|
1
|
Maung Myint T, Chong CH, von Huben A, Attia J, Webster AC, Blosser CD, Craig JC, Teixeira-Pinto A, Wong G. Serum and urine nucleic acid screening tests for BK polyomavirus-associated nephropathy in kidney and kidney-pancreas transplant recipients. Cochrane Database Syst Rev 2024; 11:CD014839. [PMID: 39606952 PMCID: PMC11603539 DOI: 10.1002/14651858.cd014839.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
BACKGROUND BK polyomavirus-associated nephropathy (BKPyVAN) occurs when BK polyomavirus (BKPyV) affects a transplanted kidney, leading to an initial injury characterised by cytopathic damage, inflammation, and fibrosis. BKPyVAN may cause permanent loss of graft function and premature graft loss. Early detection gives clinicians an opportunity to intervene by timely reduction in immunosuppression to reduce adverse graft outcomes. Quantitative nucleic acid testing (QNAT) for detection of BKPyV DNA in blood and urine is increasingly used as a screening test as diagnosis of BKPyVAN by kidney biopsy is invasive and associated with procedural risks. In this review, we assessed the sensitivity and specificity of QNAT tests in patients with BKPyVAN. OBJECTIVES We assessed the diagnostic test accuracy of blood/plasma/serum BKPyV QNAT and urine BKPyV QNAT for the diagnosis of BKPyVAN after transplantation. We also investigated the following sources of heterogeneity: types and quality of studies, era of publication, various thresholds of BKPyV-DNAemia/BKPyV viruria and variability between assays as secondary objectives. SEARCH METHODS We searched MEDLINE (OvidSP), EMBASE (OvidSP), and BIOSIS, and requested a search of the Cochrane Register of diagnostic test accuracy studies from inception to 13 June 2023. We also searched ClinicalTrials.com and the WHO International Clinical Trials Registry Platform for ongoing trials. SELECTION CRITERIA We included cross-sectional or cohort studies assessing the diagnostic accuracy of two index tests (blood/plasma/serum BKPyV QNAT or urine BKPyV QNAT) for the diagnosis of BKPyVAN, as verified by the reference standard (histopathology). Both retrospective and prospective cohort studies were included. We did not include case reports and case control studies. DATA COLLECTION AND ANALYSIS Two authors independently carried out data extraction from each study. We assessed the methodological quality of the included studies by using Quality Assessment of Diagnostic-Accuracy Studies (QUADAS-2) assessment criteria. We used the bivariate random-effects model to obtain summary estimates of sensitivity and specificity for the QNAT test with one positivity threshold. In cases where meta-analyses were not possible due to the small number of studies available, we detailed the descriptive evidence and used a summative approach. We explored possible sources of heterogeneity by adding covariates to meta-regression models. MAIN RESULTS We included 31 relevant studies with a total of 6559 participants in this review. Twenty-six studies included kidney transplant recipients, four studies included kidney and kidney-pancreas transplant recipients, and one study included kidney, kidney-pancreas and kidney-liver transplant recipients. Studies were carried out in South Asia and the Asia-Pacific region (12 studies), North America (9 studies), Europe (8 studies), and South America (2 studies). INDEX TEST blood/serum/plasma BKPyV QNAT The diagnostic performance of blood BKPyV QNAT using a common viral load threshold of 10,000 copies/mL was reported in 18 studies (3434 participants). Summary estimates at 10,000 copies/mL as a cut-off indicated that the pooled sensitivity was 0.86 (95% confidence interval (CI) 0.78 to 0.93) while the pooled specificity was 0.95 (95% CI 0.91 to 0.97). A limited number of studies were available to analyse the summary estimates for individual viral load thresholds other than 10,000 copies/mL. Indirect comparison of thresholds of the three different cut-off values of 1000 copies/mL (9 studies), 5000 copies/mL (6 studies), and 10,000 copies/mL (18 studies), the higher cut-off value at 10,000 copies/mL corresponded to higher specificity with lower sensitivity. The summary estimates of indirect comparison of thresholds above 10,000 copies/mL were uncertain, primarily due to a limited number of studies with wide CIs contributed to the analysis. Nonetheless, these indirect comparisons should be interpreted cautiously since differences in study design, patient populations, and methodological variations among the included studies can introduce biases. Analysis of all blood BKPyV QNAT studies, including various blood viral load thresholds (30 studies, 5658 participants, 7 thresholds), indicated that test performance remains robust, pooled sensitivity 0.90 (95% CI 0.85 to 0.94) and specificity 0.93 (95% CI 0.91 to 0.95). In the multiple cut-off model, including the various thresholds generating a single curve, the optimal cut-off was around 2000 copies/mL, sensitivity of 0.89 (95% CI 0.66 to 0.97) and specificity of 0.88 (95% CI 0.80 to 0.93). However, as most of the included studies were retrospective, and not all participants underwent the reference standard tests, this may result in a high risk of selection and verification bias. INDEX TEST urine BKPyV QNAT There was insufficient data to thoroughly investigate both accuracy and thresholds of urine BKPyV QNAT resulting in an imprecise estimation of its accuracy based on the available evidence. AUTHORS' CONCLUSIONS There is insufficient evidence to suggest the use of urine BKPyV QNAT as the primary screening tool for BKPyVAN. The summary estimates of the test sensitivity and specificity of blood/serum/plasma BKPyV QNAT test at a threshold of 10,000 copies/mL for BKPyVAN were 0.86 (95% CI 0.78 to 0.93) and 0.95 (95% CI 0.91 to 0.97), respectively. The multiple cut-off model showed that the optimal cut-off was around 2000 copies/mL, with test sensitivity of 0.89 (95% CI 0.66 to 0.97) and specificity of 0.88 (95% CI 0.80 to 0.93). While 10,000 copies/mL is the most commonly used cut-off, with good test performance characteristics and supports the current recommendations, it is important to interpret the results with caution because of low-certainty evidence.
Collapse
Affiliation(s)
- Thida Maung Myint
- John Hunter Hospital, Newcastle, Australia
- Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - Chanel H Chong
- Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - Amy von Huben
- Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - John Attia
- University of Newcastle, Newcastle, Australia
| | - Angela C Webster
- Sydney School of Public Health, University of Sydney, Sydney, Australia
- NHMRC Clinical Trials Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
- Westmead Applied Research Centre, The University of Sydney at Westmead, Westmead, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, Australia
| | - Christopher D Blosser
- Department of Medicine, Nephrology, University of Washington & Seattle Children's Hospital, Seattle, WA, USA
| | - Jonathan C Craig
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
| | | | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, Australia
| |
Collapse
|
|
2
|
Sexton DJ, Bagnasco S, Kant S. Transplant Nephrology. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:566-573. [PMID: 39577891 DOI: 10.1053/j.akdh.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 11/24/2024]
Abstract
The progressive rise in the number of kidney transplant recipients in the last 2 decades is reflective of the technological advances in the field. Nephrologists are responsible for providing long-term longitudinal care to these patients. It is pertinent that nephrologists understand the various nuances of aspects such as immunosuppression, opportunistic infections, and identification of causes associated with graft dysfunction.
Collapse
Affiliation(s)
- Donal J Sexton
- Department of Renal Medicine, St. James Hospital, Trinity College School of Medicine, Dublin, Ireland
| | - Serena Bagnasco
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sam Kant
- Department of Renal Medicine, Cork University Hospital, University College Cork School of Medicine, Cork, Ireland.
| |
Collapse
|
|
3
|
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: 42] [Impact Index Per Article: 14.0] [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.
Collapse
|
|
4
|
Komorniczak M, Król E, Lizakowski S, Dębska-Ślizień A. Screening for Polyomavirus Viruria Like Early Detection of Human Polyomavirus Infection and Replication: The Results of a Single-Center Observation. Transplant Proc 2022; 54:989-994. [DOI: 10.1016/j.transproceed.2022.02.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 02/18/2022] [Indexed: 11/17/2022]
|
|
5
|
Uppin M, Veduruvada R, Madireddy N, Koyya S, Guditi S, Taduri G, Raju S. Clinicopathologic features of polyomavirus nephropathy: Our experience - A retrospective observational study. INDIAN JOURNAL OF TRANSPLANTATION 2022. [DOI: 10.4103/ijot.ijot_115_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
6
|
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]
|
|
7
|
Zanotto E, Allesina A, Barreca A, Sidoti F, Gallo E, Bottino P, Iannaccone M, Bianco G, Biancone L, Cavallo R, Costa C. Renal Allograft Biopsies with Polyomavirus BK Nephropathy: Turin Transplant Center, 2015-19. Viruses 2020; 12:v12091047. [PMID: 32962215 PMCID: PMC7550990 DOI: 10.3390/v12091047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/16/2020] [Accepted: 09/18/2020] [Indexed: 12/22/2022] Open
Abstract
Background: In kidney transplant patients, polyomavirus-associated nephropathy (PVAN) represents a serious complication; the key factor for the development of PVAN is immunosuppression level and modulation of anti-rejection treatment represents the first line of intervention. Allograft biopsy and histology remain the criterion standard for diagnosing PVAN. Methods: All consecutive renal biopsies with the diagnosis of PVAN carried out at the University Hospital City of Health and Science of Turin over a five-years period were studied. Renal allograft biopsy was performed due to renal function alterations associated to medium-high polyomavirus BK (BKV)-DNA levels on plasma specimen. Results: A total of 21 patients underwent a first biopsy to diagnose a possible BKV nephropathy, in 18, a second biopsy was made, in eight, a third biopsy, and finally, three underwent the fourth renal biopsy; following the results of each biopsies, immunosuppressant agents dosages were modified in order to reduce the effect of PVAN. Conclusions: In this study, the clinical and histological features of 21 kidney transplant recipients with BKV reactivation and development of PVAN are described. To date, the only treatment for PVAN consists in the reduction of immunosuppressive agents, constantly monitoring viral load.
Collapse
Affiliation(s)
- Elisa Zanotto
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
- Correspondence:
| | - Anna Allesina
- Nephrology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (A.A.); (E.G.); (L.B.)
| | - Antonella Barreca
- Pathology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy;
| | - Francesca Sidoti
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
| | - Ester Gallo
- Nephrology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (A.A.); (E.G.); (L.B.)
| | - Paolo Bottino
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
| | - Marco Iannaccone
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
| | - Gabriele Bianco
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
| | - Luigi Biancone
- Nephrology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (A.A.); (E.G.); (L.B.)
| | - Rossana Cavallo
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
| | - Cristina Costa
- Microbiology and Virology Unit, University Hospital City of Health and Science of Turin, Corso Bramante 88, 10126 Turin, Italy; (F.S.); (P.B.); (M.I.); (G.B.); (R.C.); (C.C.)
| |
Collapse
|
|
8
|
Atilla E, Ateş C, Uslu A, Ataca Atilla P, Dolapçı I, Tekeli A, Topçuoğlu P. Prospective Analysis of Hemorrhagic Cystitis and BK Viremia in Allogeneic Hematopoietic Stem Cell Transplantation. Turk J Haematol 2020; 37:186-192. [PMID: 31852035 PMCID: PMC7463211 DOI: 10.4274/tjh.galenos.2019.2019.0296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023] Open
Abstract
Objective BK virus (BKV) infection has been shown to be related to hemorrhagic cystitis (HC) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). There are conflicting data regarding the association between BKV titers in plasma and clinical disease as well as the risk factors for BKV-related HC. Our aim is to study the risk factors and relationship with plasma BK viral load for development of HC in a prospective analysis. Materials and Methods We prospectively evaluated 59 patients who received allo-HSCT between 2014 and 2016 by quantitative BK virus polymerase chain reaction (PCR) (Altona Diagnostics, Germany) from blood samples at days 0, 30, 60, and 90 after allo-HSCT. The patients were monitored for signs and symptoms of HC. Results HC was diagnosed in 22 patients (37%) at a mean of 100 days (range: 0-367 days). In multivariate analysis, the usage of cyclophosphamide (sub-distribution hazard ratio [sdHR]: 7.82, confidence interval [CI]: 1.375-39.645, p=0.02), reactivated CMV (sdHR: 6.105, CI: 1.614-23.094, p=0.008), and positive BKV viremia (sdHR: 2.15, CI: 1.456-22.065, p=0.01) significantly increased the risk of developing HC. Patients with higher viral loads at day 30 and day 60 were diagnosed with more severe HC (p<0.001). Median BK viral loads of >101.5 copies/mL at day 0 (sensitivity 0.727, specificity 0.875), >98.5 copies/mL at day 30 (sensitivity 0.909, specificity 0.875), and >90.0 copies/mL at day 60 (sensitivity 0.909, specificity 0.875) were indicative of HC. Conclusion Our study showed that administration of cyclophosphamide, CMV reactivation, and BK virus positivity were associated with HC. Plasma BK virus PCR titers at days 0, 30, and 60 after transplant were sensitive tools for predicting clinically proven HC.
Collapse
Affiliation(s)
- Erden Atilla
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Can Ateş
- Van Yüzüncü Yıl University Faculty of Medicine, Department of Biostatistics, Van, Turkey
| | - Atilla Uslu
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Pınar Ataca Atilla
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Istar Dolapçı
- Ankara University Faculty of Medicine, Department of Microbiology, Ankara, Turkey
| | - Alper Tekeli
- Ankara University Faculty of Medicine, Department of Microbiology, Ankara, Turkey
| | - Pervin Topçuoğlu
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| |
Collapse
|
|
9
|
Li P, Cheng D, Wen J, Ni X, Li X, Xie K, Chen J. The immunophenotyping of different stages of BK virus allograft nephropathy. Ren Fail 2019; 41:855-861. [PMID: 31535918 PMCID: PMC6758702 DOI: 10.1080/0886022x.2019.1617168] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 04/29/2019] [Accepted: 04/30/2019] [Indexed: 01/01/2023] Open
Abstract
Objectives: To investigate the immunohistochemical features of different stages of BK virus allograft nephropathy (BKVN) and further elucidate the underlying immunological mechanism involved in the evolution of BKVN. Methods: Fifty-two renal transplant recipients with biopsy proven BKVN were retrospectively selected. According to the third edition of the American Society of Transplantation Infection guidelines, 10 patients were categorized as having mild BKVN (stage A), 25 were moderate (stage B) and 17 were severe (stage C). The differential infiltrations of CD3+ (T lymphocytes), CD4+ (helper T lymphocytes), CD8+ (cytotoxic T lymphocytes), CD20+ (B lymphocytes), CD68+ (macrophages) and CD138+ (plasma cells) cells and the expression of interleukin-2 receptor (IL-2R) and human leukocyte antigen DR (HLA-DR) were compared among the three groups. Results: CD3+, CD4+, CD8+, CD20+, CD138+ and CD68+ cells infiltrations, IL-2R and HLA-DR expression were positive in the BKVN patients. Moreover, with increasing stages of BKVN, the numbers of positively stained inflammatory cells and the expression of IL-2R were significantly increased in the severe group compared to the mild group, whereas no statistically significant differences were observed with regard to HLA-DR expression. Eosinophil and neutrophil infiltration could also be observed in moderate to advanced BKVN. Conclusion: Renal allograft damage caused by BKVN involved T lymphocyte-, B lymphocyte- and mononuclear macrophage-mediated immune responses. Inflammatory cell infiltrations in the renal allograft were probably the driving force for BKVN progression. Additionally, eosinophils and neutrophils may be involved in the pathophysiological mechanism of BKVN.
Collapse
Affiliation(s)
- Ping Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Dongrui Cheng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jiqiu Wen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xuefeng Ni
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xue Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Kenan Xie
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jinsong Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| |
Collapse
|
|
10
|
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.
Collapse
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
| |
Collapse
|
|
11
|
Chong S, Antoni M, Macdonald A, Reeves M, Harber M, Magee CN. BK virus: Current understanding of pathogenicity and clinical disease in transplantation. Rev Med Virol 2019; 29:e2044. [PMID: 30958614 DOI: 10.1002/rmv.2044] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 12/19/2022]
Abstract
BK polyomavirus (BKV) is an important cause of graft loss in renal transplant recipients that continues to pose a significant challenge to clinicians due to its frequently unpredictable onset, persistence, and the lack of effective antiviral agents or prevention strategies. This review covers our current understanding of epidemiology, viral transmission and disease progression, and treatment and prevention strategies that have been used to manage this disease.
Collapse
Affiliation(s)
- Stephanie Chong
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Michelle Antoni
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, London, UK
| | - Andrew Macdonald
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, London, UK
| | - Matthew Reeves
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK
| | - Mark Harber
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Ciara N Magee
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| |
Collapse
|
|
12
|
David-Neto E, Agena F, Silva Ribeiro David D, Paula FJD, Camera Pierrotti LC, Domingues Fink MC, Fonseca de Azevedo LS. Effect of polyoma viremia on 3-year allograft kidney function. Transpl Infect Dis 2019; 21:e13056. [PMID: 30712328 DOI: 10.1111/tid.13056] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 01/10/2019] [Accepted: 01/27/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Polyoma viremia is associated with damage to renal tubular and urothelial cells. This may imply that a certain level of viremia, even cleared thereafter, could be associated with long-term renal dysfunction. METHODS We, retrospectively, analyzed 390 first renal transplants adult recipients (≥18 years) who were monitored for BK viremia in the first 12 months and evaluated estimated GFR (MDRD-4 equation) at 1 month and at the last follow-up (959 ± 392 days). RESULTS One hundred and ninety-nine patients (51%) developed at least one positive viremia: 105 (53%) low viremia (<104 copies/mL), 36 (18%) high viremia (4 × 104 > viremia ≥ 104 copies/mL) and 58 (15%) viremia (≥4 × 104 copies/mL) consistent with polyoma virus associated nephropathy (PyVAN). Out of these 58 patients, 24 (6%) developed bx-proven (SV40+) PyVAN and 34(8.7%) presumptive PyVAN (SV40-). Baseline characteristics, immunosuppression, KDRI, rejection episodes, etc., did not differ among groups but there were more deceased donors and ATG induction therapy in the high viremia group. At last follow-up, all patients in the low, high viremia and presumptive PyVAN (except 2) had cleared BK viremia. Bx-proven PyVAN led to 14 graft losses, 10 due to PyVAN. In the presumptive PyVAN there was only one graft loss registered as due to PyVAN. eGFR, at 1 month after KTx, did not differ among groups (51 ± 22 vs 48 ± 24 vs 45 ± 27 vs 43 ± 18 vs 46 ± 22 mL/min/1.73 m2 ), for no, low and high viremia as well for presumptive PyVAN and bx-proven PyVAN groups, respectively. At the last follow-up, eGFR did not differ between the no, low, and high viremia compared to baseline and to each other but was statistically lower in the presumptive and bx-proven PyVAN (38 ± 15 and 17 ± 7 mL/min/1.73 m2 ) either compared to baseline or to the other groups. CONCLUSIONS This study shows that low and high levels of BK viremia do not lead to GFR changes although very high viremia levels, compatible with presumptive or bx-proven PyVAN, even if cleared thereafter, lead to allograft damage and decreased GFR.
Collapse
Affiliation(s)
- Elias David-Neto
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil.,Division of Nephrology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | - Fabiana Agena
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | - Daisa Silva Ribeiro David
- Division of Pathology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | - Flavio Jota de Paula
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| | | | | | - Luiz Sergio Fonseca de Azevedo
- Renal Transplantation Service, Division of Urology, Hospital das Clínicas, Sao Paulo University School of Medicine, São Paulo, Brazil
| |
Collapse
|
|
13
|
Trang VD, Rockett R, Jeoffreys N, Trung NV, Hai An HP, Kok J, Dwyer DE. BK polyomavirus: a review of the virology, pathogenesis, clinical and laboratory features, and treatment. Future Virol 2017. [DOI: 10.2217/fvl-2017-0013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BK polyomavirus (BKPyV) is a non-enveloped, circular dsDNA virus with a genome of approximately 5100 base pairs. It can be divided into four major genotypes, but the effects of different genotypes on clinical disease are uncertain. Primary BKPyV infection is generally acquired asymptomatically in childhood. It establishes low-level persistence in many tissues, particularly the genitourinary tract. Reactivation can lead to severe disease including BKPyV-associated nephropathy confirmed by renal biopsy, hemorrhagic cystitis and meningoencephalitis. Nucleic acid amplification testing of blood and urine is the main diagnostic and prognostic test for BKPyV infection. The treatment of BKPyV infection has concentrated on reduction in immunosuppressive therapy. Recent studies suggest that antiviral drugs have demonstrated only modest benefit, but adoptive T-cell therapies offer potential advances.
Collapse
Affiliation(s)
- Van Dinh Trang
- Clinical Laboratory, National Hospital of Tropical Diseases, 78-Giai Phong, Dong Da, Hanoi, Vietnam
- Western Clinical School, Westmead Hospital, The University of Sydney, NSW 2006, Australia
| | - Rebecca Rockett
- Center for Infectious Diseases & Microbiology Laboratory Services, Institute of Clinical Pathology & Medical Research, NSW Health Pathology, Westmead Hospital, Westmead NSW 2145, Australia
| | - Neisha Jeoffreys
- Center for Infectious Diseases & Microbiology Laboratory Services, Institute of Clinical Pathology & Medical Research, NSW Health Pathology, Westmead Hospital, Westmead NSW 2145, Australia
| | - Nguyen Vu Trung
- Clinical Laboratory, National Hospital of Tropical Diseases, 78-Giai Phong, Dong Da, Hanoi, Vietnam
- Department of Medical Microbiology, Hanoi Medical University, No. 1 Ton That Tung St, Dong Da, Hanoi, Vietnam
| | - Ha Phan Hai An
- Department of International Cooperation, Hanoi Medical University, No. 1 Ton That Tung St, Dong Da, Hanoi, Vietnam
- Kidney Diseases & Dialysis Department, Viet Duc Hospital, No. 40 Trang Thi St, Hoan Kiem, Hanoi, Vietnam
| | - Jen Kok
- Center for Infectious Diseases & Microbiology Laboratory Services, Institute of Clinical Pathology & Medical Research, NSW Health Pathology, Westmead Hospital, Westmead NSW 2145, Australia
| | - Dominic E Dwyer
- Western Clinical School, Westmead Hospital, The University of Sydney, NSW 2006, Australia
- Center for Infectious Diseases & Microbiology Laboratory Services, Institute of Clinical Pathology & Medical Research, NSW Health Pathology, Westmead Hospital, Westmead NSW 2145, Australia
| |
Collapse
|
|
14
|
Abstract
Similarly to the general population, genitourinary tract infections are common conditions in theimmunocompromised host. They can be furthermore divided into infections of the urinary tract and genital tract infections. Transplant recipients are more likely to have infections of the urinary tract infections while persons with human immunodeficiency virus (HIV) are at higher risk for the second group of infections, especially sexually transmitted infections (STIs). Manifestations of these diseases can be associated with more complications and can be more severe. We provide an overview of manifestations, diagnosis, and management of these disorders.
Collapse
|
|
15
|
Agrawal N, Echenique IA, Meehan SM, Limaye AP, Cook L, Chang A, Harland RC, Javaid B, Kadambi PV, Matushek S, Williams J, Josephson MA. Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach - a retrospective analysis. Transpl Int 2017; 30:670-678. [PMID: 28295760 DOI: 10.1111/tri.12951] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 12/31/2016] [Accepted: 03/08/2017] [Indexed: 12/22/2022]
Abstract
Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.
Collapse
Affiliation(s)
- Neerja Agrawal
- Department of Transplant Nephrology, Cleveland Clinic Florida, Weston, FL, USA
| | | | | | - Ajit P Limaye
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - Linda Cook
- Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
| | - Anthony Chang
- Department of Pathology, University of Chicago, Chicago, IL, USA
| | | | - Basit Javaid
- MedStar Georgetown Transplant Institute, Georgetown University Hospital, Georgetown, DC, USA
| | | | - Scott Matushek
- Department of Clinical Microbiology, University of Chicago, Chicago, IL, USA
| | | | | |
Collapse
|
|
16
|
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.
Collapse
|
|
17
|
El Ansary M, Abd Elhamid S, Saadi G, Ismail W, Ibrahim N, Bahaa El-Din N, Alhsyek S. Prevalence of polyoma BK virus infection among living-donor renal transplant recipients. Transpl Infect Dis 2016; 18:529-537. [PMID: 27226063 DOI: 10.1111/tid.12557] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 02/25/2016] [Accepted: 03/17/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Polyomavirus nephropathy (PVN) mainly caused by BK polyomavirus (BKPyV) remains the most common productive viral infection of the kidney in immunosuppressed patients. The diagnosis of PVN is based on the detection of BK viruria and BK viremia in conjunction with histological findings in the graft biopsy. METHODS Our study was aimed to estimate the prevalence of productive BKPyV infection among renal transplant patients within the first year post-transplant and identify those at risk of developing PVN. Our cross-sectional study was conducted on 134 kidney transplant patients. Evidence of BKPyV replication was assessed by viral quantification of blood and urine samples of studied patients using a quantitative real-time polymerase chain reaction (Q-PCR)PCR), detection of decoy cells in urine cytology smears, histological examination of graft biopsies from Q-PCR BKPyV-positive patients, and immunohistochemical staining by simian virus 40 (SV40) antibody. RESULTS Significant BKPyV infection was prevalent in 8% (n = 11) of our patients, with a peak of BKPyV infection about 8 months post transplant. BKPyV viral load by Q-PCR assay in these patients varied from 1350 to 20,000,000 (1.35 × 10(3) to 2 × 10(7) ) copies/mL for urine samples and 935 to 18,920 (9.35 × 10(2) to 1.89 × 10(4) ) copies/mL for blood samples. All the 11 patients were positive for decoy cells but only 3 developed PVN based on histology and positive SV40 staining. BKPyV infection was more prevalent in older patients. All patients responded to reduction in their immunosuppressive regimens, apart from 2 patients who required replacement of calcineurin inhibitors-based regimen with mammalian target of ramapycin inhibitors with an overall good response. CONCLUSION Protocol screening programs based on detection of viral replication by viruria, viremia, and decoy cells in urine are necessary to shed light on patients with high virus replication and hence increased risk of developing PVN, and to allow early diagnosis and intervention.
Collapse
Affiliation(s)
- M El Ansary
- Department of Clinical Pathology, Kasr El-Aini, Cairo University, Cairo, Egypt
| | - S Abd Elhamid
- Department of Clinical Pathology, Kasr El-Aini, Cairo University, Cairo, Egypt
| | - G Saadi
- Department of Internal Medicine & Nephrology, Kasr El-Aini, Cairo University, Cairo, Egypt
| | - W Ismail
- Department of Pathology, Faculty of Medicine, BeniSuef University, BeniSuef, Egypt
| | - N Ibrahim
- Department of Clinical Pathology, Kasr El-Aini, Cairo University, Cairo, Egypt
| | - N Bahaa El-Din
- Department of Clinical Pathology, Kasr El-Aini, Cairo University, Cairo, Egypt
| | - S Alhsyek
- Department of Biochemistry, Faculty of Science, Trebles University, Trebles, Libya
| |
Collapse
|
|
18
|
Abstract
The kidney is involved in a wide range of bacterial, viral, fungal, and parasitic diseases. In most systemic infections, renal involvement is a minor component of the illness, but in some, renal failure may be the presenting feature and the major problem in management. Although individual infectious processes may have a predilection to involve the renal vasculature, glomeruli, interstitium, or collecting systems, a purely anatomic approach to the classification of infectious diseases affecting the kidney is rarely helpful because most infections may involve several different aspects of renal function. In this chapter, a microbiological classification of the organisms affecting the kidney is adopted. Although they are important causes of renal dysfunction in infectious diseases, urinary tract infections and hemolytic uremic syndrome (HUS) are not discussed in detail because they are considered separately in chapters XX and XX, respectively.
Collapse
Affiliation(s)
- Ellis D. Avner
- Department of Pediatrics, Medical College of Wisconsin, Children’s Research Institute, Children’s Hospital, Health System of Wisconsin, Milwaukee, Wisconsin USA
| | - William E. Harmon
- Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts USA
| | - Patrick Niaudet
- Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Université Paris-Descartes, Paris, France
| | | | - Francesco Emma
- Division of Nephrology, Bambino Gesù Children’s Hospital – IRCCS, Rome, Italy
| | - Stuart L. Goldstein
- Division of Nephrology and Hypertension, The Heart Institute, Cincinnati Children’s Hospital Medical Center, College of Medicine, Cincinnati, Ohio USA
| |
Collapse
|
|
19
|
Abstract
BACKGROUND Reactivation of BK polyoma virus can result in destructive viral allograft nephropathy (BKVAN) with limited treatment options. Screening programs using surrogate markers of viral replication are important preventive strategies, guiding immunosuppression reduction. METHODS We prospectively evaluated the diagnostic test performance of urinary decoy cells and urinary SV40T immunochemistry of exfoliated cells, to screen for BKVAN, (defined by reference histology with SV40 immunohistochemistry, n = 704 samples), compared with quantitative viremia, from 211 kidney and 141 kidney-pancreas transplant recipients. RESULTS The disease prevalence of BKVAN was 2.6%. Decoy cells occurred in 95 of 704 (13.5%) samples, with a sensitivity of 66.7%, specificity of 88.6%, positive predictive value (PPV) of 11.7%, and negative predictive value of 98.5% to predict histologically proven BKVAN. Quantification of decoy cells improved the PPV to 32.1% (10 ≥ cells threshold). Immunohistochemical staining of urinary exfoliated cells for SV40T improved sensitivity to 85.7%, detecting atypical or degenerate infected cells (specificity of 92.3% and PPV of 33.3%), but was hampered by technical failures. Viremia occurred in 90 of 704 (12.8%) with sensitivity of 96.3%, specificity of 90.3%, PPV of 31.5%, and negative predictive value of 99.8%. The receiver-operator curve performance of quantitative viremia surpassed decoy cells (area under the curve of 0.95 and 0.79, respectively, P = 0.0018 for differences). Combining decoy cell and BK viremia in a diagnostic matrix improved prediction of BKVAN and diagnostic risk stratification, especially for high-level positive results. CONCLUSIONS Although quantified decoy cells are acceptable surrogate markers of BK viral replication with unexceptional test performances, quantitative viremia displayed superior test characteristics and is suggested as the screening test of choice.
Collapse
|
|
20
|
Kamel M, Kadian M, Salazar MN, Mohan P, Self S, Srinivas T, Salas MAP. A Case of BK Nephropathy without Detectable Viremia or Viruria. AMERICAN JOURNAL OF CASE REPORTS 2015; 16:532-5. [PMID: 26270823 PMCID: PMC4539997 DOI: 10.12659/ajcr.894314] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Patient: Male, 49 Final Diagnosis: BK nephropathy without detectable viremia or viruria Symptoms: — Medication: — Clinical Procedure: Kidney biopsy Specialty: Nephrology
Collapse
Affiliation(s)
- Mahmoud Kamel
- Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Manish Kadian
- Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Maria Nieva Salazar
- Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Prince Mohan
- Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Sally Self
- Department of Pathology, Medical University of South Carolina, Charleston, SC, USA
| | - Titte Srinivas
- Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Maria Aurora Posadas Salas
- Division of Nephrology and Hypertension, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| |
Collapse
|
|
21
|
Teutsch K, Schweitzer F, Knops E, Kaiser R, Pfister H, Verheyen J, Göbel H, Cingöz T, Di Cristanziano V. Early identification of renal transplant recipients with high risk of polyomavirus-associated nephropathy. Med Microbiol Immunol 2015; 204:657-64. [DOI: 10.1007/s00430-015-0398-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 02/21/2015] [Indexed: 02/07/2023]
|
|
22
|
Kang HR, Kwon SS, Yoon SY, Kim EN, Kwon SH, Jeon JS, Noh H, Han DC, Jin SY. Treatment of Presumptive BK Nephropathy with Ciprofloxain in Kidney Transplant Recipients: Three Case Reports. KOREAN JOURNAL OF TRANSPLANTATION 2014. [DOI: 10.4285/jkstn.2014.28.4.254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Hye Ran Kang
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seong Soon Kwon
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Seug Yun Yoon
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Eun Na Kim
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Soon Hyo Kwon
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jin Seok Jeon
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Hyunjin Noh
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Dong Cheol Han
- Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - So Young Jin
- Department of Pathology, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| |
Collapse
|
|
23
|
Screening for BK viremia reduces but does not eliminate the risk of BK nephropathy: a single-center retrospective analysis. Transplantation 2013; 95:949-54. [PMID: 23545506 DOI: 10.1097/tp.0b013e31828423cd] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND This study reviewed the outcomes of a screening protocol for BK viremia to determine if early diagnosis, followed by immunosuppression minimization, would prevent progression to nephropathy and graft loss. METHODS This review included 369 renal transplant recipients tested for BK virus at serial time points after transplantation. Management included immunosuppression minimization plus cidofovir treatment for BK nephropathy. RESULTS Recipients received tacrolimus-based immunosuppression, with 8% prednisone-free and 6% who received desensitization. With a mean follow-up of 22 ± 10 months, 16% (n = 57) of recipients became BK viremia positive. The median (range) time to diagnosis was 3 (1-17) months. Because renal biopsy was performed selectively, 59% of recipients underwent biopsy, with 47% showing BK nephropathy. Seventy-four percent of recipients cleared the virus at a median (range) time of 9 (3-33) months, with four grafts lost to BK nephropathy. Cidofovir-treated recipients displayed a higher viral load at diagnosis but showed equivalent renal function at last evaluation. In multivariate analysis, recipient age, Asian ethnicity, deceased donor, and prednisone use were factors independently associated with BK viremia. Actuarial survival of BK-positive grafts was worse than that of BK-negative grafts (P<0.01, log-rank test). At 9 and 12 months, the mean estimated glomerular filtration rate of the BK-positive group was lower than that of the BK-negative cohort (P = 0.02). CONCLUSIONS Despite using a screening protocol combined with immunosuppression minimization, BK-positive recipients had a greater risk of graft loss and impaired function than recipients free of infection. Future investigations should focus on practices to prevent BK viremia.
Collapse
|
|
24
|
Rau S, Schönermarck U, Jäger G, Stangl M, Guba M, Meiser B, Fischereder M, Habicht A. BK virus-associated nephropathy: neutrophil gelatinase-associated lipocalin as a new diagnostic tool? Clin Transplant 2013; 27:E184-91. [DOI: 10.1111/ctr.12081] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2012] [Indexed: 11/27/2022]
Affiliation(s)
- Simon Rau
- Medizinische Klinik und Poliklinik IV; Nephrologisches Zentrum; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Ulf Schönermarck
- Medizinische Klinik und Poliklinik IV; Nephrologisches Zentrum; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Gundula Jäger
- Max von Pettenkofer-Institut; Virologie; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Manfred Stangl
- Chirurgische Klinik; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Markus Guba
- Chirurgische Klinik; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Bruno Meiser
- Transplantationszentrum München; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Michael Fischereder
- Medizinische Klinik und Poliklinik IV; Nephrologisches Zentrum; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| | - Antje Habicht
- Transplantationszentrum München; Klinikum der Universität München; Ludwig-Maximilians-University; Munich; Germany
| |
Collapse
|
|
25
|
Costa C, Cavallo R. Polyomavirus-associated nephropathy. World J Transplant 2012; 2:84-94. [PMID: 24175200 PMCID: PMC3782238 DOI: 10.5500/wjt.v2.i6.84] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 08/14/2012] [Accepted: 10/31/2012] [Indexed: 02/05/2023] Open
Abstract
Polyomaviruses BK and JC are ubiquitous viruses with high seroprevalence rates in general population. Following primary infection, polyomaviruses BK and JC persist latently in different sites, particularly in the reno-urinary tract. Reactivation from latency may occur in normal subjects with asymptomatic viruria, while it can be associated to nephropathy (PVAN) in kidney transplantat recipients. PVAN may occur in 1%-10% of renal transplant patients with loss of the transplanted organ in 30% up to 80% of the cases. Etiology of PVAN is mainly attributable to BK virus, although approximately 5% of the cases may be due to JC. Pathogenesis of PVAN is still unknown, although viral replication and the lack of immune control play a major role. Immunosuppression represents the condicio sine qua non for the development of PVAN and the modulation of anti-rejection treatment represents the first line of intervention, given the lack of specific antiviral agents. At moment, an appropriate immunemodulation can only be accomplished by early identification of viral reactivacation by evaluation of polyomavirus load on serum and/or urine specimens, particularly in the first year post-trasplantation. Viro-immunological monitoring of specific cellular immune response could be useful to identify patients unable to recover cellular immunity posttransplantation, that are at higher risk of viral reactivation with development of PVAN. Herein, the main features of polyomaviruses BK and JC, biological properties, clinical characteristics, etiopathogenesis, monitoring and diagnosing of PVAN will be described and discussed, with an extended citation of related relevant literature data.
Collapse
Affiliation(s)
- Cristina Costa
- Cristina Costa, Rossana Cavallo, Virology Unit, University Hospital San Giovanni Battista di Torino, 10126 Turin, Italy
| | | |
Collapse
|
|
26
|
Yamanaka K, Oka K, Nakazawa S, Hirai T, Kishikawa H, Nishimura K, Kyo M, Ichikawa Y. Immunohistochemical features of BK virus nephropathy in renal transplant recipients. Clin Transplant 2012; 26 Suppl 24:20-4. [DOI: 10.1111/j.1399-0012.2012.01636.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Kazuaki Yamanaka
- The Department of Urology; Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| | - Kazumasa Oka
- Pathology Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| | - Shigeaki Nakazawa
- The Department of Urology; Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| | - Toshiaki Hirai
- The Department of Urology; Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| | - Hidefumi Kishikawa
- The Department of Urology; Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| | - Kenji Nishimura
- The Department of Urology; Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| | | | - Yasuji Ichikawa
- The Department of Urology; Hyogo Prefectural Nishinomiya Hospital; Osaka; Japan
| |
Collapse
|
|
27
|
Hricik DE, Glassock RJ, Bleyer AJ. Nephrology quiz and questionnaire: transplantation. Clin J Am Soc Nephrol 2012; 7:1190-4. [PMID: 22595824 DOI: 10.2215/cjn.01730212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Presentation of the Nephrology Quiz and Questionnaire (NQQ) has become an annual "tradition" at the meetings of the American Society of Nephrology. It is a very popular session judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, to those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. Topics presented here include transplantation issues. These cases, along with single best answer questions, were prepared by Dr. Hricik. After the audience responses, the "correct" and "incorrect" answers were then briefly discussed and the results of the questionnaire were displayed. This article aims to recapitulate the session and reproduce its educational value for a larger audience-that of the readers of the Clinical Journal of the American Society of Nephrology. Have fun.
Collapse
Affiliation(s)
- Donald E Hricik
- Division of Nephrology and Hypertension, Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio, USA
| | | | | |
Collapse
|
|
28
|
BK-virus infections: A literature review. Med Mal Infect 2012; 42:181-7. [DOI: 10.1016/j.medmal.2012.04.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Accepted: 04/16/2012] [Indexed: 11/18/2022]
|
|
29
|
Predominance of TH2 cells and plasma cells in polyoma virus nephropathy: a role for humoral immunity? Hum Pathol 2012; 43:1453-62. [PMID: 22406372 DOI: 10.1016/j.humpath.2011.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Revised: 11/02/2011] [Accepted: 11/03/2011] [Indexed: 11/24/2022]
Abstract
The differential diagnosis of T cell-mediated rejection (TCMR) and BK-virus nephropathy (BKVN) in renal transplant biopsies is notoriously difficult. Therefore, attempts were made to differentiate between the two by characterizing the immune cell infiltrate. Using immunohistochemistry, the distribution of immune cell (sub)populations such as CD4(+) T helper (TH), TH1, TH2, CD8(+) cytotoxic T cells, regulatory T cells, B cells, plasma cells and follicular dendritic cells was determined in a total of 38 renal biopsy specimens. In addition, the expression of the HLA class I antigen presentation machinery (APM) components was investigated. In general, the frequency of T cells was higher than B cells, and TH cells outnumbered cytotoxic T cells with a predominance of TH2 over TH1 cells. In BKVN, a significantly higher number of plasma cells was observed (P = .028), and interstitial fibrosis and tubular atrophy was more pronounced in BKVN (P = .007) compared to TCMR. The expression of components of the HLA class I APM was not affected by the infection with BK virus compared to TCMR. These findings indicate a TH2 shift in renal transplants in the context of alloreactive and virus-induced inflammation maybe as a consequence of immunosuppression, which usually targets T cell reaction. The predominance of plasma cells might underline an important role of humoral immunity in BKVN. Moreover, BK virus does not seem to modulate the expression of HLA class I APM as a strategy of immune evasion.
Collapse
|
|
30
|
Chan GCW, Leung AYH, Wong ASY, Chan KW, Kwong YL, Lai KN, Tang SCW. Quantification of BK viral load in asymptomatic renal allograft recipients. Ren Fail 2012; 34:550-4. [PMID: 22390257 DOI: 10.3109/0886022x.2012.664808] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
INTRODUCTION Polyoma BK virus (BKV) has recently been identified to cause renal allograft dysfunction, which manifests as polyomavirus-associated nephropathy (PVAN). However, the presence and level of BKV DNA in renal allograft patients with good and stable renal function have remained undetermined. METHODS In this prospective study, serum samples were collected from a total of 45 renal allograft recipients with serum creatinine <155 μmol/L. In 17 patients, whose duration of transplantation was under 2 years, samples were collected at 3-4-month intervals for up to 2 years after transplantation. BK viral load was quantified using quantitative polymerase chain reaction (Q-PCR). RESULTS The BK viral load in asymptomatic renal allograft recipients was independent of the duration of transplantation and did not correlate with allograft function. The mean (± SD) level of viremia was 552.80 ± 1931.00 genome copies/mL, with 92.9% of patients having low levels of viremia corresponding to <1 × 10(3) copies/mL. In contrast, patients with proven PVAN had levels in the range of 10(6) copies/mL. CONCLUSIONS The prevailing BK viral load in asymptomatic renal allograft patients is quantifiably low. Our findings may guide optimal immunosuppressive modulation in PVAN cases, where judicious manipulation of immunosuppression is required without inciting allograft rejection.
Collapse
Affiliation(s)
- Gary C W Chan
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | | | | | | | | | | | | |
Collapse
|
|
31
|
|
|
32
|
Mindlova M, Boucek P, Saudek F, Skibova J, Jedinakova T, Lipar K, Adamec M, Hirsch HH. Prevalence and risk factors of polyomavirus BK replication in simultaneous pancreas/kidney transplant recipients from a single transplant center. Clin Transplant 2011; 26:267-74. [DOI: 10.1111/j.1399-0012.2011.01488.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
|
|
33
|
Abstract
Chronic allograft dysfunction is associated with a variety of fibrosing/sclerosing changes in the allograft. Fibrosis is multifactorial, a final pathway following varying types of injury. Using a range of diagnostic criteria, the pathologist can and should define specific lesions enabling identification of pathogenic processes affecting the allograft. Although some cases remain 'interstitial fibrosis and tubular atrophy, no specific cause', specific diagnoses can be made in most cases. Drug toxicity, bacterial or viral infection, hypertension, obstruction, recurrent or de novo renal diseases, and acute and chronic cell- and/or antibody-mediated rejection can be diagnosed in this setting. Of particular concern is a combination of persistent inflammation and fibrosis, which has repeatedly been shown to be correlated with poor graft outcomes. Identification of ongoing activity, and the stage of evolution of fibrosis/sclerosis provides important diagnostic and therapeutic information for patient management. Histological, immunohistological, ultrastructural, and molecular studies may be needed to adequately assess the kidney in the setting of chronic allograft dysfunction. Protocol biopsies may provide diagnostic insights in early stages of late graft deterioration, or even before evident dysfunction develops.
Collapse
|
|
34
|
Helanterä I, Egli A, Koskinen P, Lautenschlager I, Hirsch HH. Viral Impact on Long-term Kidney Graft Function. Infect Dis Clin North Am 2010; 24:339-71. [DOI: 10.1016/j.idc.2010.02.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
|
|
35
|
Miller DC, Qazi Y, Smogorzewski M, Azen CG, Shah T, Koss MN. Foxp3 staining in BK virus allograft nephropathy and comparison with acute cellular rejection. Transplant Proc 2010; 41:4188-92. [PMID: 20005366 DOI: 10.1016/j.transproceed.2009.09.062] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Accepted: 09/02/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND Foxp3(+)CD4(+)CD25(+) regulatory T cells are involved in maintaining immunologic self-tolerance. These cells have been investigated in acute cellular rejection (ACR) of renal allografts. In this retrospective pathological study, we evaluated Foxp3(+) immunostaining in BK virus nephropathy (BKVN). In some circumstances, BKVN may be difficult to distinguish histologically from ACR. METHODS Sequential sections were made of 30 allograft core biopsies and stained for hematorylin and eosin (H&E), C4d, cytomegalovirus (all negative), SV40, CD3, CD20, and Foxp3. Twelve biopsies were from diagnosed BKVN cases, 12 were from diagnosed ACR cases, and six showed neither BKVN nor ACR (controls). The 100x field of maximum cellular inflammation was located and marked on the H&E stain. The same area on the CD3, CD20, and Foxp3 slides was marked. Staining lymphocytes were counted under 400x magnification. Degree of BKVN was assessed according to the Drachenberg scale; degree of ACR was assessed by the Banff criteria. RESULTS The range of Foxp3(+) staining (cells/mm(2)) was much larger in BKVN (0-270) compared to ACR (0-35). The mean difference did not reach statistical significance owing to a large degree of overlap between the two groups. In BKVN, the Foxp3(+) infiltrate correlated with the degree of CD3(+) infiltrate (P = .012), and median Foxp3(+) infiltrate increased with Drachenberg grade of BKVN. CD3(+) cell levels were not significantly different in BKVN versus ACR. CONCLUSIONS BKVN cases with high levels of Foxp3(+) graft infiltrates may be manifesting an immune response different from that of ACR. Positive Foxp3 correlation with Drachenberg grade suggests a down-regulatory response.
Collapse
Affiliation(s)
- D C Miller
- University of Southern California Keck School of Medicine, LA County Hospital, Room 6610, 1200 N. State Street, Los Angeles, CA 90033, USA
| | | | | | | | | | | |
Collapse
|
|
36
|
Urinary proinflammatory cytokine response in renal transplant recipients with polyomavirus BK viruria. Transplantation 2010; 88:1109-16. [PMID: 19898207 DOI: 10.1097/tp.0b013e3181ba0e17] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Polyomavirus BK (BKV) has emerged as an important complication after kidney transplantation. BKV-associated nephropathy develops in approximately 5% to 8% of renal transplant recipients, and its prognosis is poor. The relationship between urine cytokines and BK viruria in kidney recipients has not been defined. PATIENTS AND METHODS We compared posttransplant urine cytokine levels of 65 renal transplant outpatients with (BK-positive) or without BK viruria (BK-negative, n=33), low- (n=16) or high-level (n=16) BK viral load (VL), and 24 healthy controls (HCs). Soluble interleukin-1 receptor antagonist (sIL-1RA), interleukin (IL)-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-10, IL-17, transforming growth factor-beta2, interferon-gamma, and tumor necrosis factor-alpha levels were determined using commercially available ELISA kits. RESULTS BK-positive patients showed higher urine IL-3 (P=0.006), sIL-6R (P=0.010), IL-6 (P=0.020), and sIL-1RA (P=0.050) than BK-negative patients. Compared with HCs, BK-negative patients had lower urine sIL-1RA (P=0.003), sIL-6R (P=0.001), and IL-17 (P<0.001), whereas BK-positive patients had higher urine IL-3 (P=0.004) and IL-6 (P=0.001) and lower IL-17 (P<0.001), suggesting cytokine suppression by immunosuppression and upregulation by BK-infection. Urine sIL-6R (P=0.003) and IL-6 (P=0.010) were higher in patients with high VL than in patients with low VL. Additionally, patients with high VL showed higher urine IL-6 (P=0.001), sIL-6R (P=0.001), sIL-1RA (P=0.016), and IL-3 (P=0.047) than BK-negative patients, and higher urine IL-6 (P<0.001) and lower IL-17 (P<0.001) than HCs. CONCLUSION BK-positive renal transplant recipients, especially those with high VL, showed strong inflammatory cytokine responses with increases of urine sIL-1RA, IL-3, IL-6, and sIL-6R. Our data suggest that monocyte- and Th-2-induced cytokines are involved in the pathogenesis of BKV-associated nephropathy.
Collapse
|
|
37
|
Tolkoff-Rubin NE, Rubin RH. Infection in solid organ transplantation. Infect Dis (Lond) 2010. [DOI: 10.1016/b978-0-323-04579-7.00075-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
|
|
38
|
Marcén R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs 2009; 69:2227-43. [PMID: 19852526 DOI: 10.2165/11319260-000000000-00000] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Renal transplant recipients have increased mortality rates when compared with the general population. The new immunosuppressive drugs have improved short-term patient survival up to 95% at 1-2 years, but these data have to be confirmed in long-term follow-up. Furthermore, no particular regimen has proved to be superior over others with regard to patient survival. Cardiovascular diseases are the most common cause of mortality in renal transplant recipients and while no immunosuppressive drug has been directly associated with cardiovascular events, immunosuppressive drugs have different impacts on traditional risk factors. Corticosteroids and ciclosporin are the agents with the most negative impact on weight gain, blood pressure and lipids. Tacrolimus increases the risk of new-onset diabetes mellitus. Sirolimus and everolimus have the most impact on risk factors for post-transplant hyperlipidaemia. Modifications in immunosuppression could improve the cardiovascular profile but there is little evidence regarding the beneficial effects of these changes on patient outcomes. Malignancies are also an increasing cause of mortality, overtaking cardiovascular disease in some series. Induction therapy, azathioprine and calcineurin inhibitors (CNIs) are probably the immunosuppressive agents most linked with post-transplant malignancies. Mycophenolate mofetil (MMF) has no negative impact on the incidence of malignancies. Target of rapamycin (mTOR) inhibitors have antioncogenic properties and they are associated with a lower incidence of malignancies. In addition, these agents have been recommended for use to decrease the dose or withdrawal of CNIs in patients with malignancies. Infections are still an important cause of morbidity and mortality in renal transplant recipients. Some immunosuppressive agents such as MMF increase the incidence of cytomegalovirus infection and the need for prophylactic measures in risk recipients. The use of potent immunosuppressive therapy has resulted in the appearance of BK virus nephropathy, which progresses to graft failure in a high percentage of patients. Although first associated with tacrolimus and MMF immunosuppression, recent data suggest that BK nephropathy appears with any kind of triple therapy. In conclusion, reducing risk factors for patient death should be a major target to improve outcomes after renal transplantation. Effort should be made to control cardiovascular diseases, malignancies and infections with improved use of immunosuppressive drugs. Preliminary results with belatacept suggest its safety and efficacy, and open new perspectives in the immunosuppression of de novo renal transplant recipients.
Collapse
Affiliation(s)
- Roberto Marcén
- Department of Nephrology, Ramón y Cajal Hospital, Alcalá de Henares University, Madrid, Spain.
| |
Collapse
|
|
39
|
Cimbaluk D, Pitelka L, Kluskens L, Gattuso P. Update on human polyomavirus BK nephropathy. Diagn Cytopathol 2009; 37:773-9. [PMID: 19626630 DOI: 10.1002/dc.21147] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Polyomavirus BK (BKV) has ebeen identified as the main cause of polyomavirus-associated nephropathy, a major cause of renal allograft failure. Although BKV-associated nephropathy develops in only 2% to 5% of renal transplant recipients, its prognosis when present is very poor, with irreversible graft failure developing in 45% of affected patients. While the use of urine cytology for the detection of decoy cells has been in use for decades, other diagnostic modalities to detect BKV have emerged, including tissue biopsy, polymerase chain reaction, viral culture, and serology. Currently, there is no consensus regarding the laboratory technique best suited for clinical monitoring. This review article will discuss essential and clinical features of polyomavirus, followed by a discussion pertaining to the various diagnostic modalities that contribute to detecting polyomavirus-associated nephropathy.
Collapse
Affiliation(s)
- David Cimbaluk
- Department of Pathology, Rush University Medical Center, Chicago, Illinois 60612, USA
| | | | | | | |
Collapse
|
|
40
|
O’Donnell PH, Swanson K, Josephson MA, Artz AS, Parsad SD, Ramaprasad C, Pursell K, Rich E, Stock W, van Besien K. BK virus infection is associated with hematuria and renal impairment in recipients of allogeneic hematopoetic stem cell transplants. Biol Blood Marrow Transplant 2009; 15:1038-1048.e1. [PMID: 19660716 PMCID: PMC2723723 DOI: 10.1016/j.bbmt.2009.04.016] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2009] [Accepted: 04/27/2009] [Indexed: 12/21/2022]
Abstract
BK virus (BKV) is an important pathogen and cause of nephropathy in renal transplant recipients, but its significance following hematopoetic stem cell transplantation (HSCT) is less well described. We measured blood and urine BKV in 124 allogeneic HSCT patients (67 had undergone prior HSCT [surveillance cohort]; 57 were monitored from transplant day 0 [prospective cohort]). BK viruria was manifest in 64.8% of the patients; 16.9% developed viremia. In the prospective cohort, the median time from transplantation to BK viremia development (128 days) was longer than for viruria (24 days; P < .0001). Among clinical factors (sex, disease, transplant type, alemtuzumab use, cytomegalovirus [CMV] viremia, graft-versus-host disease [GVHD], donor HLA C7 allele), only CMV viremia was more common in patients with BKV infection (P < or = .04). There was a direct relationship between blood and urine BKV levels and the occurrence, and degree, of hematuria (P < or = .03). Finally, BKV infection was analyzed along with other clinical factors in relation to the development of post-HSCT renal impairment. On multivariate analysis, only BK viremia (P=.000002) and alternative-donor transplantation (P=.002) were independent predictors of development of post-HSCT renal impairment, with BK viremia associated with a median 1.62mg/dL rise in creatinine from the pretransplant baseline. Among 8 patients in the surveillance cohort with BK viremia, 2 developed biopsy-proven BKV nephropathy requiring hemodialysis. Investigation of whether prophylaxis against, or treatment of, BKV in the post-HSCT setting mitigates the associated morbidities, especially kidney injury, warrants prospective evaluation.
Collapse
Affiliation(s)
- Peter H. O’Donnell
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Kate Swanson
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Michelle A. Josephson
- Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Andrew S. Artz
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Sandeep D. Parsad
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Charulata Ramaprasad
- Section of Infectious Diseases, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Kenneth Pursell
- Section of Infectious Diseases, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Elizabeth Rich
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Wendy Stock
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| | - Koen van Besien
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637, USA
| |
Collapse
|
|
41
|
Boudreault AA, Courtemanche C, Latulippe É, Côté I, Houde I, Deschênes L. Screening for polyomavirus associated nephropathy in renal transplantation with blood viral load measurement. J Clin Virol 2009; 45:318-21. [DOI: 10.1016/j.jcv.2009.05.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 04/01/2009] [Accepted: 05/19/2009] [Indexed: 10/20/2022]
|
|
42
|
Wiseman AC. Polyomavirus nephropathy: a current perspective and clinical considerations. Am J Kidney Dis 2009; 54:131-42. [PMID: 19394729 DOI: 10.1053/j.ajkd.2009.01.271] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2008] [Accepted: 01/30/2009] [Indexed: 12/16/2022]
Abstract
During the last decade, the human polyomaviruses (BK virus and, much less commonly, JC virus) have entered the realm of routine clinical decision making for providers caring for kidney transplant recipients. The emergence of polyomavirus-associated nephropathy (PVAN) as an important clinical entity coincided with the development and use of more potent immunosuppression agents, currently the only clear risk factor for reactivation of the virus. Ongoing efforts to define the pathogenesis, clinical presentation, and appropriate management of PVAN have led to a greater ability to prevent and control viral-induced interstitial nephritis despite continued deficiencies in our understanding of risk factors for disease and lack of published prospective polyomavirus-specific antiviral trials. The purpose of this review is to summarize advances made during the last decade and highlight emerging data that address common clinical considerations the clinician currently faces in the understanding and management of PVAN.
Collapse
Affiliation(s)
- Alexander C Wiseman
- Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Aurora, CO 80045, USA.
| |
Collapse
|
|
43
|
BK Virus Nephropathy in Kidney Transplant – an Overview. APOLLO MEDICINE 2008. [DOI: 10.1016/s0976-0016(11)60158-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
|
|
44
|
|
|
45
|
Mischitelli M, Bellizzi A, Anzivino E, Fioriti D, Boldorini R, Miglio U, Chiarini F, Di Monaco F, Pietropaolo V. Complications post renal transplantation: literature focus on BK virus nephropathy and diagnostic tools actually available. Virol J 2008; 5:38. [PMID: 18315864 PMCID: PMC2268664 DOI: 10.1186/1743-422x-5-38] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2008] [Accepted: 03/03/2008] [Indexed: 12/11/2022] Open
Abstract
Clinical diagnosis of kidney transplants related illnesses is not a simple task. Several studies were conducted to define diseases and complications after renal transplantation, but there are no comprehensive guidelines about diagnostic tools for their prevention and detection. The Authors of this review looked for the medical literature and pertinent publications in particular to understand the role of Human Polyomavirus BK (BKV) in renal failure and to recognize analytical techniques for BK virus associated nephropathy (BKVAN) detection.
Collapse
Affiliation(s)
- Monica Mischitelli
- Department of Public Health Sciences, La Sapienza University, Rome, Italy.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
|
|
47
|
Polyoma virus nephropathy with simian virus 40 antigen–containing tubular basement membrane immune complex deposition. Hum Pathol 2008; 39:73-9. [DOI: 10.1016/j.humpath.2007.05.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2007] [Revised: 05/08/2007] [Accepted: 05/09/2007] [Indexed: 11/22/2022]
|
|
48
|
Faulhaber JR, Nelson PJ. Virus-induced cellular immune mechanisms of injury to the kidney. Clin J Am Soc Nephrol 2007; 2 Suppl 1:S2-5. [PMID: 17699506 DOI: 10.2215/cjn.00020107] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Cellular immune systems play an important role in determining renal outcomes in virus-induced kidney diseases. Highlighted briefly are five different locations along the development of adaptive immune responses to viral infection that may promote injury to the renal parenchyma and the loss of renal function. This may occur because adaptive immune cells directly target infected renal parenchymal cells or because the kidney becomes a bystander organ of adaptive immune cell-mediated injury. Examples from recent studies are provided to illustrate how this may lead to clinically relevant renal disease.
Collapse
Affiliation(s)
- Jason R Faulhaber
- Division of Infectious Diseases, New York University School of Medicine, New York, New York 10016, USA
| | | |
Collapse
|
|
49
|
Abstract
Nephropathy from BK virus (BKV) infection is an evolving challenge in kidney transplant recipients. It is the consequence of modern potent immunosuppression aimed at reducing acute rejection and improving allograft survival. Untreated BKV infections lead to kidney allograft dysfunction or loss. Decreased immunosuppression is the principle treatment but predisposes to acute and chronic rejection. Screening protocols for early detection and prevention of symptomatic BKV nephropathy have improved outcomes. Although no approved antiviral drug is available, leflunomide, cidofovir, quinolones, and intravenous Ig have been used. Retransplantation after BKV nephropathy has been successful.
Collapse
Affiliation(s)
- Daniel L Bohl
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | | |
Collapse
|
|
50
|
|