Evaluation of the progression of non-azotemic proteinuric chronic kidney disease in dogs.

Proteinuria is a recognized risk factor for progression of canine chronic kidney disease (CKD). However, the prognosis of non-azotemic proteinuric CKD in dogs has been studied only to a limited extent. Moreover, the degree to which proteinuria should be decreased to delay CKD progression remains unknown. The purposes of this study were (1) to identify factors associated with disease progression and (2) to investigate the degree of proteinuria, albuminuria, and blood pressure during the course of treatment associated with the progression using time-averaged urine protein:creatinine ratio (UPC) and urine albumin:creatinine ratio (UAC) in canine non-azotemic proteinuric CKD. Twenty-one dogs with non-azotemic proteinuric CKD were included in the study. High UPC and UAC were associated with CKD progression (P < .05). Time-averaged high UPC and UAC were significantly related to progression (P < .05). The cutoff values of these time-averaged parameters for predicting the progression were 4.1 and 2.0, respectively. In dogs with non-azotemic proteinuric CKD, more severe proteinuria and albuminuria were associated with progression. The present study suggests that because UPC ≥ 4.1 and UAC ≥ 2.0 during treatment were associated with a faster progression of non-azotemic proteinuric CKD, therapeutic intervention is warranted.

Fibroblast growth factor-23 as an early marker of CKD-mineral bone disorder in dogs: preliminary investigation.

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.

Use of vertebral left atrial size for staging of dogs with myxomatous valve disease.

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.

Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs.

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.

Pharmacokinetics of single-dose sildenafil administered orally in clinically healthy dogs: Effect of feeding and dose proportionality.

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.

Evaluation of the effect of an angiotensin-converting enzyme inhibitor, alacepril, on drug-induced renin-angiotensin-aldosterone system activation in normal dogs.

INTRODUCTION: To determine if alacepril, an angiotensin-converting enzyme inhibitor, has a long duration of action for inhibition of drug-induced renin-angiotensin-aldosterone system (RAAS) activation in normal dogs. ANIMALS: Five healthy laboratory dogs were used in this study. MATERIALS AND METHODS: Each dog received amlodipine (0.5 mg/kg, q12h, p.o.) for 14 days, followed by amlodipine (0.5 mg/kg, q12h, p.o.) and alacepril (1.5 mg/kg, q12h, p.o.) for 56 days. Blood pressure (systolic blood pressure [SBP]; mean blood pressure; and diastolic blood pressure), heart rate, and urinary aldosterone-to-creatinine ratio (UAld:Cre), as an indicator of RAAS activation, were measured on days -14, 0 (baseline [BL]), 1, 7, 14, 28, and 56. RESULTS: SBP decreased by 10% (p=0.08), and UAld:Cre increased significantly (p=0.04) relative to the BL level after administration of amlodipine. SBP increased after 14 days of alacepril administration relative to BL (p=0.97), and statistically significant increase was first observed on day 28 (p=0.02). Heart rate significantly decreased after alacepril administration on days 14, 28, and 56 (p=0.02). UAld:Cre significantly decreased after alacepril administration on days 14 and 28 (p≤0.03) relative to the BL level but increased on day 56 such that the difference was no longer significant (p=0.32). DISCUSSION: These incomplete and temporary pharmacological blockade of RAAS activation by alacepril suggest that aldosterone breakthrough may have occurred. CONCLUSIONS: Alacepril inhibited activation of RAAS in the short term but is not expected to have a long duration of action.