BK polyomavirus (BKPyV) is recognized as a significant viral complication of kidney transplantation. Prompt immunosuppression reduction reduces early graft failure rates due to BK polyomavirus-associated nephropathy (BKPyVAN), however, modulation of immunosuppression can lead to acute rejection. Medium-to-long-term graft outcomes are negatively affected by BKPyVAN, probably due to a combination of virus-induced graft damage and host immune responses against graft alloantigens potentiated by immunosuppression reduction. Kidney biopsy remains the gold-standard diagnostic test, however, false-negative findings are common due to the focal nature of BKPyVAN. BKPyV DNAemia, as measured by quantitative polymerase chain reaction, is established as a screening test but there is at present no (inter)national standardization of these assays to allow collation and comparison of data between centres. Randomized controlled trials are lacking both in terms of optimal immunosuppression reduction strategies, and for the medications variably used to attempt treatment in clinical practice. Much of the fundamental biology of BKPyV is not yet understood, and further elucidation is required to promote rational direct-acting antiviral drug design. Insights into the role of adaptive immunity in control of BKPyV have informed the design of novel treatments such as adoptive immunotherapies and neutralizing antibodies that require evaluation in clinical studies. Here, we review the current standards of diagnosis and treatment of BKPyVAN and discuss novel developments in the pathophysiology, diagnosis, outcome prediction, and management.

Polyomaviruses (PyVs) are non-enveloped double-stranded DNA viruses that can cause significant morbidity in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, particularly BK polyomavirus (BKPyV) and JC polyomavirus (JCPyV). BKPyV is primarily associated with hemorrhagic cystitis (HC), while JCPyV causes progressive multifocal leukoencephalopathy (PML). The pathogenesis of these diseases involves viral reactivation under immunosuppressive conditions, leading to replication in tissues such as the kidney, bladder, and central nervous system. BKPyV-HC presents as hematuria and urinary symptoms, graded by severity. PML, though rare after allo-HSCT, manifests as neurological deficits due to JCPyV replication in glial cells. Diagnosis relies on nucleic acid amplification testing for DNAuria or DNAemia as well as clinical criteria. Management primarily involves supportive care, as no antiviral treatments have proven consistently effective for either virus and need further research. This review highlights the virology, clinical presentations, and management challenges of PyV-associated diseases post-allo-HSCT, emphasizing the need for improved diagnostic tools and therapeutic approaches to mitigate morbidity and mortality in this vulnerable population.

Though antimicrobial stewardship programs (ASPs) are required for hospitals, the involvement of transplant recipients in programmatic interventions, protocols, and metrics has historically been limited. Though there is a growing interest in studying stewardship practices in transplant patients, optimal practices have not been clearly established. A component of ASPs, antiviral stewardship (AVS), specifically targeting cytomegalovirus (CMV), has been more recently described. Understanding AVS opportunities and interventions is particularly important for transplant recipients, given the morbidity and mortality associated with viral infections, challenging clinical syndromes, ultrasensitive molecular diagnostic assays, antiviral resistance, and costs of viral disease and medications, as well as antiviral drug toxicities. This review highlights opportunities for AVS for CMV, EBV, HSV, VZV, SARS-CoV-2, respiratory syncytial virus, and BK polyomavirus in transplant patients.

BK polyomavirus (BKPyV) infection of the kidney graft remains a major clinical issue in the field of organ transplantation. Risk factors for BKPyV-associated nephropathy (BKPyVAN) and molecular tools for determining viral DNA loads are now better defined. BKPyV DNAemia in plasma, in particular, plays a central role in diagnosing active infection and managing treatment decisions. However, significant gaps remain in the development of reliable biomarkers that can anticipate BKPyV viremia and predict disease outcomes. Biomarkers under active investigation include urine-based viral load assays, viral antigen detection, and immune responses against BKPyV, which may offer more precise methods for monitoring disease progression. In addition, treatment of BKPyVAN is currently based on immunosuppression minimization, while the role of adjunctive therapies remains an area of active research, highlighting the need for more personalized treatment regimens. Ongoing clinical trials are also exploring the efficacy of T-cell-based immunotherapies. The clinical management of BKPyV infection, based on proactive virological monitoring, immune response assessment, integrated histopathology, and timely immunosuppression reduction, is likely to reduce the burden of disease and improve outcomes in kidney transplantation.

BK virus-associated nephropathy (BKVAN), caused by infection with or reactivation of BK virus, remains a challenge in kidney transplantation. Screening is recommended for all kidney transplant recipients. For those with clinically significant infection, reduction of immunosuppression is the cornerstone of management. There is no specific antiviral or immunomodulatory therapy sufficiently effective for routine use.

This review aimed to examine the benefits and harms of interventions for BK virus infection in kidney transplant recipients.

We searched the Cochrane Kidney and Transplant Register of Studies up to 5 September 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

All randomised controlled trials (RCTs) and cohort studies investigating any intervention for the treatment or prevention of BKVAN for kidney transplant recipients.

Two authors independently assessed the study quality and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Twelve RCTs (2669 randomised participants) were included. Six studies were undertaken in single centres, and six were multicentre studies; two of these were international studies. The ages of those participating ranged from 44 to 57 years. The length of follow-up ranged from three months to five years. All studies included people with a kidney transplant, and three studies included people with signs of BK viraemia. Studies were heterogeneous in terms of the type of interventions and outcomes assessed. The overall risk of bias was low or unclear. Intensive screening for the early detection of BK viraemia or BK viruria prevents graft loss (1 study, 908 participants: RR 0.00, 95% CI 0.00 to 0.05) and decreases the presence of decoy cells and viraemia at 12 months (1 study, 908 participants: RR 0.06, 95% CI 0.03 to 0.11) compared to routine care (high certainty evidence). No other outcomes were reported. Compared to placebo, fluoroquinolones may slightly reduce the risk of graft loss (3 studies, 393 participants: RR 0.37, CI 0.09 to 1.57; I2 = 0%; low certainty evidence), probably makes little or no difference to donor-specific antibodies (DSA), may make little or no difference to BK viraemia and death, had uncertain effects on BKVAN and malignancy, but may increase the risk of tendonitis (2 studies, 193 participants: RR 5.66, CI 1.02 to 31.32; I2 = 0%; low certainty evidence). Compared to tacrolimus (TAC), cyclosporin (CSA) probably makes little or no difference to graft loss and death, may make little or no difference to BKVAN and malignancy, but probably decreases BK viraemia (2 studies, 263 participants: RR 0.61, 95% CI 0.26 to 1.41; I2 = 38%) and probably reduces the risk of new-onset diabetes after transplantation (1 study, 200 participants: RR 0.41, 95% CI 0.12 to 1.35) (both moderate certainty evidence). Compared to azathioprine, mycophenolate mofetil (MMF) probably makes little or no difference to graft loss and BK viraemia but probably reduces the risk of death (1 study, 133 participants: RR 0.43, 95% CI 0.16 to 1.16) and malignancy (1 study, 199 participants: RR 0.43, 95% CI 0.16 to 1.16) (both moderate certainty evidence). Compared to mycophenolate sodium (MPS), CSA has uncertain effects on graft loss and death, may make little or no difference to BK viraemia, but may reduce BKVAN (1 study, 224 participants: RR 0.06, 95% CI 0.00 to 1.20; low certainty evidence). Compared to immunosuppression dose reduction, MMF or TAC conversion to everolimus or sirolimus may make little or no difference to graft loss, BK viraemia or BKVAN (low certainty evidence). TAC conversion to sirolimus probably results in more people having a reduced BK viral load (< 600 copies/mL) than immunosuppression reduction (1 study, 30 participants: RR 1.31, 95% CI 0.90 to 1.89; moderate certainty evidence). Compared to MPS, everolimus had uncertain effects on graft loss and BK viraemia, may reduce BKVAN (1 study, 135 participants: 0.06, 95% CI 0.00 to 1.11) and may increase the risk of death (1 study, 135 participants: RR 3.71, 95% CI 0.20 to 67.35) (both low certainty evidence). Compared to CSA, everolimus may make little or no difference to BK viraemia, has uncertain effects on graft loss and BKVAN, but may increase the risk of death (1 study, 185 participants: RR 3.71, 95% CI 0.42 to 32.55; low certainty evidence). Compared to immunosuppression reduction, the leflunomide derivative FK778 may make little or no difference to graft loss, probably results in a greater reduction in plasma BK viral load (1 study, 44 participants: -0.60 copies/µL, 95% CI -1.22 to 0.02; moderate certainty evidence), but had uncertain effects on BKVAN and malignancy. Aggravated hypertension may be increased with KF778 (1 study, 46 participants: RR 8.23, 95% CI 0.50 to 135.40; low certainty evidence). There were no deaths in either group.

Intense monitoring early after transplantation for BK viruria and BK viraemia is effective in improving BK virus infection outcomes as it helps with early detection of the infection and allows for a timely reduction in immunosuppression reduction. There is insufficient evidence to support any other intervention for BK virus infection in kidney transplant recipients.

BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.

BK viral infection remains to be a challenging post-transplant infection, which can result in kidney dysfunction. The mainstay approach to BK infection is reduction of immunosuppression. Alterations in immunosuppressive regimen with minimization of calcineurin inhibitors, use of mechanistic target of rapamycin inhibitors, and leflunomide have been attempted with variable outcomes. Over the past few years, investigators have explored potential therapeutic options for BK infection. Fluoroquinolone prophylaxis and treatment was found to have no benefit in kidney transplant recipients. The utility of cidofovir is limited by its nephrotoxicity. Intravenous immunoglobulin is becoming a popular option for treatment and prophylaxis for BK infection, as it increases the neutralizing antibody titers against the most common BK virus serotypes. Virus-specific T cell therapy is an emerging treatment option for BK viremia. In this review, we will explore management and therapeutic options for BK infection and recent evidence available in literature.

Pediatric data on risk factors and the clinical course of BK DNAemia are limited. We aimed to determine the effects of BK DNAemia on transplant outcomes and delineate the safety and efficacy of various treatment approaches.

This retrospective-cohort study included 161 transplants (age ≤ 21 years) performed at a single center between 1/1/2012 and 1/1/2020. We used Cox proportional models to evaluate the effects of BK DNAemia on patient survival (PS), graft survival (GS), and acute rejection (AR), using BK as a time-dependent covariate. We also assessed the effects of pharmacological intervention on BK DNAemia duration using intervention as a time-dependent covariate.

BK-free survival was 69.1% at 1-year and 54.6% at 3-year posttransplant. After multivariate adjustment, BK DNAemia was associated with young age at transplant (aHR, age 5-<12 vs. ≥12 (years): 2.5 (1.4-4.5); p = .001) and steroid-based immunosuppression (IS) (aHR: 2.2 [1.1-4.5]; p = .03). We found no effect of DNAemia on AR (aHR: 1.25; p = .5), PS (aHR: 2.85; p = .22), and GS (aHR: 0.56; p = .41). Of 70 patients with DNAemia, 22 (31.4%) received no treatment, 20 (28.6%) received IS reduction alone, and 28 patients (40%) received treatment with at least one pharmacological agent (leflunomide, IVIG, ciprofloxacin, cidofovir). Sixty-three patients (90%) cleared DNAemia with median time to resolution of 2.4 months (IQR:1.4-5.6). We found no significant effect of BK-directed pharmacological treatment on time to resolution (aHR: 0.64;p = .13). BK-directed agents were well tolerated.

BK DNAemia is associated with a young age at transplant and steroid-based maintenance IS. We found no effect of BK DNAemia on AR, GS, and PS.

BK virus maintains a latent infection that is ubiquitous in humans. It has a propensity for reactivation in the setting of a dysfunctional cellular immune response and is frequently encountered in kidney transplant recipients. Screening for the virus has been effective in preventing progression to nephropathy and graft loss. However, it can be a diagnostic and therapeutic challenge. In this in-depth state-of-the-art review, we will discuss the history of the virus, virology, epidemiology, cellular response, pathogenesis, methods of screening and diagnosis, evidence-based treatment strategies, and upcoming therapeutics, along with the issue of re-transplantation in patients.

To provide a summary of complications of antimicrobials and opportunities for antimicrobial stewardship (AS) in solid organ transplant (SOT) patient care.

Personalized, precision antimicrobial prescribing in SOT aiming to avoid negative consequences of antimicrobials is essential to improving patient outcomes. The positive impact AS efforts in transplant care has been recognized and bespoke activities tailored to special interests of transplant patients and providers are evolving. Strategies to optimize stewardship interventions targeting antibacterial, antiviral, and antifungal drug selection and dosing in the transplant population have been recently published though clinical integration using a 'handshake' stewardship model is an optimal starting point in transplant care. Other recent studies involving transplant recipients have identified opportunities to shorten duration or avoid antimicrobials for certain commonly encountered clinical syndromes. This literature, informing recent consensus clinical practice guidelines, may help support institutional practice guidelines and protocols. Proposals to track and report stewardship process and outcome measures as a routine facet of programmatic transplant quality reporting have been published. However, developing novel metrics accounting for nuances of transplant patients and programs is critical. Important studies are needed to evaluate organizational transplant prescribing cultures and optimal behavioral science-based interventions relevant to antimicrobial use in this population.

Consequences of antimicrobial use, such as drug toxicities, and Clostridiodes difficile (CDI) and multidrug-resistant organisms colonization and infection disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Stewardship programs encompassing transplant patients aim to personalize antimicrobial prescribing and optimize outcomes. Further studies are needed to better understand optimal intervention strategies in SOT.

Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%-90% of the human population without significant illness. Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus-associated nephropathy (PyVAN), polyomavirus-associated haemorrhagic cystitis (PyVHC), polyomavirus-associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC), Trichodysplasia spinulosa (TS) and pruritic hyperproliferative keratinopathy. Although virus-specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus-specific immunity. However, the small dsDNA genome of only 5 kb of the non-enveloped HPyVs only encodes 5-7 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus-encoded antiviral targets. Lack of cost-effective high-throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case numbers, poorly efficacious compounds and absence of proper randomized trial design. Here, we review preclinical and clinical studies that evaluated small molecules with presumed antiviral activity against HPyVs and provide an outlook regarding potential new antiviral strategies.

Reactivation of BK virus (BKV) remains a dreaded complication in immunosuppressed states. Conventionally, BKV is known as a cause for BKV-associated nephropathy and allograft dysfunction in kidney transplant recipients. However, emerging studies have shown its negative impact on native kidney function and patient survival in other transplants and its potential role in diseases such as cancer. Because BKV-associated nephropathy is driven by immunosuppression, reduction in the latter is a convenient standard of care. However, this strategy is risk prone due to the development of donor-specific antibodies affecting long-term allograft survival. Despite its pathogenic role, there is a distinct lack of effective anti-BKV therapeutics. This limitation combined with increased morbidity and health care cost of BKV-associated diseases add to the complexity of BKV management. While summarizing recent advances in the pathogenesis of BKV-associated nephropathy and its reactivation in other organ transplants, this review illustrates the limitations of current and emerging therapeutic options and provides a compelling argument for an effective targeted anti-BKV drug.

BK polyomavirus (BKV) causes two distinct complications after transplantation, hemorrhagic cystitis (BKV-HC) after hematopoietic stem cell transplantation (HSCT), and BKV-associated nephropathy (BKVAN) after kidney transplantation (KT). Although fluoroquinolones show efficacy against BKV proliferation in vitro, the clinical effect remains uncertain; thus, we performed meta-analysis to assess its efficacy in the prophylaxis.

Articles published before March 2020 were searched from PubMed, the Cochrane Library, ISRCTN registry, and ClinicalTrials.gov. Primary outcomes were BKV-HC after HSCT and BKVAN after KT. Secondary outcomes were BK viremia, viruria after KT, and fluoroquinolone-related adverse events.

Three trials with 281 patients post-HSCT and 11 trials with 1882 patients post KT were included as for prophylaxis. Fluoroquinolone prophylaxis did not show effects on BKV-HC (OR 0.54, 95% CI 0.13-2.25), BKVAN (OR 0.74, 95% CI 0.35-1.55), and BK viremia (OR 0.79, 95% CI 0.49-1.28), but significantly decreased BK viruria (OR 0.64, 95% CI 0.45-0.91). Fluoroquinolone prophylaxis was associated with the higher percentage of fluoroquinolone-resistant infection among identified bacteria (OR 2.38, 95% CI 1.16-4.88), but the incidence of fluoroquinolone-resistant infection was similar (OR 1.15, 95% CI 0.71-1.86), due to the decrease of infection itself (OR 0.52, 95% CI 0.34-0.81).

This meta-analysis showed that fluoroquinolones did not prevent BKV-HC after HSCT or BKVAN after KT, although the effect against BKV-HC should be further investigated by randomized controlled trials. Fluoroquinolones could reduce the rate of BK viruria to some extent but may not have clinically sufficient effects.

To provide an update on the current landscape of antimicrobial stewardship in solid organ transplant (SOT) recipients.

Constructing personalized antimicrobial prescribing approaches to avoid untoward consequences of antimicrobials while improving outcomes is an emerging and critical aspect of transplant medicine. Stewardship activities encompassing the specialized interests of transplant patients and programs are evolving. New literature evaluating strategies to optimize antimicrobial agent selection, dosing, and duration have been published. Additionally, consensus guidance for certain infectious clinical syndromes is available and should inform institutional clinical practice guidelines. Novel metrics for stewardship-related outcomes in transplantation are desperately needed. Though exciting new molecular diagnostic technologies will likely be pivotal in the care of immunocompromised patients, optimal clinical adaptation and appropriate integration remains unclear. Important studies understanding the behaviors influencing antimicrobial prescribing in organizational transplant cultures are needed to optimize interventions.

Consequences of antimicrobial use, such as Clostridiodes difficile and infections with multidrug-resistant organisms disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Application of ASP interventions tailored to SOT recipients is recommended though further studies are needed to provide guidance for best practice.

Transplants have become common with excellent patient and graft outcomes owing to advances in surgical technique, immunosuppression, and antimicrobial prophylaxis. In 2017, 34,770 solid organ transplants were performed in the United States. For solid organ transplant recipients, infection remains a common complication owing to the regimens required to prevent rejection. Opportunistic infections, which are infections that are generally of lower virulence within a healthy host but cause more severe and frequent disease in immunosuppressed individuals, typically occur in the period 1 month to 1 year after transplantation. This article focuses on opportunistic infections in the solid organ transplant recipient.