Are NSAIDS safe in dogs with liver and kidney disease? (Proceeding)

Chronic kidney disease (CKD) is a common problem that affects an estimated 0.5 to 7% of dogs. Radiographic signs of osteoarthritis (OA) occur in 20% of dogs. The majority of OA and CKD are acquired and both conditions are more prevalent in older dogs. Use of non-steroidal anti-inflammatory drugs (NSAIDs) has dramatically improved the quality of life for many dogs with OA. The potential nephrotoxicity of NSAIDs however make their use problematic in dogs with CKD. Thorough evaluation of renal function prior to the use of NSAIDs and follow-up monitoring for any adverse effects on renal function is extremely important in the older dog. Newer evidence suggests that the cyclooxygenase (COX) II enzyme is important in maintaining renal blood flow (RBF) in dogs and therefore, COX II selective/specific NSAIDs have the potential to adversely affect renal function in dogs. In contrast, the hepatotoxicity associated with NSAIDs in dogs appears to idiosyncratic and unrelated the COX selectivity of the drug.

Potential nephrotoxicity of NSAIDs

Renal damage and disease can be caused by acute or chronic insults to the kidney. The terms renal disease and renal damage are used to denote the presence of renal lesions; these terms however imply nothing about renal function or the cause, distribution, or severity of the renal lesions. Acute kidney injury (AKI) often results from ischemic or toxic insults and usually affects the tubular portion of the nephron. Early detection of AKI facilitates appropriate intervention that can arrest or at least attenuate tubular cell damage and the development of established acute renal failure (ARF). In contrast, nephron damage associated with CKD is usually irreversible and can be progressive. Pre-existing CKD increases the risk of AKI associated with the use of potentially nephrotoxic drugs.

Renal prostaglandins help regulate RBF and glomerular filtration rate (GFR), renin release, and sodium excretion. Potential adverse effects of renal prostaglandin inhibition with NSAIDs can include decreased RBF and GFR, hypertension, salt retention and edema. Since both COX-1 and COX-2 enzymes are present/expressed in the canine kidney, any NSAID, regardless of its COX specificity or sparing properties, has the potential to produce adverse renal effects. In particular, dogs express higher basal levels of COX-2 in the kidney than some other species and may be uniquely sensitive to the nephrotoxic effects of COX-2 selective drugs. Although a number of studies have shown no adverse effects of the commonly used NSAIDs in dogs with normal kidneys, increased BUN and creatinine are common adverse events listed for NSAIDs at the FDA Adverse Drug Event website. Dogs in field trials of deracoxib and firocoxib had increased BUN at the end of the trials, while dogs treated with etodolac did not. In cases where RBF is decreased (e.g., dehydration and decreased cardiac output), the vasodilatory effects of renal prostaglandins are critical and the potential for adverse effects associated with NSAID use is increased. There is also concern that patients treated with drugs that can decrease GFR (such as angiotension-converting enzyme (ACE) inhibitors) may have increased renal toxicity when treated with NSAIDs. Studies of elderly human patients have confirmed this effect, but in a study of normal dogs treated with enalapril and tepoxalin no alteration of GFR was noted.

Risk factors for acute kidney injury

Dehydration and volume depletion are perhaps the most common and most important risk factors for development of AKI/ARF. Hypovolemia not only decreases renal perfusion which can enhance ischemic damage, but also decreases the volume of distribution of potentially nephrotoxic drugs. In addition to hypovolemia, renal hypoperfusion may be caused by decreased cardiac output, decreased plasma oncotic pressure, increased blood viscosity, systemic hypotension, and decreased renal prostaglandin synthesis. Any of these conditions can increase the risk of AKI associated with the use of NSAIDs.

Pre-existing renal disease can increase the potential for nephrotoxicity and ischemic damage by several mechanisms. The pharmacokinetics of potentially nephrotoxic drugs can be altered in the face of decreased renal function. Gentamicin clearance is decreased in dogs with sub-clinical renal dysfunction, and the same is probably true for other nephrotoxicants that are excreted via the kidneys. Animals with renal insufficiency also have reduced urine concentrating ability and, therefore, decreased ability to compensate for prerenal influences. Renal disease may also compromise the local production of prostaglandins that help maintain renal vasodilatation and blood flow. Age has been identified as a risk factor because many geriatric dogs have pre-existing renal lesions and sub-clinical loss of renal function.

Use of NSAIDs in dogs with chronic kidney disease

In dogs with pre-existing renal disease, the use of NSAIDs has the potential to exacerbate the renal disease and further decrease renal function and therefore NSAIDs should be avoided whenever possible in such animals. Hypertension and proteinuria associated with CKD are negative prognostic indicators and the potential for NSAID adverse effects may be increased in dogs with these complications. Certainly, the more advanced the stage of CKD, the greater the relative contraindication for the use of NSAIDs. It is important to remember that as early as stage II, > than 75% of the patient's nephrons are no longer functional and the patient's ability to auto-regulate RBF is compromised.

Recommendations surrounding the use of NSAIDs in CKD patients are largely speculative, but practical suggestions include:

1. Maintain good hydration in these patients at all times

2. Increase the monitoring of these patients for early signs of AKI

3. Increase the monitoring of these patients for hypertension.

4. Use the lowest efficacious dose of a NSAID

5. Use analgesic drugs with less renal toxicity in place of NSAIDs

6. Monitor quality of life indices on a regular basis. In people, small stable increases in BUN and creatinine are often tolerated in rheumatoid and osteoarthritis patients on NSAIDs, because no other drugs maintain adequate quality of life.

Early recognition of acute kidney injury

Numerous urine parameters can herald the development of ARF in patients with initially normal renal function. The value of monitoring these parameters in CKD patients receiving NSAIDs has not been assessed. Increased urine turbidity or changes in urine sediment (increasing numbers of renal epithelial cells or cellular or granular casts) are other indications of acute renal damage along with increased excretion of sodium and chloride. The acute onset of tubular glucosuria (normoglycemic glucosuria) or the acute onset or increases in proteinuria may also be indicative of AKI. The interpretation of all of the above parameters is enhanced by knowledge of baseline values.

Detection of enzymes in the urine such as gamma-glutamyl transpeptidase (GGT) and N-acetyl-beta-D-glucosaminidase (NAG) has proven to be a sensitive indicator of early renal tubular damage. These enzymes are too large to be normally filtered by the glomerulus, and, therefore, enzymuria indicates cell leakage, usually associated with tubular epithelial damage or necrosis. Urinary GGT originates from the proximal tubule brush border and NAG is present in proximal tubule lysosomes. In studies of gentamicin-treated dogs, increased urinary GGT and NAG activity was one of the earliest markers of renal damage/dysfunction. Interpretation of enzymuria is aided by baseline values obtained prior to a potential renal insult; 2 to 3-fold increases over baseline suggest significant tubular damage. Urine enzyme/creatinine ratios have been shown to be accurate in dogs prior to the onset of azotemia obviating the need for time urine collections.

Potential hepatotoxicity of NSAIDs

Hepatocellular toxicosis associated with administration of carprofen has been reported in a retrospective study of 21 dogs. Thirteen of these dogs were Labrador retrievers. The most common clinical signs were anorexia, vomiting, lethargy, and diarrhea. All of the dogs had elevations in serum ALT, 20 had elevations in serum ALP, and 18 were hyperbilirubinemic. The elevations in serum ALT were greater than the elevations in serum ALP in 16 dogs. Eighteen of the dogs had histologic evidence of hepatic necrosis characterized by multifocal to extensive vacuolar change, lytic necrosis, and apoptosis. It's interesting to note that 7 of 9 dogs evaluated by urinalysis had changes ranging from mild to severe proteinuria, normoglycemic glucosuria, and/or renal epithelial cells and casts in the urine sediment. Four of the affected dogs died or were euthanized within 3-5 days of presentation (all of the Labrador retriever dogs survived). The authors speculated that an idiosyncratic hepatopathy that may have been caused by the interaction of glucuronide metabolites of the acidic NSAID with plasma and hepatocellular proteins; resulting in the formation of antigenic NSAID-altered proteins causing immune-mediated damage to the liver.

Early recognition of hepatic damage

NSAID-associated hepatotoxicity appears to be a sub-acute toxicity (within 2-3 weeks of initiation of treatment) and unrelated to the type (COX selectivity) of the NSAID. Baseline liver enzyme values should be established prior to treatment. Post-treatment, any anorexia, vomiting, lethargy, or diarrhea should prompt NSAID discontinuation and re-assessment of liver enzymes compared to baseline values. In dogs that remain clinically normal, reassessment of liver enzymes should be performed between 2-3 weeks after the NSAID treatment is started. If pre-treatment assessment reveals mild to moderate elevations in liver enzymes, pre- and post-prandial bile acid concentrations should be measured. Most authors state that an elevation in liver enzyme in the absence of liver dysfunction is not a risk factor for NSAID-associated hepatotoxicity. In dogs with reduced liver function, NSAIDs should be avoided, if at all possible.

Recommendations surrounding the use of NSAIDs in patients with decreased liver function are largely speculative, but practical suggestions include:

1. Maintain good hydration in these patients at all times

2. Increase the monitoring of these patients for early signs of hepatotoxicity

3. Use the lowest efficacious dose of a NSAID/increasing the interval between doses

4. Use alternative analgesic drugs in place of NSAIDs