Presence of decoy cells for 6 months on urine cytology efficiently predicts BK virus nephropathy in renal transplant recipients.

OBJECTIVES: To investigate the association between duration of consecutive presence of decoy cells on urine cytology and BK virus nephropathy after kidney transplantation. METHODS: In total, 121 kidney transplant recipients were retrospectively evaluated. The best duration of consecutive presence of decoy cells that could be used to predict BK virus nephropathy was analyzed using the area under the curve for each duration, and recipients were divided into two groups based on the best predictive performance. The effectiveness of SV40 immunostaining on urinary cytology was also analyzed. RESULTS: In total, 2534 urine specimens as well as SV40 immunostaining in 2241 urine specimens were analyzed. Six consecutive months of decoy cell positivity had the best predictive performance for BK virus nephropathy (area under the curve = 0.832). The incidence of BK virus nephropathy in recipients with positive decoy cells for 6 months or more consecutive months (5/44) was significantly higher than in those who had positive decoy cells for less than 6 months (0/77; P = 0.005). Decoy cell positivity had a sensitivity, specificity, positive predictive value, and negative predictive value for BK virus nephropathy of 100%, 66%, 11%, and 100% respectively. SV40 immunostaining provided slightly better specificity (68%) and positive predictive value (12%). CONCLUSIONS: The detection of decoy cells at 6 months or more on urine cytology had high predictive value for BK virus nephropathy in kidney transplant recipients. SV40 immunostaining on urine cytology added minimal diagnostic accuracy.

The Importance of Kidney Medullary Tissue for the Accurate Diagnosis of BK Virus Allograft Nephropathy.

BACKGROUND AND OBJECTIVES: The published tissue adequacy requirement of kidney medulla for BK virus allograft nephropathy diagnosis lacks systematic verification and competes against potential increased procedural risks from deeper sampling. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated whether the presence of kidney medulla improved the diagnostic rate of BK nephropathy in 2244 consecutive biopsy samples from 856 kidney transplants with detailed histologic and virologic results. RESULTS: Medulla was present in 821 samples (37%) and correlated with maximal core length (r=0.35; P<0.001). BK virus allograft nephropathy occurred in 74 (3% overall) but increased to 5% (42 of 821) with medulla compared with 2% (32 of 1423) for cortical samples (P<0.001). Biopsy medulla was associated with infection after comprehensive multivariable adjustment of confounders, including core length, glomerular number, and number of cores (adjusted odds ratio, 1.81; 95% confidence interval, 1.02 to 3.21; P=0.04). In viremic cases (n=275), medulla was associated with BK virus nephropathy diagnosis (39% versus 19% for cortex; P<0.001) and tissue polyomavirus load (Banff polyomavirus score 0.64±0.96 versus 0.33±1.00; P=0.006). Biopsy medulla was associated with BK virus allograft nephropathy using generalized estimating equation (odds ratio, 2.04; 95% confidence interval, 1.05 to 3.96; n=275) and propensity matched score comparison (odds ratio, 2.24; 95% confidence interval, 1.11 to 4.54; P=0.03 for 156 balanced pairs). Morphometric evaluation of Simian virus 40 large T immunohistochemistry found maximal infected tubules within the inner cortex and medullary regions (P<0.001 versus outer cortex). CONCLUSIONS: Active BK virus replication concentrated around the corticomedullary junction can explain the higher detection rates for BK virus allograft nephropathy with deep sampling. The current adequacy requirement specifying targeting medulla can be justified to minimize a missed diagnosis from undersampling.

Incidence and risk factor of hemorrhagic cystitis after allogeneic transplantation with fludarabine, busulfan, and anti-thymocyte globulin myeloablative conditioning.

BACKGROUND: Hemorrhagic cystitis (HC) is a complication of allogeneic stem cell transplantation (SCT), associated with factors such as BK polyomavirus reactivation, age, conditioning regimen, and presence of graft-versus-host disease (GVHD). The incidence and impact of HC in patients receiving fludarabine (Flu), busulfan (Bu), and anti-thymocyte globulin (ATG) conditioning is unknown. METHODS: We conducted a case-control study of patients undergoing SCT at our center between January 1, 2003 and Dec 31, 2012, to determine the incidence of HC and its effect on patient outcomes including overall survival (OS), relapse, non-relapse mortality (NRM), GVHD, and healthcare resource use. RESULTS: In total, 94 cases of HC were identified and matched to controls based on age, donor type, disease type, and disease status at transplantation. The total incidence of HC was 17.7% (117 of 661 patients). Cases had a higher rate (43.6% vs 27.1%, P=.0394) of acute GVHD (Grade II-IV), and chronic GVHD requiring systemic steroids (34.9% vs 18.6%, P=.004). Male gender was found to be a risk factor (hazard ratio [HR]=1.725, P=.017). OS and progression-free survival did not differ between cases and controls (OS HR=1.128, 95% confidence interval [CI] 0.7807-1.639; progression-free survival HR=0.8809, 95% CI 0.6320-1.234), however the rate of NRM was higher in cases (HR=1.632, 95% CI 1.007-2.830). Median length of hospitalization was longer for patients with HC than matched controls (65.5 days vs 40.5 days, P<.0001). CONCLUSION: HC is common in patients undergoing allogeneic SCT with FluBuATG conditioning, and affects the duration of hospitalization. Rate of GVHD is higher among patients with HC. While OS is not affected, an association was seen with higher NRM in our study. Improvement in treatment for HC may lead to reductions in morbidity and healthcare resource utilization.

Polyomavirus infections and its clinical relevance in cancer patients: A Prospective Study.

BK and JC polyomaviruses (PyV) have been demonstrated to be associated with the pathogenesis of various human cancers. We aimed to investigate the impact of BK and JC polyomavirus infections on several clinical parameters in different human cancers. A total of 150 cancer patients were included in the study (51 patients with solid tumors, 48 patients with lymphomas and 51 patients with leukemias). Amplification of PyV DNA was performed using a semi-nested version of Polymerase chain reaction targeting the T genomic region of PyV. The polyomavirus load was determined using real-time PCR assay. The clinical data were collected. Polyomavirus DNA could be detected in 84 (56%) of 150 of all cancerous patients. The solid tumors had the lowest proportion of JCV (6 (11.8%) of 51), whereas had the highest proportion of JCV (200copies/µl). JCV was more frequent among NHL patients (30%) and absent in HL patients (0%). During follow-up, PyV positivity decreased significantly (p=0.004) in lymphoma patients (n=28). Although PyV positivity decreased significantly from 39% to 7% in 28 of 48 lymphoma patients after treatment, it significantly persisted in leukemic patients after treatment (from 22% to 38%). JC was more frequent among leukemic patients with leukopenia. The presence of JC polyomavirus was more frequent among leukemic patients without any significant impact on their overall survival.

Human JC polyomavirus in normal colorectal mucosa, hyperplastic polyps, sporadic adenomas, and adenocarcinomas in Portugal.

John Cunningham virus (JCV) infects chronically human populations worldwide and probably might confer a higher risk for colorectal cancer (CRC). The prevalence of JCV DNA has been determined in normal colon mucosa and compared it with different degrees of colorectal lesions, as well as viral presence in the urine of the individuals in the study. JCV DNA was detected by a nested-PCR approach targeting the JCV small-t antigen in 100 healthy controls, and 100 patients undergoing biopsy for diagnosis of colorectal disorders. JCV DNA was detected in 40% of normal mucosa from controls and patients. JCV DNA presence in urine was also similar in controls and patients (37-41% range). JCV DNA detection in normal mucosa and urine reflects the infected population in Portugal. However, in cases with colorectal tumor lesions, JCV DNA was detected in 90% cases, independently of histological type or grade, and this increase was significantly higher with respect to its normal surrounding mucosa. This higher detection of JCV DNA in tumor lesions with respect to its own normal mucosa suggested that a selection for virus containing cells has occurred at some early stage in tumor initiation or progression. JCV may have a specific tropism for colon epithelial cells with some inherent predisposition that makes them more prone to oncogenic transformation, with selection of infected cells. Several p53 polymorphisms in intron 2, common to both groups, were more frequently detected in colorectal pathology cases. A novel p53 mutation in the 3' untranslated region (exon 11) was identified in 10 patients.

Clinicopathological features of polyomavirus-associated nephropathy / 中华肾脏病杂志

Objective To interpret the clinicopathological features and the key factors for diagnosis of polyomavirus-associated nephropathy (PVAN).Methods Clinicopathological data of 13casesof polyomavirus-associatednephropathyduring2008-2011inour hospitalwere retrospectively analyzed.Three cases received repeat biopsy.The clinicopathological features were analyzed according to thelight microscopicsceneandSV40-Timmunochemicalexpression.Results Recipients had a peak incidence of PVAN in 12 to 18 months period after renal transplantation,accompanied by elevated serum creatinine.Due to the progression of the disease,3patterns of histological findings could be identified.The early lesion was confined to the collected ducts,with slightly inflammatory infiltration in medullary interstitium,viral inclusions were not necessarily seen.The only findings could be enlarged nuclear and irregular arrangement of the tubular epithelial cells.At the developing stage,prominent tubulointerstitial nephritis was detected,and the involved tubules extended to other segments of renal tubule,even the parietal epithelial cells of Bowman's capsule could be compromised.The epithelial cells shed off,leading the tubular basement membrane exposed.Typical intra-nuclear inclusions as well as variable nuclear changes were found.At the end stage,the allograft showed notable chronic tubulointersititial change,with diffuse tubular atrophy and interstitial fibrosis.Although in this period,typical viral inclusions were rare, stillIHCshowedpositiveexpression of SV40-T. After immunosuppressantreductionor exchange,2 cases developed renal failure,4 cases showed sustained increment in serum creatinine,while 7 cases had a stabilized serum creatinine level.Conclusions Polyomavirus-associated nephropathy can display uneven pathological changes,as well as the morphology of the infected epithelial cells.Segments of the involved tubule are associated with the course of disease.Reduction of immunosuppressant at the early stage has a favorable effect.A prompt renal biopsy should be done in renal transplant recipient if who shows increased serum creatinine,and a routine polyomavirus immunohistochemical staining should be applied as well.

Polyomavirus Disease in Kidney Transplantation / 대한이식학회지

Polyomavirus disease is a re-emerging infectious complication in renal transplantation. It manifests as symptomless renal dysfunction and progresses to graft loss unless the prompt diagnosis and intervention are initiated. A gold standard for diagnosis is the renal biopsy. Recently, the molecular diagnosis can be made using plasma PCR technique before histologic confirmation. Reduction of immunosuppression is a mainstay of treatment. Leflunomide and other antiviral agents could be used successfully in selected cases. The screening using urine decoy cell and subsequent plasma PCR may detect the BK viral replication, and preemptive intervention will prevent development of overt nephropathy without risk of rejection. This review will cover the recent advances and clinical issues in diagnosis and management of polyomavirus disease, mainly BK virus associated nephropathy.