BK Virus Nephropathy Research Articles

Single-cell RNA-sequencing of BK polyomavirus replication in primary human renal proximal tubular epithelial cells identifies specific transcriptome signatures and a novel mitochondrial stress pattern.

BK polyomavirus (BKPyV) contributes to premature renal failure in 10%-20% of kidney transplant recipients. Current treatment relies on reducing immunosuppression to regain BKPyV-specific immune control. Subsequently, declining allograft function may result from persisting viral cytopathology, BKPyV-specific immune reconstitution, or alloimmunity/rejection, all being poorly distinguishable by current histological or molecular approaches. To reduce the complexity encountered in BKPyV-replicating kidneys, we analyzed differentially expressed genes (DEGs) in primary human renal proximal tubular epithelial cells at 24 and 48 h post-infection (hpi) using single-cell RNA-sequencing (10x-Genomics-3´ kit). At 24 hpi, viral transcript reads predominantly mapped to the early viral gene region (EVGR) and shifted to >100-fold higher late viral gene region (LVGR) levels at 48 hpi, matching the sequential bi-directional viral protein expression from the circular double-stranded BKPyV-DNA genome. Besides expected coverage "hills" at viral 3´-poly-A sites, unexpected "spike" and "pulse" reads resulted from off-target TSO priming. "Spike" and "pulse" patterns were rare for the mostly unidirectional reads mapping to the circular mitochondrial genome. Bioinformatic curation removed "spikes" and "pulses" and reclassified 10% of DEGs in renal proximal tubular epithelial cells (RPTECs). Up-regulated gene ontologies included S and G2/M phase, double-stranded DNA repair, proximal tubulopathy, and renal tubular dysfunction, whereas allograft rejection, antigen presentation, innate immunity, translation, and autophagy were down-regulated. BKPyV-LVGR expression induced a novel mitochondrial cell stress pattern consisting of discordant up-regulation and down-regulation of mitochondria-encoded and nucleus-encoded mitochondrial genes, respectively. We explored which top-scoring gene sets of late-phase BKPyV-replicating RPTECs can identify BKPyV-associated nephropathy in kidney transplant biopsies. The results should facilitate distinguishing BKPyV-associated pathology from other entities in kidney transplant biopsies.IMPORTANCEBK polyomavirus (BKPyV) infects more than 90% of the general population and then persists in the reno-urinary tract. Subsequently, low-level urinary shedding is seen in 10% of healthy BKPyV-seropositive persons, indicating that BKPyV replication occurs despite the presence of virus-specific cellular and humoral immunity. Notably, transplantation of donor kidneys with low-level BKPyV replication is a risk factor for progression to high-level BKPyV viruria, new-onset BKPyV-DNAemia and biopsy-proven BKPyV nephropathy. Here, we identify a short list of robust up- and down-regulated nucleus-encoded differentially expressed genes potentially allowing to discriminate viral from allograft immune damage. By carefully curating viral and mitochondrial transcriptomes, we identify a novel virus-associated mitochondrial stress pattern of up-regulated mitochondria-encoded and down-regulated nucleus-encoded mitochondrial transcripts which heralds the BKPyV-agnoprotein-mediated immune escape by breakdown of the mitochondrial membrane potential and network and mitophagy. The results may prove useful when assessing the role of BKPyV replication in kidney transplant patients with suspected acute rejection and/or BKPyV nephropathy.

Proteome profiling of polyomavirus nuclear replication centers using iPOND.

Polyomaviruses (PyVs) cause diverse diseases in a variety of mammalian hosts. During the life cycle, PyVs recruit nuclear host factors to viral genomes to facilitate replication and transcription. While host factors involved in DNA replication, DNA damage sensing and repair, and cell cycle regulation have been observed to bind PyV DNA, the complete set of viral and host proteins comprising the PyV replisome remains incompletely characterized. Here, the iPOND-MS technique (Isolation of Proteins on Nascent DNA coupled with Mass Spectrometry) was used to identify the proteome bound to murine PyV (MuPyV) DNA immediately following synthesis and 2 hours post-synthesis. Several novel MuPyV DNA interactors were identified on newly synthesized viral DNA (vDNA), including MCM complex members, DNA primase, DNA polymerase alpha, DNA ligase, and replication factor C. Though displaying partial overlap, the host and viral proteins bound to MuPyV DNA 2 hours post-synthesis lacked many of the replication proteins found on newly synthesized vDNA. These data help distinguish between the host factors critical for MuPyV DNA replication and those involved in downstream processing.IMPORTANCEPolyomaviruses are the causative agents of serious diseases in humans, including progressive multifocal leukoencephalopathy (PML), BK virus nephropathy, and Merkel cell carcinoma. The exact mechanisms by which the virus replicates, and which host cell proteins are required, are incompletely characterized. Identifying the host proteins necessary for efficient viral replication in the cell may reveal targets for downstream targets that may suppress viral replication in vivo.

Successful prevention of BK-polyomavirus nephropathy using extracorporeal photopheresis for immunosuppression minimisation following severe BK polyomavirus replication after kidney transplantation in a double lung transplant recipient, a case report

BackgroundBK-polyomavirus (BKpyV) nephropathy (BKVN) is associated with end-stage kidney disease in kidney and non-kidney solid organ transplantation, with no curative treatment.Case presentationA 45-year-old woman with a past medical history of double lung transplantation subsequently developed end-stage kidney disease, of undetermined origin. One month after receiving a kidney transplant, a diagnosis of early BKVN was suspected, and in retrospect was a reasonable cause for the loss of her native kidneys. Minimisation of immunosuppression, achieved through extracorporeal photopheresis, allowed clearance of BKpyV and so prevented nephropathy. Both lung and kidney grafts had a satisfactory and stable function after one year of follow-up, with no rejection.ConclusionsExtracorporeal photopheresis may have facilitated minimisation of immunosuppression and BKpyV clearance without lung allograft rejection.

BK Virus Nephropathy After Kidney Transplantation and Its Diagnosis Using Urinary Micro RNA

BK virus-associated nephritis (BKVAN) is an important cause of graft loss in renal transplant recipients B K viremia occurs in up to 30% of renal transplant recipients. Since the discovery of BKV in 1971, effective prophylaxis and treatment have not been established, and it is not uncommon for a transplant kidney to be lost without cure of BKVAN. BK virus infection is reactivated when cellular immunity is suppressed, which is often during the first year after kidney transplantation when cellular immunity is most suppressed. Clinically, it is caused by reactivation of latent infection or new infection from the donor kidney, leading to viremia, viremia, and transplant nephropathy. BK virus nephropathy is currently diagnosed definitively by measuring the amount of BK virus DNA in the blood and proving SV40-positive cells in transplant kidney tissue obtained by transplant kidney biopsy, but the time required for diagnosis and the low sensitivity of immunohistochemistry using antibodies are problematic. Therefore, we investigated whether the diagnosis of BK virus nephropathy could be made earlier by searching for miRNAs in the urine of renal transplant recipients.

Native BK Virus Nephropathy in a Patient with Multiple Myeloma

Native BK Virus Nephropathy in a Patient with Multiple Myeloma

Treating Refractory BK Virus Nephropathy with Allogenic BK Virus-Specific T Cells in Kidney Transplant Recipients

Treating Refractory BK Virus Nephropathy with Allogenic BK Virus-Specific T Cells in Kidney Transplant Recipients

A Rare Cause of Kidney Failure: Native Kidney BK Polyomavirus Nephropathy after Lung Transplant

A Rare Cause of Kidney Failure: Native Kidney BK Polyomavirus Nephropathy after Lung Transplant

Pretransplantation assessment of BK virus seropositivity in kidney donors and recipients

Background: BK virus (BKV) is a member of the polyomavirus family. The determination of anti-BKV immunoglobulin G (IgG) antibody levels in kidney donors and recipients has been reported as a possible predictor of the risk of BK nephropathy. Allograft dysfunction is a significant risk factor. The main objective of this study was to address the high prevalence of renal failure due to BKV nephropathy in kidney transplant recipients. This investigation aims to determine whether donors and recipients of renal transplants had BKV IgG antibodies before transplantation. Methods: Blood samples were collected from 46 kidney transplant recipients and their corresponding 46 donors. An enzyme-linked immunosorbent assay was used to qualitatively analyze human BKV IgG. Results: Ninety-two participants, 46 kidney transplant donors, and 46 kidney transplant recipients, were analyzed. Pretransplantation anti-BKV antibody levels were higher in kidney transplant donors (73%) than in recipients (63%). Donors and recipients included in the study were grouped into seropositive and seronegative recipients, with the highest proportion of seropositive recipient-donor groups (48%) and the lowest percentages in the seronegative donor and seronegative recipient groups. Fifty-one percent of the participants were male and 49% were female. The age distribution of most subjects was >50 years old. Conclusion: BKV can cause kidney transplant rejection. Routine screening of transplant recipients and donors for BKV IgG seropositivity is recommended before renal transplantation. This can improve transplant outcomes and prevent rejection.

342.7: BKV nephropathy in kidney transplant recipients: Management and outcome.

342.7: BKV nephropathy in kidney transplant recipients: Management and outcome.

P.220: BK virus associated Urothelial cancer in the background of BK polyomavirus nephropathy post renal transplantation: A case report and review of literature.

P.220: BK virus associated Urothelial cancer in the background of BK polyomavirus nephropathy post renal transplantation: A case report and review of literature.

Risk factors and outcome of BK polyomavirus infection in pediatric kidney transplantation.

BK polyomavirus (BKV) infection is a critical complication hindering graft survival after kidney transplantation. We aimed to investigate the risk factors and outcome of BKV infection in pediatric kidney transplantation. The clinical and follow-up data of pediatric kidney transplant recipients at the Children's Hospital of Fudan University from Jan 2015 to June 2023 were retrospectively analyzed. A total of 217 patients were included in the study with mean follow-up time of 24.3 ± 19.9 months. The mean age at transplantation was 9.7 ± 4.2years. The patient survival rate and graft survival rate were 98.2% and 96.8%, respectively. Twenty-nine patients (13.4%) developed BKV infection, which was detected at 5.8 ± 3.2months after transplantation. Among these 29 patients with BKV infection, 8 patients (3.6%) developed BKV nephropathy (BKVN), which was diagnosed at 8.3 ± 2.9months after transplantation, and 2 patients developed graft failure eventually. Compared with the non-BKV infection group (eGFR 76.7 ± 26.1mL/min/1.73 m2) and BKV infection without BKVN group (eGFR 85.2 ± 23.8mL/min/1.73 m2), BKVN group had lowest eGFR during follow-up (33.5 ± 11.0ml/min/1.73 m2, P < 0.001). Younger age at transplant (OR 0.850, 95%CI 0.762-0.948, P = 0.005), CAKUT disease of primary etiology (OR 2.890, 95%CI 1.200-6.961, P = 0.018), and CMV negative recipient serostatus before transplantation (OR 3.698, 95%CI 1.583-8.640, P = 0.003) were independent risk factors for BKV infection. Incidence of BKV infection is quite high within 12months after pediatric kidney transplantation and children with BKVN have poor graft function. Younger age at transplant, CAKUT disease, and CMV negative recipient serostatus before transplantation increase the risk of BKV infection after kidney transplantation.

The Prevalence and Outcomes of BK Polyoma Virus Nephropathy in Living Donor Kidney Transplant Recipients

The Prevalence and Outcomes of BK Polyoma Virus Nephropathy in Living Donor Kidney Transplant Recipients

Screening for BK Virus Infection in Kidney Transplant Recipients at Mohamed V Military Teaching Hospital

After kidney transplantation, BK polyomavirus reactivation can manifest as nephropathy in 1% to 10% of patients. PCR testing of urine and blood is commonly used to screen for BK polyomavirus nephropathy. The study aims to detect BK virus infection in kidney transplant patients to prevent tubulointerstitial nephropathy and graft loss. This retrospective study includes 26 patients who underwent kidney transplants between January 2019 and December 2023. We diagnosed BK virus infection by performing real-time PCR on blood and urine samples. BKV DNA was detected in 3 patients. Reducing immunosuppressive therapy led to negative PCR results and favorable clinical and biological outcomes in these 3 patients.

Biopsy-proven BK virus nephropathy inrenal transplant recipients: A multi-central study from Turkey (BK-TURK STUDY).

BK polyomavirus infection is a challenging complication of renal transplantation. The management is not standardized and is based on reports from transplantation centers' experiences, usually with small sample sizes. Therefore, we aimed to present our countrywide experience with BK virus nephropathy (BKVN) in renal transplant recipients. Our study was carried out with the participation of 30 transplantation centers from all regions of Turkey. Only cases with allograft biopsy-proven BKVN were included in the study. 13,857 patients from 30 transplantation centers were screened, and 207 BK nephropathy cases were included. The mean age was 46.4± 13.1 years, and 146 (70.5%) patients were male. The mean time to diagnosis of BK nephropathy was 15.8±22.2 months after transplantation. At diagnosis, the mean creatinine level was 1.8± 0.7 mg/dL, and the mean estimated glomerular filtration rate was 45.8 ± 19.6 mL/min/1.73m2. In addition to dose reduction or discontinuation of immunosuppressive drugs, 18 patients were treated with cidofovir, 11 patients with leflunomide, 17 patients with quinolones, 15 patients with intravenous immunoglobulin (IVIG), 5 patients with cidofovir plus IVIG, and 12 patients with leflunomide plus IVIG. None of the patients receiving leflunomide or leflunomide plus IVIG had allograft loss. During follow-up, allograft loss occurred in 32 (15%) out of 207 patients with BK nephropathy. BKVN is still a frequent cause of allograft loss in kidney transplantation and is not fully elucidated. The results of our study suggest that leflunomide treatment is associated with more favorable allograft outcomes.

BK virus nephropathy in kidney transplantation (literature review

BK virus nephropathy in kidney transplantation (literature review

Protocol biopsy of kidney allograft enables early detection of BK virus nephropathy to preserve kidney allograft function.

The Banff Working Group has updated the histological classification of BK virus nephropathy (BKVN), highlighting the importance of early detection. However, an early detection strategy for BKVN using biopsy has not yet been established. Our investigation aimed to assess the efficacy of protocol biopsy for the diagnosis of BKVN. We performed a retrospective cohort study of 314 patients who had undergone kidney transplantation between 2006 and 2021. Kidney allograft biopsies were performed as part of a protocol biopsy at 3 months and 1 year post-transplantation. Following the diagnosis of BKVN, the immunosuppressant dose was reduced. Twelve patients (3.8%) were diagnosed with BKVN by biopsy. Most diagnoses are established during the early stages of BKVN (polyomavirus nephropathy class 1 in six, class 2 in five, and class 3 in one). Following the reduction in immunosuppressant dose, kidney allograft function did not deteriorate in any patients. Additionally, test for BK virus DNA in the blood was negative. All but one patient demonstrated histological resolution of BKVN, and the other had a very slight positivity for the simian virus 40 large T antigen. The median follow-up time after BKVN diagnosis was 6 years. One patient developed de novo donor-specific antibody and subclinical acute antibody-mediated rejection that was successfully cured. Our analysis indicates that protocol biopsy may enable the early detection of BKVN, resulting in the preservation of kidney function.

Incidence and Outcomes of BK Virus Nephropathy in Kidney Transplant Recipients With Steroid-Free Maintenance Immunosuppression

BackgroundBK virus nephropathy (BKVN) is a significant complication in kidney transplant recipients, resulting in graft dysfunction and potentially leading to graft loss. This study aims to investigate the incidence and outcomes of BKVN in kidney transplant recipients receiving steroid-free maintenance immunosuppression in a Latin -American cohort. MethodsCase series study of BKVN among kidney transplant recipients who underwent transplantation between 2008 and 2023. The primary outcome was graft loss caused by BKVN, excluding death with function. Secondary outcomes included graft function and acute rejection episodes. The statistical analysis involved descriptive statistics and the Kaplan-Meier (K-M) method to plot the overall probabilities of not initiating dialysis. ResultsDuring the 15-year period, 2236 kidney transplants were performed, BKVN was histologically diagnosed in 38 kidney recipients and 33 cases were analyzed. Median age was 50 years and men were 48.5% of patients. A total of 45.4% of BKVN occurred within the first 12 months of transplant. The incidence of BKVN was 1.6% but it varied by era. The rate of graft loss was 75.7% (25 cases). The K-M graft survival probability at 6 months and 12 months after diagnosis of BKVN was 38.3% (95% CI 24.7–59.4) and 22.3% (95% CI 11.7–42.8), respectively. ConclusionBKVN affected 1.6% of transplant recipients and it was associated with high-rate of graft loss. We observed that significant graft disfunction at the time of diagnosis resulted in worse outcomes with a reduced probability of graft survival.

#2082 Effectiveness of a surveillance protocol and early mTORi conversion according to Urine BK viral load in Thai kidney transplant recipients

Abstract Background and Aims BK viral nephropathy (BKVN) is a crucial cause of early kidney allograft failure. Early detection and prompt treatment in the case of a high urine viral load might be more advantageous than waiting until BK viremia occurs. Data regarding outcome of BK infection based on adjustments of immunosuppression according to urine viral load is limited. Method A prospective cohort study of kidney transplant (KT) recipients at Siriraj Hospital, conducted between January 2015 and June 2020, involved monitoring urine BK viral load (RT-PCR) at 1, 2, 3, 6, 12, 18, and 24 months after KT. Determination of BK viremia and adjustments to immunosuppression were performed in patients with urine BK viral loads exceeding 1,000,000 copies/ml or demonstrating progressive increments in BK viruria. Initially, mycophenolate (MPA) dosage was reduced, and subsequently, conversion to mTOR inhibitors was considered for non-responsive cases. Data on the overall incidence and risk factors of BK viremia and/or BKVN were collected. Results Out of a total of 339 enrolled patients, 234 (69%) underwent deceased KT, and 49 (14.5%) received induction therapy with anti-thymocyte globulin. The incidence of BK viruria, viremia, and BKVN were 38.6% (131 patients), 9.7% (33 patients), and 4.1% (14 patients), respectively. The median time of occurrence for BK viruria and BKVN was 3 (IQR 1-12) and 4.5 (IQR 3–18) months after KT, respectively. Most BKVN cases (71.4%) developed within the first six months post KT. We did not find any significant risk factors associated with the occurrence of BK viremia or BKVN. Regarding the adjustment of immunosuppression, the initial reduction of MPA dosage was effective in 48 out of 92 patients (52.17%). In cases with an extremely high urine BK viral load or no response to MPA reduction, 46 patients received a change from MPA to everolimus, which was successful in 38 patients (82.6%). No graft loss due to BKVN was observed throughout the study. Conclusion The incidence of BK infection after KT in Thai recipients is high, comparable to western population. A surveillance protocol with urine BK viral load and early mTORi conversion is effective for prevention of allograft loss from BKVN.

#2825 BK virus in transplant patients: an enemy to fear or a challenge to accept? The 17-year experience of our transplant center

Abstract Background and Aims Reactivation of the BK virus in immunosuppressed patients is a risk factor for the development of BKV nephropathy. Ten percent of transplant patients are affected by BKV nephropathy, and 50% of them experience graft loss. The purpose of this study is to assess the medium to long-term effects of an early immunosuppression reduction strategy in the presence of urinary and/or serum BKV replication in a large population of kidney transplant recipients from our center. Method A retrospective observational study was conducted on 681 patients from immediate post-transplant with at least 6 months of observation. 91.5% of them were on the same immunosuppressive therapy (MMF, Steroid, tacrolimus). A total of 16200 samples were collected from blood and urine simultaneously for PCR quantification of BKV over a post-transplant period of 54.4 ± 34.2 months. Immunosuppression reduction began after two repeated biweekly detections of viruria &amp;gt;105 copies/ml and/or viremia &amp;gt;103 copies/ml. Results 35% of cases tested positive for viruria, with 19% also positive for viremia. Onset and peak viruria and viremia were observed at 4.1 ± 3.3 months and 4.2 ± 3.5 months, and 5.3 ± 4.6 and 5.4 ± 4.1 months, respectively. Viruria negativization occurred in 79.4% of patients after 13.2 ± 9.7 months, while viremia disappeared in 94.6% after 9.2 ± 7.5 months. In 5 patients with persistent viruria and viremia, therapy with Cidofovir or Leflunomide was initiated following biopsy. 14.3% of patients with persistent viruria maintained low replication and stable renal function. No episodes of acute rejection occurred. Only one case of irreversible BKV nephropathy was observed. Conclusion Timely reduction of immunosuppression allows excellent control of BKV replication, stability of renal function in the medium to long term, and makes the occurrence of irreversible chronic BKV nephropathy rare.

#2362 Clinical utility Anti-human T-lymphocyte Immunoglobulin (ATLG) as an induction agent in a living donor kidney transplantation: 5-year follow-up data

Abstract Background and Aims The usage of induction agents for living donor kidney transplants in India is varied. Polyclonal antibodies currently in use are anti-thymocyte globulin (ATG) and anti-T-lymphocyte globulin (ATLG). The role and dose of ATLG need to be defined. This study is focused on ATLG usage and the outcome with long-term follow-up. Method This is an analysis of 206 patients who received ATLG as an induction agent from 2017 to 2023. Patients received triple immunosuppression therapy: Tacrolimus, Mycophenolate Mofetil (MMF), and prednisolone for maintenance immunosuppression. Results A total of 206 patients received ATLG as an induction agent for living donor kidney transplants. The mean age of the patients was 39.13 ± 12.56 years. There were 87.3% (n = 180) males and 12.6% (n = 26) females. The majority of transplants in our study were ABO-compatible (94.6%, n = 195) and ABO-incompatible (5.2%, n = 11). The mean age of donors was 41 ± 13.7 years. Males were 38.3% (n = 79), and females were 61.6% (n = 127). Overall survival observed in the current study was 98% (n = 202), Post-transplant, 4 patients died (n = 2 died due to COVID-19, 1 due to Heart failure and 1 was infectious mortality.) The mean cumulative dose of ATLG in the current study was 305.1 ± 61.8 mg, and the mean dose was 5.4 ± 1.4 mg/kg. The baseline etiologies of patients who underwent transplant were chronic glomerulonephritis (47.5% n = 98), diabetic nephropathy (16.9% n = 35), hypertension (29.1% n = 60), CIN, and other GMB diseases. In the current study, the figure shows overall 11.6% (n = 24) rejections and 5-year follow-up data of Serum creatinine within a normal range. Post-transplant BK Virus Nephropathy was observed in 3.39% (n = 7) cases, CMV infection in two cases, TB was observed in three cases and fungal pneumonia in one case. Conclusion Long-term 5 year follow-up of Living donor kidney transplant shows that ATLG is an effective and safe induction agent. Good compliance with Oral immunosuppressant can improve graft survival as per the current study.