Search Results (74)

Polyomavirus-associated nephropathy was first reported over 50 years ago. However, it still represents a cause of renal injury in kidney transplant recipients, particularly in the first two years post-transplantation, with occurrence rates of 1–10%. The role played by immunosuppression in viral reactivation is well acknowledged, and the modulation of its level is the main strategy for clinical management. Viral and immunological evaluation are fundamental for optimizing its diagnostic and therapeutic pathway. In this review, the main features of BK polyomavirus and associated nephropathy in renal transplant patients are addressed and discussed from a virological point of view; the role of BK polyomavirus in hematopoietic stem cell transplantation and other solid-organ transplant patients is also briefly reported. Full article

BK polyomavirus (BKPyV) causes severe urinary tract diseases, including BKPyV-associated nephropathy (BKPyVN) and ureteric stenosis, in immunocompromised individuals such as renal transplant recipients. Effective antiviral therapies for BKPyV infection remain an unmet clinical need. While the interferon-stimulated gene 20 (ISG20) exhibits broad-spectrum antiviral activity against RNA viruses, its role and mechanisms against DNA viruses are poorly defined. This study demonstrates, for the first time, potent antiviral activity of ISG20 against BKPyV. This restriction was observed with both endogenous levels of ISG20 and upon overexpression, and this effect was confirmed by ISG20 knockout and immunofluorescence imaging. We observed that ISG20 expression is dynamically regulated during BKPyV infection: it is upregulated both during early infection and by expression of the viral large T antigen (LT) alone. However, endogenous ISG20 expression becomes significantly suppressed during later stages of infection, coinciding with declining LT levels. The physical interaction between LT and both wild-type and mutant ISG20 suggests a potential viral strategy to sequester this restriction factor. These findings establish ISG20 as a novel host restriction factor against BKPyV and suggest that BKPyV employs LT-mediated mechanisms to evade or counteract ISG20’s antiviral effects. Our results elucidate a complex biphasic interplay between BKPyV and host innate immunity, identifying ISG20 as a potential therapeutic target for BKPyV-associated diseases. Full article

The reactivation of BK polyomavirus (BKPyV) during severe immunosuppression plays a crucial role in two significant syndromes observed in transplant recipients: BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant patients and BK polyomavirus-associated hemorrhagic cystitis (BKPyV-HC) in hematopoietic cell transplant (HCT) recipients. This review aims to summarize the current understanding and lingering ambiguity by looking at three primary questions: (1) In cases with BKPyV-related illnesses in transplant patients, which diagnostic methods have the best track record of accuracy and success? (2) Which therapy approaches have the best track records of safety and efficacy in real-world clinical settings? (3) What can immunological research teach us about the development of future tailored treatments? Diagnosis involves the patient’s appearance, ruling out other potential causes, and employing quantitative PCR to identify active viral replication in urine or plasma. BKPyV-HC can vary from self-limited hematuria to potentially fatal bleeding, while BKPyVAN may lead to loss and dysfunction of the allograft. Reducing immunosuppression remains the key aspect of treatment. However, the effectiveness of antivirals (such cidofovir and leflunomide) is not always the same, and supporting measures depend on the syndrome. Researchers are looking into new immunotherapies, such as virus-specific cytotoxic T cells. Due to the intricate viro-immunopathology and lack of defined treatment regimens, future initiatives should focus on prospective studies to establish validated thresholds, enhance management algorithms, and integrate immune surveillance into individualized therapy. Full article

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT. Full article

Background: BK polyomavirus (BKPyV) reactivation is a common complication after kidney transplantation and may result in nephropathy and graft loss. As there is no effective antiviral therapy, management focuses on early detection and reduction of immunosuppression, which increases the risk of rejection. Identifying patients at higher risk remains challenging. Monitoring BKPyV-specific T-cell responses could aid in predicting reactivation. This study evaluated the usefulness of ELISpot to monitor BKPyV-specific cellular immunity before and after kidney transplantation. Methods: A prospective multicenter study was conducted between October 2020 and March 2022. ELISpot assays were performed prior to transplantation and two months afterward. Results: Seventy-two patients were included, with a median age of 56 years; 61% were men, and 24% had undergone previous transplantation. Nine patients developed presumptive BKPyV-nephropathy. No significant differences were found in donor type, induction therapy, or rejection rates between patients with or without nephropathy (p = 0.38). Based on ELISpot results, patients were classified into three groups according to their risk of BKPyV-nephropathy. The high-risk group included those who changed from positive to negative at 2 months post-transplant, representing 40% of presumptive BKPyV-nephropathy cases. Patients who remained negative at 2 months were classified as moderate risk (14.5%), while those with a positive ELISpot at 2 months comprised the low-risk group (0%). In the logistic regression analysis, both the ELISpot risk category [OR 19 (CI 1.7–2.08)] and the use of mTOR inhibitors from the start of transplantation [OR 0.02 (CI 0.01–0.46)] were significantly associated with BKPyV-nephropathy. Conclusions: Monitoring BKPyV-specific T cells with ELISpot before and after kidney transplantation may help stratify patients by risk of reactivation. Loss of BKPyV immunity at two months is associated with nephropathy, while mTOR-based immunosuppression appears protective. This strategy could guide personalized immunosuppression and surveillance. Full article

Protocol biopsies are a fundamental component in the management of kidney transplant recipients, offering critical insights into graft health by detecting subclinical pathological changes undetectable through routine clinical and laboratory assessments. Conducted at predetermined intervals, these biopsies enable early identification of subclinical rejection, chronic allograft nephropathy, drug-induced toxicities, viral infections such as BK polyomavirus nephropathy, and recurrence of primary glomerular diseases. Early detection facilitates timely therapeutic interventions, including immunosuppressive regimen adjustments, which are pivotal in preserving graft function and improving long-term outcomes. While the optimal timing and frequency of protocol biopsies vary, early post-transplant biopsies within the first year are widely advocated. High-risk groups, including ABO- and HLA-incompatible recipients and those with recurrent primary nephropathies, particularly benefit from surveillance biopsies. Despite the invasive nature and associated risks of biopsy procedures, most experts agree that the benefits outweigh the risks in selected populations. However, the role of routine protocol biopsies in low-risk patients remains debated due to unclear long-term outcome improvements and resource considerations. Retrospective observational studies have demonstrated the ability of protocol biopsies to detect subclinical pathological changes such as rejection, drug toxicity, viral infections, and recurrent diseases before clinical or laboratory abnormalities appear. These studies also highlight the impact of biopsy-guided interventions on graft survival and management in high-risk groups (e.g., HLA- and ABO-incompatible recipients, and patients at risk for disease recurrence). Furthermore, randomized controlled trials provide higher-level evidence showing that protocol biopsy-guided interventions improve graft function, reflected by better serum creatinine levels and glomerular filtration rates, compared to indicated biopsies alone. They also emphasize the importance of both early and late surveillance biopsies for predicting long-term outcomes. Expert opinion and consensus acknowledge the benefits of protocol biopsies for early detection and tailored management but also highlight ongoing debates regarding their routine use in low-risk patients due to risks, costs, and resource considerations. Overall, protocol biopsies represent a valuable tool for personalized graft monitoring and management, aiding in early detection of complications, guiding immunosuppressive therapy, and enhancing graft longevity. Further multicenter randomized trials are needed to refine guidelines and optimize their clinical utility. Full article

Polyomaviruses have the potential to cause significant morbidity not only in transplant medicine, but also in other forms of disease or variants of immunosuppression. In kidney transplant recipients or recipients of human stem cell transplants, the BK-Virus is the major proponent of manifestations such as BKPyV-associated nephropathy or hemorrhagic cystitis. As no polyomavirus-specific drug with proven in vivo effects has been developed so far, methods to screen for such drugs are important. This work describes the establishment of a virus-secreting cell line. By infecting a pre-established monkey kidney cell line (COS-1) with a non-rearranged human BK polyomavirus isolated from a kidney transplant patient suffering from BKPyV-associated nephropathy, a continuously replicating cell type with consistent virus secretion could be established and was termed COSSA. Measurements of BKPyV replication, virion production, and secretion were performed both intracellularly and in the cell supernatant. Viral proteins such as VP1 and LTAg were accurately tracked by confocal microscopy, as well as by immunoblot and qPCR. An intracellular flow cytometry (FACS) assay detecting VP1 protein was established and revealed an expanded range of positive intracellular signals. The viruses produced proved to be infectious in human tubular epithelial cell lines. Long-range sequencing of the COSSA genome using Oxford Nanopore Technology revealed a total of five distinct BKPyV integration events. One integration of a partial BKPyV genome was located upstream of the epidermal growth factor receptor gene. The second and third, both truncated forms of integration, were close to histocompatibility gene locuses, while the fourth was characterized by a ninefold and the fifth by a fourfold tandem repeat of the BKPyV genome. From both of the repeat forms, virus replicates were derived showing deletions/duplications on early and late genes and inversions within the non-coding control region (NCCR). This pattern of repetitive viral genome integration is a potential key driver of enhanced viral replication and increased virion assembly, ultimately supporting efficient virus egress. Quantitative PCR analysis confirmed the release of approximately 10⁸/mL viral units per 48 h from 2 × 10⁵ COSSA cells into the culture supernatant. Notably, the NCCR region of the most frequent copies of circular virus and the integrated tetrameric tandem repeat exhibited a rearranged configuration, which may contribute to the observed high replication dynamics. The establishment of a consistent methodology to generate and secrete BKPyV from a cell line is expected to significantly facilitate antiviral drug development. Full article

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. Full article

BK polyomavirus (BKPyV) is a pathogen responsible for infectious complications in hematopoietic stem cell transplant (HSCT) recipients. This review aims to give an insight into recent data about the structure and genomic organization, epidemiology, clinical manifestations, diagnosis, and current treatment options of BKPyV infections in children after HSCT. News regarding viral replication and pathogenesis include the generation of miRNA, new mechanisms of viral shedding by releasing infectious particles via extracellular vesicles, and human bladder microvascular endothelial cells probably acting as viral reservoirs enabling low-level viral replication and persistence. In studies conducted over the past five years, BKPyV hemorrhagic cystitis (BKPyV-HC) has a prevalence rate of 4 to 27% in children undergoing HSCT. Diagnostics still has unsolved dilemmas like whole blood or plasma samples as well as the standardization of molecular methods to allow for reporting in international units. In terms of treatment, new approaches have been used in the past five years, including the use of mesenchymal stem cells (MSCs), virus-specific T cells (VSTs), and recombinant human keratinocyte growth factor (rH-KGF), although the efficacy of some of these treatments has only been documented in isolated studies. This complication continues to pose a substantial clinical challenge, characterized by an absence of effective preventive and therapeutic measures. Full article

Kidney transplant recipients require a lifelong protocol of immunosuppressive therapy to prevent graft rejection. However, these same medications leave them susceptible to opportunistic infections. One pathogen of particular concern is human polyomavirus 1, also known as BK virus (BKPyV). This virus attacks kidney tubule epithelial cells and is a direct threat to the health of the graft. Current standard of care in BK virus-infected transplant recipients is reduction in immunosuppressant therapy, to allow the patient’s immune system to control the virus. This requires a delicate balance; immune suppression must be strong enough to prevent rejection, yet weak enough to allow viral clearance. We seek to model viral and immune dynamics with the ultimate goal of applying optimal control methods to this problem. In this paper, we begin with a previously published model and make simplifying assumptions that reduce the number of parameters from 20 to 14. We calibrate our model using newly available patient data and a detailed sensitivity analysis. Numerical results for multiple patients are given to show that the newer model reflects observed dynamics well. Full article

Polyomavirus BK (BKPyV)-associated nephropathy (BKPyV-nephropathy) remains a significant cause of premature kidney allograft failure. In the absence of effective antiviral treatments, current therapeutic approaches rely on immunosuppression (IS) reduction, possibly at the risk of inducing alloimmunity. Therefore, we sought to explore the long-term effects of a tailored viro-immunologic surveillance and treatment program for BKPyV on the development of alloimmunity and kidney graft outcome. Forty-five pediatric kidney transplant recipients were longitudinally monitored for BKPyV replication, virus-specific immunity, and donor-specific HLA antibodies (DSAs). DNAemia developed in 15 patients who were treated with stepwise IS reduction. Among the other 30 patients, 17 developed DNAuria without DNAemia and 13 always resulted as BKPyV-negative. All patients with DNAemia cleared BKPyV after having mounted a virus-specific cellular immune response, and no biopsy-proven BKPyV-nephropathy was observed. The presence of cytotoxic populations directed to the BKPyV Large-T (LT) antigen early after transplantation protected kidney recipients from developing BKPyV replication, and the appearance of LT-specific T cells in viruric patients prevented the development of BKPyV-DNAemia. In our cohort, no significant correlation was observed between BKPyV-DNAemia and the development of DSA and antibody-mediated rejection. However, patients who experienced and cleared BKPyV-DNAemia had a worse allograft survival at a median follow-up of 18.9 years (p = 0.048). These data need to be confirmed in larger cohorts. Full article

BK viremia (BKPyV-DNAemia) and nephropathy (BKPyVAN) are significant causes of morbidity and mortality in kidney transplant recipients (KTRs). Vitamin D supports immune function, yet low 25-hydroxyvitamin D [25(OH)D] is common among KTRs. The association between serum 25(OH)D, measured 61 days to 2 years post-transplant, and subsequent incident BKPyV-DNAemia and BKPyVAN was examined in KTRs without previous BKPyV-DNAemia or BKPyVAN, respectively. Out of 3308 KTRs, 399 (12%) were vitamin D deficient [25(OH)D ≤ 20 ng/mL], and 916 (27.7%) were insufficient [25(OH)D 21–29 ng/mL]. A total of 184 KTRs developed BKPyV-DNAemia and 44 developed BKPyVAN. The incidence rate (/100 person-years) for BKPyV-DNAemia was 2.88 in the 25(OH)D sufficient group, 2.22 in the insufficient group, and 2.37 in the deficient group. The incidence rate (/100 person-years) for BKPyVAN was 0.30 in the 25(OH)D sufficient group, 0.75 in the insufficient group, and 1.28 in the deficient group. Vitamin D deficiency (adjusted hazard ratio [aHR] compared to 25(OH)D sufficiency: 3.92; 95% CI: 1.66–9.23) and insufficiency (aHR: 2.22; 95% CI: 1.11–4.45) remained significantly associated with the incidence of BKPyVAN after adjustment for baseline characteristics. Low serum 25(OH)D was associated with an increased risk of BKPyVAN but not BKPyV-DNAemia. Full article

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. Full article

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. Full article

Introduction: Polyomavirus-associated nephropathy (BKPyVAN) is a common complication in kidney transplant recipients. The histological changes in the context of BKPyVAN and their association with the viral load and outcomes are still being investigated. Methods: This retrospective study involved 100 adult patients transplanted between 2000 and 2021, with available archived biopsy slides, aiming to analyze associations between viral load clearance in the blood (reduction in BKPyVAN-DNAemia below detection level) and histological features in biopsy-proven BKPyVAN. A kidney pathologist blinded to the clinical data reassessed the BANFF 2019 lesion scores in the BKPyVAN index biopsy. The primary endpoint was viral clearance three months after the diagnosis. Results: The presence of tubulointerstitial inflammation, peritubular capillaritis, and higher PVN Class at the diagnosis was linked to a reduced likelihood of viral clearance three months later (interstitial inflammation OR = 0.2, 95% CI [0.07–0.55], tubulitis OR = 0.39, 95% CI [0.21–0.73], peritubular capillaritis OR = 0.25, 95% CI [0.08–0.82], PVN Score OR = 0.1, 95% CI [0.03–0.4]), independently of other covariates. Combining the four lesions using the ROC analysis enhanced their capability to predict persistent BK viremia after 3 months with an AUC of 0.94. Conclusions: The presence of interstitial inflammation, tubulitis, and peritubular capillaritis, as well as the higher PVN Score, was associated with an up to 90% lower likelihood of viral load clearance three months post-diagnosis. These findings underscore the importance of histological evaluation as a surrogate of subsequent viral clearance and offer valuable insights for the management of BKPyVAN. Full article