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.     

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.     

Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐center analysis of incidence,reduction in immunosuppression and clinical course

Huang G, Chen L‐Z, Qiu J, Wang C‐X, Fei J‐G, Deng S‐X, Li J, Chen G‐D, Zhang L, Fu Q, Zeng W‐T, Zhao D‐Q. Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐center analysis of incidence, reduction in immunosuppression and clinical course.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01141.x
© 2009 John Wiley & Sons A/S. Abstract: Background: BK virus (BKV)‐associated nephropathy (BKVAN) in renal transplant recipients is an important cause of renal transplant dysfunction. Our aim was to determine the kinetics of BKV load within one yr after kidney transplantation under the impact of intensive monitoring and reduction in maintenance immunosuppression, the incidence of BKVAN, and the outcome of BKVAN treatment. Methods: Urine and peripheral blood (PB) were taken from 90 renal transplant recipients for BKV cytological testing and real‐time PCR for BKV DNA at one, three, six, nine, and 12 months after transplantation and treatment. Graft biopsies and urinary sediments of recipients with BKVAN were taken to monitor viral particles by conventional transmission electron microscopy (TEM). Results: By one post‐transplant year, urinary decoy cells (median, 8/10 HPF), BKV viruria (median, 2.60 × 10⁵ copies/mL), viremia (median, 9.65 × 10³ copies/mL ) , and BKVAN occurred in 42.2%, 45.6%, 22.2%, and 5.6% of patients, respectively. The incidence of BK infection was lower in patients who received cyclosporine A (CsA) (28.9%) compared to tacrolimus (FK506) (57.7%) (p = 0.007). An increased hazard of BK infection was associated with the use of FK506 (HR 2.6, p = 0.009) relative to CsA. After reduction in immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction, or graft loss. BKVAN was diagnosed in five patients (5.6%). The treatment of immunosuppression reduction was effective (i.e., decreased the viral load and number of decoy cells, and improved graft function) in our five patients with BKVAN. Quantitative count of decoy cells (e.g., >10 per 10 HPF) as a marker of viremia and BKVAN had increased positive predictive values of 85.7% and 57.1%, respectively. Conclusions: Choice of FK506 as immunosuppressive agent is an independent risk factor affecting BKV infection. Monitoring and pre‐emptive of immunosuppression reduction were associated with resolution of viremia and showed effective in BKVAN recipients at the early stage without acute rejection or graft loss. Quantitative count of urine cytology is a very convenient, useful, and sensitive method for evaluating BKV infection in renal transplant recipients.     

Role of BK virus infection in end‐stage renal disease patients waiting for kidney transplantation – viral replication dynamics from pre‐ to post‐transplant

We report the prevalence of BK virus (BKV) infection before renal transplantation and the dynamics of BKV viremia from pre‐ to post‐transplantation. We assessed 60 kidney transplanted patients from a single cohort in Italy, treated with identical immunosuppressive therapy, for BK viremia at pre‐transplantation, 12 h, and three and six months post‐transplantation. Polymerase chain reaction showed that the prevalence of plasma BKV replication – considered a marker of infection – was 20% in pre‐transplant patients. All pre‐transplant‐positive patients remained positive post‐transplant, whereas the majority of pre‐transplant‐negative patients remained negative. Viremia dynamics classification revealed three clusters of patients: Cluster A++, pre‐transplant‐positive patients (20%) who tested positive at least once post‐transplant; Cluster B?+, pre‐transplant‐negative patients (28%) who tested positive at least once post‐transplant; and Cluster C– –, pre‐transplant‐negative patients (52%) who remained negative throughout. These clusters presented significant differences related to the prevalence of substantially positive patients with high plasma viral load (>10³ copies/mL) in cluster A, but not in donors’ or grafts’ characteristics. We suggest that pre‐transplant viral status should be considered as an additional risk factor for post‐transplant BKV replication. Therefore, pre‐transplant BKV infection screening in kidney transplant patients should be performed for improving planning of personalized immunosuppressant schemes and specific post‐transplant surveillance.     

Predictors and outcomes of delayed graft function after living‐donor kidney transplantation

Delayed graft function (DGF) following deceased donor kidney transplantation is associated with inferior outcomes. Delayed graft function following living‐donor kidney transplantation is less common, but its impact on graft survival unknown. We therefore sought to determine risk factors for DGF following living‐donor kidney transplantation and DGF's effect on living‐donor kidney graft survival. We analyzed living‐donor kidney transplants performed between 2000 and 2014 in the UNOS dataset. A total of 64 024 living‐donor kidney transplant recipients were identified, 3.6% developed DGF. Cold ischemic time, human leukocyte antigen mismatch, donor age, panel reactive antibody, recipient diabetes, donor and recipient body mass index, recipient race and gender, right nephrectomy, open nephrectomy, dialysis status, ABO incompatibility, and previous transplants were independent predictors of DGF in living‐donor kidney transplants. Five‐year graft survival among living‐donor kidney transplant recipients with DGF was significantly lower compared with graft survival in those without DGF (65% and 85%, respectively, P < 0.001). DGF more than doubled the risk of subsequent graft failure (hazard ratio = 2.3, 95% confidence interval: 2.1–2.6; P < 0.001). DGF after living‐donor kidney transplantation is associated with inferior allograft outcomes. Minimizing modifiable risk factors may improve outcomes in living‐donor kidney transplantation.     

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.     

Renal vessel reconstruction in kidney transplantation using a polytetrafluoroethylene (PTFE) vascular graft.

BACKGROUND: We report a rare experience in reconstructing short renal vessels in kidney transplantation using polytetrafluroethylene (PTFE) vascular grafts. METHODS: The short renal vessels in three kidney grafts were managed by the interposition of PTFE vascular grafts. Two grafts were from deceased donors and the third was a renal auto-transplant graft. RESULTS: PTFE grafts were used to lengthen short renal veins in two kidney grafts and a short renal artery in one. The warm ischaemia time was under 1 h and all kidneys functioned well post-operatively. Excellent blood perfusion in the three renal grafts was present on postoperative MAG 3 renal scan. No intra-operative or post-operative complications were encountered. CONCLUSIONS: In the three described patients, the use of PTFE vascular graft presented no additional morbidity to the kidney transplant operation and no post-oerative complication was related to its use. However, more data are necessary to conclude that PTFE graft can be used safely in kidney transplantation.     

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。     

BK virus infection,replication, and diseases in pediatric kidney transplantation

Polyomavirus-associated nephropathy is diagnosed in 2–8% of pediatric renal transplants and often precedes renal allograft dysfunction. Without intervention, however, significant graft dysfunction is observed in more than 50% of cases, although progressive early graft loss is reported in only three of 32 (9%) of cases. No specific treatment is available, but early decrease in immunosuppression is followed by declining human polyomavirus type 1 (BK virus) replication and improved outcome. The data suggest differences between pediatric and adult kidney transplantation. Possibly, pediatric patients might be able to mount a more vigorous BK virus-specific immune response than adult patients under similar modulation of immunosuppression. Also the role of cidofovir and leflunomide is still unresolved in pediatric patients. Larger prospective trials are needed to better define the impact of BK virus immunity for replication and disease as well as the role of reducing immunosuppression with or without cidofovir or leflunomide in pediatric transplant patients.     

Does intra‐operative verapamil administration in kidney transplantation improve graft function

The role of the calcium channel blocker (verapamil) in kidney transplant is controversial. Verapamil has been hypothesized to mitigate ischemia reperfusion injury (IRI) to the allograft. Herein, we evaluated the effect of intra‐operative verapamil administration in a large cohort of kidney transplants. Total 684 transplants were performed during 2007‐2017. Of these, 348 (50.9%) transplants received verapamil (2.5 mg) Ver (+), and 336 (49.1%) did not, Ver (?). Based on the donor type, the study was divided into three groups; living donor (LD) (N = 270), neurological determination of death (NDD) (N = 394), and donation after cardiac death (DCD) (N = 20). Ver (?) subgroup had more diabetic recipients as compared to Ver (+) subgroup in LD and NDD groups (P < 0.05). No significant difference was found for delayed graft function in any of the group (P > 0.05). Cold ischemia time and dialysis requirement were significantly higher in Ver (+) LD and NDD groups, respectively. Except for DCD group, there was no significant difference in eGFR (mL/min) immediately and 6 months after kidney transplant in any of the groups. Furthermore, univariate and multivariate logistic regression analysis was performed to account for potential confounders, but verapamil administration did not improve graft function in any of the groups (P > 0.05) after transplant.     

Financial impact of delayed graft function in kidney transplantation

Increased utilization of suboptimal organs in response to organ shortage has resulted in increased incidence of delayed graft function (DGF) after transplantation. Although presumed increased costs associated with DGF are a deterrent to the utilization of these organs, the financial burden of DGF has not been established. We used the Premier Healthcare Database to conduct a retrospective analysis of healthcare resource utilization and costs in kidney transplant patients (n = 12 097) between 1/1/2014 and 12/31/2018. We compared cost and hospital resource utilization for transplants in high-volume (n = 8715) vs low-volume hospitals (n = 3382), DGF (n = 3087) vs non-DGF (n = 9010), and recipients receiving 1 dialysis (n = 1485) vs multiple dialysis (n = 1602). High-volume hospitals costs were lower than low-volume hospitals ($103 946 vs $123 571, P < .0001). DGF was associated with approximately $18 000 (10%) increase in mean costs ($130 492 vs $112 598, P < .0001), 6 additional days of hospitalization (14.7 vs 8.7, P < .0001), and 2 additional ICU days (4.3 vs 2.1, P < .0001). Multiple dialysis sessions were associated with an additional $10 000 compared to those with only 1. In conclusion, DGF is associated with increased costs and length of stay for index kidney transplant hospitalizations and payment schemes taking this into account may reduce clinicians’ reluctance to utilize less-than-ideal kidneys.     

The impact of early cytomegalovirus infection after kidney transplantation on long‐term graft and patient survival

This prospective observational cohort study is an extension of a previous study reporting effects of cytomegalovirus (CMV) on graft and patient survival in 471 patients who underwent kidney transplantation between 1994 and 1997. CMV pp65 antigen was measured every 7–14 d during the first three months after transplantation, given as number of CMV pp65‐positive cells per 10⁵ leukocytes. A positive test was defined as CMV infection. None of the patients received CMV prophylaxis or preemptive treatment. During a median of 13.7 (7.1–14.9) yr, the number of death‐censored graft losses was 118 (25%) and of patient deaths 224 (48%). CMV infection was an independent significant risk factor for mortality in multivariate analysis (HR = 1.453, 95% CI 1.033–2.045, p = 0.032), adjusting for patient and donor age, preemptive transplantation, HLA‐DR and ‐AB mismatches, living donor, acute rejection during the first three months, donor–recipient CMV IgG antibody status and diabetic nephropathy. In univariate analysis, CMV infection was significantly associated with death‐censored graft loss but the association was not significant in multivariate model. CMV infection early after kidney transplantation is a predictor of overall mortality but not of death‐censored graft loss after a median observation period of 13.7 yr.     

High incidence of delayed graft function in HIV‐infected kidney transplant recipients

Kidney transplantation (KT) outcomes in human immunodeficiency virus (HIV)‐infected recipients are under continuous research. High incidence of early post‐transplant complications such as acute rejection has been observed. A multicenter study including HIV‐infected patients who underwent KT in Spain, from 2001 to 2011, was performed. The study population included 108 recipients, 36 HIV‐infected, and 72 matched HIV‐negative KT recipients. HIV‐infected recipients developed more delayed graft function (DGF) (52% vs. 21%, P < 0.001). One‐ and 3‐year graft survival was 91.6% and 86.2% in HIV‐infected patients, and 97.1% and 94.7% in HIV‐negative patients (P = 0.052). In two‐variate Cox analysis, HIV infection was not a predictor of graft loss after adjusting for time on dialysis, acute rejection, and DGF. Multivariate analysis for DGF revealed HIV‐positive status as independent risk factor. We analyzed the evolution of immunosuppressive and antiretroviral therapy (ART). In HIV‐infected patients tacrolimus trough levels were very high in the first week and significantly lower in the second week post‐transplant (P = 0.042). Post‐transplant ART was significantly changed: protease inhibitors use decreased (P = 0.034) and integrase inhibitor use increased (P < 0.001). DGF is another frequent early complication in HIV‐infected recipients that can affect graft survival. Strategies to prevent DGF and antiretroviral regimes with less drug interactions could improve outcomes.     

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.     

HLA Mismatching Increases the Risk of BK Virus Nephropathy in Renal Transplant Recipients

BK virus (BKV) nephropathy is a serious complication in kidney transplant recipients that may lead to irreversible graft failure. We have analyzed the degree of donor/recipient HLA compatibility and HLA antigen association in 40 kidney transplant patients with BKV nephropathy in comparison with a control group of 404 unaffected transplant recipients who were on tacrolimus-based immunosuppression with no induction. HLA compatibility was assessed by determining the number of HLA-A, -B, -DR-mismatched antigens. BK virus nephropathy was diagnosed histologically and confirmed by immunochemistry. Univariate and multiple logistic regression statistical analyses have shown a significant association between BKV nephropathy and HLA mismatching. This analysis showed also that BKV nephritis is associated with a greater number of rejection episodes and a higher incidence of steroid-resistant rejection requiring antilymphocyte treatment. There was no association between BKV nephropathy and any specific HLA allele. We propose that HLA mismatching promotes the development of BKV nephropathy through rejection-related inflammatory processes and heavy immunosuppression which cause virus reactivation and injury of the tubular epithelium.     

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。