BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection.
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SUBMITTER: Shen CL
PROVIDER: S-EPMC7998398 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abstract Introduction BK polyomavirus (BKPyV)‐associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV‐specific immunity is associated with viral containment. This study investigated BKPyV‐specific immunological factors among KT recipients. Methods This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV‐cell‐specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon‐gamma (IFN‐γ)‐producing CD4+ T, CD8+ T, natural killer (NK), and natural killer T (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1). Results In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1‐year cumulative incidence of high‐level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre‐KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077–1.469; p = .004) and %VP1‐specific NK cells (HR, 1.209; 95% CI, 1.055–1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1‐specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05). Conclusion Individuals with nonspecific and VP1‐specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high‐level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV‐specific innate immune surveillance in predicting the occurrence of BKPyVAN. Initial levels and post‐KT increases in NK, NKT, and VP1‐specific NK cells were greater in KT recipients who exhibited BKPyV DNAuria within 1 year after KT. BKPyV‐specific NK‐ and NKT‐cell immune surveillance could be used to identify patients at risk for post‐transplant viral reactivation.
| S-EPMC10461421 | biostudies-literature
Project description:Kidney transplant injury processes are associated with molecular changes in renal tissue, primarily related to immune cell activation and infiltration. How these processes are reflected by molecular alterations in circulating immune cells is poorly understood. We performed RNA-sequencing on 384 biobanked blood samples from four transplant centers, taken at time of a kidney allograft biopsy, selected for their phenotype (acute T cell- and antibody-mediated rejection, polyomavirus-associated nephropathy, and control). We performed differential expression analysis and pathway analysis per phenotype. In peripheral blood, differentially expressed genes in rejection vs. no rejection samples demonstrated upregulation of glucocorticoid receptor and NOD-like receptor signaling pathways. Pathways enriched in antibody-mediated rejection were strongly immune-specific, whereas pathways enriched in T cell-mediated rejection were less immune related. Differentially expressed genes in polyoma viremia and polyomavirus-associated nephropathy were similar and demonstrated upregulation of mitochondrial dysfunction and interferon signaling pathways. Our results highlight the immune activation pathways in peripheral blood leukocytes at time of antibody-mediated rejection and polyomavirus nephropathy and provide a framework for future therapeutic interventions.
2022-05-06 | GSE175718 | GEO
Project description:BackgroundBK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is a major threat for kidney transplant recipients (KTRs). The role of specific BKPyV genotypes/serotypes in development of BKPyVAN is poorly understood. Pretransplantation serotyping of kidney donors and recipients and posttransplantation genotyping of viremic recipients, could reveal the clinical relevance of specific BKPyV variants.MethodsA retrospective cohort of 386 living kidney donor-recipient pairs was serotyped before transplantation against BKPyV genotype I-IV viral capsid protein 1 antigen, using a novel BKPyV serotyping assay. Replicating BKPyV isolates in viremic KTRs after transplantation were genotyped using real-time polymerase chain reaction and confirmed by means of sequencing. BKPyV serotype and genotype data were used to determine the source of infection and analyze the risk of viremia and BKPyVAN.ResultsDonor and recipient BKPyV genotype and serotype distribution was dominated by genotype I (>80%), especially Ib, over II, III and IV. Donor serotype was significantly correlated with the replicating genotype in viremic KTRs (P < .001). Individual donor and recipient serotype, serotype (mis)matching and the recipient replicating BKPyV genotype were not associated with development of viremia or BKPyVAN after transplantation.ConclusionsBKPyV donor and recipient serotyping and genotyping indicates the donor origin of replicating BKPyV in viremic KTRs but provides no evidence for BKPyV genotype-specific virulence.
| S-EPMC6440680 | biostudies-literature
Project description:Genetic determinants of BK polyomavirus infection after kidney transplantation remain poorly investigated. We assessed the potential impact of 13 different single nucleotide polymorphisms within genes mainly involved in innate immune responses on the risk of BKPyV viremia in 204 KT recipients. After a median follow-up of 1121.5 days, the cumulative incidence of any-level BKPyV viremia was 24.5% (50/204). There was a significant association between the minor T allele of TLR3 (rs3775291) SNP and the development of BKPyV viremia (adjusted hazard ratio [aHR]: 2.16; 95% confidence interval [CI]: 1.08-4.30; P value = 0.029), whereas the minor G allele of CD209 (rs4804803) SNP exerted a protective role (aHR: 0.54; 95% CI: 0.29-1.00; P value = 0.050). A higher incidence of BKPyV viremia was also observed for the minor G allele of IL10 (rs1800872) SNP, although the absence of BKPyV events among homozygotes for the reference allele prevented multivariable analysis. The BKPyV viremia-free survival rate decreased with the increasing number of unfavorable genotypes (100% [no unfavorable genotypes], 85.4% [1 genotype], 70.9% [2 genotypes], 52.5% [3 genotypes]; P value = 0.008). In conclusion, SNPs in TLR3, CD209 and IL10 genes play a role in modulating the susceptibility to any-level BKPyV viremia among KT recipients.
| S-EPMC9255529 | biostudies-literature
Project description:BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy.
| S-EPMC3325208 | biostudies-literature
Project description:IntroductionBK polyomavirus-associated nephropathy (BKPyVAN) is associated with graft dysfunction and loss; however, knowledge of immunosuppression reduction strategies and long-term graft, and patient outcomes across the disease spectrum is lacking.MethodsThis cohort study included 14,697 kidney transplant recipients in Australia and New Zealand (2005-2019), followed for 91,306 person years.ResultsBKPyVAN occurred in 460 recipients (3%) at a median posttransplant time of 4.8 months (interquartile range, 3.1-10.8). Graft loss (35% vs. 21%, P < 0.001), rejection (42% vs. 25%, P < 0.001), and death (18% vs. 13%, P = 0.002) were more common in the BKPyVAN group. The most frequent changes in immunosuppression after BKPyVAN were reduction (≤50%) in tacrolimus (172, 51%) and mycophenolate doses (134, 40%), followed by the conversion of mycophenolate to leflunomide (62, 19%) and tacrolimus to ciclosporin (20, 6%). Factors associated with the development of BKPyVAN included (adjusted hazard ratio [HR]; 95% confidence interval) male sex (1.66; 1.34-2.05), recipient age (≥70 vs. <20 [2.46; 1.30-4.65]), recipient blood group (A vs. B [2.00; 1.19-3.34]), donor age (≥70 vs. <20 [2.99; 1.71-5.22]), earlier era (1.74; 1.35-2.25), donor/recipient ethnic mismatch (1.52; 1.23-1.87), tacrolimus use (1.46; 1.11-1.91), and transplantation at a lower-volume transplant center (1.61; 1.24-2.09). The development of BKPyVAN was associated with an increased risk of all-cause (1.75; 1.46-2.09) and death-censored graft loss (2.49; 1.99-3.11), but not mortality (1.15; 0.91-1.45).ConclusionsBKPyVAN is associated with an increased risk of all-cause and death-censored graft loss, but not death. Interventional trials are urgently needed to evaluate the efficacy of immunosuppression reduction and novel strategies to minimize the adverse outcomes associated with BKPyVAN.
| S-EPMC10014440 | biostudies-literature
Project description:BK virus-associated nephropathy (BKVN) is associated with an increased risk of graft failure.Levels of mRNAs encoding proteins implicated in inflammation and fibrosis were measured in urine collected at the time of biopsy diagnosis of BKVN in 29 kidney graft recipients and analyzed for prognosticating graft failure using logistic regression.Ten of 29 BKVN patients had graft failure within 36 months of BKVN diagnosis and the remaining 19 patients did not. Serum creatinine level, BKVN biopsy stage, and urinary cell levels of mRNA for plasminogen activator inhibitor (PAI)-1, vimentin, tissue inhibitor of metalloproteinase-1, fibronectin, granzyme B, or perforin were associated with graft failure. A combination of PAI-1 mRNA level, BKVN biopsy stage, and creatinine level (P = 0.0015, by logistic regression) and a combination of PAI-1 mRNA and creatinine levels (P = 0.001) were the best-fitting models for prognosticating graft failure, and PAI-1 mRNA level was the only independent predictor (odds ratio, 2.8; 95% confidence interval [CI], 1.1-6.8; P = 0.03) by multivariable analysis. The area under the curve for the combination of PAI-1 mRNA, biopsy, and creatinine was 0.92 (95% CI, 0.80-1.0; P < 0.001) by receiver operating characteristic curve analysis, and the area under the curve was 0.92 (95% CI, 0.80-1.0; P < 0.001) for the combination of PAI-1 mRNA and creatinine. Graft outcome was correctly predicted in 27 of 29 BKVN patients by either model.Urinary cell level of PAI-1 mRNA, measured at the time of BKVN diagnosis, is an independent prognosticator of graft failure and a prediction model of serum creatinine and PAI-1 mRNA is as accurate as the model that includes the biopsy result.
| S-EPMC3950314 | biostudies-literature
Project description:BackgroundThe immunosuppressive agents mycophenolate acid (MPA) and tacrolimus (Tac) are associated with a higher incidence of BK polyomavirus nephropathy (BKPyVAN). In this observational retrospective cohort study, the frequency of BK polyomavirus (BKPyV) complications over a 24-month period was studied.Methods358 renal transplant recipients (RTR) treated with MPA, with either cyclosporine A (CsA) (CsAM group) or Tac (TacM group) and mostly prednisolone, were included.ResultsIncidence of BKPyV-viremia was not significantly different between the CsAM (n = 42/191) (22.0%) and the TacM (n = 36/167) (21.6%) group. Biopsy proven BKPyVAN occurred more often in the TacM group (6.6%) versus the CsAM group (2.1%) (p = 0.03). Longitudinal data analysis showed a significant earlier decline of viral load in plasma in the CsAM group compared to the TacM group (p = 0.005). The incidence of biopsy proven acute rejection (BPAR) was significantly higher in the CsAM (19.9%) compared to the TacM (10.8%) (p = 0.02) group. Graft loss, estimated glomerular filtration rate and mortality rate did not differ in both treatment groups.ConclusionIn conclusion, this study shows that immunosuppressive treatment with Tac and MPA compared to CsA and MPA is associated with a lower incidence of BPAR, but at the cost of an increased risk of developing BKPyVAN in the first two years post-transplant.
| S-EPMC5469458 | biostudies-literature
Project description:BK polyomavirus (BKPyV) is a ubiquitous pathogen in the human population that is asymptomatic in healthy individuals, but can be life-threatening in those undergoing kidney transplant. To-date, no vaccines or anti-viral therapies are available to treat human BKPyV infections. New therapeutic strategies are urgently required. In this study, using a rational pharmacological screening regimen of known ion channel modulating compounds, we show that BKPyV requires cystic fibrosis transmembrane conductance regulator (CFTR) activity to infect primary renal proximal tubular epithelial cells. Disrupting CFTR function through treatment with the clinically available drug glibenclamide, the CFTR inhibitor CFTR172, or CFTR-silencing, all reduced BKPyV infection. Specifically, time of addition assays and the assessment of the exposure of VP2/VP3 minor capsid proteins indicated a role for CFTR during BKPyV transport to the endoplasmic reticulum, an essential step during the early stages of BKPyV infection. We thus establish CFTR as an important host-factor in the BKPyV life cycle and reveal CFTR modulators as potential anti-BKPyV therapies.
| S-EPMC7322401 | biostudies-literature
Project description:BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.
| S-EPMC11335089 | biostudies-literature