Relevant Equine Renal Anatomy, Physiology, and Mechanisms of Acute Kidney Injury: A Review.

Regulation of renal blood flow is by both extrinsic and intrinsic systems. Intrinsic regulation occurs via the afferent and efferent arterioles and tubuloglomerular feedback mechanisms with activation of the juxtaglomerular apparatus. Mechanisms of acute kidney injury are frequently associated with changes in renal blood flow. Acute tubular necrosis and apoptosis are common in horses following ischemic or toxic insults and in sepsis-associated acute kidney injury. Sepsis-associated renal injury often has a complex mechanism of disease involving both functional and obstructive changes in intrarenal circulation. Acute interstitial nephritis may occur following Leptospira sp infection or can be secondary to tubular necrosis.

Feline Morbillivirus Infection Associated With Tubulointerstitial Nephritis in Black Leopards (Panthera pardus).

Feline morbillivirus (FeMV) is an emerging RNA virus in the Paramyxoviridae family that was recently discovered in domestic cats (Felis catus). To date, 2 genotypes (FeMV-1 and FeMV-2) have been detected in cats from various countries, and FeMV-1 is recognized as a pathogen associated with nephritis. However, information regarding the pathological roles and potential transmission to other felids is limited. In this article, we describe the identification of FeMV in 2 black leopards (Panthera pardus) in Thailand that showed severe azotemia and tubulointerstitial nephritis. Molecular analysis of the partial coding sequence of the L gene revealed that these leopard FeMV strains were genetically close to the FeMV-1 isolate from domestic Thai cats. Immunohistochemistry and immunofluorescence analyses using polyclonal IgG antibodies against the FeMV matrix (M) protein showed FeMV-M antigen in renal tubular epithelial cells. These analyses also showed infiltrating lymphocytes in the renal parenchymal lesions and in the cytoplasm of lymphoid cells residing in the spleen, suggesting viral tropism and a possible pathological role. These findings are the first evidence that indicates that the black leopard could be a possible host for FeMV infection. As for other cats, the role of FeMV as a potential cause of renal disease remains to be established. The pathogenesis of FeMV infection in black leopards, or in other wild felids, through a viral transmission mechanism warrants further investigation.

Naturally Acquired Mouse Kidney Parvovirus Infection Produces a Persistent Interstitial Nephritis in Immunocompetent Laboratory Mice.

Mouse kidney parvovirus (MKPV), also known as murine chapparvovirus (MuCPV), is an emerging, highly infectious agent that has been isolated from laboratory and wild mouse populations. In immunocompromised mice, MKPV produces severe chronic interstitial nephropathy and renal failure within 4 to 5 months of infection. However, the course of disease, severity of histologic lesions, and viral shedding are uncertain for immunocompetent mice. We evaluated MKPV infections in CD-1 and Swiss Webster mice, 2 immunocompetent stocks of mice. MKPV-positive CD-1 mice (n = 30) were identified at approximately 8 weeks of age by fecal PCR (polymerase chain reaction) and were subsequently housed individually for clinical observation and diagnostic sampling. Cage swabs, fecal pellets, urine, and blood were evaluated by PCR at 100 and 128 days following the initial positive test, which identified that 28 of 30 were persistently infected and 24 of these were viremic at 100 days. Histologic lesions associated with MKPV in CD-1 (n = 31) and Swiss mice (n = 11) included lymphoplasmacytic tubulointerstitial nephritis with tubular degeneration. Inclusion bodies were rare; however, intralesional MKPV mRNA was consistently detected via in situ hybridization within tubular epithelial cells of the renal cortex and within collecting duct lumina. In immunocompetent CD-1 mice, MKPV infection resulted in persistent shedding of virus for up to 10 months and a mild tubulointerstitial nephritis, raising concerns that this virus could produce study variations in immunocompetent models. Intranuclear inclusions were not a consistent feature of MKPV infection in immunocompetent mice.

Cistus salviifolius Toxicity in Cattle.

Toxicity related to consumption of Cistus sp. pl. has been described in ruminants in some countries. This report describes the clinical and pathological findings of Cistus salviifolius toxicosis in 3 beef cattle herds located in 2 different areas of Sicily, Italy. Outbreaks were observed after grazing in poor winter pasture where C. salviifolius was abundant. Mean morbidity and mortality were 29% and 21%, respectively. Most of the affected animals (6 to 36 months old) showed anorexia, weight loss, and pollakiuria culminating in recumbency and death. Occasionally, abortion and neurological signs were observed. In animals with acute signs, there was a moderate decrease of sodium and chloride concentrations in serum. Animals with chronic signs showed an increase of serum urea, creatine phosphokinase (CPK), aspartate transaminase (AST), lactate dehydrogenase (LDH), and phosphorus and a decrease in total serum protein, calcium, chloride, and magnesium concentrations. Moderate anemia and slight neutropenia, lymphocytosis, and eosinophilia were detected in all groups. At necropsy, the main lesion was severe distention of the urinary bladder with turbid hemorrhagic urine and crystalluria. Histologically, chronic cystitis, interstitial nephritis, eosinophilic enteritis, and nonsuppurative necrotizing hepatitis were observed. To our knowledge, this is the first report of C. salviifolius toxicosis in cattle in Italy.

Biomarkers and renal arterial resistive index in dogs naturally infected with Leishmania infantum.

Canine visceral leishmaniasis frequently causes glomerulonephritis and tubulointerstitial nephritis, nephropathies for which diagnosis has been limited by the low sensitivity of traditional tests. The aim of this study was to evaluate serum cystatin C and urinary gamma-glutamyltransferase (uGGT) levels and the urinary GGT/urinary creatinine ratio (uGGT/uCR) and to measure the renal arterial resistive index (RARI) in dogs with leishmaniasis with varying degrees of renal injury based on the urine protein: creatinine ratio (UP/C) and serum creatinine (SCr) level. We tested 59 untreated adult dogs of both sexes and undefined breeds naturally infected with Leishmania infantum. The dogs were grouped into four groups based on UP/C and SCr level: group 1 (n = 15), dogs with SCr levels < 1.4 mg/dL and UP/C < 0.5; group 2 (n = 13), dogs with SCr levels < 1.4 mg/dL and UP/C of 0.5-1.0; group 3 (n = 16), dogs with SCr levels < 1.4 and UP/C > 1.0; and group 4 (n = 15), dogs with SCr levels > 1.4. A fifth group of healthy dogs (n = 10) was the control. uGGT concentrations and uGGT/uCR were higher in dogs with proteinuria and SCr < 1.4 mg/dL, whereas the serum cystatin C concentrations and RARI were higher only in dogs with SCr levels > 1.4. In conclusion, uGGT and uGGT/uCR may be useful tools for early detection and assessment of renal lesions associated with leishmaniasis; however, cystatin C is useful for monitoring the progression of kidney disease when measured sequentially.

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.

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.

Pathology and Epidemiology of Oxalate Nephrosis in Cheetahs.

To investigate cases of acute oxalate nephrosis without evidence of ethylene glycol exposure, archived data and tissues from cheetahs ( Acinonyx jubatus) from North America ( n = 297), southern Africa ( n = 257), and France ( n = 40) were evaluated. Renal and gastrointestinal tract lesions were characterized in a subset of animals with ( n = 100) and without ( n = 165) oxalate crystals at death. Crystals were confirmed as calcium oxalate by Raman spectroscopy in 45 of 47 cheetahs tested. Crystals were present in cheetahs from 3.7 months to 15.9 years old. Cheetahs younger than 1.5 years were less likely to have oxalates than older cheetahs ( P = .034), but young cheetahs with oxalates had more oxalate crystals than older cheetahs ( P < .001). Cheetahs with oxalate crystals were more likely to have renal amyloidosis, interstitial nephritis, or colitis and less likely to have glomerular loop thickening or gastritis than those without oxalates. Crystal number was positively associated with renal tubular necrosis ( P ≤ .001), regeneration ( P = .015), and casts ( P ≤ .001) but inversely associated with glomerulosclerosis, renal amyloidosis, and interstitial nephritis. Crystal number was unrelated to the presence or absence of colitis and was lower in southern African than American and European animals ( P = .01). This study found no evidence that coexisting chronic renal disease (amyloidosis, interstitial nephritis, or glomerulosclerosis), veno-occlusive disease, gastritis, or enterocolitis contributed significantly to oxalate nephrosis. Oxalate-related renal disease should be considered as a potential cause of acute renal failure, especially in young captive cheetahs. The role of location, diet, stress, and genetic predisposition in the pathogenesis of oxalate nephrosis in cheetahs warrants further study.

Adverse effects of a 10-day course of ibuprofen in Holstein calves.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended for various conditions in cattle. Ibuprofen is an inexpensive short-acting NSAID and is readily available in liquid formulation for administration to bottle-fed calves. We compared the adverse effects of a 10-day course of ibuprofen and placebo in 16 five- to six-week-old Holstein bull calves that were being treated for experimentally induced bovine respiratory syncytial virus infection. Ibuprofen was administered as a liquid in milk replacer at 30 mg/kg divided three times daily. We found an increased prevalence of abomasal ulceration 5 of 8 in the ibuprofen compared to placebo group 2 of 6 (P = NS). There was one (1 of 8) case of mild interstitial nephritis in the ibuprofen and none (0 of 8) in the placebo group (P = NS). Renal function as measured by serum BUN and creatinine levels was not different between groups; no animal demonstrated an increase in creatinine.

Genetic diversity of feline morbilliviruses isolated in Japan.

Feline morbillivirus (FmoPV) is an emerging virus in domestic cats and considered to be associated with tubulointerstitial nephritis. Although FmoPV was first described in China in 2012, there has been no report of the isolation of this virus in other countries. In this report, we describe the isolation and characterization of FmoPV from domestic cats in Japan. By using reverse transcription (RT)-PCR, we found that three of 13 urine samples from cats brought to veterinary hospitals were positive for FmoPV. FmoPV strains SS1 to SS3 were isolated from the RT-PCR-positive urine samples. Crandell-Rees feline kidney (CRFK) cells exposed to FmoPV showed cytopathic effects with syncytia formation, and FmoPV N protein was detected by indirect immunofluorescence assays. In addition, pleomorphic virus particles with apparent glycoprotein envelope spikes were observed by electron microscopy. By sequence analysis of FmoPV H and L genes, we found that FmoPVs showed genetic diversity; however, signatures of positive selection were not identified.

Polyomavirus-associated nephritis in 2 horses.

Polyomaviruses produce latent and asymptomatic infections in many species, but productive and lytic infections are rare. In immunocompromised humans, polyomaviruses can cause tubulointerstitial nephritis, demyelination, or meningoencephalitis in the central nervous system and interstitial pneumonia. This report describes 2 Standardbred horses with tubular necrosis and tubulointerstitial nephritis associated with productive equine polyomavirus infection that resembles BK polyomavirus nephropathy in immunocompromised humans.

Feline Morbillivirus: Clinical Relevance of a Widespread Endemic Viral Infection of Cats.

Feline morbillivirus (FeMV) was first isolated in 2012 from stray cats in Hong Kong. It has been found in association with tubulointerstitial nephritis (TIN), the most common cause of feline chronic kidney disease (CKD). However, viral host spectrum and virus tropism go beyond the domestic cat and kidney tissues. The viral genetic diversity of FeMV is extensive, but it is not known if this is clinically relevant. Urine and kidney tissues have been widely tested in attempts to confirm associations between FeMV infection and renal disease, but samples from both healthy and sick cats can test positive and some cross-sectional studies have not found associations between FeMV infection and CKD. There is also evidence for acute kidney injury following infection with FeMV. The results of prevalence studies differ greatly depending on the population tested and methodologies used for detection, but worldwide distribution of FeMV has been shown. Experimental studies have confirmed previous field observations that higher viral loads are present in the urine compared to other tissues, and renal TIN lesions associated with FeMV antigen have been demonstrated, alongside virus lymphotropism and viraemia-associated lymphopenia. Longitudinal field studies have revealed persistent viral shedding in urine, although infection can be cleared spontaneously.

Herpes virus infection associated with interstitial nephritis in a beaked whale (Mesoplodon densirostris).

BACKGROUND: The capacity for herpesvirus to cause disease in cetaceans is unclear and may be varied depending on the different conditions of individuals and between different species. Kidney pathology and intralesional virus-associated infection have been rarely reported in cetaceans. RESULT: On April 2004, an old adult male Blainville's beaked whale (Mesoplodon densirostris) 420 cm long with a poor body condition was stranded on Tenerife Island. During necropsy, no gross lesions were observed in the kidneys. However, membranous glomerulonephritis, multifocal interstitial lymphoplasmacytic nephritis and acute multifocal necrotizing tubulointerstitial nephritis with intranuclear inclusion bodies was diagnosed by histological analysis. Tissue samples were submitted for bacteriological analysis and molecular viral screening. CONCLUSION: A novel alpha herpesvirus associated with interstitial nephritis was identified in an old adult male Blainville's beaked whale (M. densirostris) with a poor body condition stranded in the Canary Islands. This report suggests that identification of herpesvirus infection could be used as a differential diagnosis for interstitial nephritis in cetaceans.

Clarifying expression patterns by renal lesion using transcriptome analysis and vanin-1 as a potential novel biomarker for renal injury in chickens.

Bird death is often caused by renal lesions induced by chemicals. The avian kidney has a renal portal system with significant blood flow that is sensitive to many chemicals. However, early avian biomarkers for kidney injury are yet to be identified. This study aimed to identify novel renal biomarkers. Acute kidney injury (AKI) can be divided into acute interstitial nephritis (AIN) and acute tubular necrosis (ATN). A chicken model of kidney damage was created by an injection of diclofenac or cisplatin, which caused either AIN or ATN, respectively. Microarray analysis was performed to profile the gene expression patterns in the chickens with nephropathy. A gene enrichment analysis suggested that the genes related to responses to external stimuli showed expression changes in both AIN and ATN. However, hierarchical clustering analyses suggested that gene expression patterns differed between AIN and ATN, and the number of biomarkers relating to renal damage was low. To identify early biomarkers for nephropathy, we focused on genes that were induced at various levels of renal damage. The gene, vanin-1 (VNN1) was highly induced in the early stages of renal damage. A quantitative real-time PCR analysis supported this finding. These results suggest VNN1 could be a useful early biomarker of kidney injury in avian species.

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.

Characterization of a novel virus causing a lethal disease in carp and koi.

Since 1998 a lethal disease of carp and ornamental koi (Cyprinus carpio) has afflicted fisheries in North America, Europe, and Asia, causing severe economic losses to the fish farming industry. This review summarizes the isolation and identification of the disease-causing agent and describes the currently known molecular characteristics of this newly isolated virus, distinguishing it from other known large DNA viruses. In addition, we summarize the clinical and histopathological manifestations of the disease. Providing information on the immune response to this virus and evaluating the available means of diagnosis and protection should help to reduce the damage induced by this disease. This review does not discuss the economic aspects of the disease or the debate on whether the disease should be registered; both of these issues were recently reviewed in detail (O. L. M. Haenen, K. Way, S. M. Bergmann, and E. Ariel, Bull. Eur. Assoc. Fish Pathol. 24:293-307, 2004; D. Pokorova, T. Vesely, V. Piackova, S. Reschova, and J. Hulova, Vet. Med. Czech. 50:139-147, 2005).

Expression of major histocompatibility complex class II antigens in porcine leptospiral nephritis.

Class II major histocompatibility complex (MHCII) is required for the presentation of antigens to CD4 helper T cells. During nephritis, not only primary antigen presenting cells such as histiocytes and lymphocytes, but also cytokine-stimulated tubular epithelial cells express MHCII. Leptospirosis in fattening pigs is characterized by several degrees of nephritis, from absence of lesions to severe multifocal tubulo-interstitial inflammation. Renal tissue from 20 8-month-old pigs with spontaneous nephritis and 6 control pigs without renal lesions were investigated for leptospirosis by indirect immunohistochemistry (IHC) and polymerase chain reaction (PCR). IHC for MHCII also was performed on renal samples. Serum samples were tested for different serovars of Leptospira interrogans. Control pigs were free of interstitial nephritis and negative for leptospirosis by all tests. In pigs with nephritis, serology was positive for serovar Pomona in 19/20 pigs. In 16 of these 19 pigs, leptospiral renal infection was confirmed by PCR and/or indirect IHC. Nephritic lesions were classified histologically into perivascular lymphocytic (4 pigs), lymphofollicular (6 pigs), lymphohistiocytic (8 pigs), and neutrophilic (2 pigs) pattern. MHCII expression by histiocytes and lymphocytes was observed in all lesions. Prominent MHCII expression in regenerating tubular epithelium was observed in lymphofollicular and lymphohistiocytic nephritis. No tubular colocalization between leptospiral and MHCII antigen was observed. Results suggest that during leptospiral nephritis, MHCII contributes to the intensity of the inflammatory response. Furthermore de novo MHCII expression in regenerating tubules may play a role in the defence mechanism against leptospiral tubular colonization.

Intermediate-grade mammary gland adenocarcinoma in an 18-year-old female black leopard (Panthera pardus) with acute pancreatic necrosis and chronic interstitial nephropathy.

An 18-year-old female black leopard (Panthera pardus) showed renal failure, leukocytosis and presence of subcutaneous masses in the lower abdominal region and right shoulder; she eventually died. Histopathological observations included a mammary gland carcinoma with comedo, solid and tubulopapillary patterns in subcutaneous tissue, and highly proliferated tumor cells in systemic organs. The tumor cells were positive for cytokeratin AE1/AE3. The mammary gland tumor was diagnosed as intermediate-grade adenocarcinoma, based on a previously reported histological grading system of feline mammary carcinomas. Chronic interstitial nephritis was estimated to have been ongoing for 5 years, whilst acute necrotic pancreatitis in relation to tumor metastasis could have been the cause of death.

Tubulointerstitial nephritis causes decreased renal expression and urinary excretion of cauxin, a major urinary protein of the domestic cat.

Cauxin, a member of mammalian carboxylesterases (EC 3.1.1.1), is excreted as a major urinary protein in the domestic cat. Urinary cauxin is derived from the kidney proximal straight tubules. Here, we report changes in the renal expression and urinary excretion of cauxin in cats with tubulointerstitial nephritis (TIN). Immunohistochemistry using anti-cauxin antibody showed fewer cauxin-positive tubules in 15 TIN cases than in normal animals. In areas with tubulointerstitial damage, fibroblasts and inflammatory cells replaced renal tubules, and cauxin-positive tubules consequently disappeared. Urine was analysed in six of the 15 cases. In the two cases with mild tubulointerstitial changes, urinary cauxin was detected using SDS-PAGE with Coomassie staining. In the four cases with severe tubulointerstitial changes, urinary cauxin was below the detection limit using Western blotting. These results indicate that the renal expression and urinary excretion of cauxin decrease with the progression of TIN in cats.

Detection of maedi-visna virus in the kidneys of naturally infected sheep.

Infections with maedi-visna virus (MVV) cause progressive inflammation in different organs, mainly the lung, mammary gland, brain and joints. The aim of the present study was to investigate whether the kidney represents a viral target in natural MVV infection. For this, kidney samples from 13 sheep naturally infected with MVV were examined by histology, polymerase chain reaction (PCR), and immunohistochemistry. The kidneys of nine animals showed membranoproliferative glomerulonephritis and interstitial nephritis. The inflammatory infiltrate consisted of lymphocytes, plasma cells and macrophages. Interestingly, lymphoid follicles resembling those known to occur in other MVV-infected tissues were observed. Lung tissue from the same animals had typical MVV lesions, such as lymphofollicular hyperplasia and interstitial pneumonia. Maedi-visna proviral DNA sequences were detected in renal and lung tissue samples from these nine sheep by PCR, and the specificity of the amplified products was further verified by DNA sequencing. Moreover, MVV-specific immunohistochemistry revealed viral antigen in affected kidneys and lungs. These results suggest that the kidney may be a common target in natural MVV infection, and raise the issue of the role of this organ in the disease.