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Hillenbrand CA, Akbari Bani D, Follonier O, Kaur A, Weissbach FH, Wernli M, Wilhelm M, Leuzinger K, Binet I, Bochud PY, Golshayan D, Hirzel C, Manuel O, Mueller NJ, Schaub S, Schachtner T, Van Delden C, Hirsch HH. BK polyomavirus serotype-specific antibody responses in blood donors and kidney transplant recipients with and without new-onset BK polyomavirus-DNAemia: A Swiss Transplant Cohort Study. Am J Transplant 2025; 25:985-1001. [PMID: 39580075 DOI: 10.1016/j.ajt.2024.11.019] [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: 09/12/2024] [Revised: 11/03/2024] [Accepted: 11/17/2024] [Indexed: 11/25/2024]
Abstract
BK polyomavirus (BKPyV) causes premature renal failure in 10% to 30% of kidney transplant recipients (KTRs). Current guidelines recommend screening for new-onset BKPyV-DNAemia/nephropathy and reducing immunosuppression to regain BKPyV-specific immune control. Because BKPyV encompasses 4 major genotype (gt)-encoded serotypes (st1,-2,-3,-4), st-specific antibodies may inform the risk and course of BKPyV-DNAemia/nephropathy. Using BKPyV st-virus-like particle (VLP) enzyme-linked immunosorbent assay, we analyzed plasma from 399 blood donors (BDs) and 428 KTRs (134 KTR-cases with BKPyV-DNAemia, 294 KTR-controls). BDs were anti-BKPyV-VLP immunoglobulin G-seropositive in 85% compared to 93% of KTRs at the timepoint at transplantation (T0) (P < .001). Anti-st1 was predominant in both groups followed by anti-st4, anti-st2, and anti-st3. Antibody levels and quadruple sero-reactivity at T0 were higher in KTR-controls than in KTR-cases (P = .026) or in BDs (P < .001). In KTR-cases, anti-st increased posttransplant (P < .0001) and independently of ongoing or cleared BKPyV-DNAemia. However, anti-st levels were significantly higher at T0 in KTR-cases able to clear at timepoint 6-month posttransplant or timepoint 12-month posttransplant. In 34 KTR-cases with deep genome sequencing, BKPyV-gtI was predominant, and anti-st1 and st1-neutralizing antibodies were significantly lower at T0 than in KTR-controls. Thus, BKPyV st-specific antibody levels at transplantation might reflect gt/st-BKPyV-specific immunity clearing or preventing BKPyV-DNAemia in KTR-cases or KTR-controls, respectively. Accordingly, active or passive immunization may be most efficient pretransplant or early posttransplant.
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Affiliation(s)
- Caroline A Hillenbrand
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Dorssa Akbari Bani
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Océane Follonier
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland; Biozentrum, University of Basel, Basel, Switzerland; SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Amandeep Kaur
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Fabian H Weissbach
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Marion Wernli
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | - Maud Wilhelm
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland
| | | | - Isabelle Binet
- Nephrology & Transplantation Medicine, Kantonsspital St Gallen, St Gallen, Switzerland
| | - Pierre-Yves Bochud
- Transplantation Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Dela Golshayan
- Transplantation Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Cédric Hirzel
- Department of Infectious Diseases, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Nicolas J Mueller
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
| | - Stefan Schaub
- Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Thomas Schachtner
- Department of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Christian Van Delden
- Transplant Infectious Diseases Unit, University Hospitals Geneva, Geneva, Switzerland
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department of Biomedicine, Medical Faculty, University of Basel, Basel, Switzerland.
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Al-Talib M, Welberry-Smith M, Macdonald A, Griffin S. BK Polyomavirus-associated nephropathy - diagnostic and treatment standard. Nephrol Dial Transplant 2025; 40:651-661. [PMID: 39794277 PMCID: PMC11960737 DOI: 10.1093/ndt/gfaf002] [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: 08/28/2024] [Indexed: 01/13/2025] Open
Abstract
BK polyomavirus (BKPyV) is recognized as a significant viral complication of kidney transplantation. Prompt immunosuppression reduction reduces early graft failure rates due to BK polyomavirus-associated nephropathy (BKPyVAN), however, modulation of immunosuppression can lead to acute rejection. Medium-to-long-term graft outcomes are negatively affected by BKPyVAN, probably due to a combination of virus-induced graft damage and host immune responses against graft alloantigens potentiated by immunosuppression reduction. Kidney biopsy remains the gold-standard diagnostic test, however, false-negative findings are common due to the focal nature of BKPyVAN. BKPyV DNAemia, as measured by quantitative polymerase chain reaction, is established as a screening test but there is at present no (inter)national standardization of these assays to allow collation and comparison of data between centres. Randomized controlled trials are lacking both in terms of optimal immunosuppression reduction strategies, and for the medications variably used to attempt treatment in clinical practice. Much of the fundamental biology of BKPyV is not yet understood, and further elucidation is required to promote rational direct-acting antiviral drug design. Insights into the role of adaptive immunity in control of BKPyV have informed the design of novel treatments such as adoptive immunotherapies and neutralizing antibodies that require evaluation in clinical studies. Here, we review the current standards of diagnosis and treatment of BKPyVAN and discuss novel developments in the pathophysiology, diagnosis, outcome prediction, and management.
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Affiliation(s)
- Mohammed Al-Talib
- Systems Immunity Research Institute, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
- Bristol Medical School, University of Bristol, 5 Tyndall Avenue, Bristol, UK
| | - Matthew Welberry-Smith
- Faculty of Biological Sciences, University of Leeds, Woodhouse, Leeds, UK
- Department of Renal Medicine and Transplantation, Leeds Teaching Hospitals NHS Trust, Beckett Street, Leeds, UK
| | - Andrew Macdonald
- Faculty of Biological Sciences, University of Leeds, Woodhouse, Leeds, UK
| | - Siân Griffin
- Department of Nephrology and Transplantation, Cardiff and Vale University Health Board, Cardiff, UK
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Imlay H, Gnann JW, Rooney J, Peddi VR, Wiseman AC, Josephson MA, Kew C, Young JH, Adey DB, Samaniego‐Picota M, Whitley RJ, Limaye AP. A randomized, placebo-controlled, dose-escalation phase I/II multicenter trial of low-dose cidofovir for BK polyomavirus nephropathy. Transpl Infect Dis 2024; 26:e14367. [PMID: 39226143 PMCID: PMC11666883 DOI: 10.1111/tid.14367] [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: 06/26/2024] [Revised: 08/13/2024] [Accepted: 08/19/2024] [Indexed: 09/05/2024]
Abstract
BACKGROUND BK polyomavirus-associated nephropathy (BKPyVAN) is an important cause of allograft dysfunction and failure in kidney transplant recipients (KTRs) and there are no proven effective treatments. Case reports and in vitro data support the potential activity of cidofovir against BK polyomavirus (BKPyV). METHODS We report the results of a phase I/II, double-blind, placebo-controlled randomized dose-escalation trial of cidofovir in KTRs with biopsy-confirmed BKPyVAN and estimated glomerular filtration rate ≥30 mL/min. Intravenous cidofovir (0.25 mg/kg/dose or 0.5 mg/kg/dose) or placebo was administered on days 0, 7, 21, and 35, with final follow-up through day 49. RESULTS The trial was prematurely discontinued due to slow accrual after 22 KTRs had completed the study. Cidofovir was safe and tolerated at the doses and duration studied. The proportion of subjects with any adverse event (AE) was similar between groups (9/14 [64%] in the combined cidofovir dose groups and 6/8 [75%] in the placebo group); 84% of AEs were mild. BKPyV DNAemia reduction by day 49 was similar between groups (>1 log10 reduction in (2/9 [22.2%] of 0.25 mg/kg group, 1/5 [20%] of 0.5 mg/kg group, and 2/8 [25%] of placebo group). CONCLUSIONS These preliminary results indicate that low-dose cidofovir was safe and tolerated but had no significant BKPyV-specific antiviral effect in KTRs with BKPyVAN.
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Affiliation(s)
- Hannah Imlay
- Department of Internal MedicineUniversity of UtahSalt Lake CityUtahUSA
| | - John W. Gnann
- Department of MedicineMedical University of South Carolina University Medical CenterCharlestonSouth CarolinaUSA
| | | | - V. Ram Peddi
- Department of TransplantationCalifornia Pacific Medical CenterSan FranciscoCaliforniaUSA
| | - Alexander C. Wiseman
- Department of MedicineUniversity of Colorado at Denver Health Sciences CenterDenverColoradoUSA
| | | | - Clifton Kew
- Department of MedicineUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Jo‐Anne H. Young
- Department of MedicineUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Deborah B. Adey
- Department of MedicineUniversity of California at San FranciscoSan FranciscoCaliforniaUSA
| | | | | | - Ajit P. Limaye
- Department of Internal MedicineUniversity of WashingtonSeattleWashingtonUSA
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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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Abend JR, Sathe A, Wrobel MB, Knapp M, Xu L, Zhao L, Kim P, Desai S, Nguyen A, Leber XC, Hein A, Scharenberg M, Shaul J, Ornelas E, Wong K, Pietzonka T, Sterling LM, Hodges MR, Pertel P, Traggiai E, Patick AK, Kovacs SJ. Nonclinical and clinical characterization of MAU868, a novel human-derived monoclonal neutralizing antibody targeting BK polyomavirus VP1. Am J Transplant 2024; 24:1994-2006. [PMID: 38996969 DOI: 10.1016/j.ajt.2024.07.002] [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: 07/02/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024]
Abstract
Reactivation of BK polyomavirus (BKPyV) can cause significant kidney and bladder disease in immunocompromised patients. There are currently no effective, BKPyV-specific therapies. MAU868 is a novel, human immunoglobulin (Ig) G1 monoclonal antibody that binds the major capsid protein, VP1, of BKPyV with picomolar affinity, neutralizes infection by the 4 major BKPyV genotypes (EC50 ranging from 0.009-0.093 μg/mL; EC90 ranging from 0.102-4.160 μg/mL), and has comparable activity against variants with highly prevalent VP1 polymorphisms. No resistance-associated variants were identified in long-term selection studies, indicating a high in vitro barrier-to-resistance. The high-resolution crystal structure of MAU868 in complex with VP1 pentamer identified 3 key contact residues in VP1 (Y169, R170, and K172). A first-in-human study was conducted to assess the safety, tolerability, and pharmacokinetics of MAU868 following intravenous and subcutaneous administration to healthy adults in a randomized, placebo-controlled, double-blinded, single ascending dose design. MAU868 was safe and well-tolerated. All adverse events were grade 1 and resolved. The pharmacokinetics of MAU868 was typical of a human IgG, with dose-proportional systemic exposure and an elimination half-life ranging between 23 and 30 days. These results demonstrate the potential of MAU868 as a first-in-class therapeutic agent for the treatment or prevention of BKPyV disease.
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Affiliation(s)
- Johanna R Abend
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA.
| | - Atul Sathe
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Matthias B Wrobel
- Novartis Institutes for BioMedical Research, Biologics, Basel, Switzerland
| | - Mark Knapp
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Lucy Xu
- Novartis Institutes for BioMedical Research, Translational Medicine, East Hanover, New Jersey, USA
| | - Lihong Zhao
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Peter Kim
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Sachin Desai
- Novartis Institutes for BioMedical Research, Translational Medicine, East Hanover, New Jersey, USA
| | - Amanda Nguyen
- Novartis Institutes for BioMedical Research, Translational Medicine, East Hanover, New Jersey, USA
| | | | - Andreas Hein
- Novartis Institutes for BioMedical Research, Biologics, Basel, Switzerland
| | - Meike Scharenberg
- Novartis Institutes for BioMedical Research, Biologics, Basel, Switzerland
| | - Jacob Shaul
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Elisabeth Ornelas
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Kelly Wong
- Novartis Institutes for BioMedical Research, Infectious Disease Area, Emeryville, California, USA
| | - Thomas Pietzonka
- Novartis Institutes for BioMedical Research, Biologics, Basel, Switzerland
| | | | | | - Peter Pertel
- Novartis Institutes for BioMedical Research, Translational Medicine, East Hanover, New Jersey, USA
| | | | - Amy K Patick
- Amplyx Pharmaceuticals, San Diego, California, USA
| | - Steven J Kovacs
- Novartis Institutes for BioMedical Research, Translational Medicine, East Hanover, New Jersey, USA
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6
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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: 0] [Impact Index Per Article: 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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7
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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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8
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Carrillo J, Del Bello A, Sallusto F, Delas A, Colombat M, Mansuy JM, Izopet J, Kamar N, Belliere J. Effect of steroid pulses in severe BK virus allograft nephropathy with extensive interstitial inflammation. Transpl Infect Dis 2024; 26:e14260. [PMID: 38547002 DOI: 10.1111/tid.14260] [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: 08/21/2023] [Revised: 02/09/2024] [Accepted: 02/12/2024] [Indexed: 04/12/2024]
Abstract
INTRODUCTION As there is no specific antiviral treatment currently available for BK polyomavirus associated nephropathy (BKVAN), its management relies on immunosuppression reduction in kidney transplant patients. Data on efficacy of steroid pulses in this indication are lacking. METHODS We performed a retrospective monocenter study on 64 patients diagnosed with biopsy-proven BKVAN. Patients within the "pulse group" (n = 37) received IV methylprednisolone 10 mg/kg 3 days consecutively. In the "low dose" steroid group (n = 27), patients were continued oral prednisone 5 mg daily. RESULTS Mean follow up was 78 months in the steroid pulse group and 56 months in the low dose group (p = 0.15). Mean eGFR values at diagnosis were comparable, as well as other demographic characteristics. Mean BK plasma viral load was higher in "pulse" than in "low dose" steroid group. Pulse group had higher inflammation and tubulitis (p < 0.05). Graft loss reached 57% in the "pulse" group versus 41% in the "low dose" group, p = 0.20. Rejection events were similar. No major adverse event was statistically associated with steroid pulse, including infections, cancer, and de novo diabetes. CONCLUSION No significant differences were found in the evolution of both groups of patients, despite patients receiving "pulse" steroids were identified as the most severe sharing higher BK viral load and more frequent active lesions on histology.
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Affiliation(s)
- Julien Carrillo
- Department of Nephrology and Organ Transplantation, Referral Centre for Rare Kidney Diseases, French Intensive Care Renal Network, University Hospital of Toulouse, Toulouse, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, Referral Centre for Rare Kidney Diseases, French Intensive Care Renal Network, University Hospital of Toulouse, Toulouse, France
| | - Federico Sallusto
- Department of Urology and Kidney Transplantation, CHU Rangueil, Toulouse, France
| | - Audrey Delas
- Department of Pathology, University Hospital of Toulouse, University Cancer Institute of Toulouse, Toulouse, France
| | - Magali Colombat
- Department of Pathology, University Hospital of Toulouse, University Cancer Institute of Toulouse, Toulouse, France
- Université Toulouse III, Toulouse, France
| | - Jean Michel Mansuy
- Laboratory of Virology, Institut fédératif de Biologie, University Hospital of Toulouse, Toulouse, France
| | - Jacques Izopet
- Laboratory of Virology, Institut fédératif de Biologie, University Hospital of Toulouse, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Referral Centre for Rare Kidney Diseases, French Intensive Care Renal Network, University Hospital of Toulouse, Toulouse, France
- Université Toulouse III, Toulouse, France
- INSERM UMR1291-CNRS UMR5051, Toulouse, France
| | - Julie Belliere
- Department of Nephrology and Organ Transplantation, Referral Centre for Rare Kidney Diseases, French Intensive Care Renal Network, University Hospital of Toulouse, Toulouse, France
- Université Toulouse III, Toulouse, France
- INSERM U1297, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
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9
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Seifert ME, Mannon RB, Nellore A, Young J, Wiseman AC, Cohen DJ, Peddi VR, Brennan DC, Morgan CJ, Peri K, Aban I, Whitley RJ, Gnann JW. A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation. Transpl Infect Dis 2024; 26:e14237. [PMID: 38341645 PMCID: PMC11285626 DOI: 10.1111/tid.14237] [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: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 02/12/2024]
Abstract
BACKGROUND BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. METHODS We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. RESULTS We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. CONCLUSIONS We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.
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Affiliation(s)
- Michael E. Seifert
- Heersink School of Medicine, University of Alabama, Birmingham, Alabama, USA
| | - Roslyn B. Mannon
- Heersink School of Medicine, University of Alabama, Birmingham, Alabama, USA
| | - Anoma Nellore
- Heersink School of Medicine, University of Alabama, Birmingham, Alabama, USA
| | - JoAnne Young
- School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - David J. Cohen
- Columbia University Medical Center, New York, New York, USA
| | - V. Ram Peddi
- California Pacific Medical Center, San Francisco, California, USA
| | | | - Charity J. Morgan
- Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kalyani Peri
- Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Inmaculada Aban
- Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Richard J. Whitley
- Heersink School of Medicine, University of Alabama, Birmingham, Alabama, USA
| | - John W. Gnann
- Medical University of South Carolina, Charleston, South Carolina, USA
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Rasmussen DB, Møller DL, Hamm SR, Borges ÁH, Nielsen ACY, Kirkby NS, Sørensen SS, Nielsen SD. BKPyV DNAemia in Kidney Transplant Recipients Undergoing Regular Screening: A Single-Centre Cohort Study. Microorganisms 2023; 12:65. [PMID: 38257892 PMCID: PMC10819282 DOI: 10.3390/microorganisms12010065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/16/2023] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
Infection with BK polyomavirus (BKPyV) is a common opportunistic infection after kidney transplantation (KT) and may affect graft function. We aimed to determine the incidence, risk factors, and clinical outcomes of BKPyV DNAemia in a prospective cohort of 601 KT recipients transplanted from 2012 to 2020. BKPyV PCR on plasma was performed at days 60, 90, 180, 270, and 360 post-KT. Any BKPyV DNAemia was defined as a single BKPyV DNA of ≥1000 copies/mL. Severe BKPyV DNAemia was defined as two consecutive BKPyV DNA of ≥10,000 copies/mL. Cumulative incidences were investigated using the Aalen-Johansen estimator, and the risk factors were investigated in Cox proportional hazard models. The incidence of any BKPyV DNAemia and severe BKPyV DNAemia was 21% (18-25) and 13% (10-16) at one year post-KT, respectively. Recipient age > 50 years (aHR, 1.72; 95% CI 1.00-2.94; p = 0.049), male sex (aHR, 1.96; 95% CI 1.17-3.29; p = 0.011), living donors (aHR, 1.65; 95% CI 1.03-2.74; p = 0.045), and >3 HLA-ABDR mismatches (aHR, 1.72; 95% CI 1.01-2.94; p = 0.046) increased the risk of severe BKPyV DNAemia. Any BKPyV DNAemia was associated with an increased risk of graft function decline (aHR, 2.26; 95% CI 1.00-5.12; p = 0.049), and severe BKPyV DNAemia was associated with an increased risk of graft loss (aHR, 3.18; 95% CI 1.06-9.58; p = 0.039). These findings highlight the importance of BKPyV monitoring post-KT.
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Affiliation(s)
- Daniel B. Rasmussen
- Viro-Immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (D.B.R.); (D.L.M.); (S.R.H.)
| | - Dina L. Møller
- Viro-Immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (D.B.R.); (D.L.M.); (S.R.H.)
| | - Sebastian R. Hamm
- Viro-Immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (D.B.R.); (D.L.M.); (S.R.H.)
| | - Álvaro H. Borges
- Department of Infectious Disease Immunology, Statens Serum Institut, 2300 Copenhagen, Denmark;
- Centre of Excellence for Health, Immunity and Infections (CHIP), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Alex C. Y. Nielsen
- Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (A.C.Y.N.); (N.S.K.)
| | - Nikolai S. Kirkby
- Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (A.C.Y.N.); (N.S.K.)
| | - Søren S. Sørensen
- Department of Nephrology, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark;
- Department of Clinical Medicine, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Susanne D. Nielsen
- Viro-Immunology Research Unit, Department of Infectious Diseases 8632, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; (D.B.R.); (D.L.M.); (S.R.H.)
- Department of Clinical Medicine, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark
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11
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Zhong C, Chen J, Yan Z, Xia R, Zeng W, Deng W, Xu J, Wang Y, Miao Y. Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis. Transpl Immunol 2023; 81:101953. [PMID: 37931665 DOI: 10.1016/j.trim.2023.101953] [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: 09/05/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023]
Abstract
BACKGROUND The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. METHODS We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. RESULTS A total of 33 published studies involving 986 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I2 = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I2 = 83%), 71% (95% CI: 0.63-0.78; I2 = 0), 87% (95% CI: 0.82-0.93; I2 = 45%), and 80% (95% CI: 0.59-1.00; I2 = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. CONCLUSIONS Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.
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Affiliation(s)
- Cuiyu Zhong
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jiayi Chen
- Department of Biostatistics, School of Public Health (Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, Guangzhou 510515, China
| | - Ziyan Yan
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Renfei Xia
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wenli Zeng
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Wenfeng Deng
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jian Xu
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuchen Wang
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
| | - Yun Miao
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
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12
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Characteristics, risk factors and outcome of BKV nephropathy in kidney transplant recipients: a case-control study. BMC Infect Dis 2023; 23:74. [PMID: 36747162 PMCID: PMC9903532 DOI: 10.1186/s12879-023-08043-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Following kidney transplantation, BK virus associated nephropathy (BKVN) occurs in 1 to 10% of kidney transplant recipients (KTR) and represents a major cause of graft loss. We aim at identifying factors associated with biopsy proven BKVN among KTR. METHODS We conducted a retrospective case-control study including all KTR with a biopsy-proven diagnosis of BKVN between 2005 and 2019. Clinical characteristics and outcome were described. For each case, one control KTR without BKV infection was identified and matched by age, transplant date, and donor status. Factors associated with BKVN diagnosis were identified using exact conditional logistic regression. Comparative survival was described using Kaplan-Meier estimator. RESULTS Sixty-four cases of BKVN were identified among 1737 new kidney transplantation (3.7% prevalence). Clinical characteristics did not differ between groups, except for a higher c-PRA among cases. BKVN occurred in a median time of 11 (5-14.5) months after KT, and was associated with a significantly impaired graft function at diagnosis. Following BKVN, 61 (95%) of the patients had immunosuppression reduction, which led to BKV DNAemia resolution in 49% of cases. In multivariate analysis, factors associated with BKVN diagnosis were lymphopenia < 500/mm3 and a prednisone dose > 7.5 mg/day. Median duration of follow-up was 40 months for both groups. BKVN was associated with a significantly increased risk of graft rejection (P = 0.02) and return to dialysis (P = 0.01). CONCLUSIONS BKVN remains a severe complication in KTR and is associated with an increased risk for acute rejection and return to dialysis. Lymphopenia below 500/mm3 and corticosteroid maintenance therapy are significantly associated with biopsy-proven BKVN diagnosis.
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13
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Abeywardana KDST, Rajamanthri RGLS, Wazil AWM, Nanayakkara N, Muthugala MARV. Longitudinal viral kinetic study of BK virus in renal transplant patients-A single-centre study in Sri Lanka. JOURNAL OF CLINICAL VIROLOGY PLUS 2022. [DOI: 10.1016/j.jcvp.2022.100125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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14
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BK Virus Nephropathy in Kidney Transplantation: A State-of-the-Art Review. Viruses 2022; 14:v14081616. [PMID: 35893681 PMCID: PMC9330039 DOI: 10.3390/v14081616] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/10/2022] [Accepted: 07/22/2022] [Indexed: 11/16/2022] Open
Abstract
BK virus maintains a latent infection that is ubiquitous in humans. It has a propensity for reactivation in the setting of a dysfunctional cellular immune response and is frequently encountered in kidney transplant recipients. Screening for the virus has been effective in preventing progression to nephropathy and graft loss. However, it can be a diagnostic and therapeutic challenge. In this in-depth state-of-the-art review, we will discuss the history of the virus, virology, epidemiology, cellular response, pathogenesis, methods of screening and diagnosis, evidence-based treatment strategies, and upcoming therapeutics, along with the issue of re-transplantation in patients.
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15
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Avcı B, Baskın E, Gülleroğlu K, Ecevit Z, Ayvazoğlu Soy E, Moray G, Haberal M. BK Polyomavirus Infection and Risk Factors in Pediatric Patients Undergoing Kidney Transplant. EXP CLIN TRANSPLANT 2022; 20:105-111. [PMID: 35570612 DOI: 10.6002/ect.pediatricsymp2022.o34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES BK polyomavirus infection is a critical complication affecting graft survival after kidney transplant. We aimed to determine the frequency, the effect on graft function, and the risk factors of BK polyomavirus infection in pediatric kidney transplant patients. MATERIALS AND METHODS We retrospectively reviewed data of 144 pediatric patients (female/male: 67/77; 0-18 years of age) who received kidney transplants in the past 10 years at our center. Demographic/ laboratory data, kidney failure etiologies, donor types, and immunosuppressive treatments were recorded. Patients were grouped as those with and without BKV infection, with groups compared in terms of transplant age, sex, kidney failure etiology, donor type, immunosuppressive treatments, presence of ureteral stents, acute rejection episodes, accompanying viral infections, glomerular filtration rate, and graft loss rate. RESULTS Twelve patients (8.3%) had BK polyomavirus infection. All 12 patients had viruria (8.3%), 8 (5.5%) had viremia, and 4 (2.8%) had BK polyomavirus nephropathy. Two patients (1.4%) had graft loss because of BK polyomavirus nephropathy. When patients with and without infection were compared, no significant differences were found in terms of sex, transplant age, donor type, presence of a ureteral stent, acute rejection, graft loss, or immunosuppressive treatment (P > .05). Rates of congenital anomalies of the kidney and urinary tract were 30.3% and 66.6% in those without and with BK polyomavirus infection, respectively (P < .05). The group positive for BK polyomavirus had a significantly higher incidence of cytomegalovirus infection versus the group without infection (P < .05). Glomerular filtration rate values at years 1 and 3 were similar between groups (P > .05). CONCLUSIONS Frequency of BK polyomavirus nephropathy in pediatric patients undergoing kidney transplant in our center was consistent with data from other centers. Graft loss can be prevented by early detection and treatment through close periodic control and adequate evaluation of risk factors.
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Affiliation(s)
- Begüm Avcı
- From the Department of Pediatric Nephrology, Başkent University Faculty of Medicine, Ankara, Turkey
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16
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Chukwu CA, Mahmood K, Elmakki S, Gorton J, Kalra PA, Poulikakos D, Middleton R. Evaluating the antibody response to SARS-COV-2 vaccination amongst kidney transplant recipients at a single nephrology centre. PLoS One 2022; 17:e0265130. [PMID: 35271655 PMCID: PMC8912185 DOI: 10.1371/journal.pone.0265130] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/23/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Kidney transplant recipients are highly vulnerable to the serious complications of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infections and thus stand to benefit from vaccination. Therefore, it is necessary to establish the effectiveness of available vaccines as this group of patients was not represented in the randomized trials. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 707 consecutive adult kidney transplant recipients in a single center in the United Kingdom were evaluated. 373 were confirmed to have received two doses of either the BNT162b2 (Pfizer-BioNTech) or AZD1222 (Oxford-AstraZeneca) and subsequently had SARS-COV-2 antibody testing were included in the final analysis. Participants were excluded from the analysis if they had a previous history of SARS-COV-2 infection or were seropositive for SARS-COV-2 antibody pre-vaccination. Multivariate and propensity score analyses were performed to identify the predictors of antibody response to SARS-COV-2 vaccines. The primary outcome was seroconversion rates following two vaccine doses. RESULTS Antibody responders were 56.8% (212/373) and non-responders 43.2% (161/373). Antibody response was associated with greater estimated glomerular filtration (eGFR) rate [odds ratio (OR), for every 10 ml/min/1.73m2 = 1.40 (1.19-1.66), P<0.001] whereas, non-response was associated with mycophenolic acid immunosuppression [OR, 0.02(0.01-0.11), p<0.001] and increasing age [OR per 10year increase, 0.61(0.48-0.78), p<0.001]. In the propensity-score analysis of four treatment variables (vaccine type, mycophenolic acid, corticosteroid, and triple immunosuppression), only mycophenolic acid was significantly associated with vaccine response [adjusted OR by PSA 0.17 (0.07-0.41): p<0.001]. 22 SARS-COV-2 infections were recorded in our cohort following vaccination. 17(77%) infections, with 3 deaths, occurred in the non-responder group. No death occurred in the responder group. CONCLUSION Vaccine response in allograft recipients after two doses of SARS-COV-2 vaccine is poor compared to the general population. Maintenance with mycophenolic acid appears to have the strongest negative impact on vaccine response.
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Affiliation(s)
- Chukwuma A. Chukwu
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Kassir Mahmood
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
| | - Safa Elmakki
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
| | - Julie Gorton
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
| | - Phillip A. Kalra
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Dimitrios Poulikakos
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Rachel Middleton
- Department of Nephrology, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
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Kurašová E, Štěpán J, Krejčí K, Mrázek F, Sauer P, Janečková J, Tichý T. Current Status, Prevention and Treatment of BK Virus Nephropathy. ACTA MEDICA (HRADEC KRALOVE) 2022; 65:119-124. [PMID: 36942701 DOI: 10.14712/18059694.2023.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
All renal transplant recipients should undergo a regular screening for BK viral (BKV) viremia. Gradual reduction of immunosuppression is recommended in patients with persistent plasma BKV viremia for 3 weeks after the first detection, reflecting the presence of probable or suspected BKV-associated nephropathy. Reduction of immunosuppression is also a primary intervention in biopsy proven nephropathy associated with BKV (BKVN). Thus, allograft biopsy is not required to treat patients with BKV viremia with stabilized graft function. There is a lack of proper randomised clinical trials recommending treatment in the form of switching from tacrolimus to cyclosporin-A, from mycophenolate to mTOR inhibitors or leflunomide, or the additive use of intravenous immunoglobulins, leflunomide or cidofovir. Fluoroquinolones are not recommended for prophylaxis or therapy. There are on-going studies to evaluate the possibility of using a multi-epitope anti-BKV vaccine, administration of BKV-specific T cell immunotherapy, BKV-specific human monoclonal antibody and RNA antisense oligonucleotides. Retransplantation after allograft loss due to BKVN can be successful if BKV viremia is definitively removed, regardless of allograft nephrectomy.
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Affiliation(s)
- Ester Kurašová
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, Olomouc, Czech Republic.
| | - Jakub Štěpán
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, Olomouc, Czech Republic
| | - Karel Krejčí
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, Olomouc, Czech Republic
| | - František Mrázek
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Immunology, Olomouc, Czech Republic
| | - Pavel Sauer
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Microbiology, Olomouc, Czech Republic
| | - Jana Janečková
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Surgery II, Olomouc, Czech Republic
| | - Tomáš Tichý
- University Hospital Olomouc and Palacký University Olomouc, Faculty of Medicine and Dentistry, Department of Clinical and Molecular Pathology, Olomouc, Czech Republic
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18
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Affiliation(s)
- Sundaram Hariharan
- From the University of Pittsburgh Medical Center, Pittsburgh (S.H.); Hennepin Healthcare, the University of Minnesota, and the Scientific Registry of Transplant Recipients - all in Minneapolis (A.K.I.); and the University of California, Los Angeles, Los Angeles (G.D.)
| | - Ajay K Israni
- From the University of Pittsburgh Medical Center, Pittsburgh (S.H.); Hennepin Healthcare, the University of Minnesota, and the Scientific Registry of Transplant Recipients - all in Minneapolis (A.K.I.); and the University of California, Los Angeles, Los Angeles (G.D.)
| | - Gabriel Danovitch
- From the University of Pittsburgh Medical Center, Pittsburgh (S.H.); Hennepin Healthcare, the University of Minnesota, and the Scientific Registry of Transplant Recipients - all in Minneapolis (A.K.I.); and the University of California, Los Angeles, Los Angeles (G.D.)
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19
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BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection. Viruses 2021; 13:v13030487. [PMID: 33809472 PMCID: PMC7998398 DOI: 10.3390/v13030487] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/16/2022] Open
Abstract
BK polyomavirus nephropathy (BKVN) and allograft rejection are two closely-associated diseases on opposite ends of the immune scale in kidney transplant recipients. The principle of balancing the immune system remains the mainstay of therapeutic strategy. While patient outcomes can be improved through screening, risk factors identification, and rapid reduction of immunosuppressants, a lack of standard curative therapy is the primary concern during clinical practice. Additionally, difficulty in pathological differential diagnosis and clinicopathology’s dissociation pose problems for a definite diagnosis. This article discusses the delicate evaluation needed to optimize immunosuppression and reviews recent advances in molecular diagnosis and immunological therapy for BKVN patients. New biomarkers for BKVN diagnosis are under development. For example, measurement of virus-specific T cell level may play a role in steering immunosuppressants. The development of cellular therapy may provide prevention, even a cure, for BKVN, a complex post-transplant complication.
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20
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Lebel E, Chen C, Paul H, Trudel S, Tiedemann R. Symptomatic BK Virus Disease in Patients With Heavily Pretreated Multiple Myeloma. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:e506-e509. [PMID: 33608216 DOI: 10.1016/j.clml.2021.01.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/31/2020] [Accepted: 01/11/2021] [Indexed: 11/19/2022]
Affiliation(s)
- Eyal Lebel
- Princess Margaret Cancer Centre, Toronto, Canada.
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21
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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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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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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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Prom A, Jorgenson M, Alagusundaramoorthy S, Parajuli S. Persistent BK polyomavirus-DNAemia may warrant cystoscopy to rule out urologic carcinoma: A case report and review of the literature. Transpl Infect Dis 2020; 22:e13316. [PMID: 32386093 DOI: 10.1111/tid.13316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/20/2020] [Accepted: 05/02/2020] [Indexed: 12/14/2022]
Abstract
There is minimal literature describing the clinical workup of patients with persistent BKPyV-DNAemia despite aggressive immunosuppressive reduction. We present a case herein of persistent BKPyV-DNAemia with significant discordance of BK viruria level in a kidney transplant recipient found to have bladder carcinoma. Based on our findings, we recommend evaluating the urine of patients with persistent BKPyV-DNAemia for BK viruria. If there is significant discordance in the level of BKPyV-DNAemia and viruria, cystoscopy should be pursued to rule out bladder or uroepithelial malignancies.
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Affiliation(s)
- Alyson Prom
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Margaret Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI, USA
| | - Sayee Alagusundaramoorthy
- Division of Nephrology, Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health Madison, WI, USA
| | - Sandesh Parajuli
- Division of Nephrology, Department of Internal Medicine, University of Wisconsin School of Medicine and Public Health Madison, WI, USA
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25
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Beyond Cytomegalovirus and Epstein-Barr Virus: a Review of Viruses Composing the Blood Virome of Solid Organ Transplant and Hematopoietic Stem Cell Transplant Recipients. Clin Microbiol Rev 2020; 33:33/4/e00027-20. [PMID: 32847820 DOI: 10.1128/cmr.00027-20] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Viral primary infections and reactivations are common complications in patients after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) and are associated with high morbidity and mortality. Among these patients, viral infections are frequently associated with viremia. Beyond the usual well-known viruses that are part of the routine clinical management of transplant recipients, numerous other viral signatures or genomes can be identified in the blood of these patients. The identification of novel viral species and variants by metagenomic next-generation sequencing has opened up a new field of investigation and new paradigms. Thus, there is a need to thoroughly describe the state of knowledge in this field with a review of all viral infections that should be scrutinized in high-risk populations. Here, we review the eukaryotic DNA and RNA viruses identified in blood, plasma, or serum samples of pediatric and adult SOT/HSCT recipients and the prevalence of their detection, with a particular focus on recently identified viruses and those for which their potential association with disease remains to be investigated, such as members of the Polyomaviridae, Anelloviridae, Flaviviridae, and Astroviridae families. Current knowledge of the clinical significance of these viral infections with associated viremia among transplant recipients is also discussed. To ensure a comprehensive description in these two populations, individuals described as healthy (mostly blood donors) are considered for comparative purposes. The list of viruses that should be on the clinicians' radar is certainly incomplete and will expand, but the challenge is to identify those of possible clinical significance.
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26
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Kane JR, Fong S, Shaul J, Frommlet A, Frank AO, Knapp M, Bussiere DE, Kim P, Ornelas E, Cuellar C, Hyrina A, Abend JR, Wartchow CA. A polyomavirus peptide binds to the capsid VP1 pore and has potent antiviral activity against BK and JC polyomaviruses. eLife 2020; 9:50722. [PMID: 31960795 PMCID: PMC6974358 DOI: 10.7554/elife.50722] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/30/2019] [Indexed: 12/18/2022] Open
Abstract
In pursuit of therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen-residue peptide binds to major structural protein VP1 with single-digit nanomolar affinity. Alanine-scanning of the peptide identified three key residues, substitution of each of which results in ~1000 fold loss of binding affinity with a concomitant reduction in antiviral activity. Structural studies demonstrate specific binding of the peptide to the pore of pentameric VP1. Cell-based assays demonstrate nanomolar inhibition (EC50) of BKV infection and suggest that the peptide acts early in the viral entry pathway. Homologous peptide exhibits similar binding to JC polyomavirus VP1 and inhibits infection with similar potency to BKV in a model cell line. Lastly, these studies validate targeting the VP1 pore as a novel strategy for the development of anti-polyomavirus agents.
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Affiliation(s)
- Joshua R Kane
- Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States.,Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Susan Fong
- Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Jacob Shaul
- Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Alexandra Frommlet
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Andreas O Frank
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Mark Knapp
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Dirksen E Bussiere
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Peter Kim
- Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Elizabeth Ornelas
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Carlos Cuellar
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Anastasia Hyrina
- Chemical Biology and Therapeutics, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Johanna R Abend
- Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, United States
| | - Charles A Wartchow
- Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Emeryville, United States
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27
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Rohan V, Taber D, Palanisamy A, Mcgillicuddy J, Chavin K, Baliga P, Bratton C. Impact of Type 1 and Type 2 Diabetes Mellitus on Pancreas Transplant Outcomes. EXP CLIN TRANSPLANT 2019; 17:796-802. [DOI: 10.6002/ect.2017.0296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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28
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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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29
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El-Husseini A, Hassan W, Yaseen M, Suleiman B, Saleh S, Malik O, Ashqar H, Maibam A, Mei X, Castellanos AL, Cornea V, Gedaly R, Waid T. Impact of human leukocyte antigen and calculated panel reactive antibody on BK viremia in kidney transplant recipients: A single-center experience and literature review. Transpl Infect Dis 2019; 21:e13071. [PMID: 30866136 DOI: 10.1111/tid.13071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/25/2019] [Accepted: 02/15/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND The aim of this retrospective analysis was to investigate the effect of human leukocyte antigen (HLA) and calculated panel reactive antibody (cPRA) on BK virus activation as evidenced by BK viremia (BKV). PATIENTS AND METHODS At our institution, 649 kidney transplant patients were screened for BKV from 2009 to 2017. Patients were considered to have BKV if they had >10 000 copies/mL of BK DNA in their blood. Donor and recipient HLA and cPRA, demographic, clinical and laboratory data, as well as immunosuppressive medications were collected. RESULTS We identified 122 BK positive and 527 BK negative patients. Only 25% of the patients had cPRA of 20% or more, and 64% had more than three HLA-A, -B, and -DR mismatches. In both univariate and multivariate analyses, male gender, age, and maintenance of steroid therapy significantly increased the risk of BKV (P = 0.005, 0.005 and <0.001, respectively). The degree of cPRA and the individual HLA allele and HLA allele matching did not significantly affect BKV. CONCLUSION Neither the degree of HLA mismatching nor cPRA appears to affect BKV. Moreover, no specific HLA allele, HLA allele matching, or cPRA were associated with BKV.
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Affiliation(s)
- Amr El-Husseini
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Waleed Hassan
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Maria Yaseen
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Belal Suleiman
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Sherif Saleh
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Omar Malik
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Hasan Ashqar
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Amita Maibam
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Xiaonan Mei
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Ana L Castellanos
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Virgilius Cornea
- Department of Surgical Pathology, University of Kentucky, Lexington, Kentucky
| | - Roberto Gedaly
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
| | - Thomas Waid
- Division of Nephrology and Transplant Program, University of Kentucky, Lexington, Kentucky
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30
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Cho YH, Hyun HS, Park E, Moon KC, Min SI, Ha J, Ha IS, Cheong HI, Ahn YH, Kang HG. Higher Incidence of BK Virus Nephropathy in Pediatric Kidney Allograft Recipients with Alport Syndrome. J Clin Med 2019; 8:jcm8040491. [PMID: 30978953 PMCID: PMC6517952 DOI: 10.3390/jcm8040491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/28/2019] [Accepted: 04/08/2019] [Indexed: 01/29/2023] Open
Abstract
A retrospective review was performed to assess the risk factors and outcomes of BK virus infection and nephropathy (BKVN), an early complication in pediatric kidney allograft recipients. The study investigated the incidence, risk factors, and clinical outcomes of BK viremia and BKVN in a Korean population of pediatric patients who received renal transplantation from 2001–2015 at the Seoul National University Hospital. BKVN was defined as biopsy-proven BKVN or plasma BK viral loads >10,000 copies/mL for >3 weeks. BK viremia was defined as a BK viral load >100 copies/mL in blood. Among 168 patients assessed for BK virus status, 30 patients (17.9%) tested positive for BK viremia at a median of 12.6 months after transplantation. BKVN was diagnosed in six patients (3.6%) at a median of 13.4 months after transplantation. Three of the six BKVN patients had Alport syndrome (p = 0.003), despite this disease comprising only 6% of the study population. Every patient with BK viremia and Alport syndrome developed BKVN, while only 11.1% of patients with BK viremia progressed to BKVN in the absence of Alport syndrome. Multivariate analysis revealed that Alport syndrome was associated with BKVN development (hazard ratio 13.2, p = 0.002). BKVN treatment included the reduction of immunosuppression, leflunomide, and intravenous immunoglobulin. No allografts were lost in the two years following the diagnosis of BKVN. In summary, the incidence of BKVN in pediatric kidney allograft recipients was similar to findings in previous reports, but was higher in patients with underlying Alport syndrome.
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Affiliation(s)
- Young Hoon Cho
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
| | - Hye Sun Hyun
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
- Department of Pediatrics, St. Vincent's Hospital, College of Medicine, The Catholic University College of Korea, Seoul 06591, Korea.
| | - Eujin Park
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
- Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Korea.
| | - Kyung Chul Moon
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Sang-Il Min
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Jongwon Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul 03080, Korea.
- Transplantation Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.
| | - Il-Soo Ha
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
| | - Hae Il Cheong
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
| | - Yo Han Ahn
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam 13620, Korea.
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Hospital, Seoul 03080, Korea.
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31
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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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32
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Reduced Risk of BK Polyomavirus Infection in HLA-B51–positive Kidney Transplant Recipients. Transplantation 2019; 103:604-612. [DOI: 10.1097/tp.0000000000002376] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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33
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Wunderink HF, De Brouwer CS, Gard L, De Fijter JW, Kroes ACM, Rotmans JI, Feltkamp MCW. Source and Relevance of the BK Polyomavirus Genotype for Infection After Kidney Transplantation. Open Forum Infect Dis 2019; 6:ofz078. [PMID: 30949528 PMCID: PMC6440680 DOI: 10.1093/ofid/ofz078] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 02/14/2019] [Indexed: 12/23/2022] Open
Abstract
Background BK polyomavirus (BKPyV)–associated nephropathy (BKPyVAN) is a major threat for kidney transplant recipients (KTRs). The role of specific BKPyV genotypes/serotypes in development of BKPyVAN is poorly understood. Pretransplantation serotyping of kidney donors and recipients and posttransplantation genotyping of viremic recipients, could reveal the clinical relevance of specific BKPyV variants. Methods A retrospective cohort of 386 living kidney donor-recipient pairs was serotyped before transplantation against BKPyV genotype I–IV viral capsid protein 1 antigen, using a novel BKPyV serotyping assay. Replicating BKPyV isolates in viremic KTRs after transplantation were genotyped using real-time polymerase chain reaction and confirmed by means of sequencing. BKPyV serotype and genotype data were used to determine the source of infection and analyze the risk of viremia and BKPyVAN. Results Donor and recipient BKPyV genotype and serotype distribution was dominated by genotype I (>80%), especially Ib, over II, III and IV. Donor serotype was significantly correlated with the replicating genotype in viremic KTRs (P < .001). Individual donor and recipient serotype, serotype (mis)matching and the recipient replicating BKPyV genotype were not associated with development of viremia or BKPyVAN after transplantation. Conclusions BKPyV donor and recipient serotyping and genotyping indicates the donor origin of replicating BKPyV in viremic KTRs but provides no evidence for BKPyV genotype–specific virulence.
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Affiliation(s)
- H F Wunderink
- Department of Medical Microbiology, Leiden University Medical Center, the Netherlands
| | - C S De Brouwer
- Department of Medical Microbiology, Leiden University Medical Center, the Netherlands
| | - L Gard
- Department of Medical Microbiology, University Medical Center Groningen, the Netherlands
| | - J W De Fijter
- Department of Internal Medicine, Leiden University Medical Center, the Netherlands
| | - A C M Kroes
- Department of Medical Microbiology, Leiden University Medical Center, the Netherlands
| | - J I Rotmans
- Department of Internal Medicine, Leiden University Medical Center, the Netherlands
| | - M C W Feltkamp
- Department of Medical Microbiology, Leiden University Medical Center, the Netherlands
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34
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van Rijn AL, Wunderink HF, de Brouwer CS, van der Meijden E, Rotmans JI, Feltkamp MCW. Impact of HPyV9 and TSPyV coinfection on the development of BK polyomavirus viremia and associated nephropathy after kidney transplantation. J Med Virol 2019; 91:1142-1147. [PMID: 30624811 PMCID: PMC6590353 DOI: 10.1002/jmv.25397] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 10/16/2018] [Accepted: 12/09/2018] [Indexed: 11/12/2022]
Abstract
Background BK polyomavirus (BKPyV) persistently infects the urinary tract and causes viremia and nephropathy in kidney transplantation (KTx), recipients. In a previous study, we observed an increased incidence and load of BKPyV viremia in KTx patients coinfected with human polyomavirus 9 (HPyV9). Here we sought confirmation of this observation and explored whether novel HPyVs that have been detected in urine (HPyV9 and trichodysplasia spinulosa polyomavirus [TSPyV]) potentially aggravate BKPyV infection. Methods A well‐characterized cohort of 209 KTx donor‐recipient pairs was serologically and molecularly analyzed for HPyV9 and TSPyV coinfection. These data were correlated with the occurrence of BKPyV viremia and BKPyVAN in the recipients within a year after KTx. Results Seropositivity for HPyV9 (19%) and TSPyV (89%) was comparable between donors and recipients and did not correlate with BKPyV viremia and BKPyVAN that developed in 25% and 3% of the recipients, respectively. Two recipients developed TSPyV viremia and none HPyV9 viremia. Modification of the predictive effect of donor BKPyV seroreactivity on recipient BKPyV viremia by HPyV9 and TSPyV was not observed. Conclusions Our data provide no evidence for a promoting effect of HPyV9 and TSPyV on BKPyV infection and BKPyVAN in renal allograft patients. Therefore, we do not recommend including HPyV9 and TSPyV screening in KTx patients.
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Affiliation(s)
- Aline L van Rijn
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Herman F Wunderink
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Caroline S de Brouwer
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Els van der Meijden
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Joris I Rotmans
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Mariet C W Feltkamp
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Elfadawy N, Yamada M, Sarabu N. Management of BK Polyomavirus Infection in Kidney and Kidney-Pancreas Transplant Recipients: A Review Article. Infect Dis Clin North Am 2018; 32:599-613. [PMID: 30146025 DOI: 10.1016/j.idc.2018.04.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BK virus (BKV) can cause graft dysfunction or failure in kidney transplant recipients and hemorrhagic cystitis in allogeneic hematopoietic stem cell transplant patients. BKV-associated nephropathy (BKVAN) emerged as a common complication in the late 1990s, probably due to the introduction of potent immunosuppressive agents. BKVAN occurred in up to 5% of kidney transplant recipients, with graft failure in up to 70%. Since universal implementation of effective screening and treatment strategies, BKV is no longer a common cause of graft failure; reported graft loss is only 0% to 5%. This article briefly describes BK virology, epidemiology, diagnosis, and management.
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Affiliation(s)
- Nissreen Elfadawy
- Department of Nephrology and Hypertension, University Hospitals, Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
| | - Masaaki Yamada
- Division of Nephrology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Suite 6213, Cincinnati, OH 45267-0585, USA
| | - Nagaraju Sarabu
- Department of Nephrology and Hypertension, University Hospitals, Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USA
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Wunderink HF, de Brouwer CS, van der Meijden E, Pastrana DV, Kroes ACM, Buck CB, Feltkamp MCW. Development and evaluation of a BK polyomavirus serotyping assay using Luminex technology. J Clin Virol 2018; 110:22-28. [PMID: 30529638 DOI: 10.1016/j.jcv.2018.11.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 09/22/2018] [Accepted: 11/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND The BK polyomavirus (BKPyV) is subdivided into four genotypes. The consequences of each genotype and of donor-recipient genotype (mis)match for BKPyV-associated nephropathy (BKPyVAN) in kidney transplant recipients (KTRs) are unknown. OBJECTIVES To develop and evaluate a genotype-specific IgG antibody-based BKPyV serotyping assay, in order to classify kidney transplant donors and recipients accordingly. STUDY DESIGN VP1 antigens of six BKPyV variants (Ib1, Ib2, Ic, II, III and IV) were expressed as recombinant glutathione-s-transferase-fusion proteins and coupled to fluorescent Luminex beads. Sera from 87 healthy blood donors and 39 KTRs were used to analyze seroreactivity and serospecificity against the different BKPyV genotypes. Six sera with marked BKPyV serotype profiles were analyzed further for genotype-specific BKPyV pseudovirus neutralizing capacity. RESULTS Seroreactivity was observed against all genotypes, with seropositivity rates above 77% comparable for KTRs and blood donors. Strong cross-reactivity (r > 0.8) was observed among genotype I subtypes, and among genotypes II, III and IV. Seroresponses against genotypes I and IV seemed genuine, while those against II and III could be out(cross)competed. GMT (Luminex) and IC50 (neutralization assay) values showed good agreement in determining the genotype with the strongest seroresponse within an individual. CONCLUSIONS Despite some degree of cross-reactivity, this serotyping assay seems a useful tool to identify the main infecting BKPyV genotype within a given individual. This information, which cannot be obtained otherwise from nonviremic/nonviruric individuals, could provide valuable information regarding the prevalent BKPyV genotype in kidney donors and recipients and warrants further study.
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Affiliation(s)
- Herman F Wunderink
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands.
| | - Caroline S de Brouwer
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Els van der Meijden
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Diana V Pastrana
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892-4263, USA
| | - Aloysius C M Kroes
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Christopher B Buck
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892-4263, USA
| | - Mariet C W Feltkamp
- Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands
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Plafkin C, Singh T, Astor BC, Parajuli S, Bhutani G, Safdar N, Panzer SE. Kidney transplant recipients with polycystic kidney disease have a lower risk of post-transplant BK infection than those with end-stage renal disease due to other causes. Transpl Infect Dis 2018; 20:e12974. [PMID: 30102820 PMCID: PMC6289763 DOI: 10.1111/tid.12974] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 07/17/2018] [Accepted: 08/06/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Polyomavirus-associated nephropathy is associated with high risk of kidney allograft loss. Whether the cause of native end-stage renal disease influences the risk of BK infection is unclear. METHODS A retrospective, single-center study of 2741 adult kidney transplant recipients between 1994 and 2014 was performed. Recipients had end-stage renal disease due to polycystic kidney disease (PKD, n = 549), diabetes mellitus (DM, n = 947), hypertension (HTN, n = 442), or glomerulonephritis (GN, n = 803). RESULTS A total of 327 recipients (12%) developed post-transplant BK viremia over a median follow-up time of 5 years. The incidence rate of BK viremia was lowest in patients with PKD (1.46 per 100 person-years) compared to other causes of ESRD (DM = 2.06, HTN = 2.65, and GN = 2.01 per 100 person-years). A diagnosis of PKD was associated with a lower risk of post-transplant BK viremia (adjusted HR (95% CI) = 0.67 (0.48-0.95), P = 0.02). BK nephropathy was significantly less common in patients with PKD (0.21 per 100 person-years) compared to those with HTN (0.80 per 100 person-years, P ≤ 0.001). Among patients with PKD, the risk of BK viremia was lower in patients with nephrectomy, compared to those without nephrectomy (adjusted HR (95% CI) = 0.42 (0.19-0.92), P < 0.05). CONCLUSION ESRD due to PKD is associated with a lower risk of post-transplant BK infection. The renal tubular epithelial cells in PKD are unique; they are in a proliferative but non-differentiated state. Whether this characteristic of renal tubular epithelial cells alters the BK viral reservoir or replication in PKD patients warrants further study.
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Affiliation(s)
- Callie Plafkin
- Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - Tripti Singh
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Brad C. Astor
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Department of Population Health Sciences, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA
| | - Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Gauri Bhutani
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Nasia Safdar
- Division of Infectious Disease, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Division of Infectious Disease, Department of Medicine, William S. Middleton Memorial Hospital, Madison, WI, USA
| | - Sarah E. Panzer
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
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BKV, CMV, and EBV Interactions and their Effect on Graft Function One Year Post-Renal Transplantation: Results from a Large Multi-Centre Study. EBioMedicine 2018; 34:113-121. [PMID: 30072213 PMCID: PMC6116415 DOI: 10.1016/j.ebiom.2018.07.017] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 07/06/2018] [Accepted: 07/13/2018] [Indexed: 01/15/2023] Open
Abstract
Background BK virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivations are common after kidney transplantation and associated with increased morbidity and mortality. Although CMV might be a risk factor for BKV and EBV, the effects of combined reactivations remain unknown. The purpose of this study is to ascertain the interaction and effects on graft function of these reactivations. Methods 3715 serum samples from 540 kidney transplant recipients were analysed for viral load by qPCR. Measurements were performed throughout eight visits during the first post-transplantation year. Clinical characteristics, including graft function (GFR), were collected in parallel. Findings BKV had the highest prevalence and viral loads. BKV or CMV viral loads over 10,000 copies·mL−1 led to significant GFR impairment. 57 patients had BKV-CMV combined reactivation, both reactivations were significantly associated (p = 0.005). Combined reactivation was associated with a significant GFR reduction one year post-transplantation of 11.7 mL·min−1·1.73 m−2 (p = 0.02) at relatively low thresholds (BKV > 1000 and CMV > 4000 copies·mL−1). For EBV, a significant association was found with CMV reactivation (p = 0.02), but no GFR reduction was found. Long cold ischaemia times were a further risk factor for high CMV load. Interpretation BKV-CMV combined reactivation has a deep impact on renal function one year post-transplantation and therefore most likely on long-term allograft function, even at low viral loads. Frequent viral monitoring and subsequent interventions for low BKV and/or CMV viraemia levels and/or long cold ischaemia time are recommended. Fund Investigator Initiated Trial; financial support by German Federal Ministry of Education and Research (BMBF).
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Hertz-Tang AL, Astor BC, Mandelbrot DA, Mohamed MA, Djamali A, Parajuli S. BK viremia is not associated with adverse outcomes in the absence of BK nephropathy. Clin Transplant 2018; 32:e13283. [PMID: 29774593 DOI: 10.1111/ctr.13283] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/02/2018] [Indexed: 01/02/2023]
Abstract
There are limited data regarding the association of different levels of BK viremia and BK nephropathy (BKN), and graft outcomes. We studied the BK plasma PCR levels of all kidney transplant recipients (KTR) transplanted at our institution between 01/01/2006 and 06/30/2014. Patients were divided into groups based on their highest BK plasma PCR level within the first year following transplantation: undetectable, low (<1000 copies/mL), moderate (1000-10 000 copies/mL), high (>10 000-100 000 copies/mL), very high (>100 000 copies/mL), and those that had biopsy-proven BKN. There were a total of 1146 KTR during the study period: 813 with undetectable BK levels and 333 with any detectable BK level (87 with low, 79 with moderate, 88 with high, 34 with very high level BK, and 45 that had BKN). Compared to KTR with an undetectable BK level, incidence of mortality, graft failure, rejections,and infections were not significantly different for those with low, moderate, high, or very high BK level. Patients with BKN had a higher rate of infection and higher rates of total graft failure or death-censored graft failure compared to those with undetectable BK levels. BK viremia in the absence of BKN does not significantly increase the risk of rejection, infections, or graft failure compared to an undetectable BK level.
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Affiliation(s)
- Amber L Hertz-Tang
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Brad C Astor
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Didier A Mandelbrot
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Maha A Mohamed
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Arjang Djamali
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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Imlay H, Whitaker K, Fisher CE, Limaye AP. Clinical characteristics and outcomes of late-onset BK virus nephropathy in kidney and kidney-pancreas transplant recipients. Transpl Infect Dis 2018; 20:e12928. [PMID: 29809315 DOI: 10.1111/tid.12928] [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] [Received: 11/10/2017] [Revised: 05/01/2018] [Accepted: 05/08/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND BK virus nephropathy (BKPyVAN) is a major complication in kidney transplant recipients (KTR) and typically occurs within 1 year of transplant. Guidelines vary in recommendations for BKPyV screening beyond 1 year. A systematic characterization of risk factors and outcomes of late-onset (>1 year) BKPyVAN has not previously been reported. METHODS We retrospectively compared characteristics and outcomes of early- (<1 year) and late-onset BKPyVAN (definitive [biopsy-confirmed] or presumptive [plasma BKPyV >10 000 copies/mL]) in a cohort of 671 KTR and simultaneous kidney-pancreas transplant (SPK) recipients between 2008 and 2013 at a single US transplant center. Proportions were compared using Chi-square or Fisher's exact test with P < .05 considered significant. RESULTS BKPyVAN was diagnosed in 96 (14.3%) patients (proven 16.7%, presumptive 83.3%): 79 (82.3%) early- and 17 (17.7%) late-onset. The proportion with late-onset BKPyVAN was significantly higher among SPK than KTR (4 of 7 [57.1%] vs 13 of 89 [14.6%], P = .017). Late-onset represented "de novo" infection (no BKPyV detection within the first year) in 14 (82.4%) and progression of earlier lower grade BKPyV reactivation in 3 (17.6%). Clinical outcomes were similar for early- and late-onset BKPyVAN (P > .05 all comparisons). In a pooled analysis of prior studies of BKPyVAN in SPK recipients, 62.9% (17 of 27) were late-onset. CONCLUSION A significant proportion of BKPyVAN is late-onset, especially among SPK recipients, and supports a longer duration of BKPyV monitoring for SPK recipients than recommended in some guidelines.
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Affiliation(s)
- Hannah Imlay
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Kathryn Whitaker
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Cynthia E Fisher
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Ajit P Limaye
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA, USA
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Knight RJ, Graviss EA, Nguyen DT, Kuten SA, Patel SJ, Gaber L, Gaber AO. Conversion from tacrolimus-mycophenolate mofetil to tacrolimus-mTOR immunosuppression after kidney-pancreas transplantation reduces the incidence of both BK and CMV viremia. Clin Transplant 2018; 32:e13265. [PMID: 29676018 DOI: 10.1111/ctr.13265] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND We sought to determine whether conversion from tacrolimus/mycophenolate mofetil (TAC-MMF) into tacrolimus/mTOR inhibitor (TAC-mTOR) immunosuppression would reduce the incidences of BK and CMV viremia after kidney/pancreas (KP) transplantation. METHODS In this single-center review, the TAC-mTOR cohort (n = 39) was converted at 1 month post-transplant to an mTOR inhibitor and reduced-dose tacrolimus. Outcomes were compared to a cohort of KP recipients (n = 40) maintained on TAC-MMF. RESULTS At 3 years post-transplant, KP survivals and incidences of kidney/pancreas rejection were equivalent between mTOR and MMF-treated cohorts. (P = ns). BK viremia-free survival was better for the mTOR vs MMF-treated group (P = .004). In multivariate analysis, MMF vs mTOR immunosuppression was an independent risk factor for BK viremia (hazard ratio 12.27, P = .02). Similarly, mTOR-treated recipients displayed better CMV infection-free survival compared to the MMF-treated cohort (P = .01). MMF vs mTOR immunosuppression (hazard ratio 18.77, P = .001) and older recipient age (hazard ratio 1.13 per year, P = .006) were independent risk factors for CMV viremia. Mean estimated GFR and HgbA1c levels were equivalent between groups at 1, 2, and 3 years post-transplantation. CONCLUSION Conversion from TAC/MMF into TAC/mTOR immunosuppression after KP transplantation reduced the incidences of BK and CMV viremia with an equivalent risk of acute rejection and similar renal/pancreas function.
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Affiliation(s)
- Richard J Knight
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Edward A Graviss
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Duc T Nguyen
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Samantha A Kuten
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Samir J Patel
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
| | - Lillian Gaber
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - A Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
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Korth J, Widera M, Dolff S, Guberina H, Bienholz A, Brinkhoff A, Anastasiou OE, Kribben A, Dittmer U, Verheyen J, Wilde B, Witzke O. Impact of low-level BK polyomavirus viremia on intermediate-term renal allograft function. Transpl Infect Dis 2018; 20. [PMID: 29156086 DOI: 10.1111/tid.12817] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 07/10/2017] [Accepted: 08/13/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND BK polyomavirus (BKPyV)-associated nephropathy (PyVAN) is a significant cause of premature renal transplant failure. High-level BKPyV viremia is predictive for PyVAN; however, low-level BKPyV viremia does not necessarily exclude the presence of PyVAN. As data are limited regarding whether or not low-level BKPyV viremia has an effect on intermediate-term graft outcome, this study analyzes the impact of low-level BKPyV viremia on intermediate-term graft function and outcome compared with high-level viremia and non-viremic patients. METHODS All renal transplant patients received follow-up examinations at the Department of Nephrology, University Hospital Essen. Patients were screened for BKPyV viremia and stratified into three groups according to their maximum BKPyV load in serum (low-level viremia, high-level viremia, and no viremia). RESULTS In 142 of 213 (67%) patients, BKPyV was never detected in serum; 42 of 213 (20%) patients were found positive for low-level viremia (≤104 copies/mL); and 29 of 213 (13%) patients showed high-level viremia (>104 copies/mL). No significant differences regarding transplant function and graft failure were observed between patients without BKPyV viremia (delta estimated glomerular filtration rate [eGFR] +0.1 mL/min [month 1 vs last visit at month 44]) and patients with low-level BKPyV viremia (delta eGFR -1.7 mL/min). In patients with high-level viremia, transplant function was significantly restricted (delta eGFR -6.5 mL/min) compared with low-level viremia until the last visit at 44 ± 9.7 months after transplantation. Although the graft function and graft loss were worse in the high-level viremia group compared with no viremia (eGFR 37 vs 45 mL/min), the difference was not significant. CONCLUSIONS High-level viremia was associated with impaired graft function. In contrast, low-level BKPyV viremia had no significant impact on intermediate-term graft function.
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Affiliation(s)
- Johannes Korth
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.,Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Marek Widera
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sebastian Dolff
- Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Hana Guberina
- Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Anja Bienholz
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Alexandra Brinkhoff
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Olympia Evdoxia Anastasiou
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.,Department of Gastroenterology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Andreas Kribben
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ulf Dittmer
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Jens Verheyen
- Institute of Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Benjamin Wilde
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Oliver Witzke
- Department of Infectious Diseases, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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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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Azar MM, Assi R, Valika AK, Banach DB, Hall IE, Landry ML, Malinis MF. Graft loss among renal-transplant recipients with early reduction of immunosuppression for BK viremia. World J Transplant 2017; 7:269-275. [PMID: 29104861 PMCID: PMC5661124 DOI: 10.5500/wjt.v7.i5.269] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Revised: 06/28/2017] [Accepted: 08/02/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To review the incidence of graft loss and acute rejection among renal transplant recipients with early reduction of immunosuppression for BK viremia.
METHODS We performed a retrospective analysis of consecutive de-novo kidney-only transplants from January 2009 to December 2012 to evaluate the incidence of Polyoma-virus associated nephropathy (PyVAN). Recipient plasma was screened for BKV DNA via quantitative polymerase chain reaction (PCR) at months 1, 3, 6, 9 and 12 post-transplant and on worsening graft function. Immunosuppression was reduced at ≥ 3-log copies/mL. Those with viremia of ≥ 4-log copies/mL (presumptive PyVAN) underwent renal transplant biopsy. Presumptive PyVAN (PP) and definitive PyVAN (DP; biopsy-proven) were treated by immunosuppression reduction (IR) only.
RESULTS Among 319 kidney transplant recipients, the median age was 53 years (range 19-83), 65.8% were male, and 58.9% were white. Biopsy-proven acute rejection was found in 18.5% within 0-168 wk. Death-censored graft loss occurred in 5.3% (n = 17) and graft loss attributable to PyVAN was 0.6% (n = 2). Forty-seven patients were diagnosed with PP (14.7%) and 18 (5.6%) with DP. Graft loss among participants with PyVAN (8.5%) and those without (4.8%) was not significantly different. Deceased donor kidney transplantation (OR = 2.3, 95%CI = 1.1-4.6) and AR (OR = 2.3, 95%CI = 1.2-4.7) were associated with PyVAN in the multivariate analysis. BK viremia between 3 and 4-log copies/mL occurred in 27 patients, all of whom underwent IR. Of these, 16 (59%) never developed PyVAN while 11 (41%) developed PyVAN (4 DP, 7 PP) within a range of 11-39 wk.
CONCLUSION Instituting an early reduction of immunosuppression, in the absence of adjunctive antivirals, is effective at preventing PyVAN and may be associated with a lower incidence of graft-loss without a reciprocal increase in the incidence of acute rejection.
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Affiliation(s)
- Marwan M Azar
- Department of Pathology, Section of Microbiology, Massachusetts General Hospital, Boston, MA 02145, United States
- Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, United States
| | - Roland Assi
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Aziz K Valika
- Adventist Health Partners, Chicago, IL 60521, United States
| | - David B Banach
- Division of Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06032, United States
| | - Isaac E Hall
- Division of Hypertension and Nephrology, University of Utah School of Medicine, Dalt Lake City, UT 84132, United States
| | - Marie-Louise Landry
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Maricar F Malinis
- Section of Infectious Diseases, Yale School of Medicine, New Haven, CT 06510, United States
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06510, United States
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45
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Mycophenolate Mofetil Withdrawal With Conversion to Everolimus to Treat BK Virus Infection in Kidney Transplant Recipients. Transplant Proc 2017; 49:1773-1778. [DOI: 10.1016/j.transproceed.2017.06.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 06/01/2017] [Indexed: 01/05/2023]
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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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47
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Correlation of BK Virus Neutralizing Serostatus With the Incidence of BK Viremia in Kidney Transplant Recipients. Transplantation 2017; 101:1495-1505. [PMID: 27854236 DOI: 10.1097/tp.0000000000001261] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND BK virus (BKV)-associated nephropathy is the second leading cause of graft loss in kidney transplant recipients. Due to the high prevalence of persistent infection with BKV in the general population, it is possible that either the transplant recipient or donor may act as the source of virus resulting in viruria and viremia. Although several studies suggest a correlation between donor-recipient serostatus and the development of BK viremia, specific risk factors for BKV-related complications in the transplant setting remain to be established. METHODS We retrospectively determined the pretransplant BKV neutralizing serostatus of 116 donors (D)-recipient (R) pairs using infectious BKV neutralization assays with representatives from the 4 major viral serotypes. The neutralizing serostatus of donors and recipients was then correlated with the incidence of BK viremia during the first year posttransplantation. RESULTS There were no significant differences in baseline demographics or transplant data among the 4 neutralizing serostatus groups, with the exception of calculated panel-reactive antibody which was lowest in the D+/R- group. Recipients of kidneys from donors with significant serum neutralizing activity (D+) had elevated risk for BK viremia, regardless of recipient serostatus (D+ versus D-: odd ratio, 5.0; 95% confidence interval, 1.9-12.7]; P = 0.0008). Furthermore, donor-recipient pairs with D+/R- neutralizing serostatus had the greatest risk for BK viremia (odds ratio, 4.9; 95% confidence interval, 1.7-14.6; P = 0.004). CONCLUSIONS Donor neutralizing serostatus correlates significantly with incidence of posttransplant BK viremia. Determination of donor-recipient neutralizing serostatus may be useful in assessing the risk of BKV infection in kidney transplant recipients.
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Graft Function and Intermediate-Term Outcomes of Kidney Transplants Improved in the Last Decade: Analysis of the United States Kidney Transplant Database. Transplant Direct 2017; 3:e166. [PMID: 28620650 PMCID: PMC5464785 DOI: 10.1097/txd.0000000000000654] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 12/27/2016] [Indexed: 02/07/2023] Open
Abstract
Supplemental digital content is available in the text. Background Previous analyses of the United States transplant database regarding long-term outcomes in kidney transplantation have shown minimal improvement in the rate of long-term graft loss. This study sought to analyze intermediate-term outcomes and graft function at 6 months in kidney transplantation in adult living and deceased donor recipients in the last decade. Methods Survival analysis was performed based on the year of transplant between 6 months and 3 years’ posttransplant. The Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) was determined at 6 months. Results The unadjusted graft survival between 6 months and 3 years improved significantly in the latter half of the decade in both deceased and living donor kidney recipients. Cox analysis showed a 33% reduction in the rate of graft loss and that the improvement in graft survival was due to similar improvements in both death-censored graft and death with graft function survival. A 10% improvement in median eGFR occurred despite worsening donor demographics over time in both donor types. This improvement in eGFR and graft survival occurred in association with a consolidation of chronic discharge immunosuppression from a variety of combinations to over 85% of recipients receiving tacrolimus and mycophenolate derivative immunosuppression. Conclusions In the latter half of last decade graft survival improved in adult kidney transplant recipients. The improvement in graft survival occurred in temporal association with an improvement in median eGFR at 6 months and consolidation of discharge immunosuppression in most patients to tacrolimus and mycophenolate derivatives.
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49
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van Doesum WB, Gard L, Bemelman FJ, de Fijter JW, Homan van der Heide JJ, Niesters HG, van Son WJ, Stegeman CA, Groen H, Riezebos-Brilman A, Sanders JSF. Incidence and outcome of BK polyomavirus infection in a multicenter randomized controlled trial with renal transplant patients receiving cyclosporine-, mycophenolate sodium-, or everolimus-based low-dose immunosuppressive therapy. Transpl Infect Dis 2017; 19. [DOI: 10.1111/tid.12687] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/02/2016] [Accepted: 12/04/2016] [Indexed: 02/06/2023]
Affiliation(s)
- Willem B. van Doesum
- Department of Internal Medicine; Division of Nephrology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Lilli Gard
- Department of Clinical Virology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Frederike J. Bemelman
- Renal Transplant Unit; Academic Medical Center; University of Amsterdam; Amsterdam The Netherlands
| | - Johan W. de Fijter
- Renal Transplant Unit; Department of Nephrology; Leiden University Medical Center; Leiden The Netherlands
| | | | - Hubert G. Niesters
- Department of Clinical Virology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Willem J. van Son
- Department of Internal Medicine; Division of Nephrology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Coen A. Stegeman
- Department of Internal Medicine; Division of Nephrology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Henk Groen
- Department of Epidemiology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Annelies Riezebos-Brilman
- Department of Clinical Virology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
| | - Jan Stephan F. Sanders
- Department of Internal Medicine; Division of Nephrology; University Medical Center Groningen; University of Groningen; Groningen The Netherlands
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50
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Simard-Meilleur MC, Bodson-Clermont P, St-Louis G, Pâquet MR, Girardin C, Fortin MC, Cardinal H, Hébert MJ, Lévesque R, Renoult E. Stabilization of renal function after the first year of follow-up in kidney transplant recipients treated for significant BK polyomavirus infection or BK polyomavirus-associated nephropathy. Transpl Infect Dis 2017; 19. [DOI: 10.1111/tid.12681] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 10/25/2016] [Accepted: 11/19/2016] [Indexed: 12/20/2022]
Affiliation(s)
| | - Paule Bodson-Clermont
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Gilles St-Louis
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Michel R. Pâquet
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Catherine Girardin
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Marie-Chantal Fortin
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Héloïse Cardinal
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Marie-Josée Hébert
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Renée Lévesque
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
| | - Edith Renoult
- Département de Médecine; Service de Néphrologie; Centre Hospitalier de l'Université de Montréal; Montréal QC Canada
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