BK Virus Infection Research Articles

2105. Early-onset and Late-onset BK Polyomavirus-associated Nephropathy: A 10-year Retrospective Analysis

Abstract Background Polyomavirus-associated nephropathy (BKVAN) is one of the serious causes of allograft dysfunction and allograft loss in kidney transplant (KT) patients. Most of the patients were diagnosed with BKVAN within the first year after transplantation but some more cases of BKVAN occur later. A study focused on the differentiation between early and late-onset BKVAN is needed. Methods We conducted a retrospective cohort study among KT recipients at Ramathibodi Hospital between January 2010 – December 2020. The incidence of early-onset (diagnosed within 1 year) and late-onset (diagnosed after 1 year) BKVAN, as well as composite kidney allograft outcomes, were compared. Results From 1032 KT recipients, 645 (62.5%) were screened for BK viral infection. BKVAN was diagnosed in 83 (12.8%) patients. Of those, 46 (55.4%) and 37 (44.6%) were diagnosed with early-onset and late-onset BKVAN, respectively. Composite kidney allograft outcomes of GFR decline≥ 40% from baseline, graft loss or death were greater in early-onset BKVAN compared to late-onset BKVAN (7.5 vs 5.52 per 1000 person-months; hazard ratio 0.47; 95%CI, 0.23-0.95; P=0.037). In multivariate analysis, female gender and living-related kidney transplantation (LRKT) were independently associated with late-onset BKVAN compared to early-onset BKVAN. The more advanced the BKVAN diagnosis, the worse the allograft outcome occurs, even with optimizing immunosuppressive drugs and adjunctive therapy. Conclusion BKVAN could occur later after one-year post-transplantation, although relatively better composite kidney outcomes were observed compared to early-onset BKVAN. Female individuals who underwent living-related KT should be considered for BK virus preemptive monitoring beyond one year to detect this late-onset BK virus infection. Disclosures All Authors: No reported disclosures.

Complications of rabbit anti-thymocyte globulin induction immunosuppression in HIV-infected kidney transplant recipients.

Kidney transplantation in HIV-infected individuals with end-stage kidney disease is associated with improved survival compared to dialysis. Rabbit anti-thymocyte globulin (rATG) induction in HIV-infected kidney transplant recipients has been associated with a lower risk of acute rejection, but data on the rates of de novo malignancy and BK viremia in these patients is lacking. We performed a single-center retrospective cohort study of adult HIV-infected individuals who underwent kidney transplantation with rATG induction between January 2006 and December 2016. The primary outcome was the development of de novo malignancy. Secondary outcomes included the development of BK viremia, infections requiring hospitalization, HIV progression, biopsy-proven acute rejection, and patient and allograft survival. Twenty-seven HIV-infected individuals with end-stage kidney disease received deceased (n=23) or living (n=4) donor kidney transplants. The cumulative rate of malignancy at five years was 29%, of whom 29% died because of advanced malignancy. BK viremia was detected in six participants (22%), of whom one had biopsy-proven BK virus-associated nephropathy and all of whom cleared the BK viremia. Five-year acute rejection rates, patient survival and death-censored allograft survival were 17%, 85% and 80% respectively. rATG induction in HIV-infected kidney transplant recipients was associated with a low risk of acute rejection, but a potentially higher risk of de novo malignancies and BK viremia in this cohort. Screening strategies to closely monitor for BK virus infection and malignancy post-transplantation may improve outcomes in HIV-infected kidney transplant recipients receiving rATG induction.

Proteomic analysis of urinary extracellular vesicles of kidney transplant recipients with BKV viruria and viremia: A pilot study.

To better define the biological machinery associated with BK virus (BKV) infection, in kidney transplantation, we performed a proteomics analysis of urinary extracellular vesicles (EVs). Twenty-nine adult kidney transplant recipients (KTRs) with normal allograft function affected by BKV infection (15 with only viremia, 14 with viruria and viremia) and 15 controls (CTR, KTRs without BKV infection) were enrolled and randomly divided in a training cohort (12 BKV and 6 CTR) used for the mass spectrometry analysis of the EVs (microvesicles and exosomes) protein content and a testing cohort (17 BKV and 9 CTR) used for the biological validation of the proteomic results by ELISA. Bioinformatics and functional analysis revealed that several biological processes were enriched in BKV (including immunity, complement activation, renal fibrosis) and were able to discriminate BKV vs. CTR. Kinase was the only gene ontology annotation term including proteins less abundant in BKV (with SLK being the most significantly down-regulated protein). Non-linear support vector machine (SVM) learning and partial least squares discriminant analysis (PLS-DA) identified 36 proteins (including DNASE2, F12, AGT, CTSH, C4A, C7, FABP4, and BPNT1) able to discriminate the two study groups. The proteomic profile of KTRs with BKV viruria alone vs. viremia and viruria was quite similar. Enzyme-linked immunosorbent assay (ELISA) for SLK, BPNT1 and DNASE2, performed on testing cohort, validated proteomics results. Our pilot study demonstrated, for the first time, that BKV infection, also in the viruric state, can have a negative impact on the allograft and it suggested that, whether possible, an early preventive therapeutic strategy should be undertaken also in KTRs with viruria only. Our results, then, revealed new mechanistic insights into BKV infection and they selected potential biomarkers that should be tested in future studies with larger patients' cohorts.

Outcomes with Viral Specific T-Cells in Cytomegalovirus, Adenovirus, and BK Virus Infections after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Outcomes with Viral Specific T-Cells in Cytomegalovirus, Adenovirus, and BK Virus Infections after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Epidemiology, Risk Factors and Outcome of Bacterial, Fungal, and Viral Infections in Pediatric Allogeneic and Autologous Hematopoietic Stem Cell Transplantation Recipients

Objectives Infection remains a major cause of morbidity and mortality after hematopoietic stem cell transplant (HSCT). With recent changes in transplant practices, such as the increasing use of alternative donors and T-cell depletion, how various risk factors interplay and affect the timeline of infections have not been well elucidated in children. While the epidemiology and risk factors for viral infections post-HSCT were well described for cytomegalovirus (CMV) and Epstein-Barr virus (EBV), the corresponding information on human herpes virus 6 (HHV-6), adenovirus (ADV) and BK virus (BKV) infection in children is limited. This study aims to review comprehensively the epidemiology, risk factors and outcome of bacterial, viral and fungal infections after contemporary HSCT to inform future infection prophylaxis strategies. Method We retrospectively reviewed the first 100 consecutive HSCT for malignant and non-malignant diseases from April 2019 to October 2021 in the only pediatric HSCT center in Hong Kong. The incidences were recorded and risk factors were analyzed for bacterial, viral and fungal infections and infection-related mortality. Results The vast majority of the allogeneic transplant recipients (69/74, 93.2%) had infections after HSCT, amongst which bacterial, viral and fungal infection rate was 35.1%, 90.5% and 9.5% respectively. In contrast, only 30.8% (8/26) of autologous transplant recipients had infections, and their respective rate of bacterial, viral and fungal infection was 19.2%, 15.4% and 3.8%. HHV-6 and BKV typically occurred early after HSCT, ADV and varicella zoster virus (VZV) thereafter, and CMV and EBV throughout the entire 2.5-year observation period. The cumulative incidences of HHV-6 and BKV were significantly higher in patients receiving umbilical cord blood (UCB) or haploidentical stem cell transplant (p = 0.0001; p <0.0001, respectively) when compared with matched sibling (MSD) or matched unrelated donor (MUD) transplant (Figure 1 and 2). Ex vivo T-cell depletion was a general risk factor for viral infection with HHV-6 (HR = 3.03), BKV (HR = 3.36), CMV (HR = 4.45) and EBV (HR = 7.15); all p < 0.02. Cancer in second- compared with first-complete remission was a risk factor for bacterial infection in multivariate analyses (OR = 6.0, 95% CI = 1.12-32.2, p = 0.037). Patients with gut graft-versus-host disease were at risk for fungal infections (OR = 12.3, 95% CI = 1.33-114.4, p = 0.027). The infection-related mortality (IRM) rate was 10%, which occurred only in allogeneic HSCT patients with hematological malignancies receiving cord blood (n = 4) or haploidentical HSCT (n = 6). History of bacterial infection after HSCT was associated with an increased risk of IRM (HR = 4.13, 95% CI = 1.05-16.3, p = 0.042). Conclusion Not all HSCT recipients are of equal risk to infections and IRM. Our findings in pediatric patients after contemporary HSCT support both time-dependent and risk-adapted measures against infective complications to improve transplant outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Clinical Outcomes from a Phase 2 Trial of Posoleucel, an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Clinically Significant Viral Infections Post-HCT

Background: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are highly susceptible to reactivation of double-stranded DNA viruses. Approximately 70% of high-risk allo-HCT recipients develop clinically significant infections (CSI, defined as viremia + treatment or end organ disease). We present results from a phase 2 trial evaluating the safety and efficacy of posoleucel, a partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product, for preventing CSIs due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), or JC virus (JCV). Methods: This open-label trial enrolled high-risk allo-HCT recipients, including those with grafts from haploidentical, umbilical cord blood, mismatched unrelated donors, and matched unrelated donors with lymphocytes <180/mm3 as well as recipients who underwent T cell depletion. To be eligible, patients had to be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD and those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment were ineligible. Patients received up to 7 infusions of posoleucel once every 14 days and were tested weekly for viremia using quantitative PCR assays. The primary endpoint was the number of CSIs due to AdV, BKV, CMV, EBV, HHV-6, or JCV by week 14. IFN-γ ELISpot analysis was performed for each targeted virus on serial peripheral blood samples to assess functional T cell immune reconstitution and determine the frequency of circulating virus-specific T cells detected over time. To evaluate the persistence and potential contribution of posoleucel to antiviral immune reconstitution, T-cell receptor (TCR) β immunosequencing was performed at selected timepoints. TCR sequences unique to posoleucel were identified computationally and used to track in vivo persistence in serial samples. Results: Twenty-six patients were dosed. Posoleucel dosing began a median of 42 days after allo-HCT. Twenty (77%) patients had viral DNA detected in blood (reactivation) from one or more viruses, 13 (50%) had 2 or more viral reactivations, and 7 (27%) had 3 or more viral reactivations in the 14 weeks after the initiation of posoleucel dosing (Figure). However, by week 14, only 3 patients (12%) had CSIs (2 CMV viremia requiring treatment and 1 EBV-post-transplant lymphoproliferative disorder). No patient had a CSI with more than 1 virus. Nine patients (35%) experienced adverse events that were possibly or probably related to treatment. Eight patients (31%) had serious adverse events (SAEs), 2 of which were judged to be possibly related to treatment (skin and pulmonary GVHD) and 1 probably related to treatment (allergic reaction). Overall, 8 patients (31%) had acute GVHD Grade II-IV. One patient (4%) discontinued posoleucel due to a treatment-emergent SAE of chronic pulmonary GVHD. No patient experienced cytokine release syndrome. TCR sequencing data (N=12) indicated that posoleucel was detectable in vivo during the dosing phase of the study and for up to 12 weeks after the last infusion, with polyclonal VSTs detected in all 12 patients. Six of the 7 patients with available ELISpot data demonstrated IFN-γ-producing virus-specific T cell responses coincident with viral replication. The confirmed persistence of posoleucel and expansion of IFN-γ-producing virus-specific T cells directed against reactivating viruses, suggests a contribution of posoleucel to functional immune reconstitution. Conclusion: Results from this open-label phase 2 trial show that high-risk allo-HCT patients who received posoleucel had lower than expected rates of clinically significant viral infections from the 6 targeted viruses despite the observed and expected low-level viral reactivations throughout the study. Repeat dosing of posoleucel was generally safe and well tolerated. Posoleucel VSTs were detected in vivo for up to 26 weeks, and reconstituting T cells demonstrated functional specificity for multiple viruses. A placebo-controlled global phase 3 trial evaluating the safety and tolerability of posoleucel for the prevention of clinically significant AdV, BKV, CMV, EBV, HHV-6, and JCV infections is ongoing (NCT05305040). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CT-321 Uncommon Viral Infections in Patients Treated With CAR-T Cell Therapy: Concurrent Adenovirus and BK Virus Infection in a Mantle Cell Lymphoma Patient Within 30 Days After Receiving Brexucabtagene Autoleucel

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. We report a single-institution experience of adenovirus (AdV) infection treatment following CAR-T cell therapy. Case report. Academic referral center. 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. 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. AdV viremia and viruria, BK virus viremia and viruria, symptoms. 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. 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.

Böbrek nakli yapılan hastalarda nakil öncesi ve nakil sonrası enfeksiyon etkenlerinin sıklığı

Amaç: Böbrek nakli, böbrek yetmezliğinin en önemli ve başarılı tedavi yöntemidir. Bu çalışmada, böbrek nakli alıcılarında nakil öncesi ve nakil sonrası ilk altı ayda Cytomegalovirus (CMV), BK virüs (BKV) ve bakteriyel etkenlerin sıklığının araştırılması amaçlanmıştır. &#x0D; Gereç ve Yöntem: Fakültemiz Organ Nakli Merkezinde böbrek nakli yapılan hastalardan, nakilden bir hafta önce ve nakilden sonra birinci, üçüncü ve altıncı aylarda alınan kan örneklerinde Real-time PCR ile CMV ve BKV araştırıldı. Kan, idrar, balgam/yara (gerekiyor ise) kültürleri yapıldı. İdrar sitolojisinde Decoy hücreleri değerlendirildi. &#x0D; Bulgular: Böbrek nakli alıcılarının yaş ortalaması 32,60±11,71 28 (% 62,2)’i erkek ve 39 (% 86,7)’u akraba olan canlı vericili, altısı kadavra vericili idi. Nakil sonrası 11/38 (% 28,9) hastada BKV, 25/41 (% 60,9) hastada CMV, 11/31 (% 35,4) hastada Decoy hücre pozitiflikleri saptandı. Real-time PCR pozitifliği en yüksek oran BKV için üçüncü ve altıncı aylarda iken, CMV için birinci ay olup altıncı aya doğru giderek azalma gösterdi. İdrar kültüründe Escherichia coli, Klebsiella pneumoniae, albicans-dışı Candida, Enterococcus faecalis, kan kültüründe Staphylococcus hominis, Streptecoccus epidermidis, solunum yolu örneklerinin kültüründe Acinetobacter baumannii, Klebsiella pneumoniae, Aspergillus fumigatus ve Candida albicans üredi..&#x0D; Sonuç: Böbrek nakli alıcılarımızda bakteriyel enfeksiyonlar erken dönemde gelişti. Real-time PCR pozitiflik oranı en yüksek BKV için üçüncü ve altıncı aylarda iken CMV için birinci ay olup altıncı aya doğru giderek azalma gösterdi. Böbrek nakil hastalarında Decoy hücre pozitifliği de BKV enfeksiyonu tanısı için önemli olabilir.

Viral Infection Profile in Children Treated for Acute Lymphoblastic Leukemia-Results of Nationwide Study.

Viral infections can be a serious complication of therapy in children with acute lymphoblastic leukemia (ALL). In this study, we focused on the incidence and the profile of viral infection in children with ALL treated in 17 pediatric oncology centers in Poland in the two-year periods of 2018–2019 and 2020–2021. We also compared the frequency of viral infections in 2018–2019 to that in 2020–2021. In 2020–2021, a total of 192 children with ALL had a viral infection during intensive chemotherapy. A total number of 312 episodes of viral infections were diagnosed. The most common infections detected in the samples were: COVID-19 (23%), rhinovirus (18%), and respiratory syncytial virus (14%). COVID-19 and BK virus infections were the reason for the death 1% of all patients. In 2018–2019, a total of 53 ALL patients who had a viral infection were reported and 72 viral events were observed, mainly adenovirus (48.6%), rotavirus (31.9%), and herpes zoster (8.3%). No deaths were reported during this period. The cumulative incidence of viral infections in 2018–2019 was 10.4%, while for 2020–2021, it was 36.7%. In conclusion, a high incidence of COVID-19 infection was observed among pediatric patients with ALL in Poland. The mortality rate in our material was low. The viral profile in ALL children undergoing chemotherapy can be useful for clinicians to improve prophylactic and therapeutic strategies.

Preoperative CD52 Level Predicts Graft Survival following Kidney Transplantation.

Several factors have been reported to affect graft survival following kidney transplantation. CD52 molecules may increase T cell proliferation and activation, which may contribute to acute graft rejection and graft survival. In the current study, we studied the possible value of preoperative CD52 levels in predicting graft survival following renal transplantation. Ninety-six patients with end-stage renal disease who had kidney transplantation were included in the study from our prospective cohort. Blood samples were taken one day before surgery, and plasma CD52 levels were measured using ELISA (Cloud-Clone Corp., Houston, TX, USA). Acute rejection, acute tubular necrosis, delayed graft function, graft loss, BK infection, cytomegalovirus infection, and graft survival were evaluated. The mean age of recipients was 50.08 ± 12.82 years, and 64.6% were male. The incidence of delayed graft function, acute rejection, graft loss (p < 0.01), BK virus infection, and serum creatinine levels were significantly higher in recipients with high preoperative CD52 levels six months after transplantation (p < 0.05). Kaplan-Meier analysis revealed that three-year graft survival was significantly higher in patients with low preoperative CD52 levels (p < 0.0001). Univariate and multivariate Cox regression analyses showed that serum creatinine levels (hazard ratio [HR] = 1.7, p < 0.05), acute rejection (HR = 2.919, p < 0.05), and preoperative CD52 levels (HR = 3.114, p < 0.05) were independent prognostic factors for graft survival after kidney transplantation. We showed that high preoperative CD52 levels are associated with higher rates of acute rejection, delayed graft function, and BK virus infection and lower rates of graft survival after kidney transplantation.

S100A8/A9, an Upregulated Host Factor in BK Virus Infection after Kidney Transplantation, Is Associated with Allograft Function Impairment.

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.

Correlation between CYP3A5 gene polymorphism and BK virus infection in kidney transplant recipients

BackgroundCytochrome 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. MethodsAccording 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. ResultsThe 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. ConclusionAfter 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.

P2.12: Single-Cell Transcriptomic Analysis of Peripheral Blood Reveals the Disparate Subsets of Innate Immune Cells in Kidney Transplant Recipient With BK Virus Infection

Purpose: BK virus (BKV) infection is a common problem in kidney transplant recipients receiving immunosuppressive therapy, resulting in a serious complications including BKV-associated nephropathy and subsequent allograft loss. The purpose of this study was to characterize the disparate blood subsets in BKV infection/nephropathy at the single-cell transcriptional level. Methods: We isolated peripheral blood mononuclear cells from three kidney transplant recipients with stable status, BK viremia and BK nephropathy. Single-cell libraries were generated using the 10x Genomics Chromium Platform. We analyzed multiplexing data in Cell-Ranger Pipeline and used R and “Seurat” packages for downstream analysis. Results: A total of 14,031 cells were analyzed, including 5473 cells from stable patients, 3976 cells from patients with BK viremia, and 4582 cells from patients with BK nephropathy obtained from Illumina HiSeq X. We characterized 17 distinct clusters representing different cell types. Of these, 13 clusters had differentially expressed transcripts for each sample, and the most differentially expressed markers were S100A8, CCR7, LTB, GNLY, GZMK, GZMH, MT-CO1, LINC02446, IGKC, AIF1, HLA-DRA, STMN1. Stable patient had more mRNA upregulated in B cells compared to patients with BK virus infection. In BK viremia, NK cells and monocytes were downregulated, whereas in BK nephropathy, mRNA expression was high in gamma delta T cells. Conclusions: Our study revealed that BK virus infection/nephropathy induce unique characteristics in lymphocytes, which could be confirmed through single-cell RNA analysis. Further studies are needed to characterize the innate immune cells involved in the progression of BK nephropathy.

248.6: BK Virus Infection in Kidney Transplant Patients at Hospital De Clinicas - Paraguay

248.6: BK Virus Infection in Kidney Transplant Patients at Hospital De Clinicas - Paraguay

423.11: Long-term Compromised Immune Regulation After Rituximab Induction in Blood Group Incompatible Living-Donor Renal Transplantation - 5 Year Results of a Prospective Pilot Study

Background: An increased frequency of severe infectious diseases and BK viremia has been described after ABOi renal transplantation. As rituximab induction may alter immunoregulation in these patients, we analyzed clinically relevant immune parameters in a prospective renal transplant study up to 5 years posttransplant. Materials and Methods: Mononuclear cell subsets (peripheral blood; lymph nodes taken during transplant surgery), intracellular cytokine responses, CD4 helper function and in-vitro B cell responses were assessed pretransplant and up to 5 years posttransplant in 85 renal transplant recipients (living donation: n=25 ABO incompatible (ABOi) and n=30 ABO compatible (ABOc); deceased donation (DD): n=30, all ABO compatible). Results: Severe infectious diseases occurred more often in ABOi than ABOc recipients within 2 years posttransplant (11/24 (46%) versus 6/30 (20%), P=0.042) but not beyond. The incidence of BK viremia was significantly enhanced in rituximab versus non-rituximab treated patients (1 year: 9/29 (31%) versus 4/54 (7%), P=0.009; 5 years: 10/30 (33%) versus 7/53 (13%), P=0.029). After rituximab induction in ABOi recipients, counts of peripheral blood B cell subsets were profoundly downregulated even 3 years posttransplant and reached the level of non-ABOi recipients after 4 years (memory B cells after 5 years). T-dependent and T-independent B cell responses were significantly impaired in ABOi patients up to 2 years posttransplant (P=0.010 and P=0.053, respectively) whereas CD4 helper activity was not compromised. CD4+ T cell counts were significantly lower in ABOi compared to ABOc recipients at 3 and 6 months (P=0.025 and P=0.046, respectively), but showed no differences in the percentage of Tregs. In regional lymph nodes of ABOi patients, we found a significant downregulation of CD20+ but not CD19+ B cells (P<0.0005), of naive B cells (P=0.031) and short lived plasma cells (P<0.0005) at the time of transplantation. Conclusion: An increased frequency of severe infectious diseases and BK viremia in rituximab treated ABOi renal transplant recipients may be explained by significantly downregulated CD4+ T cell counts up to 6 months and a profoundly delayed B cell repopulation, most pronounced with regard to memory B cells, together with compromised B cell responses up to 2 years posttransplant. IL-10, as a key player in chronic BK virus infection, was not upregulated in rituximab-treated ABOi transplant recipients.

POS-099 BK POLYOMAVIRUS NEPHROPATHY IN RENAL TRANSPLANT PATIENTS: A RACE WITH TIME?

BK polyomavirus-associated nephropathy (BKVAN) affects up to 15% of renal transplant recipients and is an important cause of graft failure. Higher prevalence of BK virus infection in recent years has been correlated with declining acute rejection rates and the use of potent immunosuppressive agents.

310.3: Posoleucel as Preemptive Therapy for BKV Infection in Kidney Transplant Recipients: Safety, Tolerability and Efficacy in a Phase 2 Trial

Purpose: Kidney transplant (KT) recipients with BK viremia are at risk for BK virus (BKV) nephropathy and graft loss. There are no approved therapies for BKV infection. Posoleucel (PSL) is an off-the-shelf, allogeneic multivirus-specific T cell therapy that targets BKV as well as adenovirus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and JC virus. In a phase 2 trial of PSL in hematopoietic cell transplant recipients, 100% (27/27) of those with BKV disease had a clinical response. Methods: We are conducting a phase 2 double-blind placebo (PBO)-controlled study of PSL in 60 KT recipients with BK viremia (NCT04605484) in which patients are randomized 1:1:1 to receive PSL (Groups 1 and 2) or placebo for 12 weeks. PSL (4 × 107 PSL cells) is infused once a week for 3 weeks, then every 14 days (Group 1) or every 28 days (Group 2). After these 12-week dosing periods, patients are followed for 12 more weeks (observation period). The primary objective is safety and tolerability with a key secondary objective to assess changes in BK viremia. Results: This interim analysis of the ongoing study includes the first 37 patients enrolled as of 22 Feb 2022; 29 (78%) patients were male and 8 (22%) were female; 20 (54%) Caucasian, 10 (27%) African American, 4 (11%) Asian, and 3 (8%) were other race or not reported; 3 (8%) patients were of Hispanic ethnicity. Patients’ median age was 58.5 years, with a range from 32 to 75 years. Median day of PSL or PBO initiation post KT was 472 days (range 59 to 5158 days). Mean eGFR at start of the dosing period was 48 mL/min/1.73m2 (SD ∓18), and median plasma BK viral load was 5060 copies/mL (range 242 to 5,421,939 copies/mL). At a median follow-up of 40.5 days (range 1 to 173 days), PSL was well tolerated with no treatment-related serious adverse events, and 12 mild (grade 1), transient treatment-related adverse events in 4 patients. There were no discontinuations due to adverse events or adverse events of special interest, specifically no episodes of graft versus host disease, cytokine release syndrome, infusion reactions, or rejection. No patients developed de novo donor-specific antibodies. Kidney allograft function as measured by eGFR and creatinine remained stable during the study, with no change from baseline to latest assessment in either measurement. Mean (95% CI) changes in eGFR and creatinine were 0.9 mL/min/1.73 m2 (-2.9, 4.7) and 0.0 mg/dL (-0.2, 0.1), respectively. Updated safety and viral load data from all enrolled patients will be presented, including analyses of the effect of PSL versus PBO on other immune and viral endpoints. Conclusions: In this ongoing trial—the first randomized, double-blind placebo-controlled therapeutic trial of virus-specific T cell therapy in KT recipients with BK viremia—PSL was generally safe and well tolerated, supporting its continued evaluation as a preemptive therapy in KT recipients at risk for BKV nephropathy. This study was funded by AlloVir.

Infection, Rejection, and the Connection.

Solid organ transplantation is a life-saving treatment for people with end-stage organ disease. Immune-mediated transplant rejection is a common complication that decreases allograft survival. Although immunosuppression is required to prevent rejection, it also increases the risk of infection. Some infections, such as cytomegalovirus and BK virus, can promote inflammatory gene expression that can further tip the balance toward rejection. BK virus and other infections can induce damage that resembles the clinical pathology of rejection, and this complicates accurate diagnosis. Moreover, T cells specific for viral infection can lead to rejection through heterologous immunity to donor antigen directly mediated by antiviral cells. Thus, viral infections and allograft rejection interact in multiple ways that are important to maintain immunologic homeostasis in solid organ transplant recipients. Better insight into this dynamic interplay will help promote long-term transplant survival.

BK Virus Infection and BK-Virus-Associated Nephropathy in Renal Transplant Recipients.

Poliomavirus BK virus (BKV) is highly infective, causing asymptomatic infections during childhood. After the initial infection, a stable state of latent infection is recognized in kidney tubular cells and the uroepithelium with negligible clinical consequences. BKV is an important risk factor for BKV-associated diseases, and, in particular, for BKV-associated nephropathy (BKVN) in renal transplanted recipients (RTRs). BKVN affects up to 10% of renal transplanted recipients, and results in graft loss in up to 50% of those affected. Unfortunately, treatments for BK virus infection are restricted, and there is no efficient prophylaxis. In addition, consequent immunosuppressive therapy reduction contributes to immune rejection. Increasing surveillance and early diagnosis based upon easy and rapid analyses are resulting in more beneficial outcomes. In this report, the current status and perspectives in the diagnosis and treatment of BKV in RTRs are reviewed.

Early Postoperative Kidney Transplant Complications Related to Immunomodulator Regimen in Pediatric Recipients.

Calcineurin inhibitors (cyclosporine and tacrolimus) are widely used in kidney transplant to prevent acute transplantrejection; however,the effects of these medications on graft sequelae after transplant remain unclear. We aimed to compare early complications, including graftrejectionandinfectionrates after kidney transplant, in childrenbetween the cyclosporine and tacrolimus immunomodulator regimens. In this prospective cohort study, 105 pediatric patients who were candidates to receive kidney transplant in the age range of 4 to 18 years were included. There were 28 patients who received cyclosporine, and 77 patients who received tacrolimus. Participants were routinely tested for cytomegalovirus, BK virus, and bacterial infection on a monthly basis for the first 3 months and once every 3 months thereafter for the first year. The graft rejection rate was also assessed and compared between the 2 treatment regimens. There were no significant differences between the 2 groups receiving cyclosporine or tacrolimus in graft rejection rate (P = .719), cytomegalovirus viremia (P = .112), BK viremia (P = .278), and bacterial infection (P = .897). Graftfailure was significantly more frequent in male than in female patients (30.9% vs 8.2%; P = .004). The rates of graft failure in study patients with and without previous history of graftfailure were found to be statistically similar (16.7% vs 20.4%; P = .825). History of infection in donors did not affect the graft complications posttransplant in recipients. The use of either tacrolimus or cyclosporine leads to similar consequences in terms of graft rejection or posttransplant viral and bacterial infection, so either drug may be exchanged for the other if needed for tolerability.