Nonsteroidal anti-inflammatory drugs are widely used in veterinary medicine to control chronic pain associated with osteoarthritis. Although the quality of life for dogs with osteoarthritis can be improved with NSAIDs, the number of ADEs associated with NSAID use reported to the FDA Center for Veterinary Medicine is higher than for any other companion animal drug; gastrointestinal, renal, hematologic, and hepatic adverse reactions are most commonly reported.1 Several studies2–5 have suggested that long-term use of NSAIDs is tolerated well by dogs with osteoarthritis; however, the duration of these studies was 30 to 60 days.
Nonsteroidal anti-inflammatory drugs induce analgesic and toxic effects via inhibition of COX, which results in a decrease in the production of prostanoids. In the kidneys, prostaglandins have a role in regulation of GFR, renin release, and sodium excretion.6 Prostaglandins are synthesized by both COX-1 and COX-2 in healthy kidneys; however, when angiotensin is systemically administered to mice, there is an increase in COX-2 expression in the macula densa and thick ascending loop7 and synthesis of prostacyclin and prostaglandin E2 shifts to the COX-2 pathway. This shift may be attributable to direct effects on the kidneys or systemic effects secondary to IV administration of angiotensin. There are important species differences in the renal expression of COX-1 and COX-2. For example, rats and dogs have higher COX-2 expression in the kidneys, compared with expression in humans,6 and dogs with CKD have an increase in expression of COX-2.8 For these reasons, NSAIDs that target COX-2 may be expected to adversely affect kidney function in dogs, especially dogs with CKD.
In addition to COX-1 and COX-2, the LOX pathway is another route for arachidonic acid metabolism. The enzyme 5-LOX may have the most clinical relevance in promoting inflammation because one of its end products, leukotriene β4, attracts leukocytes via chemotaxis.9 This pathway may also influence kidney function because synthesis of the vasoconstrictor leukotriene C4 can decrease renal blood flow in rats with experimentally induced glomerulonephritis.10 Therefore, dual-inhibitor NSAIDs that can inhibit both the COX and LOX pathways may have different adverse effects on the kidneys, compared with the adverse effects for traditional NSAIDs. Tepoxalin is the first dual inhibitor approved for use in veterinary medicine.11 The carboxylic acid metabolite is a nonselective COX inhibitor, whereas the parent drug, tepoxalin, is a COX-LOX inhibitor.9 Although the half-life of tepoxalin is only 2 hours, the carboxylic acid metabolite has a half-life of 12 hours. Therefore, the COX-inhibitory effects of tepoxalin predominate during a 24-hour dosing schedule. The objective of the study reported here was to assess kidney function in dogs with IRIS stage 2 or 3 CKD and osteoarthritis that received tepoxalin.
Materials and Methods
Animals—Client-owned dogs with IRIS stage 2 or 3 CKD and osteoarthritis were enrolled in a prospective clinical trial at the Kansas State University Veterinary Medical Teaching Hospital. Patients were recruited from referring veterinarians as well as from dogs examined at the Kansas State University Veterinary Medical Teaching Hospital. The study was approved by the Kansas State University Institutional Animal Care and Use Committee, and all owners signed a consent form prior to enrollment of their dogs in the study.
Inclusion criteria—Dogs with CKD (IRIS stage 2 or 3; serum creatinine concentration, 1.6 to 3.5 mg/dL) and osteoarthritis were eligible for inclusion in the study. Osteoarthritis was suspected on the basis of history and signs of pain or crepitus during orthopedic examination that were confirmed by radiography of the affected joints. In addition, owners were asked to complete a questionnaire that detailed the mobility and activity level of their dogs. A diagnosis of CKD was made on the basis of a combination of the following: history of chronic (≥ 2 months) weight loss, polydipsia and polyuria, or persistent azotemia (serum creatinine concentration, ≥ 1.6 but ≤ 3.5 mg/dL) superimposed on isosthenuric or minimally concentrated urine. In addition, abdominal radiography and ultrasonographic evaluations and bacterial culture of urine were performed, and blood pressure was indirectly measured (Doppler).a Urine protein-to-creatinine concentration ratio, urine GGT-to-creatinine concentration ratio, and iohexolb plasma clearancec to estimate GFR were determined to further evaluate the kidneys and to rule out concurrent diseases. Short-term stable CKD was confirmed via the evaluation of serum creatinine concentration, iohexol plasma clearance, urine protein-to-creatinine concentration ratio, urine GGT-to-creatinine concentration ratio, and systolic arterial blood pressure twice before treatment (baseline evaluation; once between −14 and −7 days and again at day 0; day of first tepoxalin treatment = day 0). Evaluation of patients at 2 time points prior to the start of the treatments prevented the inclusion of dogs with acute kidney injury, acute-on-chronic kidney disease, and prerenal azotemia.
Exclusion criteria—Dogs were excluded from the study because of unstable azotemia (serum creatinine concentration or iohexol plasma clearance that varied by > 20% for the 2 pretreatment evaluations), positive results of bacterial culture of urine, evidence of obstructive uropathy, a fractious nature, or evidence of concurrent disease (eg, hyperadrenocorticism, diabetes mellitus, or neoplasia). Gastrointestinal protectants (eg, H2-receptor blockers and proton-pump blockers) were not routinely administered as part of this study; however, administration of protectants was not a reason for exclusion. If a dog with CKD was receiving gastrointestinal protectants prior to enrollment, the treatment was continued during NSAID administration.
Study protocol—Tepoxalind was orally administered (10 mg/kg/d) to each dog for 4 weeks in the acute phase. Tepoxalin prescriptions were refilled on a weekly basis, and owners were asked to bring their prescription vials to each recheck examination. To verify compliance, pills were counted and owners were questioned with regard to their ability to administer the pills. Each dog was reexamined weekly; diagnostic testing included physical examination, measurement of body weight, a CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine concentration ratio, determination of urine GGT-to-creatinine concentration ratio, and indirect measurement of systolic arterial blood pressure. Plasma clearance of iohexol was measured at weeks 2 and 4 after the start of tepoxalin treatment. Owners completed the mobility and activity questionnaire again at the end of the 4-week treatment period.
After completion of the acute phase, owners were given the option of enrolling their dogs in the chronic phase (an additional 6-month period). In the chronic phase, dogs continued to receive tepoxalin orally at a dosage of 10 mg/kg/d and were reexamined at 1, 3, and 6 months. History (owner compliance with tepoxalin administration), physical examination, measurement of body weight, a CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine concentration ratio, determination of urine GGT-to-creatinine concentration ratio, determination of iohexol plasma clearance, and indirect measurement of systolic arterial blood pressure were performed at each recheck examination during the chronic phase. Owners also completed questionnaires regarding the mobility and activity level of their dogs at the end of the chronic phase.
Statistical analysis—Data for each variable were analyzed via a repeated-measures ANOVAe that accounted for animal and repeated measures on each animal over treatment time. Treatment time was entered as a factor variable that accounted for each animal visit during the course of the study. Significance of the effect of treatment time was tested via the Box conservative correction factor to adjust for nonindependence of the repeated measurements. Results were considered significant at values of P < 0.05.
Results
Sixteen dogs were included in the acute phase of the study, and 10 of these dogs were included in the chronic phase. Dogs ranged from 4 to 15 years of age (median, 12 years). Of the 16 dogs, 12 were spayed females and 4 were males (1 sexually intact male and 3 castrated males). A wide range of purebred and mixed-breed dogs were represented. Border Collie (n = 3) and Labrador Retriever (2) were the only breeds with multiple dogs. Fourteen of 16 dogs completed the acute phase of the study, and 7 of 10 dogs completed the chronic phase of the study.
Adverse drug events that resulted in discontinuation of tepoxalin included an increase in serum creatinine concentration (1 dog; week 1), collapse (1 dog; week 1), increase in liver enzyme activities (1 dog; week 4), vomiting and diarrhea (1 dog; week 8), hematochezia (1 dog; week 24), and gastrointestinal ulceration and perforation (1 dog; week 26). None of the dogs with gastrointestinal ADEs were receiving gastrointestinal protectants. Discontinuation of the tepoxalin treatment resulted in stabilized kidney function in the dog with the increase in serum creatinine concentration and resolution of ADEs in 4 of the 5 remaining dogs (the exception was the dog with gastrointestinal ulceration and perforation).
Acute deterioration in kidney excretory function was detected in 1 dog. The baseline kidney function of the dog was 74.5% less than the mean GFR for the canine population tested at Michigan State University as determined on the basis of the mean of the 2 iohexol plasma clearance values obtained before tepoxalin treatment. Systemic hypertension had also been diagnosed in the dog prior to inclusion in the study; however, systolic arterial blood pressure (170 mm Hg) did not change as a result of tepoxalin treatment. In contrast, the serum creatinine concentration increased from 1.6 to 2.5 mg/dL within the first week of treatment, and the urine protein-to-creatinine concentration ratio increased from 0.4 to 0.6. Other serum biochemical values, urine GGT-to-creatinine concentration ratio, urine specific gravity, and urine sediment were unchanged from baseline values at the 1-week recheck examination.
One dog collapsed during the first week of tepoxalin treatment. The dog was mildly hyperkalemic (6.2 mmol/L) and moderately hypertensive (systolic arterial blood pressure, 160 mm Hg) at 1 baseline time point before treatment. On day 7 of tepoxalin treatment, the dog collapsed in the hospital during the recheck examination. Supportive care consisting of tracheal intubation and IV administration of fluids was provided. The dog made a full recovery within minutes. No change in potassium concentration or blood pressure was observed as a result of tepoxalin treatment, although the dog gained 1.1 kg during the first week of tepoxalin treatment. That dog's serum creatinine concentration also increased from 1.7 mg/dL at baseline to 2.4 mg/dL. On the day after the collapse, the dog's serum creatinine concentration returned to pretreatment values.
One dog had an increase of liver enzyme activities with hyperbilirubinemia at the end of the acute phase of the study. Baseline ALT and ALP activities were 62 and 82 U/L, respectively, and baseline total bilirubin concentration was 0.1 mg/dL. No elevation in liver enzyme activities was detected until the fourth week of tepoxalin treatment. At week 4, the ALT and ALP activities were 874 and 290 U/L, respectively, and total bilirubin concentration was 1.1 mg/dL. The dog remained otherwise clinically normal. Eleven days after tepoxalin treatment was discontinued, the ALT and ALP activities were 181 and 200 U/L, respectively, and total bilirubin concentration was 0.1 mg/dL.
Three dogs had signs of gastrointestinal tract abnormalities during the chronic phase of the study, which resulted in discontinuation of the tepoxalin treatment for those dogs. One dog had vomiting and diarrhea at week 8 (1 month after inclusion in the chronic phase of the study). Retrospectively, the referring veterinarian's records indicated that a steroid-responsive enteropathy was suspected but had not been definitively diagnosed, and the dog was being treated with prednisone. The second dog developed hematochezia at week 24. For both of these dogs, discontinuation of the tepoxalin treatment resulted in resolution of the gastrointestinal signs.
The third dog with gastrointestinal tract abnormalities had vomiting and was anorectic at week 26. Hypertension (systolic arterial blood pressure, 170 mm Hg) was detected for the first time during the second month of tepoxalin administration. At week 26, the dog was evaluated at the Kansas State University Veterinary Medical Teaching Hospital. The dog was laterally recumbent; supportive care consisting of IV administration of fluids and administration of gastrointestinal protectants and antiemetics was initiated. Melena and hematemesis were evident the following day. Segmental thickening of the greater curvature of the body of the stomach, a corrugated duodenum, hyperechoic mesentery, and free fluid in the peritoneal cavity were visible during abdominal ultrasonography. Cytologic evaluation of the fluid revealed findings consistent with septic inflammation. The owner declined laparotomy and elected that the dog be euthanatized. Gastric perforation and a right-sided pheochromocytoma were diagnosed during necropsy. Chronic kidney disease was also confirmed at necropsy; both kidneys had marked interstitial fibrosis and degeneration, necrosis, and loss of tubules. Many of the remaining tubules were dilated and contained proteinaceous eosinophilic material. There was also multifocal infiltration of the interstitium and renal pelvis by moderate numbers of lymphocytes and plasma cells. The glomerular tufts were relatively small, and there was dilatation of the Bowman space in the glomeruli.
No significant change was detected in any of the kidney function variables in the acute or chronic phase of the study in dogs that completed each phase (Table 1). Review of owner questionnaires revealed that mobility and activity scores improved or remained unchanged throughout both phases of the study (data not shown).
Mean ± SD values for renal function variables in dogs with CKD and osteoarthritis that received tepoxalin (10 mg/kg/d, PO) during acute and chronic phases.
| Variable | Baseline* | 4 weeks (n = 14) | 7 months (n = 7) |
|---|---|---|---|
| BUN (mg/dL) | 33 ± 13 | 31 ± 18 | 31 ± 8 |
| Serum creatinine (mg/dL) | 1.9 ± 0.3 | 1.8 ± 0.3 | 2.0 ± 0.4 |
| Plasma clearance of iohexol (mL/min/kg) | 1.14 ± 0.35 | 1.06 ± 0.24 | 1.01 ± 0.19 |
| Urine protein-to-creatinine ratio | 0.87 ± 1.3 | 0.80 ± 1.3 | 1.11 ± 1.5 |
| Urine GGT-to-creatinine ratio | 0.30 ± 0.21 | 0.24 ± 0.12 | 0.17 ± 0.06 |
| Systolic arterial blood pressure (mm Hg) | 148 ± 16 | 156 ± 16 | 154 ± 19 |
| Sodium (mmol/L) | 149 ± 2.3 | 148 ± 2.2 | 148 ± 1.0 |
| Potassium (mmol/L) | 4.9 ± 0.5 | 5.0 ± 0.4 | 4.7 ± 0.3 |
Represents the mean of 2 measurements obtained before treatment with tepoxalin.
Discussion
Nonsteroidal anti-inflammatory drugs are widely used to treat osteoarthritis, but there have been few long-term studies of their safety. Adverse drug events observed in the present study included an increase in serum creatinine concentration (n = 1), increase in liver enzyme activities (1), collapse (1), and gastrointestinal problems (3). Although specific retrospective data on ADEs attributable to NSAIDs in dogs are scant, NSAID-related ADEs typically occur within the first 14 to 30 days of treatment (range, 3 to 90 days).1 Dogs 10 to 15 years old are most likely to be affected, followed by dogs 6 to 10 years old.1 In the present study, ADEs were detected from days 7 to 182 of treatment with tepoxalin. Four of 5 dogs for which tepoxalin was discontinued because of ADEs were 10 to 15 years old, and the fifth dog was 8 years old.
In addition to the paucity of long-term studies conducted to assess NSAID-associated ADEs, the authors are not aware of any studies conducted to assess the effects of NSAIDs on kidney function in dogs with naturally occurring CKD. In previous studies,12,13 investigators assessed the effects of coxibs on kidney function in older cats with degenerative joint disease (some of the cats had naturally occurring CKD) and cats with surgically induced remnant kidneys. No evidence of ADEs on kidney function was detected in older cats with CKD and degenerative joint disease that received meloxicam at a low dosage (0.02 mg/kg/d) for 6 months.12 Administration of meloxicam or acetylsalicylic acid did not decrease GFR in cats with surgically reduced kidney mass with the equivalent of IRIS stage 2 or 3 CKD,13 which prompted the investigators of that study to conclude that the cats were not dependent on COX-derived prostanoids for maintenance of kidney function.
Dehydration is a common complication of CKD that can predispose a patient to the nephrotoxic effects of NSAIDs. When an animal is dehydrated, the autoregulatory vasodilatory mechanisms that involve increased production of prostaglandins, which would typically protect the kidneys from transient decreases in renal blood flow, can make the kidneys more susceptible to the effects of NSAIDs.14 In 2 recent studies,15,16 investigators evaluated the effects of ibuprofen, carprofen, and etodolac on the kidneys of euvolemic and volume-depleted dogs. In both studies,15,16 no change was detected in GFR of euvolemic healthy Beagles receiving an NSAID alone, but coadministration of an NSAID and furosemide caused a significant increase in serum creatinine concentration and decrease in GFR, which was reversible when NSAID treatment was discontinued. There was no advantage for any particular NSAID with regard to the effects on kidney hemodynamics, which suggested that both nonselective and selective COX inhibitors can cause excretory impairment in the kidneys of volume-contracted dogs.
In the present study, tepoxalin treatment was discontinued in 1 dog at 1 week because of an increase in the serum creatinine concentration. That dog was receiving both enalapril and amlodipine for hypertension at the time of inclusion in the study. The effect of an angiotensin-converting enzyme inhibitor and a calcium-channel blocker administered concurrently with tepoxalin may have caused a decrease in renal perfusion. No change in GFR or renal blood flow was observed in healthy Beagles treated with enalapril and tepoxalin,17 but to our knowledge, concurrent use of these medications has not been evaluated in dogs with CKD. In the present study, the dog with the increase in serum creatinine concentration progressed from IRIS stage 2 CKD to IRIS stage 3 CKD during the first week of tepoxalin treatment. Repeated injections of iohexol in dogs can be associated with a mild form of contrast-induced nephrotoxicosis.18 It is possible that the 2 baseline iohexol injections in this dog contributed to the increase in serum creatinine concentration at the end of week 1, although we did not observe this adverse effect in any of the other dogs in the study. Another possibility is that CKD was not stable in this dog. Although the inclusion criteria were established to exclude dogs with prerenal azotemia and acute kidney injury, a 2-week pretreatment period was not a sufficient amount of time to determine long-term CKD stability. After tepoxalin treatment was discontinued, this dog remained in IRIS stage 3 CKD for 2 months before progressing to IRIS stage 4 CKD. Seven months later (9 months after discontinuation of tepoxalin and removal from the study), this dog was euthanatized because of progressive CKD. Two events that may have contributed to progressive renal dysfunction in this dog were persistent systemic hypertension and inadvertent ingestion of raisin bread 3 months after the dog was removed from the study; ingestion of the raisin bread was temporally associated with an increase in the serum creatinine concentration. Hypertension has been associated with progression of CKD.19 Half of the dogs in the present study were moderately hypertensive (systolic arterial blood pressure ≥ 160 mm Hg, as determined on the basis of the mean of 2 pretreatment measurements), and 4 of 5 dogs that were removed from the study because of ADEs had moderate hypertension.
Proteinuria has also been associated with the progression of CKD20; however, only 5 of 16 dogs in the present study were proteinuric (urine protein-to-creatinine concentration ratio ≥ 0.5). Two of the 5 dogs that were removed from the study because of ADEs were proteinuric, although one of the dogs also had concurrent hypertension.
Another ADE was evident in 1 dog that had an increase in liver enzyme activities and hyperbilirubinemia at the end of the fourth week of the acute phase of the study. Hepatocellular toxicosis has been reported as an idiosyncratic reaction secondary to carprofen administration,21 and hepatotoxicosis has been reportedly associated with administration of all veterinary-approved NSAIDs.1 Although further diagnostic testing to confirm hepatic necrosis was not performed, liver enzyme activities decreased substantially within 11 days after discontinuation of tepoxalin administration to this dog, which suggested that there had been a reversible NSAID-related idiosyncratic reaction.
Collapse has been reported to the FDA Center for Veterinary Medicine as an ADE after administration of tepoxalin.22 The owner of the dog that collapsed in the present study mentioned that there was intermittent trembling of the dog's hind limbs prior to the start of tepoxalin administration. This dog also gained 1.1 kg during treatment with tepoxalin, which could have been associated with fluid retention or subclinical edema. Inhibition of COX-2 by NSAIDs can result in impaired natriuresis and sodium retention in humans.14 In another study,23 antinatriuresis was more severe in dogs than in monkeys despite a lower plasma concentration of naproxen in the dogs, which suggested that dogs have a higher reliance on COX-2-mediated prostanoids for sodium excretion. In the dog of the study reported here, there were no additional adverse events after discontinuation of the tepoxalin treatment, and the dog's body weight returned to the pretreatment value.
A multicenter field study24 included 107 dogs that received 20 mg of tepoxalin/kg/d on day 1 followed by 10 mg of tepoxalin/kg/d for 27 days. Adverse effects involving the gastrointestinal tract, including diarrhea (n = 23), vomiting (21; both vomiting and diarrhea were evident in 8 dogs and therefore the total for vomiting or diarrhea [or both] was 36), loss of appetite (9), and enteritis (4), were observed in 49 (46%) dogs of the study population.24 Although ADEs involving the gastrointestinal tract were not detected in any dog during the acute phase of the present study, 3 of 10 dogs developed ADEs involving the gastrointestinal tract (vomiting and diarrhea, hematochezia, or gastrointestinal ulceration or perforation) during the chronic phase of the study. The referring veterinarian suspected that one of these 3 dogs had an enteropathy, and that dog had been treated with prednisone. A pheochromocytoma was diagnosed during necropsy in the dog with gastrointestinal ulceration and perforation. It is possible that both of these underlying conditions as well as the prednisone treatment could have contributed to the gastrointestinal tract abnormalities. It is also possible that routine use of gastrointestinal protectants in the dogs with CKD that received tepoxalin would have decreased the number of gastrointestinal ADEs observed in the present study.
Limitations of the present study included a small sample size. In addition, because all of the dogs were client-owned animals and remained under their owner's care at home, we could not confirm that the correct dose of tepoxalin was administered daily. Plasma concentrations of tepoxalin and its metabolites were not measured in this study. Although a medical history was part of each recheck examination, it is possible that other medications were concurrently administered that were not mentioned by the owners. Specifically, prednisone and tepoxalin were apparently administered concurrently to 1 dog, which may have been responsible, at least in part, for the observed adverse gastrointestinal effects. Finally, the cause of the underlying CKD was unknown, so differing rates of progression would be expected for each dog.
To our knowledge, the present study is the first in which kidney function was assessed in dogs with CKD that received NSAIDs. Results for kidney function variables were unchanged, compared with baseline values, after the acute (4 weeks) and chronic (an additional 6 months) phases of tepoxalin treatment. Analysis of the results of this study suggests that with appropriate monitoring, tepoxalin may be used for the treatment of osteoarthritis pain in dogs with IRIS stage 2 or 3 CKD. Use of gastrointestinal protectants should be considered in dogs with CKD that are receiving tepoxalin. Additional caution is warranted in dogs that are hypertensive or concurrently receiving medications such as angiotensin-converting enzyme inhibitors.
ABBREVIATIONS
| ADE | Adverse drug event |
| ALP | Alkaline phosphatase |
| ALT | Alanine transaminase |
| CKD | Chronic kidney disease |
| COX | Cyclooxygenase |
| GFR | Glomerular filtration rate |
| GGT | γ-Glutamyl transpeptidase |
| IRIS | International Renal Interest Society |
| LOX | Lipoxygenase |
Doppler ultrasonic flow detector, Parks Medical Electronics Inc, Aloha, Ore.
Omnipaque, GE Healthcare Inc, Princeton, NJ.
Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Mich.
Zubrin, Schering Corp, Kenilworth, NJ.
STATA, version 11, STATA Corp LP, College Station, Tex.
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