Diagnosis Of BK Virus-associated Nephropathy Research Articles

Dynamics of torque teno virus load in kidney transplant recipients with indication biopsy and therapeutic modifications of immunosuppression.

Following kidney transplantation, lifelong immunosuppressive therapy is essential to prevent graft rejection. On the downside, immunosuppression increases the risk of severe infections, a major cause of death among kidney transplant recipients (KTRs). To improve post-transplant outcomes, adequate immunosuppressive therapy is therefore a challenging but vital aspect of clinical practice. Torque teno virus load (TTVL) was shown to reflect immune competence in KTRs, with low TTVL linked to an elevated risk for rejections and high TTVL associated with infections in the first year post-transplantation. Yet, little is known about the dynamics of TTVL after the first year following transplantation and how TTVL changes with respect to short-term modifications in immunosuppressive therapy. Therefore, we quantified TTVL in 106 KTRs with 108 clinically indicated biopsies, including 65 biopsies performed >12 months post-transplantation, and correlated TTVL to histopathology. In addition, TTVL was quantified at 7, 30, and 90 days post-biopsy to evaluate how TTVL was affected by changes in immunosuppression resulting from interventions based on histopathological reporting. TTVL was highest in patients biopsied between 1 and 12 months post-transplantation (N = 23, median 2.98 × 107 c/mL) compared with those biopsied within 30 days (N = 20, median 7.35 × 103 c/mL) and > 1 year post-transplantation (N = 65, median 1.41 × 104 c/mL; p < 0.001 for both). Patients with BK virus-associated nephropathy (BKVAN) had significantly higher TTVL than patients with rejection (p < 0.01) or other pathologies (p < 0.001). When converted from mycophenolic acid to a mTOR inhibitor following the diagnosis of BKVAN, TTVL decreased significantly between biopsy and 30 and 90 days post-biopsy (p < 0.01 for both). In KTR with high-dose corticosteroid pulse therapy for rejection, TTVL increased significantly between biopsy and 30 and 90 days post-biopsy (p < 0.05 and p < 0.01, respectively). Of note, no significant changes were seen in TTVL within 7 days of changes in immunosuppressive therapy. Additionally, TTVL varied considerably with time since transplantation and among individuals, with a significant influence of age and BMI on TTVL (p < 0.05 for all). In conclusion, our findings indicate that TTVL reflects changes in immunosuppressive therapy, even in the later stages of post-transplantation. To guide immunosuppressive therapy based on TTVL, one should consider inter- and intraindividual variations, as well as potential confounding factors.

BK virus genotypes and humoral response in kidney transplant recipients with BKV associated nephropathy.

Among kidney transplant recipients (KTR) with BK virus associated nephropathy (BKVN), BKV genotypes' evolution and anti-BKV humoral response are not well established. We aim to analyze BKV replication and genetic evolution following transplantation, and characterize concomitant anti-BKV-VP1 humoral response. We retrospectively analyzed 32 cases of biopsy-proven BKVN. Stored plasma and kidney biopsies were tested for BKV viral load, and VP1 sequencing performed on positive samples. BKV-VP1 genotype-specific neutralizing antibodies (NAbs) titers were determined at transplantation and BKVN. At the time of BKVN diagnosis, BKV viral load was 8.2 log10 IU/106 cells and 5.4 log10 IU/mL in kidney and plasma, respectively. VP1 sequencing identified the same BKV-subtype in both compartments in 31/32 cases. At the time of transplantation, 8/20 (40%) of biopsies tested positive for BKV detection, whereas concomitant BKV viremia was negative. VP1 sequencing identified a different subtype compared to BKVN in 5/6 of these samples. This was confirmed following transplantation: 8 patients had a BKV+ biopsy before BKV viremia, and VP1 sequencing identified a different subtype compared to BKVN in all of them. After the onset of BKV viremia and prior to BKVN diagnosis, the BKV subtype in BKV+ plasma and kidney biopsy was the same as the one isolated at BKVN. BKV-VP1 NAbs titers were significantly higher at the time of BKVN compared to transplantation (p=.0031), with similar titers across genotypes. Altogether, our data suggest that among some KTR with BKVN, the BKV genotype from the donor may not be responsible for BKVN pathogenesis.

Characteristics, risk factors and outcome of BKV nephropathy in kidney transplant recipients: a case–control study

BackgroundFollowing kidney transplantation, BK virus associated nephropathy (BKVN) occurs in 1 to 10% of kidney transplant recipients (KTR) and represents a major cause of graft loss. We aim at identifying factors associated with biopsy proven BKVN among KTR.MethodsWe conducted a retrospective case–control study including all KTR with a biopsy-proven diagnosis of BKVN between 2005 and 2019. Clinical characteristics and outcome were described. For each case, one control KTR without BKV infection was identified and matched by age, transplant date, and donor status. Factors associated with BKVN diagnosis were identified using exact conditional logistic regression. Comparative survival was described using Kaplan–Meier estimator.ResultsSixty-four cases of BKVN were identified among 1737 new kidney transplantation (3.7% prevalence). Clinical characteristics did not differ between groups, except for a higher c-PRA among cases. BKVN occurred in a median time of 11 (5–14.5) months after KT, and was associated with a significantly impaired graft function at diagnosis. Following BKVN, 61 (95%) of the patients had immunosuppression reduction, which led to BKV DNAemia resolution in 49% of cases. In multivariate analysis, factors associated with BKVN diagnosis were lymphopenia < 500/mm3 and a prednisone dose > 7.5 mg/day. Median duration of follow-up was 40 months for both groups. BKVN was associated with a significantly increased risk of graft rejection (P = 0.02) and return to dialysis (P = 0.01).ConclusionsBKVN remains a severe complication in KTR and is associated with an increased risk for acute rejection and return to dialysis. Lymphopenia below 500/mm3 and corticosteroid maintenance therapy are significantly associated with biopsy-proven BKVN diagnosis.

Identifying RBBP7 as a Promising Diagnostic Biomarker for BK Virus-Associated Nephropathy

BK virus-associated nephropathy (BKVN) remains a major infectious complication due to powerful immunosuppression in kidney transplant recipients, and its histologic appearance can mimic rejection, leading to diagnostic and treatment dilemmas thus molecular diagnostic methods would be beneficial. We collected gene expression profiles of 169 kidney biopsies taken from BKVN, rejection, and stable functioning allografts, based on single sample gene set enrichment analysis and random forest algorithm, and three hallmark activities associated with DNA damage and proliferation were found to be relatively specific in BKVN. Subsequently, weighted gene co-expression network analysis and support vector machines (SVM) algorithm identified RBBP7 as a robust and promising biomarker with high accuracy in both training and validation cohorts (AUC =0.938, 0.977, respectively). Besides, potential drugs for BKVN treatment such as mepacrine were discovered, which may contribute to targeted antiviral therapy and effective patient management rather than simply reducing the doses of immunosuppressive agents in clinical practice. RBBP7 (retinoblastoma binding protein 7) serves as component of serval complexes that regulate chromatin metabolism and functions in affecting DNA replication and controlling cell proliferation. In this research, upregulation of RBBP7 was found to be associated with the higher infiltration of CD8 naïve T, iTreg, and neutrophil cells and the lower amounts of Th1, central memory T, NKT, CD8 T, and dendritic cells. Moreover, the infiltration of Th1, Th17, and NKT cells was steadily different between BKVN and rejection allografts through immune cell assessment. In conclusion, we identified and verified RBBP7 as a molecular biomarker for BKVN diagnosis, which demonstrated great distinguishing ability with allograft rejection and would support clinical decision-making.

DIFFERENTIAL IMPACT OF ALLOGRAFT REJECTION ON KIDNEY TRANSPLANT PATIENTS WITH BKV INFECTION

Background: BK virus-associated nephropathy (BKVAN) is a known risk factor for allograft dysfunction and graft failure in kidney transplant recipients. The mainstay of treatment for BKVAN is reduction of immunosuppression and this may increase risk for acute rejection. We proposed to observe the effects of acute rejection on patients with BKVAN. Methods: Using data from the Korean Organ Transplantation Registry, a nationwide organ transplantation database, we com pared graft function, and allograft survival in BKVAN patients with or without biopsy proven acute rejection (BPAR). Results: Among the 5,403 patients who received kidney transplantation between 2014 and June 2019, a total of 97 patients were diagnosed with BKVAN. Twenty-six patients (27%) developed BPAR within 6 months of BKVAN diagnosis, 71 patients did not. There were no differences in baseline characteristics, immunosuppression or BKVAN treatment methods between the BPAR and no BPAR groups. There was a significant decrease in allograft function in the BPAR group compared to the no BPAR group in both the 1-year (BPAR creatinine [Cr], 2.5±1.9 mg/dL vs. no BPAR Cr, 1.9±0.9 mg/dL; P=0.044) and 2-year follow-up period (BPAR Cr, 3.8±3.6 mg/dL vs. no BPAR Cr, 2.2±1.0 mg/dL; P=0.015). The BPAR group had lower allograft survival rates compared to the no BPAR group, although not statistically significant (P=0.474). On multivariate Cox regression analysis, MMF discontinuation was observed as a significant risk factor for rejection in BKVAN patients (hazard ratio, 4.000; 95% confidence interval [CI], 1.014- 15.775; P=0.048). Conclusions: Acute rejection with BKVAN is associated with poorer allograft function and survival. Also, discontinuation of MMF as treatment for BKVAN increases risk for acute rejection.

Prognosis of BK polyomavirus nephropathy: 10-year analysis of 133 renal transplant recipients at a single center.

Background:BK virus-associated nephropathy (BKVN) is an important cause of chronic allograft dysfunction. The objective of our study was to evaluate the prognosis of BKVN.Methods:We retrospectively reviewed the data of 133 renal transplant recipients with BKVN treated at the First Affiliated Hospital of Sun Yat-Sen University between July 2007 and July 2017. BK viral loads, graft function, and pathologic indexes were compared between initial diagnosis and last follow-up.Results:After a mean follow-up period of 14.4 (range, 0.3–109.6) months after diagnosis of BKVN, BK viruria, and BK viremia become negative in 19.5% and 90.2% of patients, respectively. The mean estimated glomerular filtration rate (eGFR) at last follow-up was lower than at diagnosis of BKVN (18.3 ± 9.2 vs. 32.8 ± 20.6 mL·min−1·1.73 m−2, t = 7.426, P < 0.001). Eight (6.0%) patients developed acute rejection after reducing immunosuppression. At last follow-up, the eGFR was significantly lower in patients with subsequent rejection than those without (21.6 ± 9.8 vs. 33.5 ± 20.9 mL·min−1·1.73 m−2, t = 3.034, P = 0.011). In 65 repeat biopsies, SV40-T antigen staining remained positive in 40 patients and became negative in the other 20 patients. The eGFR (42.6 ± 14.3 vs. 26.5 ± 12.3 mL·min−1·1.73 m−2), urine viral loads (median, 1.3 × 105vs. 1.4 × 107 copies/mL), and plasma viral load (median, 0 vs. 0 copies/mL) were all significantly lower in patients with negative SV40-T antigen staining than those with persistent BK involvement (all, P < 0.05). Five (3.8%) recipients lost their graft at diagnosis of BKVN, and 13 (9.8%) lost their graft during the follow-up period. The 1-, 3-, and 5-year graft survival rates after diagnosis of BKVN were 99.2%, 90.7%, and 85.7%, respectively. Higher pathologic stage correlated with lower allograft survival rate (χ2 = 6.341, P = 0.042).Conclusion:Secondary rejection and persistent histologic infection in BKVN lead to poor prognosis.

Screening for BK Viremia/Viruria and the Impact of Management of BK Virus Nephropathy in Renal Transplant Recipients.

The prevalence of BK-induced nephritis in renal transplant recipients is estimated to be 1% to 10%; the rate of graft loss within 1 year is 30% to 65%. We conducted this study to evaluate screening of BK virus in blood and/or urine among renal transplant recipients and to assess the effects of different therapeutic modalities in renal transplant recipients with BK nephropathy. Kidney transplant recipients were screened at the time of transplant and then at 1, 2, 3, 6, 9, 12, 18, and 24 months posttransplant. Fiftynine patients were diagnosed with BK virus viremia. Patients were divided into 2 groups according to treatment: group 1 (n = 29) received an active treatment and group 2 (n = 30) received minimized immunosuppression. Most patients required graft biopsies to confirm diagnosis (86.2% in group 1 vs 50% in group 2; P = .03). Both groups were comparable regarding demographic data. Initial posttransplant graft function was significantly better in group 1 (P = .017); ultimately, there was no significant difference between both groups regarding graft survival (P= .51). Fifty percent of patients had biopsy-proven acute T-cell-mediated rejection before BK virus-associated nephropathy diagnosis (significantly higher in group 1). Serum creatinine levels were significantly better in group 2 at 3, 4, and 5 years after BK nephropathy (P = .001, .017, and .003, respectively). The prevalence of BK nephropathy in our renal transplant recipients was 5.9% with a rate of graft loss ranging from 43% to 51%. Regular screening, less intensive immunosuppressive therapy, and early intervention by reduction of immunosuppressive medications are advisable to obtain early diagnosis and to have better outcomes of BK virus-associated nephropathy with antiviral agents.

Long-term prognosis of BK virus-associated nephropathy in kidney transplant recipients

BackgroundThe long-term prognosis of BK virus-associated nephropathy (BKVAN) in kidney transplant recipients (KTRs) is uncertain. We evaluated the long-term prognosis in KTRs with BKVAN and the clinical significance of BKVAN on post-transplant clinical outcome.MethodsWe retrospectively analyzed the medical records of 582 patients who underwent kidney transplant (KT) between 2001 and 2014. We divided the patients into a BKVAN group (15 patients) diagnosed by allograft biopsy and a control group (356 patients).ResultsThe incidence of BKVAN was 4.0%, and the mean follow-up duration was 93.1 ± 52.3 months. Median time from KT to BKVAN diagnosis was 5.9 months (interquartile range [IQR], 4.4–8.7). In the BKVAN group, 9 (60.0%) KTRs with combined acute rejection progressed to graft failure, and the median time from BKVAN diagnosis to graft failure was 36.2 months (IQR, 9.7–65.5). Death-censored graft survival rate and patient survival rate in the BKVAN group were significantly lower than those in the control group. BKVAN and rejection were independent risk factors for graft failure. In the subgroup analysis, death-censored graft survival rate of KTRs with BKVAN with acute rejection was significantly worst in comparison with similar patients without BKVAN regardless of acute rejection (P < 0.001).ConclusionThe long-term prognosis of BKVAN with acute rejection was very poor because of graft failure caused by inadequate treatment for acute rejection considering BKVAN. Therefore, we should carefully monitor the allograft status of KTRs through regular surveillance tests after treatment for BKVAN with acute rejection.

BK Virus Associated Nephropathy, a Cause of Early Renal Allograft Dysfunction: A Single Centre Study.

BK virus associated nephropathy (BKVN) is an important cause of early graft dysfunction in renal transplant recipients. The present study was carried out to determine the burden of BKVN in a single renal transplant centre in Australia. A retrospective analysis of de novo renal transplant recipients from 2010 to 2013 was performed to identify biopsy proven BKVN. Estimated glomerular filtration rate (eGFR) was compared at baseline, at BKVN diagnosis and 3 and 12 months postdiagnosis. Of the 317 de novo renal transplants recipients in the study period, 20 (6.3%) developed BKVN. The mean age was 54.8 ± 13.1 years and 13 (65%) were male. The mean time from transplant to BKVN was 8.7 ± 6.7 months with 17 (85%) diagnosed within 12 months. Four recipients each were diagnosed BKVN on 3 and 12 month surveillance biopsy. Six (30%) had normal eGFR at diagnosis. Mean eGFR at diagnosis was 38.8 ± 19.2 ml/min/1.73 m2, which was significantly lower (p < 0.01) than that at baseline (50.3 ± 16.4 ml/min/1.73 m2). eGFR improved numerically at 3 and 12 months post-diagnosis, however the difference was not significant. One patient had graft failure, 19 months after diagnosis. BKVN generally occurs in first post-transplant year and is an important cause of early graft dysfunction. Surveillance biopsy helps in detecting subclinical BKVN.

Risk factors in the progression of BK virus-associated nephropathy in renal transplant recipients.

Background/Aims:BK virus-associated nephropathy (BKVAN) is an important cause of allograft dysfunction in kidney transplant recipients. It has an unfavorable clinical course, and no definite treatment guidelines have yet been established. Here, we report our center’s experience with biopsy-proven BKVAN and investigate factors associated with its progression.Methods:From January 2004 to April 2013, 25 patients with BKVAN were diagnosed by biopsy at Seoul St. Mary’s Hospital. Of the 25 patients, 10 were deceaseddonor transplant recipients and 15 were living-donor transplant recipients. Three of the patients underwent retransplantation. The primary immunosuppressant used was tacrolimus in 17 patients and cyclosporine in eight patients.Results:BKVAN was observed at a mean duration of 22.8 ± 29.1 months after transplantation. The mean serum creatinine level at biopsy was 2.2 ± 0.7 mg/dL. BKVAN occurred with acute rejection in eight patients (28%). Immunosuppression modification was performed in 21 patients (84%). Additionally, leflunomide and intravenous immunoglobulin were administered to 13 patients (52%) and two (8%), respectively. Allograft loss occurred in five patients (27.8%) during the follow- up period at 0.7, 17.1, 21.8, 39.8, and 41.5 months after the BKVAN diagnosis. Advanced stages of BKVAN, increased creatinine levels, and accompanying acute rejection at the time of BKVAN diagnosis increased the risk of allograft failure.Conclusions:The clinical outcomes in patients with biopsy-proven BKVAN were unfavorable in the present study, especially in patients with advanced-stage BKVAN, poor renal function, and acute allograft rejection.

Clinical Impact of BK Virus Surveillance on Outcomes in Kidney Transplant Recipients

BackgroundThe objective of this study was to investigate the clinical impact of BK virus surveillance on graft injury in kidney transplantation. MethodsBK viremia in kidney transplant recipients was evaluated by use of plasma quantitative polymerase chain reaction. The prevalence of BK viremia and BK virus–associated nephropathy (BKVAN) and the clinical impact of BK viremia on graft outcomes were assessed. ResultsThis study took place between January 2008 and June 2013. A total of 213 kidney transplant recipients were included. The prevalence of BK viremia and high BK viremia (≥1 × 104 copies/mL) was 66.7% (142/213) and 17.4% (37/213), respectively. A diagnosis of BKVAN was confirmed by means of allograft biopsy in 9 patients (4.2%). The estimated glomerular filtration rate after transplantation was similar in both the low BK viremia (<1 × 104 copies/mL) and non–BK viremia groups but was significantly lower in the high BK viremia group after 18 months. In receiver operating characteristic curve analysis, the area under the curve value of plasma polymerase chain reaction was 0.980. We found that a viral load >92,850 copies/mL was able to predict BKVAN with 89% sensitivity and 94.6% specificity. The risk factors for viral loads ≥1 × 104 copies/mL were cytomegalovirus infection, steroid pulse therapy, and acute rejection. ConclusionsHigh BK viremia was associated with poor graft function after kidney transplantation. The serial monitoring of BK viremia in kidney transplant recipients was helpful in predicting BKVAN and might prevent further progression.

Efficacy of Intravenous Immunoglobulin in the Treatment of Persistent BK Viremia and BK Virus Nephropathy in Renal Transplant Recipients

BK virus–associated nephropathy (BKVN) can cause clinically significant viral infection in renal transplant recipients, leading to allograft dysfunction and loss. The usual management of BKVN involves the reduction of immunosuppression and the addition of leflunomide, quinolones, and cidofovir, but the rate of graft loss remains high. The aim of this study was to assess the impact of treatment with intravenous human immunoglobulin (IVIG) on the outcome of BKVN in renal transplant recipients. Upon diagnosis of BKVN, patients remained on anti-polyomavirus treatment, consisting of the reduction of immunosuppression and the use of leflunomide therapy. Treatment with IVIG was given only to patients who did not respond to 8 weeks of the adjustment of immunosuppression and leflunomide. All 30 patients had persistent BKV viremia and BKVN with their mean BK viral loads higher than the baseline (range, 15,000–2 million copies/mL). Mean peak BK load was 205,314 copies/mL compared with 697 copies/mL after 1 year of follow-up. Twenty-seven patients (90%) had a positive response in clearing viremia. The actuarial patient and graft survival rates after 12 months were 100% and 96.7%, respectively. IVIG administration appeared to be safe and effective in treating BKV viremia and BKVN and preventing graft loss in patients who had inadequate response to immunosuppression reduction and leflunomide therapy.

The Clinical Impact of BK Virus Surveillance On Outcomes in Kidney Transplant Recipients.

Purpose: The objective of this study was to investigate the clinical impact of BK virus surveillance to prevent BK virus-associated graft injury in kidney transplantation. Methods: We evaluated the prevalence of BK viremia using plasma quantitative polymerase chain reaction (PCR) and BK virus associated nephropathy (BKVAN) and the clinical impact of BK viremia on graft outcomes in the kidney transplant recipients between January 2008 and June 2013. Results: In this study, 1136 tests from 423 kidney transplant recipients were performed. The prevalence of BK viremia and high BK viremia (>1X104 copies/mL) were 60.3% (255/423) and 13.5% (57/423) respectively. Nine cases were finally diagnosed as BKVAN by allograft biopsy. Although low BK viremia (<1X104 copies/mL) group had comparable creatinine levels after transplantation, high BK viremia group showed significantly higher creatinine levels at 6, 12 and 18 months after transplantation when compared with no viremia group. In receiver operating characteristic curve analysis, area under the curve of peak BK viremia for the diagnosis of BKVAN was 0.986. We found 92,850 copies/mL was significant cut-off level to predict BKVAN with 89% sensitivity and 97% specificity. Conclusion: High BK viremia was associated with poor graft function after kidney transplantation. The serial monitoring of BK viremia in kidney transplant recipients was helpful to predict BKVAN and might prevent further progression.

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

BK virus (BKV)-associated nephropathy (BKVAN) is a major cause of renal dysfunction and graft loss in renal transplant recipients. Monitoring plasma BK viral load (BKVL) is the recommended screening tool to predict BKVAN. American Society of Transplantation (AST) guidelines define a BKVL of ≥4 log10/mL (10,000 copies) as presumptive BKVAN and recommend reduction in immunosuppression. We evaluated the clinical sensitivity of the quantitative BKV DNA assay in predicting risk for BKVAN using the AST-recommended BKVL cutoff. In a retrospective, single-center study, all patients who underwent renal transplant at Henry Ford Hospital from January 2008 to August 2011 were analyzed (n = 490). Plasma BKVL Assay A (commercial large T antigen-based polymerase chain reaction [PCR]) was done in all patients. Renal biopsy was done if there was a rise in serum creatinine ≥0.5 mg from baseline. BKVAN was confirmed by biopsy. As a subset to this study, from the same cohort, data for a set of 20 consecutive Assays A and B (in-house VP1-based PCR assay) from 15 patients over a period of 3 months were collected. Differences in physicians' clinical decision-making (CDM) were analyzed between the 2 assays using chi-square test. A total of 413 patients met the inclusion criteria, of which 222 patients had BK viremia. Among the 248 patients who had a renal biopsy done, 31 (12.5%) were found to have BKVAN. Eleven of the 31 (35%) patients had BKVL consistently <4 log10/mL, and thus were not diagnosed to have BKVAN using the AST-recommended BKVL cutoff of ≥4 log10/mL. A total of 8 patients lost their graft owing to BKVAN, including 3 patients with BKVL <4 log10/mL. Using a cutoff point of plasma BKVL of ≥4 log10/mL, the sensitivity, specificity, positive predictive value, and negative predicative value of the PCR Assay A for the diagnosis of biopsy-proven BKVAN were 64.5%, 98.4%, 87.0%, and 94.5%, respectively, and for the diagnosis of presumptive nephropathy were found to be 76.6%, 99.4%, 95.8%, and 96.4%, respectively. In the second part of the study, presumptive nephropathy was detected in 8 samples using Assay A and 14 samples using Assay B. Six samples in Assay A would have led to no changes in the CDM in terms of reduction in immunosuppression. Kidney biopsy was carried out in 5 patients, 4 of whom had BKVAN and had Assay B log count of ≥5. If Assay A had been used in CDM, BKVAN would have been missed in 1 patient. 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.

Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney‐pancreas transplant recipients

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney-pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add-on test to qualitative polyoma NAT for the diagnosis of BK virus-associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10(3) serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1-99.8) and specificity 79.1% (95%: CI 67.4-88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8-57.7%) and 98.6% (95% CI: 98.3-99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85-0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add-on test to qualitative polyomavirus NAT for kidney and kidney-pancreas transplant recipients at risk of BKVAN.

Impact of Combined Acute Rejection on BK Virus-Associated Nephropathy in Kidney Transplantation

BK virus-associated nephropathy (BKVAN) is one of the major causes of allograft dysfunction in kidney transplant (KT) patients. We compared BKVAN combined with acute rejection (BKVAN/AR) with BKVAN alone in KT patients. We retrospectively analyzed biopsy-proven BKVAN in KT patients from 2000 to 2011 at Seoul National University Hospital. Among 414 biopsies from 951 patients, biopsy-proven BKVAN was found in 14 patients. Nine patients had BKVAN alone, while 5 patients had both BKVAN and acute cellular rejection. BKVAN in the BKVAN alone group was detected later than in BKVAN/AR group (21.77 vs 6.39 months after transplantation, P=0.03). Serum creatinine at diagnosis was similar (2.09 vs 2.00 mg/dL). Histological grade was more advanced in the BKVAN/AR group (P=0.034). Serum load of BKV, dose of immunosuppressants, and tacrolimus level showed a higher tendency in the BKVAN alone group; however it was not statistically significant. After anti-rejection therapy, immunosuppression was reduced in the BKVAN/AR group. Renal functional deterioration over 1 yr after BKVAN diagnosis was similar between the two groups (P=0.665). These findings suggest that the prognosis of BKVAN/AR after anti-rejection therapy followed by anti-BKV therapy might be similar to that of BKVAN alone after anti-BKV therapy.

Urgent Standardization of Plasma BK Viral Load Assays (BKVL) Is Necessary to Reduce Graft Loss from BK Virus-Associated Nephropathy (BKVAN)

Background: BK virus-associated nephropathy (BKVAN) is a major cause of renal dysfunction and graft loss in renal transplant recipients (RT). Monitoring plasma BK viral load (BKVL) is the recommended screening strategy to predict BKVAN. American Society of Transplantation (AST) guidelines define a BKVL of ≥4 log10/mL (10,000 copies) as “presumptive BKVAN and recommend reduction in immunosuppression. We evaluated the clinical sensitivity of the quantitative BKV DNA assay in predicting risk for BKVAN using the AST recommended BKVL cut off. Methods: In a retrospective, single-center study all patients (pts) who underwent RT at Henry Ford Hospital from 2008-2011 were analyzed (n=460). Pts were included if they had atleast 1 yr of follow-up post-RT and a minimum of 4 visits/yr. Plasma BKVL assay (commercial send-out assay) was done in all pts as per protocol (at least every 3 months during the first 2 yr post-RT). Renal biopsy was done in all pts if there was a rise in serum creatinine >0.5mg from baseline. BKVAN was confirmed by biopsy. Results: 413 pts met inclusion criteria and were included.in the analysis. Of these 222 pts had BK viremia; 23/222 (10%) had BKVL of ≥4 log10/mL and 20/23 (87%) had BKVAN confirmed on biopsy. Among the 248 pts who had a renal biopsy done for rising sr creatinine 31(12.5%) were found to have BKVAN. Eleven of The 31(35%) pts had BKVL consistently < 4 log10/mL and hence, were not diagnosed as presumptive BKVAN using the ATS recommended BKVL cutoff of ≥4 log10/mL. A total of 8 patients lost their graft due to BKVAN including 3 patients with BKVL < 4 log10/m. Using a cut point of plasma BKVL of ≥4 log10/mL the sensitivity, specificity, positive predictive value and negative predicative value of the PCR assay for the diagnosis of BKVAN is 64.5%, 98.4%, 87.0%, and 94.5% respectively. Conclusion: Utilizing the current AST guideline cut off of ≥4 log10/mL the PCR assay used at our center underestimated the diagnosis of presumptive BKVAN. Urgent standardization of the various BKVL assays and establishment of universal cut-points is imperative to avoid BKVAN related graft loss.

Clinical feature and analysis on the clinical related factors of BK virus associated nephropathy

To determine the incidence of BK virus associated nephropathy (BKVAN) in renal-transplantation recipients, observe its histological features. A total of 137 renal allograft biopsy specimens collected at our hospital during December 1999 to January 2008 were analyzed by routine histologic examination, immunohistochemistry and transmission electron microscopy (TEM) to screen for BKV. The case records of involved recipients were accessed to know their clinical manifestations, diagnostic characteristic and treatment regimens at that time. And the 1-, 3-year graft survival rate were analyzed by Kaplan-Meier analysis. A total of 16 renal biopsy specimens (11.7%) were positive for BKV. Viral particales on the size of 35 - 40 nm were seen in the tubular epithelial cells of 3 biopsy specimens and 7 urinary sediment samples. The numbers of BKVAN recipients suffering acute rejection, using ALG/ATG/OKT3 and using FK506+MMF immunosuppressive protocol were 7, 7 and 10 respectively. In 14 cases of BKVAN, there was an elevated level of serum creatine concentrations. Four cases lost their grafts after using a large dose of immunosuppressives. And renal functions improved by a reduction of immunosuppression or a replacement of FK506 with CsA in 8 cases. And graft functions deteriorated or had already failed in the remaining 4 cases whose immunosuppressive protocol were not changed. The 1-, 3-year graft survival rates were 81.3% and 54.2% in BKVAN recipients respectively. The diagnosis of BKVAN should be considered in recipients when their graft functions are deteriorating, especially for those with the accompanied risk factors. The morphological hallmarks of BKVAN are similar to those of acute rejection. The differentiation may be made by either immunohistochemistry or TEM. A proper modification of maintenance immunosuppression is effective in slowing down the progression of BKVAN.

Cidofovir May Be Deleterious in BK Virus-Associated Nephropathy

Cidofovir May Be Deleterious in BK Virus-Associated Nephropathy

Clinical diagnosis of BK virus associated nephropathy in renal transplant recipients

Objective To investigate the methods for clinical diagnosis of BK virus associated nephropathy(BKVAN)in renal transplant recipients.Methods Urine and peripheral blood(PB)were taken from90 renaltransplant recipients fo rBKV cytological testing and real-time PCR for BKV DNA at the post-transplantafion month 1,3,6,9,and 12.Graft biopsies were analysed for SV40-T by immunohistochemical method.Graft biopsies and urinary sediments of recipients with BKVAN were taken to momtor viral partieles by conventional transmission electron microscopy(EM).Results By one post-transplant year,urinary decoy cells(median,8/10 HPF),BKV viruria(mediall,2.60×10~5 copies/ml),viremia(median,9.65×10~3copies/ml).and BKVAN occurred in 42.2%,45.6%,22.2%,and 5.6%of patients,respectively.BKVAN was diagnosed in 5 calves.Conclusion Intensive and regular BKV monitoring is necessary for renal transplant recipients.The correct diagnosis of BKVAN depends on routine histopathological examination combined with immunohistochemistry or electron microscopy and the clinical manifestationa. Key words: Kidney transplantation; Virus; Detection; Diagnosis