NSAIDs acute renal insufficiency

Care should be taken with all patients taking non-steroidal anti-inflammatory drugs (NSAIDs) to be aware of their potential to cause acute renal insufficiency, especially in patients stressed by major surgery, or by sepsis. 

A retrospective analysis of acute renal insufficiency related to NSAID therapy in France showed that clo-metacin was most frequently implicated. Cases of functional renal insufficiency and interstitial nephritis with nephrotic syndrome were reported (SEDA-12, 84). 

In contrast, published case reports and case series have provided more insight into the potential nephrotoxicity associated with COX-2-selective inhibitors. Taken together, these case reports suggest that COX-2 inhibitors, like non-selective NSAIDs, produce similar and consistent renal adverse effects in patients with one or more risk factors that induce prostaglandin-dependent renal function (that is patients with renal and cardiovascular disease and taking a number of culprit medications, such as diuretics and ACE inhibitors). Acute renal insufficiency, disturbances in volume status (edema, heart failure), metabolic acidosis, hyperkalemia, and hyponatremia have been commonly described. The duration of treatment with COX-2 inhibitors before the development of chnically recognized renal impairment ranged from a few days to 3-4 weeks. Withdrawal of COX-2 inhibitors and supportive therapy most often resulted in resolution of renal dysfunction, but in some patients hemodialysis was required (102,108-112). 

The interaction between potassium-sparing diuretics and NSAIDs is well documented (SED-14, 674). The major complications are deterioration of renal function and hjrper-kalemia. The risk associated with the non-selective COX-2 inhibitors is unknown. However, three patients had hyperkalemia (8.5, 5.4, and 5.1 mmol/1) after developing acute renal insufficiency while taking these drugs (8). 

A 62-year-old woman developed acute renal insufficiency after using topical ketoprofen for 5 days (11). She had several predisposing factors to NSAID-induced acute renal insufficiency, such as advanced age, chronic renal impairment due to polycystic kidney disease, and treatment with an ACE inhibitor and furosemide. 

There have been several reports of impaired renal function in patients taking ketorolac (SEDA-17, 112) (SEDA-18, 105) (SEDA-22, 117). The severity varies from slight to severe forms of renal insufficiency, which may even occur after a single dose of 30 mg. Because recent major surgery is considered a risk factor for renal insufficiency, particularly in elderly patients, the use of ketorolac, or other NSAIDs, for postoperative pain management is warranted only in carefully selected patients. Furthermore, a case report confirmed that oral ketorolac can cause acute renal insufficiency in young subjects without any predisposing factors (SEDA-21,106). 

A series of 11 spontaneously reported cases in which renal impairment was associated with the use of nimesulide has been described (17). The adverse events were represented by acute renal insufficiency n — 2), acute deterioration of chronic renal insufficiency n — 3), fluid retention n = 4), and oliguria and macro hematuria n = 1 each). The patients had a median age of 57 (range 17-81) years and six had some predisposing condition (chronic renal insufficiency, heart failure, diabetes, use of diuretics) to NSAID-induced functional renal impairment. Apart from one patient, nimesulide was taken for a very short time (less than 8 days). A favorable outcome ensued after withdrawal of therapy in aU patients. The acute deterioration of renal function described in these patients pointed to hemodynamically mediated renal impairment in all cases, with the exception of one man in whom interstitial nephritis was suspected. 

A case-control study provided convincing epidemiological evidence that the use of NSAIDs was associated with the risk of hospitalization for acute renal insufficiency (relative risk about 2.0) (SEDA-19, 95) (157). 

In two case-control studies, topical NSAIDs were not significantly associated with upper gastrointestinal bleeding or perforation, after adjustment for the confounding effect of concomitant use of oral NSAIDs (229), nor with hospitalization for acute renal insufficiency (157), although renal adverse effects have been described, albeit rarely, with these topical formulations (SEDA-18, 100). 

Acute renal insufficiency has been reported after the use of rofecoxib in patients with predisposing conditions, such as chronic renal insufficiency, renal transplantation, heart disease, liver cirrhosis, and dehydration (2-5). COX-2 inhibitors should be used with great caution, if at all, in patients with medical problems that are associated with prostaglandin-depen-dent renal function. From this point of view they do not differ from traditional NSAIDs (6). 

The nonsalicylate NSAIDs can also affect renal function. Risk factors fc>r NSAID-induced acute renal failure include congestive heart feilure, glomerulonephritis, chronic renal insufficiency, cirrhosis, systemic lupus erythematosus, diabetes mellitus, significant atherosclerotic disease in the elderly and use of diuretics. NSAIDs can adversely affect cardiovascular homeostasis and can be a risk factor for the onset or exacerbation of heart feilure. 

NSAIDs should be avoided in patients with chronic renal insufficiency due to the risk of inducing further kidney damage. In patients at risk, acute renal feilure can occur after a single dose of drug. Risk fectors include dehydration, hypertension, congestive heart failure, concomitant use of angiotensin-converting enzyme inhibitors, and advanced age. 

Whether selective COX-2 inhibitors can cause the other types of renal toxicity that are associated with non-selective NSAIDs (that is acute interstitial nephritis, nephrotic syndrome with or without renal insufficiency) is not known. 

Like many other NSAIDs, ketoprofen can cause acute interstitial nephritis (10). Renal insufficiency and the nephrotic syndrome due to membranous glomerulonephritis (an unusual cause of NSAID-induced nephrotic syndrome) have been described in an elderly patient taking long-term ketoprofen (SEDA-12, 86). 

The actual risk of NSAID-associated acute renal dysfunction also continues to be the subject of controversy. There is adequate evidence that underlying renal insufficiency, congestive heart failure, or hepatic cirrhosis are conditions that carry a high risk of NSAID-related renal functional impairment. It is still not known whether old age is a risk factor, whether the risk of renal impairment varies with different NSAIDs, or whether renal function continues to deteriorate, stabilize, or even improve in affected patients with continued use of NSAIDs. Three cases of renal insufficiency caused by topical NSAIDs have been described (SEDA-18,100). 

Over 30 billion tablets of NSAID were dispensed in the United States in 2000 approximately 16% represent prescriptions for NSAIDs [43]. These compounds enjoy a remarkable benefit/risk ratio when used in the treatment of acute self-limited pain syndromes. However, when taken chronically by the elderly or individuals with certain co-morbid conditions, the frequency of adverse reactions rises dramatically. Unfortunately, the real incidence of nephrotoxicity due to NSAIDs is unknown due to a lack of an accurate method of detection. The overall incidence could be very low, considering that up to 40 million people in the United States take NSAIDs on a regular basis [44]. In the 10 year-period 1972-1982,8 miUion prescriptions for mefenamic acid were given in the United Kingdom, and only 23 cases of mefenamic acid nephropathy were observed [45]. This is in contrast to the higher incidence of nephrotoxicity in selected and prospective studies. Corwin and Bonventre [46] found that renal insufficiency secondary to NSAIDs accounted for approximately 6% of cases of ARF seen during a two-year period. In a prospective collaborative study, NSAIDs rep-... 

Patients with chronic parenchymal renal disease show a fall in RBF and GFR during treatment with NSAID, including aspirin . In chronic glomerulonephritis, afferent arteriolar dilatation may be a compensatory mechanism in the maintenance of filtration. A study of patients with systemic lupus erythematosus revealed an abnormal increase in basal PGE2 excretion consistent with the postulated means of compensation. In other aetiologies of renal insufficiency, including diabetes, hypertension and interstitial nephritis, there is acute worsening of renal function with NSAID " ... 

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