renal effects of nsaid

8/14/2019 Renal Effects of NSAID

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20TH ANNIVERSARY Vol. 21, No. 10 October 1999

Refereed Peer Review

FOCAL POINT

KEY FACTS

#Inhibition of renal prostaglandinsby NSAIDs may cause acute renal

failure (ARF) that usually is

reversible with appropriate

treatment.

Renal Effectsof Nonsteroidal

Antiinflammatory

DrugsVirginia Tech

S. Dru Forrester, DVM, MSGregory 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.

Nonsteroidal antiinflammatory drugs are used in veterinary patients fortheir analgesic, antiinflammatory, and antineoplastic effects.14 Themost common complications of NSAID use in dogs are gastrointestinal

(GI) ulceration and hemorrhage.58 Hepatotoxicosis has also occurred in dogs re-ceiving NSAIDs.5,9 Renal side effects are less common and most often occur indogs that have renal disease or a concurrent disorder that causes renal hypoper-fusion.917

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 PRODUCTIONProstaglandins 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-

CE

V

I 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.

INSAIDs may cause ARF in patientswith renal disease or conditions

characterized by decreased renal

perfusion.

I Appropriate treatment for

NSAID-induced ARF includes

administration of intravenous

fluids and H2 receptor

antagonists.

I Administration of drugs to

stimulate diuresis is generallyunnecessary in patients with

NSAID-induced ARF.

I 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.


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lease. Cyclooxygenase (COX)acts on AA to form PGG2and then PGH2, the latter of

which is subsequently con-verted to PGE2, PGF2, pros-tacyclin (PGI2), and throm-boxane (TXA2).15,1821 Theproducts of AA metabolismare produced at or near theirsite of action and have littlesystemic effect. In the renalcortex, PGI2, the predomi-nant prostaglandin, is pro-duced in glomeruli, arteri-oles, and cortical collectingtubules.22,23 PGE2, the pri-mary renal medullary pros-taglandin, is produced incollecting tubules and inter-stitial cells.22,23

Renal PGs play an impor-tant role in several physio-logic processes in the kid-neys.2327 Under conditionsof decreased renal perfusion(e.g., volume or salt deple-tion), PGE2 and PGI2 causeafferent arteriolar dilation,

which maintains renal bloodflow and counteracts the ef-fects of systemic vasoconstric-tors (e.g., angiotensin, nor-epinephrine, vasopressin).2527

It has been suggested thatthese vasodilatory PGs may help maintain renal bloodflow and glomerular filtration in surviving nephrons ofpatients with chronic renal disease.27

In addition to their effects on renal vascular tone, re-nal PGs, particularly PGI2, are necessary for the releaseof renin from the kidney23,27; renal PGs increase intra-cellular cyclic adenosine monophosphate (cAMP) in

juxtaglomerular cells, which in turn stimulates reninsynthesis and secretion. Renin stimulates the release ofaldosterone, which is necessary for renal tubular secre-tion of potassium. PGs are therefore indirectly involvedin maintaining potassium homeostasis.23

Finally, renal medullary PGs are necessary for renaltubular excretion of sodium and water.25,27 Natriuresisoccurs because renal PGs increase renal blood flow; in-hibit sodium transport from the thick ascending limb ofthe loop of Henle into the medullary interstitium; andantagonize the action of vasopressin on collecting ducts,

which decreases their permeability to water.21,22,27,28

THERAPEUTICEFFECTS OF NSAIDs

The beneficial effects ofNSAIDs result from theirability to inhibit COX, the

enzyme that facilitates pro-duction of inflammatorymediators (e.g., PGs, TXA2)from AA (Figure 1).29 Thetwo forms or isoenzymes ofCOX are COX-1 and COX-2.COX-1 appears to exist nat-urally in the body and is ac-tive in autoregulatory func-tions (e.g., maintenance ofrenal blood flow), whereasCOX-2 is responsible for

production of inflammatorymediators.30,31 It has beensuggested that inhibition ofCOX-2 decreases inflamma-tion whereas inhibition ofCOX-1 appears to be re-sponsible for side effects as-sociated with NSAID use,such as GI ulceration and re-nal dysfunction.31

Many NSAIDs (e.g., as-pirin, piroxicam) preferen-

tially inhibit COX-1, whichmay increase the likelihoodof GI and renal side ef-fects.32 In contrast, NSAIDsthat inhibit COX-1 and

COX-2 equally (e.g., carprofen) or that preferentiallyinhibit COX-2 (e.g., etodolac, meloxicam) may be lesslikely to cause side effects.3133 Thus carprofen andetodolac may be relatively safer NSAIDs that are lesslikely to adversely affect renal function. However, renalfailure has been observed in dogs receiving carprofen.9

It is therefore likely that factors other than COX selec-

tivity are involved in determining whether an NSAIDcauses renal dysfunction.It is possible that COX-2 plays an important role in

maintaining renal blood flow in volume-depleteddogs.26 Expression of COX-2 occurs at low levels innormal dogs but is greatly increased in salt-depleteddogs.26 Thus administration of NSAIDs that preferen-tially inhibit COX-2 may not spare patients from re-nal side effects. Additional studies evaluating the ef-fects of newer NSAIDs on renal function in dogs,especially those with subclinical renal disease, wouldbe helpful.

Compendium October 1999 20TH ANNIVERSARY Small Animal/Exotics

V A S O D I L A T O R Y P G S I R E N I N I N A T R I U R E S I S I C O X - 1 I C O X - 2

Figure 1All cell membranes contain arachidonic acid (AA),a polyunsaturated fatty acid that serves as the precursor forprostaglandin (PG) production. A variety of stimuli cause re-lease of AA, a process facilitated by the enzyme phospholi-pase. Cyclooxygenase then acts on AA to produce intermedi-ate prostaglandins (PGG2, PGH2), which subsequently aremetabolized to form prostacyclin (PGI2), PGE2, PGF2, andthromboxane (TXA2). These AA metabolites participate inthe inflammatory response by causing vasodilation, increasedvascular permeability, and neutrophilic chemotaxis. In addi-tion, they are involved in several important physiologic pro-cesses in the kidneys.

PGI2 PGE2 PGF2 TXA2

Cell Membrane

Phospholipase

Arachidonic Acid

Cyclooxygenase

PGG2 PGH2


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EFFECTS OF NSAIDs ON RENAL FUNCTIONRenal effects of NSAIDs primarily result from de-

creased synthesis of renal PGs. The most common re-nal side effect of NSAIDs, ARF, is most likely to occurin patients that are volume depleted or have preexisting

renal disease.15,2023,27,28

In both conditions, renal va-sodilatory PGs are believed to be important for main-taining renal blood flow.27 Administration of NSAIDsto these patients is associated with afferent arteriolarconstriction, which subsequently leads to decreased re-nal blood flow and ARF.27

Other renal side effects of NSAIDs (i.e., hyper-kalemia, hypernatremia, edema, hyponatremia) mayoccur but often are not as obvious. Hyperkalemia mayoccur in patients that receive NSAIDs because PGs areinvolved in synthesis and secretion of renin. Inhibitionof renal PGs by NSAIDs also interferes with the kid-

neys ability to excrete sodium, resulting in sodium re-tention and hypernatremia.21,24,27 Because renal PGs arenecessary for renal excretion of water, administration ofNSAIDs may decrease free water clearance; patientsthat receive NSAIDs are therefore predisposed to devel-oping edema. If water retention occurs in excess ofsodium retention, hyponatremia may occur.21,27

The most clinically important renal complication as-sociated with administration of NSAIDs to dogs is

ARF (see NSAIDs Associated with Acute Renal Failurein Dogs).9,10,1214,16,17,34 In 1967, renal failure and severehemorrhage were reported in a dog that had received

phenylbutazone for 5 weeks.10

In a more recent report,a 10-month-old Labrador retriever developed GI hem-orrhage and ARF after ingesting 6000 mg of ibuprofen.The dog recovered after supportive care was providedbut continued to have polyuria and polydipsia 2months later; in addition, theglomerular filtration rate wassignificantly decreased.16 A 9-year-old Samoyed developed GIhemorrhage, severe anemia,and ARF after it was givennaproxen that had been pre-

scribed for the owner; the dogrecovered after 5 days of sup-portive treatment.

Five dogs used in a studentlaboratory developed ARF afterreceiving a single intravenous(IV) dose of flunixin meglu-mine (1 mg/kg) and the neuro-muscular blocker gallamineduring inhalation anesthesia

with methoxyflurane.14 Four ofthe dogs survived following

supportive treatment for 6days. An experimental studyconfirmed that ARF oc-curred in dogs receiving flu-nixin during methoxyflu-

rane anesthesia but notduring anesthesia withhalothane.14 On the otherhand, ARF was reported intwo healthy dogs undergo-ing ovariohysterectomy thatreceived flunixin while anes-thetized with halothane.12

Both dogs recovered from ARF, but one died of neuro-logic disease shortly afterward. ARF was recently re-ported in two dogs receiving carprofen (2.2 mg/kgtwice daily); both dogs also had hepatic failure.9

Necropsy and histologic evaluation revealed GI ulcera-tion, jejunal perforation, renal tubular necrosis, andglomerulonephritis in one of these dogs.9

Although there have been reports of ARF associatedwith NSAID use in dogs, the overall occurrence is low.In a retrospective study of 29 dogs with nosocomial

ARF, only 1 dog had a history of NSAID use.34 In an-other study, only 2 of 99 dogs with ARF had receivedan NSAID.17 Based on all reported cases, most dogsthat develop ARF with NSAID treatment either ingestan excessive quantity of the drug or have a concomitantdisorder that makes them more susceptible to ARF (see

Potential Risk Factors for Developing NSAID-Associat-ed Renal Dysfunction). The following cases illustratethe characteristic findings in dogs that develop ARF af-ter administration of NSAIDs.

CASE EXAMPLESCase 1

A 6-year-old intact male Do-berman pinscher was presented

with a 1-day history of lethar-gy, inappetence, and diarrheacharacterized by melena. The

owner reported that the dogconsumed two aspirin tablets(presumably 325 mg each) thathad been placed in anotherdogs food the previous day.Physical examination revealedan alert dog in good body con-dition (weight, 36 kg) with dryand pink mucous membranes;prolonged capillary refill time(more than 2 seconds); anddark, tarry feces on rectal ex-

Small Animal/Exotics 20TH ANNIVERSARY Compendium October 1999

A F F E R E N T A R T E R I O L A R C O N S T R I C T I O N I A C U T E R E N A L F A I L U R E I I N H A L A T I O N A N E S T H E S I A

I Aspirin

I Carprofen

I Flunixin meglumine

I Ibuprofen

I Naproxen

I Phenylbutazone

NSAIDs Associated withAcute Renal Failure

in Dogs9,10,1214,16

I Dehydration

I Concomitant drugs (e.g., other NSAIDs,

corticosteroids, diuretics)I Third-space disease (e.g., ascites)

I Hepatic failure

I Congestive heart failure

I Hypotension

I Old age

I Renal disease

I Sepsis

I Inhalation anesthesia

Potential Risk Factors for DevelopingNSAID-Associated Renal Dysfunction


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amination. Abnormal findings on initial diagnosticevaluation (i.e., complete blood count, serumchemistries, urinalysis, and fecal flotation) includedazotemia (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 to5), 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 laboratoryevaluation were consistent with ARF. Because of thehistory of aspirin ingestion, NSAID-induced ARF wasconsidered a possibility.

The dog was placed in the intensive care unit fortreatment and periodic monitoring. Blood was collect-ed for baseline measurement of selected serumchemistries (Table I). Lactated Ringers solution (200

ml/hour IV) was administered to correct dehydration,replace ongoing losses due to diarrhea, and providemaintenance fluid requirements during the first 24hours. Cimetidine (5 mg/kg orally three times daily)

was administered throughout hospitalization to helpdecrease signs of GI ulceration. The dog was monitoredfor the occurrence of vomiting and diarrhea, changes inhydration 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 toincreased.

On day 3, the dog began drinking water and eatingsmall amounts of canned food. Azotemia resolved, andthe rate of fluid administration was gradually decreased.Potassium chloride (28 mEq/L of fluids) was added toIV fluids to prevent further lowering of serum potassi-um (Table I). The dog continued to improve, and IVfluids 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 (1mg/dl) and a urine specific gravity of 1.030.

This case was unusual because there was no obviouspredisposing condition for the development of ARFand because the dog ingested a low dose of aspirin (18mg/kg) that was within the recommended dosagerange. 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 hadsubclinical renal disease that was exacerbated by con-comitant dehydration (due to vomiting and diarrhea)and NSAID administration. This dogs response tosupportive treatment is typical ARF associated withNSAIDs 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 painwas present on physical examination, and a tentativediagnosis of intervertebral disk disease was made. Treat-ment included IV dexamethasone sodium phosphate (2mg/kg once), oral prednisone (0.7 mg twice daily for 7days), and oral carprofen (1.7 mg twice daily for 10days). 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) thatcorrected to normal, low-normal total protein (5.24

g/dl), increased alkaline phosphatase (1358 IU/L), andanemia (29%). Treatment included IV administrationof lactated Ringers solution with 5% dextrose, calciumgluconate (53 mg/kg slow IV), and cefazolin (27 mg/kgIV). After 12 hours of treatment, the dog appeared tobe 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 milddehydration. Initial laboratory evaluation revealed non-


S E R U M C H E M I S T R I E S I L A B O R A T O R Y F I N D I N G S I C I M E T I D I N E I F U R O S E M I D E

TABLE I

Results of Serial Serum Chemistries in a Dog (Case 1) with Aspirin-Associated Acute Renal Failure

Day

Parameter 0 1 2 3 4 5 Reference Range

Urea nitrogen (mg/dl) 73 89 50 20 10 7 628

Creatinine (mg/dl) 6.3 6.4 3.3 1.8 1.3 1.2 0.81.9

Potassium (mmol/L) 3.9 4 3.6 3.32 3.63 4.4 3.34.6

Phosphorus (mg/dl) 7.7 7.1 4.1 3.1 3.3 3.3 1.35


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regenerative anemia (hematocrit = 26.3%; RR, 37 to62; reticulocytes = 0.9%), leukocytosis (28,200/l; RR,5400 to 16,600) characterized by mature neutrophilia(23,688/l; RR, 3200 to 10,700) and a mild left shift

(846 bands/l; RR, 0 to 200), panhypoproteinemia(total protein = 4.6 g/dl; RR, 5.3 to 7.4; albumin = 2.3g/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 to167), 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), mildlydecreased total carbon dioxide (16.3 mmol/L; RR, 17.4to 27.9), increased anion gap (23; RR, 8 to 15), mildhypocalcemia (corrected calcium = 8.97 mg/dl; RR, 9.7to 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), mildglucosuria, and 2+ proteinuria with normal urine sedi-ment. Urine culture was negative for bacterial growth.Both kidneys were small on abdominal ultrasonographybut appeared to have normal architecture.

On the basis of initial findings, tentative diagnoses ofGI ulceration and ARF were made and the dog wasplaced in the intensive care unit for treatment andmonitoring. A jugular catheter was placed, and 0.9%saline was begun at 90 ml/hour to correct dehydrationand provide maintenance needs. Because of the history

of decreased urination and concern about the presenceof oliguria, an indwelling urinary catheter was placed.Body weight and urine volume were measured every 4hours so that fluid administration could be adjusted tomaintain adequate hydration. Oral sucralfate (0.5 gtwice 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 offluids. The rate of fluid administration varied from 10

to 15 ml/hour depending on urine volume and bodyweight. Similar treatment and monitoring were contin-ued for the next 9 days (Table II). The dog began todrink water on day 3 and eat small amounts of canned

food on day 5. The urinary catheter was removed onday 7; urine was submitted for bacterial culture, whichrevealed growth of more than 10,000 Escherichia coli/ml of urine.

Intravenous fluids and cimetidine were discontinuedon day 10 because the dog was eating, drinking, andable to maintain hydration and body weight. The dog

was discharged from the hospital with owner instruc-tions to administer oral amoxicillinclavulanate (33 mg/kgthree 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 = 2.2mg/dl) and isosthenuria (urine specific gravity =1.012). Three months after discharge, BUN was nor-mal and serum creatinine was slightly increased (1.86mg/dl) at the referring veterinarians 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 developNSAID-associated ARF. It is likely that the excessivedose of dexamethasone combined with concurrent useof prednisone and carprofen caused GI ulceration inthis dog. Initial laboratory evaluation by the referring

veterinarian was consistent with GI hemorrhage butnot ARF because BUN was markedly increased andserum creatinine was normal. Administration offurosemide in addition to treatment with carprofen in adog that was probably dehydrated may have contribut-ed to worsening of renal function. Based on the age ofthe dog and the presence of small kidneys, we suspectchronic renal disease was present and that a combina-tion of factors (i.e., dehydration and hypovolemia dueto GI ulceration and hemorrhage, treatment withfurosemide and carprofen) caused ARF. The dog re-sponded well to supportive care and renal failure was


O L I G U R I A I F L U I D A D M I N I S T R A T I O N I N S A I D - A S S O C I A T E D A R F I G I U L C E R A T I O N

TABLE II

Results of Serial Serum Chemistries in a Dog (Case 2) with Gastrointestinal Hemorrhage andAcute 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) 184 127 115 69 39 33 19 628

Creatinine (mg/dl) 4.6 3.2 3.4 2.8 2.4 2.2 1.8 0.81.9

Potassium (mmol/L) 6.31 3.86 2.63 3.44 3.98 4.2 4.89 3.34.6

Phosphorus (mg/dl) 12.8 12.4 10.8 5.9 5 6.2 6.3 1.35


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reversible, which is expected in most dogs with NSAID-induced ARF.

DIAGNOSISA tentative diagnosis of NSAID-associated ARF is

usually made on the basis of history, physical examina-tion findings, and results of laboratory evaluation. Mostdogs have an acute (less than 7 days) onset of clinicalsigns. Inappetence, vomiting, diarrhea, and melena arecommon 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 ingood body condition. Physical examination findingsmay include pale mucous membranes, evidence of de-hydration, and melena on rectal examination. Renalfailure is confirmed by finding azotemia and decreasedurine 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 isconfirmed, a thorough search for an underlying cause,including asking owners about potential exposure tosuch nephrotoxic substances as NSAIDs (see NSAIDs

Associated with Acute Renal Failure in Dogs), shouldbe conducted.

TREATMENTThere is no specific treatment for NSAID-induced

renal dysfunction; in general, supportive care is indicat-

ed.

11

The NSAID should be discontinued, and otherdrugs that are potentially nephrotoxic should not beused. Diuretics (e.g., furosemide) should be avoided be-cause they may cause dehydration and subsequent renalhypoperfusion. To avoid additional renal injury sec-ondary to decreased renal perfusion, hydration deficitsshould 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 isprobably best to assume subclinical dehydration (i.e.,less than 5%) and replace the deficit. An appropriatevolume 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 forrehydration. Lactated Ringers solution or 0.9% sodiumchloride is usually appropriate for correcting dehydra-tion in most dogs.

In our experience, most dogs with NSAID-inducedARF are not oliguric after rehydration and employingmethods to stimulate diuresis (e.g., administration offurosemide, dextrose, mannitol, dopamine) are unnec-essary. Excessive fluid administration (i.e., two to threetimes maintenance requirements) or osmotic diuresismay cause volume overload because NSAIDs interfere

with renal excretion of sodium and water.11,20,21,24,27 If itis unclear whether oliguria (urine production of lessthan 1 ml kg/hour) exists after rehydration, an in-dwelling urinary catheter can be placed and connectedto a closed drainage system to accurately quantitate

urine volume.When the patient has been rehydrated and oliguriadoes not exist, the volume of fluid to administer equalsurine volume plus insensible losses (20 ml/kg/day) plusongoing losses. If the volume of ongoing losses cannot bedetermined, it is generally safe to assume that patients

with ARF lose at least 3% to 5% of their body weightthrough ongoing losses during a 24-hour period. After re-hydration, maintenance fluids (e.g., Plasma-LyteM[Baxter International, Deerfield, IL], Normosol-M [Ab-bott Laboratories, North Chicago, IL], 0.45% sodiumchloride, 2.5% dextrose) may be preferred over 0.9%

sodium chloride and lactated Ringers solution, both ofwhich may cause hypernatremia. Treatment should be ad-justed depending on changes in body weight, urine vol-ume, fluid intake, and laboratory parameters. IV fluidsare continued until the patient is eating and drinking andshould be gradually discontinued over several days whilehydration status and body weight are closely monitored.

Depending on severity of clinical signs and whetherthere is evidence of GI ulceration, additional treatmentmay be indicated. H2 receptor antagonists may helpcontrol 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 orallytwice daily) are most often used. If the patient is notvomiting, oral sucralfate (0.5 to 1 g three or four timesdaily) 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 administeredfor 4 to 6 weeks to ensure adequate healing of ulcers.

PROGNOSIS AND PREVENTIONMost 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 ifchronic 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., serialmeasurements of BUN, serum creatinine, and urinespecific gravity) is measured periodically after recoveryfrom ARF.

The best method for preventing NSAID-induced ARF


C L I N I C A L S I G N S I P H Y S I C A L E X A M I N A T I O N F I N D I N G S I H 2 R E C E P T O R A N T A G O N I S T


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is to avoid using these agents unless the potential benefitsoutweigh the risks, especially in patients with predispos-ing conditions (see Potential Risk Factors for DevelopingNSAID-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 NSAIDsare dispensed. Laboratory evaluation, including completeblood count, serum chemistries, and urinalysis, shouldbe performed to detect evidence of renal disease (e.g.,anemia, azotemia, hypoalbuminemia, persistent isos-

thenuria, proteinuria). WhenNSAIDs are prescribed,owners should be advised ofpotential toxicoses and asso-ciated clinical signs. If inap-petence, vomiting, diarrhea,

or melena is observed, own-ers should immediately dis-continue the NSAID andseek veterinary attention fortheir pets.

Guidelines for monitor-ing renal function in pa-tients that receive NSAIDshave not been firmly estab-lished; however, it seemsreasonable that serumchemistries and urinalyses

should be monitored peri-odically. We recommendmonitoring serum chem-istries during the first 1 to2 weeks after beginningtreatment with NSAIDsand every 6 months there-after. Of particular concernare patients with subclinicalrenal disease (i.e., decreasedglomerular filtration in theabsence of clinical and lab-

oratory abnormalities ofrenal disease) that may ex-perience an acute exacerba-tion of renal dysfunctionafter treatment with NSAIDs.Perhaps these patients couldbe identified if glomerularfiltration rate were mea-sured; however, this maynot be practical in the clini-cal setting.

Misoprostol, a synthetic

PGE1 analogue, has been suggested as a potential agentfor preventing renal dysfunction associated with NSAIDuse.36,37 Misoprostol has been used successfully to preventGI 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 thatmisoprostol, a vasodilatory PG, would protect against re-nal vasoconstriction associated with NSAIDs. However,in a recent experimental study of dogs, administration ofmisoprostol (3 g/kg orally three times daily) did notlessen the severity of gentamicin-induced ARF and mayhave actually worsened renal injury.40 Therefore, pendingresults of additional studies, misoprostol should be usedcautiously in dogs with renal dysfunction.

CONCLUSIONThe most common renal side effect of NSAID ad-

ministration is ARF, which is most likely to occur indogs that have preexisting renal disease or conditionsthat cause hypovolemia, such as dehydration, or in con-

junction with inhalation anesthesia. In these patients,renal vasodilatory PGs are necessary for maintenance ofrenal 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, includingdiscontinuation of the NSAID and administration ofIV fluids, and recover from ARF. To help prevent ARF,NSAID use should be avoided in dogs with preexistingrenal disease and owners educated about signs of GIand 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.

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efficacy of carprofen (Rimadyl-V) in 209 clinical cases of ca-nine degenerative joint disease. Vet Comp Orthop Trauma5:140144, 1992.

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M O N I T O R I N G R E N A L F U N C T I O N I G L O M E R U L A R F I L T R A T I O N I M I S O P R O S T O L

A LookBack

COMP

ENDIUMS

20thANNIVERSARY

1 97 9 -

1 9 9 9

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

of NSAIDs. As the canine

population ages and NSAIDs

are prescribed for more geriatric

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.


8/8

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About the AuthorsDrs. Forrester and Troy are affiliated with the Department

of Small Animal Clinical Sciences, VirginiaMaryland 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.


renal effects of nsaid

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