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To describe the signalment, clinicopathological findings and outcome in dogs presenting with acute kidney injury (AKI) and skin lesions between November 2012 and March 2014, in whom cutaneous and renal glomerular vasculopathy (CRGV) was suspected and renal thrombotic microangiopathy (TMA) was histopathologically confirmed. The medical records of dogs with skin lesions and AKI, with histopathologically confirmed renal TMA, were retrospectively reviewed. Thirty dogs from across the UK were identified with clinicopathological findings compatible with CRGV. These findings included the following: skin lesions, predominantly affecting the distal extremities; AKI; and variably, anaemia, thrombocytopaenia and hyperbilirubinaemia. Known causes of AKI were excluded. The major renal histopathological finding was TMA. All thirty dogs died or were euthanised. Shiga toxin was not identified in the kidneys of affected dogs. Escherichia coli genes encoding shiga toxin were not identified in faeces from affected dogs. CRGV has previously been reported in greyhounds in the USA, a greyhound in the UK, without renal involvement, and a Great Dane in Germany. This is the first report of a series of non-greyhound dogs with CRGV and AKI in the UK. CRGV is a disease of unknown aetiology carrying a poor prognosis when azotaemia develops.

Miniature Schnauzer dogs are predisposed to idiopathic hypertriglyerceridemia, which increases risk for diseases such as pancreatitis and gallbladder mucocele. Recently, elevated triglyceride concentrations have been associated with proteinuria in this breed, although it is difficult to determine which abnormality is primary. Retrospective review of renal tissue from 27 proteinuric Miniature Schnauzers revealed that 20 dogs had ultrastructural evidence of osmophilic globules consistent with lipid in glomerular tufts. Seven of these dogs had lipid thromboemboli in glomerular capillary loops that distorted their shape and compressed circulating erythrocytes. Triglyceride concentrations were reported in 6 of these 7 dogs, and all were hypertriglyceridemic. In addition, glomerular lipidosis (defined as accumulation of foam cells within peripheral capillary loops) was identified in a single dog. The remaining 12 dogs had smaller amounts of lipid that could only be identified ultrastructurally. Neither signalment data nor clinicopathologic parameters (serum albumin, serum creatinine, urine protein-to-creatinine ratio, and blood pressure) differed among the various types of lipid lesions. During the time course of this study, all dogs diagnosed with glomerular lipid thromboemboli were Miniature Schnauzers, underscoring the importance of recognizing these clear spaces within capillary loops as lipid. [ABSTRACT FROM AUTHOR]

Given the irreversible nature of nephron loss, aging of the kidney is of special interest to diagnostic and toxicologic pathologists. There are many similarities among histologic lesions in aged human and canine kidneys, including increased frequency of glomerulosclerosis, interstitial fibrosis, and tubular atrophy. Unfortunately, there are few studies in which renal tissue from aged healthy dogs was adequately examined with advanced diagnostics—namely, transmission electron microscopy and immunofluorescence—so age-associated changes in canine podocytes and glomerular basement membranes are poorly characterized. An age-associated decrease in the glomerular filtration rate in humans and dogs (specifically small breed dogs) has been documented. Although lesions in aged rats and mice differ somewhat from those of aged dogs and humans, the knowledge gained from rodent models is still vital to elucidating the pathogenesis of age-associated renal disease. Many novel molecules implicated in renal aging have been identified through genetically modified rodent models and transcriptomic and proteomic analysis of human kidneys. These molecules represent intriguing therapeutic targets and diagnostic biomarkers. Likewise, influencing critical pathways of cellular aging, such as telomere shortening, cellular senescence, and autophagy, could improve renal function in the elderly. [ABSTRACT FROM AUTHOR]

Evaluation of canine renal biopsy tissue has generally relied on light microscopic (LM) evaluation of hematoxylin and eosin–stained sections ranging in thickness from 3 to 5 µm. Advanced modalities, such as transmission electron microscopy (TEM) and immunofluorescence (IF), have been used sporadically or retrospectively. Diagnostic algorithms of glomerular diseases have been extrapolated from the World Health Organization classification scheme for human glomerular disease. With the recent establishment of 2 veterinary nephropathology services that evaluate 3-µm sections with a panel of histochemical stains and routinely perform TEM and IF, a standardized objective species-specific approach for the diagnosis of canine glomerular disease was needed. Eight veterinary pathologists evaluated 114 parameters (lesions) in renal biopsy specimens from 89 dogs. Hierarchical cluster analysis of the data revealed 2 large categories of glomerular disease based on the presence or absence of immune complex deposition: The immune complex–mediated glomerulonephritis (ICGN) category included cases with histologic lesions of membranoproliferative or membranous patterns. The second category included control dogs and dogs with non-ICGN (glomerular amyloidosis or focal segmental glomerulosclerosis). Cluster analysis performed on only the LM parameters led to misdiagnosis of 22 of the 89 cases—that is, ICGN cases moved to the non-ICGN branch of the dendrogram or vice versa, thereby emphasizing the importance of advanced diagnostic modalities in the evaluation of canine glomerular disease. Salient LM, TEM, and IF features for each pattern of disease were identified, and a preliminary investigation of related clinicopathologic data was performed. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is prevalent in elderly cats. Frequently, a diagnosis is made in later stages of disease, by which time many renal lesions are irreversible. As such, little headway has been made in identifying an etiology and preventing this common disease. The aim of this study was to evaluate the presence and severity of both reversible and irreversible histopathologic changes in the kidneys of cats at each stage of CKD and, in addition, to determine if lesion prevalence and character were different between stages. A total of 46 cats with CKD were classified according to the International Renal Interest Society (IRIS) as stage I (3 cats), stage II (16 cats), stage III (14 cats), and stage IV (13 cats). Eleven young, nonazotemic and 10 geriatric, nonazotemic cats were included as controls. The severity of tubular degeneration, interstitial inflammation, fibrosis, and glomerulosclerosis was significantly greater in later stages of CKD compared with early stages of disease. Proteinuria was associated with increased severity of tubular degeneration, inflammation, fibrosis, tubular epithelial single-cell necrosis, and decreased normal parenchyma. Presence of hyperplastic arteriolosclerosis, fibrointimal hyperplasia, or other vascular lesions were not found to be significantly different between hypertensive and normotensive cats. The greater prevalence and severity of irreversible lesions in stage III and IV CKD implies that therapeutic interventions should be targeted at earlier stages of disease. [ABSTRACT FROM PUBLISHER]

Human cytomegalovirus (HCMV) infection is associated with renal allograft failure. Allograft damage in animal models is accelerated by CMV-induced T helper 17 (Th17) cell infiltrates. However, the mechanisms whereby CMV promotes Th17 cell-mediated pathological organ inflammation are uncharacterized. Here we demonstrate that murine CMV (MCMV)-induced intragraft Th17 cells have a Th1/17 phenotype co-expressing IFN-γ and/or TNF-α, but only a minority of these cells are MCMV specific. Instead, MCMV promotes intragraft expression of CCL20 and CXCL10, which are associated with recruitment of CCR6 + CXCR3 + Th17 cells. MCMV also enhances Th17 cell infiltrates after ischemia-reperfusion injury, independent of allogeneic responses. Pharmacologic inhibition of the Th17 cell signature cytokine, IL-17A, ameliorates MCMV-associated allograft damage without increasing intragraft viral loads or reducing MCMV-specific Th1 cell infiltrates. Clinically, HCMV DNAemia is associated with higher serum IL-17A among renal transplant patients with acute rejection, linking HCMV reactivation with Th17 cell cytokine expression. In summary, CMV promotes allograft damage via cytokine-mediated Th1/17 cell recruitment, which may be pharmacologically targeted to mitigate graft injury while preserving antiviral T cell immunity., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Adriamycin (ADR)-induced nephropathy remains the leading model to study human primary focal segmental glomerulosclerosis (FSGS), a common pathway for podocyte damage and glomerular loss of function that leads to chronic kidney disease. However, the use of this model for reverse genetics is limited by historical categorization of C57BL/6 mice as an ADR-resistant strain, which is also the most common genetically modified strain. Additionally, conflicting reports exist utilizing C57BL/6 for ADR-nephrosis due to lack of understanding of substrain differences (J/N) and variability in ADR dosage, timing, and frequency to induce damage. We have undertaken a systematic approach to elucidate the specifics of ADR-nephrosis in C57BL/6 N and J substrains. We induced nephropathy with 2 doses of ADR, and measured albuminuria for 6 weeks and performed histological evaluations. Our findings revealed induction of robust and modest proteinuria in N and J substrains, respectively. The serum creatinine levels were elevated in N, but not J substrain. Both the substrains showed reduction in body weight with N greater than J, although mortality remained at 0% in both substrains. Histological analysis showed worse renal lesions in the N than the J substrain. Podocyte markers synaptopodin, nephrin, podocin, and WT1 were reduced to a greater extent in the N than the J substrain. In summary, we provide the nephrology community with a reproducible mouse model for FSGS, in a strain otherwise assumed to be ADR-resistant and highlight the differences between J and N substrains. This enables future studies, especially concerning genetically manipulated animal models in C57BL/6., Competing Interests: Author RC was employed by Niche Diagnostics, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bryant, Cianciolo, Govindarajan and Agrawal.)

Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular- Nphs1 , hepatic- Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular- Nrf2 , and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists., Competing Interests: The authors declare no competing interests. An Intellectual Property Application for international patent (#63/016,039) ‘PPAR Agonists for Treatment of Kidney Disease’ has been filed by SA and the Office of Technology Commercialization at Nationwide Children’s Hospital., (© 2022 The Authors.)

Subclinical stage of ehrlichiosis is characterized by absence of clinical or laboratory alterations; however, it could lead to silent glomerular/tubular changes and contribute significantly to renal failure in humans and animals. The aim of this study was to evaluate glomerular and tubular alterations in dogs with subclinical ehrlichiosis. We evaluated renal biopsies of 14 bitches with subclinical ehrlichiosis and 11 control dogs. Samples were obtained from the left kidney, and the tissue obtained was divided for light microscopy, immunofluorescence, and transmission electron microscopy. Abnormalities were identified by light microscopy in 92.9% of dogs with ehrlichiosis, but not in any of the dogs of the control group. Mesangial cell proliferation and synechiae (46.1%) were the most common findings, but focal segmental glomerulosclerosis and ischemic glomeruli (38.4%), focal glomerular mesangial matrix expansion (30.7%), mild to moderate interstitial fibrosis and tubular atrophy (23%), and glomerular basement membrane spikes (23%) were also frequent in dogs with ehrlichiosis. All animals with ehrlichiosis exhibited positive immunofluorescence staining for immunoglobulins. Transmission electron microscopy from dogs with ehrlichiosis revealed slight changes such as sparse surface projections and basement membrane double contour. The subclinical phase of ehrlichiosis poses a higher risk of development of kidney damage due to the deposition of immune complexes., Competing Interests: The authors have declared that no competing interests exist.

Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.

Background: Human cytomegalovirus (CMV) infection is associated with renal allograft dysfunction and loss, particularly in combination with acute rejection. Emerging literature suggests that non-HLA antibodies may contribute to antibody-mediated rejection, but pathogen-induced antibodies have not been investigated in this context. This study examines the presence of CMV-induced antibodies in murine CMV (MCMV)-infected renal allografts during acute rejection., Methods: Intragraft immunoglobulin G (IgG) and complement C3 immunostaining were compared among allogeneic MCMV D-/R-, D+/R-, and D+/R+ renal transplants. Intragraft antibody deposition was examined in B cell-deficient recipients treated with MCMV immune sera. Antibody binding and complement-dependent cytotoxicity (CDC) of D-/R- and D+/R+ sera against infected renal tubular epithelial cells (TECs) were measured in vitro. IgG immunostaining was performed in D+/R+ allografts and native kidneys and in D+/R- allografts treated with ganciclovir to inhibit viral replication., Results: D+/R- and D+/R+ transplants had more abundant IgG and C3 deposition compared with D-/R- recipients. Greater IgG deposition was associated with more severe allograft injury in B cell-deficient recipients treated with MCMV immune sera compared with nonimmune sera. D+/R+ sera induced greater CDC of infected TECs compared with D-/R- sera. Native kidneys had lower IgG deposition compared with allografts, despite similar organ viral loads. Ganciclovir-treated allografts had reduced IgG deposition compared with untreated allografts., Conclusions: In this murine model, complement-fixing antibodies can deposit into MCMV-infected renal allografts, are associated with allograft damage, and can induce CDC of MCMV-infected renal TECs. The allogeneic response and viral replication may also contribute to intragraft antibody deposition., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Proteinuria is an independent risk factor for morbidity and mortality in dogs. An association between proteinuria and gallbladder mucocele formation in dogs is unknown., Objective: Determine if gallbladder mucocele formation or clinicopathologic comorbidities are associated with proteinuria., Animals: Twenty-five dogs with mucocele formation and 25 breed and age-matched control dogs from a prior study., Methods: Retrospective case control study. Proteinuria defined by calculated urine dipstick protein concentration (mg/mL) to urine specific gravity (USG) ratio. Clinicopathologic findings, postcosyntropin cortisol concentration, thyroid function profile, and illness severity score were recorded., Results: Median urine dipstick protein concentration to USG ratio and number of dogs having a ratio ≥1.5 were significantly higher for dogs with mucocele formation compared to control dogs. Proteinuria was not significantly associated with CBC or serum biochemistry profile abnormalities but increased in relation to severity of illness., Conclusions and Clinical Importance: Gallbladder mucocele formation is significantly associated with proteinuria in dogs. Diagnosis and treatment of proteinuria in dogs with mucocele formation might minimize long term kidney morbidity in these patients., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC. on behalf of the American College of Veterinary Internal Medicine.)

The purpose of this work is to investigate whether imaging sequences of flash-replenishment contrast enhanced ultrasound (CEUS) of the kidney result in chronic or acute bioeffects. Kidneys of female Fischer 344 rats were imaged using the flash-replenishment technique. Animals were separated into four groups (N = 31). Imaging was conducted with a 4C1 probe, driven by an Acuson Sequoia system with Definity microbubbles as the ultrasound contrast agent. During the flash phase of the imaging sequence, one kidney in each animal was exposed to either a mechanical index (MI) of 1.0 or 1.9. For each MI, half of the animals were sacrificed shortly after imaging (4 h) or after 2 weeks. A blinded veterinary nephropathologist reviewed the histopathology of both the imaged and control (non-imaged) kidney. Blood urea nitrogen (BUN) was measured for each animal prior to imaging and at the time of necropsy. Histopathology assessments in both the 1.0 and 1.9 MI groups revealed no signs of hemorrhage at either the 4-h or 2-week time point. BUN showed minor but statistically significant elevations in both the 1.0 and 1.9 MI groups, but no significant difference was present at the 2-week time point in the 1.0 MI group. All BUN levels (at both time points) remained in the normal range. In conclusion, CEUS with flash-replenishment imaging sequences did not result in kidney bioeffects observable with histology at early or late time points. Increases in BUN levels were observed after imaging, but were minimized when using a moderate MI (1.0)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Foamy viruses (FVs) are globally prevalent retroviruses that establish apparently apathogenic lifelong infections. Feline FV (FFV) has been isolated from domestic cats with concurrent diseases, including urinary syndromes. We experimentally infected five cats with FFV to study viral kinetics and tropism, peripheral blood mononuclear cell (PBMC) phenotype, urinary parameters, and histopathology. A persistent infection of primarily lymphoid tropism was detected with no evidence of immunological or hematologic perturbations. One cat with a significant negative correlation between lymphocytes and PBMC proviral load displayed an expanded FFV tissue tropism. Significantly increased blood urea nitrogen and ultrastructural kidney changes were noted in all experimentally infected cats, though chemistry parameters were not outside of normal ranges. Histopathological changes were observed in the brain, large intestine, and other tissues. In order to determine if there is an association of FFV with Chronic Kidney Disease, we additionally screened 125 Australian pet cats with and without CKD for FFV infection and found that FFV is highly prevalent in older cats, particularly in males with CKD, though this difference was not statistically significant compared to controls. Acute FFV infection was clinically silent, and while some measures indicated mild changes, there was no overt association of FFV infection with renal disease.

With the growth of contrast-enhanced ultrasound (CEUS) clinically, there are concerns about histologic bioeffects in regards to the implementation of high mechanical index (MI) imaging, such as the imaging sequence used for a specific CEUS technique known as flash-replenishment. The data presented are results from a pilot study, which explored flash-replenishment with high and moderate MI imaging sequences at time points of 24 hours and 2 weeks post imaging. This pilot study was followed by a larger study, which can be found in a journal article entitled "Histological and Blood Chemistry Examination of the Rodent Kidney After Exposure to Flash-Replenishment Ultrasound Contrast Imaging" Nyankima et al., 2019.

Objective: To investigate the association between synthetic colloids and biomarkers of acute kidney injury (AKI) in dogs with hemorrhagic shock., Design: Experimental interventional study., Setting: University., Animals: Twenty-four healthy ex-racing Greyhounds., Interventions: Anesthetized Greyhounds subjected to hemorrhage for 60 min were resuscitated with 20 mL/kg of fresh whole blood (FWB), 6% hydroxyethyl starch (HES) 130/0.4, 4% succinylated gelatin (GELO), or 80 mL/kg of isotonic crystalloid (CRYST) over 20 min (n = 6 per treatment). Concentrations of biomarkers of AKI were measured at baseline, end of hemorrhage, and at 40 (T60), 100 (T120), and 160 (T180) min after fluid bolus. Biomarkers included neutrophil gelatinase-associated lipocalin in urine and serum (uNGAL; sNGAL), and urine cystatin C (uCYSC), kidney injury molecule-1 (uKIM), clusterin (uCLUST), osteopontin, gamma-glutamyl transferase, monocyte chemoattractant protein-1 (uMCP), interleukin-6, interleukin-8, protein (uPROT), hyaluronan, and F 2 -isoprostanes. Renal histology was scored for tubular injury and microvesiculation. Biomarker fold-change from baseline was compared between groups using mixed effects models (Bonferroni-Holm corrected P<0.05). Frequencies of histology scores were compared by Fisher's exact test., Measurements and Main Results: In dogs treated with GELO, uNGAL fold-change was markedly greater compared with all other groups at T60, T120, and T180 (all P<0.001), and uCYSC was greater at T60 compared with CRYST (P<0.001), and at T120 and T180 compared with all other groups (all P<0.001). Smaller, albeit significant, between-group differences in uKIM, uCLUST, uMCP, and urine protein concentration were observed across the FWB, GELO, and HES groups, compared with CRYST. The GELO group more frequently had marked tubular microvesiculation than the other groups (P = 0.015) although tubular injury scores were comparable., Conclusion: In dogs with hemorrhagic shock, GELO was associated with greater magnitude increases in urine biomarkers of AKI and more frequent marked tubular microvesiculation, compared with FWB, CRYST, and HES., (© Veterinary Emergency and Critical Care Society 2019.)

MicroRNAs (miRNAs) are a group of small noncoding RNAs that act as regulators of posttranslational gene/protein expression and are known to play a key role in physiological and pathological processes. The objective of our study was to compare expression of miR-21 in renal tissue from dogs affected with chronic kidney disease (CKD) caused by X-linked hereditary nephropathy (XLHN), a disease equivalent to human Alport syndrome, to that from unaffected dogs. Additionally, we sought to characterize changes in relative mRNA expression of various genes associated with miR-21 function. miRNA was isolated from kidney tissue collected from both affected dogs and unaffected, age-matched littermates at defined milestones of disease progression, including end-stage renal disease (ESRD). Additionally, autopsy samples from affected dogs at ESRD and corresponding unaffected dogs were evaluated. Samples were scored based on histological changes, and relative expression of miR-21 and kidney disease-related genes was determined using quantitative real-time polymerase chain reaction. In affected dogs, significant upregulation of kidney miR-21 was first detected at the milestone corresponding with increased serum creatinine. Furthermore, miR-21 expression correlated significantly with urine protein: urine creatinine ratio, serum creatinine concentration, glomerular filtration rate, and histologic lesions (glomerular damage, tubular damage, chronic inflammation, and fibrosis). At end-stage disease, COL1A1, TGFB1 and its receptor, TGFB2, and Serpine1 were upregulated, while PPARA, PPARGC1A, ACADM, SOD1, and EGF were downregulated. In conclusion, miR-21 is abnormally upregulated in the kidneys of dogs with CKD caused by XLHN, which may play an important pathologic role in the progression of disease by dysregulating multiple pathways.

An 8-month-old Hanoverian gelding was presented with a history of cardiac murmurs that were not apparent as a foal nor reported at the time of castration. Major echocardiographic findings included mitral valvular thickening, functional stenosis, and mitral regurgitation of sufficient severity to cause diastolic and systolic cardiac murmurs, left-sided volume overload, and pulmonary hypertension. Due to the hemodynamic severity of the lesion and poor prognosis for future performance and longevity, euthanasia was elected. On gross postmortem examination, there was focal fibrous epicarditis affecting the heart base, and the left atrium was moderately dilated. The mitral valve surface was irregular and contained several nodules along the atrial face of the cusp. Histologically, this lesion was diagnosed as a vascular hamartoma, which is rarely reported in veterinary species and has not been described in heart valves. This benign proliferative lesion, and concurrent valvular dysfunction, was associated with an unusual manifestation of clinically evident disease and should be differentiated from common incidental valvular lesions such as hematocysts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Low-boiling-point perfluorocarbon phase-change contrast agents (PCCAs) provide an alternative to microbubble contrast agents. Although parameter ranges related to in vivo bio-effects of microbubbles are fairly well characterized, few studies have been done to evaluate the potential of bio-effects related to PCCAs. To bridge this gap, we present an assessment of biological effects (e.g., hemorrhage) related to acoustically excited PCCAs in the rodent kidney. The presence or absence of bio-effects was observed after sonication with various perfluorocarbon core PCCAs (decafluorobutane, octafluoropropane or a 1:1 mixture) and as a function of activation pulse mechanical index (MI; minimum activation threshold, which was a moderate MI of 0.81-1.35 vs. a clinical maximum of 1.9). Bio-effects on renal tissue were assessed through hematology and histology including measurement of blood creatinine levels and the quantity of red blood cell (RBC) casts present in hematoxylin and eosin-stained kidney tissue sections after sonication. Short-term (24 h) and long-term (2 and 4 wk) analyses were performed after treatment. Results indicated that bio-effects from PCCA vaporization were not observed at lower mechanical indices. At higher mechanical indices, bio-effects were observed at 24 h, although these were not observable 2 wk after treatment., (Copyright © 2018. Published by Elsevier Inc.)

OBJECTIVE To identify factors affecting the diagnostic quality of core needle renal biopsy specimens from dogs with suspected kidney disease. DESIGN Cross-sectional study. ANIMALS 522 client-owned dogs with suspected kidney disease for which core needle renal biopsy specimens (n = 1,089) were submitted to the International Veterinary Renal Pathology Service for evaluation and inclusion in their database. PROCEDURES Data regarding dog signalment, clinical variables, biopsy method, needle brand and gauge, biopsy results, and other variables were extracted from the database. Variables were tested for association with 3 outcomes of light microscopic evaluation of core specimens: number of glomeruli per core specimen, obtainment of < 10 glomeruli, and presence or absence of renal medullary tissue. RESULTS Number of glomeruli per core specimen was significantly associated with needle gauge, dog age, serum creatinine concentration, and degree of proteinuria, whereas biopsy method and submitting hospital were significantly associated with the presence of renal medullary tissue in specimens. Mean numbers of glomeruli per core specimen obtained with 14- or 16-gauge needles were similar, but both were significantly greater than the mean number obtained with 18-gauge needles. Needle gauge had a similar association with the likelihood of obtaining < 10 glomeruli in a core specimen. Specimens obtained via laparotomy or laparoscopic approaches more commonly contained medullary tissue than those obtained by ultrasound-guided approaches. CONCLUSIONS AND CLINICAL RELEVANCE Overall, findings suggested that ultrasound-guided biopsy with a 16-gauge needle should maximize the diagnostic quality of renal biopsy specimens from dogs with suspected kidney disease, while avoiding potential adverse effects caused by larger needles.

Background: The European Veterinary Renal Pathology Service (EVRPS) is the first Web-based registry for canine renal biopsy specimens in Europe., Hypothesis/objectives: The aim was to verify whether differences exist between the clinical and laboratory presentation of dogs with nephropathy according to renal pathological findings, as defined by light and electron microscopy of renal biopsy specimens submitted to EVRPS., Animals: Renal biopsy specimens of dogs were collected from the archive of the service (n = 254). Cases were included if both light and electron microscopy were available (n = 162)., Methods: Renal biopsy specimens were classified based on the morphological diagnoses. Thereafter, they were grouped into 3 disease categories, including immune-complex-mediated glomerulonephritis (ICGN), non-immune-complex-mediated GN (non-ICGN), and renal lesions not otherwise specified (RL-NOS). Differences among morphological diagnoses and among disease categories were investigated for clinical and laboratory variables., Results: Serum albumin concentration was lower in dogs with ICGN than in those with non-ICGN (P = 0.006) or RL-NOS (P = 0.000), and the urine protein-to-creatinine ratio (UPC) was significantly higher in ICGN than in the other 2 disease categories. Regarding morphological diagnoses, albumin was significantly lower in amyloidosis (AMY) and membranous (MGN), membranoproliferative (MPGN) or mixed glomerulonephritis (MixGN) than in minimal change disease, primary (FSGS I) or secondary (FSGS II) focal and segmental glomerulosclerosis and juvenile nephropathies (JN). The UPC was higher in MPGN than in FSGS I and FSGS II., Conclusions and Clinical Importance: Dogs with ICGN, in particular MPGN, had higher protein loss than those with non-ICGN or RL-NOS, leading to more severe hypoalbuminemia. Clinical and laboratory differentiation among dogs with the different morphological diagnoses and among dogs with different disease categories was difficult due to overlapping results., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

A 9-y-old, male ring-necked pheasant ( Phasianus colchicus) was autopsied following euthanasia because of acute distress, recumbency, and dyspnea. The bird had experienced a protracted period of neuromuscular disease localized to the left sciatic nerve. Gross and histologic examination of the large intestine revealed intramural nodules predominantly comprised of atypical, whorling spindle cells with small cores of granulomatous inflammation centered on cross-sections of immature adult nematodes. The body structures of these metazoan organisms and clinical disease manifestation are consistent with Heterakis isolonche infection. Nodular spindle cell proliferations without granulomatous inflammation or intralesional nematodes were also found throughout the liver and lungs, suggesting metastasis from the intestine. Immunohistochemical staining of the hepatic and pulmonary tumor tissue with vimentin and S100 suggests a neurofibroblastic origin.

The incidence and prevalence of paraneoplastic glomerulopathy, especially associated with carcinoma, are a matter of debate and the causal link between cancer and glomerular diseases remains unclear. The aim of this study was to evaluate renal biopsies of selected bitches with spontaneous mammary gland carcinoma. We hypothesized that dogs with mammary carcinomas would show histologic evidence of glomerular pathology. A prospective study was performed in dogs with naturally occurring mammary carcinoma that were undergoing tumor resection and ovariohysterectomy. We evaluated renal biopsies of 32 bitches with spontaneous mammary gland carcinoma and 11 control dogs without mammary gland neoplasia. Samples were obtained from the left kidney and the biopsy material was divided for light microscopy (LM), immunofluorescence (IF) and transmission electron microscopy (TEM). Light microscopy abnormalities were identified in 78.1% of dogs with mammary carcinoma (n = 25) and in none of the dogs in the control group. Focal glomerular mesangial matrix expansion was the most common alteration (n = 15, 60.0%), but mesangial cell proliferation (n = 9, 36.0%) and focal segmental glomerulosclerosis (n = 9, 36.0%), synechiae (n = 7, 28.0%), and globally sclerotic glomeruli (n = 6, 24.0%) were also frequent in dogs with malignancy. Immunofluorescence microscopy revealed strong IgM staining was demonstrated in 64.3% (n = 18) of carcinoma dogs. Transmission electron microscopy from dogs with carcinoma revealed slight changes, the most frequent of which was faint sub-endothelial and mesangial deposits of electron-dense material (78%). Mesangial cell interpositioning and segmental effacement of podocyte foot processes were identified in some specimens (45%). Changes in the glomerulus and proteinuria are common in dogs with naturally occurring mammary carcinoma and this condition appears to provide an excellent large animal model for cancer-associated glomerulopathy in humans., Competing Interests: The authors have declared that no competing interests exist.

Many recent advances in the evaluation of dogs with kidney disease have improved our diagnostic algorithms and have impacted our therapeutic strategies. Non-invasive techniques, such as urinary and serologic biomarker evaluation, can help a clinician diagnose and treat a patient that cannot undergo a renal biopsy for clinical or financial reasons. Some biomarkers might help localize the affected structure (glomerulus vs. tubule) and indicate the type or severity of injury present. Although more research is needed, studies indicate that some biomarkers (e.g. urine protein to creatinine ratio and urinary immunoglobulins) can be useful in predicting adverse outcomes. Importantly, the sensitivity and specificity of biomarkers for renal injury should be established and clinicians need to understand the limitations of these assays. If a renal biopsy is performed, then it should be evaluated by a specialty diagnostic service with expertise in nephropathology. A panel of special stains, immunofluorescence for the detection of immunoglobulins and complement factors, and transmission electron microscopy can be routinely employed in cases of glomerular disease. These advanced diagnostics can be used to detect immune deposits in order to definitively diagnose immune complex mediated glomerular disease. Integrating the results of biomarker assays and comprehensive renal biopsy evaluation, the clinician can make informed therapeutic decisions, such as whether or not to immunosuppress a patient., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Urine protein loss is common in dogs with chronic kidney disease (CKD)., Hypothesis/objectives: To evaluate new biomarkers of glomerular and tubulointerstitial (TI) damage compared with histology and as survival indicators in dogs with naturally occurring, proteinuric CKD., Animals: One hunderd and eighty dogs with naturally occurring kidney disease., Methods: Retrospective study using urine, serum, and renal biopsies from dogs with kidney disease, 91% of which had proteinuric CKD. Biomarkers were evaluated and correlated with pathologic renal damage, and significant associations, sensitivities, and specificities of biomarkers for renal disease type were determined., Results: Fractional excretions of immunogloblin M (IgM&#95;FE) and immunoglobulin G (IgG&#95;FE) correlated most strongly with glomerular damage based on light microscopy (r = 0.58 and 0.56, respectively; P < .01). Serum creatinine (SCr) correlated most strongly with TI damage (r = 0.70, P < .01). Urine IgM/creatinine and urine NAG/creatinine had the highest sensitivity (75%) and specificity (78%) for detection of immune complex-mediated glomerulonephritis. Although individually most biomarkers were significantly associated with decreased survival time (P < .05), in a multivariate analysis, SCr, IgM&#95;FE, and glomerular damage based on transmission electron microscopy (TEM) were the only biomarkers significantly associated with survival time (SCr: P = .001; IgM&#95;FE: P = .008; TEM: P = .017)., Conclusions and Clinical Importance: Novel urine biomarkers and FEs are useful for detection of glomerular and TI damage in dogs with proteinuric CKD and might predict specific disease types and survival., (Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Endocardial fibroelastosis (EFE) is a pathologic condition of abnormal deposition of collagen and elastin within the endocardium of the heart. It is seen in conjunction with a variety of diseases including hypoplastic left heart syndrome and viral endocarditis. While an experimental model using heterotopic heart transplant in rats has been described, we sought to fully describe a mouse model that can be used to further elucidate the potential mechanisms of and treatments for EFE., Materials and Methods: The hearts of 2-day-old C57BL/6 mice were transplanted into the abdomen of 7-week-old C57BL/6 mice. At 2 weeks, the hearts were harvested and histologic analysis was performed using hematoxylin and eosin, Masson's trichrome, Russell-Movat's pentachrome, Picrosirius red, Hart's, Verhoeff-Van Gieson, and Weigert's Resorcin-Fuchsin stains. Additionally, one heart was analyzed using transmission electron microscopy (TEM)., Results: Specimens demonstrated abnormal accumulation of both collagen and elastin within the endocardium with occasional expansion into the myocardium. Heterogeneity in extracellular matrix deposition was noted in the histologic specimens. In addition, TEM demonstrated the presence of excess collagen within the endocardium., Conclusions: The heterotopic transplantation of an immature heart into a mouse results in changes consistent with EFE. This model is appropriate to investigate the etiology and treatment of EFE., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Glomerulonephropathies are common causes of kidney disease in dogs., Objective: To determine the prevalence of immune-complex glomerulonephritis (ICGN) in North American dogs biopsied for suspected glomerular disease., Animals: Renal biopsies (n = 733) submitted to the Texas Veterinary Renal Pathology Service between January 1, 2007 and December 31, 2012 were reviewed. Dogs were included if the biopsy was performed for suspected glomerular disease., Methods: Specimens were evaluated by light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). Findings were retrospectively evaluated to categorize the diagnosis for each case. For the diagnosis of ICGN, TEM findings were considered conclusive when LM and IF were equivocal., Results: Of the 501 dogs included in the study, 241 (48.1%) had ICGN; 103 (20.6%) had primary glomerulosclerosis; 76 (15.2%) had amyloidosis; 45 (9.0%) had nonimmune complex (IC) glomerulopathy; 24 (4.8%) had non-IC nephropathy; and, 12 (2.4%) had primary tubulointerstitial disease. Many (66/241; 27.4%) ICGN cases required TEM for definitive diagnosis, including 14 cases (5.8%) that were not suspected on LM. Of cases not diagnosed as ICGN, a substantial proportion (60/260; 23.1%) required TEM to rule out immune complex deposits, including 14 of 189 cases (7.4%) presumptively diagnosed as ICGN on LM., Conclusions and Clinical Importance: Approximately half of all dogs biopsied for suspected glomerular disease had conditions other than ICGN. Renal biopsy is needed to accurately categorize the underlying disease and direct appropriate treatment. Additionally, TEM and IF evaluations by experienced nephropathologists are necessary to obtain an accurate diagnosis in many cases., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Background: Human renal biopsies are routinely evaluated with light microscopy (LM) using a panel of histologic stains, transmission electron microscopy (TEM), and immunofluorescence (IF) microscopy to obtain a diagnosis. In contrast, the pathologic evaluation of glomerular disease in veterinary medicine has relied mostly on LM and was of limited utility. To address this problem, recently established veterinary renal diagnostic centers have adopted methods used in human nephropathology for evaluation of renal biopsies. Three broad categories of disease, which have the greatest implications for clinical management of proteinuric dogs, have been established and include amyloidosis, immune complex-mediated glomerulonephritis (ICGN), and non-ICGN., Objective: To demonstrate histopathologic, ultrastructural, and IF findings in renal biopsy specimens that experienced veterinary nephropathologists utilize to make accurate and clinically useful diagnoses in dogs with proteinuric glomerular disease and to provide guidelines for the proper evaluation of renal biopsies., Methods: Renal biopsy specimens were routinely examined by LM, IF, and TEM. Samples were reviewed by members of the World Small Animal Veterinary Association Renal Standardization Study Group to identify lesions that were diagnostic for, or suggestive of, the presence of immune complexes (IC) or amyloidosis in all modalities. Ten guidelines for renal biopsy evaluation were formulated., Results: Each method of investigation contributed important findings that were integrated to make an accurate final morphological diagnosis. The guidelines were validated by an independent group of veterinary pathologists., Conclusions and Clinical Importance: Routine evaluation of renal biopsies with LM, TEM, and IF is feasible and necessary for making accurate, morphologic diagnoses that can be used to guide clinical management of dogs with glomerular disease., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Background: Tubular atrophy and interstitial fibrosis are well-recognized sequelae of chronic proteinuria; however, little is known regarding the molecular pathways activated within tubulointerstitium in chronic proteinuric nephropathies., Methods: To investigate the molecular mechanisms of proteinuria-associated tubulointerstitial (TI) disease, doxorubicin nephropathy was induced in rats. Progression of disease was monitored with weekly urinary biomarker assays. Because histopathology revealed multifocal TI injury, immunodirected laser capture microdissection was used to identify and isolate injured proximal tubules, as indicated by kidney injury molecule-1 immunolabeling. Adjacent interstitial cells were harvested separately. Gene expression microarray, manual annotation of gene lists, and Gene Set Enrichment Analysis were performed. A subset of the regulated transcripts was validated by quantitative PCR and immunohistochemistry., Results: Severe proteinuria preceded tubular injury biomarkers by 1 week. Histology revealed multifocal, mild TI damage at 3 weeks, which progressed in severity at 5 weeks. Affymetrix microarray analysis revealed tissue-specific regulation of gene expression. Manual annotation of gene lists, gene set enrichment analysis, and urinary biomarker assays revealed similarities to pathways activated in direct TI injuries. This suggests commonalities amongst the molecular mechanisms of TI injury secondary to proteinuria, ischemia-reperfusion, and nephrotoxicity. © 2013 S. Karger AG, Basel.

Acoustic radiation force has been proposed as a mechanism to enhance microbubble concentration for therapeutic and molecular imaging applications. It is hypothesized that once microbubbles are localized, bursting them with acoustic pressure could result in local drug delivery. It is known that low-frequency, high-amplitude acoustic energy combined with cavitation nuclei can result in bioeffects. However, little is known about the bioeffects potential of acoustic parameters involved in radiation force and microbubble destruction pulse sequences applied at higher frequencies. In this pilot study, rat kidneys are exposed to high-duty cycle, low-amplitude pulse sequences known to cause substantial bubble translation due to radiation force, as well as high-amplitude short pulse sequences known to cause microbubble destruction. Both studies are performed at 7 MHz on a clinical ultrasound system, and implemented in three-dimensions (3-D) for entire kidney exposure. Analysis of biomarkers of renal injury and renal histopathology indicate that there was no significant renal damage due to these ultrasound parameters in conjunction with microbubbles within the study group., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Sensitive and specific noninvasive biomarkers for tubulointerstitial injury are lacking, and proteomic techniques provide a powerful tool for biomarker discovery., Objective: The aim of this study was to identify novel urinary biomarkers of early tubulointerstitial injury in canine progressive renal disease using both 2-dimensional differential in-gel electrophoresis (2-D DIGE), which identifies individual proteins, and surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF), which generates protein peak profiles., Methods: Urine was collected from 6 male dogs with X-linked hereditary nephropathy (XLHN) at 2 time points (TP): 1) the onset of overt proteinuria (urine protein:creatinine ratio>2) and 2) the onset of azotemia (creatinine ≥ 1.2 mg/dL); corresponding renal biopsies were analyzed from 3 of the dogs. Urine samples from the 6 dogs were subjected to analysis by 2-D DIGE and SELDI-TOF. Urinary retinol-binding protein (RBP) was evaluated in 25 male dogs with XLHN and normal control dogs by Western blot analysis., Results: Clinical data and histologic evaluation revealed reduced renal function and increased tubulointerstitial fibrosis at TP 2. A number of urine proteins and protein peaks were differentially present at the 2 time points, with several known biomarkers of renal disease identified in addition to several promising new biomarkers. RBP was first detected in urine approximately 2 months before onset of azotemia (TP 2), but after onset of overt proteinuria, and amounts increased with progression of disease., Conclusions: Proteomic techniques were successfully used to identify urinary biomarkers of renal disease in dogs with XLHN. Urinary RBP is a promising biomarker for early detection of tubulointerstitial damage and progression to end-stage renal disease., (©2011 American Society for Veterinary Clinical Pathology.)

Renal dysplasia is a hereditary disease characterized by abnormal differentiation of renal tissue. The ultrasonographic appearance of dysplastic canine kidneys has been reported in the late stage of the disease where inflammatory and degenerative changes are already present and the dogs are in chronic renal failure. In this study, we describe the ultrasonographic appearance of the kidneys of five related Cairn Terriers affected with renal dysplasia before the onset of clinical or laboratory evidence of renal failure. Common findings included poor corticomedullary definition and multifocal hyperechoic speckles in the renal medulla, or a diffusely hyperechoic medulla. Severity of ultrasonographic changes was related to the severity of histopathologic findings. The ability to detect dysplastic changes before clinical signs develop makes ultrasound a potentially useful screening method for canine renal dysplasia.