RESUMEN
AIMS: This study aims to evaluate the presence of EBV, HCMV, and BKV genomic sequences in the plasma samples (active infection/viremia) of kidney transplant recipients suspected of rejection and to investigate host and risk factors related to the activation of these viruses in these patients. METHODS: In this cross-sectional single-center study, plasma samples were collected from 98 suspected kidney transplant rejection patients at Labafinejad Hospital, Tehran, Iran, between December 2022 and June 2023. Quantitative real-time PCR assays for HCMV, EBV, and BK were performed using GeneProof Real-time PCR kits. ROC curve analysis was used to determine the viral load cutoff point for each virus. FINDINGS: HCMV active viremia was detected in 18 (18.36%) recipients, EBV active viremia in 7 (7.14%), and BKV active viremia in 5 (5.10%). ROC results indicated viral load cutoff points of 778, 661, and 457 points for HCMV, EBV, and BKV, respectively. The duration of time after transplantation significantly differed between active viremia and no viremia groups (120.5 vs. 46 months, P = 0.014). In the BKV active viremia group, the increase in creatinine compared to baseline creatinine was significantly higher than in the no viremia group (2.7 vs. 0.8, P = 0.017). The odds ratio of HCMV active viremia in patients taking tacrolimus was 2.84 times higher, and the odds of HCMV active viremia in patients taking antithymocyte globulin was 3.01 times higher than in patients not taking these drugs. CONCLUSION: Rapid and timely diagnosis of viral active infections in kidney transplant patients is crucial for effective disease management and implementation of appropriate treatment strategies. Identifying potential risk factors, including host and treatment-related factors that influence transplantation, can facilitate the development of suitable preventive strategies.
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Virus BK , Infecciones por Citomegalovirus , Citomegalovirus , Infecciones por Virus de Epstein-Barr , Rechazo de Injerto , Herpesvirus Humano 4 , Trasplante de Riñón , Infecciones por Polyomavirus , Carga Viral , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Virus BK/aislamiento & purificación , Virus BK/genética , Adulto , Estudios Transversales , Infecciones por Polyomavirus/virología , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Citomegalovirus/virología , Citomegalovirus/aislamiento & purificación , Citomegalovirus/genética , Rechazo de Injerto/virología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Irán/epidemiología , Factores de Riesgo , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/sangre , Anciano , Adulto Joven , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
Despite the high prevalence of BK polyomavirus (BKPyV) and the associated risk for BKPyV-associated nephropathy (BKPyVAN) in kidney transplant (KTX) recipients, many details on viral processes such as replication, maturation, assembly and virion release from host cells have not been fully elucidated. VP1 is a polyomavirus-specific protein that is expressed in the late phase of its replicative cycle with important functions in virion assembly and infectious particle release. This study investigated the localization and time-dependent changes in the distribution of VP1-positive viral particles and their association within the spectrum of differing cell morphologies that are observed in the urine of KTX patients upon active BKPyV infection. We found highly differing recognition patterns of two anti-VP1 antibodies with respect to intracellular and extracellular VP1 localization, pointing towards independent binding sites that were seemingly associated with differing stages of virion maturation. Cells originating from single clones were stably cultured out of the urine sediment of KTX recipients with suspected BKPyVAN. The cell morphology, polyploidy, virus replication and protein production were investigated by confocal microscopy using both a monoclonal (mAb 4942) and a polyclonal rabbit anti-VP1-specific antibody (RantiVP1 Ab). Immunoblotting was performed to investigate changes in the VP1 protein. Both antibodies visualized VP1 and the mAb 4942 recognized VP1 in cytoplasmic vesicles exhibiting idiomorphic sizes when released from the cells. In contrast, the polyclonal antibody detected VP1 within the nucleus and in cytoplasm in colocalization with the endoplasmic reticulum marker CNX. At the nuclear rim, VP1 was recognized by both antibodies. Immunoblotting revealed two smaller versions of VP1 in urinary decoy cell extracts, potentially from different translation start sites as evaluated by in silico analysis. Oxford Nanopore sequencing showed integration of BKPyV DNA in chromosomes 3, 4 and 7 in one of the five tested primary cell lines which produced high viral copies throughout four passages before transcending into senescence. The different staining with two VP1-specific antibodies emphasizes the modification of VP1 during the process of virus maturation and cellular exit. The integration of BKPyV into the human genome leads to high virus production; however, this alone does not transform the cell line into a permanently cycling and indefinitely replicating one.
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Virus BK , Vesículas Extracelulares , Infecciones por Polyomavirus , Esparcimiento de Virus , Virus BK/fisiología , Virus BK/metabolismo , Virus BK/genética , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/virología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/metabolismo , Replicación Viral , Trasplante de Riñón , Virión/metabolismo , Proteínas de la Cápside/metabolismo , Proteínas de la Cápside/genética , Núcleo Celular/metabolismo , Ensamble de Virus , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/metabolismo , Transformación Celular Viral , Masculino , AnimalesRESUMEN
Renal transplantation is one of the primary approaches for curing end-stage kidney disease. With advancements in immunosuppressive agents, the short-term and long-term survival rates of transplanted kidneys have significantly improved. However, infections associated with potent immunosuppression have remained a persistent challenge. Among them, BK virus (BKV) reactivation following renal transplantation leading to BK virus-associated nephropathy (BKVAN) is a major cause of graft dysfunction. However, we still face significant challenges in understanding the pathogenesis, prevention, diagnosis, and treatment of BKVAN. These challenges include: 1. The mechanism of BKV reactivation under immunosuppressive conditions has not been well elucidated, leading to difficulties in breakthroughs in clinical research on prevention, diagnosis, and treatment. 2. Lack of proper identification of high-risk individuals, and effective personalized clinical management strategies. 3.Lack of early and sensitive diagnostic markers. 4. Lack of direct and effective treatment options due to the absence of specific antiviral drugs. The purpose of this review is to summarize the current status and cutting-edge advancements in BKV-related research, providing new methods and perspectives to address future research challenges.
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Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Animales , Activación Viral , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Antivirales/uso terapéuticoRESUMEN
BACKGROUND: Overall, 20-30% of all cancers are estimated to be linked to infectious agents. Polyomaviruses are oncogenic cause in rodent models, readily transform their cells, and cause chromosomal instability in animal and human cells in-vitro. Some reports have indicated the presence of JCPyV and BKPyV in some human tumors. The JCPyV and BKPyV genome encodes some transforming proteins such as LT-Ag. Thus, these viruses could cause or promote some neoplasia, such as lymphomas, pancreatic, prostate, and colorectal cancers. Colorectal cancer (CRC) is the third most common cancer in the world. Risk factors for developing CRC are associated with personal features or habits, such as age, lifestyle, and gut microbiota. MATERIALS AND METHODS: In this study, we examined the prevalence of JCPyV and BKPyV in the 23 fecal samples of CRC patients and 24 healthy samples (control group). Virus DNA was extracted by a Favorgen DNA extraction kit. The large T antigen of JCPyV and VP1 of BKPyV were investigated by optimized multiplex PCR. RESULTS: One of the samples was positive for the JCPyV (4.3%), while in the samples of healthy individuals, the JCPyV was negative. Also, positive results for BKPyV PCR were obtained for five cases (21.7%) in the samples of the CRC group and one case (4.1%) in healthy individuals. CONCLUSION: The result showed no direct correlation between tumorigenesis and polyomavirus infections in CRC development. However, the exact role of BKPyV and JCPyV is still controversial and needs further study with larger sample size.
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Virus BK , Neoplasias Colorrectales , Virus JC , Reacción en Cadena de la Polimerasa , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/virología , Virus BK/genética , Virus BK/aislamiento & purificación , Virus JC/genética , Virus JC/aislamiento & purificación , Masculino , Persona de Mediana Edad , Femenino , Anciano , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/virología , Adulto , Heces/virologíaAsunto(s)
Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Guías de Práctica Clínica como Asunto , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/patogenicidad , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/diagnóstico , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/virología , Consenso , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Antivirales/uso terapéuticoAsunto(s)
Corticoesteroides , Virus BK , Inmunosupresores , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Virus BK/inmunología , Virus BK/patogenicidad , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Corticoesteroides/uso terapéutico , Trasplante de Riñón , Resultado del Tratamiento , Factores de RiesgoRESUMEN
The BK polyomavirus (BKPyV) is a small DNA non-enveloped virus whose infection is asymptomatic in most of the world's adult population. However, in cases of immunosuppression, the reactivation of the virus can cause various complications, and in particular, nephropathies in kidney transplant recipients or hemorrhagic cystitis in bone marrow transplant recipients. Recently, it was demonstrated that BKPyV virions can use extracellular vesicles to collectively traffic in and out of cells, thus exiting producing cells without cell lysis and entering target cells by diversified entry routes. By a comparison to other naked viruses, we investigated the possibility that BKPyV virions recruit the Endosomal-Sorting Complexes Required for Transport (ESCRT) machinery through late domains in order to hijack extracellular vesicles. We identified a single potential late domain in the BKPyV structural proteins, a YPX3L motif in the VP1 protein, and used pseudovirions to study the effect of point mutations found in a BKPyV clinical isolate or known to ablate the interaction of such a domain with the ESCRT machinery. Our results suggest that this domain is not involved in BKPyV association with extracellular vesicles but is crucial for capsomere interaction and thus viral particle assembly.
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Secuencias de Aminoácidos , Virus BK , Proteínas de la Cápside , Vesículas Extracelulares , Virión , Ensamble de Virus , Virus BK/genética , Virus BK/fisiología , Virus BK/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/virología , Humanos , Proteínas de la Cápside/metabolismo , Proteínas de la Cápside/genética , Proteínas de la Cápside/química , Virión/metabolismo , Virión/genética , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Células HEK293RESUMEN
BACKGROUND: BK virus nephropathy (BKVN) is a significant complication in kidney transplant recipients, resulting in graft dysfunction and potentially leading to graft loss. This study aims to investigate the incidence and outcomes of BKVN in kidney transplant recipients receiving steroid-free maintenance immunosuppression in a Latin -American cohort. METHODS: Case series study of BKVN among kidney transplant recipients who underwent transplantation between 2008 and 2023. The primary outcome was graft loss caused by BKVN, excluding death with function. Secondary outcomes included graft function and acute rejection episodes. The statistical analysis involved descriptive statistics and the Kaplan-Meier (K-M) method to plot the overall probabilities of not initiating dialysis. RESULTS: During the 15-year period, 2236 kidney transplants were performed, BKVN was histologically diagnosed in 38 kidney recipients and 33 cases were analyzed. Median age was 50 years and men were 48.5% of patients. A total of 45.4% of BKVN occurred within the first 12 months of transplant. The incidence of BKVN was 1.6% but it varied by era. The rate of graft loss was 75.7% (25 cases). The K-M graft survival probability at 6 months and 12 months after diagnosis of BKVN was 38.3% (95% CI 24.7-59.4) and 22.3% (95% CI 11.7-42.8), respectively. CONCLUSION: BKVN affected 1.6% of transplant recipients and it was associated with high-rate of graft loss. We observed that significant graft disfunction at the time of diagnosis resulted in worse outcomes with a reduced probability of graft survival.
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Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Incidencia , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/inmunología , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/inmunología , Adulto , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Supervivencia de Injerto , Enfermedades Renales/cirugía , Enfermedades Renales/epidemiología , Terapia de Inmunosupresión , Rechazo de Injerto/inmunología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BK polyomavirus-associated nephropathy (PyVAN) remains a serious threat for renal dysfunction and graft loss in kidney transplant recipients on immunosuppressive medication. In this study, a pilot cohort of 16 kidney transplant recipients were recruited of which eight were with significant BKPV viremia (sBKPV) and the rest were controls matched to age, gender, and time since transplant. We used next-generation sequencing to characterize the miRNA expression profile in urine samples. In total, the expression of 8 miRNAs (miR-16-5p,miR-200c-3p,bkv-miR-B1-3p,let-7b-3p,miR-1269b,bkv-miR-B1-5p,miR-193a-3p,miR-944) were upregulated whereas 21miRNAs (miR-134-5p,miR-4724-5p,miR-127-3p,miR-6500-3p,miR-507,miR-378b,miR-3911,miR-211-5p,miR-486-5p,miR-143-3p,miR-3195,miR-1307-5p,miR-29a-5p,miR-378f,miR-12136,miR-378g,miR-144-3p,miR-378a-3p,let-7i-5p,miR-204-5p,miR-146a-5p) were downregulated with fold change > 2. We found that bkv-miR-B1-5p and bkv-miR-B1-3p have 19-fold and 5-fold higher expression values in BKPV viremia patient samples, respectively. A few earlier studies have reported BKV miRNA in urine and serum samples using the RT- PCR from PyVAN patients. Our results corroborated findings from earlier studies and highlighted the need for additional evaluation of the role of sequencing approaches for monitoring BKPV specific and host miRNAs to better understand the viral reactivation and disease pathogenesis.
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Virus BK , Trasplante de Riñón , MicroARNs , Infecciones por Polyomavirus , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/genética , Virus BK/aislamiento & purificación , MicroARNs/genética , MicroARNs/sangre , Infecciones por Polyomavirus/virología , Masculino , Persona de Mediana Edad , Femenino , Adulto , Infecciones Tumorales por Virus/virología , Proyectos PilotoRESUMEN
Since the significance of viral infections in children and adolescents with nephrotic syndrome (NS) is yet to be defined, this study intended to estimate the occurrence, pattern, and outcomes of some DNA viral infections in children with NS. METHODS: A prospective study was conducted to determine the genome identification of the viruses Epstein-Barr (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6 type A and type B) and 7 (HHV-7), polyomavirus (BKV), and human adenovirus (HAdV) in plasma and urine samples of pediatric patients with NS. RESULTS: A total of 35 patients aged 1 to 18 years with NS and under immunosuppressant drugs participated in the study. Plasma and urine samples were collected at regular intervals during a median follow-up of 266 days (range 133-595), and DNA was analyzed to detect the selected DNA viruses. Eleven patients (31.4%) had active virus infections, and patterns were classified as coinfection, recurrent, and consecutive. Of these, six patients (54.5%) presented viral coinfection, six (54.5%) viral recurrence, and seven patients (63.3%) had viral consecutive infection. Ten of the eleven patients with active infection had a proteinuria relapse (91%) and eight (72.7%) were hospitalized (p = 0.0022). Active HCMV infection was the most frequent infection and was observed in six patients (54.5%), three of the eleven patients (27.2%) had suspected HCMV disease in the gastrointestinal tract, and one had HHV-7 coinfection. The frequency of other infections was: 9% for HHV-6, 45.5% for BKV, 27.3% for HHV-7, 18.2% for EBV, and 18.2% for HAdV. CONCLUSION: viral infections, especially HCMV, can be an important cause of morbidity and nephrotic syndrome relapse in children.
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Virus BK , Síndrome Nefrótico , Humanos , Síndrome Nefrótico/virología , Síndrome Nefrótico/complicaciones , Adolescente , Niño , Masculino , Femenino , Preescolar , Virus BK/genética , Virus BK/aislamiento & purificación , Lactante , Estudios Prospectivos , ADN Viral/genética , Herpesviridae/genética , Herpesviridae/clasificación , Herpesviridae/aislamiento & purificación , Coinfección/virología , Infecciones por Herpesviridae/virología , Adenoviridae/genética , Adenoviridae/aislamiento & purificación , Adenoviridae/clasificaciónRESUMEN
We present a challenging clinical case of a 68-year-old female kidney transplant recipient who had a complicated posttransplant course marked by borderline T-cell-mediated rejection and BK virus nephropathy. The treatment for borderline rejection with steroids resulted in overimmunosuppression, and the patient acquired cytomegalovirus infection manifesting as colitis and SARS-CoV-2 infection. This progressed rapidly to collapsing glomerulopathy and allograft failure. This study also highlights the challenges in surveillance with donor-derived cell-free DNA in the setting of allograft injury by multiple viral infections.
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Virus BK , COVID-19 , Infecciones por Citomegalovirus , Rechazo de Injerto , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Femenino , COVID-19/complicaciones , COVID-19/inmunología , COVID-19/diagnóstico , Anciano , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/virología , Infecciones por Citomegalovirus/tratamiento farmacológico , Rechazo de Injerto/inmunología , Rechazo de Injerto/virología , Virus BK/patogenicidad , Virus BK/inmunología , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/diagnóstico , Progresión de la Enfermedad , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , CoinfecciónRESUMEN
Guidelines recommend monitoring of Epstein-Barr virus (EBV) and BK virus (BKV) in solid organ and hematopoietic stem cell transplant patients. The majority of quantitative DNA testing for EBV and BKV employs unstandardized individual laboratory-developed testing solutions (LDTs), with implications for accuracy, reproducibility, and comparability between laboratories. The performance of the cobas EBV and cobas BKV assays was assessed across five laboratories, using the World Health Organization International Standards (WHO IS) for EBV and BKV, and the National Institute of Standards and Technology Quantitative Standard for BKV, and results were compared with the LDTs in use at the time. Methods were also compared using locally sourced clinical specimens. Variation was high when laboratories reported EBV or BKV DNA values using LDTs, where quantitative values were observed to differ by up to 1.5 log10 unit/mL between sites. Conversely, results from the cobas EBV and cobas BKV assays were accurate and reproducible across sites and on different testing days. Adjustment of LDTs using the international standards led to closer alignment between the assays; however, day-to-day reproducibility of LDTs remained high. In addition, BKV continued to show bias, indicating challenges with the commutability of the BKV International Standard. The cobas EBV and cobas BKV assays are automated, aligned to the WHO IS, and have the potential to reduce the variability in viral load testing introduced by differences in LDTs. Standardization of reporting values may eventually allow different centers to compare data to allow clinical decision thresholds to be established supporting improvements in patient management.IMPORTANCEThe application of center-specific cut-offs for clinical decisions and the variability of LDTs often hinder interpretation; thus, the findings reported here support the need for standardization in the field of post-transplant monitoring of EBV and BKV to improve patient management. Alongside the choice of assay, it is also important to consider which standard to use when deciding upon a testing methodology. This is a call to action for standardization, as treatment for EBV and BKV is driven by viral load test results, and the more accurate and comparable the test results are across institutions, the more informed and better the treatment decisions can be.
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Virus BK , Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Carga Viral , Humanos , Virus BK/aislamiento & purificación , Virus BK/genética , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Carga Viral/normas , Carga Viral/métodos , Reproducibilidad de los Resultados , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/virología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/virología , ADN Viral/genética , ADN Viral/análisis , Técnicas de Diagnóstico Molecular/normas , Técnicas de Diagnóstico Molecular/métodos , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/virologíaRESUMEN
Polyomaviruses BK (BKPyV) and JC (JCPyV), belonging to the Polyomaviridae, are responsible for human pathologies. In kidney transplant recipients, BKPyV replication can lead to irreversible nephron damage whereas JCPyV replication remains asymptomatic. Concomitant replication is rare and potential competition between the infections has been described. The aim of this retrospective case-control study was to describe the molecular epidemiology and risk factors associated with BKPyV and JCPyV replication in a cohort of kidney transplant recipients. In total, 655 urine samples from 460 patients were tested for BKPyV and JCPyV DNA. Positive samples were submitted to strain genotyping. Demographic and clinical characteristics were also compared. Isolated JCPyV and BKPyV was found in 16.5% and 23.3% of patients, respectively; co-replication was rare (3.9%). BKPyV strains Ib-2, Ib-1, and IVc-2 were the most prevalent. JCPyV strains mostly belonged to genotypes 4 and 1B. During follow-up, JCPyV shedding significantly reduced the risk of BKPyV DNAuria, with an odds ratio of 0.57 (95% confidence interval: 0.35-0.99), and was associated with better prognosis than BKPyV replication, based on the estimated glomerular filtration rate. Molecular epidemiology of BKPyV and JCPyV strains in our region was similar to previous studies. This study suggests that JCPyV is benign and appears to limit damaging BKPyV replication. JCPyV DNAuria screening could thus be a useful strategy to predict BKPyV-related outcomes.
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Virus BK , Genotipo , Virus JC , Trasplante de Riñón , Epidemiología Molecular , Infecciones por Polyomavirus , Humanos , Virus BK/genética , Virus BK/aislamiento & purificación , Infecciones por Polyomavirus/epidemiología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/orina , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Virus JC/genética , Virus JC/aislamiento & purificación , Estudios de Casos y Controles , Adulto , Esparcimiento de Virus , Anciano , Receptores de Trasplantes/estadística & datos numéricos , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/orina , ADN Viral/orina , ADN Viral/genética , Aloinjertos/virologíaRESUMEN
BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.
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Virus BK , Inhibidores de la Calcineurina , Inmunosupresores , Trasplante de Riñón , Infecciones por Polyomavirus , Serina-Treonina Quinasas TOR , Tacrolimus , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Inhibidores de la Calcineurina/uso terapéutico , Viremia/tratamiento farmacológico , Infecciones por Polyomavirus/tratamiento farmacológico , Tacrolimus/uso terapéutico , Adulto , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Inmunosupresores/uso terapéutico , Carga Viral/efectos de los fármacos , Resultado del Tratamiento , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/virología , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Sirolimus/uso terapéutico , República de Corea , Estudios Retrospectivos , AncianoRESUMEN
Little is known about the urinary virome and how it interacts with the host, particularly in renal transplant diseases. Using metagenomic sequencing, we characterized the urinary virome of 23 kidney transplant recipients longitudinally (11 BKV+ patients and 12 BKV- patients). We applied linear mixed effects models, PERMANOVA, k-means clustering, and MaAsLin2 algorithms to determine virome signatures associated with post-transplant time, BK viremia status, and patient sex. We found that the richness and alpha diversity of urinary virome were significantly different in renal transplant recipients with BKV+ over time in comparison to BKV- (richness P = 0.012, alpha P < 0.0001). Female BKV- patients had significantly higher virome richness than males (P = 0.0063). Virome beta diversity was significantly different between patients by BKV status (P < 0.001). Additionally, we identified underlying interactions between patient sex and BKV status, in terms of virome beta diversity (P = 0.008). BK polyomavirus infections were primarily of subtypes IA, IB1, and IB2. The non-BK dominant samples clustered into six urinary virome community states. BKV- samples had more anelloviruses than BKV+ samples though this difference was not statistically significant. Lastly, we identified specific viruses, associated with BKV+ and time in our samples. Our results indicate that dynamic alterations in the urinary virome over the post-transplant period in kidney transplant recipients can be shaped by BK viremia and patient sex. These findings advance our fundamental understanding of the urinary virome and support a new line of investigation in renal disease and transplantation. IMPORTANCE: The urinary microbiome is increasingly implicated in renal health and disease. While most research focuses on bacteria communities of the microbiome, factors that influence the urinary virome are not understood. Here, we investigated the urinary virome of 23 adult kidney transplant recipients longitudinally over 14 weeks post-transplant. We show that alterations in the urinary virome are associated with kidney transplant recipients with BK polyomavirus viremia that can lead to BK nephropathy and allograft rejection. By modeling the temporal dynamics post-transplant, we delineated specific profiles of the urinary virome associated with patient sex and urinary community states. These findings reveal fundamental aspects of the urinary virome that can be leveraged to better manage kidney diseases.
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Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Receptores de Trasplantes , Viremia , Viroma , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/aislamiento & purificación , Virus BK/genética , Masculino , Femenino , Infecciones por Polyomavirus/orina , Infecciones por Polyomavirus/virología , Viremia/orina , Persona de Mediana Edad , Adulto , Estudios Longitudinales , Infecciones Tumorales por Virus/orina , Infecciones Tumorales por Virus/virología , Anciano , Factores Sexuales , Orina/virologíaRESUMEN
The BK virus infection is common in the immunocompetent population and is asymptomatic in the majority of cases. However, in renal transplant patients, reactivation and replication can occur, leading to the development of BK virus-associated nephropathy (BKVN), which is associated with renal injury and graft loss. The objective of this case report was to demonstrate a case of BKVN that showed a good response to the use of human immunoglobulin. A 37-year-old man who underwent a second transplant received rabbit-derived antithymocyte human immunoglobulin at a dose of 6 mg/kg intravenously as induction immunosuppressive therapy, and maintenance therapy with tacrolimus, prednisone, and mycophenolate sodium (MFS). At 3 months post-transplant, he presented sustained BK virus viremia (70,000-100,000 copies/mL), leading to a reduction in the dose of MFS and tacrolimus. A biopsy diagnosed BKVN class 2/B2, and viremia increased to over 1 million copies/mL at 22 months, prompting the discontinuation of tacrolimus without response. Intravenous human immunoglobulin (IVIG) was administered at 2 g/kg at 22 months and again at 33 months, with viremia peaking at 2 million copies 3 months later. However, it steadily declined to 5500 copies/mL at 52 months post-transplant. Currently, the only proven therapy for BKVN is the reduction of immunosuppression. However, in patients who do not respond, IVIG is considered as an option, with good results demonstrated in case reports, as shown here. Nevertheless, the data are based on case reports or case series, and the development of controlled clinical trials is necessary for confirmation of the efficacy.
Asunto(s)
Virus BK , Inmunoglobulinas Intravenosas , Inmunosupresores , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Adulto , Inmunoglobulinas Intravenosas/uso terapéutico , Infecciones por Polyomavirus/tratamiento farmacológico , Infecciones por Polyomavirus/virología , Inmunosupresores/uso terapéutico , Inmunosupresores/administración & dosificación , Infecciones Tumorales por Virus/tratamiento farmacológico , Infecciones Tumorales por Virus/virología , Resultado del Tratamiento , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Enfermedades Renales/cirugíaRESUMEN
The strategy for progressive multifocal leukoencephalopathy (PML) in solid organ transplant recipients primarily focuses on reducing immunosuppressive therapy. However, this approach offers limited efficacy and carries a high risk of graft loss. Here, we present the case of a 64-year-old male kidney transplant recipient with a high degree of immunosuppression who developed PML in October 2022. Despite the standard reduction of immunosuppressive therapy, the patient's condition continued to deteriorate, as evidenced by worsening neurological symptoms and increasing JC virus (JCV) DNA levels in cerebrospinal fluid. This prompted the innovative use of BKPyV-virus-specific T cell (BKPyV-VST) therapy, given the genetic similarities between BK and JCVs. Infusion of third-party donor BKPyV-VST resulted in clinical stabilization, a significant reduction in JCV-DNA levels, and the emergence of a JCV-specific T cell response, as observed in enzyme-linked immunospot assays and TCRß sequencing. This represents the first case report of successful third-party BKPyV-VST therapy in a kidney recipient presenting PML, without graft-versus-host disease or graft dysfunction.
Asunto(s)
Virus BK , Trasplante de Riñón , Leucoencefalopatía Multifocal Progresiva , Infecciones por Polyomavirus , Linfocitos T , Humanos , Leucoencefalopatía Multifocal Progresiva/terapia , Leucoencefalopatía Multifocal Progresiva/inmunología , Leucoencefalopatía Multifocal Progresiva/etiología , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Linfocitos T/inmunología , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/terapia , Pronóstico , Virus JC/inmunología , Receptores de Trasplantes , Tratamiento Basado en Trasplante de Células y Tejidos/métodosRESUMEN
OBJECTIVES: BK virus is a major cause of chronic renal allograft failure.Transplant ureteral stent use has been reported as a risk factorfor BK virus infection. Recently, the use of a new type of ureteral stent (Magnetic Black Star) was reported in kidney transplant recipients. The aim ofthis preliminary report was to compare BK virus viremia and viruria occurrence depending on the type of double-J stent (standard versus Magnetic Black Star). MATERIALS AND METHODS: We included all kidney transplants performed in our center from January to December 2022. Each case had double-J stent placement. Indwelling stents were either a 6- or 7-Fr standard double-J stent or a 6-Fr Magnetic Black Star double-J stent. The type of double-J stent was chosen according to the surgeon's preference. A standard BK virus screening protocol was followed during the study period, which consisted of routine polymerase chain reaction examination of plasma and urine samples during monthly follow-ups. RESULTS: We assessed 120 patients without missing data: 92 patients received standard double-J stents and 28 patients received Magnetic Black Star stents. Patients were mostly male in the standard group (70.7%) versus the Magnetic Black Star group (42.9%) (P = .01). ABO- and HLA-incompatible transplant rates were similar in both groups. BK viremia occurrence and BK viruria occurrence were similar between groups at 1 month, 3 months, and 6 months. CONCLUSIONS: This preliminary study showed no differences concerning BKvirus infection depending on the type of double-J stents used during kidney transplant.
Asunto(s)
Virus BK , Trasplante de Riñón , Infecciones por Polyomavirus , Diseño de Prótesis , Stents , Infecciones Tumorales por Virus , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/patogenicidad , Virus BK/inmunología , Masculino , Viremia/diagnóstico , Viremia/virología , Femenino , Persona de Mediana Edad , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/orina , Factores de Riesgo , Resultado del Tratamiento , Adulto , Infecciones Tumorales por Virus/virología , Infecciones Tumorales por Virus/diagnóstico , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/orina , Factores de Tiempo , Datos Preliminares , Estudios RetrospectivosRESUMEN
BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.
Asunto(s)
Virus BK , Rechazo de Injerto , Supervivencia de Injerto , Pruebas de Función Renal , Trasplante de Riñón , Infecciones por Polyomavirus , Infecciones Tumorales por Virus , Viremia , Humanos , Trasplante de Riñón/efectos adversos , Virus BK/inmunología , Virus BK/aislamiento & purificación , Femenino , Masculino , Infecciones por Polyomavirus/inmunología , Infecciones por Polyomavirus/virología , Infecciones por Polyomavirus/complicaciones , Persona de Mediana Edad , Rechazo de Injerto/etiología , Rechazo de Injerto/inmunología , Estudios de Seguimiento , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virología , Viremia/inmunología , Viremia/virología , Pronóstico , Factores de Riesgo , Tasa de Filtración Glomerular , Adulto , Complicaciones Posoperatorias , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Estudios Retrospectivos , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/inmunología , Enfermedades Renales/virología , Enfermedades Renales/inmunología , Enfermedades Renales/cirugía , Receptores de TrasplantesRESUMEN
BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.