Currently recommended <scp>BK</scp> virus (<scp>BKV</scp>) plasma viral load cutoff of ≥4 log<sub>10</sub>/mL underestimates the diagnosis of <scp>BKV</scp>‐associated nephropathy: a single transplant center experience

Hassan, Syed Adeel; Mittal, Chetan; Amer, Syed; Khalid, Fariha; Patel, Anita; Delbusto, R.; Samuel, Linoj; Alangaden, George; Mayur, Ramesh

doi:10.1111/tid.12164

Cited by 50 publications

(48 citation statements)

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“…The wide variety of in-house quantitative real-time PCR assays and the lack of international standards result in an important interlaboratory disagreement with respect to BKVL measurements (12) and thus far have hindered the establishment of a universal BKVL cutoff value with a high positive predictive value for presumptive BKVN (13,14). Commercially available quantitative PCR kits are believed to provide more repeatable and reproducible results, consequently contributing to the efforts of clinical laboratories regarding the currently ongoing accreditation process.…”

Section: Discussionmentioning

confidence: 99%

“…However, most BKV quantitative PCR methods are in-house techniques, and marked variability among assays has been described (12). A recent study demonstrated that, depending on the PCR assay, the currently recommended BKV viremia cutoff of Ն4 log 10 copies/ml may underestimate the prevalence of BKVN (13). The variability of the assays may be attributable to various criteria: features of primers and probe design, including the size of the amplicon and the choice of reference material and/or types of matrices used for the blood compartment (plasma or whole blood [WB]) (12,14).…”

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confidence: 99%

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Toward Standardization of BK Virus Monitoring: Evaluation of the BK Virus R-gene Kit for Quantification of BK Viral Load in Urine, Whole-Blood, and Plasma Specimens

et al. 2014

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Screening of BK virus (BKV) replication is recommended to identify patients at increased risk of BKV-associated diseases. However, the heterogeneity of molecular techniques hinders the establishment of universal guidelines for BKV monitoring. Here we aimed to compare the performance of the CE-marked BK virus R-gene kit (R-gene) to the performance of our in-house assay for quantification of BKV DNA loads (BKVL). A 12-specimen panel from the Quality Control for Molecular Diagnostics (QCMD) organization, 163 urine samples, and 88 paired specimens of plasma and whole blood (WB) from transplant recipients were tested. Both the R-gene and in-house assays showed a good correlation within the QCMD panel (r ‫؍‬ 0.995 and r ‫؍‬ 0.989, respectively). BKVL were highly correlated between assays, although positive biases were observed with the in-house assay in analysis of urine (0.72 ؎ 0.83 log 10 copies/ml), plasma (1.17 ؎ 0.63 log 10 copies/ml), and WB (1.28 ؎ 0.37 log 10 copies/ml). Recalibration with a common calibrator significantly reduced the bias in comparisons between assays. In contrast, BKVL was underestimated with the in-house PCR in eight samples containing BKV genotype II, presenting point mutations at primer-annealing sites. Using the R-gene assay, plasma and WB specimens were found to be equally suitable for quantification of BKVL, as indicated by the high correlation coefficient (r ‫؍‬ 0.965, P < 0.0001). In conclusion, the R-gene assay demonstrated reliable performance and higher accuracy than the in-house assay for quantification of BKVL in urine and blood specimens. Screening of BKV replication by a well-validated commercial kit may enable clinical laboratories to assess viral loads with greater reproducibility and precision.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Toward Standardization of BK Virus Monitoring: Evaluation of the BK Virus R-gene Kit for Quantification of BK Viral Load in Urine, Whole-Blood, and Plasma Specimens

et al. 2014

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“…While BKV NAAT is integral to the management of BKV in transplantation, quantification variability between assays has prevented comparisons of BKV viral load results across institutions, making result interpretation challenging and variable. Though current guidelines recommend a plasma viral load of Ն10,000 copies/ml as the threshold for clinical intervention in kidney transplantation based on a specificity of 93% for BKVN, some centers have reported that this threshold may underestimate the diagnosis of BKVN and suggest using lower viral load thresholds (1,5,15). In fact, such discrepancies may be appropriate realities for institutions using different assays that produce different quantitative results for a given sample.…”

Section: Discussionmentioning

confidence: 99%

Calibration of BK Virus Nucleic Acid Amplification Testing to the 1st WHO International Standard for BK Virus

et al. 2017

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Significant interassay variability in the quantification of BK virus (BKV) DNA precludes establishing broadly applicable thresholds for the management of BKV infection in transplantation. The 1st WHO International Standard for BKV (primary standard) was introduced in 2016 as a common calibrator for improving the harmonization of BKV nucleic acid amplification testing (NAAT) and enabling comparisons of biological measurements worldwide. Here, we evaluated the Altona RealStar BKV assay (Altona) and calibrated the results to the international unit (IU) using the Exact Diagnostics BKV verification panel, a secondary standard traceable to the primary standard. The primary and secondary standards on Altona had nearly identical linear regression equations (primary standard, Y ϭ 1.05X Ϫ 0.28, R 2 ϭ 0.99; secondary standard, Y ϭ 1.04X Ϫ 0.26, R 2 ϭ 0.99) and conversion factors (primary standard, 1.11 IU/copy; secondary standard, 1.09 IU/copy). A comparison of Altona with a laboratory-developed BKV NAAT assay in IU/ml versus copies/ml using PassingBablok regression revealed similar regression lines, no proportional bias, and improvement in the systematic bias (95% confidence interval of intercepts: copies/ml, Ϫ0.52 to Ϫ1.01; IU/ml, 0.07 to Ϫ0.36). Additionally, Bland-Altman analyses revealed a clinically significant reduction of bias when results were reported in IU/ml (IU/ml, Ϫ0.10 log 10 ; copies/ml, Ϫ0.70 log 10 ). These results indicate that the use of a common calibrator improved the agreement between the two assays. As clinical laboratories worldwide use calibrators traceable to the primary standard to harmonize BKV NAAT results, we anticipate improved interassay comparisons with a potential for establishing broadly applicable quantitative BKV DNA load cutoffs for clinical practice.

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“…This variation can be due to the appropriateness of various diagnostic tests used for the detection of these viral infections. The threshold values used for diagnosis can also be a potential source of variation (10). One study in Korea showed that 10 (5.2%) out of 191 patients with renal transplant had BK virus associated nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of cytomegalovirus and BK polyoma virus infection in post-renal transplant patients in a tertiary care centre in

Manuel¹,

Ambroise²,

Varghese³

et al. 2017

J Nephropathol

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Background: Viral infections are a significant cause of graft loss and dysfunction in kidney transplant recipients. Cytomegalovirus and BK polyomavirus have often been explained as the most common viral etiological agents. Objectives: The current study was undertaken to assess the prevalence of cytomegalovirus and BK polyomavirus infection in post-renal transplant individuals in a tertiary care centre in South India and also to study the histopathological changes of such infections in the kidney allograft biopsies. Patients and Methods:We conducted a retrospective investigation of 100 cases using archival renal biopsy specimens which were subjected to immunohistochemical stains to detect cytomegalovirus and BK polyoma virus. These findings were then correlated with the histopathological alterations detected in H&E sections. Results: We detected the prevalence of cytomegalovirus in 7% and BK polyoma virus in 3%. Cytomegalovirus was statistically associated with pre-and post-transplant infections along with diabetic status. We noted that, out of the seven patients who were immunohistochemically cytomegalovirus positive, only five had positive cytomegalovirus IgM status. With BK polyoma virus, we noted a statistical significance with pre-and posttransplant infections. However, we did not find evidence of cytomegalovirus and BK polyoma virus co-infection in any of the renal allograft biopsies. Conclusions: Routine immunohistochemical evaluation of cytomegalovirus and BK polyoma viral infections in kidney allograft recipients must be done, especially in those with preand post-transplant infections and diabetes.

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Currently recommended BK virus (BKV) plasma viral load cutoff of ≥4 log₁₀/mL underestimates the diagnosis of BKV‐associated nephropathy: a single transplant center experience

Abstract: Utilizing the current AST guideline cutoff of ≥4 log10 /mL, the PCR Assay A underestimated the diagnosis of BKVAN. Urgent standardization of the various BKVL assays and establishment of universal cutoff points is imperative to avoid BKVAN-related graft loss.

Cited by 50 publications

References 17 publications

Toward Standardization of BK Virus Monitoring: Evaluation of the BK Virus R-gene Kit for Quantification of BK Viral Load in Urine, Whole-Blood, and Plasma Specimens

Toward Standardization of BK Virus Monitoring: Evaluation of the BK Virus R-gene Kit for Quantification of BK Viral Load in Urine, Whole-Blood, and Plasma Specimens

Calibration of BK Virus Nucleic Acid Amplification Testing to the 1st WHO International Standard for BK Virus

Prevalence of cytomegalovirus and BK polyoma virus infection in post-renal transplant patients in a tertiary care centre in

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Currently recommended BK virus (BKV) plasma viral load cutoff of ≥4 log10/mL underestimates the diagnosis of BKV‐associated nephropathy: a single transplant center experience

Abstract: Utilizing the current AST guideline cutoff of ≥4 log10 /mL, the PCR Assay A underestimated the diagnosis of BKVAN. Urgent standardization of the various BKVL assays and establishment of universal cutoff points is imperative to avoid BKVAN-related graft loss.

Cited by 50 publications

References 17 publications

Toward Standardization of BK Virus Monitoring: Evaluation of the BK Virus R-gene Kit for Quantification of BK Viral Load in Urine, Whole-Blood, and Plasma Specimens

Toward Standardization of BK Virus Monitoring: Evaluation of the BK Virus R-gene Kit for Quantification of BK Viral Load in Urine, Whole-Blood, and Plasma Specimens

Calibration of BK Virus Nucleic Acid Amplification Testing to the 1st WHO International Standard for BK Virus

Prevalence of cytomegalovirus and BK polyoma virus infection in post-renal transplant patients in a tertiary care centre in

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Product

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Currently recommended BK virus (BKV) plasma viral load cutoff of ≥4 log₁₀/mL underestimates the diagnosis of BKV‐associated nephropathy: a single transplant center experience