Andrew Whelton, MD, FACP, F’CP, and Cindy W. Hamilton, PharmD

From the Department of Medicine (Dr. Whelton), Johns Hopkins University School of Medicine, Baltimore, Maryland, and Virginia Beach (Dr. Hamilton), Virginia. 

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are capable of inducing a variety of renal function abnormalities, particularly in high-risk patients with decreased renal blood perfusion who depend on prostaglandin synthesis to maintain normal renal function. Fluid retention is the most common NSAID-related renal complication, occurring to some degree in virtually all exposed individuals; however, clinically detectable edema occurs in less than 5% of patients and is readily reversible on discontinuation of the NSAID. Other electrolyte complications, notably hyperkalemia, are seen infrequently and occur in specific at-risk patients. The next most worrisome complication is acute deterioration of renal function, which occurs in high-risk patients and is also reversible. Nephrotic syndrome with interstitial nephritis is a rare problem of NSAID use and is reversible. Papillary necrosis is the only permanent complication of NSAIDs and is very rare. Altogether, these renal function abnormalities, with the exception of mild fluid retention, are clinically detectable in approximately 1% of exposed patients. Given the number of patients who take NSAIDs on a prescription or over-the-counter basis, the absolute number of at-risk patients is relatively large. Consequently, an appreciation for the risk factors and pathophysiology of NSAID-induced renal function abnormalities is required for optimal use of these drugs.

Introduction

Approximately 1-5 of persons who are exposed to a non steroidal anti-inflammatory drug (NSAID) will manifest one of a variety of renal function abnormalities. Although this percentage appears relatively low, the number of at-risk individuals is enormous because of the current use profile of NSAIDs, either as prescription or over-the-counter drugs. One in seven Americans is likely to be treated with an NSAID for a chronic rheumatologic disorder. If patients who take NSAIDs for acute problems are considered, the exposure rate will be even higher. Thus, of the 50 million Americans expected to use NSAIDs intermittently or routinely this year, at least 500,000 are likely to develop some degree of renal functional abnormality.

In descending order of frequency, the primary NSAID-related renal abnormalities are 1) fluid and electrolyte disturbances, 2) acute deterioration of renal function, 3) nephrotic syndrome with interstitial nephritis, and 4) papillary necrosis (Table I). Sodium chloride and water retention, the most commonly encountered renal effect of NSAID use, occurs to some degree in virtually all exposed persons but results in clinically detectable edema in less than 5% of patients. This rate is probably higher in selected at-risk patients. NSAID-induced fluid retention is typically benign, reversible on discontinuation of the NSAID, and easily managed in patients who require treatment. Other electrolyte abnormalities are also induced by NSAIDs, the most important of which is potassium retention and hyperkalemia. A high-risk group can also be identified for this electrolyte abnormality.

From the clinical point of view, the most worrisome renal side effect of NSAIDs is hemodynamically mediated acute renal failure, which occurs in individuals with pre-existing reduced renal blood perfusion. Ordinarily, the kidneys of such at-risk patients produce vasodilatory prostaglandins to maintain renal perfusion and function. The inhibitory effects of NSAIDs on renal prostaglandin production lead to acute, reversible renal failure in these patient. Acute deterioration of renal function occurs in 0.5 to 1% of patients who take NSAIDs on a chronic basis.

The nephrotic syndrome, with associated interstitial nephritis, is seen on rare occasions. Once again, it is reversible on discontinuation of the NSAID in question.

According to the respective manufacturers’ prescribing information, chronic administration of nearly all NSAIDs produces papillary necrosis in laboratory animals; and a few clinical case reports of papillary necrosis can be found in the recent medical literature. Within the framework of our present understanding of NSAID effects on the kidney, this appears to be the only irreversible form of renal toxicity.

Many of the renal abnormalities that are encountered as a result of NSAID use can be attributed to the action of these drugs on prostaglandins. Hence, a brief overview of the interactions between prostaglandins and renal function will be presented, followed by an analysis of the pathophysiology, clinical manifestations, patient risk factors, and  approaches to NSAID-induced renal syndromes.

THE PROSTAGLANDIN PATHWAY

Prostaglandins are ubiquitous substances that influence renal function along with a variety of other body systems.1’2 Conceptually, they may be considered local hormones or “autocoids” because they act in a paracrine or autocrine fashion. Biologic activity is limited to the site of action by the short half-life of  prostaglandins in circulation. In addition, prostaglandins are not stored in tissue, but are synthesized on demand.

Prostaglandins are derived from phospholipids by a common pathway (Figure 1). Phospholipids, of course, are widely distributed in cell membranes throughout the body. The most important precursor for prostaglandins is arachidonic acid. Cyclooxygenase is the catalyst for oxygenation of arachidonic acid, which is the step that is inhibited by NSAIDs. The interaction between aspirin and cyclooxygenase (acetylation) is irreversible, whereas that with other NSAIDs is reversible.

Arachidonic acid can also be metabolized to other mediators, depending on the cell type. For example, lipoxygenase catalyzes the production of leukotrienes, and mixed-function oxygenases catalyze the production of epoxyeicosatrienoic acids. Collectively, these oxygenated metabolites of arachidonic acid are known as eicosanoids because of their origin from a 20-carbon (eicosa-) polyunsaturated acid.3

Continuing along the common pathway (Figure 1), oxygenation of arachidonic acid results in production of prostaglandin G2, which is converted to prostaglandin H2 by hydroperoxidase and loss of a free radical. At this point, metabolism becomes highly specific for individual cell types, although many, if not all, of the metabolites are produced in the kidney. Prostaglandin E2 is a vasodilator, which, in the kidney, promotes diuresis and natriuresis. Prostaglandin E2 also inhibits lymphocytes and other cells that are involved in inflammation and allergic responses, which, as will be discussed later, may play a role in some NSAID-induced renal syndromes. Prostaglandin F2,, enhances excretion of sodium chloride and water. Prostacyclin, also known as prostaglandin 12, has a wide variety of actions including vasodilation, renin release, and inhibition of platelet aggregation. Prostaglandin D2 is a vasodilator of peripheral resistance vessels but is better known for its association with mast cell activation and bronchoconstriction. Thromboxane A2 is the principal metabolite of prostaglandin H2 in platelets and can act as a major vasoconstrictor within the kidney. These pharmacologically active metabolites of prostaglandin H2 are collectively known as prostanoids.

Prostaglandin Effects in Renal Function

Given the diversity of cell populations within the kidney and their various functions, the complexity of the interactions between prostaglandins and renal function is not unexpected. Prostaglandins are involved in renin release, local vascular tone, regional circulation, sodium and water homeostasis, and potassium
balance (Table H). The following sections describe these diverse effects. Detailed overviews of these interactions can be found in excellent reviews by Patrono and Dunn (2) and Oates and colleagues (3).

An important caveat in the following sections is that prostaglandins are not primary mediators of basal renal function in normal individuals. Prostaglandins typically operate in conjunction with a variety of other mediators, which, even in the absence of prostaglandins, can preserve homeostasis. Prostaglandin production is increased as needed in response to stress (e.g., decreased renal blood flow or blood volume). Thus, inhibition of prostaglandin function by NSAIDS is more likely to cause complications in at-risk patients with decreased renal blood perfusion than in the otherwise normal subject whose prostaglandins are merely one of many factors contributing to homeostasis.

Renin Release

Prostaglandins stimulate renin release, which plays an important role in the regulation of arterial blood  pressure, blood volume, and electrolyte balance. Prostaglandins can act independently or synergistically with the $-adrenergic system.4 Although the exact prostanoid mediator is not yet known, it is likely that prostacyclin is synthesized in response to a change in arteriole pressure or chloride reabsorption in the macula densa of the nephron.

Local Vascular Tone

Prostanoids are one of several local mediators that govern vascular tone through their actions on norepinephrine release at peripheral nerve endings. Prostaglandins E2 and D2 and, to a lesser extent, prostacydin promote vasodilation by inhibiting norepinephrine release. Prostaglandin E2 also antagonizes the effects of angiotensin II, a powerful vasopressor, on the neuroeffector junction. Conversely, prostaglandin F2,, and thromboxane A2 are vasoconstrictors. Regional Circulation Prostanoids contribute to regional circulation via their influence on local vascular tone. Under normal conditions, prostanoids do not regulate renal perfusion per se. However, certain conditions such as decreased renal blood flow are associated with the production of vasodilatory prostaglandins. Prostaglandin E2, prostacyclin, and prostaglandin D2 shift regional blood flow from cortical to juxtamedullary nephrons.

Sodium and Water Homeostasis

All prostanoids are capable of acting in the renal cortex to regulate sodium and water homeostasis; however, prostanoids are only one of many factors that share this function.3 Prostaglandins E2 and D2, prostacyclin, and, to a lesser extent, prostaglandin F2a increase the rate of salt and water excretion. Prostaglandin E2 inhibits sodium chloride transport in the thick ascending limb of the loop of Henle and the collecting duct.5’6 In addition, prostaglandins antagonize the effects of antidiuretic hormone.7’8 Prostanoids do not have a direct effect on glomerular filtration rate; however, vasodilation associated with prostaglandin E2, prostacyclin, and prostaglandin D2 increases renal blood flow, and, as previously mentioned, shunts blood flow from the cortical to juxtamedullary nephrons. The net result is enhanced diuresis and natriuresis due to reduced medullary hypertonicity and increased interstitial pressure.

Potassium Balance

Prostanoids indirectly lower potassium by their effects on glomerular filtration and renin.3 As previously mentioned, vasodilatory prostaglandins increase renal blood flow. This may enhance the direct intratubular delivery of potassium into the distal nephron for excretion. Alternatively, this may serve to quantitatively increase sodium delivery into the distal nephron with resultant reabsorption of sodium
in exchange for potassium, which is then excreted in the urine. Secondly, prostacyclin is believed to promote renin release. Activation of the renin-angiotensin pathway ultimately causes aldosterone to stimulate potassium excretion in the distal convoluted tubule and collecting duct. However, potassium balance is also regulated by a number of other factors such as insulin and the 9-adrenergic system.

Fluid and Electrolyte Disturbances

Sodium and Water Retention

The most common and universal renal complications of NSAIDs are sodium retention and edema. According to prescribing information accompanying nearly all NSAIDs, edema occurs in at least 3% of patients. The incidence is probably higher in patients who take therapeutic doses over prolonged periods. The onset of fluid retention usually occurs early in the course of therapy and can be dramatic as illustrated by the 15-kg weight gain in a 70-year-old man who took ibuprofen for only 17 days.9

Occasionally, the patient may retain water in excess of sodium. Severe, reversible hyponatremia (118 tmol Na/L) occurred in a patient who took ibuprofen for only 3 days. This patient had underlying renal impairment (CrC1 12 mL/min).1#{176}

The multiple mechanisms by which NSAIDs interfere with water and sodium metabolism may explain the frequency of this complication. As previously mentioned, NSAIDs have the potential to disrupt diuresis and natriuresis by interfering with prostaglandin-mediated sodium chloride transport,
antidiuretic hormone, and distribution of blood flow from cortical to juxtamedullary nephrons.13 The hypothesis for the pathogenesis of the nephrotic syndrome is also operative in this situation. By shunting arachidonic acid metabolism from prostaglandins to lipoxygenase products, NSAIDs may favor production of eicosanoid derivatives that increase capillary permeability.

Hyperkalemia

Hyperkalemia is an unusual complication of NSAIDs, presumably because of the multiplicity of factors that are capable of maintaining potassium balance, even in the absence of prostaglandins. Hyperkalemia is more likely to occur in patients with preexisting renal impairment,11’12 cardiac failure,13 diabetes, 12 or multiple myeloma’14 or in patients who receive potassium supplementation,15 potassiumsparing diuretics,16 or angiotensin-converting enzyme (ACE) inhibitors. Indomethacin appears to be the major NSAID associated with this complication and has produced hyperkalemia in patients without apparent risk factors.17 Thus, indomethacin may have a direct effect on the cellular uptake of potassium, 18 in addition to the known effects of NSAIDs on potassium delivery to the distal tubule as well as on the renin-angiotensin and aldosterone pathways.

NSAID-induced hyperkalemia often occurs in the setting of NSAID-induced acute renal deterioration or worsening of underlying renal impairment. However, the severity of hyperkalemia can be disproportionate to that of renal impairment. For example, Tan and colleagues reported a patient who was treated with indomethacin and had a serum potassium of 6.2 mEq/L in spite of only mildly abnormal renal function.1#{176} In this patient, plasma renin and aldosterone levels were suppressed and did not respond to furosemide or postural changes. Urinary prostaglandin E2 was also suppressed. Discontinuation of indomethacin resulted in normalization of potassium, prostaglandin E2, and a rebound of renin and aldosterone.

Acute Deterioration of Renal Function

Role of Prostanoids in Maintaining Renal Blood Flow

Although NSAIDs do not impair glomerular filtration in normal individuals,20’21 acute renal decompensation may occur in at-risk patients with various extrarenal or renal disease processes that lead to decreased renal perfusion (Table III). Renal prostaglandins play an important role in the maintenance of homeostasis in these patients, so drug-induced disruption of counter-regulatory mechanisms can produce clinically important and even severe renal functional deterioration.2’3

Acute renal deterioration in this setting can be attributed to the interruption of the delicate balance between hormonally mediated pressor mechanisms and prostaglandin-related vasodilatory effects (Figure 2). In at-risk patients, volume contraction triggers pressor responses via adrenergic and renin-angiotensin pathways. Ordinarily, vasodilatory renal prostaglandins counterbalance the vasoconstrictive effects of norepinephrine and angiotensin H. The addition of NSAIDs increases the risk of azotemia and possibly ischemic damage to the kidney by removing the protective effects of vasodilatory prostaglandins and allowing unopposed vasoconstriction.

Clinical Features of Acute Renal Failure

Initially, this NSAID-induced renal syndrome is of moderate severity and is characterized by increasing BUN, creatinine, potassium, and weight with decreasing urine output. NSAID-induced acute renal failure is usually reversible over 2 to 7 days after discontinuation of therapy; however, morbid consequences can occur if the diagnosis is not recognized early. Continued NSAID therapy in the setting of de teriorating renal function may progress rapidly to the point wherein dialysis support is required.22 Despite this profound level of renal functional impairment, the kidney will nonetheless recover several days to weeks after discontinuation of the NSAID. Development of this type of “total” renal failure, which is often inappropriately designated as “acute tubular necrosis,” represents the extreme end of the spectrum of hemodynamic insult rather than a separate clinical entity.

 

Risk Factors for Acute Renal Failure

The risk of acute renal deterioration is highest in patients with liver disease, pre-existing renal impairment, cardiac failure, protracted volume contraction due to diuretic therapy or intercurrent disease, or old age. NSAID-induce renal decompensation has been well documented in patients with cirrhosis, particularly
particularly when ascites is present.3 Urinary excretion of prostaglandin E2, prostacyclin metabolites, and thromboxane A2 is increased in these patients.23’24 An analogous situation exists in patients with underlying congestive heart failure,25 nephrotic syndrome, 26’27 or lupus nephritis.28’29

Patients with chronic renal impairment are at increased risk of NSAID-induced renal failure because of inadequate renal prostaglandin production. We documented NSAID-induced acute renal failure in patients with asymptomatic mild, but chronic, renal failure (serum creatinine between 1.5 and 3.0 mg/ dL).3#{17B6a}seline excretion of urinary prostaglandin E2 and 6-keto-prostaglandin Fia was quantitatively lower in the individuals who developed NSAID-induced renal decompensation than in those who did not, and ibuprofen proved to be more problematic than either piroxicam or sulindac. On initiation of ibuprofen, urinary prostaglandin excretion fell in all patients, but trough concentrations were quantitatively lower in the subset of patients who experienced acute renal failure.

Volume contraction due to diuretic therapy or an intercurrent disease that results in dehydration represents another important risk factor for the deve lopment of NSAID-induced acute deterioration of renal function.22’31-32 Elderly patients are also at increased risk. We estimate that age of 80 years or greater is an independent risk factor because the physiology of ageing within the kidney results in 50% loss of function in 50% of the population at age 80, primarily as a result of the progression of arteriolonephrosclerosis.

Pharmacodynamics of Acute Renal Failure

NSAID-induced acute renal decompensation is a pharmacologically predictable phenomenon that occurs in a dose-related fashion. In our triple-crossover study of 12 women with mild renal failure, ibuprofen (800 mg three times daily) was discontinued on day 8 because of worsening renal function ( 1.5 mg/dL increase in serum creatinine) or hyperkalemia (potassium 6 mEq/mL) in 3 patients. When these patients were rechallenged at a 50% lower dose of ibuprofen, two patients again had evidence of acute renal deterioration.30 Another important finding in our study was the time of onset of acute renal decompensation.3#{176} Ibuprofen- induced renal failure occurred rapidly (within days), but piroxicam and sulindac did not cause renal deterioration during the 11-day treatment period. A pharmacokinetic analysis in these patients provides insight. Ibuprofen, which has a short elimination half-life, reached maximum serum  concentrations quickly. In contrast, piroxicam and sulindac have longer half-lives and continued to accumulate throughout the treatment period. These findings are consistent with basic pharmacologic principles and suggest that NSAIDs having short elimination half-lives will reach steady state and exert maximum pharmacologic effects before NSAIDs having longer half-lives.

"Renal Sparing" NSAIDs - ?

Although all NSAIDs have the potential to induce acute renal impairment, some quantitative differences may exist. Sulindac has been hypothesized to be renal sparing, possibly because of its unusual metabolic pathway.33 The parent compound, sulindac sulfoxide, is an inactive prodrug that undergoes hepatic metabolism to sulindac sulfide, which is the metabolite that exerts anti-inflammatory activity. Sulindac sulfoxide is also metabolized to a much lesser extent to an inactive metabolite, sulindac sulfone. It has been hypothesized that, within the kidney, sulindac sulfide is reversibly oxidized to the inactive parent compound, sulindac sulfoxide, such that renal prostaglandin production would not be influenced.

In clinical studies, urinary prostaglandin levels and renal effects were unchanged in patients with normal renal function34’35 and states of proteinuria.36 However, the duration of sulindac in these studies may have been insufficient to appreciate the full pharmacologic effect of sulindac. NSAID-induced changes may not have been detectable because of the presence of only very mild renal impairment or absence of renal failure altogether in these studies. Longer courses of sulindac in patients with slightly more severe renal impairment have been associated with statistically significant reductions in urinary prostaglandins3#{176} and glomerular filtration rate.37

The ability of sulindac to  inhibit prostaglandin synthesis and impair renal function has been confirmed in a different high-risk group, namely patients with hepatic cirrhosis and ascites.38 We have also identified the development of profound acute renal failure in high-risk patients who received sulindac for several days to weeks. Collectively, these clinical experiences indicate the need for cautious and timely monitoring of high-risk patients who receive NSAIDs.

Nephrotic Syndrome With Interstitial Nephritis

NSAIDs also cause another type of renal dysfunction that is associated with various levels of functional  impairment and characterized by the development of the nephrotic syndrome with interstitial nephritis. 1’22’39’4#{17T6h}e clinical features, absence of risk factors, and pathophysiology distinguish this from other NSAID-induced renal syndromes and from classic drug-induced allergic interstitial nephritis.

The features of this NSAID-induced renal syndrome are variable. The patient may experience edema, oliguria, and/or foamy urine.41 Systemic signs of allergic interstitial nephritis such as fever, drug rash, peripheral eosinophilia, and eosinophiluria are generally absent.1’22’40’41 The urine sediment contains microscopic hematuria and pyuria.1’41 Proteinuria typically is in the nephrotic range.1’39 We have noted that renal functional deterioration can range from minimal to severe.

Characteristically, this form of nephrotic syndrome consists of minimal change glomerulonephritis with interstitial nephritis, which is an unusual combination of histologic findings. NSAID-induced nephrotic syndrome without interstitial disease is rare but has been reported in a handful of patients who took fenoprofen, sulindac, or diclofenac. Conversely, interstitial disease without nephrosis has been reported in a few patients, but this may, in fact, represent allergic interstitial nephritis.41

In spite of nephrotic-range proteinuria, the most impressive histopathologic findings involve the interstitium and tubules. A focal diffuse inflammatory infiltrate can be found around the proximal and distal tubules. We reported that the infiltrate primarily consisted of cytotoxic T lymphocytes but also contained other T cells, B cells, and plasma cells.39 Changes in the glomeruli were minimal and resembled those of minimal change glomerulonephritis with marked epithelial-foot process fusion. Other investigators have reported similar findings.1’22’41-42

The onset of NSAID-induced nephrotic syndrome is usually delayed, having a mean time of onset of 5.4 months after initiation of NSAID therapy4#{176}and ranging from 2 weeks to 18 months.1 NSAID-induced nephrotic syndrome is usually reversible 1 month to I year after discontinuation of NSAID therapy. During the recovery period, some patients may require dialysis. Corticosteroids have been used empirically, but it is not clear whether they hasten recovery.1’22’39 If proteinuria does not significantly remit within 2 weeks after discontinuation of the NSAID, we recommend a standard, 2-month trial of corticosteroid therapy as would be employed in a nephrotic adult with idiopathic minimal change or membranous glomerulonephritis.

Risk factors are not well understood. Underlying renal impairment does not appear to be a risk factor. Old age has been suggested as a risk factor, but  this may also be a reflection of the usual candidate for chronic NSAID therapy. The syndrome has been more commonly reported with fenoprofen than other NSAIDs. Approximately two-thirds of cases have been associated with fenoprofen. Hence, the structure of the drug itself appears to be of major importance. The syndrome has been attributed, nonetheless, to virtually all NSAIDs, including those from structurally distinct classes.1-22’39-40’41

The mechanism of NSAID-induced nephrotic syndrome has not been fully characterized. The association of this syndrome with structurally distinct NSAIDs suggests a common denominator. T lymphocytes may function as immune mediators instead of the humoral factors that are responsible for classic drug-induced allergic interstitial nephritis. In keeping with this hypothesis, NSAID-induced prostaglandin inhibition may play an indirect role. By inhibiting cyclooxygenase, NSAIDs may promote metabolism of arachidonic acid to non-prostaglandin eicosanoids. Indeed, leukotrienes, the products of the interaction between lipoxygenase and arachidonic acid, are known to recruit T lymphocytes and promote the inflammatory process. Leukotrienes may also contribute to proteinuria by increasing vascular permeability.

Papillary Necrosis

Papillary necrosis with interstitial nephritis is a well-known complication of chronic phenacetin abuse that has been reviewed extensively elsewhere. 43 Fortunately, the incidence of the latter complication has diminished considerably because of a better understanding of the pathophysiology and patient education. It has been suggested that chronic aspirin alone may also induce papillary necrosis,44 but it is not clear that this can actually occur. What is clinically apparent is that chronic (10 to 20 years) exposure of the kidney to high doses of analgesic combinations such as salicylate and acetaminophen (the metabolite of phenacetin), often with the addition of caffeine, can and will produce chronic, progressive papillary necrosis.

The black pigmentation found within necrotic papillae associated with phenacetin abuse (or phenacetin- containing combinations) is absent in patients who ingest aspirin alone or other NSAIDs. This black pigmentation may represent a breakdown product of phenacetin.43

In preclinical studies, nearly all of the NSAIDs produced papillary necrosis in experimental animal models. Clinical toxicity is exceedingly rare but has been reported for ibuprofen,45 phenylbutazone,46’47 fenoprofen,48 and mefenamic acid,49 and according to prescribing information, several other NSAIDs.

The typical candidate for NSAID-induced papillary necrosis is a middle-aged woman with a history of ingesting over-the-counter, combination analgesics for headache. Closer questioning may reveal that the patient takes the analgesic for the mood-altering effects of caffeine. Renal manifestations may include loin pain, macroscopic hematuria, ureteral obstruction, and/or uremia. Urinary tract infection and hypertension are common secondary findings. Reversibility is determined by the extent of deterioration and ability to discontinue NSAID therapy.43 Recent reports from the FDA5#{176o}f spontaneous gross hematuria associated with NSAIDs such as ibuprofen (three cases) suggest that papillary necrosis also occurs with newer NSAIDs. These data suggest a minor degree of papillary damage, but chronic progressive deterioration of renal function is not a feature of most reports.

The mechanism of NSAID-induced papillary necrosis is not clear. The causative role of NSAIDs is difficult to delineate because of the presence of confounding factors such as underlying disease, urinary tract infection, and/or concomitant medications. Selected NSAIDs may exert a direct toxic effect on renal papillae, particularly combinations of aspirin and acetaminophen, a major metabolite of phenacetin. Both drugs are highly concentrated in the medulla. Aspirin depletes cellular glutathione, which would otherwise neutralize the acetaminophen metabolite, N-acetyl-benzo-quinoneimine. Without glutathione, this highly reactive metabolite could lead to cell death.43

Prostaglandin inhibition may also play a role.1 Medullary ischemia, a possible precipitating factor in development of papillary necrosis, results from NSAID-induced reduction in blood flow to the renal medulla in experimental models (51, 52). 

Other NSAID Induced Renal Syndromes

Phenylbutazone, suprofen, and benoxaprofen produce unique renal syndromes that are of historic interest. These complications are rarely encountered because phenylbutazone use has diminished because of the availability of safer drugs, and suprofen and benoxaprofen have been removed from the market.

Two mechanisms have been identified for phenylbutazone- induced acute oligo-anuric renal failure.1 Phenylbutazone is known to inhibit uric acid reabsorption, which may cause hyperuricosuria, and ultimately, bilateral ureteral obstruction due to uric acid stones.53 Secondly, an idiosyncratic reaction has  been reported that results in acute tubular injury without uric acid precipitation.54 Underlying renal impairment is a risk factor for the latter reaction. Also, patients experiencing this reaction appear to be predisposed to subsequent renal injury from other NSAIDs. These observations suggest that prostaglandin inhibition may play a role in the development of the idiosyncratic reaction.1

Suprofen-induced acute renal failure is characterized by acute flank and/or abdominal pain, occurring within 12 hours after starting therapy. In a series of 16 patients described by Hart and colleagues,55 the mean peak serum creatinine was 3.6 mg/dL (range: 2-8 mg/dL) and was within normal limits at followup in most patients. Urinalysis revealed microhematuna (8/12 patients) and proteinuria (7/12 patients) but no crystals. One of our patients with suprofeninduced flank pain syndrome had birefringent crystals in the urine several hours after the injection of the drug and at a time when rehydration had already been commenced. We did not determine if these crystals were uric acid or drug metabolites.

The mechanism of suprofen-induced flank pain and acute renal failure was never conclusively identified before the drug was removed from the market. No obvious risk factors were identified in the previous series since all patients appeared to be in good health and took NSAIDs for acute symptomatic relief. It has been hypothesized that the suprofen flank pain syndrome is related to acute uric acid  crystal precipitation within the nephron leading to acute urinary flow obstruction.50’55 Suprofen is known to have uricosuric activity. The finding of hyperuricemia (mean: 10.8 mg/dL) in four of four patients suggests that this may be a risk factor.55

Benoxaprofen, an NSAID with a long half-life, was removed from the market in 1982, within weeks after its introduction, because of adverse effects. It is remembered for severe hepatic toxicity that occasionally resulted in death; however, renal failure was also a contributing factor. Risk factors for benoxaprofen- induced toxicity were old age and concomitant diuretic therapy, two factors known to increase the risk of acute functional renal failure.

Conclusions

NSAIDs are considered safe and suitable for the treatment of a variety of chronic and acute conditions. The risk of renal failure after the initiation of any given NSAID is low; however, the number of at-risk patients is high because of the widespread use of these drugs.

In most cases, NSAID-induced renal syndromes are a direct or indirect result of prostaglandin inhibition, which has important clinical implications. At this time, it is not clear whether it is possible to completely separate the effects of NSAIDs on systemic prostaglandins, which mediate anti-inflammation activity, from renal effects. Thus, under the right circumstances, virtually any NSAID can produce renal complications. Fortunately, these complications are usually reversible if the diagnosis is recognized promptly and NSAID therapy is discontinued.

With an understanding of the pathophysiology involved, preventive clinical measures can be put into operation. Risk factors have been identified for most NSAID-induced renal syndromes (Table IV). It is prudent to avoid high-dose, chronic NSAID therapy in at-risk patients (Table III). Unfortunately, this is not always possible. If NSAIDs are necessary in these high-risk groups, the patients should be monitored closely and receive appropriate counseling. Monitoring should begin within a week after initiation of a short-acting NSAID (e.g., ibuprofen) and continue indefinitely for signs of syndromes having delayed onset (e.g., nephrotic syndrome with interstitial nephritis).

In the event of NSAID-induced renal failure, the NSAID should be discontinued promptly. The patient should receive supportive care as needed. After stabilization of renal function, rechallenge with the same dose of the offending drug or even a structurally unrelated NSAID is likely to reproduce the adverse effect. (Patients who have recovered from an episode of protracted dehydration due to diuretics or intercurrent disease are an exception to this rule.) Thus, if anti-inflammatory therapy is mandatory, underlying risk factors should be identified and eliminated, if possible. Unfortunately, this is often not possible, as in the case of old age or chronic heart, kidney, or liver disease. These patients may require alternative therapy using corticosteroids or other supportive drugs such as acetaminophen or colchicine.

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