BK virus antibody titers and intensity of infections after renal transplantation

https://doi.org/10.1016/j.jcv.2008.06.009Get rights and content

Abstract

Background

The mean urine BK viral load in kidney transplant recipients increases with the intensity of infection as the infection progresses from transient viruria to sustained viremia.

Objectives

This study investigated whether the intensity of infection is associated with the humoral immune response.

Study design

We measured BKV-specific IgG antibody titers in stored samples obtained serially over a 1-year period from 70 kidney transplant recipients with BKV infection and 17 control recipients without active BKV infection.

Results

The mean pre-transplant BKV antibody level was lower in recipients who developed viremia than the mean level in those who never developed viremia (p = 0.004). Mean antibody titers in recipients who never showed evidence of active BKV infection rose slightly after transplant despite immunosuppression. The magnitude of the rise in the mean antibody titers in recipients who developed active BKV infection correlated with the intensity of infection (p < 0.001).

Conclusions

The mean antibody level increased in accordance with the intensity of the infection post-transplant. Pre-transplant seropositivity did not protect against sustained viremia and the antibody response was not associated with clearance of the virus.

Introduction

BK virus (BKV), a human polyomavirus, causes nephropathy (BKN) and allograft loss in renal transplant recipients. Although it was discovered in 1971,1 understanding of the humoral immune response to BKV is limited.

By age 10, 90% of children have antibodies to BKV.2, 3 After primary infection, BKV remains latent in the uroepithelium, but can reactivate after transplant and cause allograft dysfunction.4

The significance of the donor or the recipient BKV antibody serostatus is unclear. In pediatric kidney transplant recipients, a negative recipient serostatus was a risk factor for BK viruria5, and nephropathy.6 This is less clear in adults.7, 8, 9 In 1984, Gardner10 reported that the antibody titer was initially low, rose greater than 100-fold, and persisted in 6 kidney transplant recipients in whom BK virus was isolated by urine culture, suggesting that the antibody was non-neutralizing. In 2005, Hariharan11 showed that BKV-specific IgG, but not IgM, levels increased in 6 recipients with BKN after reduction in immunosuppression and clearance of viremia. They did not investigate titers from those without active BK infection or those without nephropathy.

We showed that the mean urine BK viral load in 70 kidney transplant recipients increases as the infection progresses from no infection, to transient viruria, sustained viruria, transient viremia, and finally sustained viremia.12 To investigate whether the intensity of infection is associated with the humoral immune response, we evaluated BKV-specific IgG levels, pre-transplant and serially post-transplant in renal transplant recipients with and without BKV infections (controls). Serial plasma samples had been tested by quantitative PCR for BK virus DNA, allowing us to compare the anti-BKV-antibody level with the BKV-viral load and correlate it with the overall severity of infection.

Section snippets

Subjects and samples

Two hundred renal transplant recipients were enrolled in a trial in which urine and blood samples were obtained weekly for 16 weeks and at months 5, 6, 9, and 12 after transplantation.12 Samples were analyzed by real-time PCR for BKV DNA. Urine, plasma, and whole blood samples and extracted DNA from the samples were stored at −70 °C. Recipients were defined as having active BKV infection if any specimen were positive for BKV by PCR. Clinical characteristics and outcomes, BKV DNA levels, and

Subjects and samples

The demographic characteristics were similar among those without evidence of active BKV infection post-transplant and those with any of the four intensities of BKV infection post-transplant (Table 1).

BKV-specific antibody responses by type of BKV infection

Pre-transplant, the mean antibody titers were lower in those who subsequently developed viremia compared to those who developed viruria without ever developing viremia (DI: 3.36 ± 1.70 vs. 4.64 ± 1.57, p = 0.004). Post-transplant, the mean BK antibody titers increased throughout the first post-transplant

Discussion

The present study is the most extensive comparison to date of serial BKV-specific antibody measurements in renal transplant recipients. A strong point of the study is the comparison of the changes in antibody titers with serial quantitative measurements of BKV DNA in urine and plasma from the same patients. A clear finding is that the BKV antibody response correlated with the intensity of infection as assessed by urine viral load. BKV antibody titers reached higher levels at 1 year after

Conflict of interest

  • 1.

    D.L. Bohl, G.A. Storch, C. Ryschkewitsch, M. Gaudreault-Keener, and E.O. Major have no conflicts of interest.

  • 2.

    D.C. Brennan grant support—Astellas, Novartis, Pfizer, Wyeth, and Genzyme. D.C. Brennan is a consultant for Pfizer, Wyeth, and Genzyme and an honorarium recipient from Genzyme.

Acknowledgments

This work was supported in part by NIH 1 K24-02886 (D.C.B.) and NKF 22 3062 38053 (D.L.B.). D.L.B. is a recipient of the 2004 Amgen Renal Fellowship Award.

References (22)

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  • Cited by (91)

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      The adaptive humoral response might play a role in controlling or limiting BKV reactivation given that seronegative recipients experience an increased risk for viremia and BKV-associated nephropathy,15,16 with the highest risk in donor-positive and recipient-negative pairs.15,17-20 Additionally, patients who develop viremia have lower pretransplantation antibody titers against BKV,21 and higher BKV antibody titers are correlated with lower plasma viral loads and shorter times until resolution of the infection.22 Although these studies underscore the importance of anti-BKV antibodies, most patients with BKV-associated nephropathy are seropositive before transplantation23,24 and develop active infection despite the development of high anti-BKV antibody titers.21

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      Additionally, there was a significant correlation between maximum decoy cell count and decoy-cell-free survival (correlation coefficient [r] = -0.7331, P < .0001) in this study group. Some previous studies reported the association between pretransplant BKV serostatus and the incidence of BKV infection [3,18,20,34–36]. KT from seropositive donors has been identified as a risk factor for developing BKV infection.

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