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1
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Weissbach FH, Follonier OM, Schmid S, Leuzinger K, Schmid M, Hirsch HH. 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. J Virol 2024; 98:e0138224. [PMID: 39513696 DOI: 10.1128/jvi.01382-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/14/2024] [Indexed: 11/15/2024] Open
Abstract
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.
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Affiliation(s)
- Fabian H Weissbach
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Océane M Follonier
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Biozentrum, University of Basel, Basel, Switzerland
- SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Svenia Schmid
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Karoline Leuzinger
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | | | - Hans H Hirsch
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
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2
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Tang Y, Wang Z, Du D. Challenges and opportunities in research on BK virus infection after renal transplantation. Int Immunopharmacol 2024; 141:112793. [PMID: 39146777 DOI: 10.1016/j.intimp.2024.112793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/26/2024] [Accepted: 07/23/2024] [Indexed: 08/17/2024]
Abstract
Renal transplantation is one of the primary approaches for curing end-stage kidney disease. With advancements in immunosuppressive agents, the short-term and long-term survival rates of transplanted kidneys have significantly improved. However, infections associated with potent immunosuppression have remained a persistent challenge. Among them, BK virus (BKV) reactivation following renal transplantation leading to BK virus-associated nephropathy (BKVAN) is a major cause of graft dysfunction. However, we still face significant challenges in understanding the pathogenesis, prevention, diagnosis, and treatment of BKVAN. These challenges include: 1. The mechanism of BKV reactivation under immunosuppressive conditions has not been well elucidated, leading to difficulties in breakthroughs in clinical research on prevention, diagnosis, and treatment. 2. Lack of proper identification of high-risk individuals, and effective personalized clinical management strategies. 3.Lack of early and sensitive diagnostic markers. 4. Lack of direct and effective treatment options due to the absence of specific antiviral drugs. The purpose of this review is to summarize the current status and cutting-edge advancements in BKV-related research, providing new methods and perspectives to address future research challenges.
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Affiliation(s)
- Yukun Tang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zipei Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Dunfeng Du
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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3
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Omić H, Eder M, Schrag TA, Kozakowski N, Kläger J, Bond G, Kikić Ž. Peritubular and Tubulointerstitial Inflammation as Predictors of Impaired Viral Clearance in Polyomavirus Nephropathy. J Clin Med 2024; 13:5714. [PMID: 39407774 PMCID: PMC11476510 DOI: 10.3390/jcm13195714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
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.
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Affiliation(s)
- Haris Omić
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (M.E.); (T.A.S.); (G.B.)
| | - Michael Eder
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (M.E.); (T.A.S.); (G.B.)
| | - Tarek A. Schrag
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (M.E.); (T.A.S.); (G.B.)
| | - Nicolas Kozakowski
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (N.K.)
| | - Johannes Kläger
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria; (N.K.)
| | - Gregor Bond
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, 1090 Vienna, Austria; (H.O.); (M.E.); (T.A.S.); (G.B.)
| | - Željko Kikić
- Department of Urology, Medical University of Vienna, 1090 Vienna, Austria
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4
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Kotton CN, Kamar N, Wojciechowski D, Eder M, Hopfer H, Randhawa P, Sester M, Comoli P, Tedesco Silva H, Knoll G, Brennan DC, Trofe-Clark J, Pape L, Axelrod D, Kiberd B, Wong G, Hirsch HH. The Second International Consensus Guidelines on the Management of BK Polyomavirus in Kidney Transplantation. Transplantation 2024; 108:1834-1866. [PMID: 38605438 PMCID: PMC11335089 DOI: 10.1097/tp.0000000000004976] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 04/13/2024]
Abstract
BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.
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Affiliation(s)
- Camille N. Kotton
- Transplant and Immunocompromised Host Infectious Diseases Unit, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France
| | - David Wojciechowski
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Michael Eder
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Hopfer
- Division of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Parmjeet Randhawa
- Division of Transplantation Pathology, The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Patrizia Comoli
- Cell Factory and Pediatric Hematology/Oncology Unit, Department of Mother and Child Health, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Helio Tedesco Silva
- Division of Nephrology, Hospital do Rim, Fundação Oswaldo Ramos, Paulista School of Medicine, Federal University of São Paulo, Brazil
| | - Greg Knoll
- Department of Medicine (Nephrology), University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada
| | | | - Jennifer Trofe-Clark
- Renal-Electrolyte Hypertension Division, Associated Faculty of the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA
- Transplantation Division, Associated Faculty of the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA
| | - Lars Pape
- Pediatrics II, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - David Axelrod
- Kidney, Pancreas, and Living Donor Transplant Programs at University of Iowa, Iowa City, IA
| | - Bryce Kiberd
- Division of Nephrology, Dalhousie University, Halifax, NS, Canada
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - Hans H. Hirsch
- Division of Transplantation and Clinical Virology, Department of Biomedicine, Faculty of Medicine, University of Basel, Basel, Switzerland
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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5
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Nast CC. Polyomavirus nephropathy: diagnosis, histologic features, and differentiation from acute rejection. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:71-89. [PMID: 38725187 PMCID: PMC11228385 DOI: 10.4285/ctr.24.0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/28/2024] [Accepted: 03/20/2024] [Indexed: 06/29/2024]
Abstract
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.
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Affiliation(s)
- Cynthia C Nast
- Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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6
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Elsayed NS, Wolfe AJ, Burk RD. Urine microbiome in individuals with an impaired immune system. Front Cell Infect Microbiol 2024; 13:1308665. [PMID: 38274734 PMCID: PMC10808152 DOI: 10.3389/fcimb.2023.1308665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/21/2023] [Indexed: 01/27/2024] Open
Abstract
With the advent of next generation sequencing, it is now appreciated that human urine is not sterile. Recent investigations of the urinary microbiome (urobiome) have provided insights into several urological diseases. Urobiome dysbiosis, defined as non-optimal urine microbiome composition, has been observed in many disorders; however, it is not clear whether this dysbiosis is the cause of urinary tract disorders or a consequence. In addition, immunologically altered disorders are associated with higher rates of urinary tract infections. These disorders include immunoproliferative and immunodeficiency diseases, cancer, and immunosuppressant therapy in transplant recipients. In this review, we examine the current state of knowledge of the urobiome in immunologically altered diseases, its composition and metabolomic consequences. We conclude that more data are required to describe the urobiome in immune altered states, knowledge that could facilitate understanding the role of the urobiome and its pathophysiological effects on urinary tract infections and other disorders of the urinary tract.
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Affiliation(s)
- Noha S. Elsayed
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Alan J. Wolfe
- Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, United States
| | - Robert D. Burk
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
- Departments of Microbiology and Immunology, Epidemiology and Population Health, and Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Bronx, NY, United States
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7
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Cleenders E, Koshy P, Van Loon E, Lagrou K, Beuselinck K, Andrei G, Crespo M, De Vusser K, Kuypers D, Lerut E, Mertens K, Mineeva-Sangwo O, Randhawa P, Senev A, Snoeck R, Sprangers B, Tinel C, Van Craenenbroeck A, van den Brand J, Van Ranst M, Verbeke G, Coemans M, Naesens M. An observational cohort study of histological screening for BK polyomavirus nephropathy following viral replication in plasma. Kidney Int 2023; 104:1018-1034. [PMID: 37598855 DOI: 10.1016/j.kint.2023.07.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 07/10/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023]
Abstract
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.
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Affiliation(s)
- Evert Cleenders
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Public Health and Primary Care, Leuven Biostatistics and Statistical Bioinformatics Centre, KU Leuven, Leuven, Belgium
| | - Priyanka Koshy
- Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Katrien Lagrou
- Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
| | - Kurt Beuselinck
- Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium; Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
| | - Graciela Andrei
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar Medical Research Institute (IMIM), Hospital del Mar, Barcelona, Spain
| | - Katrien De Vusser
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Evelyne Lerut
- Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Kris Mertens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Olga Mineeva-Sangwo
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium
| | - Parmjeet Randhawa
- Division of Transplantation Pathology, the Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center-Montefiore Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Robert Snoeck
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium
| | - Ben Sprangers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Molecular Immunology, KU Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Amaryllis Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Jan van den Brand
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Marc Van Ranst
- Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Clinical and Epidemiological Virology, KU Leuven, Leuven, Belgium
| | - Geert Verbeke
- Department of Public Health and Primary Care, Leuven Biostatistics and Statistical Bioinformatics Centre, KU Leuven, Leuven, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Public Health and Primary Care, Leuven Biostatistics and Statistical Bioinformatics Centre, KU Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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8
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Hirsch HH, Mengel M, Kamar N. BK Polyomavirus Consensus. Clin Infect Dis 2022; 75:2046-2047. [PMID: 35856634 DOI: 10.1093/cid/ciac594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Affiliation(s)
- Hans H Hirsch
- Infectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, Basel, Switzerland
- Clinical Virology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, Transplantation and Clinical Virology, University of Basel, Basel, Switzerland
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Toulouse University Hospital, Toulouse, France
- Université Paul Sabatier, Toulouse, France
- Toulouse Institute for Inflammatory and Infectious Diseases (Infinity), Inserm, CNRS, Toulouse, France
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9
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Shanmugham S, Bhadauria D, Agrawal V, Jain M, Yaccha M, Kaul A, Vamsidhar V, Meyyappan J, Prasad N. The diagnostic and therapeutic dilemma of the co-existence of BK virus nephropathy with acute rejection - an experience from a single Centre and review of the literature. Transpl Immunol 2022; 72:101581. [PMID: 35301106 DOI: 10.1016/j.trim.2022.101581] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/07/2022] [Accepted: 03/07/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION BKV nephropathy (BKVN) is one of the major causes of graft loss with the advent of potent immunosuppressive drugs. The literature on the co-existence of acute rejection (AR) and BKVN is scarce. MATERIALS AND METHODS This is a single-center retrospective analysis, where the allograft biopsies of patients transplanted between 2011 and 2021 were reviewed. The biopsies, which showed evidence of coexistent AR and BKVN, were included. In addition, demographic profiles, clinical presentation, treatment details, response to therapy, and follow-up were analyzed. RESULTS Out of 1175 live transplants done between January 2011 and March 2021, 49 had BKVN representing 4.17%. Only seven patients (0.59%) had coexistent BKVN with AR. The mean serum creatinine at presentation was 2.3 mg/dl. The mean duration to diagnosis from transplant was seven months (range 3-22 months). All had significant viremia at presentation (17450-4,750,000 copies/ml). All biopsies showed type 1 inclusion bodies with SV40 positivity except one. Coexistent acute T cell-mediated rejection (TCMR) was found in five and acute ABMR in two patients. Three patients received pulse IV methylprednisolone, five received 2 g/kg IVIG, two received plasma exchange as upfront therapies. Maintenance immunosuppression reduction was made in all. Viremia clearance was noted at a mean duration of 3.5 months. However, three patients lost their grafts on follow-up. Four had stable graft function with a mean serum creatinine of 1.54 mg/dl. CONCLUSION Intensifying immunosuppression to treat AR followed by a reduction in maintenance immunosuppression and IVIG and antiviral therapies seems better strategy and showed good long-term graft survival in patients with coexistent BKVN and AR.
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Affiliation(s)
- Sabarinath Shanmugham
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Dharmendra Bhadauria
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Vinita Agrawal
- Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Manoj Jain
- Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Monika Yaccha
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Anupma Kaul
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Veeranki Vamsidhar
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Jeyakumar Meyyappan
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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10
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Zhao J, You X, Zeng X. Research progress of BK virus and systemic lupus erythematosus. Lupus 2022; 31:522-531. [PMID: 35264023 DOI: 10.1177/09612033221084259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background: Systemic lupus erythematosus (SLE) is an autoimmune disease in which patients are often infected by viruses due to deficient immunity or immunosuppressant use. BK virus (BKV)mainly affects the kidney and can also cause multiple organ involvement throughout the body, which is similar to SLE. BKV is mostly a latent infection in vivo. The incidence of virus reactivation is higher in SLE patients. Reactivation of BKV can induce the production of autoantibodies, thereby promoting the occurrence and development of SLE.Purpose: Aim of this article is to review the prevalence and pathegenesis of BKV infection in SLE patients.Method: The literature search was conducted using four different databases including PubMed, Cochrane Library, Scopus and Web of Science.Results: BK virus is higher infection and reactivation in SLE patients. The "hapten carrier" mechanism may lead to the production of autoantibodies. Some immunosuppressive drugs, like leflumide and hydroxychloroquine, may show a protective effect.Conclusions: BKV infection plays a role in the occurrence and development of SLE, and its significance deserves further exploration.
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Affiliation(s)
- Jiawei Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 34732Peking Union Medical College, Beijing, China
| | - Xin You
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 34732Peking Union Medical College, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 34732Peking Union Medical College, Beijing, China
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11
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Omić H, Kläger JP, Herkner H, Aberle SW, Regele H, Weseslindtner L, Schrag TA, Bond G, Hohenstein K, Watschinger B, Werzowa J, Strassl R, Eder M, Kikić Ž. Clinical Relevance of Absolute BK Polyoma Viral Load Kinetics in Patients With Biopsy Proven BK Polyomavirus Associated Nephropathy. Front Med (Lausanne) 2022; 8:791087. [PMID: 35071271 PMCID: PMC8770438 DOI: 10.3389/fmed.2021.791087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/06/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: The absolute BK viral load is an important diagnostic surrogate for BK polyomavirus associated nephropathy (PyVAN) after renal transplant (KTX) and serial assessment of BK viremia is recommended. However, there is no data indicating which particular viral load change, i.e., absolute vs. relative viral load changes (copies/ml; percentage of the preceding viremia) is associated with worse renal graft outcomes. Materials and Methods: In this retrospective study of 91 biopsy proven PyVAN, we analyzed the interplay of exposure time, absolute and relative viral load kinetics, baseline risk, and treatment strategies as risk factors for graft loss after 2 years using a multivariable Poisson-model. Results: We compared two major treatment strategies: standardized immunosuppression (IS) reduction (n = 53) and leflunomide (n = 30). The median viral load at the index biopsy was 2.15E+04 copies/ml (interquartile range [IQR] 1.70E+03–1.77E+05) and median peak viremia was 3.6E+04 copies/ml (IQR 2.7E+03–3.3E+05). Treatment strategies and IS-levels were not related to graft loss. After correction for baseline viral load and estimated glomerular filtration rate (eGFR), absolute viral load decrease/unit remained an independent risk factor for graft loss [incidence rate ratios [IRR] = 0.77, (95% CI 0.61–0.96), p = 0.02]. Conclusion: This study provides evidence for the prognostic importance of absolute BK viremia kinetics as a dynamic parameter indicating short-term graft survival independently of other established risk factors.
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Affiliation(s)
- Haris Omić
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Harald Herkner
- Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
| | - Stephan W Aberle
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Heinz Regele
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Tarek Arno Schrag
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gregor Bond
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina Hohenstein
- Department of Orthopedics and Trauma Surgery at the Medical University of Vienna in the General Hospital, Vienna, Austria
| | - Bruno Watschinger
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Johannes Werzowa
- Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria
| | - Robert Strassl
- Division of Clinical Virology, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Michael Eder
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Željko Kikić
- Department of Urology, Medical University of Vienna, Vienna, Austria
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12
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Innate Immunity Response to BK Virus Infection in Polyomavirus-Associated Nephropathy in Kidney Transplant Recipients. TRANSPLANTOLOGY 2022. [DOI: 10.3390/transplantology3010003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BK polyomavirus (BKV) mainly causes infection in uroepithelial and renal tubular epithelial cells of either immunocompetent or immunocompromised hosts. Despite asymptomatic or mild clinical features in immunocompetent hosts with BK infection, serious complications are frequently found in immunocompromised patients, especially patients with kidney transplantation. Accordingly, BKV-associated nephropathy (BKVN) demonstrates a wide range of clinical manifestations, including ureteric stenosis and hemorrhagic cystitis. In addition, BKV re-infection in post-kidney transplantation is also a main cause of kidney allograft dysfunction and graft loss. Since the direct anti-BKV is unavailable, immune response against BKV infection is the main mechanism for organism control and might be a novel strategy to treat or suppress BKV. As such, the innate immunity, consisting of immune cells and soluble molecules, does not only suppress BKV but also enhances the subsequent adaptive immunity to eradicate the virus. Furthermore, the re-activation of BKV in BKVN of kidney-transplanted recipients seems to be related to the status of innate immunity. Therefore, this review aims to collate the most recent knowledge of innate immune response against BKV and the association between the innate immunity status of kidney-transplanted recipients and BKV re-activation.
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13
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Halloran PF, Madill-Thomsen KS, Böhmig GA, Myslak M, Gupta G, Kumar D, Viklicky O, Perkowska-Ptasinska A, Famulski KS. A 2-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T Cell-mediated Inflammation. Transplantation 2021; 105:2374-2384. [PMID: 34310102 DOI: 10.1097/tp.0000000000003884] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND BK nephropathy (BKN) in kidney transplants diagnosed by histology is challenging because it involves damage from both virus activity and cognate T cell-mediated inflammation, directed against alloantigens (rejection) or viral antigens. The present study of indication biopsies from the Integrated Diagnostic System in the International Collaborative Microarray Study Extension study measured major capsid viral protein 2 (VP2) mRNA to assess virus activity and a T cell-mediated rejection (TCMR) classifier to assess cognate T cell-mediated inflammation. METHODS Biopsies were assessed by local standard-of-care histology and by genome-wide microarrays and Molecular Microscope Diagnostic System (MMDx) algorithms to detect rejection and injury. In a subset of 102 biopsies (50 BKN and 52 BKN-negative biopsies with various abnormalities), we measured VP2 transcripts by real-time polymerase chain reaction. RESULTS BKN was diagnosed in 55 of 1679 biopsies; 30 had cognate T cell-mediated activity assessed by by MMDx and TCMR lesions, but only 3 of 30 were histologically diagnosed as TCMR. We developed a BKN probability classifier that predicted histologic BKN (area under the curve = 0.82). Virus activity (VP2 expression) was highly selective for BKN (area under the curve = 0.94) and correlated with acute injury, atrophy-fibrosis, macrophage activation, and the BKN classifier, but not with the TCMR classifier. BKN with molecular TCMR had more tubulitis and inflammation than BKN without molecular TCMR. In 5 BKN cases with second biopsies, VP2 mRNA decreased in second biopsies, whereas in 4 of 5 TCMR classifiers, scores increased. Genes and pathways associated with BKN and VP2 mRNA were similar, reflecting injury, inflammation, and macrophage activation but none was selective for BKN. CONCLUSIONS Risk-benefit decisions in BKN may be assisted by quantitative assessment of the 2 major pathologic processes, virus activity and cognate T cell-mediated inflammation.
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Affiliation(s)
- Philip F Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
- Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, AB, Canada
| | | | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Marek Myslak
- Department of Nephrology and Kidney Transplantation, SPWSZ Hospital in Szczecin, Pomeranian Medical University, Szczecin, Poland
| | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Ondrej Viklicky
- Department of Nephrology and Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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14
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Torres R, Montero C, Escobar C, Reina M, Acevedo A, Yomayusa N, Gayón D, Pérez J. Early Detection Strategy of BK Polyomavirus Nephropathy in Patients undergoing Renal Transplant: A Single-Center Retrospective Study. TRANSPLANTATION REPORTS 2021. [DOI: 10.1016/j.tpr.2021.100077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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15
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Wente-Schulz S, Aksenova M, Awan A, Ambarsari CG, Becherucci F, Emma F, Fila M, Francisco T, Gokce I, Gülhan B, Hansen M, Jahnukainen T, Kallash M, Kamperis K, Mason S, Mastrangelo A, Mencarelli F, Niwinska-Faryna B, Riordan M, Rus RR, Saygili S, Serdaroglu E, Taner S, Topaloglu R, Vidal E, Woroniecki R, Yel S, Zieg J, Pape L. Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: a cross-sectional web-based survey. BMJ Open 2021; 11:e047059. [PMID: 34049919 PMCID: PMC8166597 DOI: 10.1136/bmjopen-2020-047059] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. PATIENTS, DESIGN AND SETTING We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. RESULTS Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil. CONCLUSIONS Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.
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Affiliation(s)
| | - Marina Aksenova
- Department of Pediatric Nephrology, Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moskva, Russian Federation
| | - Atif Awan
- Department of Pediatric Nephrology, Temple Street Children's University Hospital, Dublin, Ireland
| | - Cahyani Gita Ambarsari
- Department of Pediatric Nephrology, Cipto Mangunkusumo Hospital, Faculty of Medicine, University of Indonesia, Central Jakarta, Indonesia
| | | | - Francesco Emma
- Department of Pediatric Nephrology, Bambino Gesù Children's Hospital, Roma, Italy
| | - Marc Fila
- Department of Pediatric Nephrology, Montpellier University, Arnaud de Villeneuve Hospital, Montpellier, France
| | - Telma Francisco
- Department of Pediatric Nephrology, Dona Estefânia Hospital, Lisboa, Portugal
| | - Ibrahim Gokce
- Department of Pediatric Nephrology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Bora Gülhan
- Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Matthias Hansen
- KfH Centre of Pediatric Nephrology, Clementine Kinderhospital, Frankfurt am Main, Germany
| | - Timo Jahnukainen
- Department of Pediatric Nephrology and Transplantation, New Children's Hospital and Helsinki University Hospital, Helsinki, Finland
| | - Mahmoud Kallash
- Department of Pediatric Nephrology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | | | - Sherene Mason
- Department of Pediatric Nephrology, Connecticut Children's Medical Center, Hartford, Connecticut, USA
| | - Antonio Mastrangelo
- Department of Pediatric Nephrology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Mencarelli
- Department of Pediatric Nephrology, Azienda Ospedaliero-Universitaria di Bologna, Ospedale S. Orsola-Malpighi, Bologna, Italy
| | - Bogna Niwinska-Faryna
- Department of Pediatric Nephrology, Karolinska University Hospital, Stockholm, Sweden
| | - Michael Riordan
- Department of Pediatric Nephrology, Temple Street Children's University Hospital, Dublin, Ireland
| | - Rina R Rus
- Department of Pediatric Nephrology, University Children's Hospital, Ljubljana, Slovenia
| | - Seha Saygili
- Department of Pediatric Nephrology, Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Erkin Serdaroglu
- Department of Pediatric Nephrology, Dr Behcet Uz Children Hospital, Izmir, Turkey
| | - Sevgin Taner
- Department of Pediatric Nephrology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Rezan Topaloglu
- Department of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Enrico Vidal
- Department of Pediatric Nephrology, University Hospital of Padova, Padova, Italy
| | - Robert Woroniecki
- Department of Pediatric Nephrology, Stony Brook Children's Hospital, Stony Brook, New York, USA
| | - Sibel Yel
- Department of Pediatric Nephrology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Jakub Zieg
- Department of Pediatric Nephrology, 2nf Faculty of Medicine, University Hospital Motol, Charles University, Praha, Czech Republic
| | - Lars Pape
- Department of Pediatrics II, University Hospital Essen, Essen, Germany
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16
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Wu Z, Graf FE, Hirsch HH. Antivirals against human polyomaviruses: Leaving no stone unturned. Rev Med Virol 2021; 31:e2220. [PMID: 33729628 DOI: 10.1002/rmv.2220] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 12/20/2022]
Abstract
Human polyomaviruses (HPyVs) encompass more than 10 species infecting 30%-90% of the human population without significant illness. Proven HPyV diseases with documented histopathology affect primarily immunocompromised hosts with manifestations in brain, skin and renourinary tract such as polyomavirus-associated nephropathy (PyVAN), polyomavirus-associated haemorrhagic cystitis (PyVHC), polyomavirus-associated urothelial cancer (PyVUC), progressive multifocal leukoencephalopathy (PML), Merkel cell carcinoma (MCC), Trichodysplasia spinulosa (TS) and pruritic hyperproliferative keratinopathy. Although virus-specific immune control is the eventual goal of therapy and lasting cure, antiviral treatments are urgently needed in order to reduce or prevent HPyV diseases and thereby bridging the time needed to establish virus-specific immunity. However, the small dsDNA genome of only 5 kb of the non-enveloped HPyVs only encodes 5-7 viral proteins. Thus, HPyV replication relies heavily on host cell factors, thereby limiting both, number and type of specific virus-encoded antiviral targets. Lack of cost-effective high-throughput screening systems and relevant small animal models complicates the preclinical development. Current clinical studies are limited by small case numbers, poorly efficacious compounds and absence of proper randomized trial design. Here, we review preclinical and clinical studies that evaluated small molecules with presumed antiviral activity against HPyVs and provide an outlook regarding potential new antiviral strategies.
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Affiliation(s)
- Zongsong Wu
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - Fabrice E Graf
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland.,Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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17
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Molecular Analysis of Renal Allograft Biopsies: Where Do We Stand and Where Are We Going? Transplantation 2021; 104:2478-2486. [PMID: 32150035 DOI: 10.1097/tp.0000000000003220] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
A renal core biopsy for histological evaluation is the gold standard for diagnosing renal transplant pathology. However, renal biopsy interpretation is subjective and can render insufficient precision, making it difficult to apply a targeted therapeutic regimen for the individual patient. This warrants a need for additional methods assessing disease state in the renal transplant. Significant research activity has been focused on the role of molecular analysis in the diagnosis of renal allograft rejection. The identification of specific molecular expression patterns in allograft biopsies related to different types of allograft injury could provide valuable information about the processes underlying renal transplant dysfunction and can be used for the development of molecular classifier scores, which could improve our diagnostic and prognostic ability and could guide treatment. Molecular profiling has the potential to be more precise and objective than histological evaluation and may identify injury even before it becomes visible on histology, making it possible to start treatment at the earliest time possible. Combining conventional diagnostics (histology, serology, and clinical data) and molecular evaluation will most likely offer the best diagnostic approach. We believe that the use of state-of-the-art molecular analysis will have a significant impact in diagnostics after renal transplantation. In this review, we elaborate on the molecular phenotype of both acute and chronic T cell-mediated rejection and antibody-mediated rejection and discuss the additive value of molecular profiling in the setting of diagnosing renal allograft rejection and how this will improve transplant patient care.
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18
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BK Virus-Associated Nephropathy after Renal Transplantation. Pathogens 2021; 10:pathogens10020150. [PMID: 33540802 PMCID: PMC7913099 DOI: 10.3390/pathogens10020150] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023] Open
Abstract
Recent advances in immunosuppressive therapy have reduced the incidence of acute rejection and improved renal transplantation outcomes. Meanwhile, nephropathy caused by BK virus has become an important cause of acute or chronic graft dysfunction. The usual progression of infection begins with BK viruria and progresses to BK viremia, leading to BK virus associated nephropathy. To detect early signs of BK virus proliferation before the development of nephropathy, several screening tests are used including urinary cytology and urinary and plasma PCR. A definitive diagnosis of BK virus associated nephropathy can be achieved only histologically, typically by detecting tubulointerstitial inflammation associated with basophilic intranuclear inclusions in tubular and/or Bowman’s epithelial cells, in addition to immunostaining with anti-Simian virus 40 large T-antigen. Several pathological classifications have been proposed to categorize the severity of the disease to allow treatment strategies to be determined and treatment success to be predicted. Since no specific drugs that directly suppress the proliferation of BKV are available, the main therapeutic approach is the reduction of immunosuppressive drugs. The diagnosis of subsequent acute rejection, the definition of remission, the protocol of resuming immunosuppression, and long-term follow-up remain controversial.
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19
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Nickeleit V, Singh HK, Dadhania D, Cornea V, El‐Husseini A, Castellanos A, Davis VG, Waid T, Seshan SV. The 2018 Banff Working Group classification of definitive polyomavirus nephropathy: A multicenter validation study in the modern era. Am J Transplant 2021; 21:669-680. [PMID: 32654412 PMCID: PMC7891590 DOI: 10.1111/ajt.16189] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/18/2020] [Accepted: 06/25/2020] [Indexed: 01/25/2023]
Abstract
Polyomavirus nephropathy (PVN) remained inadequately classified until 2018 when the Banff Working Group published a new 3-tier morphologic classification scheme derived from in-depth statistical analysis of a large multinational patient cohort. Here we report a multicenter "modern-era" validation study that included 99 patients with definitive PVN transplanted post January 1, 2009 and followed the original 2018 study design. Results validate the PVN classification, that is, the 3 PVN disease classes predicted clinical presentation, allograft function, and outcome independent of therapeutic intervention. PVN class 1 compared to classes 2 and 3 was diagnosed earlier (16.9 weeks posttransplant [median], P = .004), and showed significantly better function at 24 months postindex biopsy (serum creatinine 1.75 mg/dl, geometric mean, vs class 2: P = .037, vs class 3: P = .013). Class 1 presented during long-term follow-up with a low graft failure rate: 5% class 1, vs 30% class 2, vs 50% class 3 (P = .009). Persistent PVN was associated with an increased risk for graft failure (and functional decline in class 2 at 24 months postdiagnosis; serum creatinine with persistence: 2.48 mg/dL vs 1.65 with clearance, geometric means, P = .018). In conclusion, we validate the 2018 Banff Working Group PVN classification that provides significant clinical information and enhances comparative data analysis.
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Affiliation(s)
- Volker Nickeleit
- Division of NephropathologyDepartment of Pathology and Laboratory MedicineThe University of North Carolina School of MedicineChapel HillNorth CarolinaUSA
| | - Harsharan K. Singh
- Division of NephropathologyDepartment of Pathology and Laboratory MedicineThe University of North Carolina School of MedicineChapel HillNorth CarolinaUSA
| | - Darshana Dadhania
- Division of Nephrology and HypertensionDepartment of Transplantation MedicineWeill‐Cornell Medical Center/ New York Presbyterian HospitalWeill Cornell MedicineNew YorkNew YorkUSA
| | - Virgilius Cornea
- Department of PathologyThe University of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Amr El‐Husseini
- Division of NephrologyThe University of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Ana Castellanos
- Division of NephrologyThe University of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Vicki G. Davis
- Division of NephropathologyDepartment of Pathology and Laboratory MedicineThe University of North Carolina School of MedicineChapel HillNorth CarolinaUSA
| | - Thomas Waid
- Division of NephrologyThe University of Kentucky College of MedicineLexingtonKentuckyUSA
| | - Surya V. Seshan
- Department of PathologyWeill‐Cornell Medical Center/ New York Presbyterian HospitalNew YorkNew YorkUSA
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20
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Burek Kamenaric M, Ivkovic V, Kovacevic Vojtusek I, Zunec R. The Role of HLA and KIR Immunogenetics in BK Virus Infection after Kidney Transplantation. Viruses 2020; 12:v12121417. [PMID: 33317205 PMCID: PMC7763146 DOI: 10.3390/v12121417] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.
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Affiliation(s)
- Marija Burek Kamenaric
- Tissue Typing Center, Clinical Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia;
| | - Vanja Ivkovic
- Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10 000 Zagreb, Croatia; (V.I.); (I.K.V.)
- Department of Public Health, Faculty of Health Studies, University of Rijeka, 51 000 Rijeka, Croatia
| | - Ivana Kovacevic Vojtusek
- Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10 000 Zagreb, Croatia; (V.I.); (I.K.V.)
| | - Renata Zunec
- Tissue Typing Center, Clinical Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia;
- Correspondence:
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21
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Adam BA, Kikic Z, Wagner S, Bouatou Y, Gueguen J, Drieux F, Reid G, Du K, Bräsen JH, D'Agati VD, Drachenberg CB, Farkash EA, Brad Farris A, Geldenhuys L, Loupy A, Nickeleit V, Rabant M, Randhawa P, Regele H, Mengel M. Intragraft gene expression in native kidney BK virus nephropathy versus T cell-mediated rejection: Prospects for molecular diagnosis and risk prediction. Am J Transplant 2020; 20:3486-3501. [PMID: 32372431 DOI: 10.1111/ajt.15980] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 04/03/2020] [Accepted: 04/25/2020] [Indexed: 01/25/2023]
Abstract
Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n = 5) vs pure T cell-mediated rejection (TCMR; n = 10). Five polyomavirus genes and seven immune-related genes (five associated with BKVN and two associated with TCMR) were significantly differentially expressed between these entities (FDR < 0.05). These three sets of genes were further evaluated in samples representing a spectrum of BK infection (n = 25), followed by a multicenter validation cohort of allograft BKVN (n = 60) vs TCMR (n = 10). Polyomavirus 5-gene set expression reliably distinguished BKVN from TCMR (validation cohort AUC = 0.992), but the immune gene sets demonstrated suboptimal diagnostic performance (AUC ≤ 0.720). Within the validation cohort, no significant differences in index biopsy gene expression were identified between BKVN patients demonstrating resolution (n = 35), persistent infection (n = 14) or de novo rejection (n = 11) 6 months following a standardized reduction in immunosuppression. These results suggest that, while intragraft polyomavirus gene expression may be useful as an ancillary diagnostic for BKVN, assessment for concurrent TCMR and prediction of clinical outcome may not be feasible with current molecular tools.
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Affiliation(s)
- Benjamin A Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Zeljko Kikic
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Siegfried Wagner
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Yassine Bouatou
- Paris Translational Research Center for Organ Transplantation, Paris, France
| | - Juliette Gueguen
- Paris Translational Research Center for Organ Transplantation, Paris, France
| | - Fanny Drieux
- Department of Pathology, Necker Hospital, Paris, France
| | - Graeme Reid
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Katie Du
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Jan H Bräsen
- Nephropathology Unit, Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Vivette D D'Agati
- Department of Pathology, Columbia University Medical Center, New York, New York, USA
| | - Cinthia B Drachenberg
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Evan A Farkash
- Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA
| | | | | | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Paris, France
| | - Volker Nickeleit
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Marion Rabant
- Department of Pathology, Necker Hospital, Paris, France
| | - Parmjeet Randhawa
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Heinz Regele
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
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22
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Alquadan KF, Santos AH, Leghrouz M, Ozrazgat-Baslanti T, Bozorgmehri S, Gupta G, Womer KL. A pilot study of immunosuppression resumption following BK viremia resolution. Transpl Infect Dis 2020; 23:e13508. [PMID: 33176016 DOI: 10.1111/tid.13508] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/23/2020] [Accepted: 10/25/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against humoral immunity in patients undergoing treatment for BK viremia. METHODS Thirty-six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 to 11/18/2016 underwent immunosuppression reduction. After 4 weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every 2 weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5-7 ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after 2 months of negative viremia. RESULTS Mean tacrolimus trough level (ng/mL) was 8.3 ± 2.7 at viremia onset, 5.3 ± 3.6 at resolution, and 5.6 ± 2.0 at study end date. Mean daily dose (mg) of MMF was 1574 ± 355 at onset, 910 ± 230 at resolution, and 1377 ± 451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. CONCLUSIONS The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long-term follow up are required to determine whether such an approach improves long-term graft survival.
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Affiliation(s)
| | - Alfonso H Santos
- Medicine- Nephrology, University of Florida, Gainesville, FL, USA
| | | | | | | | - Gaurav Gupta
- Medicine-Nephrology, Virginia Commonwealth University, Richmond, VA, USA
| | - Karl L Womer
- Medicine- Nephrology, University of Florida, Gainesville, FL, USA
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23
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Saleh A, El Din Khedr MS, Ezzat A, Takou A, Halawa A. Update on the Management of BK Virus Infection. EXP CLIN TRANSPLANT 2020; 18:659-670. [DOI: 10.6002/ect.2019.0254] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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24
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Huang Y, Chen XT, Yang SC, Yang HF, Hou XT, Chen WF, Li J, Deng RH, Luo JQ, Wang JY, Shen X, Chen LZ, Wang CX, Qiu J, Huang G. Detection of Proximal Tubule Involvement by BK Polyomavirus in Kidney Transplant Recipients With Urinary Sediment Double-Immunostaining. Front Immunol 2020; 11:582678. [PMID: 33072129 PMCID: PMC7539630 DOI: 10.3389/fimmu.2020.582678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022] Open
Abstract
Background The extent and depth of BK polyomavirus (BKPyV) infection in renal allograft correlate with prognosis. This study was designed to evaluate the value of urinary sediment double-immunostaining for predicting BKPyV infection in proximal tubular epithelium. Materials and methods A total of 76 urine sediment cell blocks, as well as the corresponding transplanted kidney tissues with BK polyomavirus associated-nephropathy (BKPyVAN), were evaluated by automatic double-immunostaining with anti-58-kDa Golgi protein (58K, a proximal renal tubular marker) + anti-SV40-T and anti-homogentisate 1, 2-dioxygenase (HGD, a renal tubular marker) + anti-SV40-T. Results Immunohistochemical staining demonstrated that 58K was expressed in proximal tubular epithelium but not in distal tubular epithelium or transitional epithelium. Of the 76 patients, 28 (36.8%) had urinary 58K(+)/SV40-T(+) cells and HGD(+)/SV40-T(+) cells, 41 (53.9%) had only HGD(+)/SV40-T(+) cells, one (1.3%) had only 58K(+)/SV40-T(+) cells, and six (7.9%) had only 58K(−)/HGD(−)/SV40-T(+) cells. The presence of urinary 58K(+)/SV40-T(+) cells was correlated with BKPyV infection in proximal tubular epithelium (P < 0.001, r = 0.806). The mean extent of SV40-T staining was significantly more extensive in patients with urinary 58K(+)/SV40-T(+) cells than those without urinary 58K(+)/SV40-T(+) cells (21.4 vs. 12.0%, P < 0.001). The positive predictive value, negative predictive value, sensitivity, and specificity of urinary 58K(+)/SV40-T(+) cells for predicting BKPyV infection in proximal tubular epithelium were 89.7% (95% CI: 71.5–97.3%), 91.5% (95% CI: 78.7–97.2%), 86.7% (95% CI: 68.4–95.6%), and 93.5% (95% CI: 81.1–98.3%), respectively. Conclusion Urinary sediment double-immunostaining with anti-58K and anti-SV40-T is valuable for predicting the extent and depth of BKPyV infection in renal allograft.
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Affiliation(s)
- Yang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xu-Tao Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shi-Cong Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hui-Fei Yang
- Fuda Cancer Hospital, Jinan University, Guangzhou, China
| | - Xiao-Tao Hou
- Guangzhou KingMed Center for Clinical Laboratory Co., Ltd., Guangzhou, China
| | - Wen-Fang Chen
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rong-Hai Deng
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jin-Quan Luo
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jin-Yuan Wang
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xue Shen
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Li-Zhong Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chang-Xi Wang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiang Qiu
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Gang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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25
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Schreiber PW, Kufner V, Hübel K, Schmutz S, Zagordi O, Kaur A, Bayard C, Greiner M, Zbinden A, Capaul R, Böni J, Hirsch HH, Mueller TF, Mueller NJ, Trkola A, Huber M. Metagenomic Virome Sequencing in Living Donor and Recipient Kidney Transplant Pairs Revealed JC Polyomavirus Transmission. Clin Infect Dis 2020; 69:987-994. [PMID: 30508036 PMCID: PMC7108204 DOI: 10.1093/cid/ciy1018] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/29/2018] [Indexed: 12/29/2022] Open
Abstract
Background Before kidney transplantation, donors and recipients are routinely screened for viral pathogens using specific tests. Little is known about unrecognized viruses of the urinary tract that potentially result in transmission. Using an open metagenomic approach, we aimed to comprehensively assess virus transmission in living-donor kidney transplantation. Methods Living kidney donors and their corresponding recipients were enrolled at the time of transplantation. Follow-up study visits for recipients were scheduled 4–6 weeks and 1 year thereafter. At each visit, plasma and urine samples were collected and transplant recipients were evaluated for signs of infection or other transplant-related complications. For metagenomic analysis, samples were enriched for viruses, amplified by anchored random polymerase chain reaction (PCR), and sequenced using high-throughput metagenomic sequencing. Viruses detected by sequencing were confirmed using real-time PCR. Results We analyzed a total of 30 living kidney donor and recipient pairs, with a follow-up of at least 1 year. In addition to viruses commonly detected during routine post-transplant virus monitoring, metagenomic sequencing detected JC polyomavirus (JCPyV) in the urine of 7 donors and their corresponding recipients. Phylogenetic analysis confirmed infection with the donor strain in 6 cases, suggesting transmission from the transplant donor to the recipient, despite recipient seropositivity for JCPyV at the time of transplantation. Conclusions Metagenomic sequencing identified frequent transmission of JCPyV from kidney transplant donors to recipients. Considering the high incidence rate, future studies within larger cohorts are needed to define the relevance of JCPyV infection and the donor’s virome for transplant outcomes.
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Affiliation(s)
- Peter W Schreiber
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich
| | - Verena Kufner
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Kerstin Hübel
- Department of Nephrology, University Hospital Zurich, and University of Zurich
| | - Stefan Schmutz
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Osvaldo Zagordi
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Amandeep Kaur
- Department of Biomedicine, University of Basel, Switzerland
| | - Cornelia Bayard
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich
| | - Michael Greiner
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich
| | - Andrea Zbinden
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Riccarda Capaul
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Jürg Böni
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Hans H Hirsch
- Department of Biomedicine, University of Basel, Switzerland
| | - Thomas F Mueller
- Department of Nephrology, University Hospital Zurich, and University of Zurich
| | - Nicolas J Mueller
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich
| | - Alexandra Trkola
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
| | - Michael Huber
- Institute of Medical Virology, University Hospital Zurich, and University of Zurich
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26
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Wilhelm M, Kaur A, Wernli M, Hirsch HH. BK Polyomavirus-Specific CD8 T-Cell Expansion In Vitro Using 27mer Peptide Antigens for Developing Adoptive T-Cell Transfer and Vaccination. J Infect Dis 2020; 223:1410-1422. [PMID: 32857163 DOI: 10.1093/infdis/jiaa546] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 08/22/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND BK polyomavirus (BKPyV) remains a significant cause of premature kidney transplant failure. In the absence of effective antivirals, current treatments rely on reducing immunosuppression to regain immune control over BKPyV replication. Increasing BKPyV-specific CD8 T cells correlate with clearance of BKPyV DNAemia in kidney transplant patients. We characterized a novel approach for expanding BKPyV-specific CD8 T cells in vitro using 27mer-long synthetic BKPyV peptides, different types of antigen-presenting cells, and CD4 T cells. METHODS Langerhans cells and immature or mature monocyte-derived dendritic cells (Mo-DCs) were generated from peripheral blood mononuclear cells of healthy blood donors, pulsed with synthetic peptide pools consisting of 36 overlapping 27mers (27mP) or 180 15mers (15mP). BKPyV-specific CD8 T-cell responses were assessed by cytokine release assays using 15mP or immunodominant 9mers. RESULTS BKPyV-specific CD8 T cells expanded using 27mP and required mature Mo-DCs (P = .0312) and CD4 T cells (P = .0156) for highest responses. The resulting BKPyV-specific CD8 T cells proliferated, secreted multiple cytokines including interferon γ and tumor necrosis factor α, and were functional (CD107a+/PD1-) and cytotoxic. CONCLUSIONS Synthetic 27mP permit expanding BKPyV-specific CD8 T-cell responses when pulsing mature Mo-DCs in presence of CD4 T cells, suggesting novel and safe approaches to vaccination and adoptive T-cell therapies for patients before and after kidney transplantation.
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Affiliation(s)
- Maud Wilhelm
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Amandeep Kaur
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marion Wernli
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Hans H Hirsch
- Transplantation and Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.,Clinical Virology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.,Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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27
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Chen XT, Chen WF, Li J, Deng RH, Huang Y, Yang SC, Chen PS, Jiang TY, Liu HT, Wang CX, Chen LZ, Qiu J, Huang G. Urine Donor-Derived Cell-Free DNA Helps Discriminate BK Polyomavirus-Associated Nephropathy in Kidney Transplant Recipients With BK Polyomavirus Infection. Front Immunol 2020; 11:1763. [PMID: 32973745 PMCID: PMC7466716 DOI: 10.3389/fimmu.2020.01763] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Studies have shown that plasma donor–derived cell-free DNA (dd-cfDNA) can predict renal allograft antibody-mediated rejection. This study was performed to evaluate the value of urine dd-cfDNA concentration and dd-cfDNA fraction (%) for discriminating BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant recipients with urinary BK polyomavirus (BKPyV) infection. Methods: In this retrospective single-center observational study, we enrolled kidney transplant recipients who were diagnosed with urine BKPyV infection between August 2018 and May 2019 at the First Affiliated Hospital of Sun Yat-sen University. Urine dd-cfDNA was measured by using a novel target region capture sequencing methodology. The pathological diagnosis of BKPyVAN was confirmed by anti-SV40-T immunohistochemical staining and classified using the American Society for Transplantation schema. Receiver operating characteristic curve analysis was used to investigate the relations of urine dd-cfDNA and dd-cfDNA% to intrarenal allograft BKPyV infection states. Results: In total, 93 patients were enrolled, including 40 cases of proven BKPyVAN, seven cases of probable BKPyVAN, 23 cases of possible BKPyVAN, and 23 cases of resolving BKPyVAN. Urine dd-cfDNA level in proven BKPyVAN (22.09 ± 21.27 ng/ml) was comparable to that in probable BKPyVAN (15.64 ± 6.73 ng/ml, P = 0.434) but was significantly higher than that in possible BKPyVAN (5.60 ± 3.53 ng/ml) and resolving BKPyVAN (5.30 ± 3.34 ng/ml) (both Ps < 0.05). Urine dd-cfDNA% of proven BKPyVAN (0.71 ± 0.21) was lower than that of probable BKPyVAN (0.91 ± 0.04, P < 0.001), but was significantly higher than that of possible BKPyVAN (0.56 ± 0.30) and resolving BKPyVAN (0.46 ± 0.28) (both Ps < 0.05). For distinguishing biopsy-proven BKPyVAN from biopsy-excluded BKPyVAN, the discrimination capacity of urine dd-cfDNA (AUC: 0.842, 95% CI: 0.735, 0.918) was superior to that of plasma BKPyV DNA load (AUC: 0.660, 95% CI: 0.537, 0.769) with 0.181 (95% CI: 0.043, 0.319) difference between areas under ROC curves (P = 0.010). Conclusion: The elevated urine dd-cfDNA level may help discriminate BKPyVAN in kidney transplant recipients with BKPyV viruria.
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Affiliation(s)
- Xu-Tao Chen
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wen-Fang Chen
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rong-Hai Deng
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yang Huang
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shi-Cong Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Pei-Song Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ting-Ya Jiang
- AlloDx Biotech. Co., Suzhou Industrial Park, Suzhou, China
| | - Hai-Tao Liu
- AlloDx Biotech. Co., Suzhou Industrial Park, Suzhou, China
| | - Chang-Xi Wang
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li-Zhong Chen
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiang Qiu
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gang Huang
- Department of Organ Transplant, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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28
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Jahan S, Scuderi C, Francis L, Neller MA, Rehan S, Crooks P, Ambalathingal GR, Smith C, Khanna R, John GT. T-cell adoptive immunotherapy for BK nephropathy in renal transplantation. Transpl Infect Dis 2020; 22:e13399. [PMID: 32608543 PMCID: PMC7816252 DOI: 10.1111/tid.13399] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 01/02/2023]
Abstract
Introduction BK virus (BKPyV) nephropathy occurs in 1%‐10% of kidney transplant recipients, with suboptimal therapeutic options. Case A 54‐year‐old woman received a transplant in March 2017. BKPyV was detected at 1.5 × 102 copies/mL within a month, necessitating halving of mycophenolate and addition of leflunomide. Allograft histology in December showed polyomavirus nephropathy treated with intravenous immunoglobulin and cessation of mycophenolate. In February 2018, cidofovir and ciprofloxacin were commenced. In April, tacrolimus was reduced while introducing everolimus. A second graft biopsy in August showed increasing polyoma virus infection and a subsequent biopsy in September for worsening renal function showed 30% of tubular reactivity for simian virus 40 (SV40). Allogeneic BKPyV‐reactive T cells were generated from the patient's daughter and infused over 10 sessions starting late September. The fourth allograft biopsy in November 2018 demonstrated involvement of BKPyV in 50% of tubules. Allograft function continued to decline, requiring hemodialysis from December 2018. Allograft nephrectomy after 6 months showed <1% SV40 in preserved tubules and 80% interstitial fibrosis. Discussion We conclude that the T‐cell adoptive immunotherapy reduced BKPyV load significantly despite extensive infection, but attendant fibrosis and tubular atrophy led to graft failure. Early intervention with T‐cell therapy may prove efficacious in BKPyV nephropathy.
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Affiliation(s)
- Sadia Jahan
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, Qld, Australia
| | - Carla Scuderi
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, Qld, Australia
| | - Leo Francis
- Pathology Department, Royal Brisbane and Women's Hospital, Herston, Qld, Australia
| | - Michelle A Neller
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Sweera Rehan
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Pauline Crooks
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - George R Ambalathingal
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Corey Smith
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - Rajiv Khanna
- QIMR Berghofer Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Herston, Qld, Australia
| | - George T John
- Kidney Health Service, Royal Brisbane and Women's Hospital, Herston, Qld, Australia
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29
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Costigliolo F, Lombardo K, Arend LJ, Rosenberg AZ, Matoso A, Carter-Monroe N, Bagnasco SM. BK Virus RNA in Renal Allograft Biopsies. J Histochem Cytochem 2020; 68:319-325. [PMID: 32352851 DOI: 10.1369/0022155420922604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BK polyomavirus-associated nephropathy (BKpyVAN) remains a cause of graft loss in kidney transplant recipients on immunosuppressive therapy. Its diagnosis relies on the identification of BK virus (BKV) in the renal allograft biopsy by positive immunohistochemical (IHC) stain for the viral SV40 large T antigen, although in situ hybridization (ISH) for viral DNA is used in some centers. We examined tissue detection of BKV RNA by RNAscope, a novel, automated ISH test, in 61 allograft biopsies from 56 patients with BKpyVAN. We found good correlation between the estimate of BKV tissue load by RNAscope ISH and SV40 IHC (R2 = 0.65, p<0.0001). RNAscope ISH showed 88% sensitivity and 79% specificity and, as an alternative test, could confirm the presence of BKV tissue in presumed BKpyVAN and rule out BKV as the causative agent in JC virus nephropathy. We also used tissue BK viral load estimates by both RNAscope ISH and SV40 IHC to examine the relation between tissue and plasma BK levels and found significant correlation only between BK viremia and tissue BK measured by RNAscope ISH. Our findings suggest that the RNAscope ISH assay could be a reliable test for BKV detection in allograft biopsies.
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Affiliation(s)
- Francesca Costigliolo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kara Lombardo
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Lois J Arend
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Avi Z Rosenberg
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andres Matoso
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Naima Carter-Monroe
- Pathology and Laboratory Medicine, Veterans Administration Hospital, Baltimore, Maryland
| | - Serena M Bagnasco
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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30
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Reischig T, Kacer M, Hes O, Machova J, Nemcova J, Kormunda S, Pivovarcikova K, Bouda M. Viral load and duration of BK polyomavirus viraemia determine renal graft fibrosis progression: histologic evaluation of late protocol biopsies. Nephrol Dial Transplant 2020; 34:1970-1978. [PMID: 31071208 DOI: 10.1093/ndt/gfz061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 03/01/2019] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Polyomavirus BK (BKV) infection of the renal allograft causes destructive tissue injury with inflammation and subsequent fibrosis. METHODS Using a prospective cohort of patients after kidney transplantation performed between 2003 and 2012, we investigated the role of BKV viraemia in the development and progression of interstitial fibrosis and tubular atrophy (IFTA). The primary outcome was moderate-to-severe IFTA assessed by protocol biopsy at 36 months. RESULTS A total of 207 consecutive recipients were enrolled. Of these, 57 (28%) developed BKV viraemia with 10 (5%) cases of polyomavirus-associated nephropathy (PVAN). Transient (<3 months) BKV viraemia occurred in 70% of patients, and persistent (≥3 months) BKV viraemia in 30%. A high viral load (≥10 000 copies/mL) was detected in 18% and a low viral load (<10 000 copies/mL) in 61%, while the viral load could not be determined in 21%. Moderate-to-severe IFTA was significantly increased in high [71%; odds ratio (OR) = 12.1; 95% confidence interval (CI) 1.62-90.0; P = 0.015] or persistent BKV viraemia (67%; OR = 6.33; 95% CI 1.19-33.7; P = 0.031) with corresponding rise in 'interstitial fibrosis + tubular atrophy' scores. Only patients with transient low BKV viraemia showed similar incidence and progression of IFTA to the no-BKV group. Persistent low BKV viraemia was uncommon yet the progression of fibrosis was significant. Only recipients with PVAN experienced inferior graft survival at 5 years. CONCLUSIONS These data suggest that only transient low BKV viraemia does not negatively affect the progression of allograft fibrosis in contrast to excessive risk of severe fibrosis after high or persistent BKV viraemia.
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Affiliation(s)
- Tomas Reischig
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, Czech Republic and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Martin Kacer
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, Czech Republic and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Hes
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Czech Republic and Teaching Hospital, Pilsen, Czech Republic
| | - Jana Machova
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, Czech Republic and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jana Nemcova
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Stanislav Kormunda
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Division of Information Technologies and Statistics, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Kristyna Pivovarcikova
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, Czech Republic and Teaching Hospital, Pilsen, Czech Republic
| | - Mirko Bouda
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, Czech Republic and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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31
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Chen XT, Yang SC, Chen WF, Li J, Deng SX, Qiu J, Fei JG, Deng RH, Chen YY, Chen PS, Huang Y, Wang CX, Huang G. Glomerular Parietal Epithelial Cells Infection Is Associated With Poor Graft Outcome in Kidney Transplant Recipients With BK Polyomavirus-Associated Nephropathy. J Infect Dis 2020; 219:1879-1886. [PMID: 30649366 DOI: 10.1093/infdis/jiz022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Accepted: 01/09/2019] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The purpose of this study was to investigate the effect of BK polyomavirus (BKPyV infection of glomerular parietal epithelial cells (GPECs) on graft outcome in kidney transplant recipients with BKPyV-associated nephropathy (BKPyVAN). METHODS A total of 152 kidney transplant recipients with BKPyVAN were divided into 31 with (GPEC-positive group) and 121 without (GPEC-negative group) BKPyV-infected GPECs. Clinicopathological characteristics and allograft survival were compared between the groups. RESULTS The GPEC-positive group had more patients with advanced-stage BKPyVAN than the GPEC-negative group (P < .001). At the last follow-up, the GPEC-positive group had a significantly higher serum creatinine level than the GPEC-negative group. The graft loss rate in the GPEC-positive group was higher than that in the GPEC-negative group (32.3% vs 12.4%; P = .008). Kaplan-Meier analysis showed that the graft survival rate in the GPEC-positive group was lower than that in the GPEC-negative group (log-rank test, P = .004). Multivariate Cox regression analysis demonstrated that BKPyV infection of GPECs was an independent risk factor for graft survival (hazard ratio, 3.54; 95% confidence interval, 1.43-8.76; P = .006). CONCLUSIONS GPEC infection in patients with BKPyVAN indicates more-severe pathological damage and a rapid decline in renal function. BKPyV infection of GPECs is an independent risk factor for allograft loss.
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Affiliation(s)
- Xu-Tao Chen
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shi-Cong Yang
- Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wen-Fang Chen
- Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Su-Xiong Deng
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiang Qiu
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ji-Guang Fei
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rong-Hai Deng
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan-Yang Chen
- Department of Pathology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Pei-Song Chen
- Clinical Laboratory Department, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yang Huang
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chang-Xi Wang
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Gang Huang
- Organ Transplant Center, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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32
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The Causes of Kidney Allograft Failure: More Than Alloimmunity. A Viewpoint Article. Transplantation 2020; 104:e46-e56. [DOI: 10.1097/tp.0000000000003012] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Raupp FVV, Meinerz G, da Silva CK, Bianco PCD, Goldani JC, Pegas KL, Stolfo JB, Garcia VD, Keitel E. BK Polyomavirus-associated nephropathy managed by screening policy in a real-life setting. Transpl Infect Dis 2019; 22:e13213. [PMID: 31724282 DOI: 10.1111/tid.13213] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/13/2019] [Accepted: 11/04/2019] [Indexed: 11/28/2022]
Abstract
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.
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Affiliation(s)
| | - Gisele Meinerz
- Post Graduation Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.,Department of Nephrology and Kidney Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | - Cynthia Keitel da Silva
- Post Graduation Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.,Department of Nephrology and Kidney Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | | | - João Carlos Goldani
- Department of Nephrology and Kidney Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | - Karla Lais Pegas
- Post Graduation Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.,Department of Pathology, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | - Josiane Borges Stolfo
- Department of Pathology, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | - Valter Duro Garcia
- Department of Nephrology and Kidney Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
| | - Elizete Keitel
- Post Graduation Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.,Department of Nephrology and Kidney Transplantation, Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil
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34
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Reischig T, Kacer M, Hes O, Machova J, Nemcova J, Lysak D, Jindra P, Pivovarcikova K, Kormunda S, Bouda M. Cytomegalovirus prevention strategies and the risk of BK polyomavirus viremia and nephropathy. Am J Transplant 2019; 19:2457-2467. [PMID: 31220412 DOI: 10.1111/ajt.15507] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 06/11/2019] [Accepted: 06/13/2019] [Indexed: 01/25/2023]
Abstract
Polyomavirus BK (BKV) is the cause of polyomavirus-associated nephropathy resulting in premature graft loss. There are limited data regarding the role of cytomegalovirus (CMV) infection and its prevention in developing BKV viremia and PVAN. In a prospective study, we analyzed 207 consecutive renal transplant recipients previously enrolled in 2 randomized trials evaluating different CMV prevention regimens with routine screening for BKV and CMV. Of these, 59 received valganciclovir and 100 valacyclovir prophylaxis; 48 patients were managed by preemptive therapy. At 3 years, the incidence of BKV viremia and PVAN was 28% and 5%, respectively. CMV DNAemia developed in 55% and CMV disease in 6%. Both BKV viremia (42% vs 23% vs 21%, P = .006) and PVAN (12% vs 2% vs 2%, P = .011) were increased in patients treated with valganciclovir prophylaxis compared to valacyclovir and preemptive therapy. Using multivariate Cox proportional hazard regression, valganciclovir prophylaxis was independent predictor of BKV viremia (hazard ratio [HR] = 2.38, P = .002) and PVAN (HR = 4.73, P = .026). In contrast, the risk of subsequent BKV viremia was lower in patients with antecedent CMV DNAemia (HR = 0.50, P = .018). These data suggest valganciclovir prophylaxis may be associated with increased risk of BKV viremia and PVAN. CMV DNAemia did not represent a risk for BKV.
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Affiliation(s)
- Tomas Reischig
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Martin Kacer
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ondrej Hes
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Pathology, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic
| | - Jana Machova
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Jana Nemcova
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Daniel Lysak
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Haematology and Oncology, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic
| | - Pavel Jindra
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Department of Haematology and Oncology, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic
| | - Kristyna Pivovarcikova
- Department of Pathology, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic
| | - Stanislav Kormunda
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.,Division of Information Technologies and Statistics, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Mirko Bouda
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University, and Teaching Hospital, Pilsen, Czech Republic.,Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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35
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Intravenous Immunoglobulin Administration Significantly Increases BKPyV Genotype-Specific Neutralizing Antibody Titers in Kidney Transplant Recipients. Antimicrob Agents Chemother 2019; 63:AAC.00393-19. [PMID: 31160292 DOI: 10.1128/aac.00393-19] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/21/2019] [Indexed: 12/21/2022] Open
Abstract
BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) is one of the major causes of kidney graft dysfunction, and there are no BKPyV-specific antiviral therapies available. BKPyV neutralizing antibodies (NAbs) play key roles in protecting against BKPyV replication and represent a potential therapeutic or preventive strategy. In this study, we evaluated NAb titers in intravenous immunoglobulin (i.v. Ig) preparations and in kidney transplant recipients (KTR) before and after i.v. Ig administration. NAb titers directed against major BKPyV genotypes were measured using a BKPyV pseudovirion system. Thirty-three KTR receiving high (1 g/kg of body weight/day; n = 17) or low (0.4 g/kg/day; n = 16) i.v. Ig doses were included. Median NAb titers in i.v. Ig preparations ranged from 5.9 log10 50% inhibitory concentration (IC50) for genotype I to 4.1 log10 IC50 for genotype IV. A mean of 90% of patients (range, 88% to 100%) displaying low or negative BKPyV NAb titers against genotype I reached 4 log10 IC50 after the first i.v. Ig administration. This value was reached by a mean of 44% (range, 13% to 83%) and 19% (range, 0% to 38%) of patients against genotype II and genotype IV, respectively. The benefit of i.v. Ig administration persisted until the following course of treatment (day 22 ± 7 days) for genotypes I and II, and no cumulative effect was observed through the three doses. Our findings demonstrate that i.v. Ig administration results in a significant increase in BKPyV NAb titers in KTR. These in vitro and in vivo pharmacokinetic data provide the rationale for a proof-of-concept study investigating the efficacy of i.v. Ig for the prevention of BKPyV infection in KTR.
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36
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Bischof N, Hirsch HH, Wehmeier C, Amico P, Dickenmann M, Hirt-Minkowski P, Steiger J, Menter T, Helmut H, Schaub S. Reducing calcineurin inhibitor first for treating BK polyomavirus replication after kidney transplantation: long-term outcomes. Nephrol Dial Transplant 2019; 34:1240-1250. [PMID: 30476254 DOI: 10.1093/ndt/gfy346] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Reducing immunosuppression is the mainstay of treating BK polyomavirus (BKPyV) viraemia after kidney transplantation, but the best approach, efficacy and impact are undefined. We established a standard operating procedure (SOP) treating BKPyV viraemia based on first reducing calcineurin inhibitor ('CNI first'). The aim of this study was to investigate long-term outcomes in 644 consecutive transplantations using this SOP. METHODS Patients were monitored for active BKPyV infection by urinary decoy cells and, if positive, by BKPyV viraemia. In case of sustained BKPyV viraemia >1000 copies/mL, immunosuppression was reduced stepwise according to the SOP. Patients were classified as 'no decoy cells' [n = 432 (66%)], 'decoy cells/no viraemia' [n = 107 (17%)] and 'viraemia' [n = 105 (17%)]. RESULTS At 6-years post-transplant, graft survival was ∼84%, the clinical rejection rate was ∼25% and they were not different among the three groups (P = 0.14; P = 0.91). The median estimated glomerular filtration rate at the last follow-up was similar (range 49-53 mL/min, P = 0.08). Of 105 viraemic patients, 101 (96%) cleared BKPyV viraemia. In 39% of patients, viraemia clearance followed a tacrolimus reduction. A reduction of mycophenolic acid was required in 43% and discontinuation in 3%. No short-term graft loss was directly attributable to BKPyV-associated nephropathy. After a median follow-up of 5 years after clearance of BKPyV viraemia, 11/101 patients (11%) developed clinical rejection: 7 (7%) T-cell-mediated rejection and 4 (4%) antibody-mediated rejection (ABMR). CONCLUSIONS Immunosuppression reduction based on 'CNI first' leads to similar long-term outcomes in patients with/without BKPyV viraemia and is associated with a low risk for ABMR after clearance of BKPyV viraemia. Randomized trials are needed to compare the risks and benefits of immunosuppression reduction strategies in kidney transplant patients with BKPyV viraemia.
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Affiliation(s)
- Nicole Bischof
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Hans H Hirsch
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
- Transplantation and Clinical Virology, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland
- Division of Infection Diagnostics, Department of Biomedicine (Haus Petersplatz), University of Basel, Basel, Switzerland
| | - Caroline Wehmeier
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patricia Amico
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Michael Dickenmann
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patricia Hirt-Minkowski
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Thomas Menter
- Institute for Pathology, University Hospital Basel, Basel, Switzerland
| | - Hopfer Helmut
- Institute for Pathology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
- Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
- HLA-Diagnostic and Immunogenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
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37
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Hirsch HH, Randhawa PS. BK polyomavirus in solid organ transplantation-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13528. [PMID: 30859620 DOI: 10.1111/ctr.13528] [Citation(s) in RCA: 266] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 02/26/2019] [Indexed: 02/07/2023]
Abstract
The present AST-IDCOP guidelines update information on BK polyomavirus (BKPyV) infection, replication, and disease, which impact kidney transplantation (KT), but rarely non-kidney solid organ transplantation (SOT). As pretransplant risk factors in KT donors and recipients presently do not translate into clinically validated measures regarding organ allocation, antiviral prophylaxis, or screening, all KT recipients should be screened for BKPyV-DNAemia monthly until month 9, and then every 3 months until 2 years posttransplant. Extended screening after 2 years may be considered in pediatric KT. Stepwise immunosuppression reduction is recommended for KT patients with plasma BKPyV-DNAemia of >1000 copies/mL sustained for 3 weeks or increasing to >10 000 copies/mL reflecting probable and presumptive BKPyV-associated nephropathy, respectively. Reducing immunosuppression is also the primary intervention for biopsy-proven BKPyV-associated nephropathy. Hence, allograft biopsy is not required for treating BKPyV-DNAemic patients with baseline renal function. Despite virological rationales, proper randomized clinical trials are lacking to generally recommend treatment by switching from tacrolimus to cyclosporine-A, from mycophenolate to mTOR inhibitors or leflunomide or by the adjunct use of intravenous immunoglobulins, leflunomide, or cidofovir. Fluoroquinolones are not recommended for prophylaxis or therapy. Retransplantation after allograft loss due to BKPyV nephropathy can be successful if BKPyV-DNAemia is definitively cleared, independent of failed allograft nephrectomy.
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Affiliation(s)
- Hans H Hirsch
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Parmjeet S Randhawa
- Division of Transplantation Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Thomas E Starzl Transplantation Institute, Pittsburgh, Pennsylvania
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38
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Chen XT, Li J, Deng RH, Yang SC, Chen YY, Chen PS, Wang ZY, Huang Y, Wang CX, Huang G. The therapeutic effect of switching from tacrolimus to low-dose cyclosporine A in renal transplant recipients with BK virus nephropathy. Biosci Rep 2019; 39:BSR20182058. [PMID: 30737303 PMCID: PMC6386765 DOI: 10.1042/bsr20182058] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/30/2019] [Accepted: 02/07/2019] [Indexed: 01/08/2023] Open
Abstract
Background: There is no effective therapy for BK virus (BKV) nephropathy (BKVN). Cyclosporine A (CsA) has a lower immunosuppressive effect than tacrolimus. In vitro studies have shown that CsA inhibits BKV replication. The present study aimed to evaluate the effectiveness of switching from tacrolimus to low-dose CsA in renal transplant recipients with BKVN. Methods: Twenty-four patients diagnosed with BKVN between January 2015 and December 2016 were included. Tacrolimus was switched to low-dose CsA, and patients were followed for 24 months. Primary end points were BKV clearance in blood and graft. Secondary end points were urine specific gravity, serum creatinine, and graft loss. Results: The viremia in all patients cleared at a mean of 2.7 ± 2.0 months after switching to CsA. Urine specific gravity at 3 months after switching to CsA increased significantly compared with that at diagnosis (P=0.002). The timing and trend of urine specific gravity increase was consistent with the timing and trend of blood and urine viral load decrease. Repeated biopsies at a median of 11.2 months (range: 9.1-12.5 months) after switching to CsA showed that 8 patients (42.1%) were negative for BKV, and 11 patients (58.9%) had a decrease in BKV load (P<0.001). There was no statistical difference in the serum creatinine level between the time of diagnosis and 24 months of CsA therapy (P=0.963). The graft survival rate was 100%. Only two patients (8.3%) suffered from acute rejection. Conclusion: Switching from tacrolimus to low-dose CsA may be an effective therapy for BKVN.
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Affiliation(s)
- Xu-Tao Chen
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Jun Li
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Rong-Hai Deng
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Shi-Cong Yang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Yan-Yang Chen
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Pei-Song Chen
- Department of Clinical Laboratory, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Ze-Yuan Wang
- Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Yang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Chang-Xi Wang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
| | - Gang Huang
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, Guangdong Province, China
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David-Neto E, Agena F, Silva Ribeiro David D, Paula FJD, Camera Pierrotti LC, Domingues Fink MC, Fonseca de Azevedo LS. Effect of polyoma viremia on 3-year allograft kidney function. Transpl Infect Dis 2019; 21:e13056. [PMID: 30712328 DOI: 10.1111/tid.13056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 01/10/2019] [Accepted: 01/27/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Polyoma viremia is associated with damage to renal tubular and urothelial cells. This may imply that a certain level of viremia, even cleared thereafter, could be associated with long-term renal dysfunction. METHODS We, retrospectively, analyzed 390 first renal transplants adult recipients (≥18 years) who were monitored for BK viremia in the first 12 months and evaluated estimated GFR (MDRD-4 equation) at 1 month and at the last follow-up (959 ± 392 days). RESULTS One hundred and ninety-nine patients (51%) developed at least one positive viremia: 105 (53%) low viremia (<104 copies/mL), 36 (18%) high viremia (4 × 104 > viremia ≥ 104 copies/mL) and 58 (15%) viremia (≥4 × 104 copies/mL) consistent with polyoma virus associated nephropathy (PyVAN). Out of these 58 patients, 24 (6%) developed bx-proven (SV40+) PyVAN and 34(8.7%) presumptive PyVAN (SV40-). Baseline characteristics, immunosuppression, KDRI, rejection episodes, etc., did not differ among groups but there were more deceased donors and ATG induction therapy in the high viremia group. At last follow-up, all patients in the low, high viremia and presumptive PyVAN (except 2) had cleared BK viremia. Bx-proven PyVAN led to 14 graft losses, 10 due to PyVAN. In the presumptive PyVAN there was only one graft loss registered as due to PyVAN. eGFR, at 1 month after KTx, did not differ among groups (51 ± 22 vs 48 ± 24 vs 45 ± 27 vs 43 ± 18 vs 46 ± 22 mL/min/1.73 m2 ), for no, low and high viremia as well for presumptive PyVAN and bx-proven PyVAN groups, respectively. At the last follow-up, eGFR did not differ between the no, low, and high viremia compared to baseline and to each other but was statistically lower in the presumptive and bx-proven PyVAN (38 ± 15 and 17 ± 7 mL/min/1.73 m2 ) either compared to baseline or to the other groups. CONCLUSIONS This study shows that low and high levels of BK viremia do not lead to GFR changes although very high viremia levels, compatible with presumptive or bx-proven PyVAN, even if cleared thereafter, lead to allograft damage and decreased GFR.
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Affiliation(s)
- Elias David-Neto
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil.,Division of Nephrology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | - Fabiana Agena
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | - Daisa Silva Ribeiro David
- Division of Pathology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | - Flavio Jota de Paula
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | | | | | - Luiz Sergio Fonseca de Azevedo
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
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Zakaria ZE, Elokely AM, Ghorab AA, Bakr AI, Halim MA, Gheith OA, Nagib AM, Makkeyah Y, Balaha MA, Magdy MM, Al-Otaibi T. Screening for BK Viremia/Viruria and the Impact of Management of BK Virus Nephropathy in Renal Transplant Recipients. EXP CLIN TRANSPLANT 2019; 17:83-91. [PMID: 30777529 DOI: 10.6002/ect.mesot2018.o17] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES The prevalence of BK-induced nephritis in renal transplant recipients is estimated to be 1% to 10%; the rate of graft loss within 1 year is 30% to 65%. We conducted this study to evaluate screening of BK virus in blood and/or urine among renal transplant recipients and to assess the effects of different therapeutic modalities in renal transplant recipients with BK nephropathy. MATERIALS AND METHODS Kidney transplant recipients were screened at the time of transplant and then at 1, 2, 3, 6, 9, 12, 18, and 24 months posttransplant. Fiftynine patients were diagnosed with BK virus viremia. Patients were divided into 2 groups according to treatment: group 1 (n = 29) received an active treatment and group 2 (n = 30) received minimized immunosuppression. RESULTS Most patients required graft biopsies to confirm diagnosis (86.2% in group 1 vs 50% in group 2; P = .03). Both groups were comparable regarding demographic data. Initial posttransplant graft function was significantly better in group 1 (P = .017); ultimately, there was no significant difference between both groups regarding graft survival (P= .51). Fifty percent of patients had biopsy-proven acute T-cell-mediated rejection before BK virus-associated nephropathy diagnosis (significantly higher in group 1). Serum creatinine levels were significantly better in group 2 at 3, 4, and 5 years after BK nephropathy (P = .001, .017, and .003, respectively). CONCLUSIONS The prevalence of BK nephropathy in our renal transplant recipients was 5.9% with a rate of graft loss ranging from 43% to 51%. Regular screening, less intensive immunosuppressive therapy, and early intervention by reduction of immunosuppressive medications are advisable to obtain early diagnosis and to have better outcomes of BK virus-associated nephropathy with antiviral agents.
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Urinary CXCL10 Chemokine Is Associated With Alloimmune and Virus Compartment-Specific Renal Allograft Inflammation. Transplantation 2018; 102:521-529. [PMID: 28902772 DOI: 10.1097/tp.0000000000001931] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Urinary CXC chemokine ligand 10 (CXCL10) is a promising biomarker for subclinical tubulointerstitial inflammation, but limited data exist regarding its correlation with (micro)vascular inflammation. Furthermore, no study has evaluated whether concomitant serum CXCL10 improves the discrimination for (micro)vascular inflammation. METHODS We investigated whether serum/urinary CXCL10 reflect subclinical inflammation within different renal compartments. Patients (n = 107) with 107 surveillance biopsies were classified as: normal histology (n = 47), normal histology with polyomavirus BK (BKV) or cytomegalovirus (CMV) viremia (n = 17), moderate-severe tubulointerstitial inflammation (tubulitis ≥2, n = 18), pure microvascular inflammation (n = 15), and isolated v lesions (n = 10). Serum and urinary CXCL10 Enzyme-linked Immunosorbent Assay was performed. An independent validation set was evaluated for urine CXCL10: normal histology (n = 14), normal histology with BKV or CMV viremia (n = 19), tubulitis ≥2 (n = 15), pure microvascular inflammation (n = 41), and isolated v lesions (n = 14). RESULTS Elevated urinary CXCL10 reflected inflammation within the tubulointerstitial (urinary CXCL10/creatinine, 1.23 ng/mmol vs 0.46 ng/mmol; P = 0.02; area under the curve, 0.69; P = 0.001) and microvascular compartments (urinary CXCL10/creatinine, 1.72 ng/mmol vs 0.46 ng/mmol; P = 0.03; area under the curve, 0.69; P = 0.02) compared to normal histology. Intriguingly, urinary CXCL10 was predominantly elevated with peritubular capillaritis, but not glomerulitis (P = 0.04). Furthermore, urinary CXCL10 corresponded with BKV, but not CMV viremia (P = 0.02). These urine CXCL10 findings were confirmed in the independent validation set. Finally, serum CXCL10 was elevated with BKV and CMV viremia but was not associated with microvascular or vascular inflammation (P ≥ 0.19). CONCLUSIONS Urinary CXCL10 reflects subclinical inflammation within the tubulointerstitial and peritubular capillary spaces, but not the vascular/systemic compartments; this was consistent with BKV (tubulointerstitial) and CMV viremia (systemic). Serum CXCL10 was not a useful marker for (micro)vascular inflammation.
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Masutani K. Viral infections directly involved in kidney allograft function. Nephrology (Carlton) 2018; 23 Suppl 2:31-37. [PMID: 29968408 DOI: 10.1111/nep.13285] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2018] [Indexed: 12/22/2022]
Abstract
Modern immunosuppressive therapy has dramatically reduced the incidence of acute rejection and improved graft survival in kidney transplant patients. However, infectious complications remain an important issue. Amongst the various pathogens, viruses such as adenovirus and polyomavirus BK can directly cause acute or chronic graft dysfunction. Adenovirus mainly causes haemorrhagic cystitis and tubulointerstitial nephritis in kidney transplant patients. While patients show apparent clinical symptoms such as fever, dysuria, gross haematuria, frequency and urgency of urination, and most patients show acute graft dysfunction, these symptoms and graft dysfunction are reversible. Polyomavirus BK infection, however, is asymptomatic but graft outcome is poor if the patient develops tissue-invasive nephropathy confirmed by graft biopsy. Recently, an attempt to create a pathological classification for predicting the clinical course has been made by the Banff Working Group on Polyomavirus Nephropathy. With regards to treatment, the basic strategy is a reduction of calcineurin inhibitor and/or antimetabolites, and the effectiveness of several adjunct treatments has been investigated in several clinical trials. There are other unresolved issues, such as the diagnosis of subsequent acute rejection, the definition of remission, methods of resuming immunosuppression and long-term follow-up. Most of all, development of effective vaccines and novel drug discovery are necessary to prevent the development and progression of BKV-associated nephropathy.
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Affiliation(s)
- Kosuke Masutani
- Division of Nephrology and Rheumatology, Fukuoka University, Fukuoka, Japan
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43
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Krejci K, Tichy T, Bednarikova J, Zamboch K, Zadrazil J. BK virus-induced renal allograft nephropathy. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:165-177. [DOI: 10.5507/bp.2018.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 04/11/2018] [Indexed: 12/11/2022] Open
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Morace R, Kumar T, Tantisattamo E, Gibson J, Britton S, Li W, Kanaan HD, Cohn SR, Samarapungavan D, Zhang PL, Boyanton BL. Feasibility of BK Virus Real-Time PCR Testing in Renal Graft Biopsies With Negative SV40 Staining. Transplant Proc 2018; 49:1294-1300. [PMID: 28735997 DOI: 10.1016/j.transproceed.2017.03.095] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/14/2016] [Accepted: 03/15/2017] [Indexed: 01/30/2023]
Abstract
BACKGROUND BK virus (BKV)-associated nephropathy (BKVAN) is often associated with renal graft dysfunction. When renal transplant recipients present with high clinical suspicion for BKVAN (high serum and urine BKV titer with graft dysfunction) but their graft biopsies stain negatively for BKV, non-correlated situations between the two tests often lead to a dilemma about how to treat them. METHODS This retrospective investigation was conducted to determine how real-time quantitative PCR (qPCR) for BKV, routinely applied to serum and urine, could be helpful in identifying the existing BKV in biopsy tissue stained negatively for BKV. RESULTS DNA was extracted from each specimen through the use of five 10-μm curls from the tissue block with use of the QIAamp DNA FFPE Tissue Kit (Qiagen), followed by BKV qPCR to determine copies of BKV/μg of biopsy tissue DNA. Group 1 (11 negative renal controls for BKV) demonstrated 0 to 9 BKV copies/μg DNA. Except for 3 focally staining cases showing low BKV, the remaining 10 positive renal controls in group 2 (13 positive transplant biopsies staining positively) demonstrated elevated BKV up to 160 million copies/μg DNA. Group 3 transplants (13 uncertain transplants with negative BKV staining but positive liquid BKV) were negative for BKV (0-12 copies/μg) in 4 of 13, had low BKV copies (36-346 copies/μg) in 5 of 13, and had high BKV copies (17,240-526,945 copies/μg) in 4 of 13 cases, through the use of qPCR. CONCLUSIONS The data indicate that qPCR from paraffin-embedded tissue as a backup test is sensitive for ruling in/out BKV infection in renal transplant biopsies, particularly in uncertain cases.
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Affiliation(s)
- R Morace
- Department of Pathology and Laboratory Medicine (Anatomic Pathology), Beaumont Health, Royal Oak, Michigan
| | - T Kumar
- Department of Pathology and Laboratory Medicine (Anatomic Pathology), Beaumont Health, Royal Oak, Michigan; Department of Pathology and Laboratory Medicine (Clinical Pathology), Beaumont Health, Royal Oak, Michigan
| | - E Tantisattamo
- Department of Internal Medicine, Nephrology, Beaumont Health, Royal Oak, Michigan
| | - J Gibson
- Department of Pathology and Laboratory Medicine (Clinical Pathology), Beaumont Health, Royal Oak, Michigan
| | - S Britton
- Department of Pathology and Laboratory Medicine (Anatomic Pathology), Beaumont Health, Royal Oak, Michigan
| | - W Li
- Department of Pathology and Laboratory Medicine (Anatomic Pathology), Beaumont Health, Royal Oak, Michigan
| | - H D Kanaan
- Department of Pathology and Laboratory Medicine (Anatomic Pathology), Beaumont Health, Royal Oak, Michigan
| | - S R Cohn
- Transplant Surgery, Beaumont Health, Royal Oak, Michigan
| | - D Samarapungavan
- Department of Internal Medicine, Nephrology, Beaumont Health, Royal Oak, Michigan
| | - P L Zhang
- Department of Pathology and Laboratory Medicine (Anatomic Pathology), Beaumont Health, Royal Oak, Michigan.
| | - B L Boyanton
- Department of Pathology and Laboratory Medicine (Clinical Pathology), Beaumont Health, Royal Oak, Michigan.
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Nickeleit V, Singh HK, Rivier LH. Antibodies Can Extenuate Polyomavirus Infections. J Am Soc Nephrol 2018; 29:1577. [PMID: 29467143 DOI: 10.1681/asn.2017111211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Affiliation(s)
- Volker Nickeleit
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Harsharan K Singh
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Lauraine H Rivier
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
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46
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Hara S, Hirata M, Ito K, Mizushima I, Fujii H, Yamada K, Nagata M, Kawano M. Post-infectious acute glomerulonephritis with podocytopathy induced by parvovirus B19 infection. Pathol Int 2018; 68:190-195. [PMID: 29457859 DOI: 10.1111/pin.12643] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 12/30/2017] [Indexed: 10/18/2022]
Abstract
Human parvovirus B19 infection causes a variety of glomerular diseases such as post-infectious acute glomerulonephritis and collapsing glomerulopathy. Although each of these appears independently, it has not been fully determined why parvovirus B19 provokes such a variety of different glomerular phenotypes. Here, we report a 68-year-old Japanese man who showed endocapillary proliferative glomerulonephritis admixed with podocytopathy in association with parvovirus B19 infection. The patient showed acute onset of heavy proteinuria, microscopic hematuria and kidney dysfunction with arthralgia and oliguria after close contact with a person suffering from erythema infectiosum. In the kidney biopsy specimen, glomeruli revealed diffuse and global endocapillary infiltration of inflammatory cells, with some also showing tuft collapse with aberrant vacuolation, swelling, and hyperplasia of glomerular epithelial cells. Immunofluorescence revealed dense granular C3 deposition that resembled the "starry sky pattern". Intravenous glucocorticoid pulse therapy followed by oral prednisolone and cyclosporine combination therapy resulted in considerable amelioration of the kidney dysfunction and urinary abnormalities. The present case reveals that parvovirus B19 infection can induce different glomerular phenotypes even in the same kidney structure. This finding may provide hints useful for the further elucidation of the pathogenesis of parvovirus B19-induced glomerular lesions.
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Affiliation(s)
- Satoshi Hara
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masayoshi Hirata
- Department of Internal Medicine, Takaoka City Hospital, Takaoka, Japan
| | - Kiyoaki Ito
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Ichiro Mizushima
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Hiroshi Fujii
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kazunori Yamada
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.,Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Michio Nagata
- Department of Kidney and Vascular Pathology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Mitsuhiro Kawano
- Division of Rheumatology, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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Nickeleit V, Singh HK, Randhawa P, Drachenberg CB, Bhatnagar R, Bracamonte E, Chang A, Chon WJ, Dadhania D, Davis VG, Hopfer H, Mihatsch MJ, Papadimitriou JC, Schaub S, Stokes MB, Tungekar MF, Seshan SV. The Banff Working Group Classification of Definitive Polyomavirus Nephropathy: Morphologic Definitions and Clinical Correlations. J Am Soc Nephrol 2017; 29:680-693. [PMID: 29279304 DOI: 10.1681/asn.2017050477] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 10/11/2017] [Indexed: 01/24/2023] Open
Abstract
Polyomavirus nephropathy (PVN) is a common viral infection of renal allografts, with biopsy-proven incidence of approximately 5%. A generally accepted morphologic classification of definitive PVN that groups histologic changes, reflects clinical presentation, and facilitates comparative outcome analyses is lacking. Here, we report a morphologic classification scheme for definitive PVN from the Banff Working Group on Polyomavirus Nephropathy, comprising nine transplant centers in the United States and Europe. This study represents the largest systematic analysis of definitive PVN undertaken thus far. In a retrospective fashion, clinical data were collected from 192 patients and correlated with morphologic findings from index biopsies at the time of initial PVN diagnosis. Histologic features were centrally scored according to Banff guidelines, including additional semiquantitative histologic assessment of intrarenal polyomavirus replication/load levels. In-depth statistical analyses, including mixed effects repeated measures models and logistic regression, revealed two independent histologic variables to be most significantly associated with clinical presentation: intrarenal polyomavirus load levels and Banff interstitial fibrosis ci scores. These two statistically determined histologic variables formed the basis for the definition of three PVN classes that correlated strongest with three clinical parameters: presentation at time of index biopsy, serum creatinine levels/renal function over 24 months of follow-up, and graft failure. The PVN classes 1-3 as described here can easily be recognized in routine renal biopsy specimens. We recommend using this morphologic PVN classification scheme for diagnostic communication, especially at the time of index diagnosis, and in scientific studies to improve comparative data analysis.
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Affiliation(s)
- Volker Nickeleit
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina;
| | - Harsharan K Singh
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Parmjeet Randhawa
- Division of Transplantation Pathology, Department of Pathology, University of Pittsburgh Medical Center-Montefiore, Pittsburgh, Pennsylvania
| | - Cinthia B Drachenberg
- Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Ramneesh Bhatnagar
- Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Erika Bracamonte
- Department of Pathology, The University of Arizona College of Medicine, Tucson, Arizona
| | - Anthony Chang
- Department of Pathology, The University of Chicago, Chicago, Illinois
| | - W James Chon
- Renal Transplant Program, University of Missouri-Kansas City School of Medicine/Saint Luke's Health System, Kansas City, Missouri
| | - Darshana Dadhania
- Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York
| | - Vicki G Davis
- Division of Nephropathology, Department of Pathology and Laboratory Medicine, The University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | | | | | - John C Papadimitriou
- Department of Pathology, School of Medicine, University of Maryland, Baltimore, Maryland
| | - Stefan Schaub
- Transplantation Immunology and Nephrology, University Hospital of Basel, Basel, Switzerland
| | - Michael B Stokes
- Department of Pathology, Columbia Presbyterian Medical Center, New York, New York
| | - Mohammad F Tungekar
- Histopathology Department, St. Thomas' Hospital, Guy's and St. Thomas Foundation Trust and King's College London, London, United Kingdom; and
| | - Surya V Seshan
- Department of Pathology, Weill Cornell Medicine, New York, New York
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Scadden JRW, Sharif A, Skordilis K, Borrows R. Polyoma virus nephropathy in kidney transplantation. World J Transplant 2017; 7:329-338. [PMID: 29312862 PMCID: PMC5743870 DOI: 10.5500/wjt.v7.i6.329] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 11/17/2017] [Accepted: 12/01/2017] [Indexed: 02/05/2023] Open
Abstract
BK virus (BKV) is a polyomavirus that is able to cause renal dysfunction in transplanted grafts via BK virus-associated nephritis (BKVAN). This condition was mis-diagnosed in the past due to clinical and histopthological similarities with acute rejection. Due to the prevalence of the virus in the population, it is an important pathogen in this context, and so it is important to understand how this virus functions and its' relationship with the pathogenesis of BKVN. Screening for BKV often reveals viruria and/or viremia, which then manifests as BKVN, which can be asymptomatic or result in clinical features namely renal dysfunction. The pathogenesis of BKV infection is still unclear and needs to be further investigated; nevertheless there are a variety of hypotheses that indicate that there are a host of factors that play important roles. Treatments for BKVAN include a reduction in immunosuppression, the use of antiviral therapy or the combination of both treatment options.
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Affiliation(s)
- Jacob RW Scadden
- University of Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom
| | - Adnan Sharif
- Department of Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | - Kassi Skordilis
- Department of Renal Histopathology, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
| | - Richard Borrows
- Department of Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, United Kingdom
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Abstract
BK polyomavirus (BKV) causes frequent infections during childhood and establishes persistent infections within renal tubular cells and the uroepithelium, with minimal clinical implications. However, reactivation of BKV in immunocompromised individuals following renal or hematopoietic stem cell transplantation may cause serious complications, including BKV-associated nephropathy (BKVAN), ureteric stenosis, or hemorrhagic cystitis. Implementation of more potent immunosuppression and increased posttransplant surveillance has resulted in a higher incidence of BKVAN. Antiviral immunity plays a crucial role in controlling BKV replication, and our increasing knowledge about host-virus interactions has led to the development of improved diagnostic tools and clinical management strategies. Currently, there are no effective antiviral agents for BKV infection, and the mainstay of managing reactivation is reduction of immunosuppression. Development of immune-based therapies to combat BKV may provide new and exciting opportunities for the successful treatment of BKV-associated complications.
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Leboeuf C, Wilk S, Achermann R, Binet I, Golshayan D, Hadaya K, Hirzel C, Hoffmann M, Huynh-Do U, Koller MT, Manuel O, Mueller NJ, Mueller TF, Schaub S, van Delden C, Weissbach FH, Hirsch HH. BK Polyomavirus-Specific 9mer CD8 T Cell Responses Correlate With Clearance of BK Viremia in Kidney Transplant Recipients: First Report From the Swiss Transplant Cohort Study. Am J Transplant 2017; 17:2591-2600. [PMID: 28326672 DOI: 10.1111/ajt.14282] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Revised: 02/22/2017] [Accepted: 03/12/2017] [Indexed: 01/25/2023]
Abstract
BK polyomavirus (BKPyV) causes premature kidney transplant (KT) failure in 1-15% of patients. Because antivirals are lacking, most programs screen for BKPyV-viremia and, if positive, reduce immunosuppression. To evaluate the relationship of viremia and BKPyV-specific immunity, we examined prospectively cryopreserved plasma and peripheral blood mononuclear cells at the time of transplantation (T0) and at 6 mo (T6) and 12 mo (T12) after transplant from 28 viremic KT patients and 68 nonviremic controls matched for the transplantation period. BKPyV IgG seroprevalence was comparable between cases (89.3%) and controls (91.2%; p = 0.8635), but cases had lower antibody levels (p = 0.022) at T0. Antibody levels increased at T6 and T12 but were not correlated with viremia clearance. BKPyV-specific T cell responses to pools of overlapping 15mers (15mer peptide pool [15mP]) or immunodominant CD8 9mers (9mer peptide pool [9mP]) from the early viral gene region were not different between cases and controls at T0; however, clearance of viremia was associated with stronger 9mP responses at T6 (p = 0.042) and T12 (p = 0.048), whereas 15mP responses were not informative (T6 p = 0.359; T12 p = 0.856). BKPyV-specific T cells could be expanded in vitro from all patients after transplant, permitting identification of 78 immunodominant 9mer epitopes including 50 new ones across different HLA class I. Thus, 9mP-responses may be a novel marker of reconstituting CD8 T cell function that warrants further study as a complement of plasma BKPyV loads for guiding immunosuppression reduction.
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Affiliation(s)
- C Leboeuf
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - S Wilk
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - R Achermann
- Swiss Transplant Cohort Study, University Hospital Basel, Basel, Switzerland
| | - I Binet
- Nephrology & Transplantation Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - D Golshayan
- Transplantation Center, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - K Hadaya
- Service of Nephrology, University Hospitals Geneva, Geneva, Switzerland
| | - C Hirzel
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - M Hoffmann
- Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - U Huynh-Do
- Division of Nephrology, Hypertension and Clinical Pharmacology, Inselspital Bern, Bern, Switzerland
| | - M T Koller
- Basel Institute for Clinical Epidemiology and Biostatistics, Basel, Switzerland
| | - O Manuel
- Infectious Diseases Service & Transplantation Center, University Hospital of Lausanne (CHUV), Lausanne, Switzerland
| | - N J Mueller
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - T F Mueller
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - S Schaub
- Division of Transplant Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - C van Delden
- Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland
| | - F H Weissbach
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
| | - H H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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