Child Kidney Dis > Volume 26(1); 2022 > Article
Ahn and Kang: BK polyomavirus-associated nephropathy

Abstract

BK polyomavirus (BKPyV) is a ubiquitous virus residing in the kidney tubules and is clinically significant only in immunocompromised patients. In clinical practice, BKPyV is a causative pathogen of BKPyV-associated nephropathy (BKVAN) in kidney allograft recipients or hemorrhagic cystitis of hematopoietic stem cell transplant recipients. Currently, there is no effective treatment for BKVAN; therefore, careful monitoring and prudent modification of immunosuppression are necessary to prevent BKVAN. In this article, the epidemiology, pathophysiology, and current management strategies for BKVAN are reviewed.

Introduction

BK polyomavirus (BKPyV) is a non-enveloped double-stranded DNA virus that was first isolated from a kidney allograft recipient and described in 1971 [1]. More than 90% of the general population is infected with this virus [2]. Primary infection of BKPyV usually occurs subclinically during childhood, and the virus remains in a latent state in the uroepithelium and renal tubular epithelial cells. Upon immunosuppression, BKPyV is reactivated, leading to tubular cell lysis and viruria. One-third to one-half of those who show viruria (>108 copies/mL) develop BKPyV-DNAemia after 2 to 6 weeks along with tubulointerstitial lesions; half of these patients develop BKPyV-associated nephropathy (BKVAN) after another 2 to 6 weeks, especially if plasma BKPyV loads are >10,000 copies/mL.
BKVAN occurs more commonly with more potent immunosuppression, and it is currently one of the most important causes of kidney allograft failure [3-5]. In addition, this virus is associated with ureteral stenosis and hemorrhagic cystitis [6]. Moreover, sporadic cases of pneumonitis, retinitis, colitis, capillary‐leak syndrome, liver disease, meningoencephalitis, encephalitis, hemophagocytic syndrome, and urothelial cancer caused by BKPyV have been described [7]. BKVAN has a poor prognosis, and it has currently no treatment.

Epidemiology

BKVAN usually occurs within the first 2 years after kidney transplantation (KT). Viruria is first noted in 30% to 40% of KT recipients, with decoy cells positive in 20% to 30%, detectable BKPyV-DNA in 10% to 20%, BKVAN in approximately 10%, and graft loss from BKVAN in approximately 5% [8-11]. Interestingly, BKPyV viruria is identified in only 10% of immune-competent hosts; however, its prevalence is 30% to 60% in immunocompromised hosts. In addition, BKPyV-DNA clears within 2 to 12 hours after allograft nephrectomy for BKVAN, implying the presence of replication foci in the kidney allograft. BKPyV-DNAemia is associated with worse outcomes after KT. The 36-month graft survival rate if BKPyV is detected within 6 months post-KT is 79%, compared with 90% in controls [12]. Risk factors for BKVAN include tacrolimus use, potent immunosuppression, acute graft rejection, male gender, old age, younger age for children, delayed graft function, use of cadaveric graft, previous transplantation, human leukocyte antigen mismatches, ABO incompatibility, highly sensitized status, history of hemodialysis (vs. peritoneal dialysis), and a ureteral stent [13]. In other solid organ transplantations, BKPyV-related complications are not common, although cases have been reported following heart and lung transplantations [14,15].
In hematopoietic stem cell transplant (HCT) recipients, hemorrhagic cystitis occurs in up to one-fourth of patients [16,17], 1-month post-HCT [18] and usually lasts more than a month. BKPyV-DNAemia or viruria, which was associated with acute kidney injury, long-term poor kidney function, and mortality, were noted in 18% and 45% of HCT recipients, respectively, in the first 3 months post-HCT [19].

Pathophysiology

The BKPyV dsDNA is enclosed in a viral capsid comprised of an outer layer of VP1 pentamer and an inner layer of VP2 and VP3 proteins [20]. Its genome is composed of circular dsDNA of approximately 5 kb that contains the early viral gene region, which codes the regulatory large and small tumor antigens promoting cell cycle entry/progression and viral replication, the late viral gene region, which codes the viral capsid proteins VP1, VP2, VP3 for entry and assembly of progeny virions, and the non‐coding control region [8]. Once infection occurs, BKPyV hijacks the host cell’s DNA replication machinery for its own reproduction [20]. Therefore, antiviral agents targeting viral DNA replication are ineffective against this virus. After replication, lysis of the host cells along with inflammation and transition to the latent phase follow. Upon immunosuppression, viral replication resumes, causing acute tubular injury, interstitial nephritis, and severe interstitial fibrosis.

Screening of BKVAN

Since there is no effective treatment for BKVAN, screening for BKPyV is the most important strategy to prevent BKVAN. Recently, the American Society of Transplantation Infectious Disease Community of Practice (AST-IDCOP) recommended a monitoring and management strategy for BKVAN (Fig. 1) [7]. Prospective screening of the plasma or urine can identify early viral replication, permitting early intervention and preventing progression to nephropathy or allograft loss. For screening, plasma DNA load is measured monthly for 9 months, and then every 3 months thereafter for 2 years after KT [5,7,21] or when allograft biopsy is performed for surveillance or as indicated and when unexplained allograft dysfunction develops (Fig. 1). BKVAN is suspected when the BKPyV viral load is >10,000 copies/mL with or without serum creatinine level elevation. Histological findings of tubular atrophy, fibrosis, and inflammatory lymphocytic infiltrates need to be differentiated from those of acute cellular rejection. Intranuclear BKPyV inclusion bodies suggest BKVAN, which can be identified with special staining of large T antigen [22].

Diagnosis of BKVAN

Diagnosis of BKVAN is confirmed only by allograft kidney biopsy, with features of interstitial nephritis and large T antigen positivity with immunohistochemistry. If the plasma viral load either increases to >10,000 copies/mL in one of two measurements within 3 weeks or is sustained at >1,000 copies/mL in two measurements within 3 weeks, these are considered presumptive or probable BKVAN, respectively, which requires modification of immunosuppression and kidney biopsy if there is a risk of acute rejection and/or impaired kidney function (Fig. 1). Additionally, urine BKPyV viruria >10,000,000 copies/mL or presence of decoy cells indicates possible BKVAN, warranting plasma BKPyV viral load monitoring. If BKVAN is established, immunosuppression needs to be reduced, which can be accomplished even without biopsy confirmation. In 10% to 30% of cases, false-negative results were obtained as biopsies were taken early after BKPyV‐DNAemia onset, and medullary tissue was not sampled [21].
The pathology of BKVAN is described using the histologic patterns of BKVAN proposed by the 2013 AST-IDCOP. In addition to viral cytopathic changes, acute tubular injury, interstitial nephritis, and severe interstitial fibrosis are denoted as patterns A, B, C, respectively, along with the degree of interstitial nephritis (Table 1) [23]. Meanwhile, the Banff 2017 Working Group Classification takes into account the intrarenal PyV load (extent of virally induced tubular changes with intranuclear viral inclusion bodies and/or a positive immunohistochemistry reaction for SV40 T antigen) and Banff ci scores (Table 2) [22]. These histological patterns/classifications indicate the risks of allograft kidney loss, which range from <10% to >80%. In cases wherein there is evidence of rejection or intimal arteritis, or a positive C4d stain is observed, intensifying immunosuppression to treat rejection should first be considered before treating BKAVN.

Treatment

Reduction in immunosuppression

The first-line management for BKVAN is the reduction in immunosuppressive agents (Fig. 1). Usually, a stepwise approach to reduce immunosuppression is adapted; calcineurin inhibitors (CNI) are initially reduced by 25% to 50%, followed by mycophenolate mofetil (MMF) by 50%, and finally MMF discontinuation if there is no improvement [24]. Another approach is initial MMF reduction by 50%, then CNI reduction by 25% to 50%, and finally MMF discontinuation. Steroids are often limited to prednisolone 10 mg or less, and targets of CNI trough levels are <6 ng/mL with tacrolimus and <150 ng/mL with cyclosporine. Additionally, mammalian target of rapamycin (mTOR) inhibitors were shown to decrease BKPyV‐DNAemia and/or BKVAN [25]. Since cyclosporine and sirolimus, an mTOR inhibitor, inhibit BKPyV replication in vitro, switching immunosuppressants from tacrolimus to cyclosporine, CNI to sirolimus, MMF to sirolimus, or MMF to leflunomide can be considered, albeit with weak evidence [8,21]. However, reducing or modifying immunosuppression may be inadequate to prevent rejection, whereas excessive immunosuppression will worsen BKVAN and cause allograft dysfunction, tubulointerstitial nephritis, and fibrosis [7]. Therefore, prior to modifying immunosuppression, patient’s immunological risk, viral load, and kidney dysfunction must be considered [26].

Other management

No randomized clinical study has proven the efficacy of other adjunctive managements aside from modification of immunosuppression.

Intravenous immunoglobulins

Intravenous immunoglobulins, which have indirect immunomodulatory effects, contain high titers of potent BKPyV neutralizing antibodies that can directly neutralize BKPyV activity [7]. For BKVAN, 0.1–2.0 g/kg/dose is used.

Cidofovir

Cidofovir is a nucleoside analog licensed by the U.S. Food and Drug Administration for the treatment of cytomegalovirus retinitis [23]. Its efficacy in BKVAN is controversial; however, cidofovir concentration in renal tissues and urine is high. Therefore, cidofovir can theoretically be effective against viral infection in the kidneys. Coincidentally, drug-induced anterior uveitis has been reported in 12% to 35% of cases. Cidofovir is given as a low-dose regimen at 0.25–1.0 mg/kg/dose every 2 to 4 weeks, and serum creatinine, white blood cell count, ocular and visual symptoms should be monitored every 2 weeks [24].

Leflunomide

Leflunomide is a disease-modifying antirheumatic drug that inhibits dihydroorotate dehydrogenase, which is necessary for pyrimidine synthesis [27]. Its anti-proliferative activity and anti-inflammatory effects are a result of the selective inhibition of mTOR signaling. It has been shown to inhibit BKPyV viral DNA synthesis in vitro [28]. According to a systematic review, clearance of BKPyV‐DNAemia was reported in 33.3% to 92.3% of cases in different studies and 27 (10.1%) graft losses were reported in 267 patients [27,29]. Considering its immune-modulating effects, leflunomide is often used in place of MMF in cases of BKVAN [7]. Adverse events of leflunomide include hepatitis, hemolysis, thrombotic microangiopathy, myelosuppression, and fungal pneumonia. Thus, monitoring the complete blood count and performing liver function tests every 4 weeks is mandated.

Fluoroquinolones

Fluoroquinolones, including ciprofloxacin, inhibit BKPyV replication by affecting the helicase activity of the virus-encoded large T antigen [8]. However, in a randomized controlled trial to determine the effectivity of a 3-month course of ciprofloxacin as BKPyV prophylaxis in KT, ciprofloxacin not only failed to improve the allograft outcome but also increased levels of BKPyV-DNA and incidence of fluoroquinolone-resistant Gram-negative infections [30].

Special consideration for children

Similar to other common infections, children often require immunosuppression before primary infection with BKPyV. Therefore, they are more likely to be BKPyV-seronegative, which increases both the risk, severity, and duration of viral replication [31-34]. Thus, children may benefit more from intravenous immunoglobulins administration [35]. If they are BKPyV-seropositive, this means exposure to BKPyV was a recent event, which is why younger children harbor higher levels of immune effectors. Children with end-stage kidney disease often have urinary tract anomalies, which carry a risk of viral reactivation similar to a ureteric stent [31]. In addition, there may be hyperfiltration due to donor-recipient size mismatch in pediatric KT, which may delay the diagnosis of BKVAN [7]. Therefore, screening in children must be extended to a longer period [7].

Conclusions

BKVAN, although uncommon, threatens allograft survival in KT. Currently, there is no approved and effective treatment for BKVAN. To prevent BKVAN, meticulous screening up to the third year post-KT and appropriate modification of immunosuppression is necessary to improve outcomes.

Notes

Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author contributions
Conceptualization: YHA, HGK
Project administration: YHA, HGK
Visualization: YHA, HGK
Writing-original draft: YHA, HGK
Writing-review & editing: YHA, HGK
All authors read and approved the final manuscript.

References

1. Gardner SD, Field AM, Coleman DV, Hulme B. New human papovavirus (B.K.) isolated from urine after renal transplantation. Lancet 1971;1:1253-7.
crossref pmid
2. Hurdiss DL, Frank M, Snowden JS, Macdonald A, Ranson NA. The structure of an infectious human polyomavirus and its interactions with cellular receptors. Structure 2018;26:839-47.
crossref pmid pmc
3. Mengel M, Marwedel M, Radermacher J, Eden G, Schwarz A, Haller H, et al. Incidence of polyomavirus-nephropathy in renal allografts: influence of modern immunosuppressive drugs. Nephrol Dial Transplant 2003;18:1190-6.
crossref pmid
4. Patel H, Rodig N, Agrawal N, Cardarelli F. Incidence and risk factors of kidney allograft loss due to BK nephropathy in the pediatric population: a retrospective analysis of the UNOS/OPTN database. Pediatr Transplant 2021;25:e13927.
crossref pmid pdf
5. Cho MH. Monitoring BK virus infection in pediatric kidney transplant recipients. Korean J Pediatr 2019;62:414-5.
crossref pmid pmc pdf
6. Myint TM, Chong C, Wyld M, Nankivell B, Kable K, Wong G. Polyoma BK virus in kidney transplant recipients: screening, monitoring, and management. Transplantation 2022;106:e76-89.
crossref pmid
7. Hirsch HH, Randhawa PS; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019;33:e13528.
crossref pmid
8. Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Soc Nephrol 2007;2 Suppl 1:S36-46.
crossref pmid
9. Vanichanan J, Udomkarnjananun S, Avihingsanon Y, Jutivorakool K. Common viral infections in kidney transplant recipients. Kidney Res Clin Pract 2018;37:323-37.
crossref pmid pmc
10. Kwon Y, Kim JY, Lee Y, Cho H. Clinical manifestations of BK virus infection in pediatric kidney transplant patients. Korean J Pediatr 2019;62:422-7.
crossref pmid pmc pdf
11. Lee YH, Kang HG. Pediatric kidney transplantation. Child Kidney Dis 2021;25:8-13.
crossref
12. Schold JD, Rehman S, Kayle LK, Magliocca J, Srinivas TR, Meier-Kriesche HU. Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transpl Int 2009;22:626-34.
crossref pmid
13. Demey B, Tinez C, Francois C, Helle F, Choukroun G, Duverlie G, et al. Risk factors for BK virus viremia and nephropathy after kidney transplantation: a systematic review. J Clin Virol 2018;109:6-12.
crossref pmid
14. Ducharme-Smith A, Katz BZ, Bobrowski AE, Backer CL, Pahl E. BK polyomavirus infection in pediatric heart transplant recipients: a prospective study. Pediatr Transplant 2017;21:e12830.
crossref pmid pdf
15. Dufek S, Haitel A, Muller-Sacherer T, Aufricht C. Duct Bellini carcinoma in association with BK virus nephropathy after lung transplantation. J Heart Lung Transplant 2013;32:378-9.
crossref pmid
16. Bedi A, Miller CB, Hanson JL, Goodman S, Ambinder RF, Charache P, et al. Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. J Clin Oncol 1995;13:1103-9.
crossref pmid
17. Cesaro S, Dalianis T, Hanssen Rinaldo C, Koskenvuo M, Pegoraro A, Einsele H, et al. ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2018;73:12-21.
crossref pmid
18. Ruderfer D, Wu M, Wang T, Srivaths PR, Krance RA, Naik S, et al. BK virus epidemiology, risk factors, and clinical outcomes: an analysis of hematopoietic stem cell transplant patients at Texas Children's Hospital. J Pediatric Infect Dis Soc 2021;10:492-501.
crossref pmid pdf
19. Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, et al. The natural history of BK polyomavirus and the host immune response after stem cell transplantation. Clin Infect Dis 2020;71:3044-54.
crossref pmid pmc pdf
20. Helle F, Brochot E, Handala L, Martin E, Castelain S, Francois C, et al. Biology of the BKPyV: an update. Viruses 2017;9:327.
crossref pmid pmc
21. Sawinski D, Trofe-Clark J. BK virus nephropathy. Clin J Am Soc Nephrol 2018;13:1893-6.
crossref pmid pmc
22. Nickeleit V, Singh HK, Randhawa P, Drachenberg CB, Bhatnagar R, Bracamonte E, et al. The Banff Working Group classification of definitive polyomavirus nephropathy: morphologic definitions and clinical correlations. J Am Soc Nephrol 2018;29:680-93.
crossref pmid pmc
23. Hirsch HH, Randhawa P; AST Infectious Diseases Community of Practice. BK polyomavirus in solid organ transplantation. Am J Transplant 2013;13 Suppl 4:179-88.
crossref pmid
24. Ryu TH, Kim Hy, Oh JS, Kim JK. Combination therapy of low-dose cidofovir and leflunomide in a kidney transplant recipient with BK virus nephropathy: a case report. Korean J Transplant 2021;35(Supple 1):S61.
crossref
25. Mallat SG, Tanios BY, Itani HS, Lotfi T, McMullan C, Gabardi S, et al. CMV and BKPyV infections in renal transplant recipients receiving an mTOR inhibitor-based regimen versus a CNI-based regimen: a systematic review and meta-analysis of randomized, controlled trials. Clin J Am Soc Nephrol 2017;12:1321-36.
crossref pmid pmc
26. Ahlenstiel-Grunow T, Pape L. Immunosuppression, BK polyomavirus infections, and BK polyomavirus-specific T cells after pediatric kidney transplantation. Pediatr Nephrol 2020;35:625-31.
crossref pmid pdf
27. Schneidewind L, Neumann T, Drager DL, Kranz J, Hakenberg OW. Leflunomide in the treatment of BK polyomavirus associated nephropathy in kidney transplanted patients: a systematic review. Transplant Rev (Orlando) 2020;34:100565.
crossref pmid
28. Bernhoff E, Tylden GD, Kjerpeseth LJ, Gutteberg TJ, Hirsch HH, Rinaldo CH. Leflunomide inhibition of BK virus replication in renal tubular epithelial cells. J Virol 2010;84:2150-6.
crossref pmid pmc pdf
29. Jung YH, Moon KC, Ha JW, Kim SJ, Ha IS, Cheong HI, et al. Leflunomide therapy for BK virus allograft nephropathy after pediatric kidney transplantation. Pediatr Transplant 2013;17:E50-4.
crossref pmid
30. Patel SJ, Knight RJ, Kuten SA, Graviss EA, Nguyen DT, Moore LW, et al. Ciprofloxacin for BK viremia prophylaxis in kidney transplant recipients: results of a prospective, double-blind, randomized, placebo-controlled trial. Am J Transplant 2019;19:1831-7.
crossref pmid pdf
31. Hocker B, Schneble L, Murer L, Carraro A, Pape L, Kranz B, et al. Epidemiology of and risk factors for BK polyomavirus replication and nephropathy in pediatric renal transplant recipients: an international CERTAIN registry study. Transplantation 2019;103:1224-33.
crossref pmid
32. Schmidt T, Adam C, Hirsch HH, Janssen MW, Wolf M, Dirks J, et al. BK polyomavirus-specific cellular immune responses are age-dependent and strongly correlate with phases of virus replication. Am J Transplant 2014;14:1334-45.
crossref pmid pdf
33. Smith JM, McDonald RA, Finn LS, Healey PJ, Davis CL, Limaye AP. Polyomavirus nephropathy in pediatric kidney transplant recipients. Am J Transplant 2004;4:2109-17.
crossref pmid
34. Ginevri F, De Santis R, Comoli P, Pastorino N, Rossi C, Botti G, et al. Polyomavirus BK infection in pediatric kidney-allograft recipients: a single-center analysis of incidence, risk factors, and novel therapeutic approaches. Transplantation 2003;75:1266-70.
crossref pmid
35. Miettinen J, Lautenschlager I, Weissbach F, Wernli M, Auvinen E, Mannonen L, et al. BK polyomavirus viremia and antibody responses of pediatric kidney transplant recipients in Finland. Pediatr Transplant 2019;23:e13324.
crossref pmid pdf

Fig. 1.
Monitoring and management strategy for BK polyomavirus (BKPyV)-associated nephropathy (BKVAN). HPF, high-power field; VL, viral load; EM, electron microscopy; PyV, polyomavirus; PyVAN, polyomavirus-associate nephropathy; AST-IDCOP, American Society of Transplantation Infectious Diseases Community of Practice; Tac, tacrolimus; CsA, cyclosporine-A; MPA, mycophenolic acid or equivalent; mTOR, mammalian target of rapamycin; IVIG, intravenous immunoglobulin. a)Allograft biopsy should be considered in patients with baseline allograft function, if concurrent (subclinical) acute rejection is likely; b)If decline in plasma BKPyV-DNAemia is <1 log10 copies/mL in <4 weeks, further immunosuppression is required. Reuse from Hirsch et al. Clin Transplant [7] with permission from John Wiley and Sons.
ckd-22-029f1.jpg
Table 1.
Histological patterns fo BKVAN according to American Society of Transplantaion 2013
Pattern Biopsy findings Risk of graft loss
A <10%
 Viral cytopathic changes Mild (≤25%)
 Interstitial inflammation Minimal (≤10%)
 Tubular atrophy Minimal (≤10%)
 Interstitial fibrosis Minimal (≤10%)
B 50%
 Viral cytopathic changes Variable (11% to >50%)
 Interstitial inflammation Significant (11% to >50%)
 Tubular atrophy Moderate (<50%)
 Interstitial fibrosis Moderate (<50%)
  B1: Interstitial inflammation Moderate (11% to 25%) 25%
  B2: Interstitial inflammation Significant (26% to 50%) 50%
  B3: Interstitial inflammation Extensive (>50%) 75%
C >80%
 Viral cytopathic changes Variable (variable)
 Interstitial inflammation Variable (variable)
 Tubular atrophy Extensive (>50%)
 Interstitial fibrosis Extensive (>50%)

BKVAN, BK polyomavirus-associated nephropathy.

Adapted from Hirsch et al. Am J Transplant [23].

Table 2.
Banff histologic classification system of BKVAN
Class 1
Class 2
Class 3
pvla) Banff ci scoreb) pvla) Banff ci scoreb) pvla) Banff ci scoreb)
1 0–1 1 2–3 NA NA
NA NA 2 0–3 NA NA
NA NA 3 0–1 3 2–3

BKVAN, BK polyomavirus-associated nephropathy; ci, interstitial fibrosis in cortex; NA, not available.

a)The pvl scoring is on the basis of the extent of virally induced tubular changes. The overall percentage of positve tubular cross-sections is estimated in the entire biopsy sample (all available cores, cortes, and medullar): pvl 1, ≤1% of all tubules/ducts with viral replication; pvl 2, >1% to ≤10% of all tubules/ducts with viral replication; and pvl 3, >10% of all tubules/ducts with viral replication.

b)The Banff ci score evalutes the extent of interstitial fibrosis in cortex: ci 0, ≤5% of cortical area; ci 1, 6%–25% of cortical area (mild); ci 2, 26%–50% of cortical area (moderate); and ci 3, >50% of cortical area (severe).

Adapted from Nickeleit et al. J Am Soc Nephrol [22].

TOOLS
METRICS Graph View
  • 0 Crossref
  •  0 Scopus
  • 2,625 View
  • 80 Download
ORCID iDs

Yo Han Ahn
https://orcid.org/0000-0002-8185-4408

Hee Gyung Kang
https://orcid.org/0000-0001-8323-5320

Related articles

Editorial Office
#403 Blue, 240 Gimpohangang 1-ro, Gimpo 10078, Republic of Korea
TEL: +82-10-4391-0788   E-mail: chikd@chikd.org
© Korean Society of Pediatric Nephrology.         
Close layer