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MAJOR ARTICLE
Background. The purpose of this study was to investigate the effect of BK polyomavirus (BKPyV infection of glomerular parietal
epithelial cells (GPECs) on graft outcome in kidney transplant recipients with BKPyV-associated nephropathy (BKPyVAN).
Methods. A total of 152 kidney transplant recipients with BKPyVAN were divided into 31 with (GPEC-positive group) and 121
without (GPEC-negative group) BKPyV-infected GPECs. Clinicopathological characteristics and allograft survival were compared
between the groups.
Results. The GPEC-positive group had more patients with advanced-stage BKPyVAN than the GPEC-negative group (P < .001).
At the last follow-up, the GPEC-positive group had a significantly higher serum creatinine level than the GPEC-negative group. The
graft loss rate in the GPEC-positive group was higher than that in the GPEC-negative group (32.3% vs 12.4%; P = .008). Kaplan-
Meier analysis showed that the graft survival rate in the GPEC-positive group was lower than that in the GPEC-negative group (log-
rank test, P = .004). Multivariate Cox regression analysis demonstrated that BKPyV infection of GPECs was an independent risk
factor for graft survival (hazard ratio, 3.54; 95% confidence interval, 1.43–8.76; P = .006).
Conclusions. GPEC infection in patients with BKPyVAN indicates more-severe pathological damage and a rapid decline in
renal function. BKPyV infection of GPECs is an independent risk factor for allograft loss.
Keywords. BK polyomavirus; renal transplantation; glomerular infection; pathology; graft survival.
BK polyomavirus (BKPyV)–associated nephropathy tubular involvement, we have noticed that BKPyV infection
(BKPyVAN) is a severe complication of renal transplantation, can be occasionally observed in the Bowman space in renal bi-
affecting 1%–10% of kidney transplant recipients in the first opsy specimens from patients with BKPyVAN. Nevertheless,
2 years after transplantation [1]. Immunosuppression following glomerular BKPyV infection received minimal attention, and
kidney transplantation has been shown to increase the risk of scant literature has described this phenomenon [9–11]. Celik
BKPyV reactivation in recipients [2–4]. At present, there is no et al reviewed 124 biopsy specimens from 83 kidney transplant
effective antiviral treatment for BKPyV infection, and recipients recipients and identified 36 specimens with BKPyV infection
with BKPyVAN have an elevated risk of graft loss [1]. It has of the Bowman space [11]. However, the effect of glomerular
been reported that renal graft failure occurs in 10%–80% of BKPyV infection on graft outcome is unknown.
recipients within 2–3 years after diagnosis of BKPyVAN [1, 5]. There are 3 histological classifications of BKPyVAN, in-
The typical pathological features of BKPyVAN include cluding the original schema reported by the University of
tubulointerstitial lesions, viral cytopathic damage to tubular epi- Maryland [12] and subsequently modified by American
thelial cells, and positive results of immunohistochemical (IHC) Society of Transplantation (AST) [8], as well as another system
nuclear staining for SV40 large T antigen [6–8]. In addition to proposed by the Banff Working Group [7]. These classifications
focus on several pathological features of BKPyVAN, such as
cytopathic effects, tubulitis, interstitial inflammation, intersti-
Received 25 November 2018; editorial decision 4 January 2019; accepted 9 January 2019; tial fibrosis, and tubular atrophy, which have been shown to
published online January 12, 2019.
a
X.-T. C. and S.-C. Y. contributed equally to this work. be associated with graft loss [6, 7, 13]. However, none of these
b
G. H. and C.-X. W. contributed equally to this work. histological classifications suggests a clinical significance of glo-
Correspondence: G. Huang, MD, PhD, #58 Zhongshan Rd 2, Guangzhou, Guangdong Province,
China, 510080 (huanggang_791021@163.com). merular infection in patients with BKPyVAN. Thus, the pur-
The Journal of Infectious Diseases® 2019;219:1879–86 pose of this study was to examine the effect of BKPyV infection
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
of glomerular parietal epithelial cells (GPECs) on graft outcome
DOI: 10.1093/infdis/jiz022 in kidney transplant recipients with BKPyVAN.
Inclusion criteria
• Positive SV40 large T antigen
PyVANa n = 159
Exclusion criteria
• Concurrent myeloma
nephropathy n = 1
• JC polyomavirus
infection n = 3
GPEC positive n = 31 GPEC negative n = 121 • Glomeruli <7 n = 3
Figure 1. Flow of patients through the study. GPEC, glomerular parietal epithelial cell; PyVAN, polyomavirus-associated nephropathy. aBetween 2007 and 2016.
Patient Characteristics
Electron Microscopy
Patient characteristics are summarized in Table 1. The base-
A Philips CM10 electron microscope (Philips, Eindhoven, the
line serum creatinine level in the GPEC-negative group
Netherlands) was used to observe viral particles, especially in
was significantly higher than in the GPEC-positive group
tubular epithelial cells and the Bowman space [16]. Cells with
Sex .568
Male 77 (63.64) 18 (58.06) 95 (62.50)
Female 44 (36.36) 13 (41.94) 57 (37.50)
Age at transplantation, y 38.78 ± 8.88 41.15 ± 9.71 39.27 ± 9.08 .195
More patients developed a sustained increase in serum stage BKPyVAN than the GPEC-negative group (P < .001;
creatinine level (>30% greater than that at diagnosis) in the Supplementary Table 3). The incidence of periglomerular fi-
GPEC-positive group than in the GPEC-negative group brosis in the GPEC-positive group was higher than that in
(41.9% vs 18.2%; P = .005; Supplementary Table 2). The abso- the GPEC-negative group (P = .045; Supplementary Table 3).
lute value of the increase in serum creatinine level (calculated Positive anti-SV40 large T antigen staining in tubular epithelial
as the level at the last follow-up visit minus the level first re- cells was observed in all biopsy specimens from both groups.
corded) was significantly higher in the GEPC-positive group Notably, the mean Banff scores for the extent of SV40 large
than that in the GEPC-negative group (304.71 ± 329.89 vs T antigen staining, tubulitis, interstitial inflammation, tubular
115.74 ± 217.63 μmol/L; P < .001). These results suggest that the atrophy, and interstitial fibrosis were all significantly higher in
GPEC-positive group had worse graft function than the GPEC- the GPEC-positive group, compared with the GPEC-negative
negative group. group (P < .05 for all comparisons; Supplementary Table 3).
Correlation analysis revealed that positivity in GPECs was sig-
Pathological Findings at Initial Diagnosis of BKPyVAN nificantly positively correlated with the extent of SV40 large T
Representative images of GPEC-positive biopsy specimens antigen staining (r = 0.52), tubulitis (r = 0.17), interstitial in-
under light microscopy and electron microscopy are shown in flammation (r = 0.30), tubular atrophy (r = 0.21), and interstitial
Figure 2. Based on AST criteria, in the GPEC-positive group fibrosis (r = 0.28; P < .05 for all comparisons).
there were no patients with stage A disease, 26 (83.9%) with
stage B disease, and 5 (16.1%) with stage C disease. In the Pathological Findings During Follow-up
GPEC-negative group, there were 11 patients (9.1%) with stage During follow-up, 12 of 31 patients in the GPEC-positive
A disease, 96 (79.3%) with stage B disease, and 14 (11.6%) with group and 61 of 121 patients in the GPEC-negative group un-
stage C disease (Supplementary Table 3). The GPEC-positive derwent repeat biopsies (Supplementary Table 3). The median
group had a higher proportion of patients with advanced time between the initial biopsy and last follow-up biopsy was
C D DISCUSSION
and interstitial fibrosis were increased on the last biopsy spec- GPEC negative censored
GPEC positive censored
0.8
imen (Supplementary Table 3). During follow-up, the degrees of
Cumulative survival (proportion)
Univariate Multivariate
Abbreviations: BKPyV, BK polyomavirus; BKPyVAN, BK polyomavirus–associated nephropathy; CI, confidence interval; GPEC, glomerular parietal epithelial cell; HR, hazard ratio.
that glomerular BKPyV infection is associated with worse graft demonstrating the effectiveness of these treatment regimens. In
function, more-advanced BKPyVAN stage, and a higher rate of the GPEC-positive group, BKPyV replication also presented a
graft loss in kidney transplant recipients with BKPyVAN. To declining trend. In addition, clearance of BK viremia and BK
the best of our knowledge, this is the first study reporting the viruria occurred in 83.9% and 19.4% of patients, respectively.
prognostic value of GPEC infection on graft outcome in kidney These results suggest that, although GPEC positivity represents
transplant recipients with BKPyVAN. a more severe BKPyV infection, patients with BKPyV-infected
Nankivell et al reported that a high level of viremia was asso- GPECs still respond well to treatment.
ciated with a heavy tissue viral load [19]. Thus, we had assumed Celik et al reported that BKPyV infection in the glomerular
that the GPEC-positive group, probably having a heavier tissue epithelium was usually found in biopsy specimens with a high
viral load, might display a higher plasma BKPyV load than that viral load in the tubular epithelium [11]. In line with this obser-
in the GPEC-negative group, but this turned out to be irrelevant. vation, our pathological findings showed that BKPyV infection
On the other hand, hepatitis B virus (HBV) gene mutations were of GPECs was accompanied by more-severe tubulointerstitial
reported to cause glomerular involvement and HBV-associated inflammation, tubular atrophy, interstitial fibrosis, and a greater
glomerulonephritis [20]. Therefore, we thought it plausible that extent of SV40 large T antigen staining in the tubular epithe-
specific variant strains of BKPyV might have greater pathogenic lium, indicating that BKPyV-infected GPECs are associated
potential and viral invasiveness, resulting in GPEC infection, with more-severe pathological damage. Multivariate Cox re-
which might need further investigation. gression analysis showed that tubular atrophy score was an in-
Reducing the immunosuppression intensity is the primary dependent risk factor for graft loss. Study has shown that, in
treatment for BKPyVAN [5]. In this study, changes in the im- severely BKPyV-infected tubules, necrosis of tubular cells and
munosuppressive regimen, including reducing the dosage or tubular basement membrane denudation can be observed [13,
changing the immunosuppressant, were used in the treatment 21]. Assessment of follow-up biopsy specimens in this study
of BKPyVAN. Clearance of BKPyV DNA in the blood was showed that the degree of SV40 large T antigen staining and
observed in 92.6% of patients in the GPEC-negative group, tubulitis in the GPEC-positive group was reduced as compared
pathological damage. In addition, the increasing rate of in- 1. Sawinski D, Goral S. BK virus infection: an update on di-
crease in the serum creatinine level was higher in the GPEC- agnosis and treatment. Nephrol Dial Transplant 2015;
positive group, compared with that in the GPEC-negative 30:209–17.
group, during follow-up, indicating more-severe BKPyV 2. Schachtner T, Babel N, Reinke P. Different risk factor
infection and pathological damage in the GPEC-positive profiles distinguish early-onset from late-onset BKV-
group. Multivariate Cox regression analysis confirmed that replication. Transpl Int 2015; 28:1081–91.
the serum creatinine level at diagnosis was an independent 3. Borni-Duval C, Caillard S, Olagne J, et al. Risk factors for BK
risk factor for graft loss. In this study, the 5-year cumula- virus infection in the era of therapeutic drug monitoring.
tive allograft survival rate was 66.7% in the GPEC-positive Transplantation 2013; 95:1498–505.
group and 100% in the GPEC-negative group. The 2-year al- 4. Belliere J, Kamar N, Mengelle C, et al. Pilot conversion
lograft failure rate for all patients was 30.0%, which was the trial from mycophenolic acid to everolimus in ABO-
same as that reported by the Banff Working Group [7] but incompatible kidney-transplant recipients with BK viruria
higher than that (15.4%) reported by Drachenberg et al [13]. and/or viremia. Transpl Int 2016; 29:315–22.
The GPEC-positive group had a significantly lower death- 5. Barth H, Solis M, Lepiller Q, et al. 45 years after the dis-
censored graft survival rate, and BKPyV infection of GPECs covery of human polyomaviruses BK and JC: time to speed
was identified as a risk factor for graft loss. These results up the understanding of associated diseases and treatment
strongly suggest that GPEC infection by BKPyV predicts approaches. Crit Rev Microbiol 2017; 43:178–95.
worse graft outcome. 6. Masutani K, Shapiro R, Basu A, Tan H, Wijkstrom M,
There are some limitations of this study. This was a retrospec- Randhawa P. The Banff 2009 working proposal for
tive study, and complete pathological data during follow-up polyomavirus nephropathy: a critical evaluation of its utility
were not available for all patients. as a determinant of clinical outcome. Am J Transplant 2012;
In summary, this study found that the presence of BKPyV- 12:907–18.
infected GPECs in renal biopsy specimens from kidney 7. Nickeleit V, Singh HK, Randhawa P, et al.; Banff Working
transplant recipients with BKPyVAN indicates more-severe Group on Polyomavirus Nephropathy. The Banff
pathological damage and is associated with a rapid decline in Working Group classification of definitive polyomavirus
renal function. Furthermore, GPEC infection is an independent nephropathy: morphologic definitions and clinical
risk factor for graft loss. correlations. J Am Soc Nephrol 2018; 29:680–93.
8. Hirsch HH, Randhawa P; AST Infectious Diseases
Supplementary Data Community of Practice. BK polyomavirus in solid
Supplementary materials are available at The Journal of Infectious organ transplantation. Am J Transplant 2013; 13 Suppl
Diseases online. Consisting of data provided by the authors 4:179–88.
to benefit the reader, the posted materials are not copyedited 9. Meehan SM, Kraus MD, Kadambi PV, Chang A. Nephron
and are the sole responsibility of the authors, so questions or segment localization of polyoma virus large T antigen in
comments should be addressed to the corresponding author. renal allografts. Hum Pathol 2006; 37:1400–6.