Introduction

Benazepril^a is an angiotensin converting enzyme inhibitor (ACEi), which is used in the management of several feline diseases, including on-label use for chronic kidney disease (CKD) and proteinuria in some countries.^1,2 Benazepril is an attractive choice compared to some other ACEi, such as enalapril, for patients with renal insufficiency, because elimination is primarily through bile (85%) with the rest via urine, so dosage adjustments due to decreased renal function may not be necessary.^1,2 Benazepril is typically dosed orally once daily, as the half-life of benazepril in cats is approximately 16–23 hr.² Several reports support benazepril's tolerability in cats with kidney disease and in healthy cats.^3–6 Nonetheless, some veterinarians elect not to use benazepril in feline patients based on concerns for adverse reactions, specifically a rise in serum creatinine and/or potassium levels or development of systemic hypotension.⁷

Benazepril has been shown to reduce mean systemic blood pressure (BP) by a small but significant amount in cats with renal insufficiency.^8,9 For cats with kidney disease and systemic and/or glomerular hypertension, this BP lowering effect would be therapeutic. It has been speculated that benazepril could create a deleterious systemic hypotension via inhibition of angiotension II, a potent vasoconstrictor. Therefore, a goal of this study was to report BP readings in cats receiving benazepril and consider the clinical relevance of systemic hypotension, if found.

There are no published reports of hyperkalemia attributed to administration of benazepril in cats, although several reports document this rare event in humans.^10–12 The inherent mechanism of action for an ACEi is to reduce the activity of the renin-angiotensin-aldosterone system by blocking formation of angiotensin-II. This leads to inhibition of aldosterone secretion, which could lead to potassium retention under certain circumstances, but it is unlikely that ACEi completely suppress aldosterone production.¹³ In humans, it has been found that simultaneous treatment with ACEi and the potassium-sparing diuretic spironolactone^b increases risk for development of hyperkalemia as the spironolactone dose increases.^11,13,14 There are no publications focused on serum potassium concentrations in cats being treated with benazepril and receiving concurrent spironolactone, so this paper sought to report on that subset of patients.

A study in cats with spontaneously occurring chronic renal failure found significantly lower creatinine concentrations after 12 wk of benazepril treatment.¹⁵ Nonetheless, human studies and a feline study have shown creatinine increases in some patients after initiation of therapy with an ACEi.^5,16,17 Acute, large-magnitude increases in plasma creatinine concentration could be triggered by a reduction in glomerular filtration rate (GFR), attributed either to decreased transglomerular perfusion pressure following preferential efferent arteriolar dilatation, to decreases in glomerular perfusion due to decreased systemic BP, or to both. These hemodynamic changes create potential for initial pre-renal and reversible components to creatinine increase, with potential for eventual permanent increase.⁴

The significance of an increase in serum creatinine concentration and what constitutes an appropriate clinical response have been debated. Initially, it was thought that any rise in creatinine reflects an adverse effect on the kidneys, and ACEi therapy should be stopped.¹⁶ In humans, it is now generally accepted that a creatinine increase of less than 30% from baseline values is an indication that the ACEi is exerting a pharmacological effect, likely via decreases in glomerular capillary pressure, which mediates renoprotection.^8,16,18

The aim of this retrospective study was to review the medical records of azotemic and non-azotemic cats treated with benazepril and to determine if systemic hypotension developed and whether elevations in serum creatinine and/or hyperkalemia occurred following initiation of treatment.

Materials and Methods

Study subjects were client-owned cats at a private practice (Alamo Feline Health Center; San Antonio, TX). Patients prescribed oral benazepril were identified using the hospital's computerized database search (AVIMARK Veterinary Practice Management Software; Henry Schein, Piedmont, MO). Cats were classified as either azotemic or non-azotemic. The azotemic cats were further grouped into one of three categories: chronic kidney disease (CKD), suspected chronic kidney disease (SCKD), or acute renal failure (ARF). The non-azotemic cats were prescribed benazepril for management of cardiac disease and were included as a control group of cats without detectable kidney compromise at the time of initiation of benazepril. This group has been identified as non-azotemic cardiac (NAC) cats. The focus of this paper was to determine whether adverse events occurred after initiation of therapy rather than the initiating reason for treatment.

To be diagnosed with CKD, a patient must have had an elevation in serum creatinine (defined as >2.1 mg/dL), and concurrent urine specific gravity (USG) of less than 1.035 and/or ultrasound diagnosed polycystic kidney disease.^19,20 Diagnosis of SCKD was based on creatinine >2.1 mg/dL but without concurrent USG or ultrasound available.²¹ Patients diagnosed with ARF were clinically ill with a creatinine greater than 5.5mg/dL or a patient with known renotoxin exposure and creatinine greater than 2.1 mg/dL.²² NAC patients had baseline creatinine <2.1 mg/dL. Cardiac disease in the NAC patients was identified by an echocardiogram and electrocardiogram when allowed by the owner or by physical exam identifying a cardiac murmur or arrhythmia (including gallop rhythm). All cats ate a diet the veterinarian and client agreed upon, among a variety of commercial and therapeutic foods. Analysis of diet (e.g., potassium, phosphorous, protein content) was not performed.

All patients were prescribed oral benazepril tablets at a dose determined by the attending veterinarian. Client compliance was established by appropriate refills and client-reported administration. To be included in the study, patients had at least three chemistry profiles with creatinine included, with at least two of them after initiation of benazepril therapy, and at least one longer than 1 mo after initiation of therapy. In an attempt not to censor acute adverse events that would limit follow-up, any cats with documented acute increases in serum creatinine (>30% from baseline) or hyperkalemia (≥6.0 mEq/L) within 2 mo after initiation of therapy were also included. These thresholds for creatinine change and hyperkalemia were based on previous human literature and veterinary laboratory reference ranges, respectively.¹⁶ Blood samples were analyzed by either reference laboratories using serum samples (Antech Laboratories, Irving, CA and Idexx Laboratories, Westbrook, ME) or in-house equipment using lithium heparinized samples (Abaxis Vet Scan and Abaxis Vet Scan 2; Abaxis Veterinary Diagnostics, Union City, CA).

Study cats had the following parameters recorded: serial body weight, dose of benazepril in mg/kg (using mean body weight while the cat was receiving benazepril), and BP measurements. Other factors recorded were concurrent medications with special attention to spironolactone, furosemide, nonsteroidal anti-inflammatory drugs, corticosteroids, subcutaneous fluid administration and potassium supplementation, and route. The length of follow-up (days) and outcome by study end were noted as well.

All cats had baseline creatinine concentrations recorded as part of the inclusion criteria. Subsequent creatinine concentrations were recorded in the periods of 1–30 days or 31–60 days after initiation of therapy. When multiple creatinine concentrations were present within a time category, only one value was used for data analysis, as follows: if data values consistently trended down, then the lowest value in that range was used; if data values consistently trended up, then the highest value was used; if there was no trend in data change, then the highest creatinine for that timeframe was used. The highest potassium level in any given time period was recorded.

Blood pressure was recorded at the first available time-point after initiation of therapy. Only patients receiving benazepril at a dose of 0.5 mg/kg or greater were included, in an attempt to achieve maximal BP-lowering effect.²³ BP was measured in awake cats in the veterinary clinic, with owners present, after giving the cat at least 5 min to acclimate, but before the physical exam or procedures.²⁴ Measurements were collected by the attending veterinarian and an assistant using either a Doppler unit (Vet-dop2; Vmed Technology, Mill Creek, WA) or an oscillometric unit (HDO; Vetline LLC, Babenhausen, Germany). A cuff 35–40% of the circumference of the leg or tail was used. The Doppler measurements were made with the cat in lateral recumbency with the cuff on the “up” forelimb, distal to the elbow, or the “up” hindlimb, distal to the tarsus. Doppler readings were obtained after clipping directly over the palmar metacarpal artery or plantar metatarsal artery, and applying alcohol and ultrasound transmission gel. The oscillometric measurements were made with the cat lying in sternal recumbency, with the cuff on the base of the tail over the coccygeal artery. For both methods, at least three readings were obtained, and the mean was recorded. Systolic hypotension was defined as less than 90 mmHg and diastolic hypotension as less than 55 mmHg.²⁵

Patients were not excluded from the study due to co-morbidities. The diagnosis of diabetes mellitus, hyperthyroidism, congestive heart failure, or histopathologically-diagnosed neoplasia was also recorded.

All data were manually entered into a spreadsheet (Microsoft Excel; Microsoft, Inc., Redmond, WA) and analyzed through a commercial statistical software program (SAS Statistical Software; Cary, NC). The cats were categorized into subgroups (CKD, SCKD, ARF and NAC) for comparison. The associations between treatments and developing >30% increase in creatinine were evaluated through chi-squared and Fisher exact tests. T-tests were performed to compare the differences between initial creatinine values and 1–30 and 31–60 day creatinine values. Median survival times and subgroup comparisons were determined through Kaplan-Meier estimates, and covariate analyses were performed using Cox proportional hazard model. A p value less than .05 was considered statistically significant.

Results

Benazepril was prescribed to 1,998 cats between 2001–2012. Five hundred ten of these patients met the inclusion criteria. The study population of cats comprised 254 neutered males, 249 spayed females, three intact males, and four intact females. Represented breeds were Domestic Short Hair (n = 267), Domestic Long Hair (n = 76), Domestic Medium Hair (n = 52), Persian (n = 17), Siamese (n = 16), Maine Coon (n = 14), Himalayan (n = 8), Russian Blue (n = 7), Burmese (n = 4), and three each of Birman, Oriental Shorthair, Ragdoll, Manx, and Tonkinese, and two each of Abyssinian, American Shorthair, Bengal, and Bombay, and one each of Egyptian Mau, Norwegian Forest Cat, Ocicat, Pixie Bob, Somali, and Sphynx. There was no breed recorded for 20 patients.

Sixty-five cats had CKD, 293 had SCKD, 42 had ARF, and 110 were NAC. The median age when benazepril was initially prescribed was 14 yr (range 1–23 yr). Baseline mean body weights among the subgroups were 4.35 kg (standard deviation [SD] 1.28) (CKD), 4.69 kg (SD 1.41) (SCKD), 4.31 kg (SD 1.63) (ARF), and 5.12 kg (SD 1.50) (NAC). Mean baseline creatinine concentrations among the subgroups were 3.00 mg/dL (SD 1.12) (CKD), 2.80 mg/dL (SD 0.73) (SCKD), 7.85 mg/dL (SD 3.32) (ARF), and 1.72 mg/dL (SD 2.38) (NAC). There was no statistical difference between the baseline creatinine concentration for the cats with CKD and those with SCKD.

The mean benazepril dose administered was 0.79mg/kg (SD 0.20) per os (PO) q 24 hr with a dose range from 0.32–1.72 mg/kg PO q 24 hr). There was no difference in benazepril dose among the subgroups. Cats were compared based on actual benazepril dose as well as a categorical low dose (0.25–0.75 mg/kg, n = 240) or high dose (>0.75 mg/kg, n = 270). Benazepril dose was not associated with increased or decreased creatinine levels at 1–30 days or 31–60 days. For cats that had a greater than 30% decrease in creatinine, the mean benazepril dose was 0.79 mg/kg (SD 0.18) PO q 24 hr with a dose range from 0.42–1.25 mg/kg PO q 24 hr).

Blood pressure data were available in a total of 235 cats (26 CKD, 166 SCKD, nine ARF, and 34 NAC). Blood pressure was recorded after receiving benazepril for a median of 63 days (range 6–3192 days). One hundred twenty-five cats had a systolic BP measured with a Doppler; the median systolic BP in this group was 145 mmHg. One hundred ten cats had systolic, diastolic, and mean BP measured with an oscillometric unit; the median systolic BP in this group was 162 mmHg. No cat in either group experienced systolic systemic hypotension. In the oscillometric group, with normal systolic readings, two cats treated for CKD were found with diastolic systemic hypotension. These two patients had diastolic BP readings of 46 mmHg and 49 mmHg; both received a dose of 0.70mg/kg of benazepril.

During the 1–30 day period after starting benazepril, 155 cats had serum creatinine data available. Seventeen (11.0%) cats had a 30% or greater increase in creatinine (Table 1). Of these cats, three had a creatinine concentration still within the normal range (creatinine <2.1 mg/dL). There was no statistically significant association between >30% rises in creatinine at day 30 and treatment with oral potassium (n = 7), corticosteroids (n = 2), non-steroidal anti-inflammatory (n = 2), amlodipine (n = 1), or subcutaneous fluids (n = 9). During the initial 30 days of treatment, 50 cats (32.3%) had a 30% or greater decrease in creatinine from baseline.

TABLE 1 Creatinine Changes During 1–30 Days After Starting Benazepril

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During the 31–60 day period after starting benazepril, 197 cats had serum creatinine data available. Twenty-seven (13.7%) cats had a 30% or greater increase in creatinine from baseline (Table 2). Only IV potassium administration and treatment with spironolactone were significantly associated (n = 4, OR = 3.94, p = .05; n = 4, OR = 5.00, p = .03, respectively) with >30% increase in creatinine.

TABLE 2 Creatinine Changes During 31–60 Days After Starting Benazepril

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There was a significant overall decrease in creatinine values from initial evaluation to 30 days of treatment (mean change -1.025 mg/dL, SD 2.95, -0.56, p < .0001) and 60 days of treatment (mean change -0.45 mg/dL, SD 2.58, -0.09, p < .0114). The initial creatinine level was not associated with an increase >30% at either 30 days or 60 days.

During the first 30 days after starting benazepril, mean body weights in the subgroups changed from baseline 4.35 kg (SD 1.28) to 4.43 kg (SD 1.62) in the CKD subgroup, from 4.69 kg (SD 1.41) to 4.39 kg (SD 1.42) in the SCKD subgroup, from 4.31 kg (SD 1.63) to 4.12 kg (SD 1.60) in the ARF subgroup, and from 5.12 kg (SD 1.50) to 4.55 kg (SD 1.83) in the NAC subgroup. During the 31–60 days after starting benazepril, mean body weights in the subgroups changed from baseline 4.35 kg (SD 1.28) to 4.42 kg (SD 1.29) in the CKD subgroup, from 4.69 kg (SD 1.41) to 4.58 (SD 1.49) in the SCKD subgroup, from 4.31 kg (SD 1.63) to 4.05 kg (SD 1.58) in the ARF subgroup, and from 5.12 (SD 1.50) to 4.63 kg (SD 1.54) in the NAC subgroup. The weight differences were not significant between groups in either time period.

Serum/plasma potassium levels were not always available, even when creatinine was recorded, as some chemistry panels did not include potassium. Potassium levels were available for 389 cats at baseline, 126 cats during the 1–30 day period, and 145 cats during the 31–60 day period (Table 3). During each time period, the mean potassium level was: baseline 4.34 mEq/L, 1–30 days 4.61 mEq/L, and 31–60 days 4.54 mEq/L. The highest potassium level recorded at baseline was 7.2 mEq/L (cat in ARF subgroup), during 1–30 days was 8.0 mEq/L (cat in ARF subgroup), and during 31–60 days was 6.2 mEq/L (cat in SCKD subgroup).

TABLE 3 Potassium Levels and Hyperkalemia

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Of the 10 cats (3.7%) experiencing hyperkalemia (potassium ≥6.0 mEq/L) in the first 60 days of treatment, three were taking concurrent spironolactone. The concurrent use of spironolactone was associated with hyperkalemia (p < .05); however, the highest potassium level recorded during the first 60 days of treatment for patients taking spironolactone was 6.3 mEq/L. There was no association between benazepril dose (p > .05) or spironolactone dose (p > .05) and hyperkalemia.

At the discretion of the attending veterinarian, during the first 60 days of benazepril treatment, 202 cats received oral potassium supplementation, 16 cats received IV potassium supplementation, and nine cats had potassium added to subcutaneous fluids. Potassium supplementation was prescribed because of true hypokalemia (potassium <3.7 mg/dL) or poor appetite with potassium <4.5 mg/dL. Three cats receiving IV fluids with added potassium became hyperkalemic.

Several cats in the study were afflicted by co-morbidities. Forty-one had diabetes mellitus, 73 had hyperthyroidism, 27 experienced congestive heart failure, and 54 had histopathologically-diagnosed neoplasia.

At the conclusion of the study, 113 cats were lost to follow-up, meaning they had not been in for routine re-checks in over 12 mo. Sixty-seven were still alive, 278 were euthanized, and 52 died. The overall median survival time for study patients was 796 days (Table 4). Median survival time in the subgroups was 508 days (CKD), 806 days (SCKD), 359 days (ARF), and 1175 days (NAC). A Kaplan-Meier (Figure 1) curve shows longest survival for NAC cats followed by SCKD, CKD, and ARF. Survival times were significantly different between CKD and SCKD (p < .05) and also CKD and NAC (p < .05). The long-term survival of the cats that had >30% increases in creatinine from baseline was not statistically different than those that did not experience these increases.

TABLE 4 Survival Times for Patients Receiving Benazepril

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Discussion

Benazepril was prescribed to a heterogeneous population of cats in a primary care setting, within or above published recommended dose ranges (0.25 mg/kg–1.0 mg/kg PO q 24 hr).^4,23 It was not the intent of this report to describe specific causes for azotemia or the rationale for prescribing benazepril, but simply to screen for adverse events. The International Renal Interest Society (IRIS) classification system for CKD would be ideal, but was not used here because some cats did not have the necessary data to properly classify them (i.e., hydration assessment not recorded, lacking USG, BP, or urine protein creatinine ratio). Nonetheless, the demographics and concurrent medications of patients that experienced creatinine rises or hyperkalemia were compared to patients that did not, to determine if there are risk factors for either adverse event occurring. No patients discontinued therapy because of biochemical abnormalities, which allowed uniform evaluation of their long-term survival.

Creatinine increases of >30% from baseline values were documented in a minority of patients during the first 60 days after starting benazepril. In humans, the increase in creatinine concentrations at the start of therapy of CKD with ACEi is attributed to reduced glomerular capillary pressure (leading to reduced GFR), which is assumed to mediate the long-term therapeutic benefit of ACEi in slowing the progression of renal disease.^16,18 The same may apply to cats. However, in an experimental model of renal insufficiency in cats, benazepril increased the single nephron GFR in spite of reduced systemic BP and reduced glomerular capillary pressure, since it also increased the glomerular ultrafiltration coefficient index.⁸ Controlled studies with larger numbers of cats are needed to further evaluate this result. The data from this study found that during the first 60 days of treatment, more cats had decreases in creatinine than increases (Tables 1, 2). The mean creatinine change was negative for the CKD, SCKD, and the NAC subgroups by the 31–60 day time period (Table 2). We concluded that monitoring serum creatinine is prudent in patients receiving benazepril, but increases in serum creatinine after initiation of therapy are not a reason to discontinue the drug, considering that this may reflect the therapeutic mechanism of benazepril and yield long-term renoprotective benefits.

During the 31–60 day time period, the cats in the NAC subgroup experienced an average creatinine increase of 21% from baseline. The clinical significance of creatinine increases in non-azotemic cats with cardiac disease is unclear at this time. It is possible that BP mediated effects of benazepril account for the creatinine increases, so this could be a therapeutic effect.²⁶ The NAC subgroup also had lower baseline creatinine values, so a smaller absolute change would reflect a larger percentage of baseline. Indeed, during the first 30 days of treatment, all three cats in the NAC subgroup that had >30% increases from baseline remained within the normal range for creatinine (e.g., initial creatinine of 1.3 mg/dL, and day 30 creatinine of 1.8 mg/dL). Another explanation is that cats in the NAC subgroup had some degree of renal compromise, which was undetected because creatinine is an insensitive renal parameter.²⁷

In cats with CKD and SCKD, survival times were similar to, but slightly less than, previously published data in cats with CKD.^6,28–30 Some cats in this study were known to be afflicted by co-morbidities which could be fatal and shorten survival. The survival times for cats with ARF were higher than expected. If the patient did not have follow-up bloodwork to document acute changes, it would have been excluded, even if the cat died or was euthanized. Therefore, survival times were likely increased by cases with follow-up available.

Slight changes in body weight were observed from baseline during the first 30 and 60 days of benazepril treatment, but these changes were not statistically significant. Previous literature found benazepril administration was associated with increased feed intake and body weight in healthy growing cats.³ However, some patients in this study had other documented medical conditions that may have blunted weight gain. The time frame of this study may have also limited our ability to detect meaningful body weight changes. Further controlled studies are needed to examine the relationship between benazepril and weight gain.

Hyperkalemia of any origin can create dangerous, even fatal, cardiac arrhythmias and this would be a serious safety concern as a drug-related event. No cats in this study had documented clinically relevant potassium elevations, but rises outside the reference range did occur. Three cats that became hyperkalemic in the first 30 days of therapy had been given IV potassium supplementation; this could reflect disease-induced hyperkalemia, drug-related hyperkalemia or iatrogenic hyperkalemia. If these cats are assumed to be iatrogenic hyperkalemia and excluded, the incidence of hyperkalemia within the first 60 days of benazepril therapy was low (3.2% during days 1–30 and 2.1% during days 31–60) and consistent with previous human studies.^16,17 It is possible that transient increases were not detected, especially if they resulted in sudden death. Previous work showed that potassium levels may be higher in serum samples compared to plasma samples.³¹ In this study, there were an equal number of serum and plasma samples resulting in hyperkalemia. There was no association between benazepril dose and hyperkalemia in this study.

There was a significant association between administration of spironolactone and development of hyperkalemia (n = 3), which is in contrast to the results of a previous study in dogs taking spironolactone and an ACEi, in which hyperkalemia was not found.³² In our study, feline hyperkalemic patients taking spironolactone had only mild potassium elevations (maximum recorded 6.3 mEq/L), while none had any clinically evident adverse effects from hyperkalemia. There was also an association between spironolactone treatment (n = 4) and creatinine increases of >30% from baseline within the first 30 days of benazepril treatment. This could be associated with diuretic-induced dehydration or be an adverse drug event. Cats taking both benazepril and spironolactone are a population in which creatinine and potassium levels need to be monitored more closely; however, biochemical changes are not necessarily a reason to discontinue either therapy. Further studies with larger numbers of cats are needed to clarify these findings.

The two methods of measuring BP, Doppler and oscillometric, reflected the equipment present in the practice at the time. No systolic systemic hypotension was found by either measurement technique (n = 235) as a result of benazepril administration. Only cats with oscillometric measurements had diastolic values, and two of those experienced diastolic systemic hypotension (2/111, 1.80%). These two cats did not have any clinical signs of systemic hypotension and no changes were made to treatment based on this finding. Of the 235 patients with BP data available, 31 (13.2%) were on a dose of benazepril between 1.0–1.4 mg/kg, suggesting that higher doses of benazepril are well tolerated, consistent with a previous study.⁹ It is possible that some patients experienced hypotension that was not documented. It is also possible that hypotension was masked by the “white-coat-effect” while measuring BP in the veterinary clinic. The authors believe that benazepril can be safely prescribed at therapeutic doses, and even slightly above, without inducing systemic hypotension.

This study had several limitations. Our data assumed that owners successfully gave medication. Reported compliance may have been exaggerated to avoid disappointing the veterinarian or unreliable (e.g., cats spitting out pills without the owner knowing it). Also, this study lacked a control population of animals that did not receive benazepril treatment. Therefore, extrapolations of results from this study are limited to animals receiving treatment and cannot be used to prove efficacy. The subgroups of diagnoses (CKD, SCKD, ARF, NAC) were made to try to differentiate data patterns in a heterogeneous population. However, these designations may have been inaccurate. Cats in the ARF subgroup represent severely azotemic cats and could have included cats with IRIS stage 4 CKD and those with acute renal failure. A large number of cats in the study (n = 293) were treated for SCKD, due to azotemia; they did not have supporting diagnostic data of a urine specific gravity. Many of these cats likely did have CKD, but some could also have had pre-renal components to their azotemia, so results may reflect how benazepril is tolerated in dehydrated cats. No cats had renal biopsies performed, so the true cause of renal compromise was not determined. Dietary potassium and protein levels were not known, so their effects as confounding variables could not be evaluated. The longitudinal nature of the study resulted in inconsistent follow-up intervals, as is true in any study relying on owners for compliance, so it is reasonable to speculate that some patients experienced adverse events that were not captured on bloodwork. Thus, our data would be prone to under-reporting such events. If these events occurred, the patient may have died acutely, been treated elsewhere, experienced spontaneous resolution, or returned on a sick appointment. Controlled prospective studies are needed to detect events that this study may not have found.

Conclusion

The incidence of >30% creatinine concentration increase at the start of benazepril therapy was low (11% during days 1–30 and 13.7% during days 31–60). However, given the likely long-term renoprotective effects of ACEi for CKD patients, creatinine rises may be considered tolerable, and even expected, since they indicate effective reduction in glomerular pressure. Systolic systemic hypotension was not found in this population of cats. Hyperkalemia was a rare event, and there were no clinically relevant potassium increases, even with concurrent spironolactone. Based on the results of this study, the authors believe that benazepril can be safely administered to non-azotemic cats and those with CKD, ARF, and azotemia.