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Background Fibroblast growth factor (FGF)‐23 is increased first in the sequence of changes associated with chronic kidney disease (CKD)‐mineral and bone disorder. Thus, its measurement may serve as a predictive indicator of incident hyperphosphatemia. Objectives To investigate whether serum FGF‐23 concentration in normophosphatemic dogs with CKD is associated with the risk of the subsequent development of hyperphosphatemia and CKD progression. Animals Forty‐two normophosphatemic dogs with CKD. Methods Blood samples and medical records were retrospectively investigated. Hyperphosphatemia was defined as a serum phosphorous concentration >5.0 mg/dL. Progression was defined as a >1.5‐fold increase in serum creatinine concentration. The time periods and hazard ratios for these outcomes were assessed using Kaplan‐Meier analysis, log‐rank test, and univariate Cox regression analysis. The variables associated with the outcomes in the univariate analysis were included in the multivariate Cox regression model with backward selection. Results Serum FGF‐23 concentration >528 pg/mL was associated with a shorter time to development of hyperphosphatemia (P

The effects of different doses of orally administered sildenafil on pulmonary haemodynamics in dogs with pulmonary hypertension (PH) have not been documented in an invasive and quantitative manner. In this study, we examined the effects of oral sildenafil using a canine model of chronic embolic PH (CEPH). This CEPH model was created by repeatedly injecting microspheres through a catheter into the pulmonary artery under general anaesthesia at regular weekly intervals over several months. The CEPH dogs received 1, 2 or 4 mg/kg of sildenafil orally twice a day for seven days. Then, haemodynamic measurements including pulmonary artery pressure (PAP), systemic artery pressure (SAP), pulmonary artery wedge pressure (PAWP), right atrial pressure (RAP) and cardiac output (CO) were obtained after seven days of sildenafil administration via right heart catheterisation and oscillometric blood pressure measurements. Sildenafil was well tolerated in this study. Sildenafil administered at doses of 2 and 4 mg/kg significantly decreased systolic PAP compared with before administration. In addition, all doses of sildenafil significantly decreased the mean and diastolic PAP. Furthermore, 4 mg/kg of sildenafil significantly decreased PAP compared with 1 mg/kg. Sildenafil also significantly decreased pulmonary vascular resistance without notable changes in SAP or systemic vascular resistance. The PAWP, RAP and CO did not increase significantly at any doses. In conclusion, the oral administration of sildenafil to CEPH models decreased PAP in a dose-dependent manner.

Renal proteinuria is associated with promoted renal dysfunction and a shorter survival period in dogs with chronic kidney disease (CKD). Renin angiotensin- aldosterone system inhibitors are primarily used to treat renal proteinuria. In this retrospective, open-label study, we aimed to evaluate the anti-proteinuric and anti-hypertensive effects of telmisartan (angiotensin II receptor blocker) in dogs with proteinuric CKD. A total of 28 dogs with proteinuric CKD were included in the study, all dogs received telmisartan 1 mg/kg q24h, PO. The urine protein-to-creatinine ratio (UPC), urine albumin-to-creatinine ratio (UAC) and systolic blood pressure (SBP) decreased significantly after telmisartan administration (P 0.05). The median rate of change in UPC, UAC and SBP at Day 120 were - 65.1%, -75.9% and - 9.7%. Ten dogs (36.7%) achieved UPC 1.0 at Day 120, of which six dogs had UPC 0.5. A reduction of UPC to ≥50% was achieved in 10 dogs (36%) at Day 45 and 17 dogs (61%) at Day 120. Seventeen dogs (61%) had hypertension at baseline, of which 10 dogs (59%) had SBP 160 mmHg at Day 120. Two-way repeated measures analysis of variance did not attribute the observed changes in SBP, UPC or UAC to feeding with a renal diet. In conclusion, telmisartan therapy provides anti-proteinuric and anti-hypertensive effects in dogs with proteinuric CKD.

Introduction/Objectives The American College of Veterinary Internal Medicine (ACVIM) guidelines suggest that pimobendan should be initiated in dogs which meet all criteria of stage B2 myxomatous mitral valve disease (MMVD): murmur intensity ≥ 3/6, left atrial-to-aortic ratio ≥ 1.6, normalized left ventricular internal diameter in diastole ≥ 1.7, and vertebral heart size > 10.5. Recently, a new radiographic index for left atrial enlargement, vertebral left atrial size (VLAS), was proposed. The objective of the present study was to evaluate whether VLAS is useful in staging MMVD and if it can distinguish between ACVIM stages B1 and B2. Animals Ninety-seven client-owned dogs with MMVD were evaluated and classified as ACVIM stage B1, B2, or C-D. Materials and Methods The echocardiographs and radiographs of all the dogs were retrospectively evaluated to obtain left atrial-to-aortic ratio, normalized left ventricular internal diameter in diastole, and VLAS values. The data were analyzed to assess the correlation between these measurements and VLAS, and the optimal cutoff value of VLAS was determined. Results A VLAS cutoff value of 2.6 provided the greatest diagnostic accuracy for identification of dogs with ACVIM stage B2 MMVD (area under the curve, 0.96; sensitivity, 95%; specificity, 84%). A VLAS ≥2.5 exhibited the highest sensitivity (sensitivity, 100%; specificity, 78%), and a VLAS ≥ 3.1 exhibited the highest specificity (sensitivity, 47%; specificity, 100%). Conclusions VLAS is a helpful index for monitoring MMVD using radiography. A VLAS cutoff value of 2.5 could be used to identify dogs that may benefit from echocardiography to determine if they have reached ACVIM stage B2.

Serum cystatin C levels (CysC) are used in human medicine to document progressive kidney failure. Although CysC are not thought to be useful for the diagnosis of kidney dysfunction in dogs, there has been no specific consideration of body weight as a confounding issue. The aim of this study was to assess that the utility of CysC for the diagnosis of decreased glomerular filtration rate (GFR) in smaller vs. larger dogs. In clinically healthy dogs, serum creatinine (Cre) and CysC correlate directly with body weight; we found that dogs weighing

Information regarding the pharmacokinetics of oral sildenafil in dogs with pulmonary hypertension is limited. In this study, we examined the pharmacokinetics of oral sildenafil in a canine model of chronic embolic pulmonary hypertension (CEPH). The CEPH model was developed by repeatedly injecting microspheres into the pulmonary arteries. The pharmacokinetics of oral sildenafil at 1, 2 and 4 mg/kg was evaluated using four dogs with pulmonary hypertension in the fasted state. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil was well tolerated in this study. Proportional increments in the maximum plasma concentration and area under the curve extrapolated to infinity at drug doses of 1, 2 and 4 mg/kg were detected using a power model analysis. No significant differences were observed among the three doses in the time to maximum plasma concentration. The mean residence time and elimination half-life were slightly but significantly higher at a dose of 4 mg/kg than at a dose of 1 mg/kg.

Basic information related to the association between right heart echocardiographic parameters and invasive pulmonary artery pressure (PAP) in dogs with pulmonary hypetension (PH) is scarce. The aim of this study was to examine the association between conventional right heart echocardiographic parameters and invasive PAP by right heart catheterization (RHC) before and after PH. Five female beagle dogs regarded as clinically healthy were used. Echocardiography and RHC were conducted before and after creating chronic embolic pulmonary hypertension (CEPH) models. The acceleration time to ejection time ratio in pulmonary artery flow profile (AT/ET), the ratio of the pulmonary artery and aortic diameter in diastole (PA/Ao), the right pulmonary artery distensibility index by M-mode method (RPAD M-mode), the normalized right ventricular internal diameter in diastole (RVIDdn), and the normalized tricuspid annular plane systolic excursion (TAPSEn) were correlated with the invasive systolic PAP (sPAP), mean PAP (mPAP) and diastolic PAP (dPAP). Multiple linear regression analysis identified AT/ET and RVIDdn as independent predictors of sPAP, PA/Ao and RVIDdn as independent predictors of mPAP, and PA/Ao and RPAD M-mode as independent predictors of dPAP. AT/ET and PA/Ao had high sensitivity and specificity for predicting CEPH. In conclusion, AT/ET, PA/Ao, RPAD M-mode, RVIDdn and TAPSEn were significantly correlated with invasive PAP and alterations in PA/Ao or AT/ET might enable clinicians to predict PH, even if tricuspid regurgitation is not observed.

Plasma N-terminal pro-atrial natriuretic peptide (NT-proANP) concentration increases with progression of myxomatous mitral valve disease (MMVD) in dogs. This multicentre, prospective study compared plasma NT-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP), ANP, and cardiac troponin I (cTnI) concentrations in dogs with MMVD for their characteristics and discriminatory ability to detect cardiac dilatation and congestive heart failure (CHF). Thirty-six healthy dogs and 69 dogs with MMVD were included. Clinical variables were obtained via physical examination, thoracic radiography, and echocardiography. The discriminatory ability of each cardiac biomarker (CB) to determine the presence or absence of cardiac dilatation (event 1) and CHF (event 2) was evaluated using the receiver operating characteristic curves. Plasma NT-proANP, NT-proBNP, and ANP concentrations showed a significant association with the left atrium/aorta ratio (P

OBJECTIVES To examine the relationship between fibroblast growth factor-23 levels, chronic kidney disease severity and mineral metabolic disorders associated to chronic kidney disease in dogs. MATERIALS AND METHODS Fifteen control and 75 chronic kidney disease dogs were retrospectively included. Serum fibroblast growth factor-23 concentration and other phosphate metabolite parameters were compared between controls and each International Renal Interest Society stage. Multiple regression analysis was performed to determine the predictors of fibroblast growth factor-23. RESULTS Serum fibroblast growth factor-23 concentrations were significantly higher in dogs with IRIS stages 2, 3 and 4 chronic kidney disease than those in dogs in control group and with stage 1 and increased along with the severity of chronic kidney disease. Compared with control dogs, serum intact parathyroid hormone significantly increased from stage 2 and serum phosphorus concentrations increased in dogs with stage 4. In dogs with stage 2, fibroblast growth factor-23 levels significantly increased in those with hyperphosphatemia compared with those with normophosphatemia. While eight of 26 (30.8%) dogs with stage 2 developed hyperparathyroidism (intact parathyroid hormone>8.5 ng/L), 19 (73.1%) dogs with stage 2 had elevated fibroblast growth factor-23 levels above the reference range (>528 pg/mL). Log creatinine, log intact parathyroid hormone and log product of total calcium and phosphorus were independent predictors of log fibroblast growth factor-23. CLINICAL SIGNIFICANCE This preliminary study suggests that canine fibroblast growth factor-23 might be involved in mineral metabolic disorders associated to chronic kidney disease in dogs, and this factor could be potentially used as an early marker for this condition.

Sildenafil improves autonomic dysfunction caused by pulmonary hypertension (PH) in humans, but its effect is unknown in dogs with PH. This prospective study aimed to evaluate the autonomic nervous system function of a canine model of chronic embolic PH (CEPH) and the autonomic nervous system function of a canine model of CEPH in which sildenafil was administered. This study used five clinically healthy female beagle dogs. Evaluation parameters included hemodynamic parameters, heart rate (HR) and heart rate variability (HRV). Each evaluation parameter was compared before and after creating the CEPH model (before, BL; after, CEPHBL) and between the CEPHBL model and after the administration of sildenafil (1 mg/kg, BID) in the CEPH model dogs (CEPHSil). In the CEPHBL model, the hemodynamic parameters indicated cardiac hypofunction, and HR was significantly increased and HRV was significantly decreased compared with BL. Further, in the CEPHSil model, the hemodynamic parameters suggested improvement in cardiac function, and HRV was significantly increased. From the results of the CEPH model dogs, autonomic dysfunction was shown to occur in PH dogs. In addition, the administration of 1 mg/kg of sildenafil to CEPH model dogs may improve autonomic dysfunction.

Basic information related to the pharmacokinetics of sildenafil in dogs is scarce. This study aimed to describe the pharmacokinetic properties of oral sildenafil and determine the effect of feeding and dose proportionality. The effect of feeding on pharmacokinetics of sildenafil (1 mg/kg) was investigated using a crossover study with six dogs. In addition, the dose proportionality of sildenafil ranging 1-4 mg/kg was evaluated using five dogs in the fasted states. The plasma concentrations of sildenafil were determined using high-performance liquid chromatography, and pharmacokinetic parameters were calculated using a noncompartmental analysis. Sildenafil administrations were well tolerated in all studies. Feeding reduced the area under the curve extrapolated to infinity (AUCinf ) and the maximum plasma concentration (Cmax ) significantly. The elimination half-life (T1/2 ) did not differ between the fasted and the fed states. For dose proportionality, nonproportional increases in AUCinf and Cmax at 1-4 mg/kg doses were detected by a power model analysis.

Introduction This study examined whether the angiotensin II receptor blocker telmisartan had inhibitory effects on drug-induced renin-angiotensin-aldosterone system (RAAS) activation in normal dogs. Animals Five healthy laboratory beagles were used in this study. Methods Each dog received amlodipine (0.5 mg/kg, q12h, PO) alone for 14 days. Starting on the next day, animals received both amlodipine and telmisartan (1.0 mg/kg, q24h, PO) for 84 days. Systolic blood pressure, heart rate, plasma biochemical variables (blood urea nitrogen, creatinine, and electrolytes), plasma renin activity, and 24-h urinary aldosterone elimination (U-Aldo) were measured before amlodipine administration; at day 0; and at days 1, 7, 14, 28, 56, and 84 of telmisartan treatment. Results Telmisartan was associated with significant decreases in systolic blood pressure on day 56 (p=0.046), whereas heart rate did not significantly change during this treatment (p=0.061). Plasma renin activity was significantly increased on days 1, 7, 28, 56, and 84 during telmisartan administration (all p=0.04). No change in median U-Aldo was detected following telmisartan administration (p=0.241). When U-Aldo was evaluated in individual animals, two dogs displayed evidence of aldosterone breakthrough. Conclusions Telmisartan administration did not suppress RAAS activation. The appearance of aldosterone breakthrough supports the incomplete blockade of RAAS activation.