Literature review of allograft adenovirus nephritis and a case presenting as mass lesions in a transplanted kidney without symptoms of urinary tract infection or acute kidney injury.

Adenovirus (AdV) infection is a common complication in bone marrow/hematopoietic stem cell transplant and solid organ transplant recipients. AdV infection usually presents as hemorrhagic cystitis, but sometimes it can progress to acute kidney injury showing AdV nephritis (AdVN). We present the case of a 52-year-old Japanese female who had received a living kidney transplantation (KT) from her husband. At 21 months post-KT, the patient presented with a fever, but no renal dysfunction and no abnormal urine findings. A contrast-enhanced computed tomography (CT) scan revealed a few mass lesions with hypoperfusion in the transplanted kidney. An enhanced CT-guided biopsy targeting one of these lesions revealed a necrotizing tubulointerstitial nephritis suggesting AdVN. The polymerase chain reaction tests for ADV were negative in a urine sample but positive in the sera and the frozen kidney biopsy samples. AdVN can manifest as an unusual pattern of acute lobar nephritis/acute focal bacterial nephritis-like localization without symptoms of acute kidney injury or urinary tract infection. Enhanced CT can provide clues for clinical diagnosis.

Comparative transcriptome analysis reveals induction of apoptosis in chicken kidney cells associated with the virulence of nephropathogenic infectious bronchitis virus.

Avian infectious bronchitis virus (IBV) that causes respiratory and nephritic diseases in chicken is a major poultry pathogen leading to serious economic loss worldwide. The nephropathogenic IBV strains cause nephritis and kidney lesions intrinsically and the pathogenic mechanism is still unclear. In the present study, SPF chicks were infected with three nephropathogenic IBVs of different virulence and their gene expression profiles in chicken kidney were compared at transcriptome level. As a result, 1279 differentially expressed (DE) genes were found in very virulent SCDY2 inoculated group, 145 in virulent SCK2 group and 74 in non-virulent LDT3-A group when compared to mock infected group. Gene Ontology (GO) and KEGG pathway enrichment analysis on SCDY2 group displayed that the up-regulated DE genes were mainly involved in cell apoptosis, and the down-regulated genes were involved in metabolic processes and DNA replication. Protein-Protein Interaction (PPI) analysis showed that DE genes in SCDY2 group formed a network, and the core of the network was composed by cell apoptosis and immune response proteins. The clustering of gene expression profile among the three virus inoculated groups indicated that the majority of up-regulated DE genes on apoptosis in very virulent SCDY2 group were up-regulated more or less in virulent SCK2 group and those down-regulated on innate immune response in SCDY2 group were also down-regulated differently in SCK2 group. In addition, the number of apoptotic cells detected experimentally in kidney tissue were very different among the three virus inoculated groups and were positively accordant with the viral titer, kidney lesions and viral virulence of each group. Taken all together, the present study revealed that virulent nephropathogenic IBV infection modified a number of gene expression and induction of apoptosis in kidney cells may be a major pathogenic determinant for virulent nephropathogenic IBV.

[Clinical and morphological signs of viral damage to a kidney transplant]. / Kliniko-morfologicheskie priznaki virusnogo porazheniia pochechnogo transplantata.

AIM: Тo compare morphological changes and results of immunohistochemical (IHC) identification of viruses (polyomaviruses, adenoviruses, and herpesviruses) in the biopsy specimens with their clinical manifestations in recipients of renal transplants. MATERIAL AND METHODS: Morphological and IHC studies were conducted using 71 needle renal transplant biopsy specimens from patients in the study group and 10 renal biopsy specimens from those in the control group. A number of clinical indicators were estimated. RESULTS: IHC examination revealed the expression of adenoviral antigens more commonly in patients with posttransplant nephritis than in recipients without nephritis or in control individuals (p<0.05). The association of patient age and time after kidney transplantation with the severity of viral damage was confirmed: graft loss in children occurred within the first months of surgery (p<0.05). Polyomavirus was detected by PCR in patients with the morphological patterns of polyomavirus nephropathy. Determination of HSV-1 and HSV-2 in the biopsy specimens showed no significant associations with morphological changes. CONCLUSION: By taking into account a variety of factors that influence the development of viral nephritis, morphological and IHC examinations should be combined with evaluation of clinical findings.

Ultrasound findings of BK polyomavirus-associated nephropathy in renal transplant patients.

BK polyomavirus (BKV) is an emerging pathogen in immunocompromised patients. BKV infection occurs in 1-9 % of renal transplants and causes chronic nephropathy or graft loss. Diagnosis of BKV-associated nephropathy (BKVAN) is based on detection of viruria then viremia and at least a tubule-interstitial nephritis at renal biopsy. This paper describes the ultrasound and color Doppler (US-CD) features of BKVAN. Seventeen patients affected by BKVAN were studied using a linear bandwidth 7-12 MHz probe. Ultrasound showed a widespread streak-like pattern with alternating normal echoic and hypoechoic streaks with irregular edges from the papilla to the cortex. Renal biopsy performed in hypoechoic areas highlighted the typical viral inclusions in tubular epithelial cells. Our experience suggests a possible role for US-CD in the non-invasive diagnosis of BKVAN when combined with blood and urine screening tests. US-CD must be performed with a high-frequency linear probe to highlight the streak-like pattern of the renal parenchyma.

Hemorrhagic Herpes Simplex Virus Type 1 Nephritis: An Unusual Cause of Acute Allograft Dysfunction.

Interstitial nephritis due to viruses is well-described after solid organ transplantation. Viruses implicated include cytomegalovirus; BK polyomavirus; Epstein-Barr virus; and, less commonly, adenovirus. We describe a rare case of hemorrhagic allograft nephritis due to herpes simplex virus type 1 at 10 days after living donor kidney transplantation. The patient had a favorable outcome with intravenous acyclovir and reduction of immunosuppression.

JC polyomavirus nephropathy, a rare cause of transplant dysfunction: Case report and review of literature.

JC polyomavirus-associated nephropathy (JC-PVAN) is a rare but challenging cause of renal dysfunction. We report JC-PVAN in a renal allograft recipient and highlight the obstacles in definitive diagnosis of this disease entity. A deceased-donor renal transplant recipient was diagnosed with JC polyomavirus nephritis 4 years after transplantation. Immunosuppressive agents were subsequently reduced, resulting in an initial stabilization of renal function. We present this interesting case and discuss the challenges with diagnosing and treating this rare entity.

MICA Mutant A5.1 Influences BK Polyomavirus Reactivation and Associated Nephropathy After Kidney Transplantation.

BACKGROUND: BK polyomavirus (BKPyV) frequently reactivates in kidney transplant recipients during immunosuppressive therapy and triggers BKPyV-associated nephropathy and graft rejection. Determining effective risk factors for BKPyV reactivation is required to achieve efficient prevention. METHODS: This study investigated the role of major histocompatibility complex (MHC) class I-related chain A (MICA) in BKPyV reactivation in a cohort of 144 transplant donor/recipient pairs, including recipients with no reactivation (controllers) and those with mild (virurics) or severe (viremics) BKPyV reactivation after graft receipt. RESULTS: We show that, in the kidney, MICA is predominantly expressed in tubule epithelial cells, the natural targets of BKPyV, questioning a role for MICA in the immune control of BKPyV infection. Focusing on MICA genotype, we found a lower incidence of BKPyV reactivation in recipients of a renal graft from a donor carrying the MICA A5.1 mutant, which encodes a truncated nonconventional MICA. We established that a mismatch for MICA A5.1 between transplant donor and recipient is critical for BKPyV reactivation and BKPyV-associated nephropathy. Functionally, we found that a low prevalence of BKPyV reactivation was associated with elevated anti-MICA sensitization and reduced plasma level of soluble MICA in recipients, 2 potential effector mechanisms. DISCUSSIONS: These findings identify the MHC-related MICA as an immunogenetic factor that may functionally influence anti-BKPyV immune responses and infection outcomes.

Mining the human urine proteome for monitoring renal transplant injury.

The human urinary proteome provides an assessment of kidney injury with specific biomarkers for different kidney injury phenotypes. In an effort to fully map and decipher changes in the urine proteome and peptidome after kidney transplantation, renal allograft biopsy matched urine samples were collected from 396 kidney transplant recipients. Centralized and blinded histology data from paired graft biopsies was used to classify urine samples into diagnostic categories of acute rejection, chronic allograft nephropathy, BK virus nephritis, and stable graft. A total of 245 urine samples were analyzed by liquid chromatography-mass spectrometry using isobaric Tags for Relative and Absolute Quantitation (iTRAQ) reagents. From a group of over 900 proteins identified in transplant injury, a set of 131 peptides were assessed by selected reaction monitoring for their significance in accurately segregating organ injury causation and pathology in an independent cohort of 151 urine samples. Ultimately, a minimal set of 35 proteins were identified for their ability to segregate the 3 major transplant injury clinical groups, comprising the final panel of 11 urinary peptides for acute rejection (93% area under the curve [AUC]), 12 urinary peptides for chronic allograft nephropathy (99% AUC), and 12 urinary peptides for BK virus nephritis (83% AUC). Thus, urinary proteome discovery and targeted validation can identify urine protein panels for rapid and noninvasive differentiation of different causes of kidney transplant injury, without the requirement of an invasive biopsy.

Visual detection of goose haemorrhagic polyomavirus in geese and ducks by loop-mediated isothermal amplification.

Goose haemorrhagic polyomavirus (GHPV) is an aetiological agent of haemorrhagic nephritis and enteritis of geese occurring in geese (Anser anser). GHPV may also infect Muscovy ducks (Carina mochata) and mule ducks. Early detection of GHPV is important to isolate the infected birds from the rest of the flock thus limiting infection transmission. The current diagnosis of haemorrhagic nephritis and enteritis of geese is based on virus isolation, histopathological examination, haemagglutination inhibition assay, ELISA and polymerase chain reaction (PCR). Recently, real-time PCR assay was developed which considerably improved detection of GHPV. In spite of many advantages, these methods are still time-consuming and inaccessible for laboratories with limited access to ELISA plate readers or PCR thermocyclers. The aim of our study was to develop loop-mediated isothermal amplification (LAMP) that may be conducted in a water bath. Two pairs of specific primers complementary to VP1 gene of GHPV were designed. The results of GHPV LAMP were recorded under ultraviolet light. Our study showed LAMP was able to specifically amplify VP1 fragment of a GHPV without cross-reactivity with other pathogens of geese and ducks. LAMP detected as little as 1.5 pg of DNA extracted from a GHPV standard strain (150 pg/µl). The optimized LAMP was used to examine 18 field specimens collected from dead and clinically diseased geese and ducks aged from 1 to 12 weeks. The positive signal for GHPV was detected in three out of 18 (16.6%) specimens. These results were reproducible and consistent with those of four real-time PCR. To the best of our knowledge this is the first report on LAMP application for the GHPV detection.

Successful treatment of BK virus nephropathy using therapeutic drug monitoring of mycophenolic acid.

We report the successful management of BK virus nephropathy (BKVN) using therapeutic drug monitoring (TDM) of mycophenolic acid (MPA). A 40-year-old woman was admitted for a protocol biopsy 3 months following primary kidney transplantation. Histological features were distributed in mainly two sections: the corticomedullary junction and cortical area. In the former, massive interstitial mononuclear cell infiltration and mild to moderate tubulitis with nuclear inclusion bodies were found. SV40 staining was positive in the injured tubules. These findings were compatible with BKVN. In the latter, focal interstitial inflammation and severe tubulitis without cytopathic changes were identified outside of SV40-positive areas. Based on the histological findings, we diagnosed BKVN and we also suspected of the complication with acute T-cell-mediated rejection. We started steroid pulse therapy and reduced the dosage of immunosuppressive therapy under careful monitoring, using not only a trough level of tacrolimus but also a 12-h area under the curve (AUC0-12 ) of MPA. After the treatment, the patient maintained kidney function. This case report demonstrates the usefulness of MPA AUC0-12 for more accurate adjustment of immunosuppressive therapy and the difficulty of pathological differentiation of BKVN and acute cellular rejection.

Prospective study of BK virus infection and nephropathy during the first year after kidney transplantation.

INTRODUCTION: The aim of this study was to assess the prevalence and severity of BK virus infection, BK virus nephritis, and related risk factors among kidney transplant recipients. MATERIALS AND METHODS: BK viremia during the first year of kidney transplantation was assessed prospectively in 32 successive recipients. BK virus DNA was extracted and determined in all samples by real-time polymerase reaction assay for 1 year after kidney transplantation. RESULTS: The mean age of the patients was 33.3 ± 15.3 years. Sixteen patients (50%) received antithymocyte globulin for induction therapy. Living donor transplant consisted of 75% of the kidney donations. Maintenance immunosuppressive therapy included cyclosporine A in 27 patients (84.4%), plus tapering prednisolone and mycophenolate mofetil. BK viremia was detected in 8 patients (25%). The highest detected plasma viral load was less than 4000 copies per milliliter. BK virus was respectively positive in 5 (62.5%), 2 (25%), and 1 (12.5%) patients during the first 4, 8, and 12 months after transplantation. Biopsy-proven rejection and antirejection therapy by methylprednisolone pulses were 5 and 2.3 times more common in patients with BK virus infection (P = .01 and P = .01), respectively. CONCLUSIONS: Despite occurrence of BK virus infection in 25% of our patients, BK nephropathy did not develop in any of them. Routine screening of BK virus infection, particularly in centers with low prevalence of BK virus nephritis, may not be cost effective for predicting this disease.

Existence of feline morbillivirus infection in Japanese cat populations.

Feline morbillivirus (FmoPV) is a member of a new virus species that has only been found in the Hong Kong cat population. For the first time, however, we have now detected nucleotide sequences similar to FmoPV in samples from Japanese cat populations. The positive rates for urine and blood samples from Japanese cats were 6.1 % (5/82) and 10 % (1/10), respectively. These sequences are similar to the previously reported FmoPV, with 92-94 % identity, and substantially different from all other morbilliviruses. Phylogenetic analysis of the identified Japanese FmoPVs and other morbilliviruses demonstrated a pattern similar to those previously published for the FmoPV viruses isolated in Hong Kong. FmoPV RNA was also detected from formalin-fixed paraffin-embedded (FFPE) kidney tissues of cats with nephritis, with a positive rate of 40 % (4/10). By using nested-set primers based on the FmoPV sequence and RNA from FFPE tissues, we demonstrated the existence of FmoPV infection in Japanese cats and established the method for detection of the FmoPV RNA from kidney tissues prepared for pathology examinations, which is useful for studies on the pathogenicity of the virus.

Hemorrhagic nephritis and enteritis in a goose flock in Poland--disease course analysis and characterization of etiologic agent.

Hemorrhagic nephritis enteritis of geese (HNEG) is an epizootic viral disease caused by infection with goose hemorrhagic polyomavirus (GHPV) that affects domestic geese. This study describes the epizootic analysis, laboratory diagnosis, and molecular characterization of GHPV isolates associated with HNEG cases in Poland. HNEG symptoms persisted in infected flocks for 2 wk with a 32% mortality rate. Primary gross lesions included hemorrhaging of the kidneys, intestines, and lungs. Histopathologic examination confirmed HNEG and identified that the causative agent was similar to other GHPV isolates and identical to the Toulouse 2008 isolate.

A hamster-derived West Nile virus isolate induces persistent renal infection in mice.

BACKGROUND: West Nile virus (WNV) can persist long term in the brain and kidney tissues of humans, non-human primates, and hamsters. In this study, mice were infected with WNV strain H8912, previously cultured from the urine of a persistently infected hamster, to determine its pathogenesis in a murine host. METHODOLOGY/PRINCIPAL FINDINGS: We found that WNV H8912 was highly attenuated for neuroinvasiveness in mice. Following a systemic infection, viral RNA could be detected quickly in blood and spleen and much later in kidneys. WNV H8912 induced constitutive IL-10 production, upregulation of IFN-ß and IL-1ß expression, and a specific IgM response on day 10 post-infection. WNV H8912 persisted preferentially in kidneys with mild renal inflammation, and less frequently in spleen for up to 2.5 months post infection. This was concurrent with detectable serum WNV-specific IgM and IgG production. There were also significantly fewer WNV- specific T cells and lower inflammatory responses in kidneys than in spleen. Previous studies have shown that systemic wild-type WNV NY99 infection induced virus persistence preferentially in spleen than in mouse kidneys. Here, we noted that splenocytes of WNV H8912-infected mice produced significantly less IL-10 than those of WNV NY99-infected mice. Finally, WNV H8912 was also attenuated in neurovirulence. Following intracranial inoculation, WNV persisted in the brain at a low frequency, concurrent with neither inflammatory responses nor neuronal damage in the brain. CONCLUSIONS: WNV H8912 is highly attenuated in both neuroinvasiveness and neurovirulence in mice. It induces a low and delayed anti-viral response in mice and preferentially persists in the kidneys.

Effect of a BK viruria reaction detected by qualitative polymerase chain reaction on the renal function of kidney transplant recipients.

The number of end stage renal failure patients receiving hemodialysis or peritoneal dialysis in Taiwan is on the increase. Of the various treatment options, kidney transplantation is considered to be the ultimate choice, however, it may lead to certain complications, including the infection or reactivation of the BK virus (BKV). Such viral complications may cause nephritis of the donated kidney and eventually dysfunction and transplantation failure. Therefore the early detection of BKV may be beneficial for kidney transplant recipients. The aim of the present study was to demonstrate the impact of BKV infection on renal function and to show the feasilibility of urine qualitative polymerase chain reaction (PCR) as a screening test in renal transplantation patients. A total of 250 patients were screened for the presence of BKV or John Cunningham virus (JCV) DNA in the urine via qualitative PCR. Subjects positive for urine screening were then further tested using blood sampling. The results showed that 16 patients (6.4%) were co­infected by BKV and JCV with a prevalence of 20.4 and 38.4%, respectively. The correlations between viral infection and renal function were further analyzed to show that an infection of BKV has significant effects on the serum creatinine concentration. The mean serum creatinine concentration of the BKV­positive patients was 1.39±0.09 mg/dl, which was significantly higher than that of the BKV­negative patients (1.21±0.03 mg/dl; P<0.05). However, JCV infection has no such effect on renal function. Taken together, these results suggested that PCR monitoring of BKV with urine samples is a rapid, non­invasive and beneficial method for the prevention of renal complications during the long­term care of kidney transplant recipients.

Goose Hemorrhagic polyomavirus detection in geese using real-time PCR assay.

Goose hemorrhagic polyomavirus (GHPV) is the viral agent of hemorrhagic nephritis enteritis of geese (HNEG), a lethal disease of goslings. Although death is the most common outcome, geese that recover from HNEG are persistently infected. Here, we present the development of real-time SYBR Green real-time PCR targeted to GHPV and its use to assess the prevalence of GHPV infection in French geese flocks. When compared with classical end-point PCR, real-time PCR revealed a much better sensitivity and equivalent specificity. Real-time PCR could, therefore, be considered a gold standard for the detection of GHPV. Results of field investigations evidenced a very high prevalence of GHPV infections in French geese, largely associated with healthy carriage.

[Relationship between B/C genotype of hepatitis B virus and hepatitis B virus related-nephritis in children].

OBJECTIVE: To investigate the relationship between genotype of hepatitis B virus and hepatitis B virus related-glomerular nephritis in (HBV-GN) children. METHOD: Totally 176 HBV-DNA positive children with chronic hepatitis B were randomly collected. Among the 176 patients, 92 were HBV carriers, 84 were cases with chronic hepatitis. The genotypes of their serum HBV, liver function, and HBV-DNA load were detected. When children showed nephrotic syndrome, renal biopsy was performed. RESULT: Of the serum samples of 176 cases, 85 (48.3%) were genotype C, 72 (40.9%) were genotype B, 13 (7.4%) were genotype B/C, and 6 (3.4%) were non-B/C genotype which were excluded. Among the analyzed 157 cases, the ratio of HBV-GN in the HBeAg positive group (78.3%) was significantly higher than that in the negative group (21.7%) (χ(2) = 18.301, P < 0.001). And, the ratio of HBV-GN in the genotype C group (73.9%) was significantly higher than that in the genotype B group (26.1%) (P < 0.039). The ratio of hematuria or proteinuria in the genotype C group (20%, 18.8%) was significantly higher than that in the genotype B group (8.3%, 5.6%) (P < 0.039; P value = 0.013); and the alteration of ALT or C3 in the genotype C group (10.2%, 15.3%) was more frequent than those in the genotype B group (2.8%, 2.8%) (P = 0.005; P = 0.008). There were no significant differences in kidney dysfunction or hepatomegaly. Further, the ratio of HBV-GN was more significantly frequent in HBV-DNA highly loading group (79.2%) than which in HBV-DNA lowly loading group (20.8%) (P = 0.000). Finally, in HBV-GN group, genotype C cases (88.2%) more frequently had high HBV-DNA load condition than genotype B cases (11.8%) (P = 0.021). CONCLUSION: Children with HBV infection in Gansu province showed mainly genotypes C or B, while genotype C seemingly predominant. Patients with genotype C more frequently showed proteinuria or hematuria. The high HBV-DNA load may be related with HBV-GN. It is a potential reason in the mechanism of HBV-GN that patients with genotype C had more possibility to have HBV-DNA high load. Analysis of HBV genotype for HBV patients maybe helpful in diagnosis and treatment.

Pathological and epidemiological significance of goose haemorrhagic polyomavirus infection in ducks.

Goose haemorrhagic polyomavirus (GHPV) is the viral agent of haemorrhagic nephritis enteritis of geese, a lethal disease of goslings. It was recently shown that GHPV can also be detected in Muscovy and mule ducks. The goal of the present study was to investigate the pathobiology of GHPV in ducks. In the first experiment, field isolates of GHPV from Muscovy or mule ducks were fully sequenced and compared with goose GHPV. These duck isolates were then used to inoculate 1-day-old goslings. Typical clinical signs and lesions of haemorrhagic nephritis enteritis of geese were reproduced, indicating that "duck-GHPV" isolates are virulent in geese. In the second experiment, 1-day-old and 21-day-old Muscovy ducklings were infected by a reference GHPV strain. In both cases, neither clinical signs nor histopathological lesions were observed. However, the virus was detected in cloacal bursae and sera, and serological responses were detected at 12 days post infection. These findings suggest firstly that one common genotype of GHPV circulates among ducks and geese, and secondly that ducks may be infected by GHPV but show no pathologic evidence of infection, whereas geese express clinical signs. GHPV infection should therefore be considered as being carried in ducks and of epidemiological relevance in cases of contact with goose flocks.