Progression from Sustained BK Viruria to Sustained BK Viremia with Immunosuppression Reduction Is Not Associated with Changes in the Noncoding Control Region of the BK Virus Genome

Changes in the BK virus archetypal noncoding control region (NCCR) have been associated with BK-virus-associated nephropathy (BKVAN). Whether sustained viremia, a surrogate for BKVAN, is associated with significant changes in the BK-NCCR is unknown. We performed PCR amplification and sequencing of (1) stored urine and (2) plasma samples from the time of peak viremia from 11 patients with sustained viremia who participated in a 200-patient clinical trial. The antimetabolite was withdrawn for BK viremia and reduction of the calcineurin inhibitor for sustained BK viremia. DNA sequencing from the 11 patients with sustained viremia revealed 8 insertions, 16 transversions, 3 deletions, and 17 transitions. None were deemed significant. No patient developed clinically evident BKVAN. Our data support, at a genomic level, the effectiveness of reduction of immunosuppression for prevention of progression from viremia to BKVAN. 1. Introduction Human polyomavirus and associated infection were first identified in a urine sample of a transplant recipient with ureteric stenosis in 1971 [1]. BK-virus-associated nephropathy (BKVAN) was first recognized in kidney transplant recipients in 1995 [2]. The sequence of histopathologic events is characterized by tubular necrosis, mixed interstitial inflammatory infiltration, and finally, scarring and fibrosis of the renal interstitium [3]. BKV nephropathy currently affects 1–7% of recipients and has been associated with a 10–100% graft loss rate depending on the severity of histological involvement [4, 5]. It is likely that the last stage of an unchecked BKV infection begins as asymptomatic viruria, progresses to sustained viremia, possibly associated with subclinical nephritis, and culminates in overt nephropathy. Thus, sustained BKV detected in plasma predicts progression to BKV-associated interstitial nephritis, or nephropathy [6]. JC virus and SV40 virus are other members of the family Polyomaviridae [7] and share 75% and 70% homology, respectively, with BKV. They have three general transcription regions: the noncoding control region (NCCR); the early coding region, which codes for the small and large T antigens; and the late coding region, which codes for the viral capsid proteins VP-1, VP-2, and VP-3 [8]. A fourth region, the agnogene, encodes for the agnoprotein. The agnoprotein has recently been thought to play a role in replicative life-cycle of polyomaviruses and also in the dysregulation of cellular processes such as cell cycle control and DNA repair [9, 10]. The NCCR consists of the origin of replication [11] and the