Histologic versus Molecular Diagnosis of BK Polyomavirus–Associated Nephropathy

Drachenberg, Cinthia B.; Papadimitriou, John C.; Ramos, Emilio

doi:10.2215/cjn.02021205

Cited by 61 publications

(61 citation statements)

References 38 publications

(96 reference statements)

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“…Moreover, LT is conveniently detectable in the nuclei of renal tubular epithelial cells with activated BKV replication and precedes the late gene expression of agnoprotein or the capsid protein VP1 (24,34,44,45). In fact, positive immunohistochemistry detecting intranuclear LT has been established as the standard confirmatory assay for the diagnosis of PVAN in renal allograft biopsies (5,18,28,37,40). The lower-antibody response despite its relative abundance suggests differences in immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

et al. 2009

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BK virus (BKV)-specific immunity is critical for polyomavirus-associated nephropathy, but antibody responses are incompletely defined. We compared the hemagglutination inhibition assay (HIA) with immunoglobulin G enzyme immunoassays (EIA) to BKV proteins expressed in baculovirus-infected insect cells. N-terminal, internal, and C-terminal domains of the BKV large T antigen (BKLT) were fused to glutathione S-transferase (GST), yielding GST-BKLTD1, GST-BKLTD2, and GST-BKLTD3, respectively. The BKV capsid VP1 was expressed as a GST fusion (BKVP1) or as a native VP1 assembled into viruslike particles (BKVLP). We tested 422 sera from 28 healthy donors (HD), 99 dialysis patients (DP; median age, 15 years; range, 3 to 32 years), and 46 age-matched kidney transplant patients (KTP; median age, 15 years; range, 2 to 33 years). In HD, HIA and BKVLP EIA both yielded a 91.7% seroreactivity, whereas all other EIA responses were lower (BKVP1, 83.3%; BKLTD1, 25%; BKLTD2, 29%; BKLTD3, 40%). HIA titers significantly correlated with EIA levels for BKVLP, BKVP1, and BKLTD1 but not for BKLTD2 or BKLTD3, which were barely above the cutoff. In DP, the seroreactivities of HIA, BKVLP, and BKLTD1 were lower than that in HD (63.6%, 86.9%, and 10.1%, respectively) and they had lower titers (P < 0.001). In KTP, seropositivities for BKVLP, BKVP1, and BKLTD1 were 78%, 50%, and 17%, respectively, but anti-BKVLP levels increased significantly in KTP with viruria and viremia, whereas anti-BKLTD1 levels increased after clearing sustained BKV viremia. In conclusion, anti-BKVLP is equivalent to HIA in HD but is more sensitive to determine the BKV serostatus in DP and KTP. In KTP, anti-BKVLP responds to recent BKV viruria and viremia, whereas anti-BKLTD1 may indicate emerging BKV-specific immune control.Polyomaviruses (PyV) have been identified in many vertebrates; the main species found in humans are BK virus (BKV) and JC virus (C. Büchen-Osmond, Polyomaviridae, International Committee on Taxonomy of Viruses Database [www .ncbi.nlm.nih.gov/ICTVdb/]). PyV are small nonenveloped double-stranded DNA viruses with icosahedral particles of ϳ42 nm in diameter and are resistant to environmental inactivation (8, 31, 32; www.ncbi.nlm.nih.gov/ICTVdb/). The genome organization of the 5.1-kb circular genome is largely conserved and encodes six major proteins (20, 31, 32). The nuclear large tumor (LT) antigen and cytoplasmic small T antigen are expressed early in the viral life cycle, followed by the late cytoplasmic agnoprotein and the capsid proteins VP1, VP2, and VP3, which are transported into the nucleus for virion assembly (31,32,44). LT is a multifunctional regulatory protein with distinct domains (45,49). PyV capsids are formed by the assembly of 72 VP1 pentamers into a Tϭ7d icosahedral lattice associating with VP2 and VP3 and the circular viral genome (11,35,39).Seroprevalence data indicate that 50 to 90% of the general population has been exposed to BKV and JC virus (25,33,47).Both viruses persist in the renourinary tract as the principal site of latenc...

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Section: Discussionmentioning

confidence: 99%

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

et al. 2009

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“…There are other limitations of this study. First, given the evolution of BKVAN screening and histologic classification over time, not every patient had quantitative PCR monitoring, biopsy scoring, or prior screening for BKVAN; thus, these characteristics were not included in this analysis despite their proven value (8,9,19). We attempted to account for these deficiencies by examining BKVAN outcomes segregated into separate eras and found that there was no difference in outcomes between eras on univariate or multivariate analysis.…”

Section: Discussionmentioning

confidence: 99%

“…Although the biopsy findings at diagnosis are proposed to be a predictive tool for assessing prognosis (18,19), quantitative assessments of viral load at diagnosis have generally not been predictive of outcomes. To date, there has not been an assessment of clinical risk factors for disease progression or a comparison of immunosuppression withdrawal strategies.…”

mentioning

confidence: 99%

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Weiss¹,

Gralla²,

Chan³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Results: Of 910 kidney transplants, 35 (3.8%) cases of BKVAN were diagnosed at a median of 15 months after transplant (range, 5.5 to 90 months after transplant), 16 (46%) of which progressed to graft failure at a median of 11 months (range, 2 to 36 months) after diagnosis. Depleting antibody induction was a significant risk factor for graft loss on univariate analysis, whereas early drug withdrawal (<1 mo following diagnosis) protected against graft loss. On multivariate analysis, these findings were independent predictors of graft outcomes. Additionally, when patients were comanaged by referring nephrologists and the transplant center before the diagnosis of BKVAN, the risk of graft loss was 11-fold higher (P ‫؍‬ 0.03) than if patients were managed solely by the transplant center.Conclusions: Increased awareness and early diagnosis of BKVAN, with aggressive tapering of immunosuppression once established, is critical to preserve kidney graft function. Early drug withdrawal to low-dose two-drug therapy maintenance may be preferable to a general reduction of agents.

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“…Borderline inflammatory changes were considered to be an acute rejection. Polyoma-associated nephropathy (PVAN) was diagnosed by the presence of BK virus DNA in the allograft biopsy by in situ hybridization (15,16).…”

Section: Posttransplant Monitoringmentioning

confidence: 99%

Changing Kidney Allograft Histology Early Posttransplant: Prognostic Implications of 1-Year Protocol Biopsies

Cosio

Ters

Cornell

et al. 2016

American Journal of Transplantation

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Allograft histology 1 year posttransplant is an independent correlate to long-term death-censored graft survival. We assessed prognostic implications of changes in histology first 2 years posttransplant in 938 first kidney recipients, transplanted 1999-2010, followed for 93.4 AE 37.7 months. Compared to implantation biopsies, histology changed posttransplant showing at 1 year that 72.6% of grafts had minor abnormalities (favorable histology), 20.2% unfavorable histology, and 7.2% glomerulonephritis. Compared to favorable, graft survival was reduced in recipients with unfavorable histology (hazards ratio .00], p < 0.0001) or glomerulonephritis .0], p < 0.0001). Compared to unfavorable, in grafts with favorable histology, failure was most commonly due to death (42% vs. 70%, p < 0.0001) and less commonly due to alloimmune causes (27% vs. 10%, p < 0.0001). In 80% of cases, favorable histology persisted at 2 years. However, de novo 2-year unfavorable histology (15.3%) or glomerulonephritis (4.7%) related to reduced survival. The proportion of favorable grafts increased during this period (odds ratio ¼ 0.920 [0.871-0.972], p ¼ 0.003, per year) related to fewer DGF, rejections, polyoma-associated nephropathy (PVAN), and better function. Graft survival also improved ], p ¼ 0.015) related to better histology and function. Evolution of graft histologic early posttransplant relate to long-term survival. Avoiding risk factors associated with unfavorable histology relates to improved histology and graft survival.

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Histologic versus Molecular Diagnosis of BK Polyomavirus–Associated Nephropathy

Cited by 61 publications

References 38 publications

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

Antibody Responses to Recombinant Polyomavirus BK Large T and VP1 Proteins in Young Kidney Transplant Patients

Aggressive Immunosuppression Minimization Reduces Graft Loss Following Diagnosis of BK Virus-Associated Nephropathy

Changing Kidney Allograft Histology Early Posttransplant: Prognostic Implications of 1-Year Protocol Biopsies

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