Polyomavirus BK replication dynamics in vivo and in silico to predict cytopathology and viral clearance in kidney transplants

Am J Transplant. 2008 Nov;8(11):2368-77. doi: 10.1111/j.1600-6143.2008.02402.x.

Abstract

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 approximately 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 x 10(7) and 6 x 10(7), 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 approximately 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BK Virus / genetics
  • BK Virus / metabolism*
  • DNA Replication
  • Glomerular Filtration Rate
  • Humans
  • Inflammation
  • Kidney / virology*
  • Kidney Diseases / therapy*
  • Kidney Diseases / virology
  • Kidney Transplantation / methods*
  • Kidney Tubules / metabolism
  • Kinetics
  • Models, Theoretical
  • Polyomavirus / metabolism
  • Polyomavirus Infections / prevention & control*
  • Prospective Studies
  • Virus Replication