Description of the health condition and context

BK polyomavirus (BKPyV) is a ubiquitous deoxyribonucleic acid (DNA) virus that remains quiescent in renal and uroepithelial tissue after primary infection and is generally harmless in immunocompetent hosts. Most of the population has been exposed during childhood and BKPyV antibodies (indicating prior exposure) can be detected in 80% to 90% of the general population (Antonsson 2010; Knowles 2003). There have been isolated reports of BKPyV affecting the native kidneys of immunosuppressed patients (Al Zein 2019; Shah 2019) but the overwhelming majority of infection is seen in the allografts of kidney transplant recipients. With the advent of increasingly potent immunosuppressive regimens after kidney transplantation, BKPyV infection has become a major cause of graft dysfunction and loss. 

The earliest manifestation of the infection is detectable BKPyV in the urine (viruria). About 50% of patients with viruria will progress to develop BKPyV in their blood (viraemia) (Laskin 2010) and without intervention, the virus will propagate and may result in infiltration of the allograft leading to significant graft dysfunction and potentially graft loss. Biopsy‐proven disease is known as BKPyV‐associated nephropathy (BKPyVAN). The prevalence of BKPyVAN in the post‐kidney population is approximately 1% to 10% (Dharnidharka 2009; Nickeleit 2000; Schold 2009) but the prevalence of viruria and viraemia is much higher, with 25% to 35% (Brennan 2005; Manzano 2019) and 10% to 20% (Brochot 2019; Madden 2018) of recipients having detectable BKPyV in their urine and blood respectively, at some point post‐transplant. Graft dysfunction in the setting of high viral loads in the urine or blood is often presumed to be due to BKPyV infection even without confirmatory biopsy‐proven disease. Initial BKPyVAN outcomes were dismal with up to 50% of patients losing their graft within five years of diagnosis (Vasudev 2005), but recent outcomes have improved (Manzano 2019) temporally corresponding with the widespread adoption of screening protocols to detect BKPyV at an earlier, pre‐clinical stage. 

Because of the asymptomatic nature of BKPyV infection, and the severe consequences if left untreated, most transplant centres have adopted screening protocols using highly sensitive polymerase chain reaction (PCR) testing to detect early low‐level BKPyV in the urine or blood before overt nephropathy develops. Infection is most likely to occur in the first year post‐transplant (Dharnidharka 2009; Hocker 2019) when cellular immunity is most compromised due to high initial doses of immunosuppression. As such, current guidelines recommend that screening protocols are initiated one month post‐transplant and continue periodically for two years (Hirsch 2019; KDIGO 2009). PCR testing of blood is preferred over urine due to its superior specificity for clinically relevant infection (Hirsch 2002) and efficacy in monitoring response to therapy (Brennan 2005). 

The mainstay of BKPyV treatment is immunosuppression reduction (Hirsch 2019; KDIGO 2009). To date, there are no pharmacological therapies that have been proven effective at improving graft outcomes in those with BKPyV infection. Given that both BKPyV infection and allograft rejection are most common in the early stages post‐transplant, immunosuppression reductions in response to BKPyV infection increase the risk of allograft rejection (Hardinger 2010). In this context management decisions usually involve trying to determine the optimal balance between immunosuppression reduction facilitating viral clearance without triggering allograft rejection and graft dysfunction. The degree of immunosuppression reduction is dependent upon the severity of the infection and the individual patient’s immunological risk for rejection. 

Due to the lack of therapeutic options and the poor graft outcomes, once BKPyVAN is established, a thorough understanding of risk factors for BKPyV infection assumes additional importance. If potentially modifiable risk factors can be reliably identified, avoidance of these factors may prevent the development of BKPyV in at‐risk patients and improve outcomes throughout the transplant population by allowing for a more personalised approach to the management of kidney transplant recipients.

Description of the prognostic factors

After primary infection, BKPyV remains dormant in renal and uroepithelial cells (Chesters 1983; Drachenberg 1999; Heritage 1981). The impaired cellular immune response due to immunosuppression in the early post‐transplant period allows for the uncontrolled replication of the virus. As BKPyV overwhelmingly affects transplanted allografts (as opposed to native kidneys), additional factors that induce local inflammation at the site of transplantation (Hashim 2014), and donor characteristics (Verghese 2015), are likely to play a key role in the pathogenesis of this condition. 

Over 140 factors have been reported in association with the development of BKPyV infection (Demey 2018) but the majority of these are based on small, retrospective studies with frequently conflicting results. Almost all immunosuppressive agents have been associated, however, the strongest evidence supports a link between tacrolimus usage and BKPyV (Hirsch 2013; Mengel 2003) with the proposed pathogenesis involving activation of the FKBP‐12 pathway (Hirsch 2016). Male sex and increasing age have consistently been shown to increase the risk of BKPyV infection (Dharnidharka 2009; Kayler 2013; Thangaraju 2016) likely due to the reduction in the antibody response to BKPyV infection with increasing age (Gossai 2016; Kean 2009). 

The most clinically relevant prognostic factors have been selected to be investigated in this review. These can be categorised as relating to the recipient, the donor, or the transplant itself. Apart from age, these factors are static and will be determined by their respective values at the time of transplantation or in the immediate days thereafter. With the exception of delayed graft function, all other factors are known at the time of transplant. Delayed graft function refers to poor function of the transplanted kidney within the first week of the post‐transplant period and is recorded as a dichotomous outcome at that point. ABO‐incompatibility and the number of human leukocyte antigen (HLA) mismatches indicate the degree of immunological difference between donor and recipient and will not change over time. 

Of particular interest are potentially modifiable transplant factors. If strong associations are found, transplant recipients’ management could be tailored according to the individual patient’s risk profile to avoid certain factors resulting in a reduction in the risk of BKPyV development. 

• Recipient factors 

  • Age, sex and ethnicity

  • Primary cause of kidney failure 

  • Patient’s first or subsequent graft

• Donor factors 

  • Age, sex and ethnicity

• Transplant factors

  • Ureteric stent placement at the time of transplant 

  • Initial immunosuppression regimen at the time of transplant

  • Delayed graft function

  • ABO‐incompatibility

  • Number of HLA mismatches 

Health outcomes