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Kotton CN, Kamar N, Wojciechowski D, Eder M, Hopfer H, Randhawa P, Sester M, Comoli P, Tedesco Silva H, Knoll G, Brennan DC, Trofe-Clark J, Pape L, Axelrod D, Kiberd B, Wong G, Hirsch HH. The Second International Consensus Guidelines on the Management of BK Polyomavirus in Kidney Transplantation. Transplantation 2024; 108:1834-1866. [PMID: 38605438 PMCID: PMC11335089 DOI: 10.1097/tp.0000000000004976] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/10/2024] [Accepted: 01/18/2024] [Indexed: 04/13/2024]
Abstract
BK polyomavirus (BKPyV) remains a significant challenge after kidney transplantation. International experts reviewed current evidence and updated recommendations according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Risk factors for BKPyV-DNAemia and biopsy-proven BKPyV-nephropathy include recipient older age, male sex, donor BKPyV-viruria, BKPyV-seropositive donor/-seronegative recipient, tacrolimus, acute rejection, and higher steroid exposure. To facilitate early intervention with limited allograft damage, all kidney transplant recipients should be screened monthly for plasma BKPyV-DNAemia loads until month 9, then every 3 mo until 2 y posttransplant (3 y for children). In resource-limited settings, urine cytology screening at similar time points can exclude BKPyV-nephropathy, and testing for plasma BKPyV-DNAemia when decoy cells are detectable. For patients with BKPyV-DNAemia loads persisting >1000 copies/mL, or exceeding 10 000 copies/mL (or equivalent), or with biopsy-proven BKPyV-nephropathy, immunosuppression should be reduced according to predefined steps targeting antiproliferative drugs, calcineurin inhibitors, or both. In adults without graft dysfunction, kidney allograft biopsy is not required unless the immunological risk is high. For children with persisting BKPyV-DNAemia, allograft biopsy may be considered even without graft dysfunction. Allograft biopsies should be interpreted in the context of all clinical and laboratory findings, including plasma BKPyV-DNAemia. Immunohistochemistry is preferred for diagnosing biopsy-proven BKPyV-nephropathy. Routine screening using the proposed strategies is cost-effective, improves clinical outcomes and quality of life. Kidney retransplantation subsequent to BKPyV-nephropathy is feasible in otherwise eligible recipients if BKPyV-DNAemia is undetectable; routine graft nephrectomy is not recommended. Current studies do not support the usage of leflunomide, cidofovir, quinolones, or IVIGs. Patients considered for experimental treatments (antivirals, vaccines, neutralizing antibodies, and adoptive T cells) should be enrolled in clinical trials.
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Affiliation(s)
- Camille N. Kotton
- Transplant and Immunocompromised Host Infectious Diseases Unit, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Toulouse Rangueil University Hospital, INSERM UMR 1291, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University Paul Sabatier, Toulouse, France
| | - David Wojciechowski
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Michael Eder
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Hopfer
- Division of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Parmjeet Randhawa
- Division of Transplantation Pathology, The Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Martina Sester
- Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany
| | - Patrizia Comoli
- Cell Factory and Pediatric Hematology/Oncology Unit, Department of Mother and Child Health, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Helio Tedesco Silva
- Division of Nephrology, Hospital do Rim, Fundação Oswaldo Ramos, Paulista School of Medicine, Federal University of São Paulo, Brazil
| | - Greg Knoll
- Department of Medicine (Nephrology), University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada
| | | | - Jennifer Trofe-Clark
- Renal-Electrolyte Hypertension Division, Associated Faculty of the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA
- Transplantation Division, Associated Faculty of the Perelman School of Medicine, University of Pennsylvania, Pennsylvania, PA
| | - Lars Pape
- Pediatrics II, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - David Axelrod
- Kidney, Pancreas, and Living Donor Transplant Programs at University of Iowa, Iowa City, IA
| | - Bryce Kiberd
- Division of Nephrology, Dalhousie University, Halifax, NS, Canada
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, NSW, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - Hans H. Hirsch
- Division of Transplantation and Clinical Virology, Department of Biomedicine, Faculty of Medicine, University of Basel, Basel, Switzerland
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
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Eibensteiner F, Messner I, Uhl P, Bond G, Puchhammer-Stoeckl E, Mueller-Sacherer T, Aufricht C, Rusai K. The association of Torque Teno viral load with CMV and BKV infection in pediatric and adolescent kidney transplant patients. J Clin Virol 2024; 172:105673. [PMID: 38564881 DOI: 10.1016/j.jcv.2024.105673] [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: 01/07/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/04/2024]
Abstract
BACKGROUND Long-term allograft and patient survival after kidney transplantation (KTX) depends on the balance between over- and under-immunosuppression (IS). High levels of IS predispose to opportunistic infections. Plasma load of Torque Teno Virus (TTV), a non-pathogenic highly prevalent Annellovirus, is associated with its hosts immune status, especially after solid organ transplantation. OBJECTIVES To investigate the association of plasma TTV load and opportunistic viral infections after pediatric KTX. STUDY DESIGN This retrospective study includes all pediatric KTX patients followed at the Medical University of Vienna 2014-2020. PCR for Cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK virus (BKV), and TTV was performed every 4-8 weeks at routine follow-up visits. RESULTS 71 pediatric KTX patients were followed with TTV measurements for a median of 2.7 years. TTV plasma load was associated with CMV DNAemia at the next visit with an OR of 2.37 (95 % CI 1.15-4.87; p = 0.03) after adjustment for time after KTX and recipient age. For a cut-off of 7.68 log10 c/mL TTV a sensitivity of 100 %, a specificity of 61 %, a NPV 100 %, and a PPV of 46 % to detect CMV DNAemia at the next visit was calculated. TTV plasma loads were also associated with BKV DNAuria and BKV DNAemia at the next visit, but not with EBV DNAemia. CONCLUSIONS This is the first study to analyse associations between TTV plasma loads and opportunistic viral infections in pediatric KTX. We were able to present a TTV cut-off for the prediction of clinically relevant CMV DNAemia that might be useful in clinical care.
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Affiliation(s)
- Fabian Eibensteiner
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria.
| | - Ines Messner
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
| | - Phoebe Uhl
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
| | - Gregor Bond
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
| | | | - Thomas Mueller-Sacherer
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
| | - Christoph Aufricht
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
| | - Krisztina Rusai
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria
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Chiodini B, Guillaume-Gentil P, Vanhomwegen C, Hennaut E, Lolin K, Tram N, Le Moine A, Ismaili K. BK Polyomavirus in Pediatric Renal Transplantation-What We Know and What We Do Not. Biomedicines 2024; 12:1093. [PMID: 38791055 PMCID: PMC11118040 DOI: 10.3390/biomedicines12051093] [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: 04/05/2024] [Revised: 05/08/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
BK polyomavirus (BKPyV) is still a real threat in the management of kidney transplantation. Immunosuppressive treatment disrupts the equilibrium between virus replication and immune response, and uncontrolled BKPyV replication leads to nephropathy (BKPyV nephropathy). The first evidence of BKPyV reactivation in transplant recipients is the detection of viral shedding in urine, which appears in 20% to 60% of patients, followed by BKPyV viremia in 10-20% of kidney transplant recipients. BKPyV nephropathy eventually occurs in 1-10% of this population, mainly within the first 2 years post-transplantation, causing graft loss in about half of those patients. Few data exist regarding the pediatric population and we focus on them. In this paper, we review the existing diagnostic methods and summarize the evidence on the role of BKPyV humoral and cellular immunity in modulating the clinical course of BKPyV infection and as potential predictors of the outcome. We look at the known risk factors for BKPyV nephropathy in the immunosuppressed patient. Finally, we propose a sensible clinical attitude in order to screen and manage BKPyV infection in kidney transplant children.
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Affiliation(s)
- Benedetta Chiodini
- Department of Pediatric Nephrology, Hôpital Universitaire de Bruxelles-HUDERF (HUB-HUDERF), Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Pauline Guillaume-Gentil
- Department of Pediatric Nephrology, Hôpital Universitaire de Bruxelles-HUDERF (HUB-HUDERF), Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Charlotte Vanhomwegen
- Department of Nephrology, Hôpital Universitaire de Bruxelles-Erasme (HUB-Erasme), European Plotkin Institute for Vaccinology, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Elise Hennaut
- Department of Pediatric Nephrology, Hôpital Universitaire de Bruxelles-HUDERF (HUB-HUDERF), Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Ksenija Lolin
- Department of Pediatric Nephrology, Hôpital Universitaire de Bruxelles-HUDERF (HUB-HUDERF), Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Nathalie Tram
- Department of Pediatric Nephrology, Hôpital Universitaire de Bruxelles-HUDERF (HUB-HUDERF), Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Alain Le Moine
- Department of Nephrology, Hôpital Universitaire de Bruxelles-Erasme (HUB-Erasme), European Plotkin Institute for Vaccinology, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
| | - Khalid Ismaili
- Department of Pediatric Nephrology, Hôpital Universitaire de Bruxelles-HUDERF (HUB-HUDERF), Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
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Brochot E, Demey B, Aubry A, Descamps V, Morel V, Presne C, Brazier F, Helle F. Epidemiology and Dynamics of BK Polyomavirus Replication after Kidney Transplantation. Pathogens 2024; 13:315. [PMID: 38668270 PMCID: PMC11053930 DOI: 10.3390/pathogens13040315] [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: 03/13/2024] [Revised: 04/04/2024] [Accepted: 04/08/2024] [Indexed: 04/29/2024] Open
Abstract
BACKGROUND/OBJECTIVES In the absence of an effective antiviral treatment for BK polyomavirus (BKPyV), a better understanding of the epidemiology and time course of BKPyV replication after kidney transplantation is needed to limit the virus's impact on the graft outcome. METHODS In a 7-year study, we screened more than 430 kidney transplant recipients and analyzed the time course and virological characteristics of BKPyV replication. RESULTS Urinary viral replication was observed in 116 (27%) of the 430 patients, and 90 of the 116 (78%) had viral DNAemia. Thirty-eight patients (8.8%) were presumed to have nephropathy (DNAemia > 4 log10 copies/mL). Of the patients with BKPyV replication, 48%, 60%, 71%, and 80% were first found to be positive one, two, three, and four months post-transplantation. The initial viral load in the urine was below 7 log10 copies/mL in 100% of the patients with viral replication first detected before the first month, and this proportion was 57% when viral replication was first detected after the first month. When the BKPyV replication was first detected in a urine sample at month 3 or later, 81.5% of patients had concomitant BKPyV DNAemia. The predominant viral subtype was Ib2 (60%), and there was no apparent relationship between the subtype and the time course of BKPyV replication. CONCLUSIONS Urinary BKPyV replication occurs early after renal transplantation and in most patients will increase to a level requiring therapeutic intervention. Close monitoring for BKPyV in the early post-transplantation period would enable the pre-emptive adjustment of the immunosuppression regimen.
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Affiliation(s)
- Etienne Brochot
- Department of Virology, Amiens University Medical Center, 80054 Amiens, France; (B.D.); (A.A.)
- Agents Infectieux Résistance et Chimiothérapie Research Unit, UR4294, Jules Verne University of Picardie, 80054 Amiens, France; (V.D.); (V.M.); (F.H.)
| | - Baptiste Demey
- Department of Virology, Amiens University Medical Center, 80054 Amiens, France; (B.D.); (A.A.)
- Agents Infectieux Résistance et Chimiothérapie Research Unit, UR4294, Jules Verne University of Picardie, 80054 Amiens, France; (V.D.); (V.M.); (F.H.)
| | - Aurélien Aubry
- Department of Virology, Amiens University Medical Center, 80054 Amiens, France; (B.D.); (A.A.)
- Agents Infectieux Résistance et Chimiothérapie Research Unit, UR4294, Jules Verne University of Picardie, 80054 Amiens, France; (V.D.); (V.M.); (F.H.)
| | - Véronique Descamps
- Agents Infectieux Résistance et Chimiothérapie Research Unit, UR4294, Jules Verne University of Picardie, 80054 Amiens, France; (V.D.); (V.M.); (F.H.)
| | - Virginie Morel
- Agents Infectieux Résistance et Chimiothérapie Research Unit, UR4294, Jules Verne University of Picardie, 80054 Amiens, France; (V.D.); (V.M.); (F.H.)
| | - Claire Presne
- Department of Nephrology, Dialysis and Transplantation, Amiens University Medical Center, 80054 Amiens, France; (C.P.); (F.B.)
| | - François Brazier
- Department of Nephrology, Dialysis and Transplantation, Amiens University Medical Center, 80054 Amiens, France; (C.P.); (F.B.)
| | - François Helle
- Agents Infectieux Résistance et Chimiothérapie Research Unit, UR4294, Jules Verne University of Picardie, 80054 Amiens, France; (V.D.); (V.M.); (F.H.)
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Mohammad D, Kim DY, Baracco R, Kapur G, Jain A. Treatment of BK virus with a stepwise immunosuppression reduction and intravenous immunoglobulin in pediatric kidney transplant. Pediatr Transplant 2022; 26:e14241. [PMID: 35122460 DOI: 10.1111/petr.14241] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/04/2021] [Accepted: 01/14/2022] [Indexed: 12/22/2022]
Abstract
BACKGROUND BKV and BKVN are common in pediatric kidney transplant, but there is limited data on treatment approaches. Our objective was to study the prevalence of BKV and BKVN utilizing only plasma qPCR and report treatment outcomes with stepwise IR and IVIG. METHODS A retrospective study of all pediatric kidney transplants from 2013 to 2020. Excluded patients >21 years at transplant and immediate graft failure. Surveillance was conducted using only plasma BK qPCR at 1, 3, 6, 9, 12, 18, and 24 months and annually. BKV defined as ≥250 copies/ml and resolution as <250 copies/ml. Presumed BKVN as >10 000 copies/ml despite IR; and BKVN if confirmed on histology. RESULTS Fifty-six patients were included in the study; 20 (35.7%) had BKV. BKV was associated with longer duration of stent, 40 vs. 33.5 days (p = .004). Two patients (3.5%) had confirmed, and 2(3.5%) had presumed BKVN. The first-line treatment was IR in 100% of patients. BKVN confirmed and presumed received IVIG every month for six doses. Viral resolution was achieved in 70%, and no difference was noted in estimated glomerular filtration rate between BKV and non-BKV group (p = .438). There were no rejection episodes, and graft survival was 100% over median follow-up of 3 years. CONCLUSIONS Plasma qPCR alone is adequate for screening and monitoring treatment of BKV and BKVN. A stepwise IR and IVIG resulted in BKV resolution in the majority of patients. Larger studies are required to study the role of IVIG in the treatment of BKVN.
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Affiliation(s)
- Dunya Mohammad
- Division of Pediatrics, Children's and Women's Hospital, University of South Alabama, Mobile, Alabama, USA
| | - Dean Y Kim
- Division of Kidney Transplant Surgery, Department of Transplant Services, Children's Hospital of Michigan, Detroit, Michigan, USA
| | - Rossana Baracco
- Division of Pediatric Nephrology and Hypertension, Department of Pediatrics, Children's Hospital of Michigan, Central Michigan University, Detroit, Michigan, USA
| | - Gaurav Kapur
- Division of Pediatric Nephrology and Hypertension, Department of Pediatrics, Children's Hospital of Michigan, Central Michigan University, Detroit, Michigan, USA
| | - Amrish Jain
- Division of Pediatric Nephrology and Hypertension, Department of Pediatrics, Children's Hospital of Michigan, Central Michigan University, Detroit, Michigan, USA
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Genomic Mutations of BK Polyomavirus in Patients after Kidney Transplantation: A Cross-Sectional Study in Vietnam. J Clin Med 2022; 11:jcm11092544. [PMID: 35566670 PMCID: PMC9101345 DOI: 10.3390/jcm11092544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/16/2022] [Accepted: 04/27/2022] [Indexed: 12/10/2022] Open
Abstract
Objectives: The purpose of this study was to identify the SNP sites and determine the BKV genotype circulating in kidney-transplant Vietnamese recipients based on the VP1 gene region. Methods: 344 samples were collected from post-kidney-transplant recipients at the 103 Vietnam Military Hospital to investigate the number of BKV infections. Positive samples with a sufficient virus concentration were analyzed by nested PCR in the VP1 region, sequencing detected genotyping and single-nucleotide polymorphism. Results: BKV infection was determined in 214 patients (62.2%), of whom 11 (5.1%) were diagnosed with BKV-associated nephropathy. Among the 90 BKV-I strains sequenced, 89 (98.88%) were strains of I/b-1 and 1 (1.12%) was strain I/b-2. The 60 BKV-IV strains had a greater diversity of subgroups, including 40% IV/a-1, 1.66% IV/a-2, 56.68% IV/c-1, and 1.16% IV/c-2. Additionally, of 11 cases diagnosed with BKVN, seven belonged to subgroup I/b-1 (63.6%) and four to subgroup IV/c-1 (36.4%). Moreover, 22 specific SNPs that were genotype I or IV were determined in this Vietnamese population. Specifically, at position 1745, for the Vietnamese BKV-IV strains, the SNP position (A→G) appeared in 57/60 samples (95%). This causes transformation of the amino acid N→S. This SNP site can enable detection of genotype IV in Vietnam. It represents a unique evolution pattern and mutation that has not been found in other international strains. Conclusion: The BKV-I genotype was more common than BKV-IV; however, mutations that occur on the VP1 typing region of BKV-IV strains were more frequent than in BKV-I strains.
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Myint TM, Chong CHY, Wyld M, Nankivell B, Kable K, Wong G. Polyoma BK Virus in Kidney Transplant Recipients: Screening, Monitoring, and Management. Transplantation 2022; 106:e76-e89. [PMID: 33908382 DOI: 10.1097/tp.0000000000003801] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Polyomavirus BK virus (BKPyV) infection is an important complication of kidney transplantation and allograft failure. The prevalence of viremia is 10%-15%, compared with BK-associated nephropathy (BKPyVAN) at 3%-5%. Given that there are no effective antiviral prophylaxis or treatment strategies for BKPyVAN, active screening to detect BKPyV viremia is recommended, particularly during the early posttransplant period. Immunosuppression reduction to allow viral clearance may avoid progression to severe and irreversible allograft damage. The frequency and duration of screening are highly variable between transplant centers because the evidence is reliant largely on observational data. While the primary treatment goals center on achieving viral clearance through immunosuppression reduction, prevention of subsequent acute rejection, premature graft loss, and return to dialysis remain as major challenges. Treatment strategies for BKPyV infection should be individualized to the recipient's underlying immunological risk and severity of the allograft infection. Efficacy data for adjuvant therapies including intravenous immunoglobulin and cidofovir are sparse. Future well-powered and high-quality randomized controlled trials are needed to inform evidence-based clinical practice for the management of BKPy infection.
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Affiliation(s)
- Thida Maung Myint
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Newcastle Transplant Unit, John Hunter Hospital, Newcastle, NSW, Australia
| | - Chanel H Y Chong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
| | - Melanie Wyld
- Department of Renal Medicine, Centre for Transplant and Renal Research, Westmead Hospital, Westmead, NSW, Australia
| | - Brian Nankivell
- Department of Renal Medicine, Centre for Transplant and Renal Research, Westmead Hospital, Westmead, NSW, Australia
| | - Kathy Kable
- Department of Renal Medicine, Centre for Transplant and Renal Research, Westmead Hospital, Westmead, NSW, Australia
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
- Department of Renal Medicine, Centre for Transplant and Renal Research, Westmead Hospital, Westmead, NSW, Australia
- Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia
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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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Burek Kamenaric M, Ivkovic V, Kovacevic Vojtusek I, Zunec R. The Role of HLA and KIR Immunogenetics in BK Virus Infection after Kidney Transplantation. Viruses 2020; 12:v12121417. [PMID: 33317205 PMCID: PMC7763146 DOI: 10.3390/v12121417] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/13/2022] Open
Abstract
BK virus (BKV) is a polyomavirus with high seroprevalence in the general population with an unremarkable clinical presentation in healthy people, but a potential for causing serious complications in immunosuppressed transplanted patients. Reactivation or primary infection in kidney allograft recipients may lead to allograft dysfunction and subsequent loss. Currently, there is no widely accepted specific treatment for BKV infection and reduction of immunosuppressive therapy is the mainstay therapy. Given this and the sequential appearance of viruria-viremia-nephropathy, screening and early detection are of utmost importance. There are numerous risk factors associated with BKV infection including genetic factors, among them human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) alleles have been shown to be the strongest so far. Identification of patients at risk for BKV infection would be useful in prevention or early action to reduce morbidity and progression to frank nephropathy. Assessment of risk involving HLA ligands and KIR genotyping of recipients in the pre-transplant or early post-transplant period might be useful in clinical practice. This review summarizes current knowledge of the association between HLA, KIR and BKV infection and potential future directions of research, which might lead to optimal utilization of these genetic markers.
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Affiliation(s)
- Marija Burek Kamenaric
- Tissue Typing Center, Clinical Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia;
| | - Vanja Ivkovic
- Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10 000 Zagreb, Croatia; (V.I.); (I.K.V.)
- Department of Public Health, Faculty of Health Studies, University of Rijeka, 51 000 Rijeka, Croatia
| | - Ivana Kovacevic Vojtusek
- Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10 000 Zagreb, Croatia; (V.I.); (I.K.V.)
| | - Renata Zunec
- Tissue Typing Center, Clinical Department of Transfusion Medicine and Transplantation Biology, University Hospital Center Zagreb, 10 000 Zagreb, Croatia;
- Correspondence:
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Buder K, Zirngibl M, Bapistella S, Nadalin S, Tönshoff B, Weitz M. Current practice of antithrombotic prophylaxis in pediatric kidney transplantation-Results of an international survey on behalf of the European Society for Paediatric Nephrology. Pediatr Transplant 2020; 24:e13799. [PMID: 33119218 DOI: 10.1111/petr.13799] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 06/05/2020] [Accepted: 06/28/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Renal graft thrombosis (RGT) is one of the main causes for early graft loss in pediatric kidney transplantation (KTx). Despite the lack of evidence-based recommendations, antithrombotic prophylaxis (aP) is used to prevent RGT. METHODS An online survey supported by the European Society for Pediatric Nephrology was developed to investigate the current practice of aP in pediatric KTx recipients <18 years. RESULTS A total of 80 pediatric KTx centers from 37 countries participated in the survey. Antithrombotic prophylaxis was performed in 96% of the pediatric renal transplant centers (all/selected patients: 54%/42%). The main overall used drugs were as follows: low-molecular-weight heparin (89%), unfractionated heparin (UFH) (69%), and acetylsalicylic acid (ASS) (55%). Ten different aP management strategies were identified as follows: 51% used a single drug and 48% combined two drugs sequentially. The corresponding centers started aP predominantly within 24 hours after pediatric KTx; 51% preferred UFH for starting aP. In centers switching to a second drug (51%), this change was performed after 10 ± 6 days; of these 57% preferred ASS for maintenance aP. Reported median aP duration was 51 days (range 1-360). CONCLUSIONS Despite the use of aP in almost all responding pediatric KTx centers, there is no uniform management strategy. Notwithstanding, UFH seems to be the preferred drug for the early post-operative period of pediatric KTx, and ASS for maintenance prophylaxis following pediatric KTx. Prospective studies are needed to further evaluate the benefits and risks of aP, preferably resulting in guidelines for the management in pediatric KTx.
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Affiliation(s)
- Kathrin Buder
- Pediatric Nephrology Department, University Children`s Hospital Zurich, Zurich, Switzerland
| | - Matthias Zirngibl
- Department of General Pediatrics and Hematology/Oncology, University Hospital Tübingen, University Children`s Hospital, Tübingen, Germany
| | - Sascha Bapistella
- Department of General Pediatrics and Hematology/Oncology, University Hospital Tübingen, University Children`s Hospital, Tübingen, Germany
| | - Silvio Nadalin
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Tübingen, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Marcus Weitz
- Department of General Pediatrics and Hematology/Oncology, University Hospital Tübingen, University Children`s Hospital, Tübingen, Germany
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11
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Höcker B, Schneble L, Murer L, Carraro A, Pape L, Kranz B, Oh J, Zirngibl M, Dello Strologo L, Büscher A, Weber LT, Awan A, Pohl M, Bald M, Printza N, Rusai K, Peruzzi L, Topaloglu R, Fichtner A, Krupka K, Köster L, Bruckner T, Schnitzler P, Hirsch HH, Tönshoff B. Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study. Transplantation 2020; 103:1224-1233. [PMID: 30130322 DOI: 10.1097/tp.0000000000002414] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. METHODS We analyzed the data of 313 patients in the Cooperative European Pediatric Renal Transplant Initiative Registry, with an observation period of 3.3 years (range, 1-5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. RESULTS Presumptive BKPyVAN (defined as sustained [>3 wk] high-level BK viremia >10 copies/mL) within 5 years posttransplant occurred in 49 (15.8%) of 311 patients, and biopsy-proven BKPyVAN in 14 (4.5%) of 313. BKPyV viremia was observed in 115 (36.7%) of 311 patients, of whom 11 (9.6%) of 115 developed viremia late, that is, after the second year posttransplant. In 6 (12.5%) of 48 patients with high-level viremia and in 3 (21.4%) of 14 with BKPyVAN, this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated not only with a higher net state of immunosuppression (odds ratio [OR], 1.3; P < 0.01) and with tacrolimus-based versus ciclosporin-based immunosuppression (OR, 3.6; P < 0.01) but also with younger recipient age (OR, 1.1 per y younger; P < 0.001) and obstructive uropathy (OR, 12.4; P < 0.01) as primary renal disease. CONCLUSIONS Uncontrolled BKPyV replication affects a significant proportion of pediatric renal transplant recipients and is associated with unique features of epidemiology and risk factors, such as young recipient age, obstructive uropathy, and overall intensity of immunosuppressive therapy. BKPyV surveillance should be considered beyond 2 years posttransplant in pediatric patients at higher risk.
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Affiliation(s)
- Britta Höcker
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Lukas Schneble
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Luisa Murer
- Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Woman's and Child's Health, University Hospital of Padova, Padua, Italy
| | - Andrea Carraro
- Pediatric Nephrology, Dialysis and Transplantation Unit, Department of Woman's and Child's Health, University Hospital of Padova, Padua, Italy
| | - Lars Pape
- Hanover Medical School, Hanover, Germany
| | - Birgitta Kranz
- Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany
| | - Jun Oh
- Department of Pediatric Nephrology, University Children's Hospital, Hamburg, Germany
| | | | - Luca Dello Strologo
- Pediatric Nephrology and Renal Transplant Unit, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Anja Büscher
- Pediatric Nephrology, Pediatrics II, University Children's Hospital Essen, Essen, Germany
| | - Lutz T Weber
- Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Cologne, Germany
| | - Atif Awan
- Temple Street Children's University Hospital, Dublin, Ireland
| | - Martin Pohl
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Martin Bald
- Olga Children's Hospital, Clinic of Stuttgart, Stuttgart, Germany
| | - Nikoleta Printza
- 1st Pediatric Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Krisztina Rusai
- Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Vienna, Austria
| | - Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, Turin, Italy
| | - Rezan Topaloglu
- Hacettepe University Faculty of Medicine, Department of Pediatric Nephrology, Ankara, Turkey
| | - Alexander Fichtner
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Kai Krupka
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Lennart Köster
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany.,Institute of Medical Biometry and Informatics, University of Heidelberg, Germany
| | - Thomas Bruckner
- Institute of Medical Biometry and Informatics, University of Heidelberg, Germany
| | - Paul Schnitzler
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
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12
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Ahlenstiel-Grunow T, Pape L. Immunosuppression, BK polyomavirus infections, and BK polyomavirus-specific T cells after pediatric kidney transplantation. Pediatr Nephrol 2020; 35:625-631. [PMID: 31858227 DOI: 10.1007/s00467-019-04408-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/02/2019] [Accepted: 10/29/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND After kidney transplantation, immunosuppressive therapy increases risk of BK polyomavirus-associated nephropathy (BKPyVAN). Outcomes of BKPyV viremia are various and prognostic markers are missing. The impact of different immunosuppressive regimens on BKPyV infections is currently under discussion. METHODS We analyzed immunosuppressive therapy and BKPyV-specific cellular immunity to distinguish patients at risk of BKPyVAN from those with self-limiting viremia for purposes of risk-stratified BKPyV management. In a retrospective analysis, 46 pediatric kidney recipients with BKPyV viremia were analyzed with regard to duration of BKPyV viremia and immunosuppressive therapy; in addition, in 37/46 patients, BKPyV-specific CD4 and CD8 T cells were measured. RESULTS Nine patients showed persistent BKPyV viremia and BKPyVAN, and required therapeutic intervention, while 37 patients had asymptomatic, self-limiting viremia. At onset of viremia, 78% of patients with persistent viremia and BKPyVAN were treated with tacrolimus, whereas tacrolimus therapy was significantly less frequent in patients with self-limiting viremia (14%). The majority of patients with transient, self-limiting viremia received cyclosporine A (81%) and/or mTOR inhibitors (81%). Patients with persistent BKPyV viremia and BKPyVAN showed lack of BKPyV-specific CD4 and CD8 T cells (6/6), whereas the majority of patients with self-limiting viremia (27/31) had detectable BKPyV-specific CD4 and/or CD8 T cells ≥ 0.5 cells/μl (p < 0.001). CONCLUSIONS These results indicate that tacrolimus enhances risk of BKPyVAN with need of therapeutic intervention, whereas under cyclosporine A and mTOR inhibitors, the majority of pediatric kidney recipients showed self-limiting viremia. In patients at risk of BKPyV infections, combination of cyclosporine A and mTOR inhibitor may be advantageous.
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Affiliation(s)
- Thurid Ahlenstiel-Grunow
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
| | - Lars Pape
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
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13
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Ahlenstiel-Grunow T, Pape L. Diagnostics, treatment, and immune response in BK polyomavirus infection after pediatric kidney transplantation. Pediatr Nephrol 2020; 35:375-382. [PMID: 30539254 DOI: 10.1007/s00467-018-4164-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 11/26/2018] [Accepted: 11/29/2018] [Indexed: 12/27/2022]
Abstract
After pediatric kidney transplantation BK polyomavirus (BKPyV) infections are associated with an increased risk of graft loss by BKPyV-associated nephropathy (BkPyVAN). However, suitable prognostic markers for the individual outcome of BKPyV infections are missing and the management of therapeutic interventions remains a challenge to the success of pediatric kidney transplantation. This review gives an overview on current diagnostic and therapeutic strategies in the field of BKPyV infections after pediatric kidney transplantation. Methods determining the individual immune response to BKPyV are described and their usability is discussed. There is growing evidence that BKPyV-specific T cells (BKPyV-Tvis) may serve as prognostic markers in order to steer immunosuppressive therapy in pediatric kidney recipients with BKPyV viremia in future. Prospective randomized trials in viremic kidney recipients comparing Tvis-steered therapeutic intervention with standard reduction of immunosuppression are needed before implementation of BKPyV-Tvis monitoring in routine care of BKPyV infections.
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Affiliation(s)
- Thurid Ahlenstiel-Grunow
- Department of Pediatric Kidney, Liver and Metabolic Disease, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.
| | - Lars Pape
- Department of Pediatric Kidney, Liver and Metabolic Disease, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
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14
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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: 58] [Impact Index Per Article: 9.7] [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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15
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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: 267] [Impact Index Per Article: 44.5] [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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16
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Miettinen J, Lautenschlager I, Weissbach F, Wernli M, Auvinen E, Mannonen L, Lauronen J, Hirsch HH, Jalanko H. BK polyomavirus viremia and antibody responses of pediatric kidney transplant recipients in Finland. Pediatr Transplant 2019; 23:e13324. [PMID: 30447046 DOI: 10.1111/petr.13324] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Revised: 09/14/2018] [Accepted: 10/15/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND BKPyV is an important cause of premature graft failure after KT. Most clinical studies describe BKPyV infection in adult KT patients. We studied the prevalence of post-transplant BKPyV viremia, serology, and graft function in pediatric KT recipients. METHODS Forty-six pediatric patients transplanted between 2009 and 2014 were followed up for BKPyV DNAemia by plasma PCR for median 2.3 (range: 1-6) years. BKPyV-specific antibodies were retrospectively analyzed using virus-like particle ELISA. GFR was measured annually by 51 Cr-EDTA clearance, and serum samples were screened for DSAs by Luminex assay. RESULTS BKPyV viremia was demonstrated in nine patients at a median of 6 months post-KT. Early BKPyV viremia at 3 months post-KT associated with decreased concomitant GFR and tendency for decreased subsequent graft function. Three of nine patients with BKPyV viremia developed DSA, all against class II antigens. PyVAN developed to four patients and responded to judicious reduction in IS. One graft was lost later due to ABMR. BKPyV-IgG was found in 18 of 31 patients (58%) tested at transplantation, and seven recipients seroconverted after transplantation with a significant increase in IgG levels with IgM. Finally, BKPyV-IgG was detectable in 31 of 40 patients (78%) at the end of the study. CONCLUSIONS Post-transplant BKPyV viremia in pediatric KT patients may alter graft function and contribute to progression of chronic allograft injury. BKPyV-IgG predicts past exposure. Low or absent BKPyV-specific antibody levels were seen pretransplant in 42% of tested patients, but were not predictive of prolonged replication or poor outcome.
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Affiliation(s)
- Jenni Miettinen
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Irmeli Lautenschlager
- Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Fabian Weissbach
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Marion Wernli
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Eeva Auvinen
- Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Laura Mannonen
- Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jouni Lauronen
- Histocompatibility Laboratory, Finnish Red Cross Blood Service, Helsinki, Finland
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department of Biomedicine, University of Basel, Basel, Switzerland.,Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Hannu Jalanko
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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17
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In vitro comparison of currently available and investigational antiviral agents against pathogenic human double-stranded DNA viruses: A systematic literature review. Antiviral Res 2019; 163:50-58. [PMID: 30677427 DOI: 10.1016/j.antiviral.2019.01.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 01/10/2019] [Accepted: 01/16/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Double-stranded (ds) DNA virus infections often occur concomitantly in immunocompromised patients. We performed a systematic search of published in vitro activity for nine approved and investigational antivirals to understand the spectrum of in vitro activity against dsDNA viruses. METHODS A literature search was performed (PubMed and the WoS Core Collection) using keywords related to: 1) targeted approved/developmental antivirals (acyclovir, artesunate, brincidofovir, cidofovir, cyclopropavir (filociclovir), foscarnet, ganciclovir, letermovir, and maribavir); 2) pathogenic dsDNA viruses; 3) in vitro activity. We summarized data from 210 publications. RESULTS Activity against ≤3 viruses was documented for maribavir (cytomegalovirus, Epstein-Barr virus), and letermovir, while activity against > 3 viruses was shown for ganciclovir, cidofovir, acyclovir, foscarnet, cyclopropavir, artesunate, and brincidofovir. The EC50 values of brincidofovir were the lowest, ranging from 0.001 to 0.27 μM, for all viruses except papillomaviruses. The next most potent agents included cidofovir, ganciclovir, foscarnet, and acyclovir with EC50 values between 0.1 μM and >10 μM for cytomegalovirus, herpes simplex virus, and adenovirus. CONCLUSION Most of the identified antivirals had in vitro activity against more than one dsDNA virus. Brincidofovir and cidofovir have broad-spectrum activity, and brincidofovir has the lowest EC50 values. These findings could assist clinical practice and developmental research.
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18
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Gabardi S, Pavlakis M, Tan C, Francis J, Cardarelli F, Asch W, Bodziak K, Chobanian M, Gilligan H, Gohh R, Kung SC, Inker L, Martin S, Rodig N, Rossi A, Chandraker A. New England BK consortium: Regional survey of BK screening and management protocols in comparison to published consensus guidelines. Transpl Infect Dis 2018; 20:e12985. [PMID: 30175491 DOI: 10.1111/tid.12985] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 08/17/2018] [Accepted: 08/21/2018] [Indexed: 12/18/2022]
Abstract
INTRODUCTION BK polyomavirus (BKPyV) continues to impact renal transplant recipients (RTR). The New England BK Consortium aims to jointly optimize screening and management of BKPyV. METHODS Our first project was to survey centers' BKPyV screening protocols and compare them to consensus guidelines. RESULTS Thirteen of 15 centers (86.7%) returned the survey. Only two center reported using monitoring parameters that were in line with consensus guidelines for BKPyV screening, while the majority of centers reported less intensive methods and shorter duration. One center reported performing renal biopsies in all patients with plasma viral loads >10 000 copies/mL, while all other centers only perform for-cause biopsies. For presumptive nephropathy, 11 centers recommend a biopsy for confirmation. For management of documented BKPyV-associated nephropathy, 12 centers propose further immunosuppression reduction. Nine centers report CNI dose reduction as their primary treatment. More than half of centers surveyed reported use of leflunomide, cidofovir or intravenous immunoglobulin. CONCLUSIONS There was a large variance in BKPyV screening and management strategies among centers. Due to these results, all participating centers agreed to implement uniform screening and aim to optimize management protocols.
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Affiliation(s)
- Steven Gabardi
- Departments of Transplant Surgery, Brigham and Women's Hospital, Boston, Massachusetts.,Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Martha Pavlakis
- Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Chen Tan
- Department of Medicine, Harvard Medical School, Boston, Massachusetts.,Division of Infectious Diseases, Center for Virology and Vaccine Research, Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Jean Francis
- Boston Medical Center, Boston, Massachusetts.,Boston University School of Medicine, Boston, Massachusetts
| | - Francesca Cardarelli
- Transplant Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - William Asch
- Yale New Haven Transplantation Center and the Section of Nephrology, Yale New Haven Hospital, New Haven, Connecticut.,Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Kenneth Bodziak
- Department of Nephrology, UMass Memorial Medical Center, Worcester, Massachusetts.,Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
| | - Michael Chobanian
- Department of Nephrology and Hypertension, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.,Department of Medicine, Geisel School of Medicine of Dartmouth College, Hanover, New Hampshire
| | - Hannah Gilligan
- Department of Medicine, Harvard Medical School, Boston, Massachusetts.,Department of Nephrology, Massachusetts General Hospital, Boston, Massachusetts
| | - Reginald Gohh
- Division of Organ Transplantation, Rhode Island Hospital, Providence, Rhode Island.,Warren Alpert School of Medicine of Brown University, Providence, Rhode Island
| | - Shiang-Cheng Kung
- Department of Nephrology, Lahey Hospital and Medical Center, Burlington, Massachusetts.,Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts
| | - Lesley Inker
- Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.,Kidney and Blood Pressure Center and Kidney Function and Evaluation Center, Tufts Medical Center, Boston, Massachusetts
| | - Spencer Martin
- Department of Pharmacy Service, Hartford Hospital, Hartford, Connecticut
| | - Nancy Rodig
- Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts
| | - Ana Rossi
- Division of Nephrology, Maine Medical Center, Portland, Maine
| | - Anil Chandraker
- Department of Medicine, Harvard Medical School, Boston, Massachusetts.,Renal Division, Brigham and Women's Hospital, Boston, Massachusetts
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Navarro D, San-Juan R, Manuel O, Giménez E, Fernández-Ruiz M, Hirsch HH, Grossi PA, Aguado JM. Cytomegalovirus infection management in solid organ transplant recipients across European centers in the time of molecular diagnostics: An ESGICH survey. Transpl Infect Dis 2017; 19. [PMID: 28859257 DOI: 10.1111/tid.12773] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 05/17/2017] [Accepted: 06/11/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Scant information is available about how transplant centers are managing their use of quantitative molecular testing (QNAT) assays for active cytomegalovirus (CMV) infection monitoring in solid organ transplant (SOT) recipients. The current study was aimed at gathering information on current practices in the management of CMV infection across European centers in the era of molecular testing assays. METHODS A questionnaire-based cross-sectional survey study was conducted by the European Study Group of Infections in Immunocompromised Hosts (ESGICH) of the Society of Clinical Microbiology and Infectious Diseases (ESCMID). The invitation and a weekly reminder with a personal link to an Internet service provider (https://es.surveymonkey.com/) was sent to transplant physicians, transplant infectious diseases specialists, and clinical virologists working at 340 European transplant centers. RESULTS Of the 1181 specialists surveyed, a total of 173 responded (14.8%): 73 transplant physicians, 57 transplant infectious diseases specialists, and 43 virologists from 173 institutions located at 23 different countries. The majority of centers used QNAT assays for active CMV infection monitoring. Most centers preferred commercially available real-time polymerase chain reaction (RT-PCR) assays over laboratory-developed procedures for quantifying CMV DNA load in whole blood or plasma. Use of a wide variety of DNA extraction platforms and RT-PCR assays was reported. All programs used antiviral prophylaxis, preemptive therapy, or both, according to current guidelines. However, the centers used different criteria for starting preemptive antiviral treatment, for monitoring systemic CMV DNA load, and for requesting genotypic assays to detect emerging CMV-resistant variants. CONCLUSIONS Significant variation in CMV infection management in SOT recipients still remains across European centers in the era of molecular testing. International multicenter studies are required to achieve commutability of CMV testing and antiviral management procedures.
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Affiliation(s)
- David Navarro
- Microbiology Service, Hospital Clínico Universitario, Institute for Research INCLIVA, Valencia, Spain
- Department of Microbiology, School of Medicine, University of Valencia, Valencia, Spain
| | - Rafael San-Juan
- Unit of Infectious Diseases, Instituto de Investigación Hospital 12 de Octubre (i+12), University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain
| | - Oriol Manuel
- Transplantation Center and Service of Infectious Diseases, University Hospital of Lausanne, CHUV, Lausanne, Switzerland
| | - Estela Giménez
- Microbiology Service, Hospital Clínico Universitario, Institute for Research INCLIVA, Valencia, Spain
| | - Mario Fernández-Ruiz
- Unit of Infectious Diseases, Instituto de Investigación Hospital 12 de Octubre (i+12), University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain
| | - Hans H Hirsch
- Transplantation & Clinical Virology, Department Biomedicine, University of Basel, Basel, Switzerland
- Infectious Diseases & Hospital Epidemiology, University Hospital Basel, Basel, Switzerland
| | - Paolo Antonio Grossi
- National Centre for Transplantation, Department of Medicine and Surgery, Infectious and Tropical Diseases Unit, University of Insubria, Varese, Italy
| | - José María Aguado
- Unit of Infectious Diseases, Instituto de Investigación Hospital 12 de Octubre (i+12), University Hospital 12 de Octubre, Universidad Complutense, Madrid, Spain
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Gouvêa ALF, Cosendey RIJ, Carvalho FR, Varella RB, de Souza CF, Lopes PF, Silva AA, Rochael MC, de Moraes HP, Lugon JR, Almeida JR. Pilot Study of Early Monitoring Using Urinary Screening for BK Polyomavirus as a Strategy for Prevention of BKV Nephropathy in Kidney Transplantation. Transplant Proc 2017; 48:2310-2314. [PMID: 27742286 DOI: 10.1016/j.transproceed.2016.06.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Urine monitoring programs represent an important strategy for early diagnosis of reactivation of BK polyomavirus (BKV) in kidney transplant recipients. This study analyzes a BKV urine screening model in kidney transplant patients. METHODS Urinary screening for BKV reactivation was performed by urinary decoy cell and polymerase chain reaction (PCR) tests in samples from 32 consecutive kidney transplant patients, collected in a 6-month follow-up period. PCR in plasma samples and BKV immunohistochemical studies to assess BKV renal disease, if a kidney biopsy was indicated, were performed. RESULTS The urinary screening for BKV among 32 renal receptors was positive in 18 patients (56%) by the concomitant use of the decoy cells and/or qualitative PCR at some time during the study period. Transfusion before transplantation was significantly associated with urinary decoy cell positive screening (odds ratio = 11; 95% confidence interval = 1.47 to 82.4; P < .05); and so was male sex (odds ratio = 2.02; 95% confidence interval = 1.07 to 3.83; P < .05). The clinical management of screening positive cases consisted of decreasing or changing the immunosuppression regimen. Sixteen renal biopsies were performed. Immunohistochemistry for SV40 T antigen was negative in all biopsies. After 1 year of follow-up, no patient developed BKV-associated nephropathy, and there was no difference in renal function between patients positive and negative for BKV urinary screening. CONCLUSIONS Early urinary monitoring is effective in detection of BKV replication and represents a good strategy to minimize the deleterious effects caused by the presence of the virus on preservation of graft function.
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Affiliation(s)
- A L F Gouvêa
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil; Departamento de Patologia/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - R I J Cosendey
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - F R Carvalho
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - R B Varella
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - C F de Souza
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - P F Lopes
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil; Departamento de Patologia/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - A A Silva
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil; Departamento de Patologia/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - M C Rochael
- Departamento de Patologia/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - H P de Moraes
- Faculdade de Ciências Médicas/Anatomia Patológica/Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
| | - J R Lugon
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil
| | - J R Almeida
- Laboratório Multiusuário de Apoio à Pesquisa em Nefrologia e Ciências Médicas (LAMAP), Departamento de Medicina Clínica/Universidade Federal Fluminense, Rio de Janeiro, Brazil.
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Vigil D, Konstantinov NK, Barry M, Harford AM, Servilla KS, Kim YH, Sun Y, Ganta K, Tzamaloukas AH. BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection. World J Transplant 2016; 6:472-504. [PMID: 27683628 PMCID: PMC5036119 DOI: 10.5500/wjt.v6.i3.472] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/25/2016] [Accepted: 09/08/2016] [Indexed: 02/05/2023] Open
Abstract
Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research.
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