Polyomavirus Nephropathy Research Articles

A Mouse Model for "Definitive" Polyomavirus Nephropathy with Lytic Viral Replication

A Mouse Model for "Definitive" Polyomavirus Nephropathy with Lytic Viral Replication

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

Peritubular and Tubulointerstitial Inflammation as Predictors of Impaired Viral Clearance in Polyomavirus Nephropathy.

Introduction: Polyomavirus-associated nephropathy (BKPyVAN) is a common complication in kidney transplant recipients. The histological changes in the context of BKPyVAN and their association with the viral load and outcomes are still being investigated. Methods: This retrospective study involved 100 adult patients transplanted between 2000 and 2021, with available archived biopsy slides, aiming to analyze associations between viral load clearance in the blood (reduction in BKPyVAN-DNAemia below detection level) and histological features in biopsy-proven BKPyVAN. A kidney pathologist blinded to the clinical data reassessed the BANFF 2019 lesion scores in the BKPyVAN index biopsy. The primary endpoint was viral clearance three months after the diagnosis. Results: The presence of tubulointerstitial inflammation, peritubular capillaritis, and higher PVN Class at the diagnosis was linked to a reduced likelihood of viral clearance three months later (interstitial inflammation OR = 0.2, 95% CI [0.07-0.55], tubulitis OR = 0.39, 95% CI [0.21-0.73], peritubular capillaritis OR = 0.25, 95% CI [0.08-0.82], PVN Score OR = 0.1, 95% CI [0.03-0.4]), independently of other covariates. Combining the four lesions using the ROC analysis enhanced their capability to predict persistent BK viremia after 3 months with an AUC of 0.94. Conclusions: The presence of interstitial inflammation, tubulitis, and peritubular capillaritis, as well as the higher PVN Score, was associated with an up to 90% lower likelihood of viral load clearance three months post-diagnosis. These findings underscore the importance of histological evaluation as a surrogate of subsequent viral clearance and offer valuable insights for the management of BKPyVAN.

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.

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.

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.

Polyomavirus nephropathy: diagnosis, histologic features, and differentiation from acute rejection.

Polyomaviruses, particularly BK virus, are ubiquitous latent infections that may reactivate with immunosuppression during kidney transplantation, resulting in polyomavirus nephropathy (PVN). The levels of viruria and viremia serve as tools for screening and making a presumptive diagnosis of PVN, respectively, while a definitive diagnosis requires a kidney biopsy. There are histologic classifications of PVN based on the extent of tubular cell viral infection, interstitial fibrosis, and interstitial inflammation. These classifications correlate to some degree with graft function and loss, aiding in determining treatment efficacy and prognostication. PVN has histologic overlap with acute cell-mediated rejection, making the differential diagnosis challenging, although there are suggestive features for these different causes of graft dysfunction. This article reviews the diagnosis, histologic findings, and classifications of PVN, and discusses how to differentiate viral nephropathy from acute rejection.

Nephropathology of infectious disease

Infections can affect the kidney via different pathways. Urinary tract infections can directly involve the renal tissue by spreading along pre-existing canalicular structures. Such an ascending infection can manifest as ahighly active and purulent or even abscessing interstitial nephritis or as achronic-fibrosing process in recurrent pyelonephritis. Viral infections can also use the canalicular route as in polyomavirus nephropathy or spread via the blood stream in ahematogenous manner as in the case of cytomegalovirus or hantavirus infections. Likewise, bacterial infections can reach the kidney via the blood in the case of systemic infection. Another large group of nephropathies taking place as asequel of infections includes infection-related glomerulonephritides (IRGN), which are mediated by aseries of immunological mechanisms. These IRGN can be subdivided according to their temporal association with the infectious process, occurring either after the infection has healed (postinfectious) or accompanying the ongoing infectious process (parainfectious). The latter, in particular, is of increasing importance in the daily practice of nephropathologists, especially in older patients. Anumber of other glomerulonephritis forms, i.e., membranous or membranoproliferative forms, can occur as aconsequence of infection. In addition, infections can trigger nephropathies, such as thrombotic microangiopathy. The present article gives an overview of morphologic changes in renal parenchyma that take place as aconsequence of infectious processes, with particular focus on IRGN.

Polyomavirus Nephropathy in ABO Blood Group-Incompatible Kidney Transplantation: Torque Teno Virus and Immunosuppressive Burden as an Approximation to the Problem

IntroductionEarlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk to develop BK-virus (BKV) nephropathy (BKPyVAN). It remains elusive whether this is a result of more intense immunosuppression or an ABOi-associated ‘intrinsic attribute’. To address this question, we measured Torque-Teno-Virus (TTV) loads as a quantitative proxy for immunosuppressive depth in ABOi recipients and compared them to HLA-incompatible (HLAi, i.e. pre-transplant donor-specific antibody-positive) and standard-risk transplant recipients. MethodsOur retrospective study screened 2256 consecutive kidney transplantations performed between 2007-2020 at the Medical University of Vienna. Out of 629 in-principle eligible transplantations, we were able to include 465 patients: 42 ABOi, 106 HLAi and 317 control recipients. Longitudinal TTV- and BKV-PCR was carried out at pre-defined timepoints and ranged from pre-transplant until month 24 post-transplantation. TTV loads and immunosuppression were evaluated in the context of BKV-associated-complications. ResultsABOi recipients had a higher TTV load compared to HLAi and controls both at month three (median 1.5x109 vs. 2.4x108 vs. 9.1x107, p=0.010) and month six (3.1x109 vs. 1.4x107 vs. 6.4x107, p=0.014) post-transplantation. Tacrolimus exposure was significantly higher in ABOi patients compared to HLAi and control patients (ABOi vs. HLAi: p=0.007, ABOi vs. controls: p<0.0001). Biopsy-proven BKPyVAN was more frequent in ABOi recipients when compared to HLAi- and control-recipients (11.9% vs. 2.8% vs. 4.1%, p=0.046). ConclusionOur data support the assumption that ABOi patients are indeed at higher risk to develop BKPyVAN. A higher TTV load and immunosuppressive burden suggest that intense immunosuppression, rather than an ‘intrinsic attribute’ conferred by ABOi, may contribute to this finding.

Reproducibility and prognostic ability of chronicity parameters in kidney biopsy – Comprehensive evaluation comparing microscopy and artificial intelligence in digital pathology

IntroductionSemi-quantitative scoring of various parameters in renal biopsy is accepted as an important tool to assess disease activity and prognostication. There are concerns on the impact of interobserver variability in its prognostic utility, generating a need for computerized quantification. MethodsWe studied 94 patients with renal biopsies, 45 with native diseases and 49 transplant patients with index biopsies for Polyomavirus nephropathy. Chronicity scores were evaluated using two methods. A standard definition diagram was agreed after international consultation and four renal pathologists scored each parameter in a double-blinded manner. Interstitial fibrosis (IF) score was assessed with five different computerized and AI-based algorithms on trichrome and PAS stains. ResultsThere was strong prognostic correlation with renal function and graft outcome at a median follow-up ranging from 24 to 42 months respectively, independent of moderate concordance for pathologists scores. IF scores with two of the computerized algorithms showed significant correlation with estimated glomerular filtration rate (eGFR) at biopsy but not at the end of follow-up. There was poor concordance for AI based platforms. ConclusionChronicity scores are robust prognostic tools despite interobserver reproducibility. AI-algorithms have absolute precision but are limited by significant variation when different hardware and software algorithms are used for quantification.

Diagnosing Polyomavirus Nephropathy Without a Biopsy: Validation of the Urinary Polyomavirus-Haufen Test in a Proof-of-Concept Study Including Uromodulin Knockout Mice.

Polyomavirus (PyV) nephropathy (PyVN) leads to kidney transplant dysfunction and loss. Since a definitive diagnosis requires an invasive kidney biopsy, a timely diagnosis is often hampered. In this clinical dilemma the PyV haufen-test, centering around the detection of 3-dimensional PyV aggregates in the urine, might provide crucial diagnostic information. A multistep experimental design was used. The hypothesis was that PyV-haufen form within the kidneys under high concentrations of uromodulin, a kidney-specific protein and that PyV-haufen are, therefore, kidney-specific disease biomarkers. The first investigative step showed colocalization of uromodulin with aggregated PyV (1) in 10 kidneys with PyVN by immunohistochemistry, (2) in urine samples containing PyV-haufen by electron microscopy/immunogold labeling (n = 3), and (3) in urine samples containing PyV-haufen by immunoprecipitation assays (n = 4). In the in vitro experiments of the next step, only high uromodulin concentrations (≥1.25 mg/mL) aggregated PyV, as is expected to occur within injured nephrons. In contrast, in voided urine samples (n = 59) uromodulin concentrations were below aggregation concentrations (1.2-19.6 µg/mL). In the third investigative step, none of 11 uromodulin-/- knockout mice (0%) with histologic signs of PyVN showed urinary PyV-haufen shedding, compared with 10 of 14 uromodulin+/+ wild-type mice (71%). PyV-haufen form within kidneys under high uromodulin concentrations. Thus, PyV-haufen detected in the urine are specific biomarkers for intrarenal disease (ie, definitive PyVN).

Clinicopathologic Spectrum and Outcomes of Infections Diagnosed on Graft Biopsies and Nephrectomy in Live Renal Allograft Recipients: An Institutional Experience.

Modern immunosuppressive regimens have reduced rejection episodes in renal allograft recipients but have increased the risk of opportunistic infections. Infections are considered to be the second leading cause of death after cardiovascular complications in renal allograft recipients. Data on opportunistic infections affecting the allograft itself are scarce. The present study describes the spectrum of renal opportunistic infections and their outcomes diagnosed on renal allograft biopsies and nephrectomy specimens. Our retrospective observational study was conducted from December 2011 to December 2021. We analyzed infectious episodes diagnosed on renal allograft biopsies or graft nephrectomy specimens. We obtained clinical, epidemiological, and laboratory details for analyses from hospital records. BK virus nephropathy was the most common opportunistic infection affecting the allograft, accounting for 47% of cases, followed by bacterial graft pyelonephritis (25%). Mucormycosis was the most common fungal infection. The diagnosis of infection from day of transplant ranged from 14 days to 39 months. Follow-up periods ranged from 1 to 10 years. Mortality was highest among patients with opportunistic fungal infection (62%), followed by viral infections, and graft failure rate was highest in patients with graft pyelonephritis (50%). Among patients with BK polyomavirus nephropathy, 45% had stable graft function compared with just 33% of patients with bacterial graft pyelonephritis. BK polyoma virus infection was the most common infection affecting the renal allograft in our study. Although fungal infections caused the highest mortality among our patients, bacterial graft pyelonephritis was responsible for maximum graft failure. Correctly identifying infections on histology is important so that graft and patient life can be prolonged.

Clinicopathological Correlation of Polyomavirus Nephropathy in Renal Allograft Recipients According to the Banff 2018 Classification.

Polyomavirus nephropathy (PVN) is a rare kidney disease caused by the BK virus, a strain of polyomavirus. The disease primarily affects transplant recipients, which is related to intensive immunosuppression protocol and can lead to kidney allograft failure. The objective of this study is to analyze histopathological features of PVN using the Banff 2018 PVN classification and to determine clinical features and outcomes of patients with PVN in each histologic class. The study included 44 patients who had been diagnosed with PVNby renal allograft biopsy in a large tertiary care hospital in Thailand from January 2011 to January 2020. The kidney biopsy slides were reviewed for Banff 2018 PVN classification and other histologic features. Patient demographic information, clinical data, and laboratory results were retrospectively collected. Nine (20.45%), 27 (61.36%), and eight (18.18%) cases of PVN were Class I, Class II, and Class III, respectively. The time from transplant to PVN diagnosis for Classes I, II, and III was four, 19, and 33.5months, respectively. Class III had the worst clinical outcomes in terms of deterioration of allograft function, the lowest rate of resolution, and the highest rate of graft failure. PVN classification provides prognostic information in renal allograft biopsy. Our study confirmed the validity of the three-tier histologic PVN classification put forward by the Banff Working Group in 2018.

A Comparison of BK Polyomavirus Nephropathy Between Native and Allograft Kidneys

A Comparison of BK Polyomavirus Nephropathy Between Native and Allograft Kidneys

An observational cohort study of histological screening for BK polyomavirus nephropathy following viral replication in plasma

Systematic screening for BKPyV-DNAemia has been advocated to aid prevention and treatment of polyomavirus associated nephropathy (PyVAN), an important cause of kidney graft failure. The added value of performing a biopsy at time of BKPyV-DNAemia, to distinguish presumptive PyVAN (negative SV40 immunohistochemistry) and proven PyVAN (positive SV40) has not been established. Therefore, we studied an unselected cohort of 950 transplantations, performed between 2008-2017. BKPyV-DNAemia was detected in 250 (26.3%) transplant recipients, and positive SV40 in 91 cases (9.6%). Among 209 patients with a concurrent biopsy at time of first BKPyV-DNAemia, 60 (28.7%) biopsies were SV40 positive. Plasma viral load showed high diagnostic value for concurrent SV40 positivity (ROC-AUC 0.950, 95% confidence interval 0.916-0.978) and the semiquantitatively scored percentage of tubules with evidence of polyomavirus replication (pvl score) (0.979, 0.968-0.988). SV40 positivity was highly unlikely when plasma viral load is below 4 log10 copies/ml (negative predictive value 0.989, 0.979-0.994). In SV40 positive patients, higher plasma BKPyV-DNA load and higher pvl scores were associated with slower viral clearance from the blood (hazard ratio 0.712, 95% confidence interval 0.604-0.839, and 0.327, 0.161-0.668, respectively), whereas the dichotomy positivity/negativity of SV40 immunohistochemistry did not predict viral clearance. Although the pvl score offers some prognostic value for viral clearance on top of plasma viral load, the latter provided good guidance for when a biopsy was unnecessary to exclude PyVAN. Thus, the distinction between presumptive and proven PyVAN, based on SV40 immunohistochemistry, has limited clinical value. Hence, management of BKPyV-DNAemia and immunosuppression reduction should be weighed against the risk of occurrence of rejection, or exacerbation of rejection observed concomitantly.

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.

Polyomavirus Nephropathy in Native Kidneys of Non-Renal Transplant Recipients

Polyomavirus Nephropathy in Native Kidneys of Non-Renal Transplant Recipients

Native BK Polyomavirus Nephropathy in an Orthotopic Heart Transplant Recipient

Native BK Polyomavirus Nephropathy in an Orthotopic Heart Transplant Recipient

Human genes with relative synonymous codon usage analogous to that of polyomaviruses are involved in the mechanism of polyomavirus nephropathy.

Human polyomaviruses (HPyVs) can cause serious and deleterious infections in human. Yet, the molecular mechanism underlying these infections, particularly in polyomavirus nephropathy (PVAN), is not well-defined. In the present study, we aimed to identify human genes with codon usage bias (CUB) similar to that of HPyV genes and explore their potential involvement in the pathogenesis of PVAN. The relative synonymous codon usage (RSCU) values of genes of HPyVs and those of human genes were computed and used for Pearson correlation analysis. The involvement of the identified correlation genes in PVAN was analyzed by validating their differential expression in publicly available transcriptomics data. Functional enrichment was performed to uncover the role of sets of genes. The RSCU analysis indicated that the A- and T-ending codons are preferentially used in HPyV genes. In total, 5400 human genes were correlated to the HPyV genes. The protein-protein interaction (PPI) network indicated strong interactions between these proteins. Gene expression analysis indicated that 229 of these genes were consistently and differentially expressed between normal kidney tissues and kidney tissues from PVAN patients. Functional enrichment analysis indicated that these genes were involved in biological processes related to transcription and in pathways related to protein ubiquitination pathway, apoptosis, cellular response to stress, inflammation and immune system. The identified genes may serve as diagnostic biomarkers and potential therapeutic targets for HPyV associated diseases, especially PVAN.