Polyomavirus-associated nephropathy

Polyomaviruses BK and JC are ubiquitous viruses with high seroprevalence rates in general population.Following primary infection,polyomaviruses BK and JC persist latently in different sites,particularly in the reno-urinary tract.Reactivation from latency may occur in normal subjects with asymptomatic viruria,while it can be associated to nephropathy(PVAN)in kidney transplantat recipients.PVAN may occur in 1%-10%of renal transplant patients with loss of the transplanted organ in 30%up to 80%of the cases.Etiology of PVAN is mainly attributable to BK virus,although approximately5%of the cases may be due to JC.Pathogenesis of PVAN is still unknown,although viral replication and the lack of immune control play a major role.Immunosuppression represents the condicio sine qua non for the development of PVAN and the modulation of anti-rejection treatment represents the first line of intervention,given the lack of specific antiviral agents.At moment,an appropriate immunemodulation can only be accomplished by early identification of viral reactivacation by evaluation of polyomavirus load on serum and/or urine specimens,particularly in the first year post-trasplantation.Viro-immunological monitoring of specific cellular immune response could be useful to identify patients unable to recover cellular immunity posttransplantation,that are at higher risk of viral reactivation with development of PVAN.Herein,the main features of polyomaviruses BK and JC,biological properties,clinical characteristics,etiopathogenesis,monitoring and diag-nosing of PVAN will be described and discussed,with an extended citation of related relevant literature data.

Incidence, risk factors, and outcome of BK polyomavirus infection after kidney transplantation

BACKGROUND Polyomavirus-associated nephropathy is a leading cause of kidney allograft failure. Therapeutic options are limited and prompt reduction of the net state of immunosuppression represents the mainstay of treatment. More recent application of aggressive screening and management protocols for BK-virus infection after renal transplantation has shown encouraging results. Nevertheless,long-term outcome for patients with BK-viremia and nephropathy remains obscure. Risk factors for BK-virus infection are also unclear.AIM To investigate incidence, risk factors, and outcome of BK-virus infection after kidney transplantation.METHODS This single-centre observational study with a median follow up of 57(31-80) mo comprises 629 consecutive adult patients who underwent kidney transplantation between 2007 and 2013. Data were prospectively recorded and annually reviewed until 2016. Recipients were periodically screened for BK-virus by plasmaquantitative polymerized chain reaction. Patients with BK viral load ≥ 1000 copies/mL were diagnosed BK-viremia and underwent histological assessment to rule out nephropathy. In case of BK-viremia, immunosuppression was minimized according to a prespecified protocol. The following outcomes were evaluated: patient survival, overall graft survival, graft failure considering death as a competing risk, 30-d-event-censored graft failure, response to treatment,rejection, renal function, urologic complications, opportunistic infections, newonset diabetes after transplantation, and malignancies. We used a multivariable model to analyse risk factors for BK-viremia and nephropathy.RESULTS BK-viremia was detected in 9.5% recipients. Initial viral load was high(≥ 10000 copies/mL) in 66.7% and low(< 10000 copies/mL) in 33.3% of these patients.Polyomavirus-associated nephropathy was diagnosed in 6.5% of the study population. Patients with high initial viral load were more likely to experience sustained viremia(95% vs 25%, P < 0.00001), nephropathy(92.5% vs 15%, P <0.00001), and polyomavirus-related graft loss(27.5% vs 0%, P = 0.0108) than recipients with low initial viral load. Comparison between recipients with or without BK-viremia showed that the proportion of patients with Afro-Caribbean ethnicity(33.3% vs 16.5%, P = 0.0024), panel-reactive antibody ≥ 50%(30% vs14.6%, P = 0.0047), human leukocyte antigen(HLA) mismatching > 4(26.7% vs13.4%, P = 0.0110), and rejection within thirty days of transplant(21.7% vs 9.5%; P= 0.0073) was higher in the viremic group. Five-year patient and overall graft survival rates for patients with or without BK-viremia were similar. However,viremic recipients showed higher 5-year crude cumulative(22.5% vs 12.2%, P =0.0270) and 30-d-event-censored(22.5% vs 7.1%, P = 0.001) incidences of graft failure than control. In the viremic group we also observed higher proportions of recipients with 5-year estimated glomerular filtration rate < 30 mL/min than the group without viremia: 45% vs 27%(P = 0.0064). Urologic complications were comparable between the two groups. Response to treatment was complete in55%, partial in 26.7%, and absent in 18.3% patients. The nephropathy group showed higher 5-year crude cumulative and 30-d-event-censored incidences of graft failure than control: 29.1% vs 12.1%(P = 0.008) and 29.1% vs 7.2%(P <0.001), respectively. Our multivariable model demonstrated that Afro-Caribbean ethnicity, panel-reactive antibody > 50%, HLA mismatching > 4, and rejection were independent risk factors for BK-virus viremia whereas cytomegalovirus prophylaxis was protective.CONCLUSION Current treatment of BK-virus infection offers sub-optimal results. Initial viremia is a valuable parameter to detect patients at increased risk of nephropathy. Panelreactive antibody > 50% and Afro-Caribbean ethnicity are independent predictors of BK-virus infection whereas cytomegalovirus prophylaxis has a protective effect.

Clinical and pathological features of kidney transplant patients with concurrent polyomavirus nephropathy and rejection-associated endarteritis

AIM: To describe the clinicopathologic features of concurrent polyomavirus nephropathy(PVN) and endarteritis due to rejection in renal allografts.METHODS: We searched our electronic records database for cases with transplant kidney biopsies demonstrating features of both PVN and acute rejection(AR). PVN was defined by the presence of typical viral cytopathic effect on routine sections and positive polyomavirus SV40 large-T antigen immunohistochemistry. AR was identified by endarteritis(v1 by Banff criteria). All cases were subjected to chart review in order to determine clinical presentation, treatment course and outcomes. Outcomes were recorded with a length of follow-up of at least one year or time to nephrectomy. RESULTS: Of 94 renal allograft recipients who developed PVN over an 11-year period at our institution, we identified 7(7.4%) with viral cytopathic changes, SV40 large T antigen staining, and endarteritis in the same biopsy specimen, indicative of concurrent PVN and AR. Four arose after reduction of immunosuppression(IS)(for treatment of PVN in 3 and tuberculosis in 1), and 3 patients had no decrease of IS before developing simultaneous concurrent disease. Treatment consisted of reduced oral IS and leflunomide for PVN, and antirejection therapy. Three of 4 patients who developed endarteritis in the setting of reduced IS lost their grafts to rejection. All 3 patients with simultaneous PVN and endarteritis cleared viremia and were stable at 1 year of follow up. Patients with endarteritis and PVN arising in a background of reduced IS had more severe rejection and poorer outcome.CONCLUSION: Concurrent PVN and endarteritis may be more frequent than is currently appreciated and may occur with or without prior reduction of IS.

Prevalence of Psittacine Beak and Feather Disease Virus and Avian Polyomavirus in Captivity Psittacines from Costa Rica

Psittacine beak and feather disease virus (PBFDV) and avian polyomavirus (APV) are the most common viral diseases in psittacine birds, both affecting feathers and physical appearance of birds. Between 2005 and 2009, a total of 269 samples were collected from birds presented at veterinary clinics, shelters and rescue centers of wildlife in Costa Rica. They belonged to 19 species of psittacine birds. The most representative species in the sample were Ara macao (157), Ara ambigua (37), Amazona autumnalis (24), Amazon ochrocephala (21) and Ara ararauna (8). A prevalence of 19.7% (53/269) for PBFDV and 4.8% (13/269) for APV was determined using Polymerase Chain Reaction (PCR). In 3.3% (9/269) of the birds mixed infections were detected. Statistical analysis determined that psittacines living in shelters and rescue centers had a greater risk to be positive to PBFDV and APV than birds that were presented at veterinary clinics, while only for PBFDV it was determined, that it is more likely to detect it in feathers than in blood. Finally, birds infected with PBFDV had 6.24 times more probability to become infected with APV, than non-infected birds. This is the first report of prevalence of PBFDV and APV in captive psittacines from Costa Rica.

Management strategies for common viral infections in pediatric renal transplant recipients

Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort.Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes.Hence,prevention,early detection,and prompt treatment of such infections are of paramount importance.Among all viral infections,herpes viruses(herpes simplex virus,varicella zoster virus,Epstein-Barr virus,cytomegalovirus),hepatitis B and C viruses,BK polyomavirus,and respiratory viruses(respiratory syncytial virus,parainfluenza virus,influenza virus and adenovirus)are common in kidney transplant recipients.These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome.Recent advances in technology and antiviral therapy have improved management strategies in screening,monitoring,adoption of prophylactic or preemptive therapy and precise treatment in the immunocompromised host,with significant impact on the outcome.This review discusses the etiology,screening and monitoring,diagnosis,prevention,and treatment of common viral infections in pediatric renal transplant recipients.

Combined detection of urine specific gravity and BK viruria on prediction of BK polyomavirus nephropathy in kidney transplant recipients

Background:BK polyomavirus(BKPyV)-associated nephropathy(BKPyVAN)is an important cause of dysfunction and failure of renal transplants.This study aimed to assess the diagnostic performance of morning urine specific gravity(MUSG)in diagnosing BKPyVAN in kidney transplant recipients.Methods:A total of 87 patients,including 27 with BKPyVAN,22 with isolated BKPyV viruria,18 with T cell-mediated rejection(TCMR),and 20 with stable graft function,were enrolled in the First Affiliated Hospital of Sun Yat-Sen University from March 2015 to February 2017.MUSG at biopsy and during a follow-up period of 24 months after biopsy was collected and analyzed.Receiver operating characteristic(ROC)curve analysis was used to determine the ability of MUSG to discriminate BKPyVAN.Results:At biopsy,the MUSG of BKPyVAN group(1.008±0.003)was significantly lower than that of isolated BK viruria group(1.013±0.004,P<0.001),TCMR group(1.011±0.003,P=0.027),and control group(1.014±0.006,P<0.001).There was no significant difference in MUSG among the isolated BK viruria group,TCMR group,and control group(P=0.253).In BKPyVAN group,the timing and trend of MUSG elevate were consistent with the timing and trend of the decline of viral load in urine and plasma,reaching a statistical difference at 3 months after treatment(1.012±0.003,P<0.001)compared with values at diagnosis.ROC analysis indicated that the optimal cut-off value of MUSG for diagnosis of BKPyVAN was 1.009,with an area under the ROC curve(AUC)of 0.803(95%confidence interval[CI]:0.721–0.937).For differentiating BKPyVAN and TCMR,the optimal MUSG cut-off value was 1.010,with an AUC of 0.811(95%CI:0.687–0.934).Conclusion:Combined detection of MUSG and BKPyV viruria is valuable for predicting BKPyVAN and distinguishing BKPyVAN from TCMR in renal transplant recipients.

Polyomavirus interaction with the DNA damage response

Viruses are obligate intracellular parasites that subvert cellular metabolism and pathways to mediate their own replication—normally at the expense of the host cell. Polyomaviruses are a group of small DNA viruses, which have long been studied as a model for eukaryotic DNA replication. Polyomaviruses manipulate host replication proteins, as well as proteins involved in DNA maintenance and repair, to serve as essential cofactors for productive infection. Moreover, evidence suggests that polyomavirus infection poses a unique genotoxic threat to the host cell. In response to any source of DNA damage, cells must initiate an effective DNA damage response(DDR) to maintain genomic integrity, wherein two protein kinases, ataxia telangiectasia mutated(ATM) and ATM- and Rad3-related(ATR), are major regulators of DNA damage recognition and repair. Recent investigation suggests that these essential DDR proteins are required for productive polyomavirus infection. This review will focus on polyomaviruses and their interaction with ATMand ATR-mediated DNA damage responses and the effect of this interaction on host genomic stability.

Different behaviour of BK-virus infection in liver transplantrecipients

Polyomavirus BK(BKV) infects up to 90% of the general population. After primary infection, occurring early during childhood, a state of non-replicative infection is established in the reno-urinary tract, without complications for immunocompetent hosts. In immunocompromised individuals, particularly transplanted patients, asymptomatic BKV viremia and/or viruria can be observed. Renal grafts may also be sources of infection as BKV prefers kidneys rather than other solid organs for transplantation such as the liver. The mechanism behind the higher incidence of BKV infection in kidney transplant patients, compared to liver or heart transplantation, is unclear and the prevalence of BKV infection in non-renal solid organ transplants has not been yet thoroughly investigated. We evaluated the prevalence of Polyomavirus BK infection among liver transplant recipients. A Pub Med search was conducted using the terms BKV infection AND liver transplant recipients; BKV AND non-renal solid organ transplant*; BKV infection AND immunosuppression; the search was limited to title/abstract and English-language articles published from 2000, to March 2015. Eleven relevant studies suggest that the prevalence of BKV viruria and/or viremia among liver transplant recipients is less than that reported in kidney or heart transplant recipients, except when chronic kidney disease(CKD) is present at the same time. Data also suggest that viruric and viremic patients have higher levels of serum creatinine than BKV negative patients. Moreover, no specific immunosuppressive drugs are associated with the onset of BKV nephropathy. The comorbidity of transplantation and CKD could play a major role in promoting BKV replication.

Cancer and Infectious Causes

Various kinds of organisms, including viruses, bacteria, trematodes and fungi are known carcinogens that cause cancer. Infectious identification related to cancer may lead to better treatment for both the prevention and targeting of cancer therapy. Although nearly 20% of all cancers are caused by an infection of a microbe, the amount of evidence and information regarding the mechanisms associated with oncogenesis varies dramatically from one organism to the next. This review cannot be exhaustive because we are not aware of all infections worldwide in addition to their potential mechanisms for oncogenesis. More research is required for all of the species mentioned in this review.

Outcomes of renal transplant recipients with BK virus infection and BK virus surveillance in the Auckland region from 2006 to 2012

AIM To evaluate incidence, risk factors and treatment outcome of BK polyomavirus nephropathy(BKVN) in a cohort of renal transplant recipients in the Auckland region without a formal BK polyomavirus(BKV) surveillance programme.METHODS A cohort of 226 patients who received their renal transplants from 2006 to 2012 was retrospectively reviewed.RESULTS Seventy-six recipients(33.6%) had a BK viral load(BKVL) test and 9 patients(3.9%) developed BKVN. Cold ischaemia time(HR = 1.18, 95%CI: 1.04-1.35) was found to be a risk factor for BKVN. Four recipients with BKVN had complete resolution of their BKV infection; 1 recipient had BKVL less than 625 copies/mL; 3 recipients had BKVL more than 1000 copies/mL and 1 had graft failure from BKVN. BKVN has a negative impact on graft function [median estimated glomerular filtration rate(eG FR) 22.5(IQR 18.5-53.0) mL /min per 1.73 m^2, P = 0.015), but no statistically significant difference(P = 0.374) in renal allograft function was found among negative BK viraemia group [median e GFR 60.0(IQR 48.5-74.2) mL /min per 1.73 m^2), positive BK viraemia without BKVN group [median eG FR 55.0(IQR 47.0-76.0) mL /min per 1.73 m^2] and unknown BKV status group [median eG FR 54.0(IQR 43.8-71.0) mL /min per 1.73 m^2]. The incidence and treatment outcomes of BKVN were similar to some centres with BKV surveillance programmes.CONCLUSION Recipients with BVKN have poorer graft function. Although active surveillance for BKV has been shown to be effective in reducing incidence of BKVN, it should be tailored specifically to that transplant centre based on its epidemiology and outcomes of BKVN, particularly in centres with limited resources.

Discovery of novel DNA viruses in small mammals from Kenya

Emergence and re-emergence of infectious diseases of wildlife origin have led pre-emptive pathogen surveillances in animals to be a public health priority.Rodents and shrews are among the most numerically abundant vertebrate taxa and are known as natural hosts of important zoonotic viruses.Many surveillance programs focused more on RNA viruses.In comparison,much less is known about DNA viruses harbored by these small mammals.To fill this knowledge gap,tissue specimens of 232 animals including 226 rodents,five shrews and one hedgehog were collected from 5 counties in Kenya and tested for the presence of DNA viruses belonging to 7 viral families by PCR.Diverse DNA sequences of adenoviruses,adeno-associated viruses,herpesviruses and polyomaviruses were detected.Phylogenetic analyses revealed that most of these viruses showed distinction from previously described viruses and formed new clusters.Furthermore,this is the first report of the discovery and full-length genome characterization of a polyomavirus in Lemniscomys species.This novel polyomavirus,named Ls Py V KY187,has less than 60%amino acid sequence identity to the most related Glis glis polyomavirus 1 and Sciurus carolinensis polyomavirus 1 in both large and small T-antigen proteins and thus can be putatively allocated to a novel species within Betapolyomavirus.Our findings help us better understand the genetic diversity of DNA viruses in rodent and shrew populations in Kenya and provide new insights into the evolution of those DNA viruses in their small mammal reservoirs.It demonstrates the necessity of ongoing pathogen discovery studies targeting rodent-borne viruses in East Africa.

Construction of an immortalized neural progenitor cell strain and analysis of its immunogenicity

Neural progenitor cells(NPC)are those that are the source of neural cells for cell transplantation and gene therapy.The shortage in quantity and the limited life spans of primary cultured cells limit its widespread use in basic research.Immortalized NPC,which also possess the capacity of self-renewal and can proliferate infinitely,can produce a large number of NPCs with stable phenotype and genotype.Here we report that an immortalized neural progenitor cell strain,which we named as INPC,was suc-cessfully established by gene-transfer of simian virus 40 large T antigen gene mediated by liposomes.The INPC retained the biological characteristics of its original cells and provided a safe and reliable cell platform for the treat-ment of central nervous system diseases and transgenic cell transplantation.INPC could express low levels of MHC antigens which was down-regulated after differentiation.This indicates that INPC possesses poor immunogenicity.The immortalized cells may show good long-term survival and do not elicit an acute immunological response follow-ing transplantation.