肾移植术后的BK病毒感染.ppt

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,“,”,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,“,”,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,GuidelineBK Polyomavirus in Solid Organ Transplantation,Introduction,The human BK polyomavirus(BKV)is linked to two major complications in transplant recipients,polyomavirus-associated nephropathy(PyVAN)in 110%of kidney transplant patientsand polyomavirus-associated hemorrhagic cystitis(PyVHC)in 515%of allogeneic hematopoietic stem cell transplant(HSCT)patients.Both diseases occur only sporadically in patients with non-kidney solid organ transplantation(SOT)or with inherited,acquired or drug-induced immunodeficiency.Besides PyVAN and PyVHC,BKV has been implicated rarely in extrarenal pathologies such as pneumonia,encephalitis,hepatitis,retinitis,capillary-leak syndrome and cancer.A potential association of sustained BK viruria with acute T cell mediated rejection has also been suggested.,Epidemiology of BKV Infection and Replication,BKV and JC polyomavirus(JCV)infections are widespread in the general population.Primary infection with BKV occurs in the first decade of life as evidenced by increases in BKV seroprevalence to 90%and more.Natural BKV transmission is not resolved,but likely occurs via the respiratory or oral route.Subsequently,BKV colonizes the renourinary tract as the principle site of latent infection,most likely via a primary viremia.In healthy BKV seropositive immunocompetent individuals,reactivation and asymptomatic urinary shedding of BKV is detectable in up to 10%,with urine BKV loads of 5 log,10,genome equivalents(geq)/mL as the 75th percentile.BKV type I is found in 7080%,followed by BKV type IV in 1020%.In individuals with impaired immune functions,particularly after SOT or HSCT,asymptomatic high-level urinary BKV replication is observed with BKV loads of 7 log,10,geq/mL,appearance of“decoy cells”in urine cytology and virus particles detectable by direct negative staining electron microscopy.High-level BKV viruria only rarely leads to viremia and PyVAN in nonkidney SOT.In kidney transplant recipients,however,approximately one third of patients with high-level viruria/decoy cells develop BKV viremia,and in the absence of any intervention,progress to histologically proven PyVAN.This progressively affects graft function and increases the risk of graft loss from 4 log,10,cp/mL,a diagnosis of“presumptive PyVAN”should be made in absence of demonstrable BKV replication in biopsies.Increases in serum creatinine from baseline are not required for the diagnosis of presumptive PyVAN.,Electron microscopy,Detection of three-dimensional viral aggregates in urine by electron microscopy has been reported to have high positive and negative predictive values for BKV nephropathy reaching 90%,However,electron microscopy is not widely available and independent prospective studies confirming the utility of this diagnostic tool are warranted,Reducing immunosuppression should be considered for kidney transplant patients with sustained plasma BKV loads,Strategy 1.First dose reduction of the calcineurin inhibitor by 2550%in one or two steps;followed by reducing the antiproliferative drug by 50%;followed by discontinuing the latter,Strategy 2.First reducing the antiproliferative drug by 50%followed by reducing calcineurin inhibitors by 2550%followed by discontinuing the antiproliferative drug,Oral prednisone is typically tapered to 10 mg or less per day,Both protocols appear safe and effective in adult and pediatric patients for preventing PyVAN and clearing BKV viremia with subsequent acute rejections ranging from 812%all of which responded to steroid treatment,Diagnosis of PyVAN,Plasma BKV loads should be determined in all kidney transplant patients undergoing renal allograft biopsy for surveillance or for decline in function,The definitive diagnosis of PyVAN should be sought by demonstrating PyV cytopathic changes in allograft tissue,and confirmed by immunohistochemistry or in situ hybridization(“proven PyVAN”),For immunohistochemistry,most centers use cross-reacting antibodies raised against the large T-antigen of the Simian virus 40(clone PAb 416,Calbiochem),A minimum of two biopsy cores should be taken,preferentially containing medullary tissues because of the focal nature of PyVAN and the possibility of sampling error in at least 1036.5%of cases,The histological findings PyVAN should be semi-quantitatively assessed,The diagnosis of acute rejection concurrent with PyVAN is only considered secure if one finds endarteritis,fibrinoid vascular necrosis,glomerulitis,or C4d deposits along peritubular capillaries,Determining whether interstitial infiltration and tubulitis is directed against viral or tubular antigens cannot be reliably done by light microscopy.In PyVAN,C4d deposits have been observed in the tubular basement membranes,but not peritubular capillaries.However,one case of PyVAN with intimal arteritis and one with generalized polyomavirus vasculopathy in the skeletal muscle has been reported.MHC class II upregulation by the tubular epithelium has been proposed as a marker of rejection which is absent in PyVAN biopsies with acute viral tubular necrosis,but requires independent studies.Molecular studies attempt to identify markers in biopsies and in urine require further investigation for utility in the routine setting,Treatment of PyVAN,Immunosuppression should be reduced in kidney transplant patients with proven PyVAN.The mainstay of therapy for PyVAN in kidney transplant patients without concurrent acute rejection is reducing or discontinuing immunosuppressive drugs as outlined above.Although there are no randomized controlled trials,a number of observational studies have reported successful clearance of BKV viremia in 85%.More advanced disease may require more interventional steps,a longer time for recovery and result in a permanent loss of renal function.,Tacrolimus trough levels are commonly targeted to 6 ng/mL,cyclosporine trough levels to 150 ng/mL,sirolimus trough levels of 185 000 copies/ml at diagnosis were predictive of BK virus-associated nephropathy(BKVAN;OR:113.25,95%CI:17.22744.6,P 0.001).,Surveillance for BK viremia and rapid reduction of immunosuppression limited the incidence of BKVAN to 1.3%.,The addition of leflunomide or ciprofloxacin to immunosuppressive dose reduction did not result in greater rates of viral clearance,Levofloxacin for BK Virus Prophylaxis Following Kidney Transplantation A Randomized Clinical Trial.JAMA.2014(Vancouver,Canada),Among kidney transplant recipients,a 3-month course of,levofloxacin initiated early following transplantation did not prevent BK viruria.Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance.These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection.,