Polyomavirus BK Replication Dynamics In Vivo and In Silico to Predict Cytopathology and Viral Clearance in Kidney Transplants

Fast BK virus (BKV) replication in renal tubular epithelial cells drives polyomavirus‐BK‐associated nephropathy (PVAN) to premature kidney transplant (KT) failure. BKV also replicates in urothelial cells, but remains asymptomatic in two‐thirds of affected KT patients. Comparing 518 day‐matched plasma‐urine samples from 223 KT patients, BKV loads were ～3000‐fold higher in urine than in plasma (p < 0.000001). Molecular and quantitative parameters indicated that >95% of urine BKV loads resulted from urothelial replication and <5% from tubular epithelial replication. Fast BKV replication dynamics in plasma and urine with half‐lives of <12 h accounted for daily urothelial and tubular epithelial cell loss of 4×10⁷ and 6×10⁷, respectively. BKV dynamics in both sites were only partly linked, with full and partial discordance in 36% and 32%, respectively. Viral expansion was best explained by models where BKV replication started in the kidney followed by urothelial amplification and tubular epithelial cell cross‐feeding reaching a dynamic equilibrium after ～10 weeks. Curtailing intrarenal replication by 50% was ineffective and >80% was required for clearing viremia within 7 weeks, but viruria persisted for >14 weeks. Reductions >90% cleared viremia and viruria by 3 and 10 weeks, respectively. The model was clinically validated in prospectively monitored KT patients supporting >80% curtailing for optimal interventions.