Renal Effects Of Nsaid

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20TH ANNIVERSARY

Vol. 21, No. 10 October 1999

Refereed Peer Review

FOCAL POINT ★ Inhibition of renal prostaglandins by NSAIDs may cause acute renal failure (ARF) that usually is reversible with appropriate treatment.

KEY FACTS ■ Renal prostaglandins are necessary for maintenance of renal blood flow; tubular excretion of sodium and water; and release of renin, which indirectly is needed for renal excretion of potassium. ■ NSAIDs may cause ARF in patients with renal disease or conditions characterized by decreased renal perfusion. ■ Appropriate treatment for NSAID-induced ARF includes administration of intravenous fluids and H2 receptor antagonists. ■ Administration of drugs to stimulate diuresis is generally unnecessary in patients with NSAID-induced ARF. ■ A thorough history and physical examination should be performed before initiating NSAIDs and 1 to 2 weeks after to detect evidence of renal disease or conditions that might predispose to NSAIDinduced ARF.

Renal Effects of Nonsteroidal Antiinflammatory Drugs Virginia Tech

S. Dru Forrester, DVM, MS Gregory C. Troy, DVM, MS ABSTRACT: Nonsteroidal antiinflammatory drugs exert their beneficial effects by inhibiting cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin E2 and prostacyclin. These products of arachidonic acid metabolism play an important role in maintaining renal blood flow in patients with decreased renal perfusion. Although uncommon, administration of NSAIDs to high-risk patients can inhibit production of vasodilatory prostaglandins and cause acute renal failure. Therefore renal function should be monitored before and during NSAID administration.

N

onsteroidal antiinflammatory drugs are used in veterinary patients for their analgesic, antiinflammatory, and antineoplastic effects.1–4 The most common complications of NSAID use in dogs are gastrointestinal (GI) ulceration and hemorrhage.5–8 Hepatotoxicosis has also occurred in dogs receiving NSAIDs.5,9 Renal side effects are less common and most often occur in dogs that have renal disease or a concurrent disorder that causes renal hypoperfusion.9–17 This article discusses production of prostaglandins (PGs), their role in renal function, and mechanisms by which NSAID-associated PG inhibition causes renal dysfunction. Reported cases of dogs that developed renal dysfunction associated with NSAID use are summarized, and two additional cases are presented. Therapeutic guidelines for managing dogs with acute renal failure (ARF) associated with NSAID use are provided. Finally, prognostic information and measures for preventing ARF in dogs receiving NSAIDs are discussed.

PROSTAGLANDIN PRODUCTION Prostaglandins are derived from metabolism of arachidonic acid (AA), a polyunsaturated fatty acid contained in cellular membrane phospholipids (Figure 1).18,19 A variety of stimuli (e.g., endotoxins, hypoxia, vasopressin, angiotensin, norepinephrine) activate cellular phospholipases, resulting in AA re-

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lease. Cyclooxygenase (COX) THERAPEUTIC acts on AA to form PGG2 EFFECTS OF NSAIDs Cell Membrane and then PGH2, the latter of The beneficial effects of which is subsequently conNSAIDs result from their verted to PGE2, PGF2α, prosability to inhibit COX, the Phospholipase tacyclin (PGI2), and thromenzyme that facilitates proboxane (TXA 2). 15,18–21 The duction of inflammatory products of AA metabolism mediators (e.g., PGs, TXA2) are produced at or near their Arachidonic Acid from AA (Figure 1).29 The site of action and have little two forms or isoenzymes of systemic effect. In the renal COX are COX-1 and COX-2. cortex, PGI2, the predomiCOX-1 appears to exist natCyclooxygenase nant prostaglandin, is prourally in the body and is acduced in glomeruli, arteritive in autoregulatory funcoles, and cortical collecting tions (e.g., maintenance of PGG → PGH 2 2 tubules.22,23 PGE2, the prirenal blood flow), whereas mary renal medullary prosCOX-2 is responsible for taglandin, is produced in production of inflammatory collecting tubules and intermediators. 30,31 It has been PGF2α PGI2 PGE2 TXA2 stitial cells.22,23 suggested that inhibition of Renal PGs play an imporCOX-2 decreases inflammatant role in several physio- Figure 1—All cell membranes contain arachidonic acid (AA), tion whereas inhibition of logic processes in the kid- a polyunsaturated fatty acid that serves as the precursor for COX-1 appears to be reneys.23–27 Under conditions prostaglandin (PG) production. A variety of stimuli cause re- sponsible for side effects asof decreased renal perfusion lease of AA, a process facilitated by the enzyme phospholi- sociated with NSAID use, (e.g., volume or salt deple- pase. Cyclooxygenase then acts on AA to produce intermedi- such as GI ulceration and reate prostaglandins (PGG2, PGH2), which subsequently are 31 tion), PGE2 and PGI2 cause metabolized to form prostacyclin (PGI2), PGE2, PGF2α, and nal dysfunction. afferent arteriolar dilation, thromboxane (TXA ). These AA metabolites Many NSAIDs (e.g., asparticipate in 2 which maintains renal blood the inflammatory response by causing vasodilation, increased pirin, piroxicam) preferenflow and counteracts the ef- vascular permeability, and neutrophilic chemotaxis. In addi- tially inhibit COX-1, which fects of systemic vasoconstric- tion, they are involved in several important physiologic pro- may increase the likelihood tors (e.g., angiotensin, nor- cesses in the kidneys. of GI and renal side efepinephrine, vasopressin).25–27 fects.32 In contrast, NSAIDs It has been suggested that that inhibit COX-1 and these vasodilatory PGs may help maintain renal blood COX-2 equally (e.g., carprofen) or that preferentially flow and glomerular filtration in surviving nephrons of inhibit COX-2 (e.g., etodolac, meloxicam) may be less patients with chronic renal disease.27 likely to cause side effects. 31–33 Thus carprofen and In addition to their effects on renal vascular tone, reetodolac may be relatively safer NSAIDs that are less nal PGs, particularly PGI2, are necessary for the release likely to adversely affect renal function. However, renal of renin from the kidney23,27; renal PGs increase intrafailure has been observed in dogs receiving carprofen.9 cellular cyclic adenosine monophosphate (cAMP) in It is therefore likely that factors other than COX selecjuxtaglomerular cells, which in turn stimulates renin tivity are involved in determining whether an NSAID synthesis and secretion. Renin stimulates the release of causes renal dysfunction. aldosterone, which is necessary for renal tubular secreIt is possible that COX-2 plays an important role in tion of potassium. PGs are therefore indirectly involved maintaining renal blood flow in volume-depleted in maintaining potassium homeostasis.23 dogs.26 Expression of COX-2 occurs at low levels in Finally, renal medullary PGs are necessary for renal normal dogs but is greatly increased in salt-depleted tubular excretion of sodium and water.25,27 Natriuresis dogs.26 Thus administration of NSAIDs that preferenoccurs because renal PGs increase renal blood flow; intially inhibit COX-2 may not spare patients from rehibit sodium transport from the thick ascending limb of nal side effects. Additional studies evaluating the efthe loop of Henle into the medullary interstitium; and fects of newer NSAIDs on renal function in dogs, antagonize the action of vasopressin on collecting ducts, especially those with subclinical renal disease, would which decreases their permeability to water.21,22,27,28 be helpful. VASODILATORY PGS ■ RENIN ■ NATRIURESIS ■ COX-1 ■ COX-2

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supportive treatment for 6 EFFECTS OF NSAIDs ON RENAL FUNCTION NSAIDs Associated with days. An experimental study Renal effects of NSAIDs primarily result from deAcute Renal Failure confirmed that ARF occreased synthesis of renal PGs. The most common rein Dogs9,10,12–14,16 curred in dogs receiving flunal side effect of NSAIDs, ARF, is most likely to occur nixin during methoxyfluin patients that are volume depleted or have preexisting ■ Aspirin rane anesthesia but not renal disease.15,20–23,27,28 In both conditions, renal va■ Carprofen during anesthesia with sodilatory PGs are believed to be important for main14 27 ■ Flunixin meglumine halothane. On the other taining renal blood flow. Administration of NSAIDs hand, ARF was reported in to these patients is associated with afferent arteriolar ■ Ibuprofen two healthy dogs undergoconstriction, which subsequently leads to decreased re■ Naproxen ing ovariohysterectomy that nal blood flow and ARF.27 ■ Phenylbutazone received flunixin while anesOther renal side effects of NSAIDs (i.e., hyperthetized with halothane. 12 kalemia, hypernatremia, edema, hyponatremia) may Both dogs recovered from ARF, but one died of neurooccur but often are not as obvious. Hyperkalemia may logic disease shortly afterward. ARF was recently reoccur in patients that receive NSAIDs because PGs are ported in two dogs receiving carprofen (2.2 mg/kg involved in synthesis and secretion of renin. Inhibition twice daily); both dogs also had hepatic failure. 9 of renal PGs by NSAIDs also interferes with the kidNecropsy and histologic evaluation revealed GI ulceraneys’ ability to excrete sodium, resulting in sodium retion, jejunal perforation, renal tubular necrosis, and tention and hypernatremia.21,24,27 Because renal PGs are glomerulonephritis in one of these dogs.9 necessary for renal excretion of water, administration of Although there have been reports of ARF associated NSAIDs may decrease free water clearance; patients with NSAID use in dogs, the overall occurrence is low. that receive NSAIDs are therefore predisposed to develIn a retrospective study of 29 dogs with nosocomial oping edema. If water retention occurs in excess of ARF, only 1 dog had a history of NSAID use.34 In ansodium retention, hyponatremia may occur.21,27 other study, only 2 of 99 dogs with ARF had received The most clinically important renal complication asan NSAID.17 Based on all reported cases, most dogs sociated with administration of NSAIDs to dogs is that develop ARF with NSAID treatment either ingest ARF (see NSAIDs Associated with Acute Renal Failure an excessive quantity of the drug or have a concomitant in Dogs).9,10,12–14,16,17,34 In 1967, renal failure and severe disorder that makes them more susceptible to ARF (see hemorrhage were reported in a dog that had received Potential Risk Factors for Developing NSAID-Associatphenylbutazone for 5 weeks.10 In a more recent report, ed Renal Dysfunction). The following cases illustrate a 10-month-old Labrador retriever developed GI hemthe characteristic findings in dogs that develop ARF aforrhage and ARF after ingesting 6000 mg of ibuprofen. ter administration of NSAIDs. The dog recovered after supportive care was provided but continued to have polyuria and polydipsia 2 CASE EXAMPLES months later; in addition, the Case 1 glomerular filtration rate was Potential Risk Factors for Developing A 6-year-old intact male Dosignificantly decreased.16 A 9NSAID-Associated Renal Dysfunction berman pinscher was presented year-old Samoyed developed GI with a 1-day history of letharhemorrhage, severe anemia, ■ Dehydration gy, inappetence, and diarrhea and ARF after it was given ■ Concomitant drugs (e.g., other NSAIDs, characterized by melena. The naproxen that had been preowner reported that the dog scribed for the owner; the dog corticosteroids, diuretics) consumed two aspirin tablets recovered after 5 days of sup■ Third-space disease (e.g., ascites) (presumably 325 mg each) that portive treatment. ■ Hepatic failure had been placed in another Five dogs used in a student ■ Congestive heart failure dog’s food the previous day. laboratory developed ARF after ■ Hypotension Physical examination revealed receiving a single intravenous ■ Old age an alert dog in good body con(IV) dose of flunixin megludition (weight, 36 kg) with dry mine (1 mg/kg) and the neuro■ Renal disease and pink mucous membranes; muscular blocker gallamine ■ Sepsis prolonged capillary refill time during inhalation anesthesia ■ Inhalation anesthesia (more than 2 seconds); and with methoxyflurane.14 Four of dark, tarry feces on rectal exthe dogs survived following AFFERENT ARTERIOLAR CONSTRICTION ■ ACUTE RENAL FAILURE ■ INHALATION ANESTHESIA

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TABLE I Results of Serial Serum Chemistries in a Dog (Case 1) with Aspirin-Associated Acute Renal Failure Day Parameter Urea nitrogen (mg/dl) Creatinine (mg/dl) Potassium (mmol/L) Phosphorus (mg/dl)

0

1

2

3

4

5

Reference Range

73 6.3 3.9 7.7

89 6.4 4 7.1

50 3.3 3.6 4.1

20 1.8 3.32 3.1

10 1.3 3.63 3.3

7 1.2 4.4 3.3

6–28 0.8–1.9 3.3–4.6 1.3–5

amination. Abnormal findings on initial diagnostic evaluation (i.e., complete blood count, serum chemistries, urinalysis, and fecal flotation) included azotemia (blood urea nitrogen [BUN] = 73 mg/dl; reference range [RR], 6 to 28; creatinine = 6.3 mg/dl; RR, 0.8 to 1.9), hyperphosphatemia (7.7 mg/dl; RR, 1.3 to 5), mildly increased anion gap (18; RR 8 to 15), isosthenuria (specific gravity = 1.011), and 2+ proteinuria with normal urine sediment examination. History, physical examination findings, and results of laboratory evaluation were consistent with ARF. Because of the history of aspirin ingestion, NSAID-induced ARF was considered a possibility. The dog was placed in the intensive care unit for treatment and periodic monitoring. Blood was collected for baseline measurement of selected serum chemistries (Table I). Lactated Ringer’s solution (200 ml/hour IV) was administered to correct dehydration, replace ongoing losses due to diarrhea, and provide maintenance fluid requirements during the first 24 hours. Cimetidine (5 mg/kg orally three times daily) was administered throughout hospitalization to help decrease signs of GI ulceration. The dog was monitored for the occurrence of vomiting and diarrhea, changes in hydration status and body weight, and subjective estimation of urine volume. Vomiting was not observed, body weight remained stable after correction of dehydration, and urine output was judged to be normal to increased. On day 3, the dog began drinking water and eating small amounts of canned food. Azotemia resolved, and the rate of fluid administration was gradually decreased. Potassium chloride (28 mEq/L of fluids) was added to IV fluids to prevent further lowering of serum potassium (Table I). The dog continued to improve, and IV fluids were discontinued on day 5. The dog was discharged from the hospital on day 6, and the owners were instructed to continue cimetidine for 14 days. Results of serum chemistries 2 weeks after discharge revealed normal BUN (16 mg/dl) and creatinine (1 mg/dl) and a urine specific gravity of 1.030.

This case was unusual because there was no obvious predisposing condition for the development of ARF and because the dog ingested a low dose of aspirin (18 mg/kg) that was within the recommended dosage range. It would not be appropriate to conclude that aspirin caused ARF, only that aspirin ingestion was associated with ARF in this dog. It is possible this dog had subclinical renal disease that was exacerbated by concomitant dehydration (due to vomiting and diarrhea) and NSAID administration. This dog’s response to supportive treatment is typical—ARF associated with NSAIDs is usually reversible with appropriate care.

Case 2 A 15-year-old, 7.5-kg spayed female Finnish spitz was presented to the primary care veterinarian for evaluation of inappetence, listlessness, decreased urine production, and reluctance to move. Thoracolumbar pain was present on physical examination, and a tentative diagnosis of intervertebral disk disease was made. Treatment included IV dexamethasone sodium phosphate (2 mg/kg once), oral prednisone (0.7 mg twice daily for 7 days), and oral carprofen (1.7 mg twice daily for 10 days). Five days later, the dog was presented as an emergency for evaluation of weakness, lethargy, and decreased urine volume. Laboratory results revealed increased BUN (121.5 mg/dl), normal serum creatinine (1.65 mg/dl), mild hypocalcemia (7.19 mg/dl) that corrected to normal, low-normal total protein (5.24 g/dl), increased alkaline phosphatase (1358 IU/L), and anemia (29%). Treatment included IV administration of lactated Ringer’s solution with 5% dextrose, calcium gluconate (53 mg/kg slow IV), and cefazolin (27 mg/kg IV). After 12 hours of treatment, the dog appeared to be oliguric and two doses of furosemide (3 mg/kg IV) were administered 3 hours apart. The dog was referred to the Veterinary Teaching Hospital at Virginia Tech for continued evaluation. Abnormalities on physical examination included depression, tachypnea (72 breaths/minute), melena, and mild dehydration. Initial laboratory evaluation revealed non-

SERUM CHEMISTRIES ■ LABORATORY FINDINGS ■ CIMETIDINE ■ FUROSEMIDE

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TABLE II Results of Serial Serum Chemistries in a Dog (Case 2) with Gastrointestinal Hemorrhage and Acute Renal Failure Associated with Administration of Dexamethasone, Prednisone, Carprofen, and Furosemide Day Parameter

1

2

3

4

5

8

10

Reference Range

Urea nitrogen (mg/dl) Creatinine (mg/dl) Potassium (mmol/L) Phosphorus (mg/dl)

184 4.6 6.31 12.8

127 3.2 3.86 12.4

115 3.4 2.63 10.8

69 2.8 3.44 5.9

39 2.4 3.98 5

33 2.2 4.2 6.2

19 1.8 4.89 6.3

6–28 0.8–1.9 3.3–4.6 1.3–5

regenerative anemia (hematocrit = 26.3%; RR, 37 to 62; reticulocytes = 0.9%), leukocytosis (28,200/µl; RR, 5400 to 16,600) characterized by mature neutrophilia (23,688/µl; RR, 3200 to 10,700) and a mild left shift (846 bands/µl; RR, 0 to 200), panhypoproteinemia (total protein = 4.6 g/dl; RR, 5.3 to 7.4; albumin = 2.3 g/dl; RR, 2.8 to 3.6), azotemia (BUN = 184 mg/dl; RR, 6 to 28; creatinine = 4.6 mg/dl; RR, 0.8 to 1.9), increased alkaline phosphatase (449 IU/L; RR, 20 to 167), hyponatremia (135 mmol/L; RR, 140 to 152), hyperkalemia (6.31 mmol/L; RR, 3.3 to 4.6), hypochloremia (102 mmol/L; RR, 109 to 120), mildly decreased total carbon dioxide (16.3 mmol/L; RR, 17.4 to 27.9), increased anion gap (23; RR, 8 to 15), mild hypocalcemia (corrected calcium = 8.97 mg/dl; RR, 9.7 to 11.1), hyperphosphatemia (12.8 mg/dl; RR, 1.3 to 5), hyperglycemia (340 mg/dl; RR, 87 to 127), minimally concentrated urine (specific gravity = 1.017), mild glucosuria, and 2+ proteinuria with normal urine sediment. Urine culture was negative for bacterial growth. Both kidneys were small on abdominal ultrasonography but appeared to have normal architecture. On the basis of initial findings, tentative diagnoses of GI ulceration and ARF were made and the dog was placed in the intensive care unit for treatment and monitoring. A jugular catheter was placed, and 0.9% saline was begun at 90 ml/hour to correct dehydration and provide maintenance needs. Because of the history of decreased urination and concern about the presence of oliguria, an indwelling urinary catheter was placed. Body weight and urine volume were measured every 4 hours so that fluid administration could be adjusted to maintain adequate hydration. Oral sucralfate (0.5 g twice daily) was begun to treat GI ulceration. On day 2 of hospitalization, the dog vomited twice; sucralfate was discontinued and treatment with cimetidine (5 mg/kg IV three times daily) was initiated. Fluids were changed to 0.45% saline and 2.5% dextrose with 10 mEq of potassium chloride added per liter of fluids. The rate of fluid administration varied from 10

to 15 ml/hour depending on urine volume and body weight. Similar treatment and monitoring were continued for the next 9 days (Table II). The dog began to drink water on day 3 and eat small amounts of canned food on day 5. The urinary catheter was removed on day 7; urine was submitted for bacterial culture, which revealed growth of more than 10,000 Escherichia coli/ ml of urine. Intravenous fluids and cimetidine were discontinued on day 10 because the dog was eating, drinking, and able to maintain hydration and body weight. The dog was discharged from the hospital with owner instructions to administer oral amoxicillin–clavulanate (33 mg/kg three times daily for 14 days) for the urinary tract infection. One week after discharge, urine culture results were negative and laboratory evaluation showed mild azotemia (BUN = 31 mg/dl; serum creatinine = 2.2 mg/dl) and isosthenuria (urine specific gravity = 1.012). Three months after discharge, BUN was normal and serum creatinine was slightly increased (1.86 mg/dl) at the referring veterinarian’s office. The dog was still doing well at the time this article was written, 7 months after recovering from ARF. This case is more typical of dogs that develop NSAID-associated ARF. It is likely that the excessive dose of dexamethasone combined with concurrent use of prednisone and carprofen caused GI ulceration in this dog. Initial laboratory evaluation by the referring veterinarian was consistent with GI hemorrhage but not ARF because BUN was markedly increased and serum creatinine was normal. Administration of furosemide in addition to treatment with carprofen in a dog that was probably dehydrated may have contributed to worsening of renal function. Based on the age of the dog and the presence of small kidneys, we suspect chronic renal disease was present and that a combination of factors (i.e., dehydration and hypovolemia due to GI ulceration and hemorrhage, treatment with furosemide and carprofen) caused ARF. The dog responded well to supportive care and renal failure was

OLIGURIA ■ FLUID ADMINISTRATION ■ NSAID-ASSOCIATED ARF ■ GI ULCERATION

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reversible, which is expected in most dogs with NSAIDinduced ARF.

DIAGNOSIS A tentative diagnosis of NSAID-associated ARF is usually made on the basis of history, physical examination findings, and results of laboratory evaluation. Most dogs have an acute (less than 7 days) onset of clinical signs. Inappetence, vomiting, diarrhea, and melena are common and may result from GI ulceration or ARF. Signs of GI ulceration are common and often precede ARF. Because of the acute onset, most patients are in good body condition. Physical examination findings may include pale mucous membranes, evidence of dehydration, and melena on rectal examination. Renal failure is confirmed by finding azotemia and decreased urine specific gravity (below 1.030). Other laboratory abnormalities may include anemia, hyperphosphatemia, increased anion gap, increased total carbon dioxide, hyponatremia, and hyperkalemia. Once ARF is confirmed, a thorough search for an underlying cause, including asking owners about potential exposure to such nephrotoxic substances as NSAIDs (see NSAIDs Associated with Acute Renal Failure in Dogs), should be conducted. TREATMENT There is no specific treatment for NSAID-induced renal dysfunction; in general, supportive care is indicated.11 The NSAID should be discontinued, and other drugs that are potentially nephrotoxic should not be used. Diuretics (e.g., furosemide) should be avoided because they may cause dehydration and subsequent renal hypoperfusion. To avoid additional renal injury secondary to decreased renal perfusion, hydration deficits should be corrected within 4 to 6 hours unless contraindicated (e.g., in patients with congestive heart failure).35 If there is a history of vomiting or diarrhea, it is probably best to assume subclinical dehydration (i.e., less than 5%) and replace the deficit. An appropriate volume of fluids for maintenance (66 ml/kg/day) and replacement of ongoing losses (e.g., vomiting or diarrhea) should be given in addition to fluids needed for rehydration. Lactated Ringer’s solution or 0.9% sodium chloride is usually appropriate for correcting dehydration in most dogs. In our experience, most dogs with NSAID-induced ARF are not oliguric after rehydration and employing methods to stimulate diuresis (e.g., administration of furosemide, dextrose, mannitol, dopamine) are unnecessary. Excessive fluid administration (i.e., two to three times maintenance requirements) or osmotic diuresis may cause volume overload because NSAIDs interfere

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with renal excretion of sodium and water.11,20,21,24,27 If it is unclear whether oliguria (urine production of less than 1 ml kg/hour) exists after rehydration, an indwelling urinary catheter can be placed and connected to a closed drainage system to accurately quantitate urine volume. When the patient has been rehydrated and oliguria does not exist, the volume of fluid to administer equals urine volume plus insensible losses (20 ml/kg/day) plus ongoing losses. If the volume of ongoing losses cannot be determined, it is generally safe to assume that patients with ARF lose at least 3% to 5% of their body weight through ongoing losses during a 24-hour period. After rehydration, maintenance fluids (e.g., Plasma-Lyte® M [Baxter International, Deerfield, IL], Normosol®-M [Abbott Laboratories, North Chicago, IL], 0.45% sodium chloride, 2.5% dextrose) may be preferred over 0.9% sodium chloride and lactated Ringer’s solution, both of which may cause hypernatremia. Treatment should be adjusted depending on changes in body weight, urine volume, fluid intake, and laboratory parameters. IV fluids are continued until the patient is eating and drinking and should be gradually discontinued over several days while hydration status and body weight are closely monitored. Depending on severity of clinical signs and whether there is evidence of GI ulceration, additional treatment may be indicated. H2 receptor antagonists may help control signs of uremic gastritis and GI ulceration. Cimetidine (5 to 10 mg/kg IV or orally two to four times daily) and ranitidine (2 to 4 mg/kg IV or orally twice daily) are most often used. If the patient is not vomiting, oral sucralfate (0.5 to 1 g three or four times daily) may be used instead of an H2 receptor antagonist. There is probably no advantage of using an H2 receptor antagonist and sucralfate concurrently. Regardless of which drug is selected, it should be administered for 4 to 6 weeks to ensure adequate healing of ulcers.

PROGNOSIS AND PREVENTION Most dogs that develop NSAID-induced ARF have a favorable prognosis. They generally respond well after appropriate treatment for 5 to 10 days, and ARF is reversible. Dogs with severe concomitant disorders (e.g., hepatic failure, sepsis) may have a less favorable prognosis. The long-term prognosis is also less favorable if chronic renal disease exists. If a disorder that predisposes to NSAID-induced ARF cannot be identified, subclinical renal disease should be suspected. This may become apparent as renal function (i.e., serial measurements of BUN, serum creatinine, and urine specific gravity) is measured periodically after recovery from ARF. The best method for preventing NSAID-induced ARF

CLINICAL SIGNS ■ PHYSICAL EXAMINATION FINDINGS ■ H2 RECEPTOR ANTAGONIST

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S
M’

is to avoid using these agents unless the potential benefits outweigh the risks, especially in patients with predisposing conditions (see Potential Risk Factors for Developing NSAID-Associated Renal Dysfunction). A thorough history and physical examination should be performed to identify signs that might indicate chronic renal disease (e.g., weight loss, polyuria/polydipsia) before NSAIDs are dispensed. Laboratory evaluation, including complete blood count, serum chemistries, and urinalysis, should be performed to detect evidence of renal disease (e.g., anemia, azotemia, hypoalbuminemia, persistent isosthenuria, proteinuria). When ENDIU NSAIDs are prescribed, P M owners should be advised of potential toxicoses and assoANNIVERSARY ciated clinical signs. If inappetence, vomiting, diarrhea, or melena is observed, owners should immediately discontinue the NSAID and Nephrotoxicosis associated with seek veterinary attention for NSAIDs was first reported more their pets. than 20 years ago; however, Guidelines for monitoracute renal failure has not been ing renal function in pafrequently associated with tients that receive NSAIDs NSAID use in dogs. It appears have not been firmly estabthat no particular NSAID is lished; however, it seems more or less nephrotoxic than reasonable that serum another and, in most instances, chemistries and urinalyses gastrointestinal complications should be monitored periare the dose-limiting side effects odically. We recommend monitoring serum chemof NSAIDs. As the canine istries during the first 1 to population ages and NSAIDs 2 weeks after beginning are prescribed for more geriatric treatment with NSAIDs patients, however, it will be and every 6 months thereimportant to identify those at after. Of particular concern risk for developing NSAIDare patients with subclinical associated acute renal failure. renal disease (i.e., decreased Additional research is needed to glomerular filtration in the evaluate effects of NSAIDs on absence of clinical and labrenal function in dogs, oratory abnormalities of particularly those with renal renal disease) that may exdisease. Such information perience an acute exacerbation of renal dysfunction would help practicing after treatment with NSAIDs. veterinarians when prescribing Perhaps these patients could NSAIDs for canine patients. be identified if glomerular filtration rate were measured; however, this may not be practical in the clinical setting. Misoprostol, a synthetic
CO

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PGE1 analogue, has been suggested as a potential agent for preventing renal dysfunction associated with NSAID use.36,37 Misoprostol has been used successfully to prevent GI side effects associated with NSAID use in dogs, 38,39 but studies evaluating its efficacy for preventing renal dysfunction in dogs are lacking. Based on experimental studies in rats36 and humans,37 it would seem reasonable that misoprostol, a vasodilatory PG, would protect against renal vasoconstriction associated with NSAIDs. However, in a recent experimental study of dogs, administration of misoprostol (3 µg/kg orally three times daily) did not lessen the severity of gentamicin-induced ARF and may have actually worsened renal injury.40 Therefore, pending results of additional studies, misoprostol should be used cautiously in dogs with renal dysfunction.

CONCLUSION The most common renal side effect of NSAID administration is ARF, which is most likely to occur in dogs that have preexisting renal disease or conditions that cause hypovolemia, such as dehydration, or in conjunction with inhalation anesthesia. In these patients, renal vasodilatory PGs are necessary for maintenance of renal perfusion. Treatment with NSAIDs inhibits production of vasodilatory PGs, causing renal vasoconstriction and subsequent ARF. Most dogs with NSAIDinduced ARF respond to supportive treatment, including discontinuation of the NSAID and administration of IV fluids, and recover from ARF. To help prevent ARF, NSAID use should be avoided in dogs with preexisting renal disease and owners educated about signs of GI and renal side effects that may occur with these drugs. Newer NSAIDs such as COX-2 inhibitors (e.g., etodolac) may be less likely to cause renal side effects, but this remains to be evaluated. REFERENCES 1. Holtsinger RH, Parker RB, Beale BS, et al: The therapeutic efficacy of carprofen (Rimadyl-V) in 209 clinical cases of canine degenerative joint disease. Vet Comp Orthop Trauma 5:140–144, 1992. 2. Knapp DW, Richardson RC, Chan TCK, et al: Piroxicam therapy in 34 dogs with transitional cell carcinoma of the urinary bladder. J Vet Intern Med 8:273–278, 1994. 3. Vasseur PB, Johnson AL, Budsberg SC, et al: Randomized, controlled trial of the efficacy of carprofen, a nonsteroidal anti-inflammatory drug, in the treatment of osteoarthritis in dogs. JAVMA 206:807–811, 1995. 4. Budsberg SC, Johnston SA, Schwarz PD, et al: Efficacy of etodolac for the treatment of osteoarthritis of the hip joints in dogs. JAVMA 214:206–210, 1999. 5. Kore AM: Toxicology of nonsteroidal antiinflammatory drugs. Vet Clin North Am Small Anim Pract 20:419–430, 1990. 6. Stanton ME, Bright RM: Gastroduodenal ulceration in dogs: Retrospective study of 43 cases and literature review. J Vet Intern Med 3:238–244, 1989.

MONITORING RENAL FUNCTION ■ GLOMERULAR FILTRATION ■ MISOPROSTOL

Compendium October 1999

20TH ANNIVERSARY

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About the Authors Drs. Forrester and Troy are affiliated with the Department of Small Animal Clinical Sciences, Virginia–Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia. Both are Diplomates of the American College of Veterinary Internal Medicine.