Monthly Screening for Polyoma Virus Eliminates BK Nephropathy and Preserves Renal Function

Primary BK virus (BKV) infections acquired mainly during childhood are usually asymptomatic. Several studies revealed its seroprevalence in adult population as high as 90% worldwide. Following primary infection, virus persists as latent infection in the urogenital tract. In renal transplant recipients, primary infection and reactivations affect 10% of patients and without treatment, more than half of these patients lose their grafts. The only way of preventing graft loss due to BKV nephropathy (BKVN), seems to monitor BKV infection after transplantation and to diagnose patients developing BKVN during the early period and treat them accordingly. In this study, we analyzed BKV presence in plasma and urine samples with real-time PCR method and evaluated the renal biopsies of pediatric renal transplant recipients after transplantation, retrospectively. A total of 142 children (63 female, 79 male; mean age: 11.7 ± 3.9 years) who had renal transplantation in Akdeniz University Medical Faculty, Antalya, Turkey, between February 2006 and April 2011 were enrolled in the study. After transplantation, peripheral blood and urine samples were collected bi-weekly for the first three months, monthly till the sixth month and every three months thereafter. BKV DNA was additionally screened in patients with unexplained rise in serum creatinine or in patients receiving anti-rejection therapy. In any plasma positivity or during the BKVN therapy, BKV DNA analysis was done bi-weekly. After DNA extraction by automated system, an 83 base pair fragment in VP1 region was amplified. Signal detection for the target region was performed with a TaqMan probe dual-labelled at the 5' end with 6-carboxyfluorescein (FAM) and the 3' end with 6-carboxytetramethylrhodamine (TAMRA). Histopathological examinations of renal biopsies were done with routine histological stains and immunohistochemical staining with monoclonal antibodies directed to SV40 antigen. From 2171 plasma and 1995 urine samples without PCR inhibitors, 442 (20%) (range: 300-4.5 x 10(7) copies/ml; mean: 2.0 x 10(5) ± 2.2 x 10(6) copies/ml) and 800 (40.1%) (range: 300-3 x 10(12) copies/ml; mean: 5.9 x 10(9) ± 1.1 x 10(11) copies/ml) were found positive for BKV DNA, respectively. For 114 (80.3%) patients, at least one urine sample was positive and more than half of those patients (68/114, 59.6%) had viremia. Of the patients, 19.7% (28/142) had viral DNA above 10(4) copies/ml, which was choosen as a cut-off value for its high positive predictive value for BKVN. For all these 28 patients, prior to renal biopsy, immunosupressive treatment was decreased. Cidofovir and/or leflunomid were initiated to nine patients who did not respond to lowered immunosupressive therapy and eight of them had renal biopsy for the confirmation of BKVN. All renal biopsy results were compatible with BKVN. From these nine patients who were receiving cidofovir and/or leflunomid, two lost their grafts because of BKVN. Since viruria is frequently encountered and the viral load is usually in low quantities and transient, it is more appropriate to use blood samples for screening programmes after renal transplantation. The efficacy of antiviral treatment in BKVN could not be evaluated since it was only applied in patients non-responding to lowered immunosuppressive therapy and had decreased renal functions. Multicenter prospective studies are required to enlighten this important issue. Early diagnosis with close monitoring of renal function and viremia, seems to be the most effective way for controlling BKVN.

An outbreak of 29 cases of Pneumocystis jirovecii pneumonia (PCP) occurred among renal and liver transplant recipients (RTR and LTR) in the largest Danish transplantation centre between 2007 and 2010, when routine PCP prophylaxis was not used. P. jirovecii isolates from 22 transplant cases, 2 colonized RTRs, and 19 Pneumocystis control samples were genotyped by restriction fragment length polymorphism and multilocus sequence typing analysis. Contact tracing was used to investigate transmission. Potential risk factors were compared between PCP cases and matched non-PCP transplant patients. Three unique Pneumocystis genotypes were shared among 19 of the RTRs, LTRs, and a colonized RTR in three distinct clusters, two of which overlapped temporally. In contrast, Pneumocystis control samples harbored a wide range of genotypes. Evidence of possible nosocomial transmission was observed. Among several potential risk factors, only cytomegalovirus viremia was consistently associated with PCP (P=0.03; P=0.009). Mycophenolate mofetil was associated with PCP risk only in the RTR population (P=0.04). We identified three large groups infected with unique strains of Pneumocystis and provide evidence of an outbreak profile and nosocomial transmission. LTRs may be infected in PCP outbreaks simultaneously with RTRs and by the same strains, most likely by interhuman transmission. Patients are at risk several years after transplantation, but the risk is highest during the first 6 months after transplantation. Because patients at risk cannot be identified clinically and outbreaks cannot be predicted, 6 months of PCP chemoprophylaxis should be considered for all RTRs and LTRs.

Background: The epidemiology of BK polyoma virus nephropathy in hematopoietic cell transplant recipients is poorly characterized. Kidney dysfunction after hematopoietic cell transplant is often attributed to treatment toxicities and kidney biopsies are rarely performed. Methods: We reviewed pathology-confirmed BK polyoma virus nephropathy cases in adult and pediatric patients who had undergone a hematopoietic cell transplant between 1 January 2015 and 31 December 2017 at our institution. Plasma and urine BK polyoma virus was assessed by a quantitative polymerase chain reaction assay and were obtained at the clinician discretion. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. BK polyoma virus nephropathy was scored by the Banff Working Group Proposal. Results: Eight (7 adult and 1 pediatric) cases of BK polyoma virus nephropathy were identified among 685 hematopoietic cell transplant recipients, 14 of whom had undergone a kidney biopsy. Five patients (62.5%) had received a CD34+-selected peripheral blood hematopoietic cell transplant; two had received a cord blood allograft and one an unmodified peripheral blood hematopoietic cell transplant. Two patients developed acute graft-versus-host disease grade II. Early post–hematopoietic cell transplant BK polyoma viruria was documented with onset at a median of 54 days (range, 6–91) post–hematopoietic cell transplant and median urine BK polyoma viral load was 9.6 log10 copies/mL (range, 8.6–10.0). BK polyoma virus nephropathy was diagnosed at a median of 267 days after hematopoietic cell transplant (range, 133–637). At BK polyoma virus nephropathy diagnosis, all patients had decreased renal function with glomerular filtration rate (median 29 mL/min/1.73 m2; range, 9–98 ) and creatinine (median 2.4 mg/dL; range, 0.8–7.5) ; median plasma BK polyoma viral load was 6.3 log10 copies/mL (range, 5.5–7.1) and median CD4+ lymphocyte count was 82 cell/mcL (range, 21–172). Conclusions: We report eight biopsy-proven BK polyoma virus nephropathies in hematopoietic cell transplant recipients from a single center. BK polyoma virus nephropathy should be considered in hematopoietic cell transplant recipients with worsening kidney function and high BK polyoma viremia.

The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy

Late-Onset Hemorrhagic Cystitis in Children after Hematopoietic Stem Cell Transplantation for Thalassemia and Sickle Cell Anemia: A Prospective Evaluation of Polyoma (BK) Virus Infection and Treatment with Cidofovir

Active Management of Post–Renal Transplantation BK Virus Nephropathy: Preliminary Report

Living-donor kidney transplantation for atypical haemolytic uremic syndrome with pre-emptive eculizumab use.

Predominance of Th2 cells and plasma cells in polyoma virus nephropathy: a role for humoral immunity?

BK virus (BKV) nephropathy has increasingly become an important cause of morbidity in renal transplant recipients. We evaluated the frequency and associated factors for BKV infection in a center performing mainly living donor transplantations over a long time period. One hundred consecutive renal transplant patients were included. Quarterly visits were planned to examine urine for decoy cells and to measure the BKV DNA in the blood and urine. Renal biopsy was performed in case of deteriorated allograft function. Serological examinations for BKV immunoglobulin G (IgG) were performed in donors. Throughout the entire follow-up period, the rates of viruria, viremia, and the positivity of decoy cells were 12%, 6%, and 13%, respectively. The negative and positive predictive values of decoy cells were 93.1% and 69.2%, respectively, for viruria, and 99.2% and 45.5%, respectively, for viremia. Biopsy-proven BKV nephropathy was observed in 1 patient. The BKV IgG was positive in all living donors. Viruria and viremia were associated with deceased donor transplantation, acute rejection, and pulse steroid therapy. In addition, viremia was associated with antithymocyte globulin therapy and a short duration of the posttransplant period. The frequency of BKV infection was lower in our transplant unit compared to previous reports. Reduced doses of immunosuppression seem to be the main factor that may explain the reduced frequency. However, an active screening strategy is still of importance for this patient group.

Everolimus (Certican™) is being developed for prevention of acute and chronic rejection of solid organ transplants. A novel proliferation inhibitor, everolimus synergies with cyclosporine to prevent and reverse acute rejection in preclinical models of kidney, heart or lung transplantation. The manifestations of chronic rejection that may contribute to graft loss are also inhibited by everolimus in preclinical models. Although everolimus is metabolised by the cytochrome P450 CYP3A isoenzyme, coadministration with cyclosporine does not alter the pharmacokinetics of cyclosporine, but cyclosporine coadministration increases exposure to everolimus. Everolimus interacts with inhibitors and inducers of this system; its clearance is reduced in patients with hepatic impairment. In an immunosuppressive regimen with cyclosporine microemulsion formulation and corticosteroids, transplant recipients treated with everolimus show low rates of acute rejection and, in one heart and one renal trial, lower rates of cytomegalovirus infection. Acute rejection rates are lower than those seen with azathioprine in cardiac transplant recipients and similar to those seen with mycophenolate mofetil in renal transplant recipients. Low rates of acute rejection are maintained when everolimus is given as part of a quadruple immunosuppressive regimen with low-dose cyclosporine in renal transplant recipients, with the added benefit of better renal function compared with full-dose cyclosporine. Use of C2 monitoring to optimise cyclosporine exposure and enhance efficacy and safety of everolimus is planned in future studies. Hypertriglyceridaemia and hypercholesterolaemia have been associated with everolimus, but these effects are not dose-limiting. There is no clear upper therapeutic limit of everolimus. However, thrombocytopenia occurs at a rate of 17% at everolimus trough serum concentrations above 7.8 ng/ml in renal transplant recipients. There are limited safety data available in patients with trough concentrations > 12 ng/ml. Studies suggest everolimus targets primary causes of chronic rejection by reducing acute rejection, allowing for cyclosporine dose reduction (which may lead to improved renal function relative to full-dose cyclosporine) and by reducing cytomegalovirus infection and inhibiting vascular remodelling.

Variability in patterns of BK viral load after renal transplantation

Background: Polyomavirus nephropathy, also termed BK virus nephropathy, is an infectious complication after kidney transplantation, causing allograft failure. The state of immunosuppression of the patient is the principal risk for the infection. Most cases of BK virus nephropathy were associated with the use of potent immunosuppressive regimens like tacrolimus and mycophenolate mofetil. To the best of our knowledge, no patient with BK virus nephropathy has been reported in Southeast Asia. Objective: We report two cases of BK virus nephropathy in patients who received the immunosuppressive regimen of sirolimus with cyclosporine. We also review the literature regarding the pathogenesis, clinical manifestations, and treatment strategies.

BK virus is a polyomavirus that can cause nephropathy and graft loss after kidney transplant. The aim of our study was to screen the BK viremia prevalence, to understand the value of the inter-vention for BK virus nephropathy, and to determine the risk factors associated with BK viremia after kidney transplant in our center. Our retrospective cross-sectional study included 91 adult kidney transplant recipients who were seen between 2015 and 2017 and who had follow-up from 1 month to over 2 years. BK viremia was evaluated by use of plasma quantitative polymerase chain reaction. The prevalence of BK viremia and the clinical treatments and outcomes of BK virus nephropathy were assessed. The prevalence of BK viremia was 5.5% (5/91 patients). BK virus nephropathy was confirmed by allograft biopsy in 4.4% (4/91 patients) of all patients. Delayed graft function was found to be an independent risk factor for BK viremia (P < .001). Patients with BK viremia had significantly higher serum creatinine levels (P = .04). Patients who were diagnosed with BK viremia at 1 to 5 years after kidney transplant had higher serum creatinine (P = .02) and uric acid levels (P = .02). After reduction or discontinuation of calcineurin inhibitor, BK virus was cleared in all patients with BK virus nephropathy, with higher level of serum creatinine but no graft loss. Delayed graft function was considered as a risk factor for viremia. Early detection of BK viremia replication is important. The strategy of reduction of immunosuppression was effective for BK virus nephropathy and graft function improvement.

Introduction: Routine BK virus (BKV) screening is recommended for all renal transplant recipients and reduces rates of allograft dysfunction and loss due to BKV nephropathy. The optimal approach to BKV surveillance remains controversial. We hypothesize that BKV screening and management practices vary significantly across transplant centers. Methods: Using the United Network for Organ Sharing (UNOS) website, all US transplant centers that performed 50 or more renal transplants in 2011 were identified (N = 110). We sent a 10-question, multiple-choice, web-based survey on BKV screening and management practices to a transplant surgeon, nephrologist, and infectious disease (ID) physician at each institution. Results: We received survey responses from 48 providers from 43/110 (39%) centers. 47.9% of respondents were nephrologists, 31.3% surgeons, and 20.8% ID physicians. Reported method of BKV screening was blood PCR only (41.7%), urine and blood PCR (37.5%), urine PCR only (16.7%), urine cytology (2.1%), and no screening (2.1%). Reported timing of BKV screening during the first year post-transplant was monthly for the first 3 months, then at months 6 and 12 (33.3%), monthly for 6 months, then at months 9 and 12 (25.0%), monthly (25.0%), and every 3 months (16.7%). 100% of respondents reduce immunosuppression in response to BKV reactivation. In addition, some respondents reported utilization of leflunomide (45.8%), cidofovir (20.8%), a quinolone (14.6%), and IVIG (8.3%). The criteria for intervention varied between institutions, with the most commonly reported indications being any BK viremia (52.1%) and BK viremia > 10,000 copies/mL (39.6%). Interestingly, among the 5 centers for which there was more than one respondent, different screening and management practices were reported by respondents from the same center. Conclusions: BKV screening and management practices vary greatly between and perhaps within transplant centers. Unfortunately, this survey did not capture the impact of these differing practices on patient outcomes. Additional data on the efficacy of various BKV screening protocols and interventions could lead to the development of a standardized, simplified, and more cost-effective approach to BKV management among renal transplant recipients.

AimReactivation of latent BK polyomavirus (BKV) infection is relatively common following renal transplantation and BKV-associated nephropathy has emerged as a significant complication. JC polyomavirus (JCV) reactivation is less well studied....