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.