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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 20  |  Issue : 3  |  Page : 127-150

BK virus infection in renal transplant recipients: an overview


1 Department of Nephrology, Dubai Hospital, Dubai Health Authority, Dubai; Faculty of Medicine, Institute of Clinical Sciences, University of Liverpool, Liverpool, UK
2 Faculty of Medicine, Institute of Clinical Sciences, University of Liverpool, Liverpool; Department of Renal, Doncaster Royal Infirmary, Doncaster, UK
3 Faculty of Medicine, Institute of Clinical Sciences, University of Liverpool, Liverpool, UK
4 Department of Nephrology and Transplantation, Royal Liverpool University Hospital, Liverpool, UK
5 Faculty of Medicine, Institute of Clinical Sciences, University of Liverpool, Liverpool; Department of Nephrology and Transplantation, Royal Liverpool University Hospital, Liverpool, UK
6 Faculty of Medicine, Institute of Clinical Sciences, University of Liverpool, Liverpool; Department of Nephrology and Transplantation, Sheffield Kidney Institute, Sheffield Teaching Hospitals, Sheffield, UK

Date of Submission16-Dec-2019
Date of Decision26-Mar-2020
Date of Acceptance03-May-2020
Date of Web Publication17-Jul-2020

Correspondence Address:
Dr. Fakhriya Alalawi
Department of Nephrology, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_48_19

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  Abstract 


Although BK virus (BKV) was discovered in 1971, it took almost three decades for this virus to be routinely considered as a possibility among a plethora of causes of renal dysfunction in a kidney transplant recipient. BKV infection, an early complication of renal transplant, often presents within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis that mimics acute rejection and poses a diagnostic and therapeutic dilemma. More frequent diagnosis of BKV infection over the past 2 decades is a consequence of more potent immunosuppression (aimed to prevent acute rejection episodes and, thereby, improving allograft survival). Untreated BKV infections cause renal allograft dysfunction and subsequently allograft loss. A routine screening protocol for early recognition of asymptomatic BKV infection has been reported to result in better allograft outcomes. This review is aimed to discuss the most recent evidence addressing the virology, pathogenesis, clinical features, diagnostic tools, screening protocols, treatment strategy, and short-term and long-term renal allograft survival concerning BKV infection.

Keywords: BK virus (BKV), BK virus nephropathy, polyomavirus-associated nephropathy, polyomavirus, viremia, viruria


How to cite this article:
Alalawi F, Alnour H, El Kossi M, Jenkins J, Taku A, Sharma AK, Halawa A. BK virus infection in renal transplant recipients: an overview. J Egypt Soc Nephrol Transplant 2020;20:127-50

How to cite this URL:
Alalawi F, Alnour H, El Kossi M, Jenkins J, Taku A, Sharma AK, Halawa A. BK virus infection in renal transplant recipients: an overview. J Egypt Soc Nephrol Transplant [serial online] 2020 [cited 2020 Oct 27];20:127-50. Available from: http://www.jesnt.eg.net/text.asp?2020/20/3/127/290015




  Introduction Top


Although the two human polyomaviruses, BK virus (BKV) and JC virus (JCV), were discovered in 1971, their negative effect was poorly understood till three decades later, when BKV was identified as a significant cause of interstitial nephritis and allograft failure in renal transplant recipients. BKV infection is routinely considered as a possibility among a plethora of causes of renal dysfunction in kidney transplant recipients often occurring within the first year after transplantation. It presents as an asymptomatic gradual rise in creatinine with tubulointerstitial nephritis, which may mimic acute rejection, and thereby, producing a diagnostic and therapeutic treatment dilemma.

BK virus and renal transplantation: historical perception

In 1971, Gardner et al. [1] were the first to detect BK polyomavirus (BKV) in both urine and ureteral epithelial cells of a Sudanese kidney transplant recipient who presented with ureteric stenosis and renal failure. They named the virus ‘BK’ after the initials of this patient. Abundant large cells with intranuclear inclusions were present in the urine, named later as ‘decoy cells’ for their resemblance to malignant cells [1],[2],[3]. The relationship between kidney transplants and shedding of a polyomavirus in the urine was confirmed with subsequent studies by Lecatsas, Coleman, and others [4],[5],[6],[7]. Mackenzie et al. [8] in 1978 had defined histological changes consistent with polyomavirus nephritis in a kidney biopsy of a patient who was shedding BKV in the urine. Two further studies published in the 1980s described the patterns of JC and BKV infections in kidney transplant recipients [5],[9]. Since then, numerous reports on various aspects of BKV in renal transplant recipients have been reported [10],[11]. This virus was found to have high homology with JCV, the other human polyomavirus, discovered as a cause of progressive multifocal leukoencephalopathy [12]. BKV was recognized to cause severe interstitial nephritis and allograft failure in kidney transplant recipients [11],[13]. Increased awareness among nephrologists to recognize BKV disease at an earlier stage and the development of better diagnostic laboratory techniques contributed to the ever-increasing incidence of BKV infection [10],[14].

Polyomaviridae variants

The human BKV belongs to the Polyomaviridae (PyV) virions, a subgroup of papovaviruses comprising BKV, JCV, and simian virus 40 (SV40). It is a family of small, nonenveloped DNA viruses with icosahedral capsid of 40–45 nm in diameter that can bear heating up to 50°C for 30 min with little effect on infectivity and has a circular double-stranded DNA of ∼5000 base pairs [15],[16],[17],[18]. The name polyoma represents the viruses’ capability to create many (poly) tumors (−oma) [18].

A total of 12 additional human polyomaviruses have been isolated lately between the years 2007 till 2017. These new group members were termed based on the site of discovery, their geographical areas, the diseases they might cause, or an order of discovery: MWPyV (Malawi); WUPyV (Washington University); KIPyV or Human polyomavirus-3 (Karolinska Institute); STLPyV (Saint Louis polyomavirus or Human polyomavirus-11); MCPyV (Merkel cell carcinoma); TSPyV (trichodysplasia spinulosa); HPyV6, HPyV7, HPyV9, and HPyV12 (human polyomaviruses 6, 7, 9, and 12); New Jersey polyomavirus (NJPyV, also known as polyomavirus-13); and Lyon IARC polyomavirus (LIPyV or human polyomavirus-14) [19],[20],[21],[22],[23].

Epidemiology of BK virus

Polyomavirus hominis-1, well known as BKV, is a ubiquitous virus that infects most humans around the world. Primary infection predominantly takes place during early childhood, and then the virus stays dormant throughout life in immune-competent people [2],[10],[24],[25]. Studies showed as much as 60–85% of the general population is seropositive for BKV ([Table 1]). Unfortunately, there is scarcity in data related to BKV prevalence in Middle East countries and Africa, and a single report found was from Iran, with a seroprevalence of 41.8% [37]. Such variation in percentages can be clarified by the age of the tested population, the sample size, and the antibodies threshold that is viewed as positive.
Table 1 Seroprevalence of BK virus in general public in some countries

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BK virus structure

BKV-DNA genome can be divided into three parts ([Figure 1]) [13],[16],[24],[39],[40]:
Figure 1 BKV genome structure, adapted from De Gascun and Carr [38]. BKV, BK virus.

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The noncoding control region (NCCR): it regulates the expression of the virus early and late genes regarding differentiation and activation of the host cell.
  1. The early viral gene region: it encodes the regulatory nonstructural proteins called small T antigen (STA) and large T antigen (LTAg, large tumor antigen), which interacts and binds to cellular target proteins (tumor suppressor proteins Rb, p107, p130, and p53) to shift the host cell into S phase cycle for efficient viral replication. LTA is a regulatory molecule that drives the cell into S phase, whereas STA is involved in viral replication, cell cycle progression, and transformation.
  2. The late viral gene region (LVGR): it encodes the capsid proteins VP-1, VP-2, and VP-3 within the nucleus. These capsids can release around 10 000–100 000 virions through cell lysis. Additionally, the LVGR of BK polyomavirus and JCV encodes a small cytoplasmic protein called agnoprotein, which appears to have multiple regulatory functions, such as assistance in regulating viral replication and interrupt host cell processes.
  3. The capsid protein VP1 in the LVGR is the main capsid protein present on the surface and is responsible for receptor binding to the host cells, facilitating virus entry into the cell. Additionally, VP1 is highly immunogenic and is the target for neutralizing antibody, cellular immune recognition, and required for virion assembly and hemagglutination of human erythrocytes [15],[24],[41]. Once it gets inside the cell, the virus travels to the nucleus and establishes a dormant or lytic infection [13],[42].


BK virus variants

BKV can be categorized into four genotypes/subtypes according to the DNA sequence variations in the genomic region of VP1 [43],[44],[45]. Genotype I is the predominant subtype of all circulating viruses, accounting for greater than 80% worldwide, followed by genotype IV which is the second most frequent genotype, found approximately in 15% of the healthy human population. Alternatively, genotypes II and III are relatively rare and infect only a minority of patients [24],[45].

Phylogenetic analysis had recognized four more subgroups, subcloned of subtype I (I/a, I/b-1, I/b-2, and I/c), and six subgroups of subtype IV (IV/a-1, IV/a-2, IV/b-1, IV/b-2, IV/c-1, and IV/c-2). As with subtype I subgroups, each of the subtype IV subgroups may reflect different geographical and migration pattern of the human population [15],[24],[45],[46]. The subgroup of subtype I (I/b-2) has been noticed mostly in American and European populations, whereas subgroup I/c dominates in Asians. Among subtype IV isolates, subgroup IV/c-2 is predominant among Americans and Europeans, whereas the other subgroups are more common in Asian populations [16],[31]. Apart from the genotypic variations of VP1 region, additional two other forms of BKV present secondary to variations in the NCCR, namely, rearranged (rr) and archetype (ww) variants. Continuous duplication of BK genome during activation process can result in deletion and duplication in the NCCR sequences, with subsequent generation of rearranged variant viruses. The clinical and immunological consequences of these genotypes on clinical aspect and the course of the disease are still undefined [47].

Immunological response to BK virus

BK viral replication follows a state of immune suppression; hence, it is reported to occur in pregnancy, diabetes, HIV infection, cancer, and posttransplantation period [2]. BKV replication characteristically begins early in the posttransplant period and can follow antirejection therapy as a consequence of intense immunosuppression. The immune system plays an essential part in controlling BKV replication and resolution of BK virus nephropathy (BKVN) [48]. Possible factors that add to the pathogenesis of BKVN might be a combination of (a) defective immune surveillance by the host T-lymphocytes, (b) absence of humoral immunity to BKV, (c) alloimmune activation, and (d) viral variation in molecular sequences [13].

The role of cell-mediated immunity

CD4+ and CD8+ T cells are the major components of cellular-mediated immunity to control the BKV and play a role in BK clearance. T cells react against both nonstructural and BK capsid proteins and can be measured by the enzyme-linked immunosorbent spot (ELISPOT) and tetramer staining [2],[10]. Within the viral genome, both the LTAg and VP1 gene products contain epitopes responsible for CD4+ and CD8+ cells identification [48],[49]. Cytotoxic T cells (CTL) kill the BK-infected cells after recognition of damaged segments of viral DNA [10]. Without appropriate immunological regulation, progressive lytic infection arises and results in the formation of large nuclear and peri-nuclear viral inclusion in the tubular cells [13]. The lysis of an infected cell can lead to viral leakage into the tubular lumen and urine, as well as dissemination into the interstitium. Subsequent tubular cell necrosis leads to denudation of the basement membrane and casts formation. The damage of tubular capillary walls will cause the vascular spread of the virus, leading to dense inflammatory interstitial infiltrate and tubulitis; however, these typical features might be absent. Collateral destruction with necrosis and apoptosis of noninfected tubular cells might follow, resulting in continued intragraft inflammation, tubular injury, and up-regulation of profibrotic mediators and ends with allograft dysfunction and loss [13].

The role of humoral immunity

Humoral immunity might have a role in the pathogenesis of BKVN, as patients with prior immunity to BKV may not show the manifestation of the disease, irrespective of the number of viral copies. Bohl and colleagues found the kidney recipients from a seropositive donor were more likely to develop BK viremia compared with others who had a kidney from a seronegative donor [50],[51]. The role of antibody-mediated immunity was also validated in BKV infection. The patients with BKVN had the highest rise in BKV-specific IgG with persistently elevated IgM levels [10].

Role of alloimmune activation

Another possible immunological factor involved in the development of BKVN is the allo-human leukocyte antigen (HLA)-reactivity and heterologous immunity. The latter concerns with T cells, which cross-react to both BKV and allo-antigens. Moreover, one can propose that the host BKV-specific effector memory T cells cannot identify the allo-HLA molecules representing BKV-peptides; thus, it allows BKV to escape the immunological surveillance. Murine kidney allografts were more susceptible to polyomavirus infection, which cause an increase in allo-reactive T cells that lacked cross-reactivity to the virus [52].

Nonetheless, CD4+ T cells with cross-reactivity against allo-HLA antigens and BKV-VP1 have been detected in humans [11],[53]. Additionally, Awadalla et al. [54] had linked the higher degree of HLA mismatches with an increase in the incidences of BKVN, which hypothesizes the role of alloimmune activation. Interestingly, Drachenberg et al. [55] showed a reverse association between allograft survival and the level of HLA matches in patients with BKVN, suggesting a lack of HLA matches might predict better outcomes in recipients with BKVN.

The role of other factors

In addition to the viral variation in molecular sequences which may contribute in the pathogenesis of BKVN, BKV tropism to the renal tubular epithelial cells may play an additional role. Moriyama et al. [56] had demonstrated that a blockage of caveolin-induced endocytosis, either directly or through small interference RNA depletion of caveolin-1, produced substantial reduction in BKV infectivity as measured by immunofluorescence, as BKV particles were found in vitro to colocalize with caveolin-1, and not to a clathrin, in the human renal proximal tubular epithelium. Therefore, the pathogenesis of BKV disease is probably related to a combination of cellular and humoral immune deficiencies with alloimmune activation as well as BKV’s tropism to the renal tubular epithelium.

Pathogenesis of BK infection

Primary infection with BKV is usually subclinical or, seldom, manifests as a mild respiratory symptom in childhood [3],[4]. It has been proposed that BKV goes into the circulatory system through infected tonsils, and then infect the peripheral blood mononuclear cell that gets disseminated to secondary places including kidneys. Following a resolution of primary infection, the virus stays dormant in the uroepithelium and renal tubular cells for life, with intermittent reactivation that manifests as asymptomatic viruria [3],[4],[24]. Additionally, BKV can remain latent in leukocytes, brain tissues, and lymph nodes [57]. In the presence of immunosuppressive therapy, the virus activates and starts to proliferate inside the interstitium and crosses into the peritubular capillaries, producing a sequence of events, which begin with tubular cell lysis and viruria. The outcome relies upon the level of damage, inflammation, and fibrosis [2],[3],[4]. Tissue damage follows a combination of direct viral cytolytic effects and secondary inflammatory responses [58]. The sophisticated reactions between the BKV and the immune system result in different clinical features of BKV disease [59],[60].

Routes of transmission of primary BK virus

Several routes for the primary BKV virus transmission have been theorized. The route of infection might be respiratory, fecal-oral, transplacental, or from donor tissues.
  1. Respiratory route: several authors had speculated the primary route of transmission to be respiratory, as evident by the presence of BKV in the respiratory tract and tonsils of children. The supportive studies are mainly epidemiological, and none of them had isolated BKV on respiratory samples [61],[62],[63].
  2. Gastrointestinal transmission: BKV replication was shown in salivary gland cells and was detected in oral secretions. Moreover, in a study of 99 hospitalized pediatric patients, 45% of the collected stool samples and rectal swabs tested positive for polyomavirus DNA, supporting the fecal-oral transmission of BKV [61],[64],[65].
  3. Vertical transmission: another proposed mechanism for BKV transmission is via the transplacental passage. BK viruria can increase up to 35% during pregnancy, and BKV can cross the placenta and stay dormant in fetal organs, suggesting the possibility of vertical transmission [66]. Pietropaolo and colleagues and others confirmed BKV-DNA particles in a higher proportion in the products of healthy pregnancies and aborted fetuses [66],[67],[68],[69],[70]. However, a different study had failed to demonstrate BKV in either maternal or fetal tissues [71].
  4. Sexual transmission has been anticipated by Monini et al. [72] as he detected BKV in 57% of genital tissue samples and 95% of sperm specimens. However, as the primary infection happens before the age of sexual activity, this theory did not find any popularity.
  5. Donor-derived infection: the source of posttransplant BKV infection could be from either the donor or the recipient. A negative BK recipient who had a kidney from BKV-infected donor has been noted to have similar genotypes, thereby, supporting donor transmission [50],[73],[74].
  6. Other proposed mode for BKV transmission is through the urine and blood, as the viruses have been detected in urine samples and were present in peripheral blood leukocytes [2],[24].


Clinical manifestations

Urinary shedding of BKV was reported in 7% of healthy immunocompetent individuals (but not in plasma); nevertheless, BKV does not cause disease in immunocompetent people [2]. In immunocompromised patients, particularly in renal allograft recipients, BKV has been correlated with different clinical features, among which are the BKVN, ureteric stenosis, and late-onset hemorrhagic cystitis (HC) [2],[11],[75],[76],[77]. Outside renal transplantation, BKV is commonly encountered in patients with hematopoietic stem cell transplant (HSCT) recipients as hemorrhagic and non-HC [78],[79], whereas in HIV-infected patients, BKV may disseminate leading to severe viremia with multiorgan involvement [57],[80],[81],[82],[83],[84],[85],[86],[87],[88],[89],[90],[91] and eventually leads to death ([Figure 2]).
Figure 2 Clinically reported manifestations of BKV in immunocompromised patients, including renal transplant recipients and patients with HSCT and HIV infection. BKV, BK virus; HSCT, hematopoietic stem cell transplant.

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BK virus and renal disease

Infection with this virus starts as the virus proliferate in the uroepithelial cells followed with a viral detachment in the urine (viruria), which can progress a few weeks later to blood (viremia) and eventually to BK-polyomavirus-associated nephropathy (BKVN)/(PyVAN) [10],[13],[24]. BK viruria generally affects 30–40% of renal transplant recipients, whereas 10–15% of recipients develop BK viremia [13],[24]. The estimated incidence of BKVN in different literature ranges between 2 and 15% of kidney allograft recipients [11],[92],[93],[94],[95]. The variations in these figures can be explained by different immunosuppressive regimens and different screening strategies, including a performance of biopsy surveillance in some centers, which can detect BKVN at earlier stages.

BK virus-associated nephropathy

Clinically, BKV-associated nephropathy begins with viruria or asymptomatic hematuria and ends with extensive irreversible injury and allograft failure. The onset of nephritis might occur as early as 6 days after renal transplant or as late as 5 years [6],[13],[85],[92],[96],[97],[98].

Ureteric stenosis

The prevalence of ureteric stenosis is 2–6% [2]. Allograft dysfunction secondary to ureteric stricture and leading to hydronephrosis is rarely seen [1],[7],[11],[99], and treatment should involve a percutaneous nephrostomy (temporary) and percutaneous ureteral dilatation, with concurrent reduction of immunosuppressive medications [11].

Hemorrhagic cystitis

BKV-associated HC or non-HC is classically noticed in HSCT recipients, yet it can be rarely observed among renal allograft recipients [9],[100]. The patients might present with bladder cramps, painful voiding, hematuria, and/or flank pain [101],[102],[103],[104],[105]. Four degrees of disease severity were recognized: grade I: microscopic hematuria; grade II: macroscopic hematuria; grade III: hematuria with clots; and grade IV: hematuria with clots, clot retention, and renal failure secondary to obstructive nephropathy [101]. BKV-HC is extremely rare in renal transplant. The management involves vigorous intravenous hydration. Severe cases of BKV-HC might necessitate insertion of a supra-pubic catheter with continuous bladder irrigation. Cidofovir given locally through bladder installation (hence reducing the cumulative drug nephrotoxicity) was suggested as a therapeutic option for HC [9],[101],[106],[107]; the remission varied from 2 to 7 weeks following hematuria.

BK nephropathy in the native kidney

BKVN has been described in native kidneys of HSCT recipients, heart and lung transplant recipients, as well as in immunocompromised HIV-infected patients. All those patients had presented with acute kidney injury without significant proteinuria and had characteristic histological findings on kidney biopsy [108],[109],[110],[111].

Other less apparent clinical manifestations include the following:

Neurological manifestations: BKV is rarely identified to cause primary central nervous system disease or reactivated central nervous system infection. Such infections are primarily seen in patients with HSCT or HIV infection. Clinically, the patients might present with a picture of meningoencephalitis, encephalitis, Guillain–Barre syndrome, and vasculopathy. Clinical signs may include headache, dizziness, confusion, paraplegia, ataxia, and seizures [80],[81],[82],[83],[84],[85],[86]. Nevertheless, the association between BKV and neurological manifestations remains disputed.

Pulmonary diseases: reactivated acute respiratory infection leading to severe interstitial pneumonitis in association with BKV has been reported twice in literature; both were in HIV-infected patients, where prominent histopathological lung features with distinctive BK cytopathic changes and a positive test for BK viral DNA were found in the autopsy examination [88],[89],[90].

Ophthalmologic manifestations: to date, there is only a single case report with bilateral atypical retinitis, reported by Hedquist and colleagues in a homosexual white male with AIDS. Autopsy examination of the eye revealed several areas of retinal necrosis. BKV-DNA was detected in the retina using PCR. Furthermore, autopsy showed that BKV infection was also present in the brain, kidneys, and peripheral blood smear. As it is a single case, further data are required before labeling BKV to cause an ophthalmological manifestation [91].

BK virus and hepatic disease

Similarly, a single report in the literature regarding the association between BKV and hepatitis was reported in a patient with bone marrow transplant who had transient elevations of liver enzymes [112].

BK virus and autoimmune diseases

Outside the transplant field, a relationship between BKV and certain autoimmune diseases, mainly systemic lupus erythematosus, polymyositis, and rheumatoid arthritis, were described in different literature studies in nontransplant immune-compromised individuals [2],[113],[114]. Taguchi and colleagues were the first to report the isolation of BKV (decoy cells) from a urine sample of two patients with lupus. This was confirmed with high BK serum antibodies titers; moreover, they demonstrated BKV antigen by indirect immunofluorescence [115]. Several cases were reported since then, with a prevalence of BKV viruria of 16% in patients with systemic lupus erythematosus [115],[116],[117]. BKV infection can induce antidouble-stranded DNA and histone antibodies [118],[119],[120],[121]. Alternatively, there is an increase in the prevalence with persistence/or recurrent BK viruria in patients with lupus. Such a relationship could be explained with a compromised immune system secondary to the systemic illness or the intensified immunosuppression [115]. Till date, there is no article that describes BKV activation in patients with systemic lupus erythematosus at postrenal transplantation state, and most observational analyses on risk factors that might predispose to BKV reactivation reported no difference concerning the etiology of primary renal disease [122],[123],[124].

BK virus and malignancy: thoughts on viral oncogenesis

The BKV-DNA has been identified in tissue samples of different neoplasms, including different brain tumors of glial and neural origin (such as ependymomas, meningiomas, glioblastomas, gliomas, neuroblastomas, oligodendrogliomas, spongioblastomas, choroid plexus papillomas, pituitary adenomas, and neurinomas), pancreatic islets cell tumors, Kaposi sarcoma, Ewing sarcoma, osteogenic sarcoma, prostatic carcinoma, and urothelial tumors [74],[125],[126],[127],[128],[129],[130],[131],[132],[133],[134],[135]. It has been proposed that BKV has an oncogenic property owing to expression of the early coding region-encoded proteins such as the large tumor antigen (LTAg) and STA, which can drive the cell into a neoplastic transformation. One of BKV proteins well-known as agnoprotein may contribute to this pathogenesis. Agnoprotein and LTAg will make infected cells incapable of arresting the cell cycle and may drive the cell into a continuous dividing state [127],[136],[137],[138].

Moreover, the LTAg can bind and inhibit critical cell cycle regulators, such as Rb and p53 tumor suppressor gene products. Binding of LTAg to p53 can disrupt the cell’s capability to control cell cycle progression and counteract the normal cell apoptosis [139]. Inactivation of tumor suppressor p53 and pRb in experimental mice by BKV-LTAg can induce urothelial malignancies [140]. As BKV has variable DNA locations inside the cells, several researchers have questioned the relationship of these tumors with BKV [136],[141],[142],[143],[144],[145],[146],[147],[148]. Indeed, one tumor was formerly connected with BKV; Kaposi’s sarcoma is presently believed to be produced by the herpes-virus type-8 [74],[149]. Conversely, tumor cells are likely more vulnerable to BKV than normal urothelium, as the infection happens mainly in proliferating cells, and that positivity is a result instead of being a reason for neoplastic transformation [139]. Regardless of whether BKV has a causative part in human cancer development or not, it will remain a topic of debate.

BK virus and urothelial tumors

Many have proposed that BKV might have a fundamental part in the pathogenesis of urothelial malignancy, particularly bladder carcinoma as the BKV-DNA was isolated in these tumors. Geetha et al. [150] reported a bladder carcinoma with widespread metastases in a simultaneous pancreatic and kidney transplant recipient with concomitant BK interstitial nephritis. For both the primary tumor and its metastasis, high level of BKV-LTAg was noted in the nucleus of almost every tumor cell and none in the non-neoplastic urothelium, which supports a possible role of BKV in the development of these tumors [150]. Alexiev et al. [140] reported a similar experience, where all tumor cells had shown strong expression of BKV-LTAg, p53, p16, and Ki-67, in addition to the intranuclear virions in electron microscopy.

Despite this epidemiological evidence, urothelial malignancies concomitantly with BKV were reported to date in a few and isolated case reports [140],[151],[152]. Rollison et al. [143], had carried out a tissue-based analysis in a series of bladder tumors (189 samples from 76 transitional cell carcinoma) to determine the potential role of BKV in bladder malignancies. Nevertheless, they discovered BKV-DNA by PCR in only 5.5% of urothelial tumors, and all were negative for BKV-LTAg, questioning the association of BKV with urothelial malignancies. Similarly, Roberts et al. [139], reported no evidence of BKV-LTAg in urothelial malignancies from 20 immunocompetent patients.

Risk factors

Several risk factors were implicated in the pathogenesis of BKVN. The most consistent risk factor identified in the literature is the overall degree of immunosuppression. Other proposed risk factors for BKVN include male sex, older recipient age, previous rejection episodes, degree of HLA mismatching, prolonged cold ischemia, BK serostatus, certain ethnic groups, lower total lymphocyte percentage, and ureteral stent insertion; however, these risk factors have not been uniformly observed in all studies [153],[154],[155],[156],[157],[158],[159],[160],[161],[162],[163],[164],[165],[166],[167],[168],[169],[170].

Screening and diagnostic tools

The main objective of screening is to enable early identification of recipients with viruria or viremia and to act before graft dysfunction appears [2],[11].

Timing of screening

Prospective analyses had revealed that BKVN is primarily an early complication of a kidney transplant, and most cases arise in the first posttransplant year [10]. In a cohort of Greek postrenal transplant recipients monitored prospectively for 18 months, the incidence of viremia and viruria showed bimodal peaks. The first and the topmost peak was noticed in the third month, followed by a gradual decline and disappearance in the ninth month, whereas the second peak was noticed at 12th months after transplant, but with fewer detected cases [171]. Last American Society of Transplantation Infectious Diseases Guidelines/3rd Edition (March 2013) [172] and KDIGO guidelines [173] had recommended BKV screening to start at first month after transplant, then monthly for the first 6 months, and then every 3 months for up to 2 years.

Screening tests

Viral replication starts early after transplantation and progresses through noticeable phases: viruria then viremia followed by nephropathy. Viral replication in the urine precedes BK viremia by ∼4 weeks, and although there have been confined cases of patients developing viremia without viruria, this is uncommon. Histological changes of BKVN are observed 12 weeks after BK viruria [5],[6],[8],[9],[10].

Screening for active BKV replication may include identification of viral DNA-PCR in urine and blood. However, no single diagnostic pathway has appeared as predominant [5],[6],[92].

Monitoring of the urine

Monitoring of the urine may include detection of BKV-infected epithelial cells named as ‘decoy cells,’ or aggregates of BKV virions (named as ‘Haufen’) or through quantification of urinary BKV viral load by BKV-DNA-PCR or reverse transcription-PCR for BKV RNA [6],[10],[88],[92].

Urine cytology

Decoy cells: BKV shedding in the urine is frequent and can occur in 13–30% of renal allograft recipients [8]. Such wide variation can be explained by screening strategies that were used in different centers and different immunosuppressive regimens. Cytological analysis of urinary smear may reveal characteristic abnormal BK-infected cells, termed as decoy cells. Decoy cells are infected tubular epithelial cells, with an enlarged nucleus that contains a single, large basophilic intranuclear BK inclusion body and looks similar to those cells seen frequently in uroepithelial malignancy [3],[11],[92]. Four different phenotypes of decoy cells were identified based upon the state of viral replication, maturation, and the state of cellular preservation [174]. Presence of decoy cells is strongly suggestive of polyomavirus infection and considered a useful marker of BKV reactivation, though it is not a real diagnostic tool for BKVN. The sensitivity of decoy cells for the diagnosis of BK nephropathy varies in different publications. However, Hirsch et al. [95] reported a sensitivity of 100%, and a specificity of 71% [positive predictive value (PPV) of 29% and negative predictive value (NPV) of 100%] when they matched graft-biopsy samples as a diagnostic standard. Viscount et al. [175], in contrast, reported a 25% sensitivity and 84% specificity (5% PPV and 97% NPV) to diagnose BKVN.

Urine electron microscopy (EM Haufen): in contrast to decoy cells, Haufen is an icosahedral aggregate of BKV particles and Tamm-Horsfall protein, forming cast-like three-dimensional aggregates, which can be noticed in a urinary smear of kidney recipients using negative-staining electron microscopy [176]. Presence of Haufen bodies, which corresponds to upper levels of BK viremia (median of 1 206 325 copies/ml), had a higher sensitivity and specificity for biopsy-proven BKVN (100 and 99% correspondingly), in a retrospective, single-center study. On the contrary, Haufen particles were absent in recipients with a lower BK viremia (median level of 27 000 copies/ml) [176]. Nonetheless, as this method represents single-center data, it requires further validation. Moreover, this test cannot be applied for routine clinical practice because of the expense and inaccessibility to electron microscopy and the need for interpretation from a pathologist.

Quantitative measurements of urinary BK virus-viral loads

Compared with urine cytology, molecular analysis to quantify BK viral load using urinary BKV-PCR has 100% sensitivity and 78% specificity ([Table 2]) [175]. Persistent DNA-PCR more than 107/ml instead of episodic identification can recognize patients at risk for BKVN [175]. However, variability in laboratory measurements had generated difficulties in standardizing this technique for definite diagnosis [3],[10],[24].
Table 2 Common screening methods for BK virus

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BK virus mRNA levels in urine

Recently, BK viral capsid (VP1) protein 1-mRNA derivative from urinary cells has been analyzed as a biomarker to detect active viral replication [3],[24]. This method is considered as highly specific and sensitive (sensitivity of 100% and specificity 97%) in predicting patients who might develop BKVN, using 6.5×105 BKV-VP1 mRNAs/ng RNA in urinary cells as a cutoff value [174],[177],[178]. Though this assay is encouraging as a noninvasive tool and can provide additional diagnostic and prognostic data, yet it requires further validation. Moreover, raised mRNA levels for granzyme B (>11 mRNA copies/µg total RNA) are usually present in recipients with acute cellular rejections. These figures may overestimate the prevalence of BKVN, though it may anticipate concomitant cellular rejection, which may contribute to graft worsening in some instances [179].



Serology

Serum BK-PCR

BK viremia is noticed only among immunocompromised patients, with an estimated prevalence of 7–30% in the initial 6 months and 5–10% after that among kidney recipients [6],[13],[92]. BK viral loads are measured with real-time PCR. A BK-specific sequence amplified with a fluorescent probe, and the number of amplicons formed is compared with a standard curve generated with serial dilutions of a known concentration of BK-DNA [5],[8]. Quantitative BKV-DNA in plasma at 1, 3, 6, 12, and 24 months after transplantation has been successful in identifying early BK infection before the development of nephritis [180]. BKV-PCR has a sensitivity and specificity of 100 and 88%, respectively, for the development of BKVN than BK viruria [95],[181]; hence, it is the preferred screening technique at most transplant institutions [3],[94].

Nevertheless, not all recipients with BK viremia will develop nephritis (BK-PCR has a PPV for BKVN of 50–60% and an NPV of 100%) [95],[175]. A definite viral load cutoff associated with nephropathy has not yet been defined. Nonetheless, retrospective analyses had proposed a quantitative BKV-PCR of more than 4 logs (1×104) copies/ml to correlate strongly with findings of BKVN on allograft biopsy [94],[95]. Nephritis, however, can be seen with plasma BKV-DNA of less than 7000 copies/ml [14],[94]. BKV-PCR levels may differ substantially between assays, with a magnitude of one to two log-folds in consecutive weekly analyses in commercially available quantitative PCR assays, which may yield significant differences in quantified viral loads and may limit the threshold of assay detection [182],[183].

Additionally, most quantitative PCR primers and probes were designed against BK genotype I (Dunlop) strain as a reference. Using this genotype I strain as a reference might be as much as four-fold less sensitive for different strains (limit to detect 10 000 copies/μl for the other strains compared with 10 copies/μl for genotype I), which is risky as uncommon BKV subtypes are often associated with BKVN, and such assays are unable to detect them at low viral levels [184],[185]. A serial estimate of viremia is the best technique to date to demonstrate resolution of BK activity following reduction of immunosuppression. Furthermore, serial determinations of viremia are required to follow-up patients who lost their allograft because of BKVN and considered for retransplantation [9],[49],[90]. [Table 2] summarizes conventional BKV screening techniques.



Serum antibodies

Serum antibodies against BKV are commonly present among the general public. The significance of assessing BK antibodies serostatus at pretransplant or posttransplant period on routine bases is uncertain. Additionally, it has no clinical relevance in diagnosing acute BKV infection affecting postkidney transplant recipients [186]. Nevertheless, the positive donor BKV serostatus and negative recipient serostatus (BK D+/R−) have been implicated as a risk factor for the development of clinically significant BK disease in pediatric and adult kidney allograft recipients [48],[186],[187],[188].

Virus culture

BKV can be isolated from a urine sample before any rise in antibody titers; however, virus culture is hardly used outside a research setting. Moreover, BKV grows slowly in tissue culture, which might extend from weeks to months [189].

Kidney biopsy

The term ‘presumptive BKVN;’ has been created to recognize recipients with (a) significant viruria, suggesting viral proliferation in the urinary tract and (b) persistent viremia of more than or equal to 104 copies/ml for more than 3 weeks [94]. Although plasma BK-PCR has high sensitivity and specificity in anticipating BKVN [181], different threshold values have been proposed to anticipate the disease, with significant overlaps between recipients without BKVN, active BKVN, and resolved BKVN [190]. Thus, allograft biopsy remains the gold standard to diagnose BKVN, which ideally should be performed when BKV-PCR load insistently exceeds more than 10 000 copies/ml (4 log10 genome (copies/ml)) with or without allograft dysfunction [10],[13],[191]. Such suggestion came from a prospective analysis of Hirsch et al. [95], who demonstrated that BK viremia of more than or equal to 104 is characteristically present in recipients with proven biopsies of BKVN.

Histologically, streaky fibrosis of the medulla with circumscribed cortical scars can be seen macroscopically, whereas microscopically, sclerosed glomeruli, necrotic, atrophic tubules, with interstitial fibrosis might present with mononuclear cell infiltrates. BK viral inclusions within tubular epithelium can be identified via the conventional hematoxylin and eosin (H&E) and PAS staining [192],[193] ([Figure 3],[Figure 4],[Figure 5],[Figure 6],[Figure 7],[Figure 8]). An alternative histological detection approach is through the identification of BKV via in-situ hybridization. A novel fluorescence in-situ hybridization (FISH) analysis allows BKV identification in renal transplant tissues through bright nuclear fluorescence technique. Although fluorescence in-situ hybridization-based methodology is specific for BKV with a sensitivity of 94.7% [compared with 57.9% for H&E and 68.4% for immunohistochemistry (IHC)] for detecting BKV and a specificity of 100% (comparable to both; 94.4% for H&E and 100% for IHC), yet its use in clinical practice is limited [193]. Positive IHC using specific antibodies against BKV or the cross-reacting SV40 LTAg has a specificity of nearly100% for polyomavirus nephropathy; although it does not differentiate between BKV and JCV, JCV-related nephropathy is extremely rare [92]. Ultimately, a persistent BKVN leads to renal parenchymal scarring with advanced tubular atrophy and interstitial fibrosis [59],[93]. Three grades of histopathological severity have been identified, where grade A includes viral cytopathic changes of near-normal renal parenchyma, with no or minimal tubular atrophy, interstitial fibrosis, or inflammation, to stage C, which signifies diffuse scarred renal tissue with extensive tubular atrophy, interstitial fibrosis, and inflammation [6],[26]. Contingent upon the degree of renal parenchymal scarring, reduced allograft survival may ensue even after clearance of the infection [93]. Currently, three different histological grading systems are available ([Table 3]).
Figure 3 Arrows (a) and the circle (image b) denotes significant BK inflammatory response with focal interstitial inflammation.

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Figure 4 The focal lesions and illustrate the importance of adequate samples including two cores.

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Figure 5 Early stages with minimal inflammation, no inclusions, and normal tubular epithelial cells.

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Figure 6 (a, b) showing marked acute tubular necrosis with significant tubulitis, raises concerns for concurrent rejection.

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Figure 7 Positive immunohistochemistry (SV40). SV40, simian virus 40.

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Figure 8 Fine granular nuclear features with small virions.

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Table 3 The available histological grading systems for BK virus nephropathy [41]

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Although no standard grading system has emerged as predominant, yet only the Banff grading system was shown to have a moderately good intraobserver agreement, with a kappa score of 0.47 (0.35–0.60, P<0.001) [194]. Additionally, in a retrospective analysis of 178 patients with biopsy-proven PVN, the Banff classification system was shown to correlate with clinical outcomes [195].

BKV affects the kidney allograft in an erratic, multifocal manner; hence, false-negative biopsies may occur, specifically at early stages of the disease, making the diagnosis challenging [10],[11],[96]. If the initial biopsy did not confirm BKVN, then pre-emptive treatment or a repeat biopsy must be considered. BK-PCR of allograft biopsy tissue is not an applicable investigation to diagnose BKVN, as it can identify a latent virus, even in asymptomatic recipients [96].



Suggested algorithm for screening

Different screening protocols are present in the literature, reflecting the experience of several centers where they have been developed. Many authors had recommended a step-wise methodology for BKV screening in renal transplant recipients. For example, Hirsch et al. [95] screened patients for BKV, first with urine cytology for decoy cells every 3 months, and whenever decoy cells were detected, additional studies were carried, including quantification of viral level in the plasma with the possibility of doing allograft biopsy only with a deterioration of renal function. Similarly, Ramos et al. [196] had based his protocol on periodic screening of urine cytology. Accordingly, the persistence of decoy cells for more than or equal to 3 months will trigger the performance of quantitative measurement of PCR-viral loads in plasma and renal biopsy in patients with evidence of BK viral reactivation, irrespective of renal function.

Buehrig et al. [197] and Khamash et al. [198] had suggested routine surveillance biopsies to detect patients with silent BKVN. Allograft biopsies were performed at third/fourth month and at 12 months after transplantation, and many patients were detected with a silent disease (in Buehrig analysis, eight cases were detected vs. 10 cases were performed for increased creatinine in the nonsurveillance group, whereas Khamash had diagnosed 40 cases on surveillance biopsies vs. 34 nonsurveillance cases). Surveillance biopsies had resulted in improved allograft outcomes compared with those who had graft impairment at the time of diagnosis [197],[198]. Currently, most transplant institutes, including our center, recommend BK surveillance with plasma BK-PCR. Screening for BKV should be performed on periodic intervals, starting after 1 month, monthly for 3–6 months, and then every 3 months for the initial 1–2 years after transplantation. American Society of Transplantation guidelines recommended further annual screening till the fifth year after transplant; nevertheless, generally screening beyond 2 years is not recommended in most centers unless allograft dysfunction is present [3]. Allograft biopsy can be considered in individuals with persistent high viral loads for more than or equal to 3 weeks. Here is a suggested algorithm for BKV screening ([Figure 9]).
Figure 9 Screening algorithm for BKV after renal transplantation (modified from Jamboti [96]). BKV, BK virus.

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Differential diagnosis

Allograft rejection

The distinction of BKVN from acute rejection is challenging as the histological appearance is often similar; therefore, it should be aided by analysis of blood or urine PCR. Differentiation between these two entities is crucial as treating the presumed rejection with increased immunosuppression may result in progression of BKVN. Nevertheless, BKVN may exist concurrently with acute rejection [13],[92].

BKVN can be distinguished from acute rejection by the presence of BKV inclusion bodies and immunohistology of positive immunoperoxidase staining for SV40, highlighting the virally infected cells. Furthermore, absence of definitive features of acute cellular rejection, such as endotheliitis and extensive tubulitis and absence of C4d deposits in peritubular basement membrane are helpful, though positive C4d staining has been reported in some BKV cases and is linked with more aggressive disease [199],[200]. Another useful technique to differentiate between acute rejection and BKVN is IHC staining of renal tissues or urinary sediments with anti-HLA DR, which has been related to acute rejection [201],[202]. Besides, a higher quantity of CD20+ cells in the tissue infiltrates has been associated with BKVN as opposed to acute rejection [203]. Moreover, the expression of genes related to inflammation and acute rejection (such as CD8, interferon-gamma, CXCR3, and perforin) was higher in patients with BKVN compared with acute rejection.

Additionally, BKVN was associated with an increased expression of transcription molecules associated with graft fibrosis such as matrix collagens, transforming growth factor-beta, and MMP2 and MMP9 [204]. BKVN and acute rejection can present concurrently. The combined presence of endarteritis, fibrinoid vascular necrosis, glomerulitis, and C4d deposits along peritubular capillaries is conclusive evidence of concurrent acute rejection [92].

Another differential diagnosis

Other differential diagnosis includes any disease associated with early (1–12 weeks after transplantation) and late (≥3 months after transplantation) renal allograft dysfunction.

Treatment strategy of BK virus nephropathy

The aim of treating BKV is to eradicate the virus while saving the kidney function. Unfortunately, BKVN has limited treatment options [3]. As BK viremia and BKVN signify excessive cumulative immunosuppression, hence, decreasing immunosuppression is the only validated therapy to treat BKVN and restore antiviral immune response; however, reduction in immunosuppression should always be balanced against the risk of triggering acute or chronic rejection [3],[10]. Rapid viral load reduction has been related to steady or improved allograft function [2],[4],[13].

Treatment of presumptive BK virus nephropathy

The first treatment of BKV disease has focused on reduction/or modifications in immunosuppressive therapy with or without antiviral medications. There is no standard strategy for modifying immunosuppressant’s therapy; however, different regimens have been attempted upon recognition of viremia. These include withdrawal or reducing the dose of immunosuppressant, switching a drug within the same class or to a different class and steroid avoidance [13],[205]. Such approaches can include withdrawal of antimetabolite drugs or change from mycophenolate mofetil (MMF) to azathioprine, sirolimus, or leflunomide, reducing the dose of calcineurin inhibitor (CNI) by 25–50% (to achieve a target lower level of cyclosporine 50–100 ng/ml and tacrolimus 3–4 ng/ml, or even less) or converting tacrolimus to cyclosporine or discontinuing CNI [206],[207],[208]. Withdrawal of the antimetabolite such as MMF is the most usual method; however, a study by Egli et al. [209], showed that both cyclosporine and tacrolimus could inhibit anti-BKV-specific T-cell reaction in vitro and ex vivo, and not so much with MMF or prednisone challenging this practice. Switching tacrolimus to cyclosporine might reduce MMF levels if doses of MMF remain the same [210], though the total withdrawal of MMF might be essential if BK viremia remains. MMF may limit the proinflammatory and profibrotic cytokines [211].

Treatment of BK virus nephropathy in the setting of allograft dysfunction

Favorable renal allograft outcomes in the context of acute BKV infection were reported when immunosuppression reduction had started early upon detection of BK viremia, permitting early and appropriate therapeutic interference [164],[212]. Nevertheless, if the identification of BKVN is made at an advanced stage when nephropathy ensues, then reducing immunosuppression is probably going to be less effective, owing to the advanced disease, with severe histological changes leading to progressive, irreversible renal damage [213]. Whether reducing or discontinuing one or more of the immunosuppressive regimen can alter the prognosis is not yet clear. However, allograft function may stabilize with modifying immunosuppressants or may advance to end-stage despite therapy [98],[214],[215]. Despite the diversity in literature in the context of BKVN, reducing immunosuppression remained a rational option even in the presence of allograft dysfunction, and it may result in clearance of viremia with a steadiness of allograft functions, and it raises BKV-specific IgG-antibodies titer and increases BKV-specific cellular immunity [216].

Drugs with antiviral activities

Leflunomide

Leflunomide is an immunomodulator, prodrug, and antirheumatic disease-modifying drug which was developed to be used in rheumatoid arthritis. Leflunomide can inhibit pyrimidine synthesis, resulting in antiproliferative and anti-inflammatory effects. A metabolite of leflunomide teriflunomide (A77 1726) can inhibit BKV replication in vitro and, to a minor degree, the level of virion assembly and release [217],[218],[219]. Leflunomide is given orally, with a loading dose of 100 mg daily for 3–5 days followed with a maintenance dose of 20–40 mg/day and recommended target level of 40–100 μg/ml. Being a pyrimidine synthesis inhibitor, leflunomide cannot be combined with other antiproliferative drugs like MMF or azathioprine; thus, treatment with this drug should involve simultaneous withdrawal of antiproliferative medication and reduced CNI dosages [217],[218]. Therefore, it is uncertain whether viral suppression is secondary to leflunomide or a reduction in immunosuppression dosage.

Notwithstanding, a few factors have limited use of this medication: (a) higher dosage of the drug (≥40 mg/day) is necessary to achieve clinical efficiency, necessitating frequent liver function monitoring to discover any liver toxicity; (b) monitoring of the trough A77 1726 level is not accessible in all laboratories; and (c) the immunosuppressive effectiveness of leflunomide is weak, and the favorable results associated with the use of this drug may primarily reflect reduced immunosuppression [13]. Additionally, leflunomide has a higher rate of adverse effects such as hemolysis, aplastic anemia, thrombocytopenia, and probably thrombotic microangiopathy, hepatitis, and worsening of hypertension [217],[220].

Cidofovir

Cidofovir is a cytosine analog and viral DNA-polymerase inhibitor that is used to manage other viral infections such as CMV [221]. Cidofovir showed in-vitro inhibitory action against polyoma-viruses [222], though the mechanism of action is unclear as BKV lacks the viral polymerase gene, the known target of cidofovir [93],[97]. As opposed to the direct influence on BKV proliferation, cidofovir may re-establish p53 and pRB function (targets of the LTAg), which may induce apoptosis of the BKV-infected cells [223]. When used for treating BKVN, cidofovir has been given as slow intravenous infusion (over 2 h) at an initial dose of 0.25 mg/kg/dose every 2–3 weeks for a period of 10–15 weeks. Dosage can be increased if the BKV-PCR load does not reduce by one-log fold to a maximum dose of 1 mg/kg/dose. Cidofovir is exclusively excreted through urine, resulting in high renal tubular cell concentrations. Hence, vigorous intravenous prehydration is needed with dose adjustment if renal dysfunction is present [223],[224],[225]. Unfortunately, randomized controlled trials are lacking, and many confounders in these observational studies, including, simultaneous tapering of immunosuppression are present in most [225],[226],[227],[228],[229]. Moreover, cidofovir is a nephrotoxic drug; it may cause acute kidney injury, renal tubular acidosis, and proteinuria. Additionally, severe anterior uveitis was reported with cidofovir, which may lead to permanent visual impairment [230]; hence, it should be used carefully in kidney recipients, with frequent monitoring and informed consent for its potential complications [10].

A new promising antiviral drug brincidofovir (CMX001) is a prodrug of cidofovir, and the oral form of the medicine gets converted to cidofovir when it goes intracellular. The benefit of CMX001 is its effectiveness against all DNA viruses with no documented nephrotoxicity and ease of oral administration. Nevertheless, the use of this drug is still experimental [231],[232].

mTOR inhibitors

mTOR inhibitors have shown effectiveness in in-vitro analysis in inhibiting BK replication and early gene expression [219]. The mTOR inhibitors (sirolimus and everolimus) are thought to produce their inhibitory effect on BKV replication by restoring the down-regulation of translation that occurs under cellular stress, thus delay the viral replication.

Additionally, it inhibits the proliferation of BKV-specific T cells and controls the differentiation of memory CD8 T cells; hence, it improves the immune reaction following BKV infection [233],[234]. Similar to other therapeutic options, the administration of mTOR inhibitors was concomitantly used with lowering immunosuppression [206],[234],[235],[236], questioning its clinical efficacy against BKV.

Moreover, most of the published reports had fewer number of patients, generating contradictory results. Of those, Polanco et al. [236] had reported substantial improvement in renal function with a clearance of BK viremia in nine patients after conversion from tacrolimus to everolimus, and withdrawal of MPA. Similarly, Wali et al. [206] described a rescue therapy using sirolimus-based immunosuppression given to three patients with BKVN. In all three patients, tacrolimus and MMF were replaced with sirolimus, which resulted in reduction of the BK viral load with concurrent improvement in estimated glomerular filtration rate [206].

Intravenous immunoglobulin

Treatment with intravenous immunoglobulin (IVIG) has been used for BKVN for its immunomodulatory effects. Additionally, IVIG has potent neutralizing antibodies and is able to neutralize all major BK viral genotypes [237],[238]. Nevertheless, in-vitro analysis has shown that IVIG has the most potent antiviral influence, with a selectivity index of more than 1000 as opposed to cidofovir and leflunomide selectivity index of 3.8 and 2.3, respectively [238]. The IVIG (in a dosage of 2–3.5 g/kg divided over 2–5 days) with a concurrent decrease in immunosuppressive medications has been successful in treating BKVN with concurrent acute rejection; however, the efficiency of IVIG is uncertain, as it has been given with concomitant reduction in immunosuppression [13],[239].

Other therapeutic options for treating BK virus nephropathy

  1. Quinolones have been described to inhibit the LTAg helicase activity and have in-vitro and in-vivo activity against BKV. It has been found beneficial in combination with leflunomide for treating BKVN [240],[241],[242], with a significant decrease in BK viremia [242],[243]. Nevertheless, others failed to find any improvement in viral clearance following a short course (for 10 days) [244] or long course (up to 30 days) of quinolones [245].
  2. A latest study examined the anti‐viral influence of artesunate (an antimalarial drug) on BK viral proliferation in a primary human renal cell culture. The investigators found a decrease in BKV proliferation in a dose‐dependent way with artesunate [246].
  3. Similarly, statins (pravastatin) were found experimentally to reduce the percentage of BKV-infected cells and LTAg expression in human renal proximal tubular epithelial cells, possibly owing to inhibiting the formation of caveolin-1, resulting in blocking viral entry into the cells [247].
  4. Rituximab


Although therapy with anti-CD20mAb rituximab used for the treatment of antibody-mediated rejection was associated with several adverse effects including BKVN, CMV viremia, herpes zoster, and septic shock [248], yet Babel and colleagues had reported promising results by using rituximab in nine transplant patients with BKVN. Patients who had received rituximab as an adjuvant therapy with cidofovir had no graft failure during follow-up of 17 months, compared with 46% graft loss in the control group which had received cidofovir as monotherapy for the treatment of BKVN. In both groups, the standard triple immunosuppressive therapy was switched to cyclosporine and azathioprine. The viral load had normalized in most within 18.3±6.8 weeks [249]. This is a single report, and further prospective randomized trials are required to validate the benefit of this therapy for BKVN.

Here is a summary of available therapeutic options for BKV infection ([Table 4]).
Table 4 Available therapeutic options for BK virus

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Short-term and long-term allograft survival

In the late 1990s and early 2000s, BKVN caused permanent allograft damage in 30–60% of cases. This happened as a result of lack of awareness, delayed diagnosis, misdiagnosis, and coincidental utilization of escalated immunosuppression for possible acute rejection episodes [203],[214]. However, the renal allograft survival for recipients with BKVN had improved considerably in the past years. Therapeutic approaches have revealed substantial short-term improvements, such as eliminating the circulating viremia, though the long-term outcomes such as late acute and chronic rejections need to be further evaluated [10]. The documented acute rejection rates following a reduction in immunosuppression varied from 6 to 12% [3],[250].

Favi and colleagues reported improvement in viremia in 82% of patients in whom their immunosuppressive therapy was modified based on periodic screening. However, 27% had experienced permanent allograft dysfunction (estimated glomerular filtration rate<30 ml/min/1.73 m2 at 5 years) and 18% ultimately lost their allograft secondary to BKVN [122]. Buehrig et al. [197] reported improved allograft outcomes at 6 months in patients undergoing surveillance biopsies compared with those presented with allograft dysfunction at the time of diagnosis (8/8 patients vs. 3/10, P=0.004). Similarly, Dall and Hariharan reported an improvement in allograft survival for patients with BKVN at their center at 1, 3, and 5 years from 89.5, 57.9, and 47.4%, respectively, in 2005 to 94.8, 68.4, and 57.6%, respectively, in 2007. The author had related this improvement to either early therapeutic intervention upon immediate recognition of viremia or to the routine surveillance biopsies, which detected earlier histological changes of BKVN [10]. Chen et al. [250] reported 1-, 3-, and 5-year allograft survival rates following a diagnosis of BKVN (n=133) as 99.2, 90.7, and 85.7%, respectively, in a single Chinese center, whereas an advanced pathological stage correlated with poor allograft survival (P= 0.042).

BK nephropathy with concurrent acute rejection

Management of proven allograft biopsies of acute rejection with concomitant BKVN or management of anticipated rejection following a decrease of immunosuppression to treat BKVN remains debatable. More than half of biopsies can demonstrate tubulitis, and any decrease in immunosuppression can precipitate rejection in 10–30% of the cases [98],[197],[214]. Generally, reports have depicted clinical improvement, steady or worse allograft outcomes, following steroid pulses [95],[97],[197]. Celik et al. [215] found a reduction in immunosuppression is more than capable in reducing viral load than steroid pulses in biopsies with BKVN and tubulitis. However, Hirsch et al. [94] suggested a combination of antirejection therapy with a subsequent reduction in immunosuppression, once BKVN is diagnosed in concurrence with acute rejection. Generally, an initial decrease in immunosuppression without steroid pulses should be considered upon detection of BKVN.

Nevertheless, in the absence of typical features, such as strong peritubular capillary C4d staining, glomerulitis, vasculitis, or interstitial hemorrhage, which could be indicators for acute rejection, the management should be tailored for each patient individually [13]. The delayed improvement in renal functions following a reduction in immunosuppression is likely to reflect the slow resolution of the cellular infiltrate. Upon clearance of viremia and BKVN, the advantage of up-titrating immunosuppression to avoid further late acute rejection or chronic rejection remains obscure [13].

Postinfection monitoring

Close observation of BKV-PCR and renal function with any treatment, particularly following management of acute rejection or reduction of immunosuppression, is crucial to improve allograft outcome [10]. There are different protocols in different centers for monitoring BKVN, mostly using quantitative plasma BKV-PCR. The most common approach is to follow the transplant recipients who have their immunosuppression reduced for BKVAV, with a serum creatinine test every 1–2 weeks and plasma BK-PCR level at 2–4-week intervals for 8 weeks. Subsequently, it should be done on a monthly bases until clearance of BK viremia (or at least viral burden falls below threshold values) and stabilization of renal function achieved [3],[10],[13].

Based on different literature, BK viremia clears in 7–20 weeks. However, the initial decline might be delayed for 4–10 weeks following reduction of immunosuppression. If viremia persists despite reducing the maintenance therapy, then further reduction should be considered or to consider changing to sirolimus, or adding leflunomide [154],[251]. Inability to clear BKV can lead to worse allograft outcomes [3],[10].

Retransplantation

Retransplantation following graft loss owing to BKVN is possible and can be done successfully [10],[13]. Ramos et al. [252] described successful retransplantation in 9/10 patients without recurrent BKVN, whereas Womer et al. [253] had reported a similar experience in two patients despite active viremia. An analysis of the USA-OPTN registry data for the period 2004–2008 showed 126 individuals got retransplant of 823 who lost their graft secondary to BKVN. All kinds of induction and maintenance therapy have been used for all recipients as per their center’s protocols. Of the 126 retransplants, BKV was reported in 17.5% of the cases; however, just a single kidney was lost because of repetitive BKVN. The 1- and 3-year graft survival among the retransplanted individuals was excellent at 98.5 and 93.6%, respectively [254].

Generally, pretransplant clearance of BK viremia is essential after minimizing immunosuppression [19]. Allograft nephrectomy is not necessary before retransplantation; however, in the background of active viral replication, it appears sensible to eliminate the infected graft before getting a new transplant, though there is no evidence to support this approach [10],[13]. BKV viruria, viremia, and BK nephropathy can recur and cause allograft loss [255]. Recurring BKV might reflect a previous BK variant or a new infection (de-novo BKV) acquired, because of the long period, in the posttransplantation stage [13].


  Conclusion Top


Nearly three decades of research has led to ‘some’ comprehension of BKV and its pathophysiology. There is a bigger ‘known unknown’ that just proves the elusive nature of BKV. An early diagnosis of BKVN based on a combination of molecular techniques and tissue analysis has resulted in substantial improvement in allograft outcomes despite a lack of specific treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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