V 20TH ANNIVERSARY
10 October 1999
CE 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 NSAID-
induced ARF.
Vol. 21, No.
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 cy-
clooxygenase, 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 ad-
ministration.
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 re-
ceiving 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 hypoper-
fusion.9–17
This article discusses production of prostaglandins (PGs), their role in renal
function, and mechanisms by which NSAID-associated PG inhibition causes re-
nal dysfunction. Reported cases of dogs that developed renal dysfunction associ-
ated with NSAID use are summarized, and two additional cases are presented.
Therapeutic guidelines for managing dogs with acute renal failure (ARF) associ-
ated with NSAID use are provided. Finally, prognostic information and mea-
sures 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 (Fig-
ure 1).18,19 A variety of stimuli (e.g., endotoxins, hypoxia, vasopressin, an-
giotensin, norepinephrine) activate cellular phospholipases, resulting in AA re-
Compendium October 1999 20TH ANNIVERSARY Small Animal/Exotics

lease. Cyclooxygenase (COX) THERAPEUTIC

acts on AA to form PGG2 Cell Membrane EFFECTS OF NSAIDs
and then PGH2, the latter of The beneficial effects of
which is subsequently con- NSAIDs result from their
verted to PGE2, PGF2α, pros- ability to inhibit COX, the
tacyclin (PGI2), and throm- Phospholipase
enzyme that facilitates pro-
boxane (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 predomi- Cyclooxygenase COX-1 appears to exist nat-
nant prostaglandin, is pro- urally in the body and is ac-
duced in glomeruli, arteri- tive in autoregulatory func-
oles, and cortical collecting PGG → PGH tions (e.g., maintenance of
2 2
tubules.22,23 PGE2, the pri- renal blood flow), whereas
mary renal medullary pros- COX-2 is responsible for
taglandin, is produced in production of inflammatory
collecting tubules and inter- mediators. 30,31 It has been
PGI2 PGE2 PGF2α TXA2
stitial cells.22,23 suggested that inhibition of
Renal PGs play an impor- COX-2 decreases inflamma-
tant 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 re-
neys.23–27 Under conditions prostaglandin (PG) production. A variety of stimuli cause re- sponsible for side effects as-
of 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 re-
ate prostaglandins (PGG2, PGH2), which subsequently are
tion), PGE2 and PGI2 cause metabolized to form prostacyclin (PGI2), PGE2, PGF2α, and nal dysfunction.
31

afferent arteriolar dilation, thromboxane (TXA ). These AA metabolites participate in Many NSAIDs (e.g., as-
2
which maintains renal blood the inflammatory response by causing vasodilation, increased pirin, piroxicam) preferen-
flow 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 ef-
epinephrine, 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, re- etodolac 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 intra- failure has been observed in dogs receiving carprofen.9
cellular cyclic adenosine monophosphate (cAMP) in It is therefore likely that factors other than COX selec-
juxtaglomerular 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 secre- It 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 preferen-
occurs because renal PGs increase renal blood flow; in- tially inhibit COX-2 may not spare patients from re-
hibit sodium transport from the thick ascending limb of nal side effects. Additional studies evaluating the ef-
the 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

Small Animal/Exotics 20TH ANNIVERSARY Compendium October 1999

EFFECTS OF NSAIDs ON RENAL FUNCTION supportive treatment for 6

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

AFFERENT ARTERIOLAR CONSTRICTION ■ ACUTE RENAL FAILURE ■ INHALATION ANESTHESIA

Compendium October 1999 20TH ANNIVERSARY
TABLE I
Results of Serial Serum Chemistries in a Dog (Case 1) with Aspirin-Associated Acute Renal Failure
Parameter 0 1
Urea nitrogen (mg/dl) 73 89
Creatinine (mg/dl) 6.3 6.4
Potassium (mmol/L) 3.9 4 3.6
Phosphorus (mg/dl) 7.7 7.1
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; ref-
erence 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), isos-
thenuria (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 collect-
ed 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 esti-
mation of urine volume. Vomiting was not observed,
body weight remained stable after correction of dehy-
dration, 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 potassi-
um (Table I). The dog continued to improve, and IV
fluids were discontinued on day 5. The dog was dis-
charged from the hospital on day 6, and the owners
were instructed to continue cimetidine for 14 days. Re-
sults of serum chemistries 2 weeks after discharge re-
vealed normal BUN (16 mg/dl) and creatinine (1
mg/dl) and a urine specific gravity of 1.030.
SERUM CHEMISTRIES ■ LABORATORY FINDINGS ■ CIMETIDINE ■ FUROSEMIDE
Small Animal/Exotics
Day
2 3 4 5 Reference Range
50 20 10 7 6–28
3.3 1.8 1.3 1.2 0.8–1.9
3.32 3.63 4.4 3.3–4.6
4.1 3.1 3.3 3.3 1.3–5
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 as-
pirin caused ARF, only that aspirin ingestion was asso-
ciated with ARF in this dog. It is possible this dog had
subclinical renal disease that was exacerbated by con-
comitant 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 eval-
uation of inappetence, listlessness, decreased urine pro-
duction, and reluctance to move. Thoracolumbar pain
was present on physical examination, and a tentative
diagnosis of intervertebral disk disease was made. Treat-
ment 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 emer-
gency for evaluation of weakness, lethargy, and de-
creased urine volume. Laboratory results revealed in-
creased 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. Ab-
normalities on physical examination included depres-
sion, tachypnea (72 breaths/minute), melena, and mild
dehydration. Initial laboratory evaluation revealed non-
Small Animal/Exotics 20TH ANNIVERSARY
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
Parameter 1 2 3 4
Urea nitrogen (mg/dl) 184 127 115
Creatinine (mg/dl) 4.6 3.2 3.4
Potassium (mmol/L) 6.31 3.86 2.63
Phosphorus (mg/dl) 12.8 12.4 10.8
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), mini-
mally concentrated urine (specific gravity = 1.017), mild
glucosuria, and 2+ proteinuria with normal urine sedi-
ment. 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 cimeti-
dine (5 mg/kg IV three times daily) was initiated. Flu-
ids 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
OLIGURIA ■ FLUID ADMINISTRATION ■ NSAID-ASSOCIATED ARF ■ GI ULCERATION
Compendium October 1999
Day
5 8 10 Reference Range
69 39 33 19 6–28
2.8 2.4 2.2 1.8 0.8–1.9
3.44 3.98 4.2 4.89 3.3–4.6
5.9 5 6.2 6.3 1.3–5
to 15 ml/hour depending on urine volume and body
weight. Similar treatment and monitoring were contin-
ued 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 instruc-
tions to administer oral amoxicillin–clavulanate (33 mg/kg
three times daily for 14 days) for the urinary tract in-
fection. 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 nor-
mal 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 contribut-
ed 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 combina-
tion of factors (i.e., dehydration and hypovolemia due
to GI ulceration and hemorrhage, treatment with
furosemide and carprofen) caused ARF. The dog re-
sponded well to supportive care and renal failure was
Compendium October 1999 20TH ANNIVERSARY
reversible, which is expected in most dogs with NSAID-
induced ARF.
DIAGNOSIS
A tentative diagnosis of NSAID-associated ARF is
usually made on the basis of history, physical examina-
tion 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 de-
hydration, 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, hyperphospha-
temia, increased anion gap, increased total carbon diox-
ide, 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 indicat-
ed.11 The NSAID should be discontinued, and other
drugs that are potentially nephrotoxic should not be
used. Diuretics (e.g., furosemide) should be avoided be-
cause they may cause dehydration and subsequent renal
hypoperfusion. To avoid additional renal injury sec-
ondary to decreased renal perfusion, hydration deficits
should be corrected within 4 to 6 hours unless con-
traindicated (e.g., in patients with congestive heart fail-
ure).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 diar-
rhea) should be given in addition to fluids needed for
rehydration. Lactated Ringer’s solution or 0.9% sodium
chloride is usually appropriate for correcting dehydra-
tion 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 unnec-
essary. Excessive fluid administration (i.e., two to three
times maintenance requirements) or osmotic diuresis
may cause volume overload because NSAIDs interfere
CLINICAL SIGNS ■ PHYSICAL EXAMINATION FINDINGS ■ H2 RECEPTOR ANTAGONIST
Small Animal/Exotics
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 in-
dwelling 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 re-
hydration, maintenance fluids (e.g., Plasma-Lyte® M
[Baxter International, Deerfield, IL], Normosol®-M [Ab-
bott 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 ad-
justed depending on changes in body weight, urine vol-
ume, 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 antago-
nist. There is probably no advantage of using an H2 re-
ceptor antagonist and sucralfate concurrently. Regard-
less 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 re-
versible. Dogs with severe concomitant disorders (e.g.,
hepatic failure, sepsis) may have a less favorable prog-
nosis. The long-term prognosis is also less favorable if
chronic renal disease exists. If a disorder that predispos-
es to NSAID-induced ARF cannot be identified, sub-
clinical renal disease should be suspected. This may be-
come 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
 Small Animal/Exotics 20TH ANNIVERSARY Compendium October 1999

is to avoid using these agents unless the potential benefits
outweigh the risks, especially in patients with predispos-
ing conditions (see Potential Risk Factors for Developing
NSAID-Associated Renal Dysfunction). A thorough his-
tory 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 isos-
thenuria, proteinuria). When
MPENDIU NSAIDs are prescribed,
M’
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 dys-
function in dogs are lacking. Based on experimental stud-
ies in rats36 and humans,37 it would seem reasonable that
misoprostol, a vasodilatory PG, would protect against re-
nal 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

20th

CO

owners should be advised of results of additional studies, misoprostol should be used

S

1 9 7
9 - 1
9 9 9
ANNIVERSARY
A LookBack
Nephrotoxicosis associated with
NSAIDs was first reported more
than 20 years ago; however,
acute renal failure has not been
frequently associated with
NSAID use in dogs. It appears
that no particular NSAID is
more or less nephrotoxic than
another and, in most instances,
gastrointestinal complications
are the dose-limiting side effects odically. We recommend
of NSAIDs. As the canine
population ages and NSAIDs
are prescribed for more geriatric 2 weeks after beginning
patients, however, it will be
important to identify those at
risk for developing NSAID-
associated acute renal failure.
Additional research is needed to
evaluate effects of NSAIDs on
renal function in dogs,
particularly those with renal
disease. Such information
would help practicing
veterinarians when prescribing
NSAIDs for canine patients.
potential toxicoses and asso-
ciated clinical signs. If inap-
petence, vomiting, diarrhea,
or melena is observed, own-
ers should immediately dis-
continue the NSAID and
seek veterinary attention for
their pets.
Guidelines for monitor-
ing renal function in pa-
tients that receive NSAIDs
have not been firmly estab-
lished; however, it seems
reasonable that serum
chemistries and urinalyses
should be monitored peri-
monitoring serum chem-
istries during the first 1 to
treatment with NSAIDs
and every 6 months there-
after. Of particular concern
are patients with subclinical
renal disease (i.e., decreased
glomerular filtration in the
absence of clinical and lab-
oratory abnormalities of
renal disease) that may ex-
perience an acute exacerba-
tion of renal dysfunction
after treatment with NSAIDs.
Perhaps these patients could
be identified if glomerular
filtration rate were mea-
sured; however, this may
not be practical in the clini-
cal setting.
Misoprostol, a synthetic
cautiously in dogs with renal dysfunction.
CONCLUSION
The most common renal side effect of NSAID ad-
ministration 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 con-
junction with inhalation anesthesia. In these patients,
renal vasodilatory PGs are necessary for maintenance of
renal perfusion. Treatment with NSAIDs inhibits pro-
duction of vasodilatory PGs, causing renal vasocon-
striction and subsequent ARF. Most dogs with NSAID-
induced 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 ca-
nine 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
7. Wallace MS, Zawie MS, Garvey MS: Gastric ulceration in
the dog secondary to the use of nonsteroidal antiinflamma-
tory drugs. JAAHA 26:467–472, 1990.
8. Vonderhaar MA, Salisbury SK: Gastroduodenal ulceration
associated with flunixin meglumine administration in three
dogs. JAVMA 203:92–95, 1993.
9. MacPhail CM, Lappin MR, Meyer DJ, et al: Hepatocellular
toxicosis associated with administration of carprofen in 21
dogs. JAVMA 212:1895–1901, 1998.
10. Tandy J, Thorpe E: A fatal syndrome in a dog following ad-
ministration of phenylbutazone. Vet Rec 81:398–399, 1967.
11. Brown SA: Renal effects of nonsteroidal anti-inflammatory
drugs, in Kirk RW (ed): Current Veterinary Therapy X.
Philadelphia, WB Saunders Co, 1989, pp 1158–1161.
12. Elwood C, Boswood A, Simpson K, et al: Renal failure after
flunixin meglumine administration [letter]. Vet Rec 130:
582–583, 1992.
13. Gilmour MA, Walshaw R: Naproxen-induced toxicosis in a
dog. JAVMA 191:1431–1432, 1987.
14. Mathews KA, Doherty T, Dyson DH, et al: Nephrotoxicity
in dogs associated with methoxyflurane anesthesia and flu-
nixin meglumine analgesia. Can Vet J 31:766–771, 1990.
15. Rubin SI: Nonsteroidal antiinflammatory drugs, prosta-
glandins, and the kidney. JAVMA 188:1065–1068, 1986.
16. Spyridakis LK, Bacia JJ, Barsanti JA, et al: Ibuprofen toxico-
sis in a dog. JAVMA 188:918–919, 1986.
17. Vaden SL, Levine J, Breitschwerdt EB: A retrospective case-
control of acute renal failure in 99 dogs. J Vet Intern Med
11:58–64, 1997.
18. Badr KF, Jacobson HR: Arachidonic acid metabolites and
the kidney, in Brenner BM, Rector FC (eds): The Kidney.
Philadelphia, WB Saunders Co, 1991, pp 584–619.
19. Boothe DM: Prostaglandins: Physiology and clinical impli-
cations. Compend Contin Educ Pract Vet 6(11):1010–1021,
1984.
20. Bennett WM, Henrich WL, Stoff JS: The renal effects of
nonsteroidal anti-inflammatory drugs: Summary and recom-
mendations. Am J Kidney Dis 28(Suppl 1):S56–S62, 1996.
21. Murray MD, Brater DC: Renal toxicity of the nonsteroidal
anti-inflammatory drugs. Ann Rev Pharmacol Toxicol 32:
435–465, 1993.
22. Dunn MJ: Clinical effects of prostaglandins in renal disease.
Hosp Pract 19:99–113, 1984.
23. Stillman MT, Schlesinger PA: Nonsteroidal anti-inflamma-
tory drug nephrotoxicity. Arch Intern Med 150:268–270,
1990.
24. Raymond KH, Lifschitz MD: Effects of prostaglandins on
renal salt and water excretion. Am J Med 80(Suppl 1A):22–
33, 1986.
25. Dibona GF: Prostaglandins and nonsteroidal anti-inflamma-
tory drugs: Effects on renal hemodynamics. Am J Med
80(Suppl 1A):12–21, 1986.
26. Venturini CM, Isakson P, Needleman P: Non-steroidal anti-
inflammatory drug-induced renal failure: A brief review of
the role of cyclo-oxygenase isoforms. Curr Opin Nephrol Hy-
pertens 7:79–82, 1998.
Small Animal/Exotics
27. Clive DM, Stoff JS: Renal syndromes associated with non-
steroidal anti-inflammatory drugs. N Engl J Med 310:563–
572, 1984.
28. Patrono C, Dunn MJ: The clinical significance of inhibition
of renal prostaglandin synthesis. Kidney Int 32:1–12, 1987.
29. Vane JR: Inhibition of prostaglandin synthesis as a mecha-
nism of action for aspirin-like drugs. Nature 231:232–235,
1971.
30. Xie W, Robertson DL, Simmons DL: Mitogen-inducible
prostaglandin G/H synthase: A new target for nonsteroidal
antiinflammatory drugs. Drug Dev Res 25:249–265, 1992.
31. Pairet M, Churchill L, Trummlitz G, et al: Differential inhi-
bition of cyclooxygenase-1 (COX-1) and -2 (COX-2) by
NSAIDs: Consequences on anti-inflammatory activity versus
gastric and renal safety. Inflammopharmacology 4:61–70,
1996.
32. Frolich JC, Stichtenoth DO: NSAID: Can renal side effects
be avoided?, in Vane J, Botting J, Botting R (eds): Improved
Non-Steroid Anti-Inflammatory Drugs COX-2 Enzyme In-
hibitors. Dordrecht, The Netherlands, Kluwer Academic
Publishers and William Harvey Press, 1996, pp 203–228.
33. Glaser K, Sung ML, O’Neill K, et al: Etodolac selectively in-
hibits human prostaglandin G/H synthase 2 (PGHS-2) ver-
sus human PGHS-1. Eur J Pharmacol 281:107–111, 1995.
34. Behrend EN, Grauer GF, Mani I, et al: Hospital-acquired
acute renal failure in dogs: 29 cases (1983–1992). JAVMA
208:537–541, 1996.
35. Grauer GF: Fluid therapy in acute and chronic renal failure.
Vet Clin North Am Small Anim Pract 28:609–622, 1998.
36. Paller MS, Manivel JC: Prostaglandins protect kidneys
against ischemic and toxic injury by a cellular effect. Kidney
Int 42:1345–1354, 1992.
37. Toto RD: The role of prostaglandins in NSAID induced re-
nal dysfunction. J Rheumatol 18(Suppl 28):22–25, 1991.
38. Murtaugh RJ, Matz ME, Labato MA, et al: Use of synthetic
prostaglandin E1 (misoprostol) for prevention of aspirin-in-
duced gastroduodenal ulceration in arthritic dogs. JAVMA
202:251–256, 1993.
39. Johnston SA, Leib MS, Forrester SD, et al: The effect of
misoprostol on aspirin-induced gastroduodenal lesions in
dogs. J Vet Intern Med 9:32–38, 1995.
40. Davies C, Forrester SD, Troy GC, et al: Effects of a prosta-
glandin E1 analogue, misoprostol, on renal function in dogs
receiving nephrotoxic doses of gentamicin. Am J Vet Res
59:1048–1054, 1998.
About the Authors
Drs. Forrester and Troy are affiliated with the Department
of Small Animal Clinical Sciences, Virginia–Maryland Re-
gional College of Veterinary Medicine, Virginia Polytech-
nic Institute and State University, Blacksburg, Virginia.
Both are Diplomates of the American College of Veteri-
nary Internal Medicine.