BK DNAemia and native kidney polyomavirus nephropathy following lung transplantation.

BK virus DNAemia (BKPyV) and nephropathy are common after kidney transplant; however, there are limited data on BK infections in nonrenal solid organ transplant recipients. We examined the frequency, clinical and pathologic features, and kidney and lung outcomes of BKPyV and BK virus native kidney nephropathy (BKVN) in lung transplant recipients at our center. Among 878 recipients transplanted from 2003 to 2019, 56 (6%) developed BKPyV at a median of 30.1 months after transplant (range, 0.6-213) and 11 (1.3%) developed BKVN at a median of 46 months after transplant (range, 9-213). The incidence of end-stage kidney disease was significantly higher in patients with peak viral load ≥10 000 copies/mL (39% vs 8%, P < .001). All cases of BKVN were in patients with peak viral load of ≥10 000 copies/mL, and 55% of these patients developed end-stage kidney disease. Despite the reduction of immunosuppression to treat BKVN, only 1 patient developed acute rejection, and lung function was stable >1 year. BKPyV and nephropathy are more common after lung transplantation than previously reported. Routine screening for BKPyV should be considered in all lung transplant recipients.

BK DNAemia in pediatric kidney transplant recipients: Predictors and outcomes.

BACKGROUND: Pediatric data on risk factors and the clinical course of BK DNAemia are limited. We aimed to determine the effects of BK DNAemia on transplant outcomes and delineate the safety and efficacy of various treatment approaches. METHODS: This retrospective-cohort study included 161 transplants (age ≤ 21 years) performed at a single center between 1/1/2012 and 1/1/2020. We used Cox proportional models to evaluate the effects of BK DNAemia on patient survival (PS), graft survival (GS), and acute rejection (AR), using BK as a time-dependent covariate. We also assessed the effects of pharmacological intervention on BK DNAemia duration using intervention as a time-dependent covariate. RESULTS: BK-free survival was 69.1% at 1-year and 54.6% at 3-year posttransplant. After multivariate adjustment, BK DNAemia was associated with young age at transplant (aHR, age 5-<12 vs. ≥12 (years): 2.5 (1.4-4.5); p = .001) and steroid-based immunosuppression (IS) (aHR: 2.2 [1.1-4.5]; p = .03). We found no effect of DNAemia on AR (aHR: 1.25; p = .5), PS (aHR: 2.85; p = .22), and GS (aHR: 0.56; p = .41). Of 70 patients with DNAemia, 22 (31.4%) received no treatment, 20 (28.6%) received IS reduction alone, and 28 patients (40%) received treatment with at least one pharmacological agent (leflunomide, IVIG, ciprofloxacin, cidofovir). Sixty-three patients (90%) cleared DNAemia with median time to resolution of 2.4 months (IQR:1.4-5.6). We found no significant effect of BK-directed pharmacological treatment on time to resolution (aHR: 0.64;p = .13). BK-directed agents were well tolerated. CONCLUSIONS: BK DNAemia is associated with a young age at transplant and steroid-based maintenance IS. We found no effect of BK DNAemia on AR, GS, and PS.

BK Virus Infections and Hemorrhagic Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

BK virus (BKV) associated with hemorrhagic cystitis (HC) is the most important complication that develops after hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies. This study aims to investigate BKV infections and HC in pediatric patients after allogeneic hematopoietic stem cell transplantation. Between November 2018 and November 2019, a total of 51 patients between the ages of 11 months and 17 years were included in the study. BKV Bosphore ® v1 quantification kit (Geneworks Anatolia, Turkey) was used for the detection of BKV DNA in urine and blood samples. Among the total of 51 patients, the incidence of BKV infection was found to be 86.3%. Allogeneic HSCT was performed in 40 patients and autologous HSCT in 11 patients. BK viruria and/or viremia were detected in 85% (44) of patients who underwent allogeneic HSCT and in 90% in the autologous group. High-level BK viruria (>107 copies/mL) was found in 41% (9) of 22 patients who were BKV positive before transplantation, while in 27.5% (8) of 29 patients who were BKV negative before transplantation; thus, BKV positivity before transplantation was considered a risk factor for high-level BK viruria. Acute GVHD developed in 6 of 40 patients in the allogeneic group. HC was prevented in 12 (67%) of 18 patients who received preemptive treatment, while HC developed in 6 (33%). HC occurred at a median of 35 days (17-49 days) post-transplant. Despite preemptive treatment, 6 (15%) patients who developed HC associated with BKV were in the allogeneic group but not in the autologous group. Of these patients with HC, 5 received a myeloablative treatment regimen, and 1 patient was given a reduced-intensity treatment regimen. The viral load in urine was found to be 107-9 copies/mL within 2 weeks before the development of HC and has been identified as a prognostic indicator. In conclusion, early diagnosis of viral infections by monitoring BKV viral load in HSCT patients will be effective in preventing the progression of complications such as BKV-associated HC by providing timely initiation of preemptive treatment.

Consensus Definitions of BK Polyomavirus Nephropathy in Renal Transplant Recipients for Clinical Trials.

BACKGROUND: BK polyomavirus (BKPyV) infection and BK polyomavirus nephropathy (BKPyVAN) are important causes of allograft dysfunction and premature allograft loss in renal transplant recipients. RESULTS AND DISCUSSION: Controlled clinical trials to evaluate new agents for prevention and treatment are needed but are hampered by the lack of outcome measures that accurately assess the effect of the intervention, are clinically relevant, and are acceptable from a regulatory perspective. METHODS: To facilitate consistent end points in clinical trials and to support clinical research and drug development, definitions of BKPyV infection and disease have been developed by the BK Disease Definitions Working Group of the Transplantation Associated Virus Infection Forum with the Forum for Collaborative Research, which consists of scientists, clinicians, regulators, and industry representatives. CONCLUSIONS: These definitions refine established principles of "proven" BKPyV disease and introduce a "probable" disease category that could be used in clinical trials to prevent or treat BKPyVAN in renal transplant recipients.

In Vitro Generation of BK polyomavirus-specific T cells for adoptive cell therapy in refractory cystitis hemorrhagic patients after hematopoietic stem cell transplantation.

INTRODUCTION: BKPyV associated hemorrhagic cystitis (BKPyV-HC) is a major and prevalent outcome of hematopoietic stem cell transplantation (HSCT) with no standard treatment option. Adoptive T cell therapy (ACT) against transplant-associated viruses has shown promising potential. We sought to produce virus-specific T cells (VSTs) against BKPyV with the aim of treating refractory HSCT-associated HC. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors were isolated by Ficoll-Hypaque density gradient centrifugation. BKPyV-pulsed, monocyte-derived dendritic cells (mo-DCs) and T cells were co-cultured and expanded over 2-3 weeks with the addition of IL-2. The T cells were examined for various functional assays. RESULTS: Comparison analysis of Carboxyfluorescein diacetate succinimidyl ester (CFSE) indicated that the percentage of proliferated cells were significantly higher in donors (49.62 ± 7.09%) than controls (7.96 ± 4.55%). Furthermore, expanded T cells exhibited specificity to BKPyV antigens by IFN-γ ELISPOT assay. The expanded cells showed cytotoxic function versus human lymphoblastoid cell line (LCL). Final VST products mainly comprised of CD8/CD69 double-positive T cells, which were significantly higher in donors (46.8 ± 7.1%) than controls (16.91 ± 3.40%). CONCLUSION: In this study we demonstrated the feasibility of producing functional BKPyV-specific T cells in healthy donors using BKPyV PepMixes. These functional cells were able to proliferate and produce IFN-γ cytokine in response to BKPyV PepMixes. In addition, these T cells had cytotoxic ability against BKPyV antigen-expressing target cells.

Impact of pre-graft serology on risk of BKPyV infection post-renal transplantation.

OBJECTIVES: BK polyomavirus-associated nephropathy is a troublesome disease caused by BK polyomavirus (BKPyV) infection in immunocompromised renal graft recipients. There are no effective treatments available, making immunosuppression reduction the only management option. Thus, pre-graft predictive BKPyV replication markers are needed for identification of patients at high risk of viraemia. METHODS: We conducted a retrospective study to assess the correlation between pre-transplantation BKPyV serostatus and post-transplantation incidence of BKPyV infection. Sera from 329 recipients and 222 matched donors were tested for anti-BKPyV antibodies against BKPyV serotypes I and IV by using a virus-like particle-based immunoglobulin G enzyme-linked immunosorbent assay, and BKPyV DNA load was monitored for at least 1 year post-transplantation. RESULTS: Eighty recipients were viruric and 59 recipients were viraemic post-transplantation. In the post-transplantation period, the probability of developing viraemia for serotype I increased from 4.3% for the D-/R+ group to 12.1% for the D+/R+ group, climbing to 37.5% for the D+/R- group (P < 0.05). When calculating recipient mean titres for serotypes I and IV, we observed a clear difference in the proportions of viraemia, decreasing from 50% for mean titres <400 to 13.5% for titres ≥400 (P < 0.001), as well as a higher proportion of presumptive nephropathy (50% versus 23.1%, respectively; P < 0.05). In univariate analysis, this parameter had an odds ratio of 6.41 for the risk of developing post-transplantation BKPyV viraemia (95% confidence interval 3.16-13.07; P < 0.0001). CONCLUSIONS: Determination of both donor and recipient BKPyV seropositivity before transplantation and antibody titre measurements may serve as a predictive tool to manage clinical BKPyV infection by identification of patients at high risk.

Incidence, risk factors, outcomes, and clinical management of BK viremia in the modern era of kidney transplantation.

BK viremia is endemic among kidney transplant recipients (KTRs). Incidence, risk factors, outcomes, and clinical management of detectable versus high BK viremia have not been considered previously in KTR in the modern era. This observational study examined KTR transplanted between January 1, 2009 and December 31, 2016. Any BK viral load in the serum constituted detectable BK viremia and ≥103 copies/ml constituted high viremia. Among 1193 KTRs, the cumulative probability of developing detectable and high BK viremia within 2 years posttransplant were 27.8% and 19.6%, respectively. Significant risk factors for detectable BK viremia included recipient age (HR 1.02 [95% CI: 1.01, 1.03]) and donor age (HR 1.01 [95% CI: 1.00, 1.02]). Recipient age also predicted high BK viremia (HR 1.02 [95% CI: 1.01, 1.03]), whereas White race (HR 0.70 [95% CI: 0.52, 0.95]), nondepleting induction therapy (HR 0.61 [95% CI: 0.42, 0.89]), and delayed graft function (HR 0.61 [95% CI: 0.42, 0.88]) were protective. Mean estimated glomerular filtration rates were 4.28 ml/min/1.72 m2 (95% CI: 2.71, 5.84) lower with detectable BK viremia. Although low viral load was usually not acted upon at first presentation, antiproliferative dose reductions were the most common initial management. BK viremia remains a common early complication in a modern cohort of KTRs. These findings highlight the benefit of early BKV monitoring in addition to intensive clinical management. Clinical responses beyond first positive BK viremia tests, and their implications for graft outcomes, merit further investigation.

Cutaneous viral infections associated with ultraviolet radiation exposure.

The complex interplay between ultraviolet radiation (UVR) and cutaneous viral infections in the context of cancer etiology is challenging to unravel, given the limited information on the independent association between UVR and cutaneous viral infections. Using multiple biomarkers of infection with 24 types of cutaneous human papillomavirus (HPV) and 4 types of polyomaviruses (HPyV), we investigated cross-sectional associations with recent UVR exposure, using skin pigmentation measured by spectrophotometer. Age- and sex-adjusted associations between UVR and viral seropositivity, viral DNA present in eyebrow hairs (EBH) and skin swabs (SSW) were estimated using logistic regression. Beta-HPV seropositivity was associated with viral DNA positivity in EBH (OR = 1.40, 95% CI = 1.05-1.88) and SSW (OR = 1.86, 95% CI = 1.25-2.74). Similar associations were observed for Merkel cell polyomavirus. Participants in the highest tertile of UVR exposure were more likely to be seropositive for beta-HPV (OR = 1.81, 95% CI = 1.16-2.38), and have beta-HPV DNA in EBH (OR = 1.57, 95% CI = 1.06-2.33) and SSW (OR = 2.22, 95% CI = 1.25-3.96), compared to participants with the lowest tertile of UVR exposure. UVR exposure was positively associated with three different markers of beta-HPV infection. Therefore, future studies of HPV associated KC development should address more directly the role of HPV and UVR exposure as potential co-carcinogens.

Prospective analysis of BKV hemorrhagic cystitis in children and adolescents undergoing hematopoietic cell transplantation.

BK virus is one of the most common causes of hemorrhagic cystitis (HC) in children undergoing hematopoietic cell transplantation (HCT). Viruses can be found in urine and serum samples of immunocompromised patients. Malignant diseases, age, cell source, day of granulocyte reconstitution, conditioning regimen, or use of total body irradiation may play an important role in BKV epidemiology, development of hemorrhagic cystitis course, and outcome. The aim of this study was to evaluate the incidence, clinical course, and risk factors for BKV-HC in children undergoing HCT. A total number of 133 patients who were prospectively tested for BKV colonization/infection were enrolled into this multicenter analysis. Episodes of BKV-HC occurred in 36/133 (27%) enrolled subjects. In a univariate analysis for BKV-HC incidence, the following factors were significant: age >5 years, peripheral blood transplantation, matched unrelated donor (MUD) transplantation, busulfan-cyclophosphamide-melphalan conditioning regimen, and acute myeloblastic leukemia (AML) diagnosis. Presence of acute graft-versus-host disease (aGVHD) in liver and gut GVHD was a significant risk factor of BKV-HC. No BKV-attributed deaths were reported. In multivariate analysis, the incidence of HC was significantly higher in patients with AML, age >5 years, MUD transplants, and children with GVHD. HC is a frequent complication after HCT among children causes prolonged hospitalization but rarely contributes to death. We identified risk factors of BKV-HC development in children, with focus on aGVHD: we concluded that excessive immune reaction connected with GVHD and immunosuppression drugs might play a pivotal role in the development of BKV-HC.

Possible nosocomial transmission of virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation.

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered.

Validation of a noninvasive prognostic signature for allograft failure following BK virus associated nephropathy.

Identifying kidney transplant recipients at risk for graft failure following BK virus nephropathy (BKVN) may allow personalization of therapy. We have reported that a noninvasive composite signature of urinary cell level of plasminogen activator inhibitor-1(PAI-1) mRNA and serum creatinine level, measured at the time of BKVN diagnosis, is prognostic of graft failure. In this investigation, we determined whether the composite signature is prognostic of graft failure in an independent cohort of 25 patients with BKVN. Of the 25 patients, 8 developed graft failure and 17 did not. We measured urinary cell levels of PAI-1 mRNA, 18S rRNA, and BKV VP1 mRNA at the time of BKVN diagnosis and evaluated clinical parameters including Banff pathology scores, acute rejection, and graft function. The area under the receiver operating characteristic curve for the noninvasive composite signature was 0.95 (P < .001) for prognosticating graft failure. The previously reported threshold of -0.858 predicted graft failure with a sensitivity of 75% and a specificity of 94%. Our current study validates the use of composite signature and the threshold of -0.858 to identify those at risk for graft failure following BKVN diagnosis, and supports future studies utilizing the composite signature score to personalize treatment of BKVN.

Outcomes of kidney retransplantation after graft loss as a result of BK virus nephropathy in the era of newer immunosuppressant agents.

We conducted this study using the updated 2005-2016 Organ Procurement and Transplantation Network database to assess clinical outcomes of retransplant after allograft loss as a result of BK virus-associated nephropathy (BKVAN). Three hundred forty-one patients had first graft failure as a result of BKVAN, whereas 13 260 had first graft failure as a result of other causes. At median follow-up time of 4.70 years after the second kidney transplant, death-censored graft survival at 5 years for the second renal allograft was 90.6% for the BK group and 83.9% for the non-BK group. In adjusted analysis, there was no difference in death-censored graft survival (P = .11), acute rejection (P = .49), and patient survival (P = .13) between the 2 groups. When we further compared death-censored graft survival among the specific causes for first graft failure, the BK group had better graft survival than patients who had prior allograft failure as a result of acute rejection (P < .001) or disease recurrence (P = .003), but survival was similar to those with chronic allograft nephropathy (P = .06) and other causes (P = .05). The better allograft survival in the BK group over acute rejection and disease recurrence remained after adjusting for potential confounders. History of allograft loss as a result of BKVAN should not be a contraindication to retransplant among candidates who are otherwise acceptable.

Cellular sheddases are induced by Merkel cell polyomavirus small tumour antigen to mediate cell dissociation and invasiveness.

Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC.

The effect of human leukocyte antigen A1 and B35-Cw4 on sustained BK polyomavirus DNAemia after renal transplantation.

Human leukocyte antigen (HLA) class I presentation pathway plays a central role in natural killer (NK) cell and cytotoxic T-cell activities against BK polyomavirus (BKPyV) DNAemia. We determined the risk of sustained BKPyV DNAemia in 175 consecutive renal transplant recipients considering the simultaneous effect of donor/recipient HLA class I antigens and pre- or post-transplant variables. Median (IQR) age was 53 (44-64) years, and 37% of patients were female. 40 patients (22.9%) developed sustained BKPyV DNAemia [median (IQR) viral load: 9740 (4350-17 125) copies/ml]. In the Cox proportional hazard analysis, HLA-A1 (HR: 3.06, 95% CI: 1.51-6.17) and HLA-B35-Cw4 (HR: 4.63, 95% CI: 2.12-10.14) significantly increased the risk of sustained BKPyV DNAemia, while 2 HLA-C mismatches provided a marginally protective effect (HR: 0.32, 95% CI: 0.10-0.98). HLA-Cw4 is a ligand for NK cell inhibitory receptor, and HLA-B35 is in strong linkage disequilibrium with the HLA-Cw4 allele. The association between HLA-B35-Cw4 expression and sustained BKPyV DNAemia supports the important role of cytotoxic T cells and NK cells that would normally control BKPyV activation through engagement with immunoglobulin-like killer receptors (KIRs). Further studies are required to investigate the effect of HLA-C alleles along with NK cell activity against BKPyV DNAemia.

Intravesicular Cidofovir in the Treatment of BK Virus-Associated Hemorrhagic Cystitis Following Hematopoietic Stem Cell Transplantation.

Background: BK virus hemorrhagic cystitis (BKV-HC) is a common complication following hematopoietic stem cell transplant (HSCT); optimal management remains uncertain. Supportive care (bladder irrigation and blood transfusions) and intravenous and intravesicular cidofovir have all been used with varying success. Objective: The purpose of this study was to determine the safety and effectiveness of intravesicular cidofovir for BKV-HC following HSCT. Methods: A retrospective analysis of all HSCT patients with BKV-HC prescribed intravesicular cidofovir from 2012 to 2017. Results: 33 patients were treated for BKV-HC. The median age was 50 years (range 23-73), and 18 (55%) were male. The median HC symptom severity was 2, with a median BK urine viral load pretreatment of 100,000,000 IU/mL. Patients received a median of 2 intravesicular treatments (range 1-7) at a dosage of 5 mg/kg per instillation. In all, 19 (59%) patients demonstrated complete clinical resolution of symptoms; 9 (28%) had a partial response; and 4 (13%) had no change in symptoms. Patients with a high pretreatment BK viral load (>100 million) and high HC grade (2-4) had a lower frequency of complete remission. The main side effect of intravesicular instillation was severe bladder spasms in 4 patients (12%). Conclusion and Relevance: This is the largest study of intravesicular cidofovir treatment of BKV HC reported to date; 88% of patients with BVK-HC achieved clinical improvement of symptoms with minimal side effects. Clinical trials of intravesicular cidofovir could provide further evidence for this treatment for BKV-HC.

JC virus-associated nephropathy in a post-heart and -kidney transplantation patient.

JC virus-associated nephropathy is rare in kidney transplant recipients, and even rarer in recipients of other solid organ transplants. We present a case of JC virus-associated nephropathy in a heart-kidney transplant recipient, which to our knowledge is the first case reported in the literature. We discuss the findings on renal biopsy for JC virus nephropathy and our management approach to this rare complication.

BK Polyomavirus-associated nephropathy managed by screening policy in a real-life setting.

BACKGROUND: BK polyomavirus-associated nephropathy (PyVAN) is an important complication after kidney transplantation. Prevalence ranges from 1% to 10%, and graft loss occurs in approximately 50% of the cases. There is no effective treatment, so early viral detection with immunosuppression tapering is the current strategy to prevent PyVAN. AIMS: To verify the frequency of PyVAN in a single center and evaluate the response to immunosuppressive adjustments through graft survival analysis. METHODS: Retrospective evaluation of a cohort of kidney transplant recipients with biopsy-proven PyVAN, compared with no-PyVAN patients regarding clinical aspects, immunosuppression, and graft survival over at least 2 years. RESULTS: There were 1404 kidney transplants analyzed in the study period, 58 with biopsy-proven PyVAN. Cumulative incidence was 4.1%. Median time from transplantation to PyVAN diagnosis was 6 (1-41) months. PyVAN was associated with recipient male gender (P = .041) and deceased donation (P = .005). Graft survival was inferior for PyVAN compared to no-PyVAN patients, 81.8% vs 75.2%, P = .019. Thirteen (22.4%) PyVAN patients lost their grafts, nine (15.5%) losses attributed to BKPyV infection. Three patients with BKPyV-associated graft losses were submitted to a successful second kidney transplant, with no evidence of viral replication during follow-up. CONCLUSION: PyVAN still is an important cause of kidney graft failure. Even though implementing active vigilance and immunosuppressive adjustment, this real-life single-center study demonstrated inferior graft survival in PyVAN patients compared to non-PyVAN.

Transplant renal artery stenosis in a child with BK nephropathy.

TRAS and BK nephropathy are known complications of RT, but the association between both has not been reported. A 2-year-old girl underwent a deceased donor renal transplant from a 20-year-old donor, along with bilateral native nephrectomies. She had a DGF due to a renal artery thrombus and required thrombectomy with re-anastomosis. Heparin and aspirin were used. Immunosuppressive agents included thymoglobulin, steroid, tacrolimus, and MMF. CMV and EBV DNA PCRs were negative, but she developed BK viremia at 2 months with stable allograft function. Immunosuppression was reduced, and leflunomide was initiated. Blood pressures were well controlled on low-dose amlodipine. Five months after RT, she presented with hypertensive emergency, following a respiratory infection, and required dialysis for oliguric acute kidney injury. Allograft biopsy showed evidence of BK nephropathy. Immunosuppression was further minimized. Doppler renal US and renal artery duplex studies were both suggestive of TRAS. Angiogram showed severe proximal anastomotic TRAS (>95% occlusion). PTA with stenting was done with immediate improvement in the blood flow and reduction in the pressure gradient. BPs and renal function normalized. Ten months post-RT, she remains normotensive with stable renal function and resolution of BK viremia. Although ureteral stenosis and nephropathy are known to occur with BK infection, TRAS is an interesting association and possibly suggest the tropism of BK virus to the vascular endothelial cells. Timely recognition and management of both is important to prevent uncontrolled hypertension and allograft dysfunction.

Effects and long-term follow-up of using umbilical cord blood-derived mesenchymal stromal cells in pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis after unrelated cord blood transplantation.

This is a retrospective study to evaluate the efficacy and safety of umbilical cord blood-derived mesenchymal stromal cells (MSCs) for the treatment of pediatric patients with severe BK virus-associated late-onset hemorrhagic cystitis (BKV-HC) after unrelated cord blood transplantation (UCBT). Thirteen pediatric patients with severe BKV-HC from December 2013 to December 2015 were treated with MSCs. The number of MSCs transfused in each session was 1 × 106 /kg once a week until the symptoms improved. The median follow-up time was 1432 (89-2080) days. The median frequency of MSC infusion was 2 (1-3), with eight cured cases and five effective cases; the total efficacy rate was 100%. The copy number of urine BKV DNA was 4.43 (0.36-56.9) ×108 /mL before MSC infusion and 2.67 (0-56.3) ×108 /mL after MSC infusion; the difference was not significant (P = .219). There were no significant differences in the overall survival, disease-free survival, and the incidence of relapse and acute and chronic graft-versus-host disease between the MSC infusion group and non-MSC infusion group. There was also no significant difference in the cytomegalovirus, Epstein-Barr virus (EBV), and fungal and bacterial infection rates between the two groups. Although umbilical cord blood-derived MSCs do not reduce the number of BKV DNA copies in the urine, the cells have a high efficacy rate and minimal side effects in treating severe BKV-HC after UCBT among pediatric patients. MSCs do not affect the rates of relapse, long-term infection, or survival of patients with leukemia.

Use of intravenous immunoglobulin in a highly sensitized pediatric renal transplant recipient with severe BK DNAemia and rising DSA.

BK DNAemia in renal transplant recipients is a significant cause of allograft dysfunction and can lead to graft loss due to BK polyomavirus-associated nephropathy or to graft rejection due to immunosuppression reduction. Currently, the first-line treatment for BK DNAemia is immunosuppression reduction. Second-line treatment for BK DNAemia has not been well-established. In this report, we present a case of a highly sensitized second-time pediatric renal transplant recipient with severe and persistent BK DNAemia and rising DSA, who was treated with IVIG and subsequently found to have clearance of BK viremia with concomitant reduction in DSA.