The high incidence of BK polyoma virus infection among renal transplant recipients in India

BK polyoma virus causes allograft dysfunction as a result of tubulo-interstitial nephritis in 2% to 5% of renal transplant recipients. The incidence of BK virus infection among renal transplant recipients in India is unknown. We used routine histologic examination, immunohistochemistry, and electron microscopy to retrospectively screen for BK polyoma virus in 414 renal allograft biopsy specimens from 321 transplant recipients presenting with allograft dysfunction. All patients had received a combination of cyclosporine, azathioprine, and prednisolone. A total of 30 biopsy specimens (9.3%) were positive for BK polyoma virus, suggesting a high incidence of this infection in Indian transplant recipients. BK virus infection coexisted with acute rejection in a majority of patients. This is the first report of this infection among Indian renal transplant recipients.     

BK virus nephropathy in renal transplant recipients in Kuwait: a preliminary report

INTRODUCTION: BK virus nephropathy (BKVN) is a significant cause of graft loss among renal transplant recipients. The treatment outcomes of BKVN have been variably reported in the literature. PATIENTS AND METHODS: We prospectively investigated BKV infection and BKVN among a population of renal transplant recipients with suspected BKV infection. The 42 subjects who all had acute allograft dysfunction, were categorized in three groups: those with clinical, laboratory, and histological findings that did not suggest acute rejection, drug toxicity, or obstruction (group 1, n = 24); those with findings that suggested probable acute cellular rejection but did not respond to antirejection treatment (group 2, n = 10); and those whose renal histology suggested BKVN (group 3, n = 8). Polymerase chain reaction analysis was done to detect BKV DNA in urine and blood samples from each subject. BKV DNA was detected in 19 (45%) urine samples with 11 of these subjects (26.1% of total) having BK viremia as well. RESULTS: No evidence of BKVN was detected histologically in seven subjects with isolated BK viruria, while the others proved to be JC virus infections. Among the 11 subjects with BK viremia, eight had BKVN based on renal histology at the time of diagnosis with BKV infection, while the other three subsequently developed histological features of BKVN. BKVN developed after 5.3 +/- 2.5 (2 to 44) months after transplantation. The serum creatinine at time of BKVN diagnosis was 158.9 +/- 58 (87 to 285) micromol/L. All subjects were initially treated with a 50% reduction in immunosuppressive drug doses. Further decreases in immunosuppression were performed in all patients with close monitoring of renal function. All subjects were followed up for a of 18.2 +/- 5 (12 to 26) months. Two grafts were lost not due to BKVN, and one patient was lost to follow-up during this period. The latest serum creatinine in eight recipients is 113 + 20 (81 to 138) micromol/L, which is better than the renal function at diagnosis. CONCLUSION: The prevalence of BKVN in suspected BKV infection was 26%. Although the study period was short (30 months), BK viremia strongly correlated with BKVN, which seemed to be successfully treated with reduction in immunosuppression.     

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.     

Successful retransplantation after renal allograft loss to polyoma virus interstitial nephritis

BACKGROUND: Although polyoma virus infection is being increasingly recognized as a cause of renal allograft dysfunction and failure, the risk of polyoma recurrence in a subsequent transplant is unknown. We present the first reported case of successful retransplantation after polyoma virus-induced renal allograft loss. CASE REPORT: A 40-year-old Caucasian woman received a cadaveric kidney transplant. Baseline immunosuppression included corticosteroids, mycophenolate mofetil, and tacrolimus. Her post-transplant clinical course was complicated by an early acute rejection episode on posttransplant day (PTD) 6, that warranted treatment with OKT3. A biopsy performed on PTD 154 to evaluate a rise in creatinine revealed polyoma virus interstitial nephritis. Despite reduction in immunosuppression, the renal function progressively worsened and dialysis was initiated by PTD 160, followed by transplant nephrectomy on PTD 184. Four months later, she received a living related kidney from her sister. Immunosuppression was initiated with prednisone, azathioprine, and tacrolimus. She had immediate graft function with a decrease in serum creatinine from 12.8 to 1.1 mg/dl. Three and one-half years after her second renal transplant, her allograft functions well, with a serum creatinine of 1 mg/dl. Both quantitative and qualitative assays of blood and urine (by PCR) remain negative for BK virus, indicating the absence of virus reactivation. CONCLUSION: Judicious retransplantation should be considered as a therapeutic option in the management of polyoma virus induced graft failure. Previous graft loss secondary to polyoma virus infection is not a contraindication to retransplantation.     

BK virus nephropathy: Clinical experience in a university hospital in Japan

Objectives: To review the medical records of patients with BK virus nephropathy (BKVN) following kidney transplantation in our institution. Methods: We screened patients for decoy cells using urine cytology, assessed serum creatinine levels, and conducted a graft biopsy, as well as assessed the presence of plasma BK virus DNA by quantitative real‐time polymerase chain reaction. The treatment of BKVN was based on the decreased use of immunosuppressants. Results: Overall, six male patients were studied (mean age 40.8 years, range 18–58; mean donor age 45.2 years, range 15–67). A positive urine cytology screen led to the subsequent detection of plasma BK virus DNA in the five patients with urine cytology results positive for decoy cells. In the four patients in whom plasma BK virus DNA was detected, a maximum value of DNA of ≥10 000 copies/mL was observed. Time elapsed from transplantation to BKVN diagnosis ranged from 3 to 62 months. Although the two cadaver grafts were lost, the loss was not due to any effects directly associated with BKVN. The other four grafts are still functioning with a mean creatinine level of 1.8 mg/dL. Most of the patients with BKVN were regarded as being in a state of heightened immunosuppression. BK virus transition to blood was prevented in one patient. Conclusions: Early diagnosis of BKV infection with reduction of immunosuppression may potentially counter BK viremia and retard progression of BKV nephropathy. Decoy cell screening by urine cytology as well as plasma BK virus DNA screening should be considered in addition to the required graft biopsy in kidney transplant recipients, particularly in those with impaired graft function.     

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.     

Clinical course of hepatitis C virus infection in renal transplant recipients

Patients with end-stage renal disease are at high risk for exposure to hepatitis C virus (HCV) infection. Although both viral replication and liver disease progression are accelerated after renal transplantation, the long-term impact of chronic HCV infection is unclear. Our aim was to analyze the course of HCV infection in renal transplant recipients and the effects of HCV reactivation on patient and graft survival. METHODS: We retrospectively examined the 21-year (1985-2006) data of 1274 renal transplant recipients, 43 of whom were anti-HCV positive at the time of transplantation. RESULTS: The mean posttransplant follow-up of 43 patients was 62.0 +/- 7.3 months. At the time of transplantation, HCV RNA was positive in 11 (25.6%) patients and negative in 32 (74.4%) patients. HCV reactivation was seen in 19 (45.2%) patients at a mean time of 20.8 +/- 5.7 months. In 31 (72%) patients, acute rejection occurred, whereas graft loss occurred in 10 (23%) patients. Three (7%) patients died. Among 43 patients, 22 (51.2%) were treated with interferon before transplantation. There was a statistically significant association between pretransplant interferon therapy and pretransplant HCVRNA level (P=.024), but no significant association of HCV reactivation and graft rejection, mortality, or kidney survival. CONCLUSION: HCV reactivation occurred in nearly half of the renal transplant recipients, mostly in the second year. Patient survival and graft survival were not affected by HCV reactivation. Anti-HCV positivity should not preclude chronic renal failure patients from renal transplantation.     

A Mouse Model for Polyomavirus-Associated Nephropathy of Kidney Transplants

Polyomavirus-associated nephropathy is an important cause of dysfunction and failure of renal transplants. BK virus is an ubiquitous human polyoma virus that persistently infects the kidney. This otherwise silent infection can reactivate in immunosuppressed individuals, resulting in renal complications. Because polyoma viruses are highly species-specific, we developed a mouse polyoma virus-renal transplant model in order to investigate the pathogenesis of polyomavirus-associated nephropathy. Using this model, we found that polyoma virus preferentially replicates in the allogeneic kidney grafts, accelerating graft failure; thus, this animal model is able to mimic the polyomavirus-associated nephropathy seen in human renal transplant patients. Acute polyoma virus infection of mouse allograft recipients augmented the alloreactive CD8⁺ T-cell response, while maintaining the anti-viral CD8⁺ T-cell response. In addition to the known virus-induced cytopathology, these findings demonstrate a potential role for an enhanced anti-donor T-cell response in the pathogenesis of polyomavirus-associated nephropathy.     

Successful pregnancy in renal transplant recipient with previous known polyomavirus nephropathy

Pregnancy after renal transplantation has become increasingly common. Studies in non-immunocompromised patients have shown that pregnant women have increased susceptibility to infection or reactivation of latent virus such as BK virus. To what extent a renal transplant recipient is at risk for reactivation of polyoma virus during pregnancy remains unknown. We hereby report successful pregnancy outcome in a renal transplant recipient with a known history of BK virus nephropathy treated with cidofovir i.v. To our knowledge, this is the first published experience with a successful pregnancy in renal transplant recipients with known history of polyomavirus-associated nephropathy.     

JC virus infection in allograft kidneys: analysis by polymerase chain reaction and immunohistochemistry

BACKGROUND: Polyoma virus nephropathy after transplantation is believed to be primarily due to the BK virus. We hypothesized that some cases may be associated with the JC polyoma virus (JCV), which is also known to be latent in the kidney. METHODS: We sought polymerase chain reaction evidence of JCV infection in needle biopsy specimens with and without viral nephropathy. Cases positive by polymerase chain reaction were studied by immunohistochemistry for VP-1 antigen expression. RESULTS: JCV DNA was found in 7 (36.8%) of 19 allograft kidney biopsy specimens with viral nephropathy and 0 (0%) of 19 native or allograft biopsy specimens without viral nephropathy. Immunohistochemistry localized JCV to the nuclei of tubular epithelial cells in one case. CONCLUSIONS: JCV is detectable in a subset of renal allograft kidneys with polyoma virus nephropathy. The tubular epithelium is identified as a site capable of supporting JCV viral capsid protein VP-1 expression, and hence viral replication.     

Urine cytology as a useful screening method for polyoma virus nephropathy in renal transplant patients: a single-center experience

Polyoma virus nephropathy occurs in 3% to 4% of renal transplant recipients, causing graft loss in 50% of cases. In this study we sought to identify the incidence of polyoma virus infection among our transplanted patients on the basis of age, sex, creatinine level, and postoperative period. During this study the 1086 urine samples collected from 362 patients were centrifuged and stained with the Papaniclaou method. All slides were classified as negative or positive (>1 decoy cell/sample). Among 1086 urine cytologies from 241 men and 121 women, decoy cells were identified in 26.6% (96) of patients, including 29.9% (n = 72) men and 20% (n = 24) women. The incidence of decoy cells (26.6%) was increased among men and associated with a longer transplantation period (P < .05). A significant relation was detected between older age and positive urine cytology. The patients with positive urine cytology for decoy cells showed a greater incidence of abnormal plasma creatinine values (26%) compared with patients showing a negative urine cytology (13.5%). In conclusion, identification of cells with viral inclusions (decoy cells) may help with the diagnosis of viral replication or active infection, therefore, routine urine cytology may be used as screening method for the detection of polyoma virus infection.     

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。     

Urine cytology as a screening method for polyoma virus active infection

Polyoma virus nephropathy (PVN) occurs in 3% to 4% of renal transplants, causing graft loss in about 50% of cases. The presence of viral cytopathic changes in graft epithelial cells is the only diagnostic tool for PVN. However, identification of cells with viral inclusions (decoy cells) in urine can be used as a screening tool for viral replication of or for active infection with PV. The aim of the present study was to identify the occurrence of PV active infection in renal transplant recipients. Two hundred forty urine cytology samples, collected from 80 transplant patients with stable renal function, were collected on a monthly basis and stained with the Pap smear for decoy cells. Active infection with polyoma virus was confirmed by urine immunostaining. All samples were analyzed blindly and classified as negative or positive (>1 decoy cell/sample). Among 240 urine cytologies collected from 48 men and 32 women, decoy cells were identified in 37.5%. No differences were observed in serum creatinine or immunosuppressive regimen between patients with positive versus negative cytology. No graft losses occurred secondary to PVN in the present study setting. The incidence of decoy cells in this series (37.5%) was consistent with previous reports (20% to 40%), suggesting that active infection may be confirmed by PV immunohistochemistry. The absence of PVN in this group may be attributed to the low doses of immunosuppressive drugs in the late posttransplant transplant period, but also to the unknown incidence of polyoma virus infection in Brazil.     

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.     

Inhibitory interactions between BK and JC virus among kidney transplant recipients

BK and JC polyomaviruses can reactivate after transplantation, causing renal dysfunction and graft loss. The incidence of JC reactivation after renal transplant is not well understood. Here, we characterized JC reactivation using samples collected during the first year after transplantation from 200 kidney recipients. We detected BK and JC viruses in the urine of 35 and 16% of transplant recipients, respectively. The median viral load in the urine was 400 times higher for BK virus than JC virus. The presence of BK viruria made concurrent JC viruria less likely: JC viruria was detected in 22% of non-BK viruric recipients compared with 4% of BK viruric recipients (P=0.001). The co-detection rate was 1.5%, which is less than the expected 5.6% if reactivation of each virus was independent (P=0.001). We did not observe JC viremia, JC nephropathy, or progressive multifocal leukoencephalopathy. The onset of JC viruria was associated with donor, but not recipient, JC-specific antibody in a titer-dependent fashion and inversely associated with donor and recipient BK-specific antibody. Donor and recipient JC seropositivity did not predict BK viruria or viremia. In conclusion, among renal transplant recipients, infection with one polyomavirus inversely associates with infection with the other.     

Prevalence of Polyomavirus Positivity in Urine After Renal Transplantation

Background

Little is known about the timing of polyomavirus reactivation and its presence in urine after renal transplantation. The purpose of this study was to investigate the prevalence of positive polyomavirus in urine at various time points after renal transplantation.

Methods

From November 2008 to August 2013, 279 renal transplant patients from our institution were included in this study. One urine sample was collected at 0–3, 4–6, 7–12, 13–24, 25–60, and ≥61 months after renal transplantation. A total of 394 urine samples were assessed for the presence of the BK and JC viruses with the use of a real-time polymerase chain reaction assay.

Results

BK virus was detected in the urine of one-third of patients during the first 6 months. Thereafter, the positivity rate decreased gradually to 12% >5 years after transplantation. The positivity rate for the JC virus in urine was 33%–49% regardless of the post-transplantation phase.

Conclusions

BK virus was detected more frequently in urine during the early phase after renal transplantation, whereas the JC virus was detected more consistently.     

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.     

Polyoma BK virus reactivation in kidney and pancreas-kidney recipients

BK virus infection has become important factor affecting graft function in renal transplant recipients. One of the most important complication of BK infection is nephropathy in patients after renal transplantation. The aim of this study was to evaluate incidence of BK reactivation and nephropathy in our population of renal allograft recipients. One hundred twelve renal or pancreas-kidney allograft recipients were included for the 24 months follow-up. The incidence of BK nephropathy was 7.85% and viremia 27.96%. In the second study group there were 28 patients with graft function deterioration evaluated at the time of biopsy. In this group incidence of BK nephropathy was 7.1% and viral reactivation was diagnosed in 10.7% of patients. In our center, the incidence of BK nephropathy is the same as worldwide. The risk of BK virus replication is highest during first 15 months after the surgical procedure.     

BKV reactivation in renal transplant recipients: diagnostic and therapeutic strategy--case reports

The Polyomaviridae family includes several viruses that are ubiquitous with specific host spectra. The human polyoma viruses BK and JC were discovered in 1971. Following primary infection, transmitted by the respiratory and probably the oral route, BK remains latent in uroepithelial cells, in B lymphocytes, or in other tissues (spleen, brain). Reactivation with asymptomatic viruria may occur in both immunocompetent subjects and immunocompromised patients. In renal transplant recipients, BKV replication may cause tubulointerstitial nephropathy (BKVAN) with increasing prevalence rates--1% in 1995, 8% in 2007--leading to the loss of the transplanted organ in 30% to 80% of cases. With the availability of diagnostic programs (decoy cells in urine, amplification of viral DNA by polymerase chain reaction (PCR) on serum and urine, real time (RT)-PCR test for mRNA VP1 urine (mRNA-VP1), and renal biopsy accompanied by reduction in immunosuppression, administration of leflunomide, cidofovir (after hydration), and N-acetylcysteine, as well as immunoglobulin by intravenous injection (IVIg), the incidence of renal loss caused by BKVAN infection has been reduced by 10% to 80%. In this study, we have described 12 patients: 6 treated with tacrolimus (FK), mycophenolate mofetil (MMF), and steroids, and 6 treated with cyclosporine or with mTOR inhibitors. Two patients from the first group showed BKVAN about 3 months posttransplantation. Early diagnosis and therapeutic intervention (cidofovir + IVIg) led to reduction in the viral load, with improvement and stabilization in renal function. Considering the high positive predictive value (98%) of mRNA VP1, it should be possible to avoid renal biopsy. The level of immunosuppression--rather than the immunosuppressive drug itself (FK and MMF)--seemed to be associated with BKV reactivation.