BK Virus Allograft Nephropathy Research Articles

#3045 Understanding BK polyomavirus: surveillance and clearance in kidney transplant recipients

Abstract Background and Aims BK virus allograft nephropathy (BKVN) can develop graft loss. The aim of this study was to describe BK viraemia and BKVN related factors, our experience in treatment and the impact in graft survival. Method We introduce a retrospective cohort of 78 kidney transplant recipients (KTRs) with BKV viraemia between January 2013 from January 2020 and with follow-up until December 31, 2022 in our center. Results Thirty-four (43%) were living donor KTRs, 30 (38.5%) DBD, 11 (14.1%) DCD III, and 2 (4.3%) DCD II. Twenty-seven (34.6%) of recipients were sensitized. Immunosuppressive induction was based on Anti-CD25 in 33 (42.3%), and antilymphocytes antibodies in 44 (56.4%). Basal treatment was TAC+MPA+PDN in 44 (56.4%) and TAC+iMTOR+PDN in 31 (39.7%). Median FK levels were 7.9 (ng/ml) in the first replication. Median BK load at first replication was 3636 [1030-97151]cp/ml. Median time to replication from transplant was 6 months, and from highest load 9 months. Immunosuppression adjustment after replication was switch to imTOR+FK 25 (32.1%), low FK 17 (21.8%), imTOR 4 (5.1%). Only surveillance was chosen in 27 (35.9%). Others therapies were Leflunomide 4 (5.1%), IVIG 6 (7.7%) or both 3 (3.8%). Photopheresis was used in 2 cases. Viraemia was cleared in 17/24 (70.8%) of the cases in which conversion to mTOR was performed as an immunosuppression adjustment strategy, versus 9 (56.3%) in which it was decided to lower FK and in 3 (75%) with low MMF. Ten cases in which surveillance was carried out became negative for viremia, possibly because they were patients with a lower replicative load. BKN occurred in 28/78 (36%) cases, interstitial fibrosis (ci>2) was found in 14/28 (48.27%). Graft rejection after BKN was developed in 11/28 (37.9%). Graft loss occurred in 26/78 (33.3%) of cohort and in 19 (65%)of patients with BKN, reaching a significant value. Viraemia clearance was reached in 41 (60.3%) in mean time of 10 months [4-27]. Mean time since BKVN until graft loss was 22.3 months [10.2-34.2]. Exitus occurred in 7/78 (9%) of replication cases and in 3/28 (10.7%)of BKN patients. Maximum BK load Exp β; [1-1], p 0.033, first replication load >10.000 (cp/ml) and deceased donor status (Exp β; 6,9 [2.43-19.57] and 2.98 [1.10-8.07] p 0.031, were related to BKVN in bivariate analysis. No significant differences were found between therapy in BKVN and graft loss, maybe due to low BKVN cases. Conclusion In our cohort, maximum BK load, first replication load >10,000 (cp/ml), and deceased donor status appear to be related to nephropathy. No significant differences were found between induction, basal or adjuvant therapy and graft loss. The current challenge is to stop replication before fibrosis, without increasing the risk of rejection.

Effect of steroid pulses in severe BK virus allograft nephropathy with extensive interstitial inflammation.

As there is no specific antiviral treatment currently available for BK polyomavirus associated nephropathy (BKVAN), its management relies on immunosuppression reduction in kidney transplant patients. Data on efficacy of steroid pulses in this indication are lacking. We performed a retrospective monocenter study on 64 patients diagnosed with biopsy-proven BKVAN. Patients within the "pulse group" (n = 37) received IV methylprednisolone 10mg/kg 3 days consecutively. In the "low dose" steroid group (n = 27), patients were continued oral prednisone 5mg daily. Mean follow up was 78 months in the steroid pulse group and 56 months in the low dose group (p=0.15). Mean eGFR values at diagnosis were comparable, as well as other demographic characteristics. Mean BK plasma viral load was higher in "pulse" than in "low dose" steroid group. Pulse group had higher inflammation and tubulitis (p <0.05). Graft loss reached 57% in the "pulse" group versus 41% in the "low dose" group, p=0.20. Rejection events were similar. No major adverse event was statistically associated with steroid pulse, including infections, cancer, and de novo diabetes. No significant differences were found in the evolution of both groups of patients, despite patients receiving "pulse" steroids were identified as the most severe sharing higher BK viral load and more frequent active lesions on histology.

The Importance of Kidney Medullary Tissue for the Accurate Diagnosis of BK Virus Allograft Nephropathy.

The published tissue adequacy requirement of kidney medulla for BK virus allograft nephropathy diagnosis lacks systematic verification and competes against potential increased procedural risks from deeper sampling. We evaluated whether the presence of kidney medulla improved the diagnostic rate of BK nephropathy in 2244 consecutive biopsy samples from 856 kidney transplants with detailed histologic and virologic results. Medulla was present in 821 samples (37%) and correlated with maximal core length (r=0.35; P<0.001). BK virus allograft nephropathy occurred in 74 (3% overall) but increased to 5% (42 of 821) with medulla compared with 2% (32 of 1423) for cortical samples (P<0.001). Biopsy medulla was associated with infection after comprehensive multivariable adjustment of confounders, including core length, glomerular number, and number of cores (adjusted odds ratio, 1.81; 95% confidence interval, 1.02 to 3.21; P=0.04). In viremic cases (n=275), medulla was associated with BK virus nephropathy diagnosis (39% versus 19% for cortex; P<0.001) and tissue polyomavirus load (Banff polyomavirus score 0.64±0.96 versus 0.33±1.00; P=0.006). Biopsy medulla was associated with BK virus allograft nephropathy using generalized estimating equation (odds ratio, 2.04; 95% confidence interval, 1.05 to 3.96; n=275) and propensity matched score comparison (odds ratio, 2.24; 95% confidence interval, 1.11 to 4.54; P=0.03 for 156 balanced pairs). Morphometric evaluation of Simian virus 40 large T immunohistochemistry found maximal infected tubules within the inner cortex and medullary regions (P<0.001 versus outer cortex). Active BK virus replication concentrated around the corticomedullary junction can explain the higher detection rates for BK virus allograft nephropathy with deep sampling. The current adequacy requirement specifying targeting medulla can be justified to minimize a missed diagnosis from undersampling.

The immunophenotyping of different stages of BK virus allograft nephropathy

Objectives: To investigate the immunohistochemical features of different stages of BK virus allograft nephropathy (BKVN) and further elucidate the underlying immunological mechanism involved in the evolution of BKVN.Methods: Fifty-two renal transplant recipients with biopsy proven BKVN were retrospectively selected. According to the third edition of the American Society of Transplantation Infection guidelines, 10 patients were categorized as having mild BKVN (stage A), 25 were moderate (stage B) and 17 were severe (stage C). The differential infiltrations of CD3+ (T lymphocytes), CD4+ (helper T lymphocytes), CD8+ (cytotoxic T lymphocytes), CD20+ (B lymphocytes), CD68+ (macrophages) and CD138+ (plasma cells) cells and the expression of interleukin-2 receptor (IL-2R) and human leukocyte antigen DR (HLA-DR) were compared among the three groups.Results: CD3+, CD4+, CD8+, CD20+, CD138+ and CD68+ cells infiltrations, IL-2R and HLA-DR expression were positive in the BKVN patients. Moreover, with increasing stages of BKVN, the numbers of positively stained inflammatory cells and the expression of IL-2R were significantly increased in the severe group compared to the mild group, whereas no statistically significant differences were observed with regard to HLA-DR expression. Eosinophil and neutrophil infiltration could also be observed in moderate to advanced BKVN.Conclusion: Renal allograft damage caused by BKVN involved T lymphocyte-, B lymphocyte- and mononuclear macrophage-mediated immune responses. Inflammatory cell infiltrations in the renal allograft were probably the driving force for BKVN progression. Additionally, eosinophils and neutrophils may be involved in the pathophysiological mechanism of BKVN.

Monitoring of polyomavirus BK replication and impact of preemptive immunosuppression reduction in renal-transplant recipients in China: a 5-year single-center analysis

This provides the long-term patient/graft survival and outcome of BK viremia and BK virus allograft nephropathy (BKVAN) in renal transplant recipients in the setting of intensive monitoring and preemptive of reduction of immunosuppression. Quantitative BKV DNA PCR and urinary cytology surveillance were performed regularly after transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN were treated with 30–50% reduction in doses of tacrolimus and/or mycophenolate mofetil and were monitored for BKV every 3–6 months. All the patients were followed for 5 years. Overall 5-year patient and graft survival were 95.6% and 92.1%, respectively, and independent of presence of decoy cells, BK viruria, viremia, or BKVAN. After reduction of immunosuppression, BK viremia (n = 38) resolved in 100% of patients, without increased acute rejection. Recurrent BK viremia was not observed in viremic patients without BKVAN (n = 30). All BKVAN patients (n = 7, 3.1%) cleared viremia with a mean time of 5.9 months (range 1–15 months) and manifested no decline in estimated glomerular filtration rate from 1 month to 5 years after transplantation. Viral monitoring and preemptive reduction of immunosuppression resulted in the successful resolution of BK viremia and BKVAN with excellent graft survival and renal function at 5 years.

Urine cytology as a screening tool for BK virus nephropathy: preliminary findings in 350 samples

Background BK virus allograft nephropathy (BKVAN) is caused by reactivation of BK polyomavirus and often leads to graft failure due to unsuccessful treatment. Screening and early detection with surrogate markers of viral replication are critical to guide preventative strategies. Method We prospectively evaluated the performance of urinary decoy cells, identified in ThinPrep processed specimens, and SV40T immunochemistry, performed on cell block preparations, to predict BKVAN (defined by reference histology standard, n = 350), in comparison with quantitative viraemia in kidney transplant recipients undergoing routine screening. The decoy cells were then quantified per 10 HPF. Results Decoy cells occurred in 14.8% of samples, with a sensitivity of 71.4%, specificity of 87.7%, positive predictive value (PPV) of 22.2% and negative predictive value (NPV) of 98.6% to predict BKVAN. Quantification of decoy cells improved the PPV to 53.8% (≥10cells/10 HPF), comparable to quantitative viraemia of 52.2% (≥104copies/mL). SV40T staining of urinary cell blocks provided 100% sensitivity and 91.5% specificity, however insufficient material hampered cell block preparation in many samples. Combinations of decoy cell and viraemia in a diagnostic matrix further improved BKVAN prediction. Conclusion Our preliminary findings show both quantified decoy cells and viraemia are acceptable surrogate markers of early BK viral replication for screening of kidney transplant recipients.

Immunophenotyping in BK Virus Allograft Nephropathy Distinct from Acute Rejection

Differentiating BK virus nephropathy (BKVN) from acute rejection (AR) is crucial in clinical practice, as both of them have interstitial inflammation in the grafts. The purpose of the study is to describe the inflammatory cellular constituents of BKVN and to determine the clinical utility of immunophenotyping findings in distinguishing BKVN from AR. In addition, the expression of the HLA-DR was investigated. Sixty-five renal allograft recipients were included in this study, including 22 cases of BKVN, 31 cases of AR, and 12 cases of stable allograft. Immunostaining for infiltrating lymphocytes showed that the number of CD20 cells (P < 0.001) and the percentages of CD3 (P < 0.001), CD4 (P = 0.004), CD8 (P = 0.005), and CD20 (P = 0.002) cells were all significantly different between BKVN and AR. Moreover, there were no statistically significant differences in tubule cell HLA-DR expression (P = 0.156). This observation suggests that the number of CD20 cells and the percentages of CD3, CD4, CD8, and CD20 cells in renal biopsies would aid the distinction between BKVN and AR. On the other hand, the presence of HLA-DR upregulation may not only be specific for acute rejection but also be a response to BKVN.

BK Virus Allograft Nephropathy: Enhanced Risk for ABO-Compared to HLA-Incompatible Kidney Transplantation

Introduction: It has been observed in some studies that ABO-incompatible kidney transplant recipients have a higher incidence of BK virus allograft nephropathy (BKVAN) compared to ABO-compatible recipients. This could be related to desensitisation and induction protocols or a greater risk for rejection treatment. It is unclear whether HLA-incompatible kidney recipients, who share similar treatment protocols, share this risk or whether this phenomenon is unique to ABO-incompatible patients. Methods: We analysed adult incompatible kidney transplant recipients from a prospectively kept database. 68 ABO-incompatible and 221 HLA-incompatible, transplanted between 1998 and 2010, formed the patient cohort. Patients transplanted against both immunological barriers were excluded from analysis. Protocol biopsies were performed for all incompatible patients on months 1, 3, 6 and 12 post-transplantation and indication biopsies in the context of transplant dysfunction (creatinine rise greater than 20% from baseline and/or new-onset proteinuria). All incompatible patients diagnosed with BKVAN on biopsy (protocol or for cause) were identified. Multivariable logistic regression analysis was used to identify independent risk factors for development of BKVAN. Results: Risk of BKVAN was greater amongst ABO-incompatible compared to HLA-incompatible patients (17.7% versus 5.9%, p=0.008). This compared to the BKVAN rate of 3.0% observed amongst all kidney transplant recipients, compatible or not, at this transplant centre. 42% of BKVAN cases were subclinical and diagnosed on protocol biopsy. ABO-incompatibility, male sex and age were independent predictors for development of BKVAN on multivariable logistic regression. C4d deposition without histologic features of rejection (the typical ABO-incompatible graft ‘accommodation’ phenotype) on 1-year protocol biopsies of ABO-incompatible patients, with and without BKVAN, was 40% versus 75.8% respectively (p=0.040), a putative pathophysiological mechanism. At median follow up of 1399 days post-transplantation, ABO-incompatible patients with BKVAN had death-censored graft survival of 91% and serum creatinine of 1.8 mg/dl amongst surviving kidneys. For HLA-incompatible patients, at median of 1017 days post-transplant death-censored graft survival was also 91% and serum creatinine 1.8 mg/dl amongst surviving kidneys. In contrast compatible kidney recipients, at a median of 1117 days post-transplantation, death-censored graft survival were 69% and serum creatinine 2.6 mg/dl amongst surviving kidneys. Conclusion: This study suggests that ABO-incompatible patients have an elevated risk of developing BKVAN unrelated to desensitisation, intensity of immunosuppression or risk of antibody-mediated rejection. However risk of BKVAN related graft loss is negligible, contrary to compatible kidney transplant recipients, which we hypothesise is due to early sub-clinical detection using protocol biopsy surveillance. Thus ABO-incompatible patients may have unique risk profiles and mechanisms for development and progression of BKVAN but this speculation requires further investigation.

Incidence and Outcomes of BK Virus Allograft Nephropathy among ABO- and HLA-Incompatible Kidney Transplant Recipients

ABO-incompatible kidney transplant recipients may have a higher incidence of BK virus allograft nephropathy (BKVAN) compared with ABO-compatible recipients. It is unclear whether HLA-incompatible recipients share this risk or whether this phenomenon is unique to ABO-incompatible recipients. DESIGN, SETTING, PARTICIPATION, MEASUREMENTS: This study analyzed adult incompatible kidney transplant recipients from 1998 to 2010 (62 ABO-incompatible and 221 HLA-incompatible) and identified patients in whom BKVAN was diagnosed by biopsy (per protocol or for cause). This was a retrospective analysis of a prospectively maintained database that compared BKVAN incidence and outcomes between ABO- and HLA-incompatible recipients, respectively. BKVAN link to rejection and graft accommodation phenotype were also explored. The Johns Hopkins Institutional Review Board approved this study. Risk for BKVAN was greater among ABO-incompatible than HLA-incompatible patients (17.7% versus 5.9%; P=0.008). Of BKVAN cases, 42% were subclinical, diagnosed by protocol biopsy. ABO-incompatibility and age were independent predictors for BKVAN on logistic regression. C4d deposition without histologic features of glomerulitis and capillaritis (graft accommodation-like phenotype) on 1-year biopsies of ABO-incompatible patients with and without BKVAN was 40% and 75.8%, respectively (P=0.04). Death-censored graft survival (91%) and serum creatinine level among surviving kidneys (1.8 mg/dl) were identical in ABO- and HLA-incompatible patients with BKVAN (median, 1399 and 1017 days after transplantation, respectively). ABO-incompatible kidney recipients are at greater risk for BKVAN than HLA-incompatible kidney recipients. ABO-incompatible recipients not showing the typical graft accommodation-like phenotype may be at heightened risk for BKVAN, but this observation requires replication among other groups.

Foxp3 Staining in BK Virus Allograft Nephropathy and Comparison With Acute Cellular Rejection

Background Foxp3 +CD4 +CD25 + regulatory T cells are involved in maintaining immunologic self-tolerance. These cells have been investigated in acute cellular rejection (ACR) of renal allografts. In this retrospective pathological study, we evaluated Foxp3 + immunostaining in BK virus nephropathy (BKVN). In some circumstances, BKVN may be difficult to distinguish histologically from ACR. Methods Sequential sections were made of 30 allograft core biopsies and stained for hematorylin and eosin (H&E), C4d, cytomegalovirus (all negative), SV40, CD3, CD20, and Foxp3. Twelve biopsies were from diagnosed BKVN cases, 12 were from diagnosed ACR cases, and six showed neither BKVN nor ACR (controls). The 100× field of maximum cellular inflammation was located and marked on the H&E stain. The same area on the CD3, CD20, and Foxp3 slides was marked. Staining lymphocytes were counted under 400× magnification. Degree of BKVN was assessed according to the Drachenberg scale; degree of ACR was assessed by the Banff criteria. Results The range of Foxp3 + staining (cells/mm 2) was much larger in BKVN (0–270) compared to ACR (0–35). The mean difference did not reach statistical significance owing to a large degree of overlap between the two groups. In BKVN, the Foxp3 + infiltrate correlated with the degree of CD3 + infiltrate ( P = .012), and median Foxp3 + infiltrate increased with Drachenberg grade of BKVN. CD3 + cell levels were not significantly different in BKVN versus ACR. Conclusions BKVN cases with high levels of Foxp3 + graft infiltrates may be manifesting an immune response different from that of ACR. Positive Foxp3 correlation with Drachenberg grade suggests a down-regulatory response.

An OPTN Analysis of National Registry Data on Treatment of BK Virus Allograft Nephropathy in the United States

Published data for BK virus allograft nephropathy, a recently emerged graft-threatening complication of kidney transplantation, are from limited-center series. Since June 30, 2004, the Organ Procurement Transplant Network national registry in the United States started collecting data on treatment of BK virus (TBKV) on the kidney follow-up forms. This study determined the rates of TBKV within 24 months posttransplant time and elucidated the risk factors for TBKV from this multicenter database. We queried the database for all primary and solitary kidney transplant recipients transplanted between January 1, 2003 and December 31, 2006, followed through July 18, 2008, and who were reported to have TBKV. Cumulative incidence of TBKV over time was estimated using Kaplan-Meier (K-M) method to reduce potential under reporting. A Cox proportional hazards regression model was fitted to determine risk factors for TBKV development, and time dependent Cox model was fitted to determine if TBKV was associated with higher risk of graft loss. We included 48,292 primary and solitary kidney transplants from the US Organ Procurement Transplant Network database. The cumulative K-M incidence of BKVAN kept rising over time (0.70% at 6 months posttransplant to 2.18% at 1 year, 3.45% at 2 years and 6.6% at 5 years). Risk for BKVAN was higher with certain immunosuppressive regimens that included rabbit antithymocyte globulin or tacrolimus/mycophenolate combinations. Higher center volume and living kidney donation exerted a protective effect. Of concern, TBKV rates were significantly higher in more recent transplant years. TBKV report was associated with higher risk of subsequent graft loss (adjusted hazard ratio=1.69, P<0.001).

Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients

BKVAN affects about 5% of kidney transplant recipients and may lead to graft failure. Treatment for BKVAN is challenging. Leflunomide, an immunosuppressant with antiviral activity in vitro was used successfully in some adult patients but there are no reports of its use in pediatric patients. We present our experience with three kidney transplant recipients with BKVAN who received leflunomide. Three male patients aged 9, 12, and 20 yr developed BKVAN at 9, 12, and 2 months after a kidney transplant. Immunosuppression was reduced and cidofovir was administered in all patients 2-3 wk apart. Due to inability to travel to receive cidofovir in one, lack of reduction in BK viral load in the second, and rising serum creatinine despite cidofovir in the third patient, we discontinued cidofovir and initiated leflunomide. Teriflunomide target trough levels were 30-60 microg/mL. The patients received leflunomide for 27, 26, and 24 months, respectively. BK viral load decreased below 1000 DNA copies/mL in one and was undetectable in two patients after beginning leflunomide. All patients tolerated leflunomide without side effects. Leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients.

Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy

BKVAN has emerged as a major morbidity in kidney transplant recipients. Among treatment options is cidofovir, which can be nephrotoxic. We previously reported that intermediate dose cidofovir could be used without significant nephrotoxicity. We present extended results of the same treatment protocol in a larger cohort and with longer follow up. Diagnosis of BKVAN was based on detection of BK viral DNA from plasma and renal allograft biopsy tissue. All patients received cidofovir (0.25-1 mg/kg/dose) every 2-3 wk. Total number of cidofovir doses ranged from 1 to 18 (mean 8). This report includes eight patients, aged 5-21 yr, treated with intermediate dose cidofovir. Median follow-up was 11 months (range 4-32). Mean fall in reciprocal of serum creatinine (1/sCr) from baseline at BKVAN diagnosis was 64% (range 28-120%). A time-series plot of plasma BK virus PCR and 1/sCr showed marked reduction in viral loads without significant deterioration in 1/sCr from the initial value at BKVAN diagnosis. In this larger series with extended follow up, intermediate dose cidofovir without probenecid for the treatment of BKVAN continues to show stabilization of renal function without progression to renal failure.

Assessing the Value of Ureteral Stent Placement in Pediatric Kidney Transplant Recipients

Ureteral stent placement at kidney transplantation may reduce stenosis or leakage (S/L) complication rates. However, stent placement may also increase risk for early urinary tract infection (early UTI; <3 months after transplant) and BK virus allograft nephropathy (BKVAN). In children, the usefulness of stent placement is not well defined. We analyzed retrospective data from children transplanted at our center for the three above outcomes in relation to stents. At our center, stent placement decision is driven by surgeon preference. Among 129 transplants from 1996 to 2006, early UTI was seen in 9.3% and S/L in 4.6%. By univariate analyses, stent placement was a significant risk factor for early UTI (P=0.0399) but not protective for S/L (P=0.23). In multivariate analyses, stent placement, human leukocyte antigen match, and bladder augmentation increased the odds ratio for early UTI. Only deceased donor source increased the odds ratio for S/L. In a truncated data set from 1999 to 2006, BKVAN occurred in 9 of 93 (9.6%). Per minute increase in warm ischemia time was the only significant risk factor for BKVAN by both univariate and Cox regression analyses. Stent placement did not improve graft survival (P=0.5726) but required general anesthesia for removal in the operating room, leading to additional cost and potential risk. Routine stent placement in children in this era of low urological complication rates and BKVAN needs reevaluation.

Ureteral Stent Placement and BK Virus Allograft Nephropathy in Renal Transplant Recipients

Ureteral Stent Placement and BK Virus Allograft Nephropathy in Renal Transplant Recipients

Intermediate‐dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy

BK virus allograft nephropathy (BKVAN) is a rising complication in kidney transplant recipients. Reducing immunosuppression has been the initial form of therapy in most cases, but is not always associated with improvement in graft function. Anti-viral therapy with low-dose cidofovir (0.25-0.42 mg/kg/dose) has been used successfully in some patients, but dose-related nephrotoxicity has limited its use. We present our experience with 3 kidney transplant recipients diagnosed with BKVAN who received intermediate-dose cidofovir (0.75-1.0 mg/kg/dose) without probenecid, and without concomitant nephrotoxicity. Three female patients, ages 8, 19 and 20 yr, presented with elevated serum creatinine (SCr) values, BK virus stain positive on renal biopsy and high plasma BK viral loads. As a result of viral loads being >2 million copies/ml in two patients and a lack of response to reduction in immunosuppression in the third, we initiated therapy with low-dose cidofovir. Because of persistent positive BK stain and positive plasma viral load, we then administered intermediate-dose cidofovir, without probenecid, for several subsequent doses (seven to 15 infusions till date). All patients tolerated the intermediate-dose cidofovir with no significant rise in SCr during the course of the infusions. The most recent SCr values in all three patients were improved from those at the initial diagnosis of BKVAN. All three patients showed a marked drop in BK viral loads when on intermediate-dose cidofovir, with complete clearing of viremia in two patients. In our experience, intermediate-dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.

BK Virus in Kidney Transplantation: A Case Study

Prevention as well as treatment of viral infections in transplant recipients relies on minimal immunosuppressive therapy consistent with graft survival and the use of antiviral therapies in proportion to perceived risk. BK virus creates an even greater challenge in posttransplant management and graft survival because of difficulty in diagnosing and treatment. BK nephropathy develops in 1% to 5% of transplant recipients, with loss of allograft function occurring in 50% of the cases. We present a case of a 67-year-old man who developed BK virus allograft nephropathy 9.5 months after transplantation. His allograft function was extended through rigorous treatment with an antiviral agent, reduction of immunosuppressant, and monitoring in an outpatient setting.

BK virus in kidney transplantation: a case study

Prevention as well as treatment of viral infections in transplant recipients relies on minimal immunosuppressive therapy consistent with graft survival and the use of antiviral therapies in proportion to perceived risk. BK virus creates an even greater challenge in posttransplant management and graft survival because of difficulty in diagnosing and treatment. BK nephropathy develops in 1% to 5% of transplant recipients, with loss of allograft function occurring in 50% of the cases. We present a case of a 67-year-old man who developed BK virus allograft nephropathy 9.5 months after transplantation. His allograft function was extended through rigorous treatment with an antiviral agent, reduction of immunosuppressant, and monitoring in an outpatient setting.

Viral regulatory region sequence variations in kidney tissue obtained from patients with BK virus nephropathy

The polyomavirus genome contains a noncoding control region (NCCR), which is believed to contain the enhancer elements that are important activators of viral transcription. We hypothesized that DNA sequence variations in this region play a role in the pathogenesis of BK virus allograft nephropathy (BKVAN). Tissue sections were prepared from 26 paraffin-embedded biopsies with BKVAN obtained from 15 patients. The sections were lysed in a proteinase K buffer and subjected to DNA sequencing using Big Dye cycle sequencing reactions run on an automated DNA sequencer (ABI 310). NCCR anatomy was compared to the genomic sequence of archetype BKV strain WW. Twelve putative transcription factor binding sites showed nucleotide substitutions, deletions, or duplications in at least one of the biopsies studied. Changes were most commonly found in binding sites for granulocyte/macrophage stimulating factor promoter (24/26 biopsies) and nuclear factor-I (NF-I) transcription factor (21/22 biopsies). Less frequent changes were seen at other binding sites, including T antigen (3/22 biopsies) and the cytomegalovirus immediate early (CMV IE-1) promoter (3/22 biopsies). Five biopsies showed complex rearrangements reminiscent of those described in JC virus-associated progressive multifocal leukoencephalopathy. The regulatory region of BKV shows sequence heterogeneity in biopsy tissue with viral nephropathy. Sequence variations frequently affect putative transcription factor binding sites, with potential implications for promoter activity related to genes important in viral replication. Architectural rearrangements were found in some cases but did not appear to be a prerequisite for the pathogenesis of BKVAN.

Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy.

BK virus (BKV) allograft nephropathy (BKVAN) is a complication in renal transplantation recipients. Histopathology is the gold standard for diagnosis. Quantitative polymerase chain reaction (PCR) assay for renal biopsy has not been evaluated as a diagnostic test. Determination of renal BKV load may identify patients at risk for disease before histologic nephropathy. Quantitative PCR assay for BKV DNA was performed in 28 biopsies of patients with BKVAN; 50 biopsies were performed before a diagnosis of BKVAN, and 126 control biopsies were from patients without a history of BKVAN. BKV DNA was present in 19 of 50 (38%) biopsies performed 1 to 164 weeks before diagnosis of BKVAN. The viral load (mean 216 copies/cell) was lower than in biopsies of patients with BKVAN (mean 6063 viral copies/cell, <0.05). In 10 of 127 (7.8%) control biopsies, a low level of BKV DNA (mean 3.8 copies/cell) was found in three biopsies from chronic allograft nephropathy patients; two biopsies with acute rejection; four biopsies with borderline change; and one biopsy with cytomegalovirus nephritis. BKV load exceeding 59 copies per cell identified all cases of BKVAN. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of quantitative PCR were 100%, 92.1%, 73.6%, and 100%, respectively. Lower levels of BKV DNA were identified in biopsies performed before viral nephropathy development. Future research will determine if earlier recognition of at-risk patients allows application of antiviral strategies to improve graft outcome.