Use of Nonsteroidal Antiinflammatory Drugs in Kidney Disease

Chapter 190

Use of Nonsteroidal Antiinflammatory Drugs in Kidney Disease

Nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed analgesic agents in veterinary medicine. Their analgesic, antiinflammatory, and antipyretic effects are attributed to reduction of prostaglandin synthesis caused by inhibition of cyclooxygenase (COX) enzymes. Unfortunately, gastrointestinal, hepatic, and renal toxicities have been associated with use of these agents. Other potential adverse effects appear to be less important (e.g., delayed bone and soft tissue healing) or have not been well studied (e.g., increased systemic arterial blood pressure) in dogs and cats. The effects of NSAIDs on the kidneys, particularly in animals with chronic kidney disease (CKD), deserve special attention largely because prostaglandins play a pivotal role in the maintenance of renal function. Furthermore, the effects of newer NSAIDs on the kidneys cannot be predicted from studies of their gastrointestinal effects.

Cyclooxygenase Isoenzymes

The COX-1 isoenzyme generally is thought of as the “housekeeping” isoform that mediates the formation of constitutive prostaglandins produced by many tissues. When the presence of isoforms in the kidney was discovered, it was believed that the renal COX-1 isoenzyme was the constitutive form responsible for control of renal function and that COX-2 was the inducible form, being expressed primarily in the presence of renal inflammation associated with renal diseases. Although it still is generally accepted that COX-2 is the isoenzyme that contributes to renal inflammation, COX-2 is expressed constitutively in the kidney, is important in the control of renal blood flow and glomerular filtration rate, is up-regulated in volume depletion and in both inflammatory and noninflammatory forms of CKD, and contributes to the viability of renal tubular and interstitial cells (Cho et al, 2009; Radi, 2009). There is a third COX isoenzyme, a splice variant of COX-1, that is referred to variously as COX-1 variant or COX-3. Its role in renal function is not understood.

There are important differences between the distribution of these isoforms in human and in canine kidneys. The COX-1 isoenzyme is expressed constitutively in the canine collecting duct cells, medullary interstitial cells, endothelial cells, and smooth muscle cells of the preglomerular and postglomerular vessels. Critically, the COX-2 isoform has a wider constitutive distribution in the canine kidney and is present in the canine glomerulus, loop of Henle, macula densa, renal interstitial cells, and blood vessels. The distribution pattern is more extensive in canine kidneys than in human kidneys, and this has led to the assertion that dogs are more susceptible to nephrotoxicity from COX inhibition in general, and COX-2 inhibition in particular, than are people (Khan et al, 1998; Radi, 2009). Although isoenzyme distribution in the feline kidney is incompletely understood, a recent report has identified the presence of both isoenzymes in the feline kidney and suggested there is up-regulation of COX-2 in both canine and feline CKD (Yabuki et al, 2012).

Renal Effects of NSAIDs

NSAIDs in Normal Animals

Several inhibitors of COX enzymes have been used for management of postoperative pain and osteoarthritis in dogs and cats. These can be classified broadly into two categories: nonselective NSAIDs, which inhibit both COX-1 and COX-2 (e.g., aspirin and ibuprofen), and COX-2–selective NSAIDs, which preferentially inhibit COX-2 (e.g., carprofen, deracoxib, etodolac, firocoxib, and meloxicam). The selectivity of NSAIDs in the latter category varies, and all agents inhibit both isoenzymes to some extent.

In the kidney, prostaglandins have a variety of homeostatic effects, including a contribution to control of hemodynamic function (i.e., renal blood flow and glomerular filtration rate) and cytoprotective functions (e.g., sustaining interstitial and tubular cells in the medulla, which is a hypertonic, comparatively hypoxic environment). Although early proposals held that renal COX-1 was constitutive and was responsible for the maintenance of renal blood flow and glomerular filtration rate and that renal COX-2 was present only in renal disease or inflammation, both isoenzymes are constitutive and inducible in the kidney and both contribute to the control of renal blood flow, glomerular filtration rate, renin release, and cytoprotection. Although these roles are important in patients at risk (see later), neither preferential inhibition of COX-2 with selective NSAIDs nor inhibition of both isoenzymes with nonselective NSAIDs appears to have important effects on kidney function in normal dogs and cats (Goodman et al, 2009; Surdyk et al, 2011, 2012).

NSAID Nephrotoxicity

There are two general syndromes of NSAID nephrotoxicity (Table 190-1): acute hemodynamic insult (acute cortical nephrotoxicity) and chronic cytotoxic insult (chronic medullary cytotoxicity). Although either or both syndromes may occur in any particular patient, most reports to date in veterinary medicine implicate NSAIDs in what appears to be hemodynamically mediated acute cortical nephrotoxicity that manifests as classical acute kidney injury (Bacia et al, 1986; Poortinga and Hungerford, 1998). Most affected patients have one or more factors that place them at risk (see Table 190-1). Early clinical findings include the presence of renal tubular cells and casts in urine sediment, renal enzymuria, and proteinuria (microalbuminuria). Subsequently, there is a loss of renal concentrating ability and the development of electrolyte and acid-base disorders. Renal azotemia, with serum creatinine concentration proportional to the magnitude of renal damage, is a comparatively late finding. Although originally it was hoped that the newer generation of selective NSAIDs would pose less risk of nephrotoxicity, data to support this hypothesis are lacking. Inhibition of either or both COX isoenzymes can result in toxicity in animals at risk. In dogs, the deleterious renal hemodynamic effects of NSAIDs do not appear to differ between selective and nonselective NSAIDs (Surdyk et al, 2011, 2012).

TABLE 190-1

Syndromes of Renal Injury Associated with Nonsteroidal Antiinflammatory Drug (NSAID) Use*

  Acute Cortical Nephrotoxicity Chronic Medullary Cytotoxicity
Risk factors Extracellular fluid volume depletion, especially dehydration
Systemic hypotension
General anesthesia
Dietary salt restriction
Diuretic use
Administration of antihypertensive agents that are not renal vasodilators
Higher NSAID dosage
Genetic factors?
Chronic dehydration
Chronic hypotension or multiple acute bouts of hypotension
Administration of antihypertensive agents that are not renal vasodilators
Higher NSAID dosage
Genetic factors?
Toxic effect Loss of renoprotective effects of vasodilatory prostaglandins Loss of cytoprotective effects of prostanoids
Primary effects of toxicity Decreased renal blood flow and glomerular filtration rate Necrosis of medullary interstitial and tubular cells (papillary necrosis)
Isoenzyme Inhibition of COX-1 more important than inhibition of COX-2 Inhibition of COX-2 more important than inhibition of COX-1
Early clinical findings Renal cells and casts in urine sediment, renal enzymuria, proteinuria, or microalbuminuria None
Intermediate clinical findings Serum electrolyte abnormalities, reduced urine concentrating ability Renal enzymuria, decreased urine concentrating ability
Late clinical findings Rising serum creatinine concentration Serum electrolyte and acid-base abnormalities, rising serum creatinine concentration
Interspecies differences in susceptibility Dogs more susceptible than people; cat susceptibility unknown Dogs more susceptible than people; cat susceptibility unknown

COX, Cyclooxygenase.

*Limited clinical information is available for dogs and cats. Information is extrapolated from clinical reports of nephrotoxicity in veterinary medicine, laboratory studies in dogs and cats, and results of studies in other species.

< div class='tao-gold-member'>

Stay updated, free articles. Join our Telegram channel

Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Use of Nonsteroidal Antiinflammatory Drugs in Kidney Disease

Full access? Get Clinical Tree

Get Clinical Tree app for offline access