Kidney involvement and histological findings in two pediatric COVID-19 patients.

BACKGROUND: Histological findings of kidney involvement have been rarely reported in pediatric patients with SARS-CoV-2 infection. Here, we describe clinical, laboratory, and histological findings of two pediatric cases with almost exclusive kidney involvement by SARS-CoV-2. RESULTS: A 10-year-old girl with IgA vasculitis nephritis underwent kidney biopsy, showing diffuse and segmental mesangial-proliferative glomerulonephritis, and steroid therapy was initiated. After the worsening of the clinical picture, including an atypical skin rash, she was diagnosed with SARS-CoV-2. The re-evaluation of initial biopsy showed cytoplasmatic blebs and virus-like particles in tubular cells at electron microscopy. Despite SARS-CoV-2 clearance and the intensification of immunosuppression, no improvement was observed. A second kidney biopsy showed a crescentic glomerulonephritis with sclerosis, while virus-like particles were no longer evident. The second patient was a 12-year-old girl with a 3-week history of weakness and weight loss. Rhinitis was reported the month before. No medications were being taken. Blood and urine analysis revealed elevated serum creatinine, hypouricemia, low molecular weight proteinuria, and glycosuria. A high SARS-CoV-2-IgG titre was detected. Kidney biopsy showed acute tubular-interstitial nephritis. Steroid therapy was started with a complete resolution of kidney involvement. CONCLUSION: We can speculate that in both cases SARS-CoV-2 played a major role as inflammatory trigger of the kidney damage. Therefore, we suggest investigating the potential kidney damage by SARS-CoV-2 in children. Moreover, SARS-CoV-2 can be included among infectious agents responsible for pediatric acute tubular interstitial nephritis.

Caprine Arthritis Encephalitis Virus Is Associated with Renal Lesions.

Caprine arthritis encephalitis virus (CAEV) is a monocyte/macrophage-tropic lentivirus that primarily infects goats resulting in a well-recognized set of chronic inflammatory syndromes focused on the joint synovium, tissues of the central nervous system, pulmonary interstitium and mammary gland. Clinically affected animals generally manifest with one or more of these classic CAEV-associated tissue lesions; however, CAEV-associated renal inflammation in goats has not been reported in the peer-reviewed literature. Here we describe six goats with chronic, multisystemic CAEV infections in conjunction with CAEV-associated renal lesions. One of the animals had CAEV antigen-associated thrombotic arteritis resulting in infarction of both the kidney and heart. These goats had microscopic evidence of inflammatory renal injury (interstitial nephritis) with detectable renal immunolabeling for CAEV antigen in three of six animals and amplifiable proviral sequences consistent with CAEV in all six animals. Cardiac lesions (vascular, myocardial or endocardial) were also identified in four of six animals. Within the viral promoter (U3) region, known transcription factor binding sites (TFBSs) were generally conserved, although one viral isolate had a duplication of the U3 A region encoding a second gamma-activated site (GAS). Despite the TFBS conservation, the isolates demonstrated a degree of phylogenetic diversity. At present, the clinical consequence of CAEV-associated renal injury is not clear.

BK Polyomavirus-specific T cell immune responses in kidney transplant recipients diagnosed with BK Polyomavirus-associated nephropathy.

BACKGROUND: Adjustment of immunosuppression is the main therapy for BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) after kidney transplantation (KT). Studies of BKPyV-specific T cell immune response are scarce. Here, we investigated BKPyV-specific T cell immunity in KT recipients diagnosed with BKPyVAN. METHODS: All adult KT recipients with BKPyVAN diagnosed at our institution from January 2017 to April 2018 were included. Laboratory-developed intracellular cytokine assays measuring the percentage of IFN-γ-producing CD4+ and CD8+ T cells, after stimulation with large-T antigen (LT) and viral capsid protein 1 (VP1), were performed both at the time of diagnosis and after adjustment of immunosuppression. RESULTS: We included 12 KT recipients diagnosed with BKPyVAN (7 proven, 4 presumptive, and 1 possible). Those with presumptive BKPyVAN had a median plasma BKPyV DNA load of 5.9 log10 copies/ml (interquartile range [IQR]: 4.9-6.1). Adjusted dosing of mycophenolic acid and tacrolimus with (86%) or without (14%) adjunctive therapies were implemented after diagnosis. There was a significantly higher median percentage of IFN-γ-producing CD4+ T cells to LT at a median of 3 (IQR: 1-4) months after adjustment of immunosuppression compared with at the time of diagnosis (0.004 vs. 0.015; p = 0.047). However, the difference between the median percentage of IFN-γ-producing CD4+ T cells to VP1 and CD8+ T cells to LT and VP1 did not reach statistical significance. Four (33%) patients achieved plasma BKPyV DNA clearance, and the remaining eight (67%) patients had persistent BKPyV DNAemia. Although eight (67%) patients developed allograft dysfunction, none required hemodialysis. CONCLUSIONS: We observed a marginal trend of BKPyV-specific CD4+ T cell recovery after adjustment of immunosuppression in KT recipients diagnosed with BKPyVAN. A further study would be benefited to confirm and better assess BKPyV-specific immune response after KT.

Common Mechanisms of Viral Injury to the Kidney.

Viral infections in an immunocompetent host can cause both acute and chronic kidney diseases, either by direct damage to the infected kidney cells or as a consequence of systemic immune responses that impact the kidneys' function. Viruses have evolved mechanisms to hijack signaling pathways of the infected cell, including the mammalian target of rapamycin pathway to support viral replication, and to evade antiviral immune responses such as those mediated by miR-155 via microRNA mimetics expressed by the virus. At both the cellular and systemic levels, the host has also evolved mechanisms to counter the viral subversion strategies in the evolutionary battle for mutual survival. In the era of genomic medicine, understanding individual genetic variations that lead to differences in susceptibilities to infection and variabilities in immune responses may open new avenues for treatment, such as the recently described functions of apolipoprotein L1 risk alleles in HIV-associated nephropathy. In addition, state-of-the-art high-throughput sequencing methods have discovered new viruses as the cause for chronic diseases not previously attributed to an infection. The potential application of these methods to idiopathic kidney diseases may reveal similar occult infections by unknown viruses. Precision medicine objectives to optimize host-directed and pathogen-directed therapies for kidney diseases associated with infectious causes will only be achieved through detailed understanding of genetic susceptibility associated with immune responses and viral tropism.

Successful Treatment for BK Virus Nephropathy by Leflunomide in a Kidney Transplant Patient: A Case Report.

INTRODUCTION: The immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL. METHODS: Immunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function. RESULTS: The kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment. CONCLUSION: Early detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.

A Multicenter Application of the 2018 Banff Classification for BK Polyomavirus-associated Nephropathy in Renal Transplantation.

BACKGROUND: With current immunosuppressive regimens, BK polyomavirus-associated nephropathy (BKPyVAN) is still a matter of concern. Stratification of patients at risk for allograft loss is of uttermost importance to guide treatment choice and assess prognosis. In 2018, the Banff working group proposed a classification scheme for the prognosis of BKPyVAN, but external application on independent cohorts is yet to be performed. We investigated how the 2018 Banff classification would perform in a multicenter cohort comprising 50 cases of biopsy-proven BKPyVAN compared to previously published classification systems. METHODS: We analyzed consecutive BKPyVAN cases from two Dutch university hospitals between 2002 and 2013, retrieved clinical data, and scored all biopsies according to the Banff 2018 classification, and as a comparison, 4 previously proposed BKPyVAN classification systems. We used estimated glomerular filtration rate trajectories and death-censored graft survival as primary endpoints. RESULTS: The 2018 Banff classification did not associate with estimated glomerular filtration rate decline or graft failure and performed only slightly better than the 4 previously proposed classifiers. Anti-human leukocyte antigen donor-specific antibodies (DSAs), especially in combination with ongoing biopsy-proven BKPyVAN on follow-up, did correlate with graft function and survival. Patients who were DSA+/BKPyVAN+ on follow-up had more inflammation at the baseline biopsy, which by itself was not associated with graft outcomes. CONCLUSIONS: Neither the 2018 Banff BKPyVAN classification nor previously published stratification systems could be applied to our multicenter patient cohort. Our data suggest that there might be a prognostic value for follow-up biopsies and DSA measurements to improve risk stratification after BKPyVAN, although prospective multicenter efforts with protocol measurements are needed to confirm this.

An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

Granulomatous inflammation in BK polyomavirus-associated nephropathy.

Evolving BK polyomavirus-associated nephropathy (BKPyVAN) is characterized by tubulointerstitial inflammation that closely resembles acute T-cell-mediated allograft rejection if tubulitis is significant. The cellular composition of the inflammation varies during the course of BKPyVAN, and clusters of plasma cells may herald resolution of the infection. Less commonly, BKPyVAN can present with a predominance of histiocytes and granuloma formation. Granulomatous interstitial nephritis is uncommon in biopsies of either native or transplant kidneys. In both settings, this distinctive type of inflammatory response requires a systematic approach with careful clinicopathological assessment to determine its etiology. We present three patients with granulomatous BKPyVAN in the first year post-transplantation. These allograft biopsies at 4, 6, and 12 months post-transplant exemplify spontaneously resolving BKPyVAN, resolving infection after immunosuppression reduction, and early BKPyVAN, respectively. In immunosuppressed patients, BKPyVAN should be added to the relatively broad differential diagnosis of granulomatous tubulointerstitial nephritis.

Membranoproliferative glomerulonephritis and interstitial nephritis in the setting of Epstein-Barr virus-related hemophagocytic syndrome
.

BACKGROUND: Hemophagocytic syndrome (HPS) is a rare, aggressive disorder characterized by dysregulation of lymphocyte and macrophage activity, which culminates in tissue infiltration with hemophagocytosis and ultimately organ failure. Renal involvement frequently ensues and usually results in acute tubular necrosis with associated interstitial inflammation. Less frequently, glomerulopathy can also be found. CASE: We report a case of a 24-year-old Caucasian woman with previous asymptomatic hematuria, mild proteinuria, and normal renal function who presented to us with fever. Laboratory findings revealed pancytopenia, elevated lactate dehydrogenase, and ferritin as well as liver and kidney failure. Renal biopsy showed a tubulointerstitial nephritis superimposed in a membranoproliferative glomerulonephritis with crescents. Extensive etiologic investigation was negative except for Epstein-Barr virus (EBV) viral load. EBV-DNA was then identified by in situ hybridization in the renal biopsy. HPS could be diagnosed with the presence of six criteria: fever, splenomegaly, bicytopenia, high ferritin, hypertriglyceridemia, and high levels of soluble CD25. Steroid therapy was initiated with resolution of HPS as well as complete recovery of renal and liver function. CONCLUSION: In this case, we believe that EBV triggered both HPS and tubulointerstitial nephritis. Steroid therapy successfully treated the inflammatory syndrome, allowing renal function recovery without compromising EBV infection resolution.
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Adenoviral nephritis in a renal transplant recipient: Case report and literature review.

Adenovirus (AdV) infections in transplant recipients may cause invasive disease. We present a case of granulomatous interstitial nephritis secondary to AdV infection in a renal transplant recipient that was initially interpreted as acute graft rejection on histopathology. Specific testing based on clinical suspicion, however, aided in making an accurate diagnosis. We present a retrospective review of all cases of AdV infection in renal transplant recipients to date, and analyze outcomes based on different treatment modalities for this disease.

Acute kidney injury in symptomatic primary Epstein-Barr virus infectious mononucleosis: Systematic review.

BACKGROUND AND OBJECTIVES: Textbooks and reviews do not mention the association of symptomatic primary Epstein-Barr virus infectious mononucleosis with acute kidney injury in subjects without immunodeficiency or autoimmunity. STUDY DESIGN: Stimulated by our experience with two cases, we performed a review of the literature. RESULTS: The literature documents 38 cases (26 male and 12 female individuals ranging in age from 0.3 to 51, median 18 years) of symptomatic primary Epstein-Barr virus infectious mononucleosis complicated by acute kidney injury: 27 acute interstitial nephritides, 1 jaundice-associated nephropathy, 7 myositides and 3 hemolytic uremic syndromes. Acute kidney injury requiring renal replacement therapy was observed in 18 (47%) cases. Acute kidney injury did not resolve in one patient with acute interstitial nephritis. Two patients died because of systemic complications. The remaining 35 cases fully recovered. CONCLUSIONS: In individuals with acute symptomatic Epstein-Barr virus infectious mononucleosis, a relevant kidney injury is rare but the outcome potentially fatal. It results from interstitial nephritis, myositis-associated acute kidney injury, hemolytic uremic syndrome or jaundice-associated nephropathy.

Natural Infections With Pigeon Paramyxovirus Serotype 1: Pathologic Changes in Eurasian Collared-Doves ( Streptopelia decaocto) and Rock Pigeons ( Columba livia) in the United States.

Pigeon paramyxovirus serotype 1 (PPMV-1) is a globally distributed, virulent member of the avian paramyxovirus serotype 1 serogroup that causes mortality in columbiformes and poultry. Following introduction into the United States in the mid-1980s, PPMV-1 rapidly spread causing numerous mortality events in Eurasian collared-doves ( Streptopelia decaocto) (ECDOs) and rock pigeons ( Columba livia) (ROPIs). The investigators reviewed pathological findings of 70 naturally infected, free-ranging columbiforms from 25 different mortality events in the United States. Immunohistochemistry targeting PPMV-1 nucleoprotein was used to determine the tissue distribution of the virus in a subset of 17 birds from 10 of the studied outbreaks. ECDOs (61 birds) and ROPIs (9 birds) were the only species in which PPMV-1-associated disease was confirmed by viral isolation and presence of histologic lesions. Acute to subacute tubulointerstitial nephritis and necrotizing pancreatitis were the most frequent histologic lesions, with immunolabeling of viral antigen in renal tubular epithelial cells and pancreatic acinar epithelium. Lymphoid depletion of bursa of Fabricius and spleen was common, but the presence of viral antigen in these organs was inconsistent among infected birds. Hepatocellular necrosis was occasionally present with immunolabeling of hypertrophic Kupffer cells, and immunopositive eosinophilic intracytoplasmic inclusion bodies were present in hepatocytes of 1 ECDO. Immunopositive lymphocytic choroiditis was present in 1 ECDO, while lymphocytic meningoencephalitis was frequent in ROPIs in absence of immunolabeling. This study demonstrates widespread presence of PPMV-1 antigen in association with histologic lesions, confirming the lethal potential of this virus in these particular bird species.

Pathogenesis of Renal Lesions in Chickens After Experimental Infection With 9a5b Newcastle Disease Virus Mutant Isolate.

In this study, we investigated the pathogenesis of Newcastle disease virus (NDV) in the chicken kidney. Twenty-six 32-day-old specific pathogen-free chickens were intranasally inoculated with the 9a5b NDV mutant isolate. Kidney tissue samples, collected at 6 and 12 hours postinoculation (hpi) and 1, 2, 3, 5, and 10 days postinoculation (dpi), were analyzed by histopathology, immunohistochemistry (IHC), reverse transcription polymerase chain reaction (RT-PCR), and virus titration. Histopathologically, tubulointerstitial nephritis was detected in the renal cortex and predominantly in the medulla. Nephrotropism of 9a5b NDV was confirmed by IHC, RT-PCR, and virus isolation. Massive degenerative changes and infiltration of CD3-immunopositive cells accompanied replication of the 9a5b NDV isolate in chicken kidneys. In conclusion, pathological changes that were caused by NDV in chicken kidneys were similar to those caused by avian influenza virus, infectious bronchitis virus, and avian nephritis virus, and this highlights the importance of including NDV in the differential diagnosis of kidney disease in chickens.

Epidemiological and pathological study of feline morbillivirus infection in domestic cats in Japan.

BACKGROUND: Feline morbillivirus (FmoPV) is a novel paramyxovirus found to infect domestic cats. FmoPV has been isolated in several countries in Asia and Europe and is considered to have genetic diversity. Also, it is suspected to be associated with feline renal diseases including tubulointerstitial nephritis (TIN), which affects domestic cats with a high incidence rate. RESULTS: To clarify the state of FmoPV infection among domestic cats in Japan, an epidemiological survey was conducted. Twenty-one out of 100 cats were found to have serum antibodies (Ab) against FmoPV-N protein by indirect immunofluorescence assay (IF) using FmoPV-N protein-expressing HeLa cells. Twenty-two of the cats were positive for FmoPV RNA in the urine and/or renal tissues. In total, 29 cats were positive for Ab and/or viral RNA. These FmoPV-infected cats were classified into three different phases of infection: RNA+/Ab + (14 cats), RNA+/Ab- (8 cats) and RNA-/Ab + (7 cats). In immunohistochemistry (IHC), 19 out of 29 cats were positive for FmoPV-N protein in kidney tissues; however, the FmoPV-N protein was located in the inflammatory lesions with severe grade in only four out of the 19 cats. Since 15 out of 29 infected cats were positive for viral RNA and Ab, approximately half of the infected cats were persistently infected with FmoPV. CONCLUSIONS: A statistically significant difference was observed between infection of FmoPV and the presence of inflammatory changes in renal lesions, indicating a relationship between FmoPV infection and feline renal diseases. However, we could not obtain histopathological evidence of a relationship between FmoPV infection and TIN.

BK Polyomavirus Tubulointerstitial Nephritis With Urothelial Hyperplasia in a Kidney Transplant.

Polyomavirus nephropathy is characterized histopathologically by evidence of viral replication and acute tubular injury with interstitial inflammation, tubulitis, and intranuclear inclusions. Polyomavirus nephropathy typically develops in the kidney transplant as a combination of the unique nature of the transplanted tissue and the immunomodulated status of the patient. We present a case in which a patient had lingering BK viremia and declining kidney function following receipt of lung and kidney transplants. A kidney biopsy was performed, which demonstrated BK polyomavirus tubulointerstitial nephritis, resultant cytopathic changes and tubular/ductal injury, associated urothelial hyperplasia with foci of squamous metaplasia, suspected membranous glomerulopathy, and moderate arterial/arteriolar sclerosis. There was also evidence of more proximal nephron viral involvement, with glomerular parietal epithelium infection and injury present. This case shows impressive BK polyomavirus-associated urothelial hyperplasia in the kidney, which to our knowledge has not been previously illustrated in the literature. There have been numerous studies attempting to show the association of polyomaviruses with the development of carcinoma, and this case report is significant because it is an example of viral-induced changes that are concerning and hold potential for malignant transformation.

BK virus-associated nephropathy with hydronephrosis in a patient with AIDS: a case report and literature review.

BK virus is ubiquitous worldwide, with infection usually occurring in early childhood. BK virus replicates prolifically under immunosuppressive conditions, causing inflammation along the genitourinary tract and progressing clinically to hemorrhagic cystitis, ureteral stenosis, and tubulointerstitial nephritis. Most BK virusassociated nephropathy occurs in renal allograft patients after kidney transplantation, although some case reports have described BK virus-associated nephropathy in the native kidney, particularly in patients with human immunodeficiency virus infection. Here we present the case of a 49-year-old male with acquired immunodeficiency syndrome (AIDS) and renal dysfunction with hydronephrosis. The renal biopsy showed tubulointerstitial nephritis with lymphoplasmacytic infiltrates and intranuclear inclusions in the tubular epithelium, which are typical findings for BK virus-associated nephropathy. In addition, immunohistochemical staining revealed that the SV40 large T antigen exhibited a nuclear localization in tubular cells. To the best of our knowledge, this is the first case report of BK virus-associated nephropathy combined with hydronephrosis that was diagnosed by biopsy in a patient with AIDS.

Temporal serum creatinine increase and exacerbation of tubulointerstitial inflammation during the first two months in resolving polyomavirus BK nephropathy.

AIM: Polyomavirus BK nephropathy (BKVN) is an important complication in kidney transplantation. After immunosuppressive agents are reduced, some patients experience a temporal increase in serum creatinine (sCr) before viral clearance. The histological characteristics of re-biopsies were therefore investigated to evaluate the time course of remission. METHODS: sCr was measured and urinary cytology evaluated periodically in 14 patients with biopsy-proven BKVN. Remission of BKVN was defined as re-biopsies negative for SV40 large T antigen (SV40-TAg) or for decoy cells on at least three consecutive cytology tests. Early changes in sCr were correlated with re-biopsy findings. RESULTS: Mean sCr was 1.6 ± 0.6 mg/dL at diagnosis, increasing during the first 2 months to 2.6 ± 2.0 mg/dL, and decreasing thereafter, to 2.3 ± 1.2 mg/dL at 3-4 months. Two patients who experienced further increases in sCr at 3 months showed early graft loss, while the others showed clinical or histological remission. Nineteen re-biopsies were obtained from eight patients over 4 months. Banff i-scores were higher in re-biopsies obtained during the first 2 months than the index biopsies and re-biopsies at 2-4 months (P = 0.02). SV40-TAg positivity was common in re-biopsies during the first 2 months (10/11 biopsies), but rarer at 2-4 months (2/8 biopsies, P = 0.001). CONCLUSIONS: Temporal graft dysfunction and increased inflammation, called immune reconstitution, were observed at 2 months. Later sCr reversal is associated with remission.

Successful treatment of disseminated adenovirus infection with ribavirin and intravenous immunoglobulin in an adult renal transplant recipient: a case report.

Disseminated adenovirus infection in recipients of renal transplants is a rare but often fatal complication. We present a case of a 32-year-old woman who underwent renal transplantation from a deceased donor. Ten months after transplantation, she presented with dysuria, hematuria, and febrile illness. Despite the use of antibiotics, the patient's symptoms continued and worsened and the serum creatinine level was increased. The results of urine and serum polymerase chain reaction were positive for adenovirus. Renal biopsy revealed viral interstitial nephritis. The patient was treated with ribavirin, intravenous immunoglobulin, and reduction in immunosuppression. Her symptoms progressively improved from 7 days after the treatment. Serum and urine polymerase chain reaction for adenovirus became negative 10 and 21 days after the treatment, respectively. She remained in good health with excellent allograft function 6 months later.