Polyoma BK Virus in Kidney Transplant Recipients: Screening, Monitoring, and Management : Transplantation

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Polyoma BK Virus in Kidney Transplant Recipients: Screening, Monitoring, and Management

Myint, Thida Maung MM1,2; Chong, Chanel H. Y. MBBS1; Wyld, Melanie PhD3; Nankivell, Brian PhD3; Kable, Kathy MN3; Wong, Germaine PhD1,3,4

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Transplantation 106(1):p e76-e89, January 2022. | DOI: 10.1097/TP.0000000000003801
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Abstract

INTRODUCTION

First described and isolated in a kidney transplant recipient in 1971, BK polyomavirus (BKPyV) is recognized as a major cause of allograft failure in kidney transplant recipients.1 BKPyV is near ubiquitous in the general population, with seroprevalence of over 90% in the adult population.2-4 The infections are commonly acquired during childhood, where patients are mostly asymptomatic and do not have major clinical consequences. However, reactivation of the virus may occur with the use of immunosuppression. BKPyV reactivation in kidney transplant recipients can lead to BK polyoma virus-associated nephropathy (BKPyVAN), which is associated with graft dysfunction in >90% and graft loss in over 50% of the affected individuals.5-7 In the absence of an effective antiviral treatment, the management of BKPyVAN relies on early detection and the timely reduction of immunosuppression to prevent permanent graft dysfunction and loss. This review will focus on the epidemiology of BKPyV infections in kidney transplant recipients, and the current evidence that underpins screening and management strategies in this setting.

EPIDEMIOLOGY

BKPyV belongs to the family Polyomaviridae and is a small (45 nm, approximately 5000 base pairs), nonenveloped, circular, double-stranded DNA virus.8 It is closely linked to the JC virus (JCV) and Simian virus 40 (SV-40). BKPyV genome contains 2 regions coding for early and late proteins, separated by a noncoding control region (NCCR). The early genes encode the large tumor antigen (TAg), the small tumor antigens (tAg), and the truncated TAg (truncTAg), while the late genes encode structural capsid proteins; VP1, VP2, VP3, and the Agno protein.9 The VP1 is the major and most antigenic protein, which is responsible for attachment of the virus to host cell receptors.10,11

BKPyV is classified into at least 4 major genotypes (I, II, III, and IV) and several subgroups (including Ia, Ib1, Ib2, Ic, IVa1, IVa2, IVb1, IVb2, IVc1, and IVc2) based on DNA sequence variations.12-15 BKPyV genotype I is the most prevalent subtype distributed worldwide, followed by genotype IV in Asia and part of Europe.16-18 BKPyV genotype II and III are rarely observed but genotype III may occur more frequently in Africa.18 Subgroups of each genotype have a unique geographic distribution pattern with Ia being prevalent in Africa, Ib1 in Southeast Asia and China, Ib2 in Europe, Ic in northeast Asia, and IVc2 in Europe and America.17,19,20 Although some studies suggest that variations in the transcriptional control region of the viral genotypes (BKPyV genotype II and IV compared with genotype 1 & III) may be associated with a higher level of viremia, the impact of genotypic variance on clinical presentations is not well understood.21-25

Primary BKPyV infection is commonly acquired asymptomatically during childhood. The exact route of transmission is not well understood and may occur via the respiratory, gastrointestinal tract, or body fluids (horizontal or vertical transmission).26 Likewise, transmission may also occur through kidney donation as several studies had found an association between increased risk of viruria or viremia in recipients with the presence of high serum BKPyV antibody titers in donors27-29 and mismatched serostatus pairs: high seroreactive donor and low seroreactive recipients.30

After subclinical primary infection, the virus, which has tropism in uroepithelium and renal tubular epithelial cells, becomes dormant. Low-level virus shedding may sometimes be observed in healthy immunocompetent individuals.31-33 Such viral latency is controlled by the host’s cellular immunity mediated by BKPyV-specific CD4+ and CD8+ T cells.34,35 However, the host’s immunity can be disrupted by potent immunosuppression following kidney transplantation, resulting in reactivation and replication of the virus within renal tubular cells, leading to tubular injury, shedding of sloughed cells in the urine, and detectable viruria. In addition, direct cytopathic damage by BKPyV can cause an inflammatory interstitial nephritis with progressive fibrosis of the allograft.36-38 BKPyV viruria is the earliest presentation of infection, affecting 25%–35% of kidney transplant recipients during their first year of transplantation, while BKPyV viremia occurs in 10%–12% of patients after sustained viruria.39,40 Persistent high-level viremia may reflect high-grade viral replication within the graft and may lead to a greater risk of BKPyVAN, and subsequent graft loss in over 50% of the affected individuals.5-7 Other complications of BKPyV viremia include ureteric or urethral stenosis and may be some urothelial cancers.41 While high burden of BKPyV is associated with hemorrhagic cystitis in patients undergoing hemopoietic stem cell transplantation, this is less commonly seen in kidney transplant recipients.42

RISK FACTORS FOR BKPyV INFECTION

BKPyV replication commonly occurs early after transplantation and after treatment for rejection when cellular immunity is most suppressed. Induction with T-cell depleting agents and polyclonal antibodies are associated with development BKPyV infection posttransplantation.10,43 In addition, several studies have shown that exposure to triple immunosuppression with tacrolimus, mycophenolate-mofetil (MMF), and prednisolone and higher trough levels of tacrolimus are associated with a higher risk of BKPyV infection.44-46 Compared with kidney alone transplant recipients, recipients of simultaneous kidney pancreas transplant may experience a higher risk of BKPyV infection because of a higher immunosuppression load.47,48 Heart transplant recipients were found to have a higher overall incidence of BK viremia than other nonkidney solid organ recipients.49 Native kidney BKPyVAN in other forms of solid organ transplantation is extremely rare and has only been reported in few cases.50-52 While the most consistent risk factor for BKPyV infection is the overall intensity of immunosuppression and rejection episodes,53 other predictors also include recipient (such as older age, male sex, a history of previous transplant, delayed graft function, and use of ureteral stent)45 and donor factors (such as donor viruria, seroreactivity, and immune response)30,54-56 (Table 1). The association of BKPyV infection with diabetes and obesity is, however, inconsistent.

TABLE 1. - Risk factors for BKPyV infection in kidney transplant recipients
Risk factors Increased with Decreased with References
Immunosuppression related
 Immunosuppression regimes
 Induction regime
 Drug levels
 Antirejection treatments
 Rejection episodes
Triple immunosuppression with Tacrolimus, MMF, and Prednisolone
T-cell depleting agents
Polyclonal antibody induction
Desensitization with RituximabHigher tacrolimus levels
Thymoglobulin>1
CyclosporinmTOR inhibitorsLeflunamideBasiliximab 40,44,46,5758-6046,61-6364-666744,68
Recipient related
 Age, gender
 Ethnicity
 Comorbidities
 Number of previous transplants
 Type of transplant
 BKPyV serostatus
Older age, male
African-American
Diabetes, obesity
Multiple
Multiorgan recipient
Seronegativity in recipient
PCKD 33,69
70
71,72
73
74
75
Donor and transplant related
 Type of donor
 Immunologic injury
 Ureteric stent
 ABO status
 HLA status
 BKPyV serostatus
 CMV
Deceased donor
Prolonged cold ischemia time, delayed graft function
Use of ureteric stent
ABO incompatibility
Higher degree of HLA A, B, DR mismatches (>4 mismatches)HLA A24, HLA B55HLA-E genotype
Seropositivity in donor
Coinfection with CMV
HLA-A2, HLA-B44, HLA Cw7, HLA-DR15, HLA B51 76-78
61,7976,80-838427,56,65,85-8889-9192
BKPyV, BK polyomavirus; CMV, cytomegalovirus; MMF, mycophenolate-mofetil; mTOR, mammalian target of rapamycin; PCKD, polycystic kidney disease.

DIAGNOSIS OF BKPyVAN

The reference standard test for diagnosing BKPyVAN is histological evidence of viral cytopathic changes in tubular epithelial cells accompanied by typical viral inclusions, which are positive for SV40T antigen in a transplant allograft biopsy.93 However, transplant allograft biopsy is invasive and is associated with procedural risks including hemorrhage, arteriovenous fistula formation in the allograft,94 and institutional costs of the procedure. In addition, due to the focal and heterogenous nature of BKPyVAN, a biopsy can yield false negative results, especially in early stage disease. While a minimum of 2 core samples including some medullary tissue is recommended,95 image-guided allograft biopsy remains operator dependent.96 Hence, allograft biopsy is not routinely implemented as a screening test for BKPyVAN, but rather undertaken when there is evidence of allograft dysfunction or high-level viremia as a confirmatory test.

SCREENING FOR BKPyV INFECTION

To date, there is no effective antiviral prophylaxis strategies or proven treatment options for BKPyV infection.97,98 Currently, there is no trial-based evidence to support that routine screening will reduce the risk of allograft lost due to BKPyV nephropathy. However, several observational studies had shown that screening and preemptive reduction of immunosuppression in patients with viremia may prevent progression to BKPyV and preserve graft function.99-103 Therefore, screening for BKPyV viremia is an important strategy to detect the early infection to allow timely lowering of immunosuppression. This can lead to reconstitution of the antiviral cellular response and BKPyV-specific neutralizing antibodies, permitting clearance of viral infection.

Current Guidelines for Screening for BK Infection

The preferred screening test by most clinical practice guideline is routine screening using real-time polymerase chain reaction (RT-PCR). However, there are substantial variability in the frequency and duration of screening since the evidence underpins such recommendations is largely reliant on observation data and therefore with poor certainty. The frequency of screening is generally recommended every month initially for 6 mo but then every 3 mo based on observational data that BKPyVAN precedes BKPyV viremia by a median of 8–12 wks.5,40 The American Society of Transplantation Infectious Diseases Community of Practice guideline (AST-IDCOP) suggests screening for BKPyV viremia by quantitative testing (RT-PCR) should be performed every month until month 9, then every months until 2 y posttransplant39 whereas the Kidney Disease Improving Global Outcomes (KDIGO) guideline suggest that quantitative testing should be performed every month for the first 3–6 mo after transplantation and then every 3 mo until the end of the first posttransplant year.104 The Canadian and Australian guidelines recommendations align with KDIGO guidelines.105,106 The extended duration of screening recommendation by AST-IDCOP was based on the studies indicating 20%–30% of viremia occurs after 6 mo posttransplantation.107 Despite recommendations, there remains a substantial variability in frequency and duration of screening worldwide. A recent binational survey conducted in Australia and New Zealand indicated that frequency of screening varied between monthly (27%) to every 3 mo (18%) among transplant nephrologists.108 Similarly, a regional survey of screening protocols in United States suggested only 1 out of 11 centers (7.7%) conformed to guidelines in terms of frequency.109 Deviation of clinical practice from published consensus recommendations was also observed in other surveys.110,111 Variation in prevalence of BKPyV infection, immunosuppression practices, availability of resources, and local idiosyncrasy likely influence an individual center’s screening strategy.

Qualitative Screening Tests

Examination of Urine Cytology for Decoy Cells or Infected Cells

Decoy cells are infected urothelial cells with viral cytopathic changes that have shed into the urine and are identified under bright-field light microscopy using a Papanicolaou stain. They appear early in the natural history of BKPyV infection and are highly sensitive for virus replication, although not specific for BKPyVAN. Urine decoy test also has poor test performance with reportedly low specificity and positive predictive value.7,39 Newer methods to detect infected cells such as the SV40T immunoperoxidase staining of exfoliated urinary tubular cells have been developed for improved test specificity112-114 but they are yet to be widely adopted in clinical practice.

Examination of Urine for Haufen

Haufen (German term for cluster or stack) are densely arranged 3-dimensional viral casts composed of 6 or more individual BKPyV virions, and these are identified by negative-stain electron microscopy. A single study found that the qualitative detection of Haufen had a high sensitivity and specificity for BKPyVAN with positive and negative predictive values >95%.115 However, the test requires urinary electron microscopy and skillful pathological interpretation and is not commonly used.

Quantitative Screening Tests

Quantitative Measurement of BKPyV Viral Load in the Blood

BKPyV DNA can be extracted from blood or plasma and measured quantitatively by nucleic acid amplification testing (NAT) such as RT-PCR. The viral load is highly sensitive and relatively specific for BKPyVAN5,116 (Table 2). However, it has substantial interassay variability due to the use of different control standards, DNA extraction techniques, primers, probes sequences, target genomes (VP1 or NCCR regions), and sample source among the different laboratories.117-119

TABLE 2. - Test performance characteristics of blood real-time PCR for BKPyVAN in kidney transplant recipients
Study y Countr y Type of study N total Prevalence BKPyV viremia % Prevalence BKPy VAN % Real-time PCR (blood) Threshold values Reference test Sensitivity % (95% CI) Specificity % (95% CI) PPV % (95%CI) NPV % 95%CI)
Hirsh52002 Switzerland Cohort 76 13 8 n/a Graft biopsy 100 a 88 a 50 a 100 a
Randhawa1202002 United States Case control 147 13 6 n/a Graft biopsy 100 a 92.1 a 73.6 a 100 a
Baldanti1212007 Italy Cohort 201 6.9 nr n/a Reduced graft function 100 a 96 a 50 a 100 a
Viscount1222007 United States Cohort 114 24 3.5 >1.6E+04 copies/mL>5.0E+03 copies/mL Graft biopsy 100(40-100)100(40-100) 96(91-99)91(84-96) 29(8-58)50(16-84) 100(96-100)100(97-100)
Sung1232008 Korea Cohort 64 18.8 12.5 >4.5 log10 copies/mL Graft biopsy 100(63-100) 96.4(85-99) nr nr
Costa1242008 Italy Cohort 229 6.1 1.3 >1 × 104 copies/mL Graft biopsy 100 a 99.1 a 59.4 a 100 a
Babel1252009 Germany Cohort 233 7 21.4 n/a Graft biopsy 100 a 96 a 43 a 100 a
Boudreault1262009 Canada Cohort 60 43.3 23 >3 × 103 copies/mL Graft biopsy 100(76.8-100) 89.6(77.3-96.5) 50.0(48.8-90.9) 100(91.8-100)
Cross1272009 Australia Cohort 257 15 3.7 n/a Graft biopsy 89(57-99) 88(83-92) 22(12-38) 99.5(97.3-100)
Pollara1282010 Italy Case control 75 34.7 9.3 >4.1 log10 copies/mL Graft biopsy 94.9(94.5-99.8) 100(94.8-100) nr nr
Girmanova1292011 Czech Republic Cohort 129 5 2.5 >1 × 103 copies/mL Graft biopsy 100 a 69 a nr nr
Chung1302012 Korea Cohort 376 5.5 3.7 >1 × 104 copies/mL Graft biopsy 100 a 97.4 a nr nr
Huang1312013 China Cohort 338 8.6 7.1 >1 × 103 copies/mL>1 × 104 copies/mL Graft biopsy 83.3(68.4-98.2)45.8(25.9-65.8) 97.5(95.8-99.1)100(98.9-100) 69.0(52.1-85.8)100(71.5=100) 98.9(97.7-99.9)96.5(94.6-98.4)
Myint1322013 Australia Cohort 100 34 14 >1 × 103 copies/mL>1 × 104 copies/mL Graft biopsy 92.9(66.1-99.8)92.9%(66.1-99.8) 79.1(67.4-88.1)88.1%(77.8-94.7) 42.0(24.8-57.7)56.8(32.7-75.4) 98.6(98.3-99.9)98.7(98.5-99.9)
Westervelt1332013 United States Cohort 347 13 3.2 >500 copies/mL Graft biopsy 100(72-100) 78(52-93) 77(50-92) 100(73-100)
Hassan1342014 United States Cohort 413 54 12.5 >4.1 log10 copies/mL Graft biopsy 64.5(45.4-80.8) 98.4(95.5-99.7) 87.0(67.8-95.5) 94.5(91.4-96.5)
Kudose1352014 United States Cohort 284 nr 3.87 >3.7 log copies/mL Graft biopsy 100 a 97.6 a nr nr
Ma1362015 Hong Kong, China Cohort 95 nr 30.5 >1 × 103 copies/mL>1 × 104 copies/mL Graft biopsy 93(82-100)83(69-96) 82(72-91)91(83-97) nr nr
Nankivell1142015 Australia Cohort 352 12.8 2.6 Any copies/mL>1 × 104 copies/mL Graft biopsy 96.3 a 66.7 a 90.3 a 96.8 a 31.5 a 45 a 99.8 a 98.5 a
Boan1372016 Australia Cohort 277 nr 6.1 >3.79 log copies/mL Graft biopsy 77 a 81 a nr nr
aCI not reported.
BKPyV, BK polyomavirus; BKPyVAN, BKPyV-associated nephropathy; CI, confidence interval; N, total number of patients; n/a, not available; nr, not reported; PCR, BKPyV viral load measured by real-time polymerase chain reaction.

In 2016, the first World Health Organization International Standard for BKPyV (primary standard) was introduced for standardization of assays across different laboratories when the viral loads are expressed in IU/mL.138 The use of an international common calibrator has improved agreement between assays.139 Prior validation study has indicated that the units of measures adopted by commercial manufacturers as copies/mL are relatively similar to “IU/mL.” However, the World Health Organization BKPyV standard has variable quantification of the BKPyV, largely based on which protein regions are targeted.140

To date, quantitative viral load measurement using RT-PCR is the accepted screening tool for BKPyV infection. In the absence of an allograft biopsy, a plasma viral load above 3log10 copies/mL is considered to be probable BKPyVAN and a viral load that is persistently above 4log10 copies/mL as presumptive BKPyVAN.39

Quantitative Measurement of BKPyV in the Urine

The urinary quantification of BKPyV via RT-PCR is occasionally used in some centers due to the ease of sample collection and its fair test performance130,141 (Table 3). Expert opinion suggests that a urinary BKPyV viral load >7log copies/mL would make it highly suspicious for BKPyVAN.142 However, additional confirmation with plasma BKPyV RT-PCR is still required thus making it less cost effective.143 The quantification of urinary BKPyV RT-PCR is subject to interassay variability, similar to plasma BKPyV variability.

TABLE 3. - Test performance characteristics of urine real-time PCR for BKPyVAN in kidney transplant recipients
Study y Countr y Type of study N Prevalence BKPyV viruria % Prevalence BKPyV VAN % Screening test Threshold values Reference standard Sensitivity % (95% CI) Specificity % (95% CI) PPV (95% CI) NPV (95% CI)
Ding1442002 United States Case control 90 nr nr >6.5 × 105 copies/ng Graft biopsy 93.8 a 93.9 a nr nr
Baldanti1212007 Italy Cohort 201 61.4 6.9 n/a Reduced graft function 100 a 39.7 a 4.3 a 100 a
Viscount1222007 United States Cohort 114 9 3.5 >5.0E+03 copies/mL>2.5E+07 copies/mL Graft biopsy 100(40-100)100(40-100) 78(69-85)92(85-96) 14(4-33)31(9-61) 100(96-100)100(96-100)
Sung1232008 Korea Cohort 64 28.1 12.5 >5.9 log10 copies/mL Graft biopsy 100(63-100) 96.4(87.7-100) nr nr
Babel1252008 Germany Cohort 233 19 21.4 n/a Graft biopsy 100 a 91 a 21.4 a 100 a
Girmanova1292011 Czech Republic Cohort 129 28.5 2.5 >6.7 × 107 copies/mL Graft biopsy 100 a 83 a nr nr
Chung1302012 Korea Cohort 376 11.1 3.7 >1 × 1010copies/mL Graft biopsy 100 a 91.8 a nr nr
Huang1312013 China Cohort 338 36.4 7.1 >1 × 103 copies/mL>1 × 105 copies/mL Graft biopsy 91.7(80.6-100)91.7(80.6-100) 70.3(65.6-75.1)89.8(86.7-93.0) 17.3(10.7-23.9)37.9(25.4-50.4) 99.2(98.1-100)
99.4(98.5-100)
Kudose1352014 United States Cohort 284 3.87 3.87 >7.2 log copies/mL Graft biopsy 100 a 97.5 a nr nr
Chon1452016 United States Cohort 368 30.1 17.4 >25 million copies/mL Graft biopsy 88.57 a 87.96 a 33.55 a 99.12 a
a CI not reported.
BKPyV, BK polyomavirus; BKPyVAN, BKPyV-associated nephropathy; CI, confidence interval; N, total number of patients; n/a, not available; nr, not reported; PCR, BKPyV viral load measured by real-time polymerase chain reaction.

Pretransplant Screening for BKPyV

Multiple virus-specific antibody assays may be used to measure previous exposure to BKPyV in both kidney transplant candidates and donors. In the pediatric cohort, pretransplant seronegativity in potential transplant candidates was found to be an important predictor of active BKPyV infection following transplantation146 but pretransplant seropositivity did not protect them against BKPyV infection after transplantation.147 Currently, there is insufficient evidence to support modification of immunosuppression strategies up front or change in monitoring frequency due to BKPyV positivity in donors. Overall, there is no trial-based evidence to support routine serological testing in both donors and recipients before transplantation.39

Prevention of BKPyV Infection

Fluoroquinolones

Fluoroquinolones, such as ciprofloxacin and levofloxacin are better known for their antibacterial properties. In vitro studies suggest that they inhibit BKPyV virus replication via their effects on DNA topoisomerase and polyomavirus-associated large T-antigen helicase.148,149 The use of fluoroquinolones as prophylaxis was assessed in a well-powered randomized control trial.97 The study concluded that there were no differences in the incidence of BKPyV infection between the intervention and control arms. Overall, fluoroquinolones prophylaxis did not reduce the risks of BKPyV viremia, BKPyVAN, or graft failure due to BKPyVAN.150 The American Society of Transplantation (AST) guideline does not recommend the use of fluoroquinolone as prophylaxis or therapy.39

MANAGEMENT OF BKPyV INFECTION

Graft loss and subsequent return to dialysis is the most feared outcome for kidney transplant recipients. The 3 most important clinical predictors of graft loss in BKPyVAN include high-level BK viremia, deceased donor transplantation, and late acute rejection. The decision to initiate treatment for BKPyV infection depends on the recipients’ immunological risk and severity of the viral load, the latter reflected by a sustained viral load of >3log10 copies/mL (probable BKPyVAN) or an increasing viral load to >4log10 copies/mL (presumptive BKPyVAN) within 3 wks, or if there is proven histological evidence of BKPyVAN (Figure 1).39

F1
FIGURE 1.:
Screening and treatment algorithm for BKPyV infection. BKPyV, polyomavirus BK virus; BKPyVAN, BK-associated nephropathy; mTOR, mammalian target of rapamycin.

Dose Reduction or Withdrawal of Immunosuppressants

There is no clear consensus of how immunosuppression reduction should be implemented in the presence of BKPyV infection. Many strategies have been suggested, but typically include a gradual reduction in either or both the antiproliferative agent (such as the mycophenolic acid) and calcineurin inhibitors. For higher immunological risk recipients with a low viral load (<3log10 copies/mL), judicious reduction of the antiproliferative agent is preferred with close monitoring of serum BKPyV viral load and serum creatinine (at least fortnightly). In the absence of clinical improvement, further lowering of the immunosuppression may be required, such as eliminating the antiproliferative agent completely and reducing the dose of the calcineurin inhibitor. Target trough levels vary by the time posttransplant and often follow a structured stepwise reduction, such as aiming for tacrolimus trough level of 1–2 ng/mL lower than intended for the given time.151 The AST guideline recommends targeting a tacrolimus trough level at <6 ng/mL and cyclosporine trough level <150 ng/mL when managing BKPyV infection, although a lower tacrolimus trough level of <3 ng/mL may be required in advanced diseases.39,152,153

The incidence of acute rejection and graft loss following the reduction of immunosuppression for BKPyVAN vary between studies, with some authors reporting no episodes of acute rejection and very low incidence of allograft loss, while others found acute rejection rates to be as high as 75% and graft loss rates up to 67% within 4 y of BKPyVAN diagnosis.39,152,153 The abrupt withdrawal of mycophenolate following BKPyV infection has been associated with an increased risk of acute rejection compared with a gradual reduction of mycophenolate instead (27.4% versus 8.9%, P < 0.001).98,151,153-155 However, the certainty levels of the evidence are low to very low because most studies are nonrandomized trials, limited by small sample sizes and therefore insufficient power, with high-level of imprecision, and inclusion of transplant eras where screening for BKPyV infection was poorly described or not widely practised.156

Conversion of Immunosuppression

The AST and KDIGO guidelines have suggested conversion of standard immunosuppression to an alternative agent if viral clearance is not achieved with immunosuppression reduction alone. These strategies may include conversion of tacrolimus to low-dose cyclosporine, calcineurin inhibitor to sirolimus, or mycophenolic acid to low-dose sirolimus.39,152,156,157 A single study reported lower rates of BKPyV infection in patients on maintenance cyclosporine at 6 mo and 12 mo compared with those on tacrolimus (10.6% versus 16.3%, and 4.8% versus 12.1%, respectively, P = 0.004),151 while others found no differences in the incidences of BKPyV infection between patients allocated to the tacrolimus- and cyclosporine-maintenance arms (12% versus 11%, P = 1.0).40

Findings from in vitro studies have shown that inhibition of the mammalian target of rapamycin (mTOR) may interrupt the viral replication process in primary human renal proximal tubular epithelial cells, a desired effect that is not seen with the use of tacrolimus.158 These preclinical findings have been confirmed in recent clinical studies whereby a lower risk of BKPyV infections were reported with combined everolimus and reduced exposure to calcineurin inhibitor as maintenance therapy, compared with the group treated with combined mycophenolic acid and standard calcineurin inhibitor group.159,160 In a recent meta-analysis, combined mTOR with a calcineurin inhibitor treatment was associated with a lower risk of BKPyV infection (RR, 0.62; 95% CI, 0.50-0.76) compared with the group with mTOR and an antimetabolite, suggesting the contributory factor of antimetabolites to BKPyV infection.161 However, the use of mTOR is limited because of wound complications, and other adverse effects such as peripheral edema and dyslipidemia. Overall, 2 meta-analyses comparing mTOR to calcineurin inhibitor as maintenance therapy reported no differences in the risk of BKPyV infection when they were used in conjunction with an antimetabolite, although the certainty of the evidence is low.161,162

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIg) is well known for its immunomodulatory effects and it is widely used in the management of a range of diseases including acute rejection in kidney transplant. In vitro and in vivo studies suggest that IVIg contains high neutralizing antibody titers against major BK virus genotypes, specifically BKPyV genotype I and II. The antiviral effect of these neutralizing antibodies is thought to be crucial after the onset of BKPyV replication where early and effective neutralizing response prevents the development of viremia. Adjuvant IVIg may reduce the damage associated with BKPyV infection by binding to the free virus within the tubular interstitium released after lytic tubular cell disruption, and prevent viral spread to adjacent cells. Additionally, IVIg may act as an immunomodulator by aiding T cell–mediated clearance of BKPyV virus and regulating the innate and adaptive immune responses via the Fcγ receptors. This is supported by the reduced viral SV-40 immunohistochemistry scores on follow-up biopsies after IVIg treatment.163-165

In clinical practice, the utility of IVIg in BKPyV infection is uncertain. The evidence for IVIg is very low due to the imprecision and high risk of bias (small studies, case series, retrospective cohorts) (Table 4). Nevertheless, it holds promise based on findings from observational data which show 90%–100% of kidney transplant recipients achieved BKPyV viral clearance at 12 mo following the addition of IVIg to immunosuppression reduction.166,167 Moreover, a case-cohort study of 48 kidney transplant recipients indicated that the simultaneous use of IVIG as an adjuvant therapy to intensive antiviral treatment including cyclosporine conversion may lead to an improvement in BKPyV viral clearance in serum and on histology, compared with the standard-of-care immunosuppression reduction with cidofovir.163

TABLE 4. - Adjuvant therapies for BKPyV infection
Study group Study y Study type Treatment a (intervention/comparator) Sample size Dose of intervention Graft function b Graft loss c (%) Viral clearance d (%) Rejection e (%)
Sener et al168 2006 Case series IVIg 8 2.0 g/kg over 2–5 d Cr at:diagnosis: 293 ± 32Last follow-up: 309 ± 46 12 50 0
Anyaegbu et al166 2012 Case series IVIg 4 2 mg/kg over 12–24 h eGFR at:Last follow-up: 113 0 100 25
Vu et al167 2015 Case series IVIg 30 1.0 g/kg Median eGFR at:Diagnosis: 46Last follow-up: 63 3 90
Kable et al163 2017 Cohort IVIg 22 100 mg/kg per dose (total: 10 doses) Cr at:Diagnosis: 164 ± 52At 3-mo follow-up: 199 ± 102 27 77 64
Non-IVIg 28 N/A Cr at:Diagnosis: 184 ± 54At 3-mo follow-up: 235 ± 108 54 33 57
Matsumura et al169 2020 Case series IVIg 5 100 mg/kg/d for 5 d 0 40 0
Josephson et al170 2006 Case series Leflunomide 26 100 mg/d for 5 d, then 40 mg/d 16 42
Faguer et al171 2007 Case series Leflunomide 12 100 mg/d for 5 d, then 40 mg/d Median eGFRDiagnosis: 36Last follow-up: 45 (19-95) 17 42 8
Canivet et al172 2009 Case series Leflunomide 12 100 mg/d for 5 d, then 40 mg/d Median CrClDiagnosis: 40 (25–95)Last follow-up: 35 (18–112) 8 42 8
Zaman et al173 2014 Case series Leflunomide 19 100 mg/1.73m2 body surface area/d for 3 d, then adjusted to weight eGFRLast follow-up: 40–240 0 100 21
Keller et al174 2019 Case series Leflunomide 55 100 mg/d for 5 d, then 40 mg/d Cr atDiagnosis: 194 ± 71Last follow-up: 236 ± 140 20 76 33
Malik et al175 2019 Case series Leflunomide 122 3 24 23
Lim et al176 2003 Case series Cidofovir 2 0.3 mg/kg fortnightly Cr at:Diagnosis: 200Last follow-up: 120 50 100 50
Araya et al177 2008 Case series Cidofovir 8 0.25–1.0 mg/kg every 2–3 wks 0 75 13
Cabello et al178 2008 Case series Cidofovir 6 0.25–1 mg/kg weekly (total: 7–15 doses) Cr at:Diagnosis: 176Last follow-up: 118 17 83 33
Wu et al179 2009 Cohort Cidofovir + RIS 8 0.5 mg/kg every 2 wks (Total: 6 doses) 37 12
RIS 6 N/A 50 0
Kuypers et al180 2009 Cohort Cidofovir + RIS 26 1.0 mg/kg weekly (maximum: 10 doses) CrCl at:Diagnosis: 36 ± 11Last follow-up: 38 ± 16 15 58 15
RIS 15 N/A CrClDiagnosis: 29 ± 9Last follow-up: 50 ± 33 73 47 7
Kuten et al181 2014 Cohort Cidofovir + RIS in high-level BKPyV viremia 28 Loading 1 mg/kg, then 0.5 mg/kg fortnightly eGFRLast follow-up: 54 78
Cidofovir + RIS in BKPyVAN 47 eGFRLast follow-up: 45 65
aTreatment in conjunction with reduction of immunosuppression ± conversion of immunosuppression ± occasional adjuncts.
bGraft function reported as mean ± SD at BKPyV diagnosis and at last follow-up, unless stated otherwise. Estimates with median reported with interquartile ranges.
cReturn to dialysis and death by the end of follow-up.
dPartial and complete viral clearance on serum real-time polymerase chain reaction by the end of follow-up.
eIncludes acute rejection, antibody-mediated rejection, mixed and chronic rejection by the end of follow-up.
Cr, serum creatinine; CrCl, creatinine clearance (mL/min); eGFR, estimated glomerular filtration rate (mL/min/1.73m2); IVIg, intravenous immunoglobulin; MPA, mycophenolic acid; NA, not applicable; RIS, reduction of immunosuppression.

A recent survey of nephrologist in Australia and New Zealand reported that 63% of the responders would consider IVIG as a “rescue” when conventional therapy has failed, or if the graft function is deteriorating rapidly, despite the lack of quality evidence to inform clinical practice.108 Relative to other adjuncts, IVIg is well tolerated and the risk for complications is low, making it a favorable option to consider. However, rare adverse effects such as allergic reactions and deep vein thrombosis may occur.

Leflunomide

Leflunomide is also known for its immunomodulatory properties and acts as an immunosuppressant via its active metabolite, teriflunomide. The latter may limit the inflammatory response associated with BKPyV infection by inhibiting the enzyme, mitochondrial dihydroorotate dehydrogenase, resulting in pyrimidine depletion and cytostasis in proliferating cells such as activated lymphocytes. Leflunomide is also thought to interrupt BKPyV viral DNA synthesis, a key pathway in the development of BKPyV infection.182

The AST guideline suggests considering leflunomide as an adjunct therapy if BKPyV infection fails to improve with adequate immunosuppression reduction. The recommended loading dose for leflunomide is 100 mg for 5 d orally, followed by a maintenance dose of 40 mg or adjusted according to plasma trough concentrations.39 Previous studies reported using leflunomide as an alternative agent to mycophenolic acid, and occasionally in conjunction with cidofovir and intravenous immunoglobulin.183

Several observational studies have reported complete clearance of BKPyV viremia in a proportion of patients, with approximately 40% achieving complete viral clearance as early as 8 wks from the time leflunomide was commenced, while others observed a much longer time to clearance, sometimes extending to over 5 y167,171-174,184 (Table 4). However, some authors have also reported no additional benefit with BKPyV viral clearance following the use of leflunomide.185 The rates of graft loss and acute rejection associated with leflunomide were highly variable, with estimates varying up to 20%.98,174 Other complications associated with leflunomide include gastrointestinal disorders (diarrhea, nausea) and hematologic toxicity (bone marrow suppression, hemolysis, thrombotic microangiopathy) while prolonged use is reportedly associated with fungal pneumonia, neuropathic pain and rhabdomyolysis.39,174,184,186 It is contraindicated in pregnancy.

Cidofovir

Cidofovir is a nucleoside analogue, which inhibits BKPyV replication in primary human renal tubular epithelial cells. However, this occurs downstream of an initial large T-antigen expression as supported by in vitro studies showing that the presence of cidofovir before the cells are infected with BKPyV and during the incubation period did not influence the rate of inhibition. In other words, cidofovir is ineffective during the early viral replication cycles (receptor binding and entry).187,188

The effects of cidofovir on graft function are also very uncertain.98,178,189,190 A cohort study reported lower rates of graft loss within the mean follow-up period of 30 mo among recipients who received cidofovir in addition to immunosuppression reduction compared with those who had immunosuppression reduction alone (15 versus 73%; P < 0.001).180 However, others found that addition of cidofovir to immunosuppression reduction did not yield any benefits in the long-term graft outcomes including function and allograft survival, when compared with the noncidofovir group.179 A meta-analysis examining the different treatment strategies for BKPyVAN found that addition of cidofovir to immunosuppression reduction alone did not reduce the risk of graft loss compared with immunosuppression reduction alone.98

Cidofovir is administered intravenously at a recommended dose of 0.25–1.0 mg/kg at 1–3 weekly intervals without probenecid.39 It is contraindicated in patients with severe kidney failure. Adverse effects may include fever, nausea, and maculopapular rash at the end of infusion, although the rash may not occur on subsequent infusions. Cidofovir-related anterior uveitis can occur in up to 35% of cases, presenting as pain and loss of vision with 80% having full recovery following corticosteroids and cycloplegics. Other complications also include acute kidney injury and bone marrow toxicity (anemia, neutropaenia).149,178,179 An economic evaluation comparing between the treatment with immunosuppression reduction alone and the treatment with immunosuppression reduction and cidofovir found that the addition of cidofovir might have a small incremental health benefits and saving.191 However, uncertainties exist because of uncertain clinical data, unclear evidence of the efficacy of cidofovir for treating BKPyV infection and the extent of the complications such as nephrotoxicity associated with prolonged use.

Recommencement of Immunosuppression

Several studies had suggested that BKPyV infections were associated with development of de novo donor-specific antibodies in long-term follow-up.153,155,192 While association with de novo donor-specific antibodies and rejection is generally considered as poor graft outcomes,193,194 its impact on recipients with treated BKPyV infections is not clear. Nevertheless, a recent study suggested that re-escalation of immunosuppression may be beneficial in patients with low-level or resolved BKPyV.195 However, the timings and decisions to increase the immunosuppression following clearance of BKPyV infection should be individualized and is dependent on the patients’ underlying immunologic risk, the extent of the BKPyV infection, and achievement in reduction of viral load. Close monitoring of serum creatinine and BKPyV viral load by RT-PCR is required to monitor the recurrence of BKPyV infection if immunosuppression is increased.39,152

RETRANSPLANTATION FOLLOWING BKPyV-GRAFT FAILURE

Prior BKPyV infection and associated graft loss is a risk factor for recurrence of BKPyVAN. A judicious approach to retransplantation is preferred, ensuring undetectable BKPyV levels before surgery and close monitoring posttransplantation.152,196 However, the evidence for transplant nephrectomy before retransplantation are derived from case reports and series.197,198 The evidence for transplant nephrectomy is low although not unreasonable to remove a potential source of reinfection.

EXPERIMENTAL TREATMENT OPTIONS

With advances in adoptive immunotherapy, cellular therapy using ex vivo expanded virus-specific T cells has emerged.199-201 In a recent phase II study, BKPyV-specific T cells manufactured from peripheral blood mononuclear cells of stem cell donors or unrelated-third party donor were given to 38 hematopoietic stem cell recipients and 3 solid organ transplant recipients including heart and kidney transplant. Among solid organ recipients, 1 achieved complete response (undetectable plasma BKPyV PCR), while the remaining 2 patients had partial response (>50% reduction in BKPyV PCR) within 4-wks from the last infusion.202 While the initial results are promising, potential barriers for implementation in wider clinical settings may include scalability in terms of production and delivery of the viral specific therapy, as well as the cost-effectiveness of intervention and patient acceptance/preferences. Recently, a preclinical study has shown that the sulphonylurea, glibenclamide, could potentially be repurposed as a therapeutic agent for BKPyV infection. These agents may inhibit BKPyV infection in primary renal proximal tubular epithelial cells by disrupting the activity of a potentially important host factor, cystic fibrosis transmembrane conductance regulator.203 However, this “proof of concept” needs further validation.

CONCLUSIONS

Management of BKPyV infection remains a major challenge for healthcare professionals and patients. Current treatment strategies of BKPyV infection are largely informed by low to moderate quality evidence in the forms of case series/reports and observational studies. High-quality evidence in the form of well-powered randomized controlled trials of novel interventions such as comparing the reduction against conversion of immunosuppressants, and addition of IVIg to immunosuppression reduction against immunosuppression reduction alone are needed to inform clinical practice. Robust reporting of patient-relevant outcomes is crucial to allow parallel comparisons between studies. Finally, the views and preferences of patients should be considered in the decision-making process of treatment selection, while balancing the benefits of treatment and risk of complications.

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