BKPyV is a highly prevalent polyomavirus specific to the human host [4]. As a double-stranded DNA virus, its genome consists of the early coding region, late coding region, and a non-coding control region (NCCR) in between [5]. The early region usually codes for the replication proteins, including the small tumor antigens, the large tumor antigens (TAgs), and agnoprotein. The late region codes for structural proteins VP1, VP2, and VP3 [6]. The microRNAs expression was transcribed from the 3′ end of the TAgs and act as a regulator in BKPyV infection [7]. The NCCR contains the genome of promoters of the early and late regions, transcriptional start sites, and the origin of replication. It also provides binding sites for host cellular regulatory factors. NCCR variation exists between BKPyV isolates, and the rearranged forms of NCCR are associated with disease [8]. The high heterogeneity of NCCR allows for environmental adaptation and higher pathogenicity for disease progression [6].

Cellular immunity is critical for the immune response during BKPyV viremia and BKVN. Innate immune response serves as the first line of defense against the primary infection [9]. Dendritic cells are critical in the induction of adaptive immune response [10]. Womer et al. reported that the number of peripheral blood dendritic cells is lower in KTRs developed BKVN. They also revealed that KTRs with fewer dendritic cells before transplantation are more likely to be associated with BKVN [11]. Furthermore, BKPyV can decrease the natural killer cell-mediated cytotoxicity by inhibiting the identification of natural killer cells [12]. Other innate immune mediators are associated with renal inflammation [13]. Adaptive immune response develops after exposure to viral antigens. Humoral response works via neutralizing antibodies to defend the further viral infectious process. Studies showed seronegative recipients have higher risks in viremia and subsequent BKVN than seropositive recipients as humoral immunity may help limit BKPyV infection [14,15,16,17,18,19]. Meanwhile, recipients paired with seropositive donors have a higher post-transplant BK-specific-antibody titer than the seronegative donor group [20]. It means that BKPyV infection from the donor can induce the humoral immune response [21]. However, the virus can hide away from neutralization with a mutation in viral antibody receptors [22,23]. In this situation, latent viral reactivation can be well-controlled by antiviral memory T cells [4]. Cellular immunity offers more effective infection control because of pathogen detection and cytotoxicity [21]. Both CD4+ and CD8+ T cells are important, especially the polyfunctional BKPyV-specific T cells [24,25]. After kidney transplant, KTRs with viruria but no viremia have positive BKPyV-specific T cell response [26]. Conversely, there is no BKPyV-specific T cell response in KTRs with BKPyV viremia or BKVN [26,27,28,29,30]. Also, quick BK-specific T cell response was noted in the viremia-resolved group, while the response was only noted after reduced IS in the developed BKVN group [28,31]. These studies concluded that it is crucial for KTRs to reconstitute the BKPyV-specific T cells to fight against BKPyV infection.

During the first decade of childhood, the primary exposure to BKPyV, often with subclinical symptoms, resulted in 80–90% of adults developed antibodies against BKPyV [32,33]. The natural transmission route is still unknown [34]. After the primary infection, the virus remains latent in the kidney, peripheral-blood leukocytes, and possibly the brain [35]. The viral reactivation occurs while the host immunity is over-suppressed, resulting in viral replication with consequent tubular cell lysis and viruria. BKPyV replication ensues in the renal interstitium, leading to the destruction of the tubular capillary wall subsequently cross into the blood, causing viremia. Viral invasion of tissue progressively cause cell necrosis and tissue inflammation [36]. BKPyV reactivation presented as viremia usually happens in the first month post-transplant in KTRs. The incidence peaks around 28–31% at month 3 and month 12 after kidney transplantation, with cases rarely seen at month 18 [37,38]. In the KTR population, the incidence of BKPyV viruria is 30–40%, BKPyV viremia is 13%, and BKVN is 8% [39]. High-level BKPyV viruria progress to viremia after a median of 4 weeks, and approximately a median of 8 weeks later, viremia may lead to BKVN [40,41]. The clinical presentation of BKPyV infection may range from asymptomatic to progressive renal function decline, and others are incidental findings at protocol allograft biopsy [42]. The laboratory clues may be ranged from normal results to elevated serum creatinine, mild proteinuria (48%), or hematuria (19%) [43]. Without screening and treatment, the natural course of BKVN leads to 50% graft loss [44,45].

3. Screening and Diagnosis