Observational Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Feb 6, 2019; 7(3): 270-290
Published online Feb 6, 2019. doi: 10.12998/wjcc.v7.i3.270
Incidence, risk factors, and outcome of BK polyomavirus infection after kidney transplantation
Evaldo Favi, Carmelo Puliatti, Rajesh Sivaprakasam, Mariano Ferraresso, Federico Ambrogi, Serena Delbue, Federico Gervasi, Ilaria Salzillo, Nicholas Raison, Roberto Cacciola
Evaldo Favi, Mariano Ferraresso, Ilaria Salzillo, Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
Carmelo Puliatti, Rajesh Sivaprakasam, Roberto Cacciola, Renal Transplantation, Barts Health NHS Trust, Royal London Hospital, London E1 1BB, United Kingdom
Mariano Ferraresso, Federico Ambrogi, Federico Gervasi, Department of Clinical Sciences and Community Health, University of Milan, Milan 20122, Italy
Serena Delbue, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan 20100, Italy
Nicholas Raison, MRC Centre for Transplantation, King’s College London, London WC2R 2LS, United Kingdom
Author contributions: Favi E, data collection, data analysis, data interpretation, drafting the article, critical revision, and final approval; Puliatti C, conception of the study, design of the study, critical revision, and final approval; Sivaprakasam R, design of the study, data collection, data interpretation, critical revision, and final approval; Ferraresso M, data interpretation, critical revision, and final approval; Ambrogi F, data analysis, data interpretation, drafting the article, critical revision, and final approval; Delbue S, data interpretation, critical revision, and final approval; Gervasi F, data analysis, data interpretation, drafting the article, and final approval; Salzillo I, data collection, editing the article, and final approval; Nicholas Raison, drafting the article, language revision, critical revision, and final approval; Cacciola R, conception of the study, design of the study, data collection, critical revision, and final approval.
Institutional review board statement: This study was discussed in a regular Research Meeting at The Royal London Hospital and the consensus was that ethical approval was not required because of the observational nature and non-interventional study design.
Informed consent statement: Patients were all consented at the time of activation on the national transplant waiting list. They were aware that their anonymized data including viral status as well as other biomedical parameters would have been used for research purpose.
Conflict-of-interest statement: The authors do not have any conflicting interests.
Data sharing statement: Dataset available from the corresponding author at evaldofavi@gmail.com. Informed consent for data sharing outside formal research projects was not obtained but data are anonymized and there is no risk of patient details identification.
STROBE statement: The authors have read the STROBE Statement–checklist of items, and the manuscript was prepared and revised according to the STROBE Statement–checklist of items.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Evaldo Favi, MD, PhD, Senior Lecturer, Surgeon, Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Francesco Sforza n. 28, Milan 20122, Italy. evaldofavi@gmail.com
Telephone: +39-2-55035603 Fax: +39-2-55035630
Received: October 31, 2018
Peer-review started: October 31, 2018
First decision: November 27, 2018
Revised: December 8, 2018
Accepted: December 12, 2018
Article in press: December 12, 2018
Published online: February 6, 2019
Processing time: 92 Days and 11.6 Hours
ARTICLE HIGHLIGHTS
Research background

Polyomavirus-associated nephropathy (PVAN) is recognized as a leading cause of kidney allograft loss. Current antiviral therapies offer limited results. Clinical guideline suggests periodic screening for BK-virus replication in blood and recommends prompt reduction of the net state of immunosuppression in case of viremia. However, long-term outcome of kidney transplant recipients with BK-virus infection remains sub-optimal.

Research motivation

The development of new and more powerful immunosuppressive agents has led to a significant reduction of acute rejection rates after kidney transplantation. As a consequence, we have observed an impressive improvement in short- and mid-term graft survival rates but long-term results have only marginally improved. BK-virus is one of the most common opportunistic infection in renal transplant recipients and has been demonstrated to have a deleterious impact on allograft function and survival. Management of BK-virus infection has significantly changed and encouraging results have been obtained. Nevertheless, long-term data are scarce and previously published reports may not reflect current clinical practice. Therefore, we performed an observational study to investigate incidence, risk factors, and long-term outcome of BK-virus infection in a cohort of kidney transplant recipients managed according to an aggressive screening and diagnostic protocol for PVAN. Effectiveness of a treatment strategy based on a step by step reduction of the net state of immunosuppression was also evaluated.

Research objectives

The aim of the present study was to evaluate incidence, risk factors, and outcome of BK-virus infection after kidney transplantation.

Research methods

This single-centre observational study with a median follow up of 5 years was conducted in a National Health Service hospital in UK and comprises 629 consecutive adult patients who underwent kidney transplantation between 2007 and 2013. Data were prospectively recorded and annually reviewed until 2016. Recipients were periodically screened for BK-virus by plasma quantitative polymerized chain reaction. Patients with BK plasma viral load ≥ 1000 copies/mL were diagnosed BK-viremia and underwent histological assessment to rule out nephropathy. In case of BK-viremia, immunosuppression was minimized according to a prespecified protocol. The following outcomes were evaluated: patient survival, overall graft survival, graft failure considering death as a competing risk, 30-d-event-censored graft failure, response to treatment, rejection, renal function, urologic complications, opportunistic infections, new-onset diabetes after transplantation, and malignancies. We used a multivariable model to analyse risk factors for BK-viremia and nephropathy.

Research results

BK-viremia and PVAN were detected in 9.5% and 6.5% of the study population, rspectively. Patients with initial plasma viral load ≥ 10000 copies/mL were more likely to experience sustained viremia (95% vs 25%, P < 0.00001), nephropathy (92.5% vs 15%, P < 0.00001), and polyomavirus-related graft loss (27.5% vs. 0%, P = 0.0108) than recipients with low initial plasma viral load. Recipients with viremia showed higher 5-year crude cumulative (22.5% vs 12.2%, P = 0.0270) and 30-d-event-censored (22.5% vs 7.1%, P = 0.001) incidences of graft failure than control. In the viremic group we also observed higher proportions of recipients with 5-year estimated glomerular filtration rate < 30 mL/min than the group without viremia: 45% vs 27% (P = 0.0064). Response to treatment was complete in 55%, partial in 26.7%, and absent in 18.3% patients. The PVAN group showed higher 5-year crude cumulative and 30-d-event-censored incidences of graft failure than control: 29.1% vs 12.1% (P = 0.008) and 29.1% vs 7.2% (P < 0.001), respectively. Afro-Caribbean ethnicity, panel-reactive antibody > 50%, human leukocyte antigen mismatching > 4, and rejection were independent risk factors for BK-virus viremia whereas cytomegalovirus prophylaxis was protective.

Research conclusions

As recommended by most recent international clinical guideline, our study supports systematic screening, early histological evaluation, and prompt reduction of the net state of immunosuppression for the prevention of PVAN and BK-related graft failure after kidney transplantation. Nevertheless, we also demonstrated the limitations of current treatment strategies and the need for more specific antiviral therapies. In particular, we showed that both BK-viremia and nephropathy negatively affect long-term graft function and survival. We confirmed that an initial plasma viral load ≥ 10000 copies/mL is the strongest determinant of sustained viral replication, PVAN, and graft loss. We identified a PRA test > 50% and Afro-Caribbean ethnicity as independent predictors of BK-virus infection. Our data also suggest a protective effect of cytomegalovirus prophylaxis on BK-virus replication.

Research perspectives

Our study represents one of the largest observational study on BK-virus infection in kidney transplant recipients. We managed to confirm our preliminary hypothesis and demonstrated that despite aggressive screening and treatment strategies, long-term outcome for patients with BK-virus infection remain consistently inferior than control. We identified new risk factors for BK-viremia but larger populations are needed to further investigate risk factors for PVAN. In order to improve results, future research should be focusing on alternative prognostic markers, non-invasive diagnostic tests, and novel antiviral therapies. Properly designed multi-centre prospective randomized clinical trials are warranted.