BK病毒血症对肾移植术后受者和移植肾功能影响临床研究

目的探究肾移植术后BK病毒(BKV)血症对受者及移植肾功能的影响。 方法回顾性分析2014年1月至2018年1月于中国科学技术大学附属第一医院接受肾移植229例受者临床资料。根据移植术后24个月内受者血清BKV最大载量,将其分为无病毒组(血清BKV持续阴性)、低病毒载量组(血清BKV最大载量≤1×10⁴ copies/mL)和高病毒载量组(血清BKV最大载量>1×10⁴ copies/mL)。以估算肾小球滤过率(eGFR)作为评价移植肾功能的指标。观察受者年龄和性别、供肾来源、供肾冷/热缺血时间、免疫抑制方案、术后3个月他克莫司血药浓度谷值、排斥反应和移植肾失功发生率以及术后24个月内eGFR。采用单因素方差分析比较3组受者年龄、供肾冷/热缺血时间、术后3个月他克莫司血药浓度谷值及术后24个月内eGFR,组间两两比较采用LSD法。采用成组t检验比较低病毒载量组与高病毒载量组受者首次检测到BKV的术后时间。采用卡方检验比较3组受者供肾来源、免疫抑制方案以及排斥反应和移植肾失功发生率。P<0.05为差异有统计学意义。 结果229例受者中28%(64/229)的受者肾移植术后血清检测到BKV,其中19%(43/229)为低病毒载量,9%(21/229)为高病毒载量。截至2018年7月,229例受者平均随访时间(44±8)个月。低病毒载量组受者术后首次检测到BKV的时间为移植后(10±8)个月,高病毒载量组为(8±6)个月,差异有统计学意义(t＝2.10,P<0.05)。无病毒组受者排斥反应发生率[24.8%(41/165)]低于低病毒载量组[60.5%(26/43)]和高病毒载量组[61.9%(13/21)](χ²＝19.82和12.42,P均<0.017)。无病毒组受者细胞排斥反应发生率[13.9%(23/165)]低于低病毒载量组[39.5%(17/43)]和高病毒载量组[42.9%(9/21)](χ²＝14.38和10.94,P均<0.017)。无病毒组受者中12例发生移植肾失功,低病毒载量组受者中2例发生移植肾失功,高病毒载量组受者中4例(3例发生BKVAN,1例病因不明确)发生移植肾失功,差异无统计学意义(χ²＝4.727,P>0.05)。高病毒载量组受者术后第3个月他克莫司血药浓度谷值高于无病毒组和低病毒载量组(P均<0.05)。高病毒载量组受者术后第3、6、12、24个月eGFR均低于无病毒组和低病毒载量组(P均<0.05)。 结论肾移植术后高BKV血症会影响肾移植受者预后及移植肾功能;而低BKV血症对移植肾功能无明显不良影响,此类受者无需调整他克莫司剂量。     

肾移植受者BK病毒感染的检测方法及免疫抑制方案对BK病毒活化的影响

目的 探讨肾移植术后受者BK病毒感染的检测方法及免疫抑制方案对BK病毒活化的影响.方法 选择1999年1月至2007年1月问进行肾移植术的200例受者为研究对象,其中100例基础免疫抑制方案为他克莫司(FK506)十霉酚酸酯(MMF)的受者作为密切观察组;另100例基础免疫抑制方案不同、但在年龄和术后是否发生急性排斥反应方面与密切观察组受者相一致(按1:1匹配)的受者作为对照观察组.在肾移植术后平均15.3个月时,分别采集所有受者的血、尿样本,行BK病毒尿沉渣Decoy细胞计数与BK病毒DNA含量的检测.分析和比较尿Decoy细胞计数、尿BK病毒含量及血BK病毒含量之间的关系;比较两组Decoy细胞、BK病毒尿症与BK病毒血症阳性率的差异.结果 200例受者的尿Decoy细胞、BK病毒尿症与病毒血症的阳性率分别为:34.0%、36.0%和16.5%.尿Decoy细胞计数与尿BK病毒含量呈正相关(r=0.714,P＜0.001),但尿液和外周血中BK病毒含量无明显相关性(P＞0.05).密切观察组的尿Decoy细胞、BK病毒尿症与BK病毒血症的阳性率分别为49%、50%和24%,对照观察组上述指标的阳性率分别是19%、22%和9%,两组的差异有统计学意义(P＜0.01).结论 尿沉渣Decoy细胞计数方法简单、易行并敏感,可以做为BK病毒活化的指标;血、尿BK病毒DNA的检测可进一步了解病毒活化情况、筛杳BK病毒相关的移植肾肾病.FK506+MMF的组合免疫抑制方案易发生BK病毒的活化,受者术后需进行密切观察和相关的检测.     

移植肾BK病毒肾病的防治和预后

目的总结分析肾移植后BK病毒性肾病的防治和预后。方法回顾性分析2006年1月-2016年10月中山大学附属第一医院器官移植科行移植肾穿刺活检的101例多瘤病毒性肾病(PVN)患者的临床资料,检测尿沉渣Decoy细胞计数、血和尿BKV DNA载量。结果共纳入101例确诊为PVN的患者,其中98例为BK病毒性肾病(BKVN),感染广泛的病例电镜下可观察到肾小管上皮细胞核内的病毒颗粒,98例中的40例患者进行重复活检显示随着病毒血病的下降SV40T的染色可由片状变为局灶性,BKVN患者可合并出现细胞性或体液性排斥反应。BKV血中的检测预测BKVN阳性预测值有30%~85%,血浆BKV DNA持续阳性及负荷>104copies/ml可以作为治疗干预开始的依据。结论术后规律监测早期发现移植肾BKVN及时减少免疫抑制剂,并规律监测注意并发的排斥反应可提高移植肾BKVN的远期存活。     

肾移植受者BK病毒的感染特点

目的 探讨肾移植受者BK病毒（BKV）的感染特点。 方法 于我院门诊选取肾移植术后48个月内的患者共243例作为试验组,同时选取门诊健康体检者82例作为对照组。采集上述2组的血、尿标本,行BKV尿沉渣细胞学计数与实时荧光定量PCR检测。 结果 试验组受者的尿Decoy细胞、BKV尿症与BKV血症的阳性率分别为35.4 %、36.6%和16.9%;对照组分别为4.9%、20.7%和2.9%。试验组受者的尿Decoy 细胞阳性者Decoy细胞中位数水平为6个/10 HPF,BKV DNA阳性者尿液和外周血BKV中位数水平分别为1.50×104拷贝/ml和6.87×103拷贝/ml;对照组分别为2个/10 HPF,1.10×104拷贝/ ml和2.24×103拷贝/ml。与健康者相比,肾移植术后试验组BKV DNA阳性率及水平明显升高（P < 0.01）。肾移植受者的尿液Decoy 细胞计数与尿液BKV含量呈正相关（r = 0.636,P < 0.01）;尿Decoy大量组（＞10个/10 HPF）的血BKV DNA阳性率及水平显著高于少量组（1～5个/10 HPF）（P < 0.05）。 结论　肾移植受者较健康人群易发生BKV再活化。定量尿沉渣细胞学检测简单、易行、敏感,可以作为BKV活化的指标,预测病毒尿症及病毒血症。此外,也可检测血、尿BKV DNA,以了解病毒活化情况和筛查BKV相关的移植肾肾病。     

肾移植与BK病毒感染

探讨BK病毒感染对肾移植受体预后的影响及目前相关研究进展,以期为临床提供有效的诊断和治疗措施。肾移植术后BK病毒感染率较高,可导致BK病毒相关性肾病(BKVN),甚至移植肾功能丢失。BK病毒感染诊断主要依靠实时荧光定量聚合酶链反应技术检测血液和尿液中BK病毒载量,BKVN诊断则需移植肾穿刺活组织检查。肾移植术后BK病毒感染对受者的影响较大,但目前缺乏有效的治疗手段,所以应在肾移植术后定期、规律检测BK病毒,早期发现、尽早干预,治疗上合理使用免疫抑制剂。     

肾移植后早期受者BK病毒DNA拷贝数的影响因素研究

目的 探讨肾移植后早期受者BK病毒的负荷状况及其影响因素.方法 检测80例同种异体肾移植受者血清和尿液中的BK病毒DNA拷贝数,并且分析肾移植临床常见的参数对BK病毒负荷的影响.结果 80例中,BK病毒血症阳性者为7例(占8.75％),BK病毒尿症阳性者为30例(占37.5％).＞50岁组受者血清和尿液中BK病毒DNA拷贝数都明显高于≤50岁组(P＜0.05);他克莫司组血清BK病毒DNA拷贝数高于环孢素A(CsA)组(P＜0.05),前组受者血清BK病毒负荷高峰时间在术后14个月,而后者在术后10个月.两组尿液BK病毒负荷高峰时间提前,Tac组为术后2个月,CsA组为术后8个月.结论 年龄＞50岁、正在服用他克莫司可能为BK病毒再次激活及BK病毒肾病的高危因素.     

肾移植术后BK病毒感染的研究进展

BK病毒感染是近年来发现造成移植肾丢失的原因之一,对BK病毒的研究在不断深入。本文主要综述了国外近年来对BK病毒感染的研究进展,包括BK病毒的激活及危险因子、病理学、诊断及治疗等。     

影响肾移植受者BK病毒感染的危险因素分析

目的 探讨影响肾移植受者BK病毒(BKV)感染的危险因素.方法 选取2006年3月至2007年3月间进行肾移植术的90例受者为研究对象,分别于肾移植术后第1、3、6、9、12个月收集血、尿标本,进行尿沉渣Decoy细胞计数与BK病毒DNA含量的检测,对部分肾移植受者进行移植肾活检.根据尿液BKV DNA是否阳性分成BKV感染组与非感染组.比较2组受者在年龄、性别、术前有无糖尿病、是否为活体肾移植、是否使用抗白细胞介素-2受体单克隆抗体进行诱导、围手术期是否使用多克隆抗体及抗CD3单克隆抗体、术后免疫抑制剂方案、术后是否发生急性排斥反应、移植肾功能恢复延迟及肺部感染等临床指标的差异,应用Logistic回归法分析筛选BKV感染的危险因素.结果 90例肾移植受者尿液Decoy细胞、尿BKV DNA及血BKVA DNA的阳性率分别为42.2%(38/90)、45.6%(41/90)和22.2%(20/90).BKV感染组应用他克莫司(FK506)加霉酚酸酯(MMF)方案的比例为68.3%(28/41),明显高于BKV非感染组40.8%(20/49,P＜0.01).FKS06加MMF的免疫抑制方案是影响肾移植受者BKV感染的独立危险因素(X2=6.579,P=0.01,OR=3.123).确诊BKV相关性肾病(BKVAN)5例.结论 FK506加MMF的组合免疫抑制方案易发生BKV活化及BKVAN,术后受者需进行密切观察并进行相关检测.     

肾移植受者BK病毒的感染特点

Objective To investigate the characteristics of BK virus (BKV) infection in renal transplant recipients. Methods A total of 243 renal recipients from our clinic within 48 months after transplantation were enrolled as the trial group and 82 healthy people as the control group. Urine and peripheral blood samples of these two groups were harvested for urinary sediment BKV cytology by Decoy cell counting and BKV DNA by real-time PCR. Results The positive rates of urinary Decoy cell, BKV viruria and viremia were 35.4%, 36.6% and 16.9% in trial group, and 4.9%, 20.7% and 2.9% in control group, respectively. In trial group, the medians of urinary Decoy cell, urinary BKV and peripheral blood BKV were 6/10 HPF, 1.00×104 copy/ml and 6.87×103 copy/ml respectively, while in control group, they were 2/10 HPF, 1.10×104 copy/ml and 2.24×1(3 copy/ml. Compared with the healthy people, the positive rates and the levels of BKV DNA in urine and peripheral blood of recipients were significantly higher. The amount of urinary Decoy cells was positively correlated to urinary BKV load (r=0.636, P＜0.01). Conclusions BKV replication is easier to happen in renal recipients as compared to healthy people. Counting of urinary Decoy cells is convenient, useful and sensitive to evaluate BK viruria and viremia in renaltransplant recipients. BKV DNA detection in urine and peripheral blood can be used to screen the evidence of BK reaction in order to prevent irreversible graft damage by BKV.[ Key words ] Kidney transplantation; BK virus; Kidney diseases; Decoy cells     

肾移植受者BK病毒的感染特点

Objective To investigate the characteristics of BK virus (BKV) infection in renal transplant recipients. Methods A total of 243 renal recipients from our clinic within 48 months after transplantation were enrolled as the trial group and 82 healthy people as the control group. Urine and peripheral blood samples of these two groups were harvested for urinary sediment BKV cytology by Decoy cell counting and BKV DNA by real-time PCR. Results The positive rates of urinary Decoy cell, BKV viruria and viremia were 35.4%, 36.6% and 16.9% in trial group, and 4.9%, 20.7% and 2.9% in control group, respectively. In trial group, the medians of urinary Decoy cell, urinary BKV and peripheral blood BKV were 6/10 HPF, 1.00×104 copy/ml and 6.87×103 copy/ml respectively, while in control group, they were 2/10 HPF, 1.10×104 copy/ml and 2.24×1(3 copy/ml. Compared with the healthy people, the positive rates and the levels of BKV DNA in urine and peripheral blood of recipients were significantly higher. The amount of urinary Decoy cells was positively correlated to urinary BKV load (r=0.636, P＜0.01). Conclusions BKV replication is easier to happen in renal recipients as compared to healthy people. Counting of urinary Decoy cells is convenient, useful and sensitive to evaluate BK viruria and viremia in renaltransplant recipients. BKV DNA detection in urine and peripheral blood can be used to screen the evidence of BK reaction in order to prevent irreversible graft damage by BKV.[ Key words ] Kidney transplantation; BK virus; Kidney diseases; Decoy cells     

肾移植术后尿中多瘤病毒BK的检测及意义

目的探讨尿中多瘤病毒BK（BKV）检测在肾移植后BKV感染中的诊断价值.方法采用聚合酶链反应（PCR）结合测序方法检测61例肾移植后患者尿中BKV DNA,并与30例血液透析患者和30例健康志愿者尿液检测结果对照.结果肾移植组BKV DNA检出率为36.1%（22/61）,明显高于血液透析组的13.3%（4/30）（P＜0.05）,对照组检测均为阴性（P＜0.05）.1例BKV阳性肾移植患者出现输尿管梗阻.移植组发生排斥反应和未发生排斥反应患者的BKV DNA检出率分别为40.9%（9/22）和33.3%（13/39）,P＞0.05;肾功能正常和异常者BKV DNA的检出率分别为36.0%（18/50）和36.4%（4/11）,P＞0.05.结论肾移植患者是引起BKV尿的高危人群.肾移植后有无排斥反应史及肾功能正常与否与BKV尿无相关性.尿BKV检测可作为肾移植后BKV相关性输尿管梗阻的鉴别诊断和多瘤病毒相关性肾病的筛选方法.     

肾移植术后BK病毒感染的危险因素分析

目的 分析肾移植术后BK病毒(BKV)感染发生的危险因素.方法 应用荧光实时定量PCR技术检测129例肾移植患者血液中BKV并行尿液细胞学检查,记录BKV-DNA阳性及阴性组患者性别、年龄、供肾冷缺血时间,术前血液透析时间、急性排斥反应、是否发生移植肾功能延迟恢复、免疫抑制剂方案、合并其他病毒感染等指标.应用二项多元逻辑回归法分析肾移植术后BKV感染发生的危险因素.结果 129例患者血中BKV-DNA阳性20例(15.5%).阴性109例(84.5%);BKV-DNA阳性患者尿细胞学检测Decoy细胞阳性15例,尿Decoy细胞阳性率与血BKV-DNA阳性率之间有明显的相关性(r=0.428,P<0.01).回归分析结果 显示:供肾冷却血时间(χ~2=9.243,95%CI:1.099～1.545,P<0.05)、患者术前透析时间(χ~2=7.599,95%CI:1.038～1.243,P<0.05)、是否为亲体供肾(χ~2=4.150,95%CI:0.012～0.070,P<0.05)为BKV感染的危险因素.结论 荧光实时定量PCR及尿细胞学检查可以作为肾移植术后BKV感染的筛查指标;供肾冷缺血时间长、术前血液透析时间长、尸体供肾均可增加患者术后BKV感染的风险.     

Association of renal adenocarcinoma and BK virus nephropathy post transplantation

While most BK virus infections are asymptomatic, immunosuppression has been associated with BK virus reactivation and impaired graft function or ureteric ulceration in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. Oncogenicity is also postulated and this is the first report of a child with a carcinoma of the donor renal pelvis following BK virus allograft nephropathy. Removal of the primary tumor and cessation of immunosuppression led to regression of secondary tumors and a return to health.     

肾移植受者术后BK病毒激活危险因素的荟萃分析

目的对国内外报道的肾移植术后BK病毒(BKV)激活的危险因素进行荟萃分析，为临床BKV肾病的防治提供参考。 方法通过系统检索PubMed数据库、中国知网、万方数据库以及中国生物医学数据库从建库至2019年7月公开发表的关于肾移植术后BKV激活危险因素的相关研究论文，并通过其参考文献进行手工补充搜索。采用纽卡斯尔－渥太华量表对纳入文献进行质量评价，运用RevMan 5.3软件进行荟萃分析。 结果最终纳入22篇文献，其中英文15篇、中文7篇。结果显示血液中检测到BKV的危险因素为排斥反应(OR＝1.91，95%CI：1.30～2.80)、移植肾功能延迟恢复(OR＝1.51，95%CI：0.99～2.31)、服用他克莫司(OR＝1.50，95%CI：1.22～1.84)、使用抗胸腺细胞球蛋白(ATG)诱导(OR＝1.75，95%CI：1.02～2.98)、使用输尿管支架(OR＝1.98，95%CI：1.19～3.30)和合并CMV感染(OR＝2.23，95%CI：1.61～3.09)；而尿液中检测到BKV的危险因素为持续服用糖皮质激素(OR＝1.49，95%CI：1.09～2.04)。 结论肾移植术后服用他克莫司、合并CMV感染、使用输尿管支架和ATG诱导的受者发生BKV血症的风险更高，长期服用糖皮质激素的肾移植受者发生BKV尿症的风险更高。     

BK virus nephropathy in a patient with ABO-incompatible renal transplantation

Abstract:  A 43-year-old woman with end-stage renal disease originating from IgA nephropathy entered chronic haemodialysis therapy. She then received an ABO-incompatible living related renal transplantation. Initial immunosuppression consisted of azathioprine, methylprednisolone and tacrolimus. At 155 days after transplantation, the azathioprine was changed to mycophenolate mofetil for continuous graft dysfunction. Furthermore, a total of three courses of anti-rejection therapy was given. At 665 days after transplantation, diagnosis of BK-virus nephropathy was made by immunohistochemical analysis and viral DNA assay. Therefore the immunosuppression therapy was reduced for graft dysfunction. All five renal biopsy specimens were examined retrospectively in order to determine when the BK virus nephropathy had developed. The expressions of SV40 large T antigens were detected from the third (117 days) to the fifth (665 days) biopsies, with increasing numbers of SV40 large T antigen positive cells. In addition, many cells contained inclusion bodies which were already present in the urinary sediment for 3 months post-transplantation. Although it is difficult to make a diagnosis of early stage of BKVN, we have to consider with caution if urinary cells with inclusion body are seen. Awareness of BKVN at the earliest opportunity is important in order to avoid over-immunosuppression.     

Adverse impact of pretransplant polyoma virus infection on renal allograft function

Background: BK polyoma virus (BKV) has emerged as an important cause of acute and chronic allograft injury in renal transplant recipients. Reactivation of latent infection requires reduction in cell‐mediated immunity. We hypothesized that BKV could get reactivated in the urinary tract of patients with end‐stage renal disease (ESRD) and impact the allograft function after these individuals undergo transplantation. Methods: We prospectively examined the urine specimens of 68 ESRD patients and their donors for BKV inclusion containing decoy cells with Papanicoulau staining and immunohistochemistry. Polymerase chain reaction was carried out to confirm the presence of viral DNA. Urine examination was repeated 3–9 months after transplantation and during episodes of graft dysfunction. All graft dysfunction episodes were investigated by biopsy. BKV‐associated nephropathy was confirmed by immunoperoxidase staining. Graft loss and doubling of serum creatinine were the study end‐points. Results: Decoy cells were detected in 22 ESRD patients and four donors (P < 0.0001). All 22 continued decoy cell excretion after transplantation and two fresh excreters were noted. Patients exhibiting decoy cells had more frequent graft dysfunction episodes (67% vs 30%, P = 0.003) and higher serum creatinine value (P < 0.001). About 33% patients achieved the combined end‐points in the BK viruria group, compared with 11% in the non‐decoy cell excreters (P = 0.03). Histologically proved BKV nephropathy was noted in 7% cases; all decoy cell excreters. Conclusion: We conclude that reactivation of latent BKV infection can occur in ESRD and confers an increased risk of graft dysfunction after transplantation. The mechanism of graft dysfunction in decoy cell excreters who do not develop overt nephropathy needs more studies.