World Small Animal Veterinary Association Renal Pathology Initiative: Classification of Glomerular Diseases in Dogs.

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.

Cardiovascular-renal axis disorders in the domestic dog and cat: a veterinary consensus statement.

OBJECTIVES: There is a growing understanding of the complexity of interplay between renal and cardiovascular systems in both health and disease. The medical profession has adopted the term "cardiorenal syndrome" (CRS) to describe the pathophysiological relationship between the kidney and heart in disease. CRS has yet to be formally defined and described by the veterinary profession and its existence and importance in dogs and cats warrant investigation. The CRS Consensus Group, comprising nine veterinary cardiologists and seven nephrologists from Europe and North America, sought to achieve consensus around the definition, pathophysiology, diagnosis and management of dogs and cats with "cardiovascular-renal disorders" (CvRD). To this end, the Delphi formal methodology for defining/building consensus and defining guidelines was utilised. METHODS: Following a literature review, 13 candidate statements regarding CvRD in dogs and cats were tested for consensus, using a modified Delphi method. As a new area of interest, well-designed studies, specific to CRS/CvRD, are lacking, particularly in dogs and cats. Hence, while scientific justification of all the recommendations was sought and used when available, recommendations were largely reliant on theory, expert opinion, small clinical studies and extrapolation from data derived from other species. RESULTS: Of the 13 statements, 11 achieved consensus and 2 did not. The modified Delphi approach worked well to achieve consensus in an objective manner and to develop initial guidelines for CvRD. DISCUSSION: The resultant manuscript describes consensus statements for the definition, classification, diagnosis and management strategies for veterinary patients with CvRD, with an emphasis on the pathological interplay between the two organ systems. By formulating consensus statements regarding CvRD in veterinary medicine, the authors hope to stimulate interest in and advancement of the understanding and management of CvRD in dogs and cats. The use of a formalised method for consensus and guideline development should be considered for other topics in veterinary medicine.

Consensus recommendations for the diagnostic investigation of dogs with suspected glomerular disease.

BACKGROUND: The International Renal Interest Society (IRIS) offers guidelines for chronic kidney disease and acute kidney injury. As dogs with glomerular disease may present differently and require different treatment than those with whole nephron or tubular disease, the IRIS Canine Glomerulonephritis (GN) Study Group was convened to formulate guidelines for these cases. The Diagnosis Subgroup was asked to make recommendations for diagnostic evaluation of such cases. OBJECTIVE: To seek consensus among renal specialists for the evaluation of dogs with proteinuria because of suspected glomerular disease. METHODS: After reviewing the literature, subgroup members discussed and wrote the draft paper and recommendations, which members of the IRIS Canine GN Study Group voted upon by electronic secret ballot, with comments noted. Consensus was declared if votes showed strong or general agreement from 85% of the respondents. RESULTS: Diagnostic tests were categorized as essential, recommended, or potentially helpful, with prioritization dependent on case characteristics, eg, for cases with uncomplicated proteinuria versus complicated with hypoalbuminemia, azotemia, or both. Consensus was reached with 86-100% agreement on all questions posed. All cases should have basic examinations including blood pressure measurement, blood, and urine testing, and a search for infectious diseases relevant to their environs. The majority ranked imaging (chest radiographs, abdominal ultrasonogram) and renal biopsy procured and interpreted by experienced personnel as essential evaluations in complicated cases, but a few respondents deemed these to be essential in uncomplicated cases as well. CONCLUSIONS AND CLINICAL IMPORTANCE: Strong consensus about recommendations for diagnostic evaluation of dogs with suspected glomerular protein loss was attained. These guidelines help clinicians characterize disease processes for more informed therapeutic decision-making.

Evaluation of canine COL4A3 and COL4A4 as candidates for familial renal disease in the Norwegian elkhound.

The collagen type IV alpha3 and alpha4 chains (COL4A3 and COL4A4) are part of the specialized glomerular basement membrane in the kidney. In human these genes are responsible for Alport syndrome (a type of hereditary nephritis). Histopathological similarities between kidneys of Norwegian elkhound dogs affected with familial renal disease and human Alport syndrome were the basis for a candidate gene approach in Norwegian elkhounds. Three microsatellites-tightly linked to canine COL4A3 and COL4A4--were developed. The microsatellites were used to analyze linkage between COL4A3 and COL4A4 and familial renal disease in a Norwegian elkhound pedigree segregating this disease. Presence of one recombinant between familial renal disease and COL4A3/COL4A4 suggests that these genes are not likely candidates for familial renal disease in this breed.

Primary hyperaldosteronism, a mediator of progressive renal disease in cats.

In recent years, there has been renewed interest in primary hyperaldosteronism, particularly because of its possible role in the progression of kidney disease. While most studies have concerned humans and experimental animal models, we here report on the occurrence of a spontaneous form of (non-tumorous) primary hyperaldosteronism in cats. At presentation, the main physical features of 11 elderly cats were hypokalemic paroxysmal flaccid paresis and loss of vision due to retinal detachment with hemorrhages. Primary hyperaldosteronism was diagnosed on the basis of plasma concentrations of aldosterone (PAC) and plasma renin activity (PRA), and the calculation of the PAC:PRA ratio. In all animals, PACs were at the upper end or higher than the reference range. The PRAs were at the lower end of the reference range, and the PAC:PRA ratios exceeded the reference range. Diagnostic imaging by ultrasonography and computed tomography revealed no or only very minor changes in the adrenals compatible with nodular hyperplasia. Adrenal gland histopathology revealed extensive micronodular hyperplasia extending from zona glomerulosa into the zona fasciculata and reticularis. In three cats, plasma urea and creatinine concentrations were normal when hyperaldosteronism was diagnosed but thereafter increased to above the upper limit of the respective reference range. In the other eight cats, urea and creatinine concentrations were raised at first examination and gradually further increased. Even in end-stage renal insufficiency, there was a tendency to hypophosphatemia rather than to hyperphosphatemia. The histopathological changes in the kidneys mimicked those of humans with hyperaldosteronism: hyaline arteriolar sclerosis, glomerular sclerosis, tubular atrophy and interstitial fibrosis. The non-tumorous form of primary hyperaldosteronism in cats has many similarities with "idiopathic" primary hyperaldosteronism in humans. The condition is associated with progressive renal disease, which may in part be due to the often incompletely suppressed plasma renin activity.

Plasma lipid concentrations, macronutrient digestibility and mineral absorption in dogs fed a dry food containing medium-chain triglycerides.

In a cross-over trial with feeding periods of 2 weeks, six healthy dogs were fed a dry food with a total fat content of 13.4% and containing either 5% (w/w) corn oil (11% of dietary metabolizable energy) or an isoenergetic amount of medium-chain triglycerides (MCT). The two diets were supplied on a restricted basis. There were no food refusals and no diet difference in palatability was observed. The MCT vs. Corn oil did not significantly influence plasma lipid concentrations, but group mean triacylglycerol concentrations were increased by 23% (p=0.074). The MCT consumption did not affect the apparent digestibilities of crude protein and soluble carbohydrates and had no impact on the absorption of calcium, magnesium and phosphorus. The incorporation of MCT into the diet produced a slight increase (by 0.9 percentage units) in crude fat digestibility (p=0.061). It is concluded that MCT at the present inclusion level may not have disadvantageous effects.

Voltage-dependent action of valproate on potassium channels in frog node of Ranvier.

The influence of the anti-epileptic drug, valproate, on K conductance (gK) was investigated in voltage-clamped Ranvier nodes of Xenopus laevis. A double pulse method was used in order to eliminate the effect of accumulation of potassium ions in the perinodal space, thus enabling the determination of the 'true' magnitude of gK. Valproate (2.4 mM) had a voltage-dependent action on the magnitude of gK. With small step depolarizations more negative than about -50 mV, valproate increased gK (20 ms after the step) to approximately 12% of the maximal gK, an increase which disappeared due to a relatively rapid (less than 200 ms) inactivation process. However, with step depolarizations more positive than about -50 mV, valproate markedly reduced gK (20 ms after the step) at greater depolarizations, with a maximum of about 40% of the maximal gK. Moreover, at these voltages gK was inactivated completely (less than or equal to 10 s), whereas under control conditions the inactivation was only partial. Both the temporary increase and the steady state decrease of gK could contribute to an anti-epileptic effect by increasing the action potential threshold and by preventing excessive depolarizations of the nerve during epileptic seizures, respectively.

Spontaneous neuronal firing patterns in fetal rat cortical networks during development in vitro: a quantitative analysis.

The development of spontaneous bioelectric activity (SBA) was studied in dissociated occipital cortex cultures prepared from 19 day old rat fetuses. All cultures, recorded one per diem from 5 to 33 days in vitro (div), showed SBA. Computer analysis of 76 extracellularly recorded single unit spike trains was carried out after selection on the basis of stationarity criteria. Statistically significant developmental trends were found in (i) interspike interval dependencies and (ii) fluctuations in mean firing rate, on the order of a minute or longer. The highly dependent firing patterns, including stereotyped bursting, were present mostly in the 9-12 div group, whereas minute-to-minute fluctuations in the intensity of firing were considerably more pronounced in the oldest group (22-33 div) than in the younger cultures. In addition, firing categories defined on the basis of factor-analysis revealed that such fluctuations were almost exclusively to be found in neurons which fired in a pronounced 'burst', rather than a relatively continuous fashion. Only a few mature appearing synaptic structures were observed electron microscopically prior to 12 div, but increased steadily in number thereafter. No cultures prior to 14 div, but all cultures older than this, stained positively for the presence of glutamic acid decarboxylase. An extensive immunoreactive, putative GABAergic, network was present by three weeks in vitro.