The Relationship between Acute Rejection, Hemoglobin Level, and BK Virus Infection Among Renal Transplant Recipients.

BACKGROUND: This study aimed to explore the risk factors for BK virus (BKV) infection in renal transplant recipients (RTRs) routinely treated with tacrolimus. METHODS: Forty-two cases with BKV infections and 51 patients without BKV infections were enrolled in the study. Eighty-seven healthy individuals and 77 patients undergoing dialysis were randomly included as controls. A logistic regression model was used to analyze potential variables in order to evaluate factors related to BKV infection in the renal transplant recipients. RESULTS: The number of individuals with acute rejection in BKV positive RTRs is significantly higher than that in BKV negative RTRs. Hemoglobin levels in BKV positive RTRs were significantly lower than those in BKV negative RTRs (109.61 ± 20.11 vs. 130.16 ± 26.297, p < 0.001). There was a positive correlation between tacrolimus levels and hemoglobin concentration in RTRs (r = 0.329, p = 0.023). The results of a multivariate regression analysis indicated that a history of acute rejection (OR = 4.157, p = 0.031) and low hemoglobin (OR = 0.963, p < 0.001) were risk factors for BKV infection. CONCLUSIONS: Acute rejection and low hemoglobin were risk factors for BKV infection after renal transplantation.

Dynamic viral integration patterns actively participate in the progression of BK polyomavirus-associated diseases after renal transplantation.

The classical lytic infection theory along with large T antigen-mediated oncogenesis cannot explain the BK polyomavirus (BKPyV)-associated tumor secondary to BKPyV-associated nephropathy (BKVAN), viremia/DNAemia, and viruria after renal transplantation. This study performed virome capture sequencing and pathological examination on regularly collected urine sediment and peripheral blood samples, and BKVAN and tumor biopsy tissues of 20 patients with BKPyV-associated diseases of different stages. In the early noncancerous stages, well-amplified integration sites were visualized by in situ polymerase chain reaction, simultaneously with BKPyV inclusion bodies and capsid protein expression. The integration intensity, the proportion of microhomology-mediated end-joining integration, and host PARP-1 and POLQ gene expression levels increased with disease progression. Furthermore, multiomics analysis was performed on BKPyV-associated urothelial carcinoma tissues, identifying tandem-like structures of BKPyV integration using long-read genome sequencing. The carcinogenicity of BKPyV integration was proven to disturb host gene expression and increase viral oncoprotein expression. Fallible DNA double-strand break repair pathways were significantly activated in the parenchyma of BKPyV-associated tumors. Olaparib showed an antitumor activity dose-response effect in the tumor organoids without BRCA1/2 genes mutation. In conclusion, the dynamic viral integration patterns actively participate in the progression of BKPyV-associated diseases and thus could be a potential target for disease monitoring and intervention.

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.

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.

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.

Association of donor hepatitis C virus infection status and risk of BK polyomavirus viremia after kidney transplantation.

Kidney transplantation (KT) from deceased donors with hepatitis C virus (HCV) into HCV-negative recipients has become more common. However, the risk of complications such as BK polyomavirus (BKPyV) remains unknown. We assembled a retrospective cohort at four centers. We matched recipients of HCV-viremic kidneys to highly similar recipients of HCV-aviremic kidneys on established risk factors for BKPyV. To limit bias, matches were within the same center. The primary outcome was BKPyV viremia ≥1000 copies/ml or biopsy-proven BKPyV nephropathy; a secondary outcome was BKPyV viremia ≥10 000 copies/ml or nephropathy. Outcomes were analyzed using weighted and stratified Cox regression. The median days to peak BKPyV viremia level was 119 (IQR 87-182). HCV-viremic KT was not associated with increased risk of the primary BKPyV outcome (HR 1.26, p = .22), but was significantly associated with the secondary outcome of BKPyV ≥10 000 copies/ml (HR 1.69, p = .03). One-year eGFR was similar between the matched groups. Only one HCV-viremic kidney recipient had primary graft loss. In summary, HCV-viremic KT was not significantly associated with the primary outcome of BKPyV viremia, but the data suggested that donor HCV might elevate the risk of more severe BKPyV viremia ≥10 000 copies/ml. Nonetheless, one-year graft function for HCV-viremic recipients was reassuring.

Scientific and clinical developments in Merkel cell carcinoma: A polyomavirus-driven, often-lethal skin cancer.

Merkel cell carcinoma (MCC) is a primary neuroendocrine skin cancer that recurs in ~40% of cases. Merkel cell polyomavirus (MCPyV) and ultraviolet (UV)-induced mutations are two major causative factors of MCC. Virus-positive MCCs express polyomavirus oncoproteins that are highly immunogenic yet are required for ongoing tumor growth. Virus-negative MCCs have a high burden of UV-DNA mutations that encode tumor-specific UV-neoantigens. Thus, both UV- and virus-induced MCCs are highly immunogenic, enabling diverse T-cell targeted therapies. Optimal MCC management is challenging given its rarity, aggressive nature, rapidly evolving care guidelines, and fundamental differences in management compared to other skin cancers. MCC is often managed aggressively with extensive surgery, radiotherapy or systemic therapy, frequently leading to toxicities that might have been avoidable while still achieving optimal disease control. Thus, multi-disciplinary care is crucial for providing patients with the best possible outcomes. The outlook for many patients with advanced MCC has progressed remarkably over the past decade due to PD-1 pathway blocking agents that provide durable benefit for a substantial subset of MCC patients. The management of early-stage MCC has also improved due to better approaches to integrate surgery and radiotherapy. Prognostic accuracy and ongoing surveillance have advanced due to stage-specific recurrence data and sophisticated "liquid biopsies" that allow early detection of disease recurrence. Here we summarize both recent striking progress and pressing challenges such as PD-(L)1-refractory MCC, and management of MCC patients with immune dysfunction. We also highlight diverse resources to allow providers to take advantage of recent progress in this fast-moving field.

Human inborn errors of immunity to oncogenic viruses.

Oncoviruses are viruses that can cause tumors. Seven viruses are currently recognized as oncogenic in humans: Epstein Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV, also known as HHV8), human papillomaviruses (HPVs), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV). The clinical phenotypes resulting from infection with these oncoviruses range from asymptomatic infection to invasive cancers. Patients with inborn errors of immunity (IEI) are prone to the development of infectious diseases caused by a narrow or broad spectrum of pathogens, including oncoviruses in some cases. Studies of patients with IEI have deepened our understanding of the non-redundant mechanisms underlying the control of EBV, HHV8 and HPV infections. The human genetic factors conferring predisposition to oncogenic HBV, HCV, HTLV-1 and MCPyV manifestations remain elusive. We briefly review here what is currently known about the IEI conferring predisposition to severe infection with oncoviruses.

BK Virus and Transplantation.

As guest editors, we are pleased to present this Special Issue on BK virus (BKV) and transplantation with the intention of exploring some aspects related to BKV-associated diseases in transplant recipients, since they are still unclear [...].

Deceased-Donor Acute Kidney Injury and BK Polyomavirus in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: BK polyomavirus (BKV) infection commonly complicates kidney transplantation, contributing to morbidity and allograft failure. The virus is often donor-derived and influenced by ischemia-reperfusion processes and disruption of structural allograft integrity. We hypothesized that deceased-donor AKI associates with BKV infection in recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied 1025 kidney recipients from 801 deceased donors transplanted between 2010 and 2013, at 13 academic centers. We fitted Cox proportional-hazards models for BKV DNAemia (detectable in recipient blood by clinical PCR testing) within 1 year post-transplantation, adjusting for donor AKI and other donor- and recipient-related factors. We validated findings from this prospective cohort with analyses for graft failure attributed to BKV within the Organ Procurement and Transplantation Network (OPTN) database. RESULTS: The multicenter cohort mean kidney donor profile index was 49±27%, and 26% of donors had AKI. Mean recipient age was 54±13 years, and 25% developed BKV DNAemia. Donor AKI was associated with lower risk for BKV DNAemia (adjusted hazard ratio, 0.53; 95% confidence interval, 0.36 to 0.79). In the OPTN database, 22,537 (25%) patients received donor AKI kidneys, and 272 (0.3%) developed graft failure from BKV. The adjusted hazard ratio for the outcome with donor AKI was 0.7 (95% confidence interval, 0.52 to 0.95). CONCLUSIONS: In a well-characterized, multicenter cohort, contrary to our hypothesis, deceased-donor AKI independently associated with lower risk for BKV DNAemia. Within the OPTN database, donor AKI was also associated with lower risk for graft failure attributed to BKV. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_03_10_CJN18101120_final.mp3.

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.

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.

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.

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.

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.

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.

Clinicopathologic Characterization of Post-Renal Transplantation BK Polyomavirus-Associated Urothelial CarcinomaSingle Institutional Experience.

OBJECTIVES: To review rare cases of BK polyomavirus (BKPyV) associated urologic carcinomas in kidney transplant recipients at one institution and in the literature. METHODS: We describe the clinicopathologic features of BKPyV-associated urologic carcinomas in a single-institution cohort. RESULTS: Among 4,772 kidney recipients during 1994 to 2014, 26 (0.5%) and 26 (0.5%) developed posttransplantation urothelial carcinomas (UCs) and renal cell carcinomas (RCCs), respectively, as of 2017. Six (27%) UCs but none of the RCCs expressed large T antigen (TAg). TAg-expressing UCs were high grade with p16 and p53 overexpression (P < .05 compared to TAg-negative UCs). Tumor genome sequencing revealed BKPyV integration and a lack of pathogenic mutations in 50 cancer-relevant genes. Compared to TAg-negative UCs, TAg-expressing UCs more frequently presented at advanced stages (50% T3-T4) with lymph node involvement (50%) and higher UC-specific mortality (50%). CONCLUSIONS: Post-renal transplantation BKPyV-associated UCs are aggressive and genetically distinct from most non-BKPyV-related UCs.

Infectious Complications of Induction Therapies in Kidney Transplantation.

BACKGROUND Cytomegalovirus (CMV) and BK virus (BKV) are post-transplant opportunistic viral infections that affect patient and graft survival. This study was designed to evaluate the risk of BKV nephropathy and CMV disease in kidney transplant recipients who received induction therapy with ATG or basiliximab. MATERIAL AND METHODS We retrospectively analyzed information on 257 adult patients who underwent kidney transplantation between January 2007 and 2017. Patients were categorized into 3 groups according to the induction therapies. The primary endpoint was the onset of CMV disease or biopsy-confirmed BKV nephropathy. The secondary endpoints were biopsy-proven rejection episodes, graft loss, loss to follow-up, and death. RESULTS We followed 257 patients for a median of 55.5 months. The incidence of CMV disease was significantly higher in the only ATG group compared to the group without induction treatment (p<0.001). There was no significant difference in the incidence of BKV nephropathy among groups (p>0.05). The dosage of ATG (OR, 10.685; 95% CI, 1.343 5 to 85.009; P=0.025) was independent risk factor for death. CONCLUSIONS This study demonstrated that a higher dosage of ATG in high-risk patients is associated with an increased risk of CMV disease and patient death, also, reducing the dosage may be a rational strategy for increasing graft and patient's survival.