return to dialysis in at least 50% occurred as a rule in early years (10, 13–18). Although some predicted that PVAN was only a transiently exaggerated com- plication, it is clear now despite the significant advances that polyomavirus BK continues to represent a formidable chal- lenge in kidney transplantation. Epidemiology and Risk Factors of PVAN After natural viral transmission during childhood, BKV is known to persist in the renourinary tract with in- termittent reactivation and low-level viruria (Vr) in 5% to 10% of immunocompetent adults (19, 20). In immuno- compromissed individuals, the frequency of BK Vr increases to 20% to 60% and large Vr often with the appearance of decoy cells is common (21). 1 Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD. 2 Department of Pathology, University of Maryland School of Medicine, Bal- timore, MD. 3 Transplantation Virology, and Division of Molecular Diagnostics, Depart- ment of Biomedicine, Institute for Medical Microbiology, University of Basel, Basel, Switzerland. 4 Division Infectious Diseases and Hospital Epidemiology, University Hos- pital Basel, Basel, Switzerland. 5 Address correspondence to: Emilio Ramos, M.D., Division of Nephrology, Department of Medicine, University of Maryland Hospital, 22 South Greene Street, Baltimore, MD 21201. E-mail: eramos@medicine.umaryland.edu Received 4 August 2008. Revision requested 18 September 2008. Accepted 26 November 2008. Copyright © 2009 by Lippincott Williams & Wilkins ISSN 0041-1337/09/8705-621 DOI: 10.1097/TP.0b013e318197c17d Transplantation • Volume 87, Number 5, March 15, 2009 621