Polyomavirus BK-associated Nephropathy Research Articles

Increasing of the interferon-γ gene expression during polyomavirus BK infection in kidney transplant patients

Polyomavirus BK infection is a common complication and a major cause of morbidity after kidney transplantation. Surveillance of kidney transplant recipients was threatened by reactivation of polyomavirus BK infection can lead to polyomavirus BK-associated nephropathy (PVN). Antiviral immunoregulatory markers like Gamma interferon (IFN-γ) might also affect the polyomavirus BK pathogenesis for its role in antiviral host defense, graft rejection, and regulative of the adaptive immune responses. After screening polyomavirus BK infection, using Real time PCR (Taq-Man), the possible association between polyomavirus BK infection with IFN-γ gene expression was assessed. The mRNA levels of IFN-γ was examined in (n = 23) polyomavirus BK infected and (n = 23) non-infected kidney transplant patients in comparison with healthy controls (n = 23), using an in-house Real time PCR (SYBR Green) assay. The correlation of IFN-γ expression with viral load as well as other variables was also performed. The mRNA expression level of IFN-γ was significantly higher in polyomavirus BK infected patients (fold = 58.47) compared with non-infected ones (fold = 4.62), and healthy controls (p = 0.002). IFN-γ expression was higher in patients with higher viral load (p = 0.001). IFN-γ expression was correlated with viral load (r = 0.7, p < 0.0001). Accordingly, polyomavirus BK infection can induce IFN-γ gene over expression in kidney transplant infected patients. The results emphasized on the determinative role of IFN-γ in the pathogenesis of activated polyomavirus BK infection and also its importance in managing the clinical complications after kidney transplantation due to virus reactivation, requiring further investigation.

Polyomavirus BK-Associated Nephropathy After Kidney Transplantation

Polyomavirus BK-associated nephropathy is cause of kidney transplant morbidity and graft failure. Reported prevalence can vary significantly between centers, probably depending on the immunosuppressive regime used, averaging 5% and the reported incidence of allograft failure ranges from 15 to 50% of affected individuals. Aim To evaluate the evolution of BK virus nephropathy in our transplant center Materials: A descriptive, retrospective study of the clinical evolution of BK virus nephropathy in adult kidney transplant patients from 10 / 2011-10 / 2016. The diagnostic suspicion was through the technique of screening and / or renal dysfunction and confirm by kidney biopsy. Screening was performed by Polymerasa Chain Reaction for BKV(+ greater than 10 4 copies / ml) at 2-6-9-12-month and then annually and after the treatment episode due to graft rejection. Patients with a diagnosis of BK nephropathy we decided 1- Reduction of immunosuppression (suspension of mycophenolate by leflunomide and tacrolimus reduction (maintaining dosages average 5ng / ml )or sirolimus, corticoids and leflunomide), and following with 2-Evaluation of renal function,3- Viral load, 4-antiHLA antibodies and 5-Renal biopsy. Half of the patients also received IVIG 400mg / kg / day for 5 days as a treatment. Results 18/774 renal tx patients had BK nephropathy, at 553 ± 355 days of transplant. 6 for screening and the rest for renal dysfunction. Age 42 ± 12y, 50% women, 14 LD, 4 DD. 6/18 presented previous rejections 2 Mixed 4 cellular Kidney. Biopsies showed Stage I Nephropathy 8 patients (44.4%), S II 9 patients (50%) and S III 1 patient (5.6%). Average basal creatinine (n = 18) 2.5 ± 0.18, 6 months (n = 16) 3.1 ± 1.6, 12 m (n = 15) 2.7 ± 0.8, 24 m (n = 10) 2.62 ± 0.8, 36m (n = 6) 2.9 ± 0.2. 2 patients presented by biopsy, cellular rejection at 3 months of the diagnosis, treated with steroid pulses. No development of de novo antiHLA DSA was observed in this group of patients. The negativization of the viral load BKV was at 3 months in 5 patients and the rest at 6 months. Only 12 renal biopsies were performed(X 12m), presenting an increase in interstitial infiltration and tubulitis in 2 patients). Loss of grafts in 3 patients (16.6%), 2/18 at 4 months and 1/18 at 10 months. There were no deaths. Conclusions A low incidence (2,34%) of BK virus nephropathy is observed in this population. There were no differences in the evolution of patients treated with / without IVIG (pNS) especially in the negativization of viral load. Higher percentage of living donors (77%) with BK nephropathy due probably immunosuppression charge and / or unidentified serology of BK virus in donors.

Polyomavirus BK Induces Inflammation via Up-regulation of CXCL10 at Translation Levels in Renal Transplant Patients with Nephropathy.

Polyomavirus BK-associated nephropathy (BKAN) is an important mechanism for renal losing after kidney transplantation. It seems that Polyomavirus BK can induce nephropathy by direct cell lysis and stimulation of the immune system and induction of inflammation. CXCL10 is a pro-inflammatory cytokine which stimulates the migration and activation of immune cells to the infected sites. Therefore, the aim of the current study was to evaluate the messenger RNA (mRNA) and protein levels of CXCL10 in the Polyomavirus BK-infected and Polyomavirus BK-non-infected post renal transplanted nephropathic patients in comparison to healthy controls. In this cross-sectional study, Polyomavirus BK-infected post renal transplanted nephropathic patients, Polyomavirus BK-non-infected post renal transplanted nephropathic patients, and healthy controls were enrolled to evaluate mRNA and protein levels of CXCL10 by real-time PCR and ELISA techniques, respectively. mRNA levels of CXCL10 were not significantly different among participants, while serum levels of CXCL10 were significantly elevated in the Polyomavirus BK-infected patients when compared to non-infected patients as well as controls and in non-infected patients when compared to healthy controls. Due to the results, it seems that Polyomavirus BK may potentially induce renal losing through stimulation of inflammation via increasing translation of CXCL10, as a pro-inflammatory chemokine.

How to Improve the Positive Predictive Value of Urinary Decoy Cell Surveillance for Polyomavirus BK-Associated Nephropathy in Kidney Transplant Patients

BackgroundPolyomavirus BK-associated nephropathy (BKVN) has been a serious problem after kidney transplantation. Detection of urinary decoy cells (UDCs) and assessment of polyomavirus BK nucleic acids by polymerase chain reactions (PCRs) are currently used, noninvasive tests. PCRs have better positive predictive value (PPV) but higher cost and lower accessibility. This study investigated ways to improve the PPV of UDCs for BKVN prediction. MethodsFrom 2000 to 2013, kidney transplant recipients with sustained UDCs for more than half a month and who had received allograft biopsies were enrolled. We analyzed the PPV of UDCs for BKVN with 2 variables: (i) the percentage changes in serum creatinine (SCr) levels and (ii) the duration of sustained UDCs by receiver operating characteristic (ROC) curve analysis; we predicted the percentage changes in SCr levels with the corresponding PPV using a linear regression model. ResultsBKVN was diagnosed in 26 of 68 enrolled patients. The percentage changes in SCr levels significantly deteriorated in the BKVN group during 1–2 months of UDC positivity. According to ROC curve analysis, percentage changes in SCr levels had a significant discriminating power for BKVN during 1–1.5 month, and if the percentage changes in SCr levels were >19%, the PPV of UDCs for BKVN was 50%. ConclusionsAn UDC surveillance program is a judicious strategy to predict BKVN in kidney transplant patients, particularly when graft renal function shows deterioration after 1 month of UDC positivity.

Banff 2013 update: Pearls and pitfalls in transplant renal pathology.

The pathological classification of rejection in renal allografts (Banff classification) has undergone substantial evolution for more than 20 years, and has been the diagnostic gold standard in clinical practice. The 2013 updated Banff classification encompasses a revised scheme of antibody-mediated rejection (ABMR) that consists of donor-specific antibody (DSA) positivity, characteristic histological manifestations for both acute and chronic ABMR, and DSA-induced endothelial cell injury which is represented by either C4d positivity, microvascular inflammation or expression of activated endothelial gene transcripts. Other modified criteria include a C4d positivity threshold, and histological definition of transplant glomerulitis and transplant glomerulopathy. Morphologically, glomerulonephritis, either recurrent or de novo, can be challenging to differentiate from ABMR-mediated transplant glomerulitis. Endothelial arteritis by itself does not warrant the diagnosis of acute T-cell mediated rejection; ABMR should also be considered based on the DSA test results. With regard to polyomavirus BK-associated nephropathy, immunohistochemical examination using anti-simian virus (SV) 40 antibody can be a promising method to assess the quantitative viral load of polyomavirus BK and graft survival. In summary, the 2013 updated Banff classification strictly defines ABMR with histopathological and serological criteria irrespective of C4d positivity. Inclusion of gene expression data relevant to ABMR highlights that the Banff criteria have entered the era of 'Seeing the Unseen' schemes, reflecting recent advances in understanding the molecular events in allograft injury.

Factors Influencing Viral Clearance and Graft Outcomes Following Diagnosis of Polyomavirus BK-Associated Nephropathy After Renal Transplantation.

Factors Influencing Viral Clearance and Graft Outcomes Following Diagnosis of Polyomavirus BK-Associated Nephropathy After Renal Transplantation.

Immunity to Polyomavirus BK Infection: Immune Monitoring to Regulate the Balance between Risk of BKV Nephropathy and Induction of Alloimmunity

Polyomavirus BK-associated nephropathy (PyVAN) is the main infectious cause of allograft damage after kidney transplantation. A number of studies revealed an association between the presence of BKV-specific cellular immunity and BK viral clearance, with patients failing to recover specific T cells progressing to PyVAN. Evolution to allograft dysfunction can be prevented by restoration of BKV-specific immunity through a stepwise reduction of maintenance immunosuppressive drugs. Prospective monitoring of BK viral load and specific immunity, together with B-cell alloimmune surveillance, may allow a targeted modification/reduction of immunosuppression, with the aim of obtaining viral clearance while preventing graft injury due to deposition of de novo donor-specific HLA antibodies and late/chronic antibody-mediated allograft injury. Innovative, immune-based therapies may further contribute to BKV infection prevention and control.

Infected Donor Organs as the Main Source for BK Viremia in Kidney Recipients?

Introduction: BK-virus (BKV) infection may lead to polyomavirus BK-associated nephropathy (PVAN), which is a serious complication after renal transplantation (RTX) and may lead to allograft loss. The exact etiology is still unknown. Concerning BK-seropositivity of more than 90% in general population PVAN could either be caused by a new infection or reactivation of the virus from the recipient or by augmented replication of the persistent virus in the allograft. Aim of this retrospective single-center analysis was to detect the prevalence of BK viremia of kidney transplant recipients and search the main infection source of polymaviruses in transplanted kidneys. Methods: BKV-screening was made by serum-PCR in 506 patients (pts) who were transplanted during January 2005 and June 2011. Furthermore we examined the BK viremia of the recipients who received the “partner kidney” from the same donor of the BKV positive patients and compared them with recipients from the “partner kidney” of a negative group. Results: From 506 kidney transplant recipients with at least one assessment of BK-PCR, PCR became positive (VL > 500 cop/ml) in exactly 100 pts (19.8%). In 33 cases from these pts the contralateral kidney was also transplanted in our centre and the BK viremia of these recipients could be followed up. In 18 (54.6%) recipients of the contralateral kidney (“partner recipient”) BK viremia could also be detected. In 10 (30.3%) “partner recipients” the BKV-PCR was negative and in 5 (15.2%) cases no BKV-PCR was made. In a coincidentally chosen BKV negative group of 100 pts, in 27 cases the contralateral kidney was transplanted in our centre and therefore could be followed up. In only 1 (3.7%) case positive BK viremia could be found. In 18 (66.7%) BKV-PCR was negative and in 8 (29.6%) cases no BKV-PCR was made. Conclusion: The prevalence of BK viremia in kidney transplanted patients in our centre is high (19.8%). In 54.6% of the BKV positive cases, where the contralateral kidney was also transplanted in our centre, the recipient of the “partner recipients” also developed a BK viremia compared to only 3.7% BKV positive cases in recipients of the contralateral kidney from our BKV negative patients. This indicates that infected donor organs could be mainly responsible for BK viremia and therefore for PVAN. Multi-centre studies with more data are necessary to confirm this assumption.

Infected Donor Organs as the Main Source for BK Viremia in Kidney Recipients?

Introduction: BK-virus (BKV) infection may lead to polyomavirus BK-associated nephropathy (PVAN), which is a serious complication after renal transplantation (RTX) and may lead to allograft loss. The exact etiology is still unknown. Concerning BK-seropositivity of more than 90% in general population PVAN could either be caused by a new infection or reactivation of the virus from the recipient or by augmented replication of the persistent virus in the allograft. Aim of this retrospective single-center analysis was to detect the prevalence of BK viremia of kidney transplant recipients and search the main infection source of polymaviruses in transplanted kidneys. Methods: BKV-screening was made by serum-PCR in 506 patients (pts) who were transplanted during January 2005 and June 2011. Furthermore we examined the BK viremia of the recipients who received the “partner kidney” from the same donor of the BKV positive patients and compared them with recipients from the “partner kidney” of a negative group. Results: From 506 kidney transplant recipients with at least one assessment of BK-PCR, PCR became positive (VL > 500 cop/ml) in exactly 100 pts (19.8%). In 33 cases from these pts the contralateral kidney was also transplanted in our centre and the BK viremia of these recipients could be followed up. In 18 (54.6%) recipients of the contralateral kidney (“partner recipient”) BK viremia could also be detected. In 10 (30.3%) “partner recipients” the BKV-PCR was negative and in 5 (15.2%) cases no BKV-PCR was made. In a coincidentally chosen BKV negative group of 100 pts, in 27 cases the contralateral kidney was transplanted in our centre and therefore could be followed up. In only 1 (3.7%) case positive BK viremia could be found. In 18 (66.7%) BKV-PCR was negative and in 8 (29.6%) cases no BKV-PCR was made. Conclusion: The prevalence of BK viremia in kidney transplanted patients in our centre is high (19.8%). In 54.6% of the BKV positive cases, where the contralateral kidney was also transplanted in our centre, the recipient of the “partner recipients” also developed a BK viremia compared to only 3.7% BKV positive cases in recipients of the contralateral kidney from our BKV negative patients. This indicates that infected donor organs could be mainly responsible for BK viremia and therefore for PVAN. Multi-centre studies with more data are necessary to confirm this assumption.

Activation of innate immune defense mechanisms contributes to polyomavirus BK-associated nephropathy

Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-β mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1β or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.

BK Virus-Specific Immunity Kinetics: A Predictor of Recovery From Polyomavirus BK-Associated Nephropathy

Impaired BKV-specific immunity is associated with development of BKV-associated nephropathy. Suitable immunological parameters to identify patients at risk, however, are still debated. We monitored 18 kidney-transplant recipients through the course of self-limited BKV-reactivation (n = 11) and BKV-associated nephropathy (n = 7). BKV-specific cellular immunity directed to nonstructural small and Large T-antigen, and structural VP1-3 was analyzed in an interferon-γ Elispot assay. BKV-specific IgM and IgG were measured using an enzyme-linked immunosorbent assay simultaneously. BKV-specific cellular immunity directed to five BKV-proteins increased significantly from diagnosis to resolution of BKV-reactivation (p < 0.001). Patients with self-limited BKV-reactivation developed BKV-specific T cells without therapeutic interventions, and cleared BKV-reactivation within a median period of 1 month. Patients with BKV-associated nephropathy, however, showed BKV-specific T cells after a median period of 5 months after therapeutic interventions only, and cleared BKV-reactivation after a median period of 8 months. Anti-structural T cells were detected earlier than anti-nonstructural T cells, which coincided with BKV-clearance. Patients with BKV-associated nephropathy showed the highest frequencies of BKV-specific T cells at recovery, the highest increase in BKV-specific IgG and persistence of increased IgM levels (p < 0.05). Our results suggest prognostic values of BKV-specific immune monitoring to identify those patients at risk of BKV-associated nephropathy and to aid in the management of therapeutic interventions.

Prevalence and risk factors of polyomavirus BK replication in simultaneous pancreas/kidney transplant recipients from a single transplant center

BK virus (BKV) replication is considered as a marker of risk for polyomavirus BK-associated nephropathy (PVAN). We evaluated the occurrence and risk factors for BKV DNA positivity following simultaneous pancreas/kidney transplantation (SPK). Point prevalence of BK viruria and viremia was assessed in 183 SPK recipients. Real-time polymerase chain reaction was used with a detection threshold of 10(3) copies/mL. High-level BKV positivity was defined as viruria and/or viremia >10(7) and >10(4) copies/mL, respectively. BKV-positive patients were retested after 4-13 months and underwent an additional six-month clinical follow-up. Urine and serum BKV positivity was detected in 28 (17.3% of available samples) and 7 (3.8%) patients, with high-level viruria and viremia occurring in 6 (3.7%) and 3 (1.6%) patients, respectively. PVAN was biopsy-confirmed in 1 and suspected as a cause of progressive renal failure in another SPK recipient. Patients with single low-level viruria did not progress to high-level positivity or PVAN at follow-up. In multivariate analysis, pre-transplant diabetes duration and delayed graft function were independently associated with BKV positivity. Point prevalence of high-level BKV positivity and PVAN was low in SPK recipients from a single center. Diabetes duration and delayed graft function were independent risk factors for BKV replication.

The Decade of Polyomavirus BK-Associated Nephropathy: State of Affairs

In the last 10 years, better immunosuppression drugs have decreased the rates of acute rejection in kidney transplantation but have also led to the emergence of polyomavirus-associated nephropathy (PVAN). This occurs in 1% to 10% of patients with kidney transplantion and is caused by BK virus in more than 95% of cases. Less than 5% of cases are attributed to the JC virus. Initially, lack of recognition or late diagnosis of PVAN resulted in rapid loss of graft function in more than 50% of patients. In recent years, it has become clear that early diagnosis and timely reduction in immunosuppression is the only proven measure, which significantly affects the outcome of PVAN. Diverse interventions have been explored including the adjunctive use of cidofovir, leflunomide, fluoroquinolones, and intravenous immunoglobulins. Allograft histology is needed to definitively establish the diagnosis of PVAN, but is of limited sensitivity in the early stage of disease. Well-established techniques and protocols for systematic screening by urine cytology and quantitative molecular-genetic techniques allow now for timely intervention before irreversible parenchymal changes occur. Moreover, preemptive reduction in immunosuppression is most effective in presumptive PVAN as defined by surrogate markers (i.e., high BK virus viremia). In this setting, preservation of graft function can be considered the rule. Nevertheless, the recovery of BK virus-specific T-cell immunity may require prolonged periods during which cytopathic damage may continue to accumulate. Despite remarkable progress in the field, important challenges remain, such as the rare patient with PVAN refractory to any intervention and the newly recognized association of PVAN with urogenital tumors.

Polyomavirus BK Replication Dynamics In Vivo and In Silico to Predict Cytopathology and Viral Clearance in Kidney Transplants

Fast BK virus (BKV) replication in renal tubular epithelial cells drives polyomavirus-BK-associated nephropathy (PVAN) to premature kidney transplant (KT) failure. BKV also replicates in urothelial cells, but remains asymptomatic in two-thirds of affected KT patients. Comparing 518 day-matched plasma-urine samples from 223 KT patients, BKV loads were approximately 3000-fold higher in urine than in plasma (p < 0.000001). Molecular and quantitative parameters indicated that >95% of urine BKV loads resulted from urothelial replication and <5% from tubular epithelial replication. Fast BKV replication dynamics in plasma and urine with half-lives of <12 h accounted for daily urothelial and tubular epithelial cell loss of 4 x 10(7) and 6 x 10(7), respectively. BKV dynamics in both sites were only partly linked, with full and partial discordance in 36% and 32%, respectively. Viral expansion was best explained by models where BKV replication started in the kidney followed by urothelial amplification and tubular epithelial cell cross-feeding reaching a dynamic equilibrium after approximately 10 weeks. Curtailing intrarenal replication by 50% was ineffective and >80% was required for clearing viremia within 7 weeks, but viruria persisted for >14 weeks. Reductions >90% cleared viremia and viruria by 3 and 10 weeks, respectively. The model was clinically validated in prospectively monitored KT patients supporting >80% curtailing for optimal interventions.

Use of Leflunomide in the Treatment of Polyomavirus BK-Associated Nephropathy

To review the available literature describing the use of leflunomide for the treatment of polyomavirus BK-associated nephropathy (BKVAN) in renal transplant recipients. Relevant literature was obtained through MEDLINE (1950-May 2008) and Science Citation Index Expanded (1900-May 2008) by using search terms leflunomide, Arava, polyomavirus, polyoma, BK virus, and transplant. Additional articles were identified through a manual search of the reference lists of the articles obtained. All articles that were written in English and discussed leflunomide use for BKVAN in renal transplant recipients were evaluated. Case reports and in vitro studies were included in this review. BKVAN has emerged as a problematic infectious complication with limited treatment options in renal transplant recipients. Leflunomide, used off-label for refractory BKVAN, is postulated to possess both antiviral and immunosuppressive properties. Two in vitro culture studies, 5 case reports/series, 2 retrospective cohort studies, and 3 prospective observational trials that described leflunomide use in BKVAN were identified. Available literature suggests that leflunomide at target blood concentrations of around 40 mg/L, in addition to immunosuppressive reduction, reduces BK viremia/viruria and graft failure, with few dose-limiting adverse events. It is highly recommended that routine complete blood cell counts, hepatic function panels, and drug concentrations be monitored to detect toxicity. Leflunomide appears to be promising as adjunctive treatment of BKVAN in renal transplant patients. Due to the lack of controlled randomized trials, however, use of leflunomide as first-line treatment cannot be routinely recommended.

Polyomavirus BK with rearranged noncoding control region emerge in vivo in renal transplant patients and increase viral replication and cytopathology

Immunosuppression is required for BK viremia and polyomavirus BK–associated nephropathy (PVAN) in kidney transplants (KTs), but the role of viral determinants is unclear. We examined BKV noncoding control regions (NCCR), which coordinate viral gene expression and replication. In 286 day–matched plasma and urine samples from 129 KT patients with BKV viremia, including 70 with PVAN, the majority of viruses contained archetypal (ww-) NCCRs. However, rearranged (rr-) NCCRs were more frequent in plasma than in urine samples (22 vs. 4%; P < 0.001), and were associated with 20-fold higher plasma BKV loads (2.0 × 104/ml vs. 4.4 × 105/ml; P < 0.001). Emergence of rr-NCCR in plasma correlated with duration and peak BKV load (R2 = 0.64; P < 0.001). This was confirmed in a prospective cohort of 733 plasma samples from 227 patients. For 39 PVAN patients with available biopsies, rr-NCCRs were associated with more extensive viral replication and inflammation. Cloning of 10 rr-NCCRs revealed diverse duplications or deletions in different NCCR subregions, but all were sufficient to increase early gene expression, replication capacity, and cytopathology of recombinant BKV in vitro. Thus, rr-NCCR BKV emergence in plasma is linked to increased replication capacity and disease in KTs.

Leflunomide treatment for polyomavirus BK-associated nephropathy after kidney transplantation

Polyomavirus-associated nephropathy (PVAN) affects 1-10% of kidney-transplant (KT) patients, with graft failure/loss in approximately 90% of cases. Reducing immunosuppression is the key treatment option, but addition of leflunomide may improve BK Virus (BKV) clearance and graft survival. In a prospective open-labeled study, 12 KT patients with biopsy-proven PVAN were treated with reduced immunosuppression and leflunomide. BKV viremia and graft function were followed. PVAN was diagnosed at 6 months (3-192) post-transplant; median serum creatinine concentration (sCC) was 189 micromol/l (92-265). After 16 months (8-30) of follow-up, the sCC was 150 micromol/l (90-378, NS). Renal function improved in six cases (50%), remained stable in two (16.6%) and deteriorated in four (33.4%), with graft loss in two (17%). Clearance of BKV viremia was observed in five (42%) cases. Side effects included anemia in six cases leading to leflunomide withdrawal in two patients, and mild thrombocytopenia. In KT patients diagnosed with PVAN, leflunomide plus reduced immunosuppression improved graft function in 66.6%, cleared BKV viremia in 42%, and resulted in side effects in 17%. This limited efficacy contrasts with other reports and falls short of expectation. We conclude that active screening, earlier diagnosis and intervention remain the cornerstones of treatment.

Impact of a polyomavirus (BKV) infection on mRNA expression in human endothelial cells

Polyomavirus BK-associated nephropathy (PVAN) is an emerging cause of early renal transplant failure. In order to learn more about the cellular response to BK virus, microarrays were used to study its effect on mRNA expression in human endothelial cells. The oligo-based, 35 k arrays used cover the predicted 25,000 human protein-expressing genes, and distinguish between a number of alternatively spliced mRNAs. Four parallel experiments were performed for each of two time-points (24 and 40 h) during the first round of the 48 h viral replicative cycle. Immunoperoxidase staining demonstrated that the pulse exposure to virus caused infection in at least 75% of the cells. At 24 h, 55 genes were more than doubly up-regulated and 249 genes were similarly down-regulated; at 40 h, the numbers were 242 and 104, respectively. Gene ontology analyses suggested that immune/defence response genes were selectively down-regulated. Genes involved in cell division and DNA replication tended to be up-regulated, which may reflect an attempt on behalf of the virus to promote viral replication. Genes associated with PVAN were not induced, suggesting that these genes are not required for viral replication, but rather reflect circumstances specific for the disease. Only a few immuno-related genes were turned on, including the interferon response genes G1P2 and IFIT3. However, some of the up-regulated genes of unknown function may be involved in viral defence.

The natural history, risk factors and outcomes of polyomavirus BK-associated nephropathy after renal transplantation

The natural history, risk factors and outcomes of polyomavirus BK-associated nephropathy after renal transplantation