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1.
J Infect Chemother ; 29(1): 67-71, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36162643

RESUMO

INTRODUCTION: BK virus associated hemorrhagic cystitis(BKV-AHC) is a serious complication observed after allogeneic stem cell transplantation and the current therapeutic options are scarce with substantial renal side effects. Although the guidelines recommend intravenous cidofovir application with caution to nephrotoxicity, there are few studies which investigated intravesical administration and reported similar therapeutic results with less renal side effects. METHODS: We administered low dose, daily and consecutive (75 mg/day, for 5 days) intravesical cidofovir to 25 patients with BKV-AHC that developed after (ASCT). RESULTS: The response rate in our cohort was 92% and relapse was not encountered in 84% of the patient population during one year of follow-up. The median BK urine viral load significantly decreased from 260,000,000 IU/mL to 53,000,000 IU/mL after a week of treatment (p = 0.0001). Rise in serum creatinine was observed in 5 patients during treatment and post-treatment nephrotoxicity was seen in only 1 patient. CONCLUSIONS: Daily low dose intravesical cidofovir might be an effective treatment option for BKV-AHC after ASCT with favorable less systemic side effects.


Assuntos
Vírus BK , Cistite , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Transplante de Células-Tronco Hematopoéticas , Organofosfonatos , Infecções por Polyomavirus , Insuficiência Renal , Infecções Tumorais por Vírus , Humanos , Cidofovir/uso terapêutico , Cidofovir/farmacologia , Infecções por Polyomavirus/tratamento farmacológico , Infecções Tumorais por Vírus/tratamento farmacológico , Organofosfonatos/efeitos adversos , Citosina/efeitos adversos , Antivirais/efeitos adversos , Cistite/tratamento farmacológico , Cistite/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Insuficiência Renal/etiologia
2.
Antiviral Res ; 208: 105456, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36328070

RESUMO

BK polyomavirus-associated nephropathy is one of serious complications in transplant recipients. Everolimus-a mammalian target of rapamycin inhibitor-has been shown to reduce the incidence of BK polyomavirus infection in transplant recipients. In this study, the effects of everolimus were examined on viral replication and the spread of infection in BK polyomavirus-infected cultures. BK polyomavirus replicated in renal and pulmonary cells, contrary to that in hepatocytes, and spread as diffusely scattered patterns of infected cells, unlike plaque formation through the cell-to-cell mode. BK polyomavirus is stable to heat up to 65 °C with a particle per infectivity ratio of 5000, and the replication cycle was for approximately 34 h. Everolimus administration remarkably reduced the viral replication to 20% in cells treated with 0.1-10 ng/mL, the concentration at which everolimus reached the serum of transplant recipients. In addition, it reduced the amount of viral capsid protein 1 at 5 ng/mL without reducing the ratio of viral capsid protein 1 versus ß-actin, and it also retained the pattern of viral capsid protein 1 localization in the nuclei. Everolimus suppressed the number of infected cells to 32.8% during a 14-day treatment, indicating the reduction of BK polyomavirus-infected cell mass to 18.8% of untreated cultures by modifying cellular functions. The reduction in the total number of BK polyomavirus infected cells by everolimus indicates that everolimus alleviates BK polyomavirus infection, including nephropathy in transplant recipients.


Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Everolimo/farmacologia , Proteínas do Capsídeo , Infecções por Polyomavirus/tratamento farmacológico , Infecções Tumorais por Vírus/tratamento farmacológico
3.
Front Immunol ; 13: 1017872, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36211389

RESUMO

A 66-year-old Chinese man underwent a deceased donor kidney transplantation. Induction-immunosuppressive protocol consisted of basiliximab (BAS) and methyl prednisolone (MP), followed by maintenance immunosuppression with cyclosporin (CsA), mycophenolate mofetil (MMF), and prednisone (PED). The patient's post-transplantation course was almost uneventful, and the graft was functioning well [serum creatinine (Scr) 2.15 mg/dL]. The MMF and CsA doses were decreased 1-month post-operative as the BK virus activation was serologically positive. His Scr was elevated to 2.45 mg/dL 45 days after the transplant. A graft biopsy showed BKV nephropathy (BKVN) and acute T cell-mediated rejection (TCMR) Banff grade IIA (I2, t2, ptc2, v1, c4d1, g0, and SV40 positive). The conventional anti-rejection therapy could deteriorate his BKVN, therefore, we administered BAS to eliminate activated graft-infiltrating T cells and combined with low-dose steroid. He responded well to the therapy after two doses of BAS were given, and the kidney graft status has been stable (recent Scr 2.1 mg/dL).


Assuntos
Vírus BK , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Idoso , Basiliximab , Creatinina , Ciclosporina , Rejeição de Enxerto/tratamento farmacológico , Humanos , Nefropatias/complicações , Transplante de Rim/efeitos adversos , Masculino , Ácido Micofenólico , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/tratamento farmacológico , Prednisolona , Prednisona , Linfócitos T
4.
Curr Opin Infect Dis ; 35(6): 536-544, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36255049

RESUMO

PURPOSE OF REVIEW: Reactivation of viral infections occurs frequently in immunosuppressed populations, particularly in solid organ (SOT) or allogeneic haematopoietic cell (HCT) transplant patients. Concurrent and sequential multivirus infections are common, yet risk factors and outcomes remain unclear. This review aims to identify the patients vulnerable to multivirus infections and characterize the impact of increased viral burden to formulate prevention and treatment strategies. RECENT FINDINGS: Incidences of up to 89% in SOT and 36% in HCT have been reported for two viruses, and 32% in SOT and 28% in HCT for at least three viruses. Risk factors appear related to an increased burden of immunosuppression, with most viral coinfections occurring within 12 months of transplantation. Direct viral complications such as cytomegalovirus disease are more frequent in coinfected patients, with documented prolonged duration of viraemia, higher viral load and increased end-organ disease. Graft dysfunction, acute rejection and graft-vs.-host disease (GVHD) have also been associated. Increased mortality is reported in the HCT population. SUMMARY: Multivirus infections occur in a significant proportion of transplant patients and is linked to immunosuppressive burden. There is increasing evidence that this leads to worse graft and patient outcomes. Further prospective studies are required to further comprehensively characterise viral epidemiology, mechanisms and treatment strategies to ameliorate this risk.


Assuntos
Infecções por Adenoviridae , Vírus BK , Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Citomegalovirus , Herpesvirus Humano 4 , Adenoviridae , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Adenoviridae/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores de Risco
5.
Ann Transplant ; 27: e937771, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36281207

RESUMO

BACKGROUND The interaction of viral infection may be associated with increased morbidity after renal transplantation. This study aimed to identify the incidence and risk factors of viruria infections in renal transplant recipients. MATERIAL AND METHODS In this longitudinal study, 502 episodes recorded in 81 kidney transplant patients from 1/2019 to 12/2021 in a hospital in Vietnam were included. BK, JC polyomaviruses, CMV, EBV, and HSV were detected. Multivariable Cox regression analysis was performed to evaluate risk factors for the viruria infection. RESULTS Fifty-six patients (69.1%) had viruria co-infection. The incidence of JC, CMV, and BK infection was the most common viruria, with 67.9%, 61.7%, and 56.8%, respectively. Cox regression revealed that the risk factors for JC were single infection, dose of MMF (HR 1.002), corticoid (HR 1.02), hypertension (HR 1.65), and hematuria (HR 2.03); risk factors for CMV infection were male sex (HR 1.92) and eGFR (HR 0.98); risk factors for BK single infection were hypertension (HR 1.67), proteinuria (HR 3.80), higher tacrolimus trough level (HR 1.17), and dose of MMF (HR 1.002). Hypertension (HR 1.68), fasting plasma glucose (HR 1.13), proteinuria (HR 6.01), tacrolimus trough level (HR 1.12), and dose of MMF (HR 1.004) were independent risk factors for the viruria co-infection. CONCLUSIONS Kidney function was associated with the incidence of viruria. Higher tacrolimus trough level and dose of MMF were associated with higher risk of BK, JC, and co-infection.


Assuntos
Vírus BK , Coinfecção , Infecções por Citomegalovirus , Hipertensão , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Polyomavirus , Humanos , Masculino , Feminino , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/complicações , Citomegalovirus , Tacrolimo , Seguimentos , Coinfecção/etiologia , Estudos Longitudinais , Glicemia , Nefropatias/etiologia , Fatores de Risco , Infecções por Citomegalovirus/complicações , Proteinúria/etiologia , Hipertensão/etiologia
6.
Front Immunol ; 13: 1006970, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36275762

RESUMO

Graft-derived cell-free DNA (GcfDNA) is a promising non-invasive biomarker for detecting allograft injury. In this study, we aimed to evaluate the efficacy of programmed monitoring of GcfDNA for identifying BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant recipients. We recruited 158 kidney transplant recipients between November 2020 and December 2021. Plasma GcfDNA was collected on the tenth day, first month, third month, and sixth month for programmed monitoring and one day before biopsy. ΔGcfDNA (cp/mL) was obtained by subtracting the baseline GcfDNA (cp/mL) from GcfDNA (cp/mL) of the latest programmed monitoring before biopsy. The receiver operating characteristic curve showed the diagnostic performance of GcfDNA (cp/mL) at biopsy time and an optimal area under the curve (AUC) of 0.68 in distinguishing pathologically proven BKPyVAN from pathologically unconfirmed BKPyVAN. In contrast, ΔGcfDNA (cp/mL) had a sensitivity and specificity of 80% and 84.6%, respectively, and an AUC of 0.83. When distinguishing clinically diagnosed BKPyVAN from clinical excluded BKPyVAN, the AUC of GcfDNA (cp/mL) was 0.59 at biopsy time, and ΔGcfDNA (cp/mL) had a sensitivity and specificity of 81.0% and 76.5%, respectively, and an AUC of 0.81. Plasma ΔGcfDNA (cp/mL) was not significantly different between TCMR [0.15 (0.08, 0.24) cp/mL] and pathologically proven BKPyVAN[0.34 (0.20, 0.49) cp/mL]. In conclusion, we recommend programmed monitoring of plasma GcfDNA levels after a kidney transplant. Based on our findings from the programmed monitoring, we have developed a novel algorithm that shows promising results in identifying and predicting BKPyVAN.


Assuntos
Vírus BK , Ácidos Nucleicos Livres , Nefrite Intersticial , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Vírus BK/genética , Infecções Tumorais por Vírus/diagnóstico , Rejeição de Enxerto/diagnóstico , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/patologia , Biomarcadores , Algoritmos
7.
Front Immunol ; 13: 971531, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059544

RESUMO

Purpose: To construct a dynamic prediction model for BK polyomavirus (BKV) reactivation during the early period after renal transplantation and to provide a statistical basis for the identification of and intervention for high-risk populations. Methods: A retrospective study of 312 first renal allograft recipients was conducted between January 2015 and March 2022. The covariates were screened using univariable time-dependent Cox regression, and those with P<0.1 were included in the dynamic and static analyses. We constructed a prediction model for BKV reactivation from 2.5 to 8.5 months after renal transplantation using dynamic Cox regression based on the landmarking method and evaluated its performance using the area under the curve (AUC) value and Brier score. Monte-Carlo cross-validation was done to avoid overfitting. The above evaluation and validation process were repeated in the static model (Cox regression model) to compare the performance. Two patients were presented to illustrate the application of the dynamic model. Results: We constructed a dynamic prediction model with 18 covariates that could predict the probability of BKV reactivation from 2.5 to 8.5 months after renal transplantation. Elder age, basiliximab combined with cyclophosphamide for immune induction, acute graft rejection, higher body mass index, estimated glomerular filtration rate, urinary protein level, urinary leukocyte level, and blood neutrophil count were positively correlated with BKV reactivation, whereas male sex, higher serum albumin level, and platelet count served as protective factors. The AUC value and Brier score of the static model were 0.64 and 0.14, respectively, whereas those of the dynamic model were 0.79 ± 0.05 and 0.08 ± 0.01, respectively. In the cross-validation, the AUC values of the static and dynamic models decreased to 0.63 and 0.70 ± 0.03, respectively, whereas the Brier score changed to 0.11 and 0.09 ± 0.01, respectively. Conclusion: Dynamic Cox regression based on the landmarking method is effective in the assessment of the risk of BKV reactivation in the early period after renal transplantation and serves as a guide for clinical intervention.


Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Idoso , Vírus BK/fisiologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Infecções por Polyomavirus/urina , Estudos Retrospectivos
8.
Viruses ; 14(9)2022 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-36146883

RESUMO

Mutations in the BK polyomavirus (BKPyV) capsid accumulate in kidney transplant (KTx) recipients with persistent virus replication. They are associated with neutralization escape and appear to arise as a result of cytosine deamination by host cell APOBEC3A/B enzymes. To study the mutagenic processes occurring in patients, we amplified the typing region of the VP1 gene, sequenced the amplicons to a depth of 5000-10,000×, and identified rare mutations, which were fitted to COSMIC mutational signatures. Background mutations were identified in amplicons from plasmids carrying the BKPyV genome and compared to mutations observed in 148 samples from 23 KTx recipients in France and in Vietnam. Three mutational signatures were consistently observed in urine, serum, and kidney biopsy samples, two of which, SBS2 and SBS13, corresponded to APOBEC3A/B activity. In addition, a third signature with no known etiology, SBS89, was detected both in patient samples, and in cells infected in vitro with BKPyV. Quantitatively, APOBEC3A/B mutation rates in urine samples were strongly correlated with urine viral load, and also appeared to vary between individuals. These results confirm that APOBEC3A/B is a major, but not the only, source of BKPyV genome mutations in patients.


Assuntos
Vírus BK , Infecções por Polyomavirus , Desaminases APOBEC/genética , Vírus BK/genética , Citidina Desaminase , Citosina , Humanos , Taxa de Mutação , Proteínas
9.
Transpl Immunol ; 75: 101709, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36100194

RESUMO

BACKGROUND: Cytochrome P450 3A5 (CYP3A5) includes two active genotypes, namely CYP3A5*1/*1 or *1/*3 with the fast metabolic activity and CYP3A5*3/*3 with slow metabolic. We retrospectively analyzed the correlation between CYP3A5 gene polymorphism and the susceptibility to the BK virus (BKV) infection in renal transplant recipients. METHODS: According to the inclusion/ exclusion criteria, we selected 134 recipients who received kidney transplantation at the Renmin Hospital of Wuhan University from January 2019 to December 2019. Based on the pre-operative CYP3A5 sequencing results, 134 recipients were divided into two groups: those expressing the fast metabolic CYP3A5*1/*1 or *1/*3 genotype; and, those expressing slow metabolic CYP3A5*3/*3 genotype. These two recipient groups were then analyzed for the BKV infection rate with different metabolic types to establish the potential relationship between CYP3A5 gene polymorphism and BKV infection. RESULTS: The overall incidence of BKV viruria was 37.3%, whereas BKV viremia was 4.5% among all 134 recipients. The fast metabolism group had 9.1% incidence of BKV viremia and 49.1% incidence of BKV viruria. In contrast, the slow metabolism group had only 1.3%incidence of BKV viremia (P = 0.031) with only 29.1% BKV viruria (P = 0.011). The incidence of low levels of urinary BKV in the fast metabolism group was higher than that in the slow metabolism group (P = 0.005), while no significant statistical difference in the incidence of high levels of urinary BKV and high and low levels of blood BKV. CONCLUSION: After kidney transplantation, CYP3A5 gene polymorphism of recipients present a certain relationship with the occurrence of BKV infection, which may be of value for the prediction and prevention of BKV infection.


Assuntos
Vírus BK , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Humanos , Vírus BK/genética , Transplante de Rim/efeitos adversos , Viremia/epidemiologia , Viremia/genética , Estudos Retrospectivos , Citocromo P-450 CYP3A/genética , Infecções por Polyomavirus/epidemiologia , Infecções por Polyomavirus/genética , Transplantados , Polimorfismo Genético
10.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S442-S443, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36164215

RESUMO

CONTEXT: Chimeric antigen receptor-T (CAR-T) cell therapy has emerged as an immunotherapy option for several hematological malignancies. Patients treated with CAR-T cell therapy are immunocompromised and prone to infections. However, limited data exist regarding prophylaxis and management strategies, which vary among institutions. OBJECTIVE: We report a single-institution experience of adenovirus (AdV) infection treatment following CAR-T cell therapy. DESIGN: Case report. SETTING: Academic referral center. PATIENTS OR OTHER PARTICIPANTS: A 67-year-old man with high-risk mantle cell lymphoma previously treated with chemoimmunotherapy and ibrutinib received brexucabtagene autoleucel for refractory disease. Treatment was complicated by grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS), warranting corticosteroid treatment that was tapered over 4 weeks, and cytokine release syndrome (CRS), resolved with tocilizumab. The patient was admitted within 30 days post-CAR-T cell therapy with pancytopenia and bilateral pulmonary infiltrates. His only symptoms were fatigue and malaise. A respiratory viral panel was positive for AdV. Further infectious testing revealed AdV viremia at 128,000 copies/mL and viruria at 7.10E+07 copies/mL, as well as BK viremia at 5,200 copies/mL and viruria >62,800,000 copies/mL. INTERVENTIONS: The patient was initially treated with intravenous immune globulin and then started on intravenous cidofovir 1 mg/kg with pre- and post-hydration. Adenovirus and BK virus levels were monitored in blood and urine weekly. Cidofovir was continued until the plasma level of AdV was <400 copies/mL on two separate occasions. MAIN OUTCOME MEASURES: AdV viremia and viruria, BK virus viremia and viruria, symptoms. RESULTS: Viral levels of AdV steadily decreased over 3 weeks to <190 copies/mL in plasma and 5200 copies/mL in urine. No new symptoms other than intermittent hematuria were noted. BK virus plasma levels increased temporarily, but fluoroquinolones were not given due to allergy and scarce evidence of their efficacy. CONCLUSIONS: Immunosuppression in patients receiving CAR-T cell therapy is multifactorial. CRS and ICANS are common acute toxicities that frequently require treatment with immunosuppressive agents. Prolonged use of corticosteroids has been identified as a predictor of infection after CAR-T cell therapy. Clinical trials addressing appropriate infection prophylaxis and treatment in this population are needed.


Assuntos
Vírus BK , Nefropatias , Linfoma de Célula do Manto , Infecções por Polyomavirus , Receptores de Antígenos Quiméricos , Adenoviridae , Adulto , Idoso , Vírus BK/genética , Terapia Baseada em Transplante de Células e Tecidos , Cidofovir , DNA Viral/urina , Fluoroquinolonas , Humanos , Imunoglobulinas Intravenosas , Imunossupressores/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Nefropatias/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/terapia , Masculino , Infecções por Polyomavirus/epidemiologia , Receptores de Antígenos Quiméricos/uso terapêutico , Tomografia Computadorizada por Raios X , Viremia/diagnóstico
11.
J Proteome Res ; 21(10): 2356-2366, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36103633

RESUMO

BK virus (BKV) is one of the most common pathogens in post-transplantation infections. For kidney transplantation, BKV infection results in the impairment of allograft function and thus increases the risk of allograft loss. However, clinical evaluation of the prognosis of BKV-associated allograft impairment is difficult. In the present study, differential plasma proteins were screened using proteomic methods from ten patients with a transition from BKV-negative to BKV activation. We identified 12 differentially expressed proteins, and S100A8 and S100A9 were the top two upregulated proteins. Data from a cross-sectional study with 66 BKV-negative and 66 BKV-positive recipients of renal transplantation indicated that plasma S100A8/A9 was upregulated in BKV-infected recipients. Plasma S100A8/A9 positively correlated with the 1 month creatinine increase (ρ = 0.499, P = 0.021) and negatively correlated with the 1 month estimated glomerular filtration rate change (ρ = -0.618, P = 0.003) in recipients with BK viremia. Using least absolute shrinkage and selection operator regression models, we found that S100A8/A9 was an independent risk factor for the decrease in allograft function after BKV infection. In conclusion, S100A8/A9 is a potential host biomarker for the clinical evaluation of BKV-associated allograft function impairment in kidney transplantation.


Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Aloenxertos , Vírus BK/genética , Creatinina , Estudos Transversais , Humanos , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/complicações , Proteômica , Estudos Retrospectivos , Infecções Tumorais por Vírus/complicações
12.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36012435

RESUMO

Kidney transplantation from a donor with latent BKPyV might be the cause of serious complications, such as BK virus-associated nephropathy. The aim of the study was to determine the prevalence of BKPyV infection in donors after brain death (DBDs), to analyse the molecular variation of BKPyV and to compare clinical and inflammation parameters of DBDs infected with various genotypes of BKPyV. BKPyV was investigated in blood and urine samples of 103 DBDs using PCR followed by sequencing and bioinformatic analysis, and the viral load was assessed by qPCR. Clinical parameters, including cellular markers of inflammation were assessed. The results confirm high prevalence of BKPyV (48%),and genotype IV (49%) over genotype I (43%) and the co-infection with genotypes I and IV in 8.2%. Viral load ranged from 102 to 107 copies/mL, with an average of 1.92 × 106 copies/mL. No specific markers for BKPyV infection were detected among the parameters tested. Infection with genotype I may be associated with the adverse impact on thekidney function, while infection with genotype IV was associated with the anemia Not only the viral load but also the genotype of BKPyV may have an impact on the course of infection.


Assuntos
Vírus BK , Nefropatias , Infecções por Polyomavirus , Vírus BK/genética , Morte Encefálica , Genótipo , Humanos , Inflamação , Doadores de Tecidos , Transplantados
13.
J Immunol Res ; 2022: 6934744, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35958876

RESUMO

BK virus-associated nephropathy (BKVN) remains a major infectious complication due to powerful immunosuppression in kidney transplant recipients, and its histologic appearance can mimic rejection, leading to diagnostic and treatment dilemmas thus molecular diagnostic methods would be beneficial. We collected gene expression profiles of 169 kidney biopsies taken from BKVN, rejection, and stable functioning allografts, based on single sample gene set enrichment analysis and random forest algorithm, and three hallmark activities associated with DNA damage and proliferation were found to be relatively specific in BKVN. Subsequently, weighted gene co-expression network analysis and support vector machines (SVM) algorithm identified RBBP7 as a robust and promising biomarker with high accuracy in both training and validation cohorts (AUC =0.938, 0.977, respectively). Besides, potential drugs for BKVN treatment such as mepacrine were discovered, which may contribute to targeted antiviral therapy and effective patient management rather than simply reducing the doses of immunosuppressive agents in clinical practice. RBBP7 (retinoblastoma binding protein 7) serves as component of serval complexes that regulate chromatin metabolism and functions in affecting DNA replication and controlling cell proliferation. In this research, upregulation of RBBP7 was found to be associated with the higher infiltration of CD8 naïve T, iTreg, and neutrophil cells and the lower amounts of Th1, central memory T, NKT, CD8 T, and dendritic cells. Moreover, the infiltration of Th1, Th17, and NKT cells was steadily different between BKVN and rejection allografts through immune cell assessment. In conclusion, we identified and verified RBBP7 as a molecular biomarker for BKVN diagnosis, which demonstrated great distinguishing ability with allograft rejection and would support clinical decision-making.


Assuntos
Vírus BK , Nefropatias , Transplante de Rim , Nefrite Intersticial , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Vírus BK/genética , Rejeição de Enxerto/diagnóstico , Humanos , Nefropatias/diagnóstico , Nefropatias/etiologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/diagnóstico , Proteína 7 de Ligação ao Retinoblastoma , Infecções Tumorais por Vírus/diagnóstico
14.
Virol J ; 19(1): 131, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941650

RESUMO

BACKGROUND AND AIMS: The John Cunningham virus (JCV) is the established etiological agent of the polyomavirus-associated nephropathy among renal transplant recipients. In the present study, we aimed to determine the probable predictive factors leading to JCV replication in renal transplant patients. MATERIAL AND METHODS: Urine and plasma samples were collected from a total of 120 consecutive renal-transplanted patients without preliminary screening from Jan 2018 to Mar 2019. After DNA extraction, the simultaneous detection and quantification of JCV and BK polyomavirus (BKV) were conducted using a Real-time quantitative PCR method. Moreover, statistical analyses were performed using the statistical software packages, SPSS version 21. RESULTS: The prevalence of JCV viruria and viremia among renal transplant recipients were 26 (21.67%) and 20 (16.67%), respectively. A significant association was observed between the JCV and two risk factors, diabetes mellitus (P = 0.002) and renal stones (P = 0.015). The prevalence of JCV viremia among recipients who were grafted near time to sampling was significantly higher (P = 0.02). There was a statistically significant coexistence between BK and JC viruses among our patients (P = 0.029). The frequency of JCV viruria in males was reported almost three times more than in females (P = 0.005). The JCV shedding in urine was significantly associated with the tropical steroids like prednisolone acetate, which have been the standard regimen (P = 0.039). Multivariable analysis revealed duration of post-transplantation (OR, 0.89; P = 0.038), diabetes mellitus (OR, 1.85; P = 0.034), and renal stone (OR 1.10; P = 0.04) as independent risk factors associated with JCV viremia post-renal transplantation. CONCLUSION: It seems that the discovery of potential risk factors, including immunological and non-immunological elements, may offer a possible preventive or therapeutic approach in the JCV disease episodes. The results of this study may also help clarify the probable clinical risk factors involving in progressive multifocal leukoencephalopathy development.


Assuntos
Vírus BK , Vírus JC , Nefropatias , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , DNA Viral/genética , Feminino , Humanos , Vírus JC/genética , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Masculino , Transplantados , Viremia/epidemiologia
15.
J Med Virol ; 94(12): 6023-6027, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35927225

RESUMO

BK polyomavirus (BKPyV) is a well-known cause of nephropathy in renal transplant recipients. It has recently received much attention from researchers as a major predisposing factor for various cancers. This study aimed to investigate how BKPyV affected the advancement of papillary thyroid carcinoma (PTC). A total of 1057 samples were tested for BKPyV DNA and RNA, comprising 645 paraffin-embedded PTC biopsy samples (PEBS), 412 fresh biopsy samples (FBS), and 1057 adjacent noncancerous samples. The BKPyV DNA was found in 511 (48.3%) of the specimens, including 347 (84.2%) FBS and 164 (25.4%) PEBS. The mean BKPyV copy number was significantly lower in patients with PEBS (0.5 × 10-4 ± 0.1 × 10-4 copies/cell) than in FBS (1.3 × 10-1 ± 0.2 × 10-1 copies/cell) and non-PTC normal samples (0.3 × 10-5 ± 0.04 × 10-5 copies/cell). The PEBS had lower LT-Ag RNA expression than FBS, and no VP1 gene transcript expression was detected. In conclusion, although our findings indicated the presence of BKPyV in some Iranian PTC patients, more research is needed to corroborate these findings.


Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Neoplasias da Glândula Tireoide , Infecções Tumorais por Vírus , Vírus BK/genética , Humanos , Irã (Geográfico)/epidemiologia , Transplante de Rim/efeitos adversos , RNA , Câncer Papilífero da Tireoide/complicações , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/epidemiologia , Transplantados , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/epidemiologia
16.
Front Immunol ; 13: 929946, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967393

RESUMO

BK polyomavirus (BKPyV) often reactivates after kidney transplantation, causing BKPyV-associated nephropathy (BKPyVAN) in 1%-10% of cases with a potential detrimental effect on allograft survival. Kidney transplant recipients are regularly screened for BKPyV DNA in plasma. As this strategy may not always reduce the risk of BKPyVAN, other predictive markers are needed. To evaluate the role of pretransplant BKPyV-specific antibody, 210 kidney transplant recipients and 130 donors were screened for BKPyV DNA and BKPyV-specific antibodies. We found that the donor BKPyV immunoglobulin G (IgG) seroprevalence and antibody level were strongly associated with BKPyV-DNAemia and BKPyVAN, although multivariant analysis found the presence of anti-BKPyV-specific antibodies as a predictive factor only for BKPyV-DNAemia. The pretransplant recipient status had no effect on posttransplant BKPyV-DNAemia and BKVAN. BKPyV IgG levels remained stable in BKPyV-negative recipients during 1-year follow-up, while a considerable increase was observed in BKPyV-positive patients. The presence of anti-BKPyV-specific antibodies in kidney allograft donors is a good and reliable predictive marker for posttransplant BKPyV replication with relevance to risk stratification in transplant recipients.


Assuntos
Vírus BK , Transplante de Rim , Nefrite Intersticial , Infecções por Polyomavirus , Humanos , Imunoglobulina G , Transplante de Rim/efeitos adversos , Nefrite Intersticial/complicações , Estudos Soroepidemiológicos
17.
J Clin Microbiol ; 60(9): e0055522, 2022 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-35997500

RESUMO

Quantitative testing of BK virus (BKPyV) nucleic acid has become the standard of care in transplant patients. While the relationship between interassay harmonization and commutability has been well characterized for other transplant-related viruses, it has been less well studied for BKPyV, particularly regarding differences in commutability between matrices. Here, interassay agreement was evaluated among six real-time nucleic acid amplification tests (NAATs) and one digital PCR (dPCR) BKPyV assay. Differences in the commutability of three quantitative standards was examined across all assays using a variety of statistical approaches. Panels, including 40 samples each of plasma and urine samples previously positive for BKPyV, together with one previously negative plasma sample and four previously negative urine samples, were tested using all assays, with each real-time NAAT utilizing its usual quantitative calibrators. Serial dilutions of WHO, National Institute for Standards and Technology (NIST), and commercially produced (Exact/Bio-Rad) reference materials were also run by each assay as unknowns. The agreement of the clinical sample values was assessed as a group and in a pairwise manner. The commutability was estimated using both relativistic and quantitative means. The quantitative agreement across assays in the urine samples was within a single log10 unit across all assays, while the results from the plasma samples varied by 2 to 3 log10 IU/mL. The commutability showed a similar disparity between the matrices. Recalibration using international standards diminished the resulting discrepancies in some but not all cases. Differences in the sample matrix can affect the commutability and interassay agreement of quantitative BKPyV assays. Differences in commutability between matrices may largely be due to factors other than those such as amplicon size, previously described as important in the case of cytomegalovirus. Continued efforts to standardize viral load measurements must address multiple sources of variability and account for differences in assay systems, quantitative standards, and sample matrices.


Assuntos
Vírus BK , Ácidos Nucleicos , Vírus BK/genética , Citomegalovirus , Humanos , Padrões de Referência , Carga Viral/métodos
18.
J Immunol Methods ; 509: 113341, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36027931

RESUMO

BACKGROUND: BK virus nephropathy (BKVN) is a frequent and serious post-transplant complication and undermines realization of the full benefits of kidney transplantation. We developed a Bak amplicon-based standard curve for absolute quantification of BKV VP1 mRNA copy number in the real time quantitative PCR (RT-qPCR) assay and investigated the performance characteristics of this novel assay. METHODS: We determined analytical specificity, sensitivity, and precision of our 73 bp mouse Bak amplicon based standard curve for absolute quantification of BKV VP1 mRNA in RT-qPCR assays. The diagnostic accuracy of the Bak standard curve in the RT-qPCR assay for the noninvasive diagnosis of BKVN in human kidney allograft recipients was investigated by quantification of BKV VP1 mRNA copy number in 192 urine samples matched to 192 kidney allograft biopsies from 155 unique kidney allograft recipients. Intraclass correlation coefficients (ICC) were calculated for the threshold cycles (Ct) and BKV VP1 mRNA copy number observed in the RT-qPCR assay with the Bak standard curve or the BKV standard curve. RESULTS: Performance characteristics of the Bak amplicon-based RT-qPCR assay were exceptional with a slope of -3.291, Y-intercept of 38.60, R2 value of 1.00, efficiency of 101% and error of 0.014. Amplification was specific for the Bak amplicon. Intra assay standard deviation (SD) was 0.08 or less and inter assay SD was 0.11 or less for 31 cycles or less of amplification of the Bak amplicon. Receiver operating characteristic (ROC) curve analysis of BKV VP1 mRNA copy number in 192 biopsy matched urines yielded an area under the ROC of 0.982 (95% CI, 0.964 to 0.999, P < 0.0001) for discriminating patients with BKVN biopsies from patients without BKVN biopsies. The striking identity in the measurement of BKV VP1 mRNA copy numbers in the Bak amplicon-based RT-qPCR assay and in the BKV amplicon-based RT-qPCR assay was shown by an ICC of 1.00 when the Cts were compared, and an ICC of 0.99 when the log10 BKV VP1 mRNA copy numbers were compared. CONCLUSIONS: Bak standard curve for absolute quantification of BKV VP1 mRNA copy number in the RT-qPCR assay demonstrated high efficiency, short and long-term precision and analytical specificity. BKVN was diagnosed with high accuracy. Our new findings, viewed in the light of our earlier demonstration that absolute quantification of a panel of mRNAs encoding immunoregulatory proteins is feasible with the Bak amplicon-based RT-qPCR assays, suggest that the Bak standard curve could serve as a universal calibrator for absolute quantification of transcripts in RT-qPCR assays and help reduce the workload, costs and eliminate contamination of genes of interest by repeated amplification of gene specific standard curves.


Assuntos
Vírus BK , Infecções por Polyomavirus , Aloenxertos/química , Animais , Vírus BK/genética , DNA Viral , Humanos , Rim/química , Camundongos , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/urina , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
19.
Int J Mol Sci ; 23(13)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35806242

RESUMO

BACKGROUND: Bkv-miR-B1-5p is a viral micro-RNA (miRNA) specifically produced during BK polyomavirus (BKPyV) replication. Recent studies have suggested using bkv-miR-B1-5p as a biomarker to monitor viral infection and predict complications in kidney transplant patients. To identify the technical limitations of this miRNA quantification in biological samples, knowledge of its stability and distribution in the extracellular compartment is necessary. Moreover, a proof of concept for using bkv-miR-B1-5p as a biomarker of active replication in chronic infection is still missing in the published literature. METHODS: The stability of bkv-miR-B1-5p was evaluated in samples derived from cell cultures and in urine from BKPyV-infected kidney transplant recipients. The miRNA was quantified in different fractions of the extracellular compartment, including exosomes, and protein binding was evaluated. Finally, we developed an in vitro model for chronic culture of BKPyV clinical isolates to observe changes in the bkv-miR-B1-5p level during persistent infections. RESULTS: Bkv-miR-B1-5p is a stable biomarker in samples from humans and in vitro experiments. Marginally associated with the exosomes, most of the circulating bkv-miR-B1-5p is bound to proteins, especially Ago2, so the miRNA quantification does not require specific exosome isolation. The bkv-miR-B1-5p level is predictable of viral infectivity, which makes it a potential specific biomarker of active BKPyV replication after kidney transplantation.


Assuntos
Vírus BK , Nefropatias , Transplante de Rim , MicroRNAs , Infecções por Polyomavirus , Vírus BK/genética , Biomarcadores , Humanos , Nefropatias/etiologia , Transplante de Rim/efeitos adversos , MicroRNAs/genética , Infecções por Polyomavirus/genética , RNA Viral/genética , Replicação Viral
20.
Viruses ; 14(8)2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35893681

RESUMO

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.


Assuntos
Vírus BK , Transplante de Rim , Infecções por Polyomavirus , Infecções Tumorais por Vírus , Vírus BK/fisiologia , Humanos , Transplante de Rim/efeitos adversos , Viremia
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