Skip to main content

Advertisement

Log in

Early identification of renal transplant recipients with high risk of polyomavirus-associated nephropathy

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Polyomavirus BK (BKPyV) is ubiquitous among humans. Following primary infection, the virus remains latent predominantly in the hosts’ uroepithelial cells. Up to 10 % of renal transplant recipients show a viral reactivation that can lead to polyomavirus-associated nephropathy (PyVAN). In the absence of early treatments, the risk of graft loss is up to 80 %. Monitoring viral load in urine and plasma by real-time PCR after transplantation is the most common diagnostic tool to detect viral reactivation. In the present retrospective study, BKPyV-DNA loads in urine and plasma by quantitative real-time PCR were associated with clinical data, including HLA haplotype, blood parameters and viral genotype, of 40 renal transplant recipients at the University Clinics of Cologne. Seventeen out of 329 patients screened for BKPyV from January 2009 to October 2013 were detected BKPyV positive in urine only, whereas in 23 patients the virus became additionally detectable in plasma. Among these, ten patients progressed to PyVAN. Overall, the present study showed that the detection from the third month onwards after transplantation of a first viruric episode with a median viral load of 1 × 108 copies/mL, followed after few days by a first viremic episode with a median viral load of >1 × 104 copies/mL, was strongly associated with the development of PyVAN. In conclusion, the viral load and the temporal profile of the first viruric and viremic episode post-transplantation, in combination with specific features of the host immune response, should be considered as relevant clinical determinants of the risk of renal transplant recipients to progress to PyVAN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gardner SD, Field AM, Coleman DV, Hulme B (1971) New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 19:1253–1257. doi:10.1016/S0140-6736(71)90562-9

    Article  Google Scholar 

  2. Jin L, Gibson PE, Booth JC, Clewley JP (1993) Genomic typing of BK virus in clinical specimens by direct sequencing of polymerase chain reaction products. J Med Virol 41:11–17

    Article  CAS  PubMed  Google Scholar 

  3. Zhong S, Randhawa PS, Ikegaya H, Chen Q, Zheng HY, Suzuki M, Takeuchi T, Shibuya A, Kitamura T, Yogo Y (2009) Distribution patterns of BK polyomavirus (BKV) subtypes and subgroups in American, European and Asian populations suggest co-migration of BKV and the human race. J Gen Virol 90:144–152. doi:10.1099/vir.0.83611-0

    Article  CAS  PubMed  Google Scholar 

  4. Zheng HY, Nishimoto Y, Chen Q, Hasegawa M, Zg S, Ikegaya H, Ohno N, Sugimoto C, Takasaka T, Kitamura T, Yogo Y (2007) Relationships between BK virus lineages and human populations. Microbes Infect 9:204–213. doi:10.1016/j.micinf.2006.11.00

    Article  CAS  PubMed  Google Scholar 

  5. Chehadeh W, Nampoory MR (2013) Genotypic diversity of polyomaviruses circulating among kidney transplant recipients in Kuwait. J Med Virol 85:1624–1631. doi:10.1002/jmv.23639

    Article  CAS  PubMed  Google Scholar 

  6. Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199:837–846. doi:10.1086/597126

    Article  CAS  PubMed  Google Scholar 

  7. Hirsch HH (2005) BK virus: opportunity makes a pathogen. Clin Infect Dis 41:354–360. doi:10.1086/431488

    Article  PubMed  Google Scholar 

  8. Bennett SM, Broekema NM, Imperiale MJ (2012) BK polyomavirus: emerging pathogen. Microbes Infect 14:672–683. doi:10.1016/j.micinf.2012.02.002

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. van Aalderen MC, Heutinck KM, Huisman C, ten Berge IJM (2012) BK virus infection in transplant recipients: clinical manifestations, treatment options and the immune response. Neth J Med 70:172–183

    PubMed  Google Scholar 

  10. Lautenschlager I, Jahnukainen T, Kardas P, Lohi J, Auvinen E, Mannonen L, Dumoulin A, Hirsch HH, Jalanko H (2014) A case of primary JC polyomavirus infection-associated nephropathy. Am J Transplant 14:2887–2892. doi:10.1111/ajt.12945

    Article  CAS  PubMed  Google Scholar 

  11. Randhawa P, Ramos E (2007) BK viral nephropathy: an overview. Transplant Rev 21:77–85. doi:10.1016/j.trre.2007.03.001

    Article  Google Scholar 

  12. Bohl DL, Brennan DC (2007) BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2:36–46. doi:10.2215/CJN.00920207

    Article  Google Scholar 

  13. Hirsch HH, Randhawa P (2013) BK Polyomavirus in solid organ transplantation. Am J Transplant 13:179–188. doi:10.1111/ajt.12110

    Article  CAS  PubMed  Google Scholar 

  14. Burgos D, Jironda C, Martín M, González-Molina M, Hernández D (2010) BK-virus-associated Nephropathy. Nefrologia 30:613–617. doi:10.3265/Nefrologia.pre2010.Oct.10587

    CAS  PubMed  Google Scholar 

  15. Bechert CJ, Schnadig VJ, Payne DA, Dong J (2010) Monitoring of BK viral load in renal allograft recipients by real-time PCR assays. Am J Clin Pathol 133:242–250. doi:10.1309/AJCP63VDFCKCRUUL

    Article  CAS  PubMed  Google Scholar 

  16. Hirsch HH, Brennan DC, Drachenberg CB, Ginevri F, Gordon J, Limaye AP, Mihatsch MJ, Nickeleit V, Ramos E, Randhawa P, Shapiro R, Steiger J, Suthanthiran M, Trofe J (2005) Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 79:1277–1286. doi:10.1097/01.TP.0000156165.83160.09

    Article  PubMed  Google Scholar 

  17. Liptak P, Kemeny E, Ivanyi B (2006) Primer: histopathology of polyomavirus-associated nephropathy in renal allografts. Nat Clin Pract Nephrol 2:631–636. doi:10.1038/ncpneph0319

    Article  PubMed  Google Scholar 

  18. Sessa A, Esposito A, Giliberti A, Bergallo M, Costa C, Rossano R, Lettieri E, Capuano M (2008) BKV reactivation in renal transplant recipients: diagnostic and therapeutic strategy—case reports. Transplant Proc 40:2055–2058. doi:10.1016/j.transproceed.2008.05.007

    Article  CAS  PubMed  Google Scholar 

  19. Wu C, Randhawa P, McCauley J (2006) Transplantation: polyomavirus nephropathy and the risk of specific immunosuppression regimens. Sci World J 28:512–528. doi:10.1100/tsw.2006.93

    Google Scholar 

  20. Zeng Y, Magil A, Hussaini T, Yeung CK, Erb SR, Marquez-Alazagara V, Yoshida EM (2015) First confirmed case of native polyomavirus BK nephropathy in a liver transplant recipient seven years post-transplant. Ann Hepatol 14:137–140

    PubMed  Google Scholar 

  21. Khamash HA, Wadei HM, Mahale AS, Larson TS, Stegall MD, Cosio FG, Griffin MD (2007) Polyomavirus-associated nephropathy risk in kidney transplants: the influence of recipient age and donor gender. Kidney Int 71:1302–1309. doi:10.1038/sj.ki.5002247

    Article  CAS  PubMed  Google Scholar 

  22. Ramos E, Drachenberg CB, Papadimitriou JC, Hamze O, Fink JC, Klassen DK, Drachenberg RC, Wiland A, Wali R, Cangro CB, Schweitzer E, Bartlett ST, Weir MR (2002) Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 13:2145–2151. doi:10.1097/01.ASN.0000023435.07320.81

    Article  PubMed  Google Scholar 

  23. Sharif A, Alachkar N, Bagnasco S, Geetha D, Gupta G, Womer K, Arend L, Racusen L, Montgomery R, Kraus E (2012) Incidence and outcomes of BK virus allograft nephropathy among ABO- and HLA-incompatible kidney transplant recipients. Clin J Am Soc Nephrol 7:1320–1327. doi:10.2215/CJN.00770112

    Article  PubMed Central  PubMed  Google Scholar 

  24. Comoli P, Hirsch HH, Ginevri F (2008) Cellular immune responses to BK virus. Curr Opin Org Transplant 13:569–574. doi:10.1097/MOT.0b013e3283186b93

    Article  Google Scholar 

  25. Weist BJ, Schmueck M, Fuehrer H, Sattler A, Reinke P, Babel N (2014) The role of CD4 + T cells in BKV-specific T cell immunity. Med Microbiol Immunol 203:395–408. doi:10.1007/s00430-014-0348-z

    Article  CAS  PubMed  Google Scholar 

  26. Masutani K, Ninomiya T, Randhawa P (2013) HLA-A2, HLA-B44 and HLA-DR15 are associated with lower risk of BK viremia. Nephrol Dial Transplant 28:3119–3126. doi:10.1093/ndt/gft298

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Bohl DL, Storch GA, Ryschkewitsch C, Gaudreault-Keener M, Schnitzler MA, Major EO, Brennan DC (2005) Donor origin of BK virus in renal transplantation and role of HLA C7 in susceptibility to sustained BK viremia. Am J Transplant 5:2213–2221. doi:10.1111/j.1600-6143.2005.01000.x

    Article  CAS  PubMed  Google Scholar 

  28. Dugan AS, Gasparovic ML, Tsomaia N, Mierke DF, O’Hara BA, Manley K, Atwood WJ (2007) Identification of amino acid residues in BK virus VP1 that are critical for viability and growth. J Virol 81:11798–11808. doi:10.1128/JVI.01316-07

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Tremolada S, Delbue S, Castagnoli L, Allegrini S, Miglio U, Boldorini R, Elia F, Gordon J, Ferrante P (2010) Mutations in the external loops of BK virus VP1 and urine viral load in renal transplant recipients. J Cell Physiol 222:195–199. doi:10.1002/jcp.21937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Krautkrämer E, Klein TM, Sommerer C, Schnitzler P, Zeier M (2009) Mutations in the BC-Loop of the BKV VP1 region do not influence viral load in renal transplant patients. J Med Virol 81:75–81. doi:10.1002/jmv.21359

    Article  PubMed  Google Scholar 

  31. Boldorini R, Veggiani C, Turello E, Barco D, Monga G (2005) Are sequence variations in the BK virus control region essential for the development of polyomavirus nephropathy? Am J Clin Pathol 124:303–312. doi:10.1309/RLB1PMV33RK7CGAX

    Article  CAS  PubMed  Google Scholar 

  32. Boldorini R, Allegrini S, Miglio U, Paganotti A, Veggiani C, Mischitelli M, Monga G, Pietropaolo V (2009) Genomic mutations of viral protein 1 and BK virus nephropathy in kidney transplant recipients. J Med Virol 81:1385–1393. doi:10.1002/jmv.21520

    Article  CAS  PubMed  Google Scholar 

  33. Krumbholz A, Zell R, Egerer R, Sauerbrei A, Helming A, Gruhn B, Wutzler P (2006) Prevalence of BK virus subtype I in Germany. J Med Virol 78:1588–1598. doi:10.1002/jmv.20743

    Article  CAS  PubMed  Google Scholar 

  34. Bárcena-Panero A, Van Ghelue M, Khan MT, Echevarría JE, Fedele G, Moens U (2012) BK virus-associated infection in cerebrospinal fluid of neurological patients and mutation analysis of the complete VP1 gene in different patient groups. J Cell Physiol 227:136–145. doi:10.1002/jcp.22711

    Article  PubMed  Google Scholar 

  35. Kuppachi S, Thomas B, Kokko KE (2013) BK virus in the kidney transplant patient. Am J Med Sci 345:482–488. doi:10.1097/MAJ.0b013e31826c64ef

    Article  PubMed  Google Scholar 

  36. Drachenberg CB, Papadimitriou JC (2006) Polyomavirus-associated nephropathy: update in diagnosis. Trans Infect Dis 8:68–75. doi:10.1111/j.1399-3062.2006.00154.x

    Article  CAS  Google Scholar 

  37. Drachenberg CB, Papadimitriou JC, Hirsch HH, Wali R, Crowder C, Nogueira J, Cangro CB, Mendley S, Mian A, Ramos E (2004) Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transplant 4:2082–2092. doi:10.1046/j.1600-6143.2004.00603.x

    Article  PubMed  Google Scholar 

  38. Randhawa P, Ho A, Shapiro R, Vats A, Swalsky P, Finkelstein S, Uhrmacher J, Weck K (2004) Correlates of quantitative measurement of BK polyomavirus (BKV) DNA with clinical course of BKV infection in renal transplant patients. J Clin Microbiol 42:1176–1180. doi:10.1128/JCM.42.3.1176-1180.2004

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Babel N, Fendt J, Karaivanov S, Bold G, Arnold S, Sefrin A, Lieske E, Hoffzimmer M, Dziubianau M, Bethke N, Meisel C, Grütz G, Reinke P (2009) Sustained BK viruria as an early marker for the development of BKV-associated nephropathy: analysis of 4128 urine and serum samples. Transplantation 88:89–95. doi:10.1097/TP.0b013e3181aa8f62

    Article  PubMed  Google Scholar 

  40. Hasegawa M, Ito T, Saigo K, Akutsu N, Maruyama M, Otsuki K, Aoyama H, Matsumoto I, Asano T, Kitamura H, Kenmochi T (2014) Association of DNA amplification with progress of BK polyomavirus infection and nephropathy in renal transplant recipients. Transplant Proc 46:556–559. doi:10.1016/j.transproceed.2013.11.114

    Article  CAS  PubMed  Google Scholar 

  41. Viscount HB, Eid AJ, Espy MJ, Griffin MD, Thomsen KM, Harmsen WS, Razonable RR, Smith TF (2007) Polyomavirus polymerase chain reaction as a surrogate marker of polyomavirus associated-nephropathy. Transplantation 84:340–345. doi:10.1097/01.tp.0000275205.41078.51

    Article  CAS  PubMed  Google Scholar 

  42. Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J (2002) Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 347:488–496

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. Di Cristanziano.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Teutsch, K., Schweitzer, F., Knops, E. et al. Early identification of renal transplant recipients with high risk of polyomavirus-associated nephropathy. Med Microbiol Immunol 204, 657–664 (2015). https://doi.org/10.1007/s00430-015-0398-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-015-0398-x

Keywords

Navigation