• Nonsteroidal anti-inflammatory drug (NSAID)-associated acute renal failure (ARF) develops predominantly in patients with underlying risk factors.
  
• Clinical presentations can be asymptomatic or associated with uremic symptoms, edema (pulmonary and peripheral), hypertension, or electrolyte and acid–base disturbances.
  
• Elevated blood urea nitrogen (BUN) and serum creatinine (Cr) concentrations are present.
  
• An elevated BUN/Cr ratio (> 20) is often noted.
  
• Hyponatremia (serum [Na+] < 135 mEq/L), hyperkalemia (serum [K+] > 5.5 mEq/L), and non-anion gap metabolic acidosis (serum [HCO3−] < 20 mEq/L) are common.
  
• Urine [Na+] < 10–20 mEq/L and FeNa+ < 1.0% characterize NSAID-associated ARF.
  
• ARF is generally reversible with discontinuation of NSAIDs and treatment of concurrent disease processes.
  
• Severe ARF from NSAIDs may require dialysis.

Epidemiology of Nonsteroidal Anti-inflammatory Drug Use

NSAIDs are employed widely to treat pain, fever, and inflammation. Other potential uses for these drugs include treatment and prevention of colonic polyposis and Alzheimer-type dementia. The first NSAID discovered was sodium salicylate in 1763. In 1950, phenylbutazone was introduced into clinical practice. It was efficacious but its use faded due to bone marrow toxicity. Subsequently, indomethacin entered the market in the 1960s. More than 20 NSAIDs from seven major classes, including the selective cyclooxygenase (COX)-2 inhibitors (Table 15–1), are available in the United States. In addition to prescription NSAIDs, a large percentage of the general population consumes over-the-counter NSAIDs. Annually, more than 50 million patients ingest these drugs on an intermittent basis, while some 15–25 million people in the United States use an NSAID on a regular basis. Importantly, the elderly who are at risk for multiple complications of NSAID therapy, constitutes a growing population that has a prevalence of NSAID use as high as 15%.

Epidemiology of Nonsteroidal Anti-Inflammatory Drug-Associated Acute Renal Failure

Unfortunately, the price paid for these therapeutic benefits include a number of gastrointestinal (GI) complications and, to a lesser degree, adverse renal effects. It has been estimated that from 5% to 7% of admissions to the hospital occur due to toxicity of NSAIDs, with the major organs involved being the GI tract, kidneys, and nervous system. The nephrotoxicity of NSAIDs, in particular hemodynamic ARF, is a relatively uncommon but important problem. It has been estimated that anywhere from 1% to 5% of patients who ingest NSAIDs will develop nephrotoxicity. Some calculations approximate that 500,000 persons are likely to develop some form of NSAID-associated adverse renal impairment (Table 15–2). Exposure to NSAIDs has been noted to double the risk of hospitalization for ARF in patients with chronic kidney disease (CKD). Patients with a history of heart failure and hypertension, as well as those treated with diuretics are at greatest risk of NSAID-induced ARF. The effect also appeared to be dose related with ARF occurring with higher NSAID dose. Hospitalized patients are at even higher risk. Of the cases of drug-induced ARF that develop in the hospital, it is estimated that nearly 16% are due to NSAID therapy.

As will be discussed in more detail, the healthy general population is at less risk for ARF as compared with patients who possess multiple risk factors associated with NSAID nephrotoxicity. The majority of adverse renal effects are attributable to inhibition of renal prostaglandins by NSAIDs. The selective COX-2 inhibitors (celecoxib, valdecoxib, rofecoxib) appear to have a renal profile similar to other NSAIDs. Therefore, the term NSAIDs will refer to both nonselective NSAIDs and the selective COX-2 inhibitors. Electrolyte and acid–base disorders that occur with these drugs (hyperkalemia, hyponatremia, metabolic acidosis), hypertension that develops or is exacerbated by NSAIDs, and disturbances in sodium balance (edema formation, exacerbation of heart failure) will also be reviewed briefly in the context of ARF.

Prostaglandin Synthesis