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Objectives The objectives of this study were to validate a commercially available luteinising hormone (LH) cat ELISA, to determine whether the increases in plasma LH concentration that occur after neutering are maintained throughout cats’ lives and if other factors such as calendar seasons in both intact and neutered cats, and neutering age in neutered cats, influence plasma LH concentrations. Methods Stored plasma samples from client-owned cats were used for the measurement of LH concentrations. Clinical data, including age, sex, age at neutering and medical history, were reviewed. Two populations were included in this study: (1) a senior and geriatric cat population (⩾9 years old), including 18 intact and 18 neutered cats matched for age, sex and month of sample collection; and (2) an adult cat population (2–8 years old), including 45 neutered cats. LH concentrations were measured using a commercially available feline ELISA. Results Senior and geriatric neutered cats had higher plasma LH concentrations than age-matched intact cats ( P Conclusions and relevance Neutering causes a significant long-term increase in LH concentrations in cats and further studies are required to determine the consequences on feline health.

BACKGROUND: Iatrogenic hypothyroidism might worsen the prognosis of cats with azotemic CKD after thyroidectomy. Varying thyroxine concentrations influence utility of creatinine in assessing renal function. Symmetric dimethylarginine (SDMA) has limited studies in cats with changing thyroid status. OBJECTIVES: Thyroid status is stable 6 months post‐thyroidectomy. Symmetric dimethylarginine and creatinine are linearly associated without influence from total thyroxine concentration (tT4). ANIMALS: Electronic records of 2 first opinion practices were searched using the term “thyroidectomy” to include 81 client‐owned cats that had undergone bilateral thyroidectomy. METHODS: Retrospective cross‐sectional study assessing thyroid hormone concentrations of 68 cats within 6 months of surgery. A longitudinal study of thyroid status in 23 cats with >18 months follow‐up post‐thyroidectomy. A generalized estimating equation assessed the associations of bodyweight, tT4 and creatinine concentrations on SDMA concentration. RESULTS: Sixty‐eight cats had follow‐up within 6 months. Fifteen cats (22%) had persistent, or recurrent, hyperthyroidism and 33 cats (49%) were hypothyroid. Twenty‐three of the euthyroid/hypothyroid cats had long‐term follow‐up (595‐1955 days); 4 cats (17%) remained hypothyroid, 19 cats (83%) were euthyroid (often transiently), and 9 of 23 cats (44%) developed recurrent hyperthyroidism. Symmetric dimethylarginine and creatinine were linearly associated, but hyperthyroid cats had higher SDMA concentrations, relative to creatinine (P = .003). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats have changes in thyroid function for years after bilateral thyroidectomy, with a high incidence of recurrent hyperthyroidism. Both SDMA and creatinine are affected by thyroxine concentrations, and the effect is greater in hyperthyroid cats.

Objectives Early diagnosis of arterial hypertension is essential to prevent target organ damage. In humans, retinal arteriolar narrowing predicts hypertension. This blinded prospective observational study investigated the retinal vessel diameters in senior and geriatric cats of varying systolic blood pressure (SBP) status and evaluated retinal vascular changes in hypertensive cats after treatment. Methods Cats with a median age of 14 years (range 9.1–22 years) were categorised into five groups: group 1, healthy normotensive (SBP 160 mmHg, n = 15). Colour fundus images (Optibrand ClearView) were assessed for hypertensive lesions. Retinal vascular diameters and bifurcation angles were annotated and calculated using the Vascular Assessment and Measurement Platform for Images of the Retina annotation tool (VAMPIRE-AT). When available, measurements were obtained at 3 and 6 months after amlodipine besylate treatment. Results Ten hypertensive cats had retinal lesions, most commonly intraretinal haemorrhages and retinal exudates. Arteriole and venule diameters decreased significantly with increasing age (–0.17 ± 0.05 pixels/year [ P = 0.0004]; –0.19 ± 0.05 pixels/year). Adjusted means ± SEM for arteriole and venule diameter (pixels) were 6.3 ± 0.2 and 8.9 ± 0.2 (group 1); 7.6 ± 0.3 and 10.1 ± 0.4 (group 2); 6.9 ± 0.2 and 9.5 ± 0.3 (group 3); 7.4 ± 0.3 and 10.0 ± 0.4 (group 4); and 7.0 ± 0.3 and 9.8 ± 0.4 (group 5). Group 1 arteriole and venule diameters were significantly lower than those of groups 2 and 4. Group 2 arteriole bifurcation angle was significantly narrower than those of groups 1 and 3. Post-treatment, vessel diameters decreased significantly at 3 and 6 months in seven hypertensive cats. Conclusions and relevance Increased age was associated with reduced vascular diameters. Longitudinal studies are required to assess if vessel diameters are a risk indicator for hypertension in cats.

Feline hyperthyroidism remains a major area of interest within the veterinary field given its high prevalence, affecting nearly 10% of geriatric cats, and that causal factors leading to this disease are not completely understood.1,2 Feline hyperthyroidism shares clinical and histopathological similarities with Toxic Multinodular Goitre in humans and therefore the discovery of driving cellular mechanisms behind the pathogenesis of this feline disease may bring translational insight into the pathogenesis of the later.3,4 Gonadotropin hormones such as LH are structurally related to other glycoproteins including TSH and cross-reactivity between these and their receptors has been demonstrated.5 It is hypothesized that increased concentrations of gonadotropins in neutered cats might be implicated in the pathogenesis of hyperthyroidism. This study aimed to determine the long-term effect of neutering on plasma LH concentrations in cats. Stored plasma samples from client-owned cats were used for measurement of LH and TSH concentrations. Clinical data, including age, sex, neutering age and medical history were reviewed. Two study populations were included in this study: (1) a geriatric cat population (≥ 9 years old): 18 entire and 18 neutered cats matched for age, sex and date of sample collection; (2) an adult cat population (2-8 years old): 45 neutered cats. LH concentrations were measured using a feline ELISA and TSH concentrations were measured by the Immulite canine TSH assay. Geriatric neutered cats have higher plasma LH concentrations (median, 0.25 ng/ml [25th percentile, 0.25; 75th percentile, 2.1]) than age matched entire cats (0.25 ng/ml [0.25, 0.25], P < 0 .001). Cats neutered between 6-9 months of age have higher LH concentrations than cats neutered before or after that period (P = 0.004). No correlation was found between plasma LH and TSH concentrations (P = 0.422). In conclusion, neutering causes significant long-term increase in LH concentrations in cats. Further research to determine whether this results in activation of the TSH receptor and ultimately in thyrocyte hyperplasia and/or hyperfunction is warranted. References: 1. Mooney CT. Pathogenesis of feline hyperthyroidism. J Feline Med Surg 2002;4:167-169. 2. Peterson M. Hyperthyroidism in cats: what’s causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 3. Krohn K, Fuhrer D, Bayer Y, et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr Rev 2005;26:504-524. 4. Gunn-Moore D. Feline endocrinopathies. Vet Clin North Am Small Anim Pract 2005;35:171-210, vii. 5. Jiang X, Dias JA, He X. Structural biology of glycoprotein hormones and their receptors: insights to signaling. Mol Cell Endocrinol 2014;382:424-451.

The relationship between thyroid function and blood pressure is complex. Both hyper- and hypothyroidism have been associated with hypertension in humans, with hyperthyroidism reportedly causing isolated systolic hypertension and hypothyroidism more closely associated with diastolic hypertension and atherosclerosis (Klein and Ojamaa 2001). However, although numerous reviews on the subject of cardiovascular manifestations of thyroid disorders state that hypertension is common (Klein and Danzi 2007; Mazza et al. 2011; Osuna et al. 2017; Udovcic et al. 2017), there is a dearth of good epidemiological data to support this claim. This may be because of the difficulty of proving an association between the conditions when hypertension is in any case very common in the general population, or due to prompt treatment of hypo- and hyperthyroidism with resolution and a consequent lack of recording of the transient hypertension, or because whilst changes in blood pressure do occur they are small in magnitude and do not often result in diagnosis of hypertension.

An update to the 2007 American College of Veterinary Internal Medicine (ACVIM) consensus statement on the identification, evaluation, and management of systemic hypertension in dogs and cats was presented at the 2017 ACVIM Forum in National Harbor, MD. The updated consensus statement is presented here. The consensus statement aims to provide guidance on appropriate diagnosis and treatment of hypertension in dogs and cats.

Highlights • Feline urinary active transforming growth factor beta 1 (aTGF-β1) was measured in healthy and azotaemic cats. • There was no cross-sectional association between aTGF-β1 and development of chronic kidney disease. • Elevations in aTGF-β1 preceded development of azotaemia in a longitudinal study. • Urinary aTGF-β1 concentrations reflected severity of renal pathology., The cytokine transforming growth factor beta 1 (TGF-β1) has been widely implicated in the development and progression of renal fibrosis in chronic kidney disease (CKD) in humans and in experimental models. The aims of this study were to assess the association between urinary active TGF-β1 and (a) development of CKD in a cross-sectional study, (b) deterioration of renal function over 1 year in a longitudinal study, and (c) renal histopathological parameters in cats. A human active TGF-β1 ELISA was validated for use in feline urine. Cross-sectional analysis revealed no significant difference in urinary active TGF-β1:creatinine ratio (aTGF-β1:UCr) between groups with differing renal function. Longitudinally, non-azotaemic cats that developed CKD demonstrated a significant (P = 0.028) increase in aTGF-β1:UCr approximately 6 months before the development of azotaemia, which remained elevated (P = 0.046) at diagnosis (approximately 12 months prior, 8.4 pg/mg; approximately 6 months prior, 22.2 pg/mg; at CKD diagnosis, 24.6 pg/mg). In the histopathology study, aTGF-β1:UCr was significantly higher in cats with moderate (P = 0.02) and diffuse (P = 0.005) renal fibrosis than in cats without fibrosis. Cats with moderate renal inflammation had significantly higher urinary active aTGF-β1 concentrations than cats with mild (P = 0.035) or no inflammatory change (P = 0.004). The parameter aTGF-β1:UCr was independently associated with Log urine protein:creatinine ratio in a multivariable analysis of clinicopathological parameters and interstitial fibrosis score in a multivariable analysis of histopathological features. These results suggest that urinary aTGF-β1 reflects the severity of renal pathology. Increases in urinary aTGF-β1 followed longitudinally in individual cats may indicate the development of CKD.

Autoantibodies directed against the P450 side chain cleavage enzyme (P450scc) have been recently described in dogs affected with hypoadrenocorticism, consistent with an immune-mediated pathogenesis of this endocrinopathy. In human autoimmune Addison’s disease, autoantibodies may have a predictive value, being detectable before clinical signs developing, and have been shown to persist for a period of time after diagnosis. Furthermore, an autoantibody positive status post-diagnosis has been associated with successful remission of Addison’s disease following B-cell depletion, suggesting active immunopathology in these cases. The current study was designed to investigate changes in serum P450scc autoantibody status over time in dogs diagnosed with spontaneous hypoadrenocorticism. P450scc autoantibodies were measured using a species-specific radioimmunoprecipitation assay in an initial cohort of 213 dogs, indicating a prevalence of 24%. Thirty two of these dogs had repeat samples (n = 80 in total) available for analysis. Five dogs were consistently P450scc autoantibody positive in all samples, for up to 425 days following first sampling. Three dogs were initially autoantibody positive, then became seronegative at later time points. One dog, a 1 year old female entire standard poodle, was initially negative for P450scc autoantibodies, but seroconverted 18 months after diagnosis. The remaining 23 dogs with multiple samples available were consistently P450scc autoantibody negative. Persistence was not associated with sex (p = 0.673). This study demonstrates persistence of P450scc autoantibodies in a subset of dogs affected with hypoadrenocorticism and seroconversion over one year post-diagnosis. P450scc autoantibody reactivity in human autoimmune Addison’s disease has been associated with sex, with females having a higher prevalence, possibly due to P450scc expression in the ovary acting as an additional source of antigenic stimulation. However, there was no sex difference in autoantibody persistence in the dogs affected with hypoadrenocorticism. Autontibody persistence in dogs with hypoadrenocorticism might represent persistent pathology, due to residual antigenic stimulation and autoimmune inflammation in the adrenal gland.

Objectives The aim of this study was to describe the variability in renal function markers in non-azotaemic and azotaemic cats, and also the rate of change in the markers. Methods Plasma creatinine concentration and its reciprocal, glomerular filtration rate (GFR) and urine specific gravity (USG) were studied as markers of renal function in client-owned cats. GFR was determined using a corrected slope-intercept iohexol clearance method. Renal function testing was performed at baseline and a second time point. The within-population variability (coefficient of variation; CV%) was determined at the baseline time point. Within-individual variability (CV%) and rate of change over time were determined from the repeated measurements. Results Twenty-nine cats were included in the study, of which five had azotaemic chronic kidney disease. The within-individual variability (CV%) in creatinine concentration was lower in azotaemic cats than in non-azotaemic cats (6.81% vs 8.82%), whereas the within-individual variability in GFR was higher in azotaemic cats (28.94% vs 19.98%). The within-population variability was greatest for USG (67.86% in azotaemic cats and 38.00% in non-azotaemic cats). There was a negative rate of change in creatinine concentration in azotaemic and non-azotaemic cats (–0.0265 and –0.0344 µmol/l/day, respectively) and a positive rate of change of GFR in azotaemic and non-azotaemic cats (0.0062 and 0.0028 ml/min/day, respectively). Conclusions and relevance The within-individual variability data suggest creatinine concentration to be the more useful marker for serial monitoring of renal function in azotaemic cats. In contrast, in non-azotaemic cats, GFR is a more useful marker for serial monitoring of renal function. The majority of cats with azotaemic CKD did not have an appreciable decline in renal function during the study.

Chronic kidney disease (CKD) is common in both geriatric cats and aging humans, and is pathologically characterised by chronic tubulointerstitial inflammation and fibrosis in both species. Cats with CKD may represent a spontaneously occurring, non-rodent animal model of human disease, however little is known of feline renal cell biology. In other species, TGF-β1 signalling in the proximal tubular epithelium is thought to play a key role in the initiation and progression of renal fibrosis. In this study, we first aimed to isolate and characterise feline proximal tubular epithelial cells (FPTEC), comparing them to human primary renal epithelial cells (HREC) and the human proximal tubular cell line HK-2. Secondly, we aimed to examine and compare the effect of human recombinant TGF-β1 on cell proliferation, pro-apoptotic signalling and genes associated with epithelial-to-mesenchymal transition (EMT) in feline and human renal epithelial cells. FPTEC were successfully isolated from cadaverous feline renal tissue, and demonstrated a marker protein expression profile identical to that of HREC and HK-2. Exposure to TGF-β1 (0–10 ng/ml) induced a concentration-dependent loss of epithelial morphology and alterations in gene expression consistent with the occurrence of partial EMT in all cell types. This was associated with transcription of downstream pro-fibrotic mediators, growth arrest in FPTEC and HREC (but not HK-2), and increased apoptotic signalling at high concentrations of TGF- β1. These effects were inhibited by the ALK5 (TGF-β1RI) antagonist SB431542 (5 μM), suggesting they are mediated via the ALK5/TGF-β1RII receptor complex. Taken together, these results suggest that TGF-β1 may be involved in epithelial cell dedifferentiation, growth arrest and apoptosis in feline CKD as in human disease, and that cats may be a useful, naturally occurring model of human CKD.

Background Estimated glomerular filtration rate (eGFR) formulas are routinely used in human patients to provide a more accurate evaluation of GFR compared to serum creatinine concentration alone. Similar formulas do not exist for cats. Objectives To validate a prediction formula for eGFR in cats based on adjusting serum creatinine concentration. Animals Client‐owned cats with various levels of renal function. Methods The study was cross‐sectional. Glomerular filtration rate was determined by iohexol clearance. Variables including signalment, biochemical markers, and noninvasive measurements considered to represent surrogate markers of muscle mass were evaluated with the reciprocal of serum creatinine concentration in a multivariable regression model. The derived eGFR formula was subsequently tested in another group of cats and agreement with GFR assessed. Results The formula was developed in 55 cats. Only a single morphometric measurement (pelvic circumference) along with the reciprocal of serum creatinine concentration (creatinine−1) independently predicted GFR in the final multivariate model. The derived eGFR formula was 0.408 + (243.11 × creatinine−1 [μmol/L]) ‐ (0.014 × pelvic circumference [cm]). When the formula was tested in another 25 cats it was not found to offer any advantage over creatinine−1 alone in its relationship with GFR (eGFR, R 2 = 0.44, P

Feline chronic kidney disease (CKD) is associated with high variability in severity of CKD-mineral and bone disorder (CKD-MBD). The calcium sensing receptor (CaSR) regulates circulating parathyroid hormone (PTH) and calcium concentrations. Single nucleotide polymorphisms (SNPs) in the CaSR are associated with severity of secondary renal hyperparathyroidism and total calcium concentrations in human patients receiving haemodialysis. The objective of this study was to explore associations between polymorphisms in the feline CaSR (fCaSR) and biochemical changes observed in CKD-MBD.\ud \ud Client owned cats (≥ 9 years) were retrospectively included. SNP discovery was performed in 20 cats with azotaemic CKD and normal or dysregulated calcium concentrations. Non-pedigree cats (n = 192) (125 with azotaemic CKD and 66 healthy), Persians (n = 40) and Burmese (n = 25) were genotyped for all identified SNPs using KASP. Biochemical parameters from the date of CKD diagnosis or from first visit to the clinic (healthy cats) were used. Associations between genotype and ionized calcium, total calcium, phosphate, PTH and FGF-23 were performed for non-pedigree cats using logistic regression.\ud \ud Sequence alignment against the fCaSR sequence revealed eight novel exonic SNPs. KASP genotyping had high accuracy (99.6%) and a low failure rate (A was associated with logPTH concentration (adjusted for plasma creatinine concentration), with a recessive model having the best fit (G/G vs A/A-G/A, P = 0.031).\ud \ud Genetic variation in the fCaSR is unlikely to explain the majority of the variability in presence and severity of CKD-MBD in cats.

Our objective was to identify if changes in serum protein concentrations occur in hyperthyroidism and to assess their association with the development of azotaemia following treatment.\ud \ud Initially non-azotaemic hyperthyroid cats and healthy older cats were included. Serum concentrations of protein fractions were determined by agarose gel electrophoresis and compared between; hyperthyroid and control cats, initially non-azotaemic hyperthyroid cats which developed azotaemia in a 4 month follow up period (masked-azotaemic) and those which remained non-azotaemic, and hyperthyroid cats before and at the time of restoration of euthyroidism. Data are presented as median [25th, 75th percentiles].\ud \ud Hyperthyroid cats (n = 56) had higher serum α2 globulin concentrations (12.5 [10.9, 13.1] g/L vs. 9.8 [3.0, 11.4] g/L; P < 0.001) and lower serum γ globulin concentrations (11.4 [9.1, 13.3] g/L vs. 14.0 [12.4, 16.8] g/L; P = 0.001) than control cats (n = 26). Following treatment, serum total globulin concentration increased (from 38.6 [35.4, 42.8] g/L to 42.3 [39.0, 45.7] g/L; P < 0.001), serum α2 globulin concentration decreased (from 12.5 [10.9, 13.9] g/L to 11.5 [10.1, 12.6] g/L; P < 0.001) and serum γ globulin concentration increased (from 11.4 [9.0, 13.3] g/L to 14.0 [12.4, 16.8] g/L; P < 0.001). Serum concentrations of total globulin or globulin fractions were not significantly different between masked-azotaemic and non azotaemic groups.\ud \ud In conclusion, hyperthyroidism is associated with altered serum concentrations of the α2 and γ globulin fractions, however these changes were not associated with the development of azotaemic chronic kidney disease following treatment.

For patients that develop chronic kidney disease, the underlying aetiology may never be identified. Irrespective of the inciting injury, the histopathological response to injury in the kidneys is the same, and tubulo-interstitial nephritis and fibrosis with variable degrees of secondary glomerulosclerosis and mineralization are usually identified. This chapter concerns itself with factors associated with progression of CKD, and treatment and management strategies for patients with CKD.

Background Role of renin-angiotensin aldosterone system (RAAS) in feline systemic hypertension is poorly understood. Objectives Examine plasma renin activity (PRA) and plasma aldosterone concentrations (PAC) in normotensive and hypertensive cats with variable renal function and in response to antihypertensive therapy. Animals One hundred and ninety-six cats >9 years from first opinion practice. Methods PRA, PAC, and aldosterone-to-renin ratio (ARR) were evaluated in cats recruited prospectively and grouped according to systolic blood pressure (SBP) and renal function (nonazotemic normotensive [Non-Azo-NT], nonazotemic hypertensive [Non-Azo-HT], azotemic normotensive [Azo-NT], azotemic hypertensive [Azo-HT]). Changes in PRA and PAC were evaluated with antihypertensive therapy (amlodipine besylate). Results Plasma renin activity (ng/mL/h; P = .0013), PAC (pg/mL; P

Objective – To review the human and veterinary literature on the role of phosphorus in the pathophysiology of chronic kidney disease (CKD) and to explore why control of plasma phosphorus concentration is an important goal in the management of patients with this disease. Data Sources – Human and veterinary studies, reviews, clinical reports, textbooks, and recent research findings focused on phosphate homeostasis and CKD patient management. Human Data Synthesis – Recent studies using rodent models and human patients with CKD have focused on trying to elucidate the role of the phosphatonins, predominantly fibroblast growth factor-23, in phosphate homeostasis and the pathophysiology of secondary renal hyperparathyroidism (SRHP). Fibroblast growth factor-23 is now considered to be a key regulator of plasma phosphorus concentration in people but has only recently been investigated in companion animal species. Veterinary Data Synthesis – Cross-sectional studies of naturally occurring CKD in dogs and cats have shown hyperphosphatemia and SRHP to be highly prevalent and associated with increased morbidity and mortality in these patients. Experimental studies of surgically induced renal impairment in the dog and cat, and cases of naturally occurring CKD have emphasized the ability of renal care diets to modify plasma phosphorus and parathyroid hormone concentrations. Evidence from these studies indicates that maintaining plasma phosphorus concentrations to within the International Renal Interest Society targets for CKD patients improves survival time and reduces clinical manifestations of hyperphosphatemia and SRHP. Conclusions – The maintenance of plasma phosphorus concentrations in to within the International Renal Interest Society targets is recommended in management of CKD patients. The discovery of the phosphatonins has improved understanding of the mechanisms involved in phosphorus homeostasis and SRHP and may lead to improved ability to monitor and manage these patients.

Objective—To evaluate proteomic delineation of feline urine by mass spectrometry as a method for identifying biomarkers in cats at risk of developing azotemia. Samples—Urine samples from geriatric cats (> 9 years old) with chronic kidney disease and nonazotemic cats that either remained nonazotemic (n = 10) or developed azotemia (10) within 1 year. Procedures—Optimization studies with pooled urine were performed to facilitate the use of surface enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS) for analysis of the urinary proteome of cats. Urine samples from nonazotemic cats at entry to the study were analyzed via SELDI-TOF-MS with weak cation exchange and strong anion exchange arrays. Spectral data were compared to identify biomarkers for development of azotemia. Results—Low protein concentration in feline urine precluded direct application to array surfaces, and a buffer exchange and concentration step was required prior to SELDI-TOF-MS analysis. Three preparation conditions by use of weak cation and strong anion exchange arrays were selected on the basis of optimization studies for detection of biomarkers. Eight potential biomarkers with an m/z of 2,822, 9,886, 10,033, 10,151, 10,234, 11,653, 4,421, and 9,505 were delineated. Conclusions and Clinical Relevance—SELDI-TOF-MS can be used to detect urinary low-molecular weight peptides and proteins that may represent biomarkers for early detection of renal damage. Further study is required to purify and identify potential biomarkers before their use in a clinical setting.

Canine hypoadrenocorticism likely arises from immune-mediated destruction of adrenocortical tissue, leading to glucocorticoid and mineralocorticoid deficiency. In humans with autoimmune Addison’s disease (AAD) or autoimmune polyendocrine syndrome (APS), circulating autoantibodies have been demonstrated against enzymes associated with adrenal steroid synthesis. The current study investigates autoantibodies against steroid synthesis enzymes in dogs with spontaneous hypoadrenocorticism. Coding regions of canine CYP21A2 (21-hydroxylase; 21-OH), CYP17A1 (17-hydroxylase; 17-OH), CYP11A1 (P450 side-chain cleavage enzyme; P450scc) and HSD3B2 (3β hydroxysteroid dehydrogenase; 3βHSD) were amplified, cloned and expressed as 35S-methionine radiolabelled recombinant protein. In a pilot study, serum samples from 20 dogs with hypoadrenocorticism and four unaffected control dogs were screened by radio-immunoprecipitation assay. There was no evidence of reactivity against 21-OH, 17-OH or 3βHSD, but five dogs with hypoadrenocorticism showed immunoreactivity to P450scc compared with controls. Serum samples were subsequently obtained from 213 dogs diagnosed with hypoadrenocorticism and 110 dogs from a hospital control population. Thirty control dogs were randomly selected to establish a threshold for antibody positivity (mean + 3 × standard deviation). Dogs with hypoadrenocorticism were more likely to be P450scc autoantibody positive than hospital controls (24% vs. 1.2%, respectively; p = 0.0016). Sex was significantly associated with the presence of P450scc autoantibodies in the case population, with 30% of females testing positive compared with 17% of males (p = 0.037). Significant associations with breed (p = 0.015) and DLA-type (DQA1*006:01 allele; p = 0.017) were also found. This cross-sectional study indicates that P450scc autoantibodies are present in a proportion of dogs affected with hypoadrenocorticism.

The function of the kidneys is to regulate the volume and composition of extracellular fluid. This is achieved by the initial formation of an ultrafiltrate of plasma by the passage of solutes, small proteins and other non-scellular constituents of the blood across the glomerular filtration barrier. The chapter deals with glomerular filtration, laboratory abnormalities in patients with kidney disease, staging chronic kidney disease, acute kidney injury, glomerular barrier function and tubular function. This chapter includes case examples.

Background Chronic kidney disease (CKD) is common in geriatric cats, but often appears to be stable for long periods of time. Objectives To describe CKD progression and identify risk factors for progression in newly diagnosed azotemic cats. Animals A total of 213 cats with CKD (plasma creatinine concentration > 2 mg/dL, urine specific gravity

AIM We hypothesized that extracellular nucleotides, established as being released from renal tubular epithelial cells, act at pericytes to regulate vasa recta capillary diameter. METHODS A rat live kidney slice model and video imaging techniques were used to investigate the effects of extracellular nucleotides on in situ (subsurface) vasa recta diameter at pericyte and non-pericyte sites. In addition, RT-qPCR was used to quantify P2 receptor mRNA expression in isolated vasa recta. RESULTS Extracellular ATP, UTP, benzylbenzyl ATP (BzATP) or 2-methylthioATP (2meSATP) evoked a significantly greater vasoconstriction of subsurface vasa recta at pericytes than at non-pericyte sites. The rank order of agonist potency was BzATP = 2meSATP > ATP = UTP. The vasoconstriction evoked at pericyte sites by ATP was significantly attenuated by the P2 receptor antagonists suramin, pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) (PPADS) or Reactive Blue-2 (RB-2). UTP-evoked vasoconstriction at pericytes was attenuated by suramin or RB-2 but not PPADS. Interestingly, suramin or PPADS, when applied in the absence of a P2 receptor agonist, evoked a weak but significant vasoconstriction of vasa recta at pericyte sites, suggesting tonic vasodilation by nucleotides. Significant levels of P2X(1, 3 and 7) and P2Y(4 and 6) receptor mRNA were detected in vasa recta. CONCLUSION Extracellular nucleotides act at pericytes to cause vasoconstriction of in situ vasa recta. Pharmacological characterization, supported by RT-qPCR data, suggests that P2X(1 and 7) and P2Y(4) receptors mediate nucleotide-evoked vasoconstriction of vasa recta by pericytes. We propose that nucleotides released from renal tubular epithelial cells, in close proximity to vasa recta capillaries, are key in regulating renal medullary blood flow.

To evaluate whether the addition of a protease inhibitor (PI) to feline plasma improves the temporal stability of N-terminal pro-B-type natriuretic peptide (NT-proBNP).Forty-four EDTA blood samples were collected from 42 cats with cardiac disease or hyperthyroidism. Samples were separated within 15 min of collection and the plasma stored at -80 °C. Samples were thawed and each separated into 2 aliquots, one of which was mixed with PI. Each was subdivided into 5 aliquots, which remained at room temperature (RT) for zero, 24, 48, 96 or 120 h before being returned to storage at -80 °C. NT-proBNP was measured using a commercially-available ELISA.There was no difference in NT-proBNP measurements between plain and PI samples at time zero (P = 0.836) or 24 h (P = 0.293). At subsequent time-points NT-proBNP was higher in the PI than the plain samples (P 0.05). An overall effect of time at RT was detected for plain (P 0.001) and PI samples (P 0.001).The addition of PI to feline plasma significantly reduces, but does not eliminate, degradation of NT-proBNP at RT. This degradation occurs over a time course comparable to postal transportation of samples for laboratory analysis and may alter the clinical interpretation of results.

Background: Iatrogenic hypothyroidism can occur after treatment of hyperthyroidism, and is correlated with a reduced glomerular filtration rate in humans and dogs. Hypothesis: Cats with iatrogenic hypothyroidism after treatment for hyperthyroidism will have a greater incidence of azotemia than euthyroid cats. Animals: Eighty client owned cats with hyperthyroidism. Methods: Two retrospective studies. (1) Longitudinal study of 12 hyperthyroid cats treated with radioiodine (documented as euthyroid after treatment), to assess changes in plasma thyroid stimulating hormone (TSH) concentration over a 6-month follow-up period, (2) Cross-sectional study of 75 hyperthyroid cats (documented as euthyroid) 6 months after commencement of treatment for hyperthyroidism to identify the relationship between thyroid status and the development of azotemia. Kaplan-Meier survival analysis was performed to identify relationships between thyroid and renal status and survival. Results: Plasma TSH concentrations were not suppressed in 7 of 8 cats with hypothyroidism 3 months after radioiodine treatment. The proportion of cats with azotemia was significantly (P= .028) greater in the hypothyroid (16 of 28) than the euthyroid group (14 of 47). Twenty-eight of 41 cats (68%) with plasma TT4 concentration below the laboratory reference range had an increased plasma TSH concentration. Hypothyroid cats that developed azotemia within the follow-up period had significantly (P= .018) shorter survival times (median survival time 456 days, range 231–1589 days) than those that remained nonazotemic (median survival time 905 days, range 316–1869 days). Conclusions and Clinical Importance: Iatrogenic hypothyroidism appears to contribute to the development of azotemia after treatment of hyperthyroidism, and reduced survival time in azotemic cats.

Objective—To evaluate urine cauxin immunoreactivity in geriatric cats with variable plasma creatinine concentrations and proteinuria and to assess urinary cauxin-to-creatinine concentration ratio (UC/C) as a predictor of developing azotemia. Animals—188 client-owned geriatric (≥ 9 years of age) cats. Procedures—A direct immunoassay was developed and validated for the quantification of urinary cauxin relative to a standard curve generated from a urine sample with high cauxin immunoreactivity. Relationships among UC/C, plasma creatinine concentration, and proteinuria were assessed. Nonazotemic cats were recruited and followed for 12 months. Urinary cauxin-to-creatinine concentration ratio was evaluated as a predictor of development of azotemia in these cats. Results—No relationship was evident between UC/C and plasma creatinine concentration. A weak positive correlation was identified between UC/C and urine protein-to-creatinine concentration ratio (r = 0.212). At entry to the longitudinal study, those cats that later developed azotemia had a UC/C that was significantly higher than in those remaining nonazotemic after 12 months. Conclusions and Clinical Relevance—The UC/C did not vary with severity of azotemia but appeared contributory to the feline urinary proteome. High UC/C values were predictive of the geriatric cats in our study developing azotemia. However, it seems unlikely that UC/C will provide additional information about the measurement of urine protein-to-creatinine concentration ratio as a biomarker for the development of azotemia in cats.

Background: Hyperthyroidism complicates the diagnosis of chronic kidney disease (CKD) as it increases glomerular filtration rate. No practical and reliable means for identifying those cats that will develop azotemia after treatment for hyperthyroidism has been identified. Hyperthyroidism is associated with proteinuria. Proteinuria has been correlated with decreased survival of cats with CKD and with progression of CKD. Hypothesis: Proteinuria and other clinical parameters measured at diagnosis of hyperthyroidism will be associated with the development of azotemia and survival time. Animals: Three hundred client owned hyperthyroid cats treated in first opinion practice. Methods: Retrospective, cohort study relating clinical parameters in hyperthyroid cats at diagnosis to the development of azotemia within 240 days of diagnosis and survival time (all cause mortality). Multivariable logistic regression analysis was used to identify factors that were predictive of the development of azotemia. Multivariable Cox regression analysis was used to identify factors associated with survival. Results: Three hundred cats were eligible for survival analysis and 216 cats for analysis of factors associated with the development of azotemia. The median survival time was 417 days, and 15.3% (41/268) cats developed azotemia within 240 days of diagnosis of hyperthyroidism. Plasma concentrations of urea and creatinine were positively correlated with the development of azotemia. Plasma globulin concentration was negatively correlated with the development of azotemia. Age, urine protein : creatinine ratio, and the presence of hypertension were significantly correlated with decreased survival time. Urine specific gravity and PCV were significantly correlated with increased survival time. Conclusions and Clinical Importance: The proteinuria associated with hyperthyroidism is not a mediator of progression of CKD; however, it does correlate with all cause mortality.

Objective—To compare concentrations of urinary iodide (UI) in euthyroid and untreated hyperthyroid cats. Animals—118 euthyroid and 88 hyperthyroid client-owned cats from 2 nonreferral veterinary practices. Procedures—Iodide concentration was measured in 5 urine samples collected every 3 to 12 months from selected cats, and variability of results between euthyroid cats and hyperthyroid cats prior to the diagnosis of hyperthyroidism was evaluated via 1-way ANOVA, after logarithmic transformation of UI concentrations (logUIs). The UI concentration in hyperthyroid cats was measured at diagnosis and 2 to 6 weeks and 3 to 6 months after treatment for hyperthyroidism. The pretreatment logUI in hyperthyroid cats was compared with that in euthyroid cats, taking into account the effects of renal function on UI concentration. Iodine intake was estimated in euthyroid cats following calculation of the volume of daily urine output, with a fixed value for iodine concentration in feces. Results—The variability of UI concentrations did not differ significantly between hyperthyroid (n = 10) and euthyroid (8) cats. The logUI increased 2 to 6 weeks after initiation of treatment in hyperthyroid cats (n = 80) and was lower in azotemic versus nonazotemic cats. Hyperthyroid cats had a lower logUI than euthyroid cats, and there was no evidence of deficient iodine intake in euthyroid cats. Conclusions and Clinical Relevance—The logUI was lower in cats with azotemia and with untreated hyperthyroidism, compared with that in euthyroid cats from the same population. Additional studies are needed to determine whether iodine intake plays a role in the development of hyperthyroidism in cats.

To determine if natriuretic peptide concentrations are increased in cats with systemic hypertension and/or chronic kidney disease (CKD).22 normal cats, 13 normotensive cats with mild-moderate CKD (NT-CKD), 15 hypertensive cats with mild-moderate CKD (HT-CKD) and 8 normotensive cats with severe CKD (NT-CKD-severe).N-terminal pro-B-type (NT-proBNP) and pro-A-type (NT-proANP) natriuretic peptides were measured in plasma samples from all cats using commercially available assays and concentrations in the normal and diseased groups compared using non-parametric statistical tests. Spearman's rank correlation was used to test for an association between natriuretic peptide and creatinine concentrations.NT-proANP was significantly higher in the NT-CKD-severe than the normal group of cats (P=0.006) but there were no other differences between groups. NT-proBNP concentrations were significantly higher in the HT-CKD group than both the normal (P0.001) and the NT-CKD (P0.001) groups. NT-proBNP concentrations were also higher in the NT-CKD-severe (P0.001) and the NT-CKD (P=0.005) groups than the normal group. NT-proANP but not NT-proBNP was significantly and positively associated with plasma creatinine concentration.Measurement of NT-proBNP shows promise as a diagnostic marker for systemic hypertension in the cat. Its concentration is not significantly increased in cats with mild-moderate normotensive CKD.

Objectives: To determine if serum natriuretic peptide (NP) concentrations could distinguish cardiac from non-cardiac causes of respiratory distress (RD) in cats. Animals: Seventy-four cats from 1 university hospital were used. Methods: Serum NP concentrations were measured in 41 cats with non-cardiac respiratory distress (RD-NC) and compared to 33 cats with RD due to congestive heart failure (RD + CHF) using sandwich enzyme immunoassays (ELISA). Results: RD-NC cats had lower (P = 0.0001) median NT-proANP and NT-proBNP concentrations (614 and 45 fmol/mL, respectively) than RD + CHF cats (1690 and 523 fmol/mL, respectively). The area under the curve was 0.88 and 0.96 for the receiver operating curve analysis of the diagnostic accuracy of NT-proANP and NT-proBNP concentrations to discriminate RD + CHF from RD-NC cats (P = 0.036). An optimum cut-off concentration of 986 fmol/mL for NT-proANP and 220 fmol/mL for NT-proBNP accurately discriminated RD-NC from RC + CHF cats with a sensitivity of 93.8% and 93.9% and a specificity of 80.3% and 87.8%, respectively. Conclusions: Serum NP concentrations were different in RD + CHF cats compared to RD-NC cats. Evaluation of circulating NP concentrations may be helpful in the initial approach to cats presenting with respiratory distress, particularly if advances in ELISA technology result in a rapid cage-side test. © 2009 Elsevier B.V. All rights reserved.

Practical relevance Numerous tests are available to the practitioner for quantifying proteinuria. It is important to understand the advantages and limitations of these tests and how the information gained can contribute to optimal patient management. Patient group Cats with chronic kidney disease or systemic hypertension, as well as geriatric cats without overt evidence of disease (including renal dysfunction), are at particular risk of proteinuria. Evidence base Several longitudinal studies of cats seen in first opinion clinics have shown an association between proteinuria and decreased survival time. However, it is unknown whether the deaths that occur in proteinuric cats are due to progression of renal disease because it is often difficult to ascribe a cause of death to a single underlying aetiology in clinical patients. It is also unknown whether proteinuria is contributing to disease progression in these cats or whether proteinuric renal disease is intrinsically more rapidly progressive. Clinical significance More aggressive investigation and management of patients with proteinuria may be appropriate since they are more likely to have progressive disease and/or increased mortality.

Background: Circulating natriuretic peptide concentrations are increased in cats with myocardial dysfunction. Hypothesis: Serum N-terminal fragment of proatrial natriuretic peptide (NT-proANP) and NT-probrain natriuretic peptide (proBNP) concentrations may predict the presence of heart disease (HD) and congestive heart failure (CHF). A positive relationship is also predicted among natriuretic peptide (NP) concentrations, a noninvasive estimate of left ventricular filling pressure (E/Ea), and an echocardiographic measure of left atrial (LA) size (LA/aortic diameter [Ao]). Methods: Serum NP concentrations were measured in 28 healthy control and 50 study cats using sandwich enzyme immunoassays. The study group comprised cats, with HD but no CHF (HD − CHF, n = 17) and cats with CHF (HD + CHF, n = 33). The relationship among NP concentrations, LA size, and E/Ea was examined. The ability of NP to distinguish control from study cats, and HD − CHF from HD + CHF cats, was explored using receiver operator curve analysis. Results: NP concentrations were significantly lower in control than in study cats (P= .0001). The NT-proBNP concentrations were positively correlated with LA/Ao ratio (ρ= 0.34; P= .02) and with E/Ea ratio (ρ= 0.68; P < .05). An NT-proBNP concentration of 49 fmol/mL gave a sensitivity and specificity of 100 and 89.3%, respectively, for correctly distinguishing 96.2% of control from study cats. Pairwise comparisons of the areas under the curve identified a statistically significant difference (P= .011) between NT-proANP and NT-proBNP to distinguish control from study cats. NT-proANP and NT-proBNP concentrations were significantly higher in HD + CHF cats than in HD − CHF cats (P= .0023 and .0001, respectively). Conclusions: Serum concentrations of NT-proANP and particularly NT-proBNP were different in healthy control cats, asymptomatic cats with HD, and cats with CHF, suggesting that measurement of NP concentrations may prove clinically useful as an initial screening test for cats with suspected cardiac disease.

Hyperthyroidism in cats, caused by nodular hyperplasia or adenomas, is clinically and histologically similar to toxic nodular goiter in humans. Subclinical hyperthyroidism in humans is defined as low thyrotropin (TSH) in conjunction with within-reference-range thyroid hormone concentrations, but has not previously been defined in cats. The objective of this study was to test the hypothesis that euthyroid senior cats with low TSH have histological evidence of thyroid nodular hyperplasia and/or adenoma.Thyroid glands removed postmortem from four groups of cats (n = 73) were examined histologically and scored in a blinded fashion. Clinically euthyroid senior (7 years) cats were divided into two groups dependent on their TSH concentration--TSH below the limit of quantification (LOQ) of the assay (0.03 ng/mL; n = 15; UndetectableTSH group) and TSH above the LOQ (or=0.03 ng/mL; n = 31; DetectableTSH group)--using archived plasma samples, collected 0-6 months antemortem. Thyroids were also scored for two control groups: Young group (cats6 years old; n = 13) and Hyperthyroid group (clinically and biochemically hyperthyroid cats; n = 14).Cats in the UndetectableTSH group had a higher frequency of nodules, a greater percentage of abnormal thyroid tissue, and a higher overall histopathological grade than cats with detectable TSH had.Euthyroid (as defined by total thyroxine) senior cats with low TSH are likely to have histological evidence of nodular thyroid disease, and such cats could be considered to be subclinically hyperthyroid.

In the simplest terms, hyperthyroidism is the clinical syndrome that results from an excess of thyroid hormones. This review considers the effects of hyperthyroidism on the cardiovascular and renal systems by reviewing the available literature on the clinical manifestations of this syndrome in the cat and also considering experimental studies and experience in other species, including human beings.

Background:Systemic hypertension is a common clinical problem, often occurring in association with renal disease in cats. Limited information is available to assess the effect of blood pressure and the treatment of hypertension on survival. Hypothesis:That adequacy of blood pressure control is associated with the duration of survival in cats with systolic hypertension. Animals:One hundred and forty-one client-owned cats with systolic hypertension. Methods:Hypertensive cats were treated with amlodipine besylate and were followed until death or the study end point. Time-averaged systolic blood pressure (SBPOT) after implementation of antihypertensive medication and stabilization of systolic blood pressure (SBP) was calculated by using the equation (area under the curve/survival [days]). Cats were divided into quartiles based on their SBPOT, representing varying levels of blood pressure control (median [25th, 75th percentile]: Q1 = 137 [132, 141] mm Hg, Q2 = 148 [145, 151] mm Hg, Q3 = 157 [155, 158] mm Hg, Q4 = 170 [164, 175] mm Hg). Survival and clinical variables were compared between the quartiles. Cox proportional hazard regression analysis was used to determine the association of age, renal function, proteinuria, SBPOT, and the presence of hyperthyroidism on survival. Urine protein to creatinine ratio (UP: C) was compared at diagnosis of hypertension and after initiating treatment. Results:Only UP: C and SBP at diagnosis differed significantly between SBPOT quartiles. Proteinuria was the only variable significantly related to survival in hypertensive cats. A significant decline in UP: C was found in cats treated with amlodipine besylate. Conclusions and Clinical Importance: Proteinuria before and after treatment of hypertension is strongly associated with survival in cats with systolic hypertension. Treatment with amlodipine besylate can result in a significant reduction in UP: C.

A nine-year-old, domestic shorthair cat was diagnosed with hyperthyroidism and treated with methimazole, which resulted in lethargy, inappetence and marked generalised lymphadenomegaly within two weeks of initiation of therapy. Cytology, histopathology and immunohistochemistry were suggestive of atypical lymphoid hyperplasia. Cessation of treatment resulted in resolution of all clinical signs and physical abnormalities within two days. Subsequent treatment with radioactive iodine cured this cat of its hyperthyroidism. The lymphadenomegaly did not return at any stage and the cat is currently asymptomatic. Although methimazole administration for feline hyperthyroidism has been associated with many side effects, lymphadenomegaly has, to the authors' knowledge, not been previously reported.

BackgroundCocker spaniels are predisposed to immune-mediated haemolytic anaemia (IMHA), suggesting that genetic factors influence disease susceptibility. Dog leukocyte antigen (DLA) class II genes encode major histocompatibility complex (MHC) molecules that are involved in antigen presentation to CD4 + T cells. Several DLA haplotypes have been associated with autoimmune disease, including IMHA, in dogs, and breed specific differences have been identified. Cytotoxic T lymphocyte antigen 4 (CTLA4) is a critical molecule involved in the regulation of T-cell responses. Single nucleotide polymorphisms (SNPs) in the CTLA4 promoter have been shown to be associated with several autoimmune diseases in humans and more recently with diabetes mellitus and hypoadrenocorticism in dogs. The aim of the present study was to investigate whether DLA-DQB1 alleles or CTLA4 promoter variability are associated with risk of IMHA in Cocker spaniels.ResultsThere were a restricted number of DLA-DQB1 alleles identified, with a high prevalence of DLA-DQB1*007:01 in both groups. A high prevalence of DLA-DQB1 homozygosity was identified, although there was no significant difference between IMHA cases and controls. CTLA4 promoter haplotype diversity was limited in Cocker spaniels, with all dogs expressing at least one copy of haplotype 8. There was no significant difference comparing haplotypes in the IMHA affected group versus control group (p = 0.23). Homozygosity for haplotype 8 was common in Cocker spaniels with IMHA (27/29; 93 %) and in controls (52/63; 83 %), with no statistically significant difference in prevalence between the two groups (p = 0.22).ConclusionsDLA-DQB1 allele and CTLA4 promoter haplotype were not found to be significantly associated with IMHA in Cocker spaniels. Homozygosity for DLA-DQB1*007:01 and the presence of CTLA4 haplotype 8 in Cocker spaniels might increase overall susceptibility to IMHA in this breed, with other genetic and environmental factors involved in disease expression and progression.