No clinical benefit of rapid versus gradual tapering of immunosuppression to treat sustained BK virus viremia after kidney transplantation: a single‐center experience

Immunosuppressive drug tapering is currently the recommended treatment of BK virus (BKV) viremia after kidney transplantation; however, its exact modalities remain unclear. We retrospectively compared two consecutive strategies in 111 patients with sustained viremia: a gradual monitoring/tapering group (GT, n = 57) before 2012 and a rapid monitoring/tapering group (RT, n = 54) after 2012. At viremia diagnosis, the dose of mycophenolic acid (MPA) and tacrolimus levels (T₀) were similar among patient groups. However, following onset, the dose of MPA at 1 month (P = 0.002) and 3 months (P = 0.005) and Tac T₀ at 1 month (P = 0.030) and 3 months (P = 0.006) were lower in the RT group. This rapid minimization shortened BKV viremia (P < 0.001) and resulted in a better protection of graft function in patients with confirmed BKV‐associated nephropathy (P = 0.033) without impacting 5‐year graft survival. Survival without rejection was similar (P = 0.571), but the RT group had increased the development of de novo donor‐specific antibodies (dnDSAs; P < 0.001). Multivariate Cox analysis identified basiliximab versus Thymoglobulin^® induction [hazard ratio (HR), 3.090; P = 0.001] and the RT strategy (HR, 6.021; P = 0.002) as independently associated with dnDSAs. Compared to a gradual tapering, rapid immunosuppression tapering to treat sustained BKV viremia does not improve medium‐term clinical outcome but increases the risk of developing dnDSAs.     

The prevalence of BK polyomavirus infection in outpatient kidney transplant recipients followed in a single center

Abstract: Background: BK polyomavirus (BKV) infection has emerged as an important cause of renal allograft loss. There is no proven therapy, and much basic clinical information is still lacking. Methods: We serially enrolled 95 outpatient renal transplant recipients (43% of whom were African American) in a single center cross‐sectional screening study to determine the prevalence of BKV infection by whole blood polymerase chain reaction, and the prevalence of decoy cells by urinalysis and cytology. We also investigated the demographic and clinical factors associated with BKV infection, and the performance of urinalysis for decoy cells as a screening test for BKV infection. Results: The point prevalence of active BKV viremia was 7.4%. When subjects without active viremia but with a history of viremia and/or nephropathy were included, the overall prevalence was 15.8%. Urinary decoy cells were common, present in 50% of subjects at study entry. Urinalysis for decoy cells as a screen for BKV viremia had a sensitivity of 86%, specificity of 52%, positive predictive value of 13% and negative predictive value of 98%. Conclusions: Decoy cells on urinalysis were the only factor independently associated with an increased risk of BKV infection on multivariate analysis. Although associated with BKV infection on univariate analysis, thymoglobulin, mycophenolate mofetil, and tacrolimus use were not independently associated with BKV infection on multivariate analysis, neither were history of acute rejection, gender, race, nor cause of end‐stage renal disease.     

Longitudinal assessment of the CXCL10 blood and urine concentration in kidney transplant recipients with BK polyomavirus replication—a retrospective study

In kidney transplant recipients (KTRs), BK polyomavirus (BKPyV) replication may progress to polyomavirus-associated nephropathy (PVAN). In this retrospective study, we assessed the chemokine CXCL10 in urine and blood samples consecutively acquired from 85 KTRs who displayed different stages of BKPyV replication and eventually developed PVAN. In parallel to progression toward PVAN, CXCL10 gradually increased in blood and urine, from baseline (prior to virus replication) to BKPyV DNAuria (median increase in blood: 42.15 pg/ml, P = 0.0156), from mere DNAuria to low- and high-level BKPyV DNAemia (median increase: 52.60 and 87.26 pg/ml, P = 0.0010 and P = 0.0002, respectively) and peaked with histologically confirmed PVAN (median increase: 145.00 pg/ml, P < 0.0001). CXCL10 blood and urine levels significantly differed among KTRs with respect to simultaneous presence of human cytomegalovirus (P < 0.001) as well as in relation to the clinical severity of respective BKPyV DNAemia episodes (P = 0.0195). CXCL-10 concentrations were particularly lower in KTRs in whom BKPyV DNAemia remained without clinical evidence for PVAN, as compared to individuals who displayed high decoy cell levels, decreased renal function and/or biopsy-proven PVAN (median blood concentration: 266.97 vs. 426.42 pg/ml, P = 0.0282). In conclusion, in KTRs CXCL10 rises in parallel to BKPyV replication and correlates with the gradual development of PVAN.     

BK virus nephropathy in renal transplant recipients

BK virus nephropathy (BKVN) occurs in up to 10% of renal transplant recipients and can result in graft loss. The reactivation of BK virus in renal transplant recipients is largely asymptomatic, and routine surveillance especially in the first 12–24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and anti‐viral treatment in the early stages may be effective in stopping BK virus replication. Urinary decoy cells, although highly specific, lack sensitivity to diagnose BKVN. Transplant biopsy remains the gold standard to diagnose BKVN, good surrogate markers for surveillance using quantitative urinary decoy cells, urinary SV40 T immunochemical staining or polyoma virus‐Haufen bodies are offered by recent studies. Advanced BKVN results in severe tubulo‐interstitial damage and graft failure. Retransplantation after BKVN is associated with good outcomes. Newer treatment modalities are emerging.     

Monitoring the progress of BK virus associated nephropathy in renal transplant recipients.

BACKGROUND: Nephropathy associated with BK virus (BKVAN) has recently emerged as an important cause of allograft failure following renal transplantation. The aim of this study was to evaluate the effectiveness of laboratory markers in the follow-up of patients with BKVAN. METHODS: Serial samples from seven renal transplant recipients with biopsy proven BKVAN were studied. The median follow-up time from diagnosis was 76 weeks. Intervention after the diagnosis of BKVAN included immunosuppression dose reduction, alternative immunosuppressive agents and/or antiviral therapy with cidofovir. Serial urine samples (n = 127) were collected for electron microscopy (EM), decoy cell detection and quantitative urine BK viral load using real-time polymerase chain reaction. Serum BK viral load was also measured serially (n = 72). RESULTS: All patients showed a reduction in serum and urine viral load during the period of follow-up co-incident with the loss of decoy cells and negative urine EM. Urine samples that were negative for decoy cells or polyomavirus by EM had a urine viral load <10(6) copies/ml and a corresponding serum viral load <10(3) copies/ml. In paired serum/urine samples, there was a proportional relationship between serum and urine viral load with each urine viral load approximately 1000-fold higher than the corresponding serum level. Serum and urine viral loads that decreased to <200 and < 10(6) copies/ml, respectively, correlated with histological improvement. CONCLUSION: Negative EM and absence of decoy cells could be used as broad indicators of a response to intervention. However, measurement of BK virus DNA level provided a wider dynamic range and could be a better choice for determining the extent of viral control.     

Risk factors for BK polyomavirus nephritis in renal allograft recipients

Recurrent episodes of acute rejection (AR) and/or the intense immunosuppression used for their treatment have been proposed as risk factors for BK nephritis (BKN; BK refers to the initials of the first patient from whom this polyomavirus was isolated). To further examine the relationship between AR and BKN, we analyzed all kidney transplants performed at our center between January 1999 and August 2001 (n = 286). After a mean follow-up of 737 +/- 22 d, we identified nine cases of BKN (3.1%). The mean time to diagnosis of BKN was 326 +/- 56 d. No patient with BKN had a prior history of AR. During the same period, 62 patients were diagnosed with AR (22%). The mean time to diagnosis of AR was 197 +/- 40 d (p = 0.01 vs. time to diagnosis of BKN). Despite aggressive therapy with methylprednisolone and, in some cases, anti-lymphocyte antibody, none of these patients with AR developed BKN. We compared the baseline characteristics of patients in both groups and found that BKN patients were more likely to be white people (78 vs. 44%, p = 0.05) and male (89 vs. 53%, p = 0.04). Moreover, the mean tacrolimus (TAC) levels before diagnosis were higher in BKN than in AR patients (11.7 +/- 0.5 vs. 6.5 +/- 0.6 ng/mL, p < 0.001). In summary, our study shows that BKN often occurs in the absence of prior episodes of AR. In addition, our findings suggest that white males exposed to higher TAC levels are at greater risk of developing BKN.     

BK virus viremia in a well‐HLA‐matched kidney transplant population mainly on low‐dose cyclosporine‐based immunosuppression

The incidence and clinical course of polyomavirus‐associated nephropathy (PyVAN) in our well‐HLA‐matched kidney transplant population mainly on low‐dose cyclosporine‐based triple‐drug immunosuppression has not been described in detail. We aimed to characterize our patients with PyVAN and BK virus (BKV) viremia. Among 166 kidney transplantations between January 2007 and February 2011 followed up at Helsinki University Hospital nephrology clinic, 136 were screened for BKV viremia by quantitative analysis of BKV DNA in plasma. PyVAN was diagnosed by biopsy histopathology and SV40 T‐antigen detection. BKV viremia or PyVAN were treated by reducing immunosuppression. BKV viremia was detected in 12 (9%) patients. PyVAN was diagnosed in six patients (4%). In the six patients with no PyVAN, four had low‐level viremia (<10 000 copies/mL) of short duration (<2 months), one had high‐level viremia, and one had sustained low‐level viremia. After reduction of immunosuppression, all except one patient were able to clear viremia. No grafts were lost due to PyVAN. Even in a low‐risk population, BKV viremia and PyVAN occur, highlighting the importance of monitoring viral loads. Reduction of immunosuppression was successful, and no grafts were lost due to PyVAN.     

The impact of surveillance and rapid reduction in immunosuppression to control BK virus‐related graft injury in kidney transplantation

We prospectively screened 609 consecutive kidney (538) and kidney‐pancreas (71) transplant recipients for BK viremia over a 4‐year interval using polymerase chain reaction viral load detection and protocol kidney biopsies. We found that BK viremia is common at our center: total cases 26.7%, cases during first year 21.3% (mean 4 months), and recipients with ≥10 000 copies/ml 12.3%. We found few predictive clinical or demographic risk factors for any BK viremia or viral loads ≥10,000 copies/ml, other than prior treatment of biopsy confirmed acute rejection and/or higher immunosuppressive blood levels of tacrolimus (P = 0.001) or mycophenolate mofetil (P = 0.007). Viral loads at diagnosis (<10 000 copies/ml) demonstrated little impact on graft function or survival. However, rising copy numbers demand early reductions in immunosuppressive drug doses of at least 30–50%. Viral loads >185 000 copies/ml at diagnosis were predictive of BK virus‐associated nephropathy (BKVAN; OR: 113.25, 95% CI: 17.22–744.6, 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. These data support the role of early surveillance for BK viremia to limit the impact on transplant outcome, although the most effective schedule for screening awaits further investigation.     

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.     

A direct association of polyomavirus BK viruria with deterioration of renal allograft function in renal transplant patients

Abstract: Background:  Polyomavirus BK virus (BKV) causes a BKV-associated nephropathy (BKVAN), frequently causing allograft dysfunction in renal transplant recipients. As BK viruria is a surrogate marker for early detection of BKVAN, the aim of this study was to clarify an association between BK viruria and allograft dysfunction in renal transplant recipients.
Methods:  One hundred and six renal transplant recipients with average 5.9-yr transplant duration received screening for quantification of BK viruria detected by real time polymerase chain reaction and were followed up for 12 months.
Results:  Twenty-six patients (25%) had detectable BK viruria. In comparison of the patients without BK viruria, more patients in the BK viruria group were treated with steroids and had a past history of acute rejection. There was no difference in sex, age, transplant duration, allograft type and previous cytomegalovirus infection. During follow-up, the patients with BK viruria had higher serum creatinine levels at the sixth, ninth and 12th month. Multiple logistic regression analysis revealed that BK viruria was the only risk factor for more than 25% or 50% rise of serum creatinine level above baseline at the end of one yr follow-up.
Conclusions:  BK viruria alone is associated with allograft dysfunction and early intervention is indicated.     

肾移植术后多瘤病毒感染的临床诊断和治疗

目的 探讨肾移植术后多瘤病毒（BKV）感染的诊断方法、监测指标及初步治疗方法。方法 采集64例肾移植受者的血、尿样本，行BKV细胞学与聚合酶链反应（PCR）检测。对肾移植术后BKV感染的流行病学以及相关因素进行分析，并对BKV感染的受者进行试验性治疗。结果 64例受者的尿Decoy细胞、多瘤病毒尿症与多瘤病毒血症的阳性率分别为28．7％、17．2％和6．3％。血肌酐（Cr）升高的受者尿Decoy细胞阳性率高于血Cr稳定的受者（P=0．04）。受者的性别、年龄、诱导治疗方案、是否发生急性排斥反应以及术后肾功能恢复情况等临床因素与尿Decoy细胞、多瘤病毒尿症及多瘤病毒血症的出现无明显相关性。应用更昔洛韦试验性治疗4例BKV感染的受者，治疗2～3周后，受者的尿Decoy细胞以及血、尿BKV DNA均转为阴性。结论 血肌酐水平升高的肾移植受者易发生BKV再活化。可通过检测血BKV DNA筛查BKV相关的移植肾肾病。更昔洛韦治疗BKV具有良好的疗效，但需进一步验证。     

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。     

Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States

There has been a notable rise of BK virus among kidney transplant recipients. Single-center reports have identified risk factors for development of BK virus. However, there has not been an assessment of risk factors and incidence of this complication at a national level. This study utilized newly collected follow-up information from the national SRTR database to investigate incidence, risk factors and outcomes for solitary kidney transplant recipients associated with treatment for BK virus (TBKV) from 2004 to 2006. Logistic and Cox models were utilized to assess risk factors and evaluate graft survival associated with TBKV. Incidence of TBKV was 1.6% at 6 months and 2.6% at 1 year following transplantation. Patients with and without TBKV at 6 months had 79% and 90% 3-year overall graft survival respectively. Risk factors included advanced donor age, pediatric, African American and male recipients, human leukocyte antigen-mismatching and tacrolimus and thymoglobulin induction as baseline immunosuppression. Acute rejection episodes were more frequent prior to and following TBKV. TBKV is a common and rising incidence, varies based on transplant characteristics and should be included as a safety endpoint in studies investigating immunosuppressive protocols. Careful monitoring and further understanding of disease etiology and treatment strategies are needed.     

Risk factors for BK virus infection in living-donor renal transplant recipients: a single-center study from China

Objectives: BK virus (BKV) infection has become one of the main complications in renal transplant recipients (RTRs) with the arrival of newer potent immunosuppressive agents. However, reports on the epidemiology of BKV infection and risk factors in Chinese population after renal transplantation are scarce.

Methods: From June 2015 to July 2016, living-donor renal transplant recipients (LDRTRs) who routinely received the quantitative BKV DNA testing of urine and plasma samples using quantitative real-time polymerase chain reaction (PCR) for the first time after transplantation were selected, while dialysis patients and healthy living donors during that period served as controls. Potential variables were compared and analyzed using logistic regression model multivariate analysis to assess the BKV infection related factors in LDRTRs.

Results: Among the 52 LDRTRs identified, BKV DNA was detected in 16 urine samples (30.8%), significantly higher than that of dialysis patients (6.3%) and healthy living donors (4.2%) (p?p?=?.842). Meanwhile, BKV DNA detection in blood samples was all negative in the three groups. Univariate analysis shown tacrolimus (Tac) trough level and lymphocyte percentage were associated with BKV infection in LDRTRs. Multivariate regression analysis also showed Tac trough level (HR, 1.644; p?=?.03), lymphocyte percentage (HR, 0.878; p?=?.026) were associated with BKV infection in LDRTRs.

Conclusions: In Chinese population, the incidence of BKV infection increased significantly after living-donor renal transplantation. Significantly increased Tac trough level and decreased lymphocyte percentage might be the risk factors for BKV infection in LDRTRs.     

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.     

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.     

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.