Systemic hypertension is common in dogs with CKD1 and may lead to a more rapid progression of renal insufficiency.2 Because activation of the renin-angiotensin-aldosterone system is one of the main causes of hypertension in dogs with CKD,3 treatment with ACEIs is considered one of the most effective therapeutic strategies.4–8 Reported benefits of treatment with ACEIs include decreases in glomerular capillary hypertension and severity of proteinuria and a retardation in the progression of renal lesions.6,9,10 Currently, the question of which of the currently available ACEIs is most beneficial in the treatment of dogs with CKD is controversial, with some authors11–14 suggesting that benazepril hydrochloride is a better agent than other ACEIs and others5 suggesting that enalapril is more effective. To our knowledge, however, studies of the effects of benazepril in dogs with naturally occurring CKD have not been published.
Activation of the coagulation system is also a common problem in dogs with CKD, and for this reason, administration of anticoagulants has been suggested as a potential treatment in affected dogs.15 A previous study16 confirmed the anticoagulant effects of high doses of unfractionated heparin in dogs, and unfractionated heparin is commonly used to prevent thrombosis or treat venous thrombosis and arterial embolism in humans.17 However, the risk of thrombosis in dogs with CKD is low and the clinical utility of heparin treatment in dogs with CKD is unknown.
The purpose of the study reported here was to evaluate the effects of benazepril alone and a combination of benazepril and heparin on renal function and blood pressure in dogs with CKD. Dogs with and without systemic hypertension and proteinuria were included in the study.
Materials and Methods
Study design and patient selection—The study was conducted as a randomized, controlled clinical trial. Dogs of either sex and any breed, body weight, or age being treated at the Small Animal Clinic of the University of Veterinary Medicine, Hanover, because of CKD were eligible to participate in the study. Dogs were eligible for inclusion in the study if they had azotemia (ie, plasma creatinine concentration > 1.3 mg/dL and plasma urea nitrogen concentration > 50 mg/dL) that was persistent (ie, present for > 3 weeks) and stable (ie, < 10% deviation between initial concentrations and concentrations measured 3 weeks later) and if they had a glomerular filtration rate < 2.6 mL/min/kg.
Dogs enrolled in the study were randomly assigned to 1 of 3 groups. Dogs in group 1 were treated with benazepril hydrochloridea (0.5 mg/kg [0.23 mg/lb], PO, q 24 h) for 180 days. Dogs in group 2 were treated with benazepril (0.5 mg/kg, PO, q 24 h) for 180 days and received sodium heparinb (150 U/kg [68 U/lb], SC, q 8 h) for the first 6 days. Dogs in group 3 were treated with a placebo, PO, once a day for 180 days. Dogs in all 3 groups were fed a dietc with low protein, phosphorus, and sodium content for 180 days.
Assessments—Dogs were examined following enrollment in the study, but prior to assignment to study groups (ie, day 0). In addition, follow-up examinations were performed on days 3, 6, 30, 90, and 180, prior to drug administration. At each examination time, a complete physical examination, hematologic testing, urinalysis, hemadynometry, sonography, and funduscopy were performed. Health status was scored on a scale from 1 to 4, where 1 was defined as clinically normal, 2 was defined as slightly impaired, 3 was defined as moderately impaired, and 4 was defined as severely impaired. Scores were assigned on the basis of severity of polyuria, polydipsia, anorexia, vomiting, and weight loss.
Hematologic testing included a CBC; measurement of plasma creatinine, urea nitrogen, total protein, albumin, glucose, sodium, potassium, inorganic phosphorus, ionized calcium, bicarbonate, and total bilirubin concentrations and plasma alanine transaminase, alkaline phosphatase, and glutamate dehydrogenase activities; and determination of base excess and pH. Plasma osmolality was measured by use of the freezing point depression method. Plasma erythropoietin and parathormone concentrations were measured on days 0 and 180.
Glomerular filtration rate was measured indirectly as plasma clearance of iohexol, as described.18,19 In brief, food was withheld for 12 hours, and iohexold (1 mL/kg [0.45 mL/lb], IV) was administered. Blood samples were collected 180 and 300 minutes after iohexol administration, and plasma iodine concentration was analyzed by means of gamma radiation and x-ray fluorescence. An isotonic electrolyte solution (10 mL/kg [4.5 mL/lb], IV) was infused during measurement of glomerular filtration rate.
Information on hemostasis was obtained by measuring prothrombin time, activated partial thromboplastin time, and activity of antithrombin III. Prothrombin time was measured with a coagulometer,e modified for use with canine plasma as described.20 Activated partial thromboplastin time was measured with a coagulometer as well.f,g Antithrombin III activity was analyzed by means of the chromogenic substrate method with a commercial analyzer.g
Urine samples were obtained by means of cystocentesis. Urine samples collected prior to group assignment and at the end of the 180-day study period were submitted for bacterial culture. Concentrations of 8 marker proteins (IgG, Tamm-Horsfall protein, transferrin, albumin, dimeric hemoglobin, apolipoprotein, monomeric hemoglobin, and E2-microglobulin) were measured by means of SDS-PAGE to differentiate between glomerular and tubular proteinuria.21
Systolic and diastolic blood pressures were measured noninvasively with an oscillometric blood pressure device.h Measurements were obtained with the dog in a sitting position and the blood pressure cuff placed on a forelimb. Each measurement was repeated 3 to 5 times, with 30 to 60 seconds between readings, and a median value was calculated.
Prior to group assignment and on day 180, ultrasonography of the kidneys and urinary bladder was performed. Length and width of the kidneys were measured as described,22 and values were compared with reference values.23 Echocardiography was carried out in patients with hypertension prior to group assignment and on day 180. Left ventricular diameter and thickness of the left ventricular free wall and interventricular septum at the end of diastole were determined and compared with published values for healthy dogs.24 In addition, patients with systemic hypertension underwent funduscopy by means of indirect ophthalmoscopy.
Statistical analysis—The Kolmogorov-Smirnov test was used to determine whether data were normally distributed. Because data were found to be normally distributed, they were summarized as mean and SD. For each examination time, values were compared among the 3 groups by means of univariate ANOVA followed by the least significant difference test. For each group, values obtained at each follow-up examination were compared with baseline values by means of the repeated-measures t test. Sex distribution was compared among groups by use of the F2 test. All analyses were performed with standard software.i Values of P < 0.05 were considered significant. Precision of the blood pressure measurement device was tested by calculating the coefficient of variation.
Results
Patient characteristics—A total of 30 dogs of various breeds and ages were enrolled in the study and assigned to groups (n = 10/group). However, 4 dogs assigned to the placebo group were euthanatized within 1 week after study enrollment because of severe persistent uremia and were excluded from the study. Groups did not vary significantly with regard to age, body weight, or sex distribution at the time of study enrollment. Mean duration of disease before enrollment in the study was 8.5 months (maximum, 4 years).
For all 3 groups, mean clinical score at the beginning of the study was 2. For dogs treated with benazepril alone, clinical score was significantly improved on day 30, compared with baseline score. For dogs treated with benazepril and heparin, clinical score was significantly improved on day 90, compared with baseline score. For dogs in the placebo group, clinical score was significantly improved on days 3, 30, and 90, compared with baseline scores. On day 180, dogs in the 2 treatment groups had significantly higher clinical scores than did dogs in the placebo group.
Results of hematologic testing—For dogs in the benazepril and placebo groups, RBC (reference range, 5.5 to 8.5 × 106 RBCs/μL) and WBC (reference range, 6 to 12 × 103 WBCs/μL) counts were within reference limits throughout the study period, with RBC count significantly increased, compared with baseline values, on day 90 for dogs in the benazepril group (mean ± SD, 7.1 ± 1.14 × 106 RBCs/μL). For dogs in the benazeprilheparin group, mean RBC count was slightly low on days 3 and 6 and mean WBC count was slightly high on days 0 and 3, compared with reference values. Mean Hct was slightly below the lower reference limit (reference range, 44% to 52%) for dogs in the benazepril-heparin and placebo groups throughout the study period and for dogs in the benazepril group on days 3 and 6. There were no relevant changes in differential WBC count or platelet counts throughout the study period in any of the study groups.
Mean plasma creatinine (reference range, 0.4 to 1.2 mg/dL; Figure 1) and urea nitrogen (reference range, 20 to 50 mg/dL; Figure 2) concentrations were higher than the upper reference limits in all groups throughout the study period. For dogs in the benazepril group, plasma creatinine and urea nitrogen concentrations were significantly decreased on day 90 (1.83 ± 0.82 mg/dL and 72 ± 31.6 mg/dL, respectively), compared with baseline concentrations, and for dogs in the benazepril-heparin group, plasma creatinine and urea nitrogen concentrations were significantly decreased on day 30 (1.59 ± 0.69 mg/dL and 72 ± 54.4 mg/dL, respectively), compared with baseline concentrations. Plasma creatinine and urea nitrogen concentrations differed significantly between the benazepril-heparin and placebo groups on day 30 and between the benazepril and placebo groups on day 180.
Mean plasma creatinine concentration in dogs with CKD treated for 180 days with benazepril hydrochloride (0.5 mg/kg, PO, q 24 h; n = 10), benazepril and heparin (150 U/kg, SC, q 8 h, for the first 6 days; 10), or a placebo (6). Bars represent SD.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean plasma creatinine concentration in dogs with CKD treated for 180 days with benazepril hydrochloride (0.5 mg/kg, PO, q 24 h; n = 10), benazepril and heparin (150 U/kg, SC, q 8 h, for the first 6 days; 10), or a placebo (6). Bars represent SD.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean plasma creatinine concentration in dogs with CKD treated for 180 days with benazepril hydrochloride (0.5 mg/kg, PO, q 24 h; n = 10), benazepril and heparin (150 U/kg, SC, q 8 h, for the first 6 days; 10), or a placebo (6). Bars represent SD.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean plasma urea nitrogen concentration in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean plasma urea nitrogen concentration in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean plasma urea nitrogen concentration in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
In all 3 study groups, mean plasma total protein (reference range, 5.4 to 7.5 g/dL), total bilirubin (reference range, < 0.2 mg/dL), glucose (reference range, 55 to 120 mg/dL), sodium (reference range, 140 to 155 mmol/L), potassium (reference range, 3.5 to 5.1 mmol/L), and ionized calcium (reference range, 1.2 to 1.8 mmol/L) concentrations were within reference limits throughout the study period. Mean plasma albumin concentration (reference range, 2.5 to 4.4 g/dL) was slightly low for dogs in the benazepril-heparin group from day 0 to day 30 but was within reference limits in the other 2 groups. Mean plasma phosphorus concentration (reference range, 0.7 to 1.6 mmol/L) was higher than the upper reference limit in the benazepril group on days 3 and 6; in the benazepril-heparin group on days 0, 3, and 6; and in the placebo group on days 90 and 180. Mean plasma phosphorus concentration was significantly different between the benazepril-heparin and placebo groups on days 90 and 180.
Mean plasma alanine transaminase (reference range, < 55 U/L) and glutamate dehydrogenase (reference range, < 6 U/L) activities were within reference limits in all 3 groups throughout the study period. In contrast, mean plasma alkaline phosphatase activity (reference range, < 190 U/L) was high in all 3 groups throughout the study period, except on day 90, when mean value for the benazepril-heparin group was less than the upper reference limit. For dogs in the benazepril-heparin group, mean plasma glutamate dehydrogenase activity was decreased on days 90 and 180, compared with baseline values; mean plasma glutamate dehydrogenase activity was significantly higher in the benazepril than in the benazepril-heparin group on days 3 and 6.
Mean plasma base excess (reference range, −4.0 to 4.0 mmol/L), pH (reference range, 7.304 to 7.436), and bicarbonate concentration (reference range, 19.7 to 30.5 mmol/L) were within reference limits in all 3 groups throughout the study period. Mean plasma osmolality (reference range, 290 to 310 mOsm/kg) was within reference limits for dogs in the benazepril-heparin group throughout the study period. For dogs in the benazepril group, mean plasma osmolality was low on days 0 and 3 and high on day 180. For dogs in the placebo group, mean plasma osmolality was low on days 90 and 180.
For all 3 groups, mean plasma erythropoietin (reference range, 0 to 6 U/L) and parathormone (reference range, 8 to 45 pg/mL) concentrations were high on days 0 and 180. Mean glomerular filtration rate (reference range,25 3.3 to 7.0 mL/min/kg) was low in all 3 groups throughout the study period (Figure 3). For dogs in the benazepril and benazepril-heparin groups, mean glomerular filtration rate was significantly increased on days 30, 90, and 180, compared with baseline values.
Mean glomerular filtration rate (GFR) in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean glomerular filtration rate (GFR) in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean glomerular filtration rate (GFR) in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean prothrombin time (reference range, 75% to 130%) was within reference limits for all 3 groups throughout the study period. On day 0, mean prothrombin time was significantly higher in the benazepril group than in the placebo group. In the placebo group, mean prothrombin time on day 180 was significantly higher than mean time on day 0. On day 0, mean activated partial thromboplastin time (reference range, 14.5 to 19.0 seconds) was significantly prolonged in all 3 study groups (Figure 4). Mean activated partial thromboplastin time was within reference limits on days 30, 90, and 180 for dogs in the benazepril group, on days 90 and 180 for dogs in the placebo group, and on day 90 for dogs in the benazepril-heparin group. For dogs in the benazepril-heparin group, mean activated partial thromboplastin time was significantly decreased, compared with values on day 0, on days 30, 90, and 180 and was significantly increased, compared with values for the other 2 groups, on days 3 and 6. Mean plasma antithrombin III activity (reference range, 82% to 116%) was within reference limits at all times for dogs in the placebo and benazepril groups, except on day 6 when it was slightly low for dogs in the benazepril group. For dogs in the benazepril-heparin group, mean plasma antithrombin III activity was low on days 0, 3, 6, 30, and 90 but was within reference limits on day 180 and was significantly decreased on days 3 and 6, compared with values on day 0. Mean plasma antithrombin III activity was significantly different between the benazepril-heparin and placebo groups on days 3 and 6 and between the benazepril-heparin and benazepril groups on day 3.
Mean activated partial thromboplastin time (APTT) in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean activated partial thromboplastin time (APTT) in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean activated partial thromboplastin time (APTT) in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Results of urinalysis—For all 3 groups, mean urine specific gravity (reference range, 1.005 to 1.040) was within reference limits throughout the study period, as was mean urine pH (reference range, 5.5 to 7.0) and mean urine concentrations of glucose, bilirubin, and hemoglobin. Mean urine osmolality (reference range, 976 to 2,546 mOsm/kg) was low in all 3 groups throughout the study period. The urine protein-to-creatinine ratio (Figure 5) was in the borderline proteinuric range26 (ie, < 0.5) throughout the study period for dogs in the placebo group and was in the proteinuric range throughout the study period for dogs in the benazepril and benazepril-heparin groups. The ratio was significantly reduced, compared with baseline values, on day 180 for dogs in the benazepril group and on days 90 and 180 for dogs in the benazepril-heparin group. On day 0, mean urine protein-to-creatinine ratio was significantly lower for dogs in the placebo group than for dogs in the other 2 groups, and on day 180, mean ratio was significantly higher for dogs in the benazepril-heparin group than for dogs in the other 2 groups.
Mean urine protein-to-creatinine concentration (UPC) ratio in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean urine protein-to-creatinine concentration (UPC) ratio in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean urine protein-to-creatinine concentration (UPC) ratio in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Staphylococcus aureus and Staphylococcus intermedius were isolated from urine samples from 2 dogs in the benazepril group; both dogs were treated with amoxicillin. Escherichia coli was isolated from 2 dogs in the benazepril group and 1 dog in the placebo group, Proteus spp was isolated from 1 dog in the benazepril group, Enterobacter spp was isolated from 1 dog in the benazepril group, and Klebsiella spp was isolated from 1 dog in the placebo group.
Analysis of urine samples for marker proteins revealed proteinuria in all dogs except 1 dog in the benazepril group and 1 dog in the benazepril-heparin group. Combined tubular and glomerular proteinuria was evident mainly during the first half of the study period for dogs in the benazepril-heparin group and throughout the study period for dogs in the placebo group. For both the benazepril and benazepril-heparin groups, the number of dogs with glomerular proteinuria decreased throughout the study period, while the number of dogs with tubular proteinuria remained nearly constant. Fractional excretions of sodium (reference range, < 0.7%) and potassium (reference range, < 20%) were within reference limits throughout the study period for dogs in the benazepril group, whereas for dogs in the benazepril-heparin group, fractional excretion of sodium was high and fractional excretion of potassium was within reference limits, and for dogs in the placebo group, fractional excretions of sodium and potassium were high.
Blood pressure measurements—For all 3 groups, mean systolic blood pressure was < 160 mm Hg throughout the study period (Figure 6). Mean systolic blood pressure was significantly reduced, compared with baseline values, on day 6 for dogs in the benazepril and benazepril-heparin groups and on day 90 for dogs in the placebo group. Mean diastolic blood pressure was ≤ 101 mm Hg throughout the study period in all 3 groups (Figure 7). Mean diastolic blood pressure was significantly reduced, compared with baseline values, on day 6 for dogs in the benazepril and benazepril-heparin groups.
Mean systolic blood pressure in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean systolic blood pressure in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean systolic blood pressure in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean diastolic blood pressure in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean diastolic blood pressure in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean diastolic blood pressure in dogs with CKD treated with benazepril, benazepril and heparin, or a placebo. See Figure 1 for key.
Citation: Journal of the American Veterinary Medical Association 234, 8; 10.2460/javma.234.8.1031
Mean heart rate ranged between 80 and 102 beats/min throughout the study period. Systemic arterial hypertension (ie, systolic pressure > 160 mm Hg, diastolic pressure > 100 mm Hg, or both) was identified in 12 of the 26 (46%) dogs on day 0 (8 dogs with systolic pressure > 160 mm Hg and diastolic pressure > 100 mm Hg, 2 dogs with systolic pressure > 160 mm Hg, and 2 dogs with diastolic pressure > 100 mm Hg). Two of these dogs had hypertrophic cardiomyopathy. Subretinal hemorrhage was observed in another 2 dogs with systemic hypertension, and retinal detachment occurred in 1 of the 2.
Ultrasonographic findings—Results of renal ultrasonography on day 0 were abnormal in 12 of the 26 (46%) dogs, with the most common abnormalities being small kidneys. In 4 dogs, echogenicity of the cortex was slightly reduced, although renal size was normal. All renal abnormalities were still evident at the end of the study.
Adverse effects—In the benazepril and benazepril-heparin groups, transient reduced activity was evident in 3 dogs. Mild hyperkalemia was diagnosed in 5 dogs in the benazepril-heparin group from day 3 until the end of the study.
Discussion
In the present study, health status score at the end of the study (ie, day 180) was significantly higher for dogs in the 2 treatment groups than for dogs in the placebo group. However, throughout the first half of the study, health status score for dogs in the placebo group was significantly improved, compared with baseline score. In this instance, it seems likely that additional treatment, such as transfusions, administration of antiemetic drugs, and the therapeutic diet, was the reason for the clinical improvement in these dogs.
Mean Hct was low throughout the study period for dogs in the benazepril-heparin and placebo groups and was low on days 3 and 6 for dogs in the benazepril group. Nonregenerative anemia in dogs with CKD is most often a result of reduced renal synthesis of erythropoietin.27 Dogs with advanced CKD typically have low plasma erythropoietin concentrations, whereas dogs in the early stages of the disease often have high concentrations.28 For all 3 groups in the present study, mean erythropoietin concentration was high, and this in conjunction with the slightly low mean Hct suggested that dogs generally were in an early or moderate stage of CKD with sufficient undamaged renal parenchyma to allow for increased erythropoietin production.28 Data on the direct effects of benazepril and heparin on erythropoiesis do not yet exist, and the present study did not allow us to draw any conclusions in this regard.
In accordance with our inclusion criteria, dogs in the present study had low glomerular filtration rates. Urea nitrogen and creatinine are mainly eliminated by glomerular filtration, and in the benazepril-heparin group in the present study, the significant increase in the glomerular filtration rate from day 30 on was associated with a transient significant decrease in plasma urea nitrogen and creatinine concentrations on day 30. In the benazepril group, the significant increase in glomerular filtration rate from day 30 on was associated with transient significant decreases in plasma urea nitrogen and creatinine concentrations on day 90. For dogs in both treatment groups, glomerular filtration rate was significantly increased, compared with baseline rates, on days 30, 90, and 180, but no change in glomerular filtration rate was detected for dogs in the placebo group. This suggested that benazepril administration had a positive effect on glomerular filtration rate and is in accordance with results of previous studies8,11,12,29 in which ACEIs were found to reduce glomerular capillary hypertension and decrease the release of extracellular matrix and collagen from mesangial and tubular cells, potentially decreasing glomerular and interstitial fibrosis. The increase in glomerular filtration rate in the treatment groups in the present study could also have been a result of benazepril-mediated mesangial cell relaxation.
Transient decreases in plasma creatinine and urea nitrogen concentration were identified on day 90 for dogs in the benazepril group and on day 30 for dogs in the benazepril-heparin group in the present study. In rats, heparin decreases glomerulosclerosis and glomerulofibrosis,30 but whether it has the same effects in dogs is not known. Our findings are similar to findings of a previous studyj in which cats with CKD treated with benazepril for 12 to 24 weeks had significant decreases in serum creatinine and urea nitrogen concentrations. Other studies4,7 have also suggested that ACEIs have a positive effect on measures of renal function in dogs.
In dogs with CKD, reduced excretory renal function results in retention of inorganic phosphorus, which can lead to renal secondary hyperparathyroidism.31 In the present study, mean plasma phosphorus concentration was higher than the upper reference limit in all groups at various times during the study. This suggests that renal secondary hyperparathyroidism should be taken into consideration concerning diagnostic testing and treatment of dogs with CKD.
Mean activated partial thromboplastin time was significantly prolonged on day 0 in all 3 groups in the present study, and other authors20 have also reported prolonged activated partial thromboplastin times in dogs with nephrotic syndrome or terminal chronic renal insufficiency. Specific data concerning the cause of prolonged activated partial thromboplastin times in dogs with renal disease do not yet exist, but low plasma albumin concentration is suggested to play a role.20 Subcutaneous administration of heparin in dogs in the benazepril-heparin group in the present study had a clear effect on activated partial thromboplastin times, as times were significantly longer for dogs in this group than for dogs in the other 2 groups on days 3 and 6. Similarly, mean plasma antithrombin III activity was significantly decreased on days 3 and 6, compared with baseline values, in dogs in the benazepril-heparin group, and decreases in antithrombin III activity associated with heparin administration have been reported previously.16
A previous study32 reported that administration of an ACEI may reduce the risk of atherothrombotic events through an increased fibrinolytic effect. With regard to this, it can be assumed that vasoprotective effects of benazepril may have contributed to the improvement in renal function observed in treatment groups in the present study. Additional studies should investigate whether ACEIs can minimize renal hypercoagulability.
Mean urine osmolality was low in all 3 groups in the present study throughout the study period, suggesting that there was some loss of urine concentrating ability, and fractional excretion of sodium was high for dogs in the benazepril-heparin and placebo groups, suggesting that there was some degree of tubular damage. Various authors21,33,34 have discussed the clinical importance of tubular damage in the pathology of CKD. We did not identify any effect of benazepril administration on tubular function in the present study, which agrees with the suggestion of other authors8,35 that ACEIs have positive effects exclusively in the glomeruli. Combined tubular and glomerular proteinuria was common in the present study, in accordance with findings of other studies.5,9,34 The decrease in the numbers of dogs in the benazepril and benazepril-heparin groups with glomerular proteinuria also indicates that ACEIs act mainly on the glomeruli. Our findings agree with results of other studies4,5 in which a significant reduction in severity of proteinuria was identified in dogs with idiopathic glomerulonephritis treated for 6 months with enalapril. The significant decrease in the urine protein-to-creatinine ratio in the 2 treatment groups at the end of the study period suggested that results of treatment with benazepril were similar to findings in dogs with induced chronic renal insufficiency treated with enalapril.5
Twelve of the 26 (46%) dogs in the present study had systemic arterial hypertension, which is similar to the percentage reported in a previous study.2 This high prevalence of hypertension shows the importance of measuring blood pressure in dogs with CKD and of providing hypotensive treatment in affected dogs.
Renal ultrasonographic abnormalities were detected in only 12 of the 26 (46%) dogs in the present study, suggesting that ultrasonography is not suitable for following up dogs with CKD. Four dogs in the present study had slightly reduced echogenicity of the renal cortex, which could not be explained, as increased echogenicity of the renal cortex is expected in dogs with CKD.
Benazepril administration in dogs in the present study appeared to be safe and well tolerated, with minimal adverse effects. Similarly, administration of heparin did not appear to be associated with any clinically important adverse effects, apart from its effects on antithrombin III activity. Hemorrhage did not occur in dogs treated with heparin, but regular monitoring during treatment seems to be essential.16
In conclusion, results of the present study suggested that administration of benazepril had beneficial effects in dogs with CKD but that short-term administration of heparin in conjunction with benazepril did not appear to provide any additional benefit. On the basis of our clinical experience, we recommend that normotensive patients be treated at half the initial dosage of benazepril used in the present study for 3 to 5 days. Further, we recommend that in hypertensive patients, the dosage be increased as necessary depending on blood pressure measurement. The prevalence of systemic hypertension as well as the evidence of end-organ damage (ie, cardiomyopathy and subretinal hemorrhage) in some dogs illustrates the necessity of regular blood pressure monitoring and controlling hypertension in dogs with CKD. Additional studies are needed to identify treatments that can reduce the progression of CKD.
Abbreviations
| ACEI | Angiotensin-converting enzyme inhibitor |
| CKD | Chronic kidney disease |
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