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Adverse Effects of NSAIDs on Renal Function

Adverse Effects of NSAIDs on Renal Function

Increasing attention is being attracted to the effects of nonsteroidal anti-inflammatory drugs (NSAIDs), which are analgesic compounds that are quite effective in treating numerous musculoskeletal disorders.

Many drugs are overprescribed, and many patients consume excessive amounts of analgesic, laxative or psychoactive drugs, but the magnitude of the use of NSAIDs is almost incredible. Many new types of NSAIDs have appeared because of the potential market. Usually, their activity and adverse effects are indistinguishable. Reporting of adverse side effects is inevitable with such a large exposure, but because a few studies have identified the true incidence of a given complication within an identified population taking the offending medication, assessment of the significance of such effects is difficult. Some of the reported side effects have necessitated the removal of individual drugs from the market because they were dramatic, and the importance of side effects has been overplayed in some cases, given the evidence available.


A major television inquiry was made concerning marketing practices and the responsibility of the medical profession in postmarketing surveillance due to the removal of benoxaprofen (Opren) from the market in the United Kingdom. The rheumatologists who were filmed enjoying a trip to Venice funded by the maker of another new NSAID as well as the academic community were severely criticized for less than meticulous objectivity in reporting studies funded by pharmaceutical companies.


The necessity of vigilance in identifying and recording the effects of drugs and in collecting accurate data to allow fair evaluation of risk/benefit ratios were underscored by all of this. For reporting adverse reactions to drugs, the committee on drugs and pharmacotherapy of the Ontario Medical Association (OMA) has established a program. It issued a warning in 1983 to the medical profession about the hazards of NSAIDs.


However, this type of reporting and data collection has many drawbacks despite the fact that it’s a laudable attempt to focus attention on the problem of reactions to drugs. Some of these drawbacks were acknowledged by the committee, such as the lack of information on the true incidence of reactions related to the population at risk, and the tendency to report reactions to newer drugs more frequently.


Further reactions to NSAIDs were reported in the update from the committee. The physicians submitted only 30% of the reports received, while the hospital pharmacists submitted over half of the reports. Of all the adverse reactions reported, NSAIDs were responsible for 10%, and 53% of those were considered serious cases. Almost all of the serious reactions were episodes of gastrointestinal bleeding, with or without proven peptic ulceration. The gastrointestinal side effects of NSAIDs are now widely known and are acknowledged in package inserts and advertising material, so that most of those reactions couldn’t have been missed.

peptic ulcers

However, the less well known but potentially dangerous side effects of NSAIDs on renal function, electrolytes and blood pressure still aren’t reported by the system. After treatment with NSAIDs, there have been many recent reports of renal impairment that contain the same deficiencies as those on gastrointestinal side effects. Additionally, many nephrologists believe that a large percentage of drug-induced renal damage as well as electrolyte disturbances and difficulties with control of blood pressure are caused by NSAIDs. Numerous adverse effects of NSAIDs on renal function have been identified, some of those are:


  • Acute tubular necrosis
  • Impairment of blood pressure control
  • Reduction in renal blood flow and the glomerular filtration rate
  • Water, salt and potassium disturbances
  • Allergic interstitial nephritis, with or without accompanying nephrotic  syndrome
  • Renal papillary necrosis



Inhibition of cyclo-oxygenase and thus, reduction of prostaglandin production are probably the result of most of the actions of NSAIDs. It isn’t surprising that interference with prostaglandin synthesis might affect renal function, because prostaglandins probably play a major role in mediating changes in renal perfusion, despite the fact that the nature of these effects and their relation to other vasomotor systems have not been fully worked out yet. If pharmacologic doses are used, infusion of most prostaglandins into the kidneys of experimental animals produces increases in renal blood flow. In anesthetized animals, NSAIDs have been shown to reduce the flow of renal blood, but not in intact, conscious dogs. There’s only little evidence that inhibition of prostaglandin production has any effect on renal blood flow or the glomerular filtration rate in healthy humans.


However, it is likely that NSAIDs reduce renal blood flow and the glomerular filtration rate predictably and uniformly in patients in whom renal perfusion is stressed by other factors including reduced effective blood volume or pre-existing renal disease.


Clinical evidence suggests that NSAIDs usually produce a decrease in the glomerular filtration rate and an increase in the serum creatinine level in patients who are receiving diuretics or who have cirrhosis, nephrotic syndrome, cardiac failure, renal impairment, a salt deficit or systemic lupus erythematosus. Even though this could sometimes progress to full-blown acute tubular necrosis necessitating dialysis, but in most cases it is reversible with the cessation of therapy. The reduction in renal function may contribute significantly to morbidity and mortality because even though the reduction in renal function is reversible, but the cause of renal deterioration in these patients may not be identified, or the deterioration may be attributed to the underlying disease.


Using NSAIDs may pose a special risk in older patients, especially if it’s given in combination with a diuretic, because the glomerular filtration rate decreases with age.



NSAIDs can impair renal function by an entirely different mechanism. All of these drugs have produced classic allergic interstitial nephritis on occasion, usually presenting as acute renal failure, often nonoliguric. The lesion is clinically and pathologically indistinguishable in many of these cases from that produced by other unrelated drugs, especially diuretics and antibiotics, however, there are also more than 20 reports of the concurrent appearance of allergic interstitial nephritis and a nephrotic syndrome characterized histologically only by effacement of the foot processes in the glomeruli. It has been suggested that this combined lesion may be due to uncontrolled production of lymphokines from sensitized T lymphocytes; this combined lesion also appears to be almost specific to NSAIDs. Withdrawal of the offending drug usually resolves both interstitial nephritis and the nephrotic syndrome, whether steroid therapy is used or isn’t.



In case an underlying renal disease is present, NSAIDs seem to occasionally contribute to episodes of acute renal papillary necrosis. Episodes of hypersensitivity vasculitis and cutaneous vasculitis have been attributed by anecdotal reports to these drugs, but the frequency of these complications is very low.



The metabolism of water and electrolyte is affected by NSAIDs. A small degree of fluid retention commonly occurs, but it becomes a clinical problem only in some rare cases. Hyperkalemia is the most important and potentially dangerous electrolyte disturbance, which could become a life-threatening problem. Hyperkalemia could result from changes in transecellular potassium transport, but since it is known that NSAIDs suppress rennin production, particularly in patients with pre-existing renal disease, so hyperkalemia may also be due to hyporeninemic hypoaldosteronism.



NSAIDs are known to reduce the antihypertensive effects of diuretics (3-blockers and captopril), and they also reduce furosemide-induced natriuresis. NSAIDs have also shown to reduce the effects of antihypertensive drugs by as much as 50% in hypertensive patients, but they don’t have any significant effect on the blood pressure of healthy people. On the package inserts of most NSAIDs, warnings about drug-induced renal damage are written in very small letters, if at all. Because several renal damages don’t even rate a mention, the reports of the OMA committee on drugs and pharmacotherapy might be interpreted as providing support for this.


Nephrotic syndrome, interstitial nephritis and vasculitis probably represent allergic phenomena that could be caused by many drugs and that occur in only a very small proportion of the vast numbers of patients taking NSAIDs. Holding the tantalizing possibility of a clue to the pathogenesis of minimal change disease, concurrent interstitial nephritis and nephrotic syndrome is of great academic interest, but it’s so rare that it doesn’t have an impact on decisions whether to use NSAIDs or not. The risk of hyperkalemia usually exists in patients with pre-existing renal disease whose potassium level would be monitored anyway; but despite this, the risk of hyperkalemia seems definite. The risk of loss of blood pressure control should present a major problem only in some rare cases, so this risk should be more widely recognized.


However, the reduction in the flow of renal blood and the rate of glomerular filtration may be a different matter. There’s a possibility that a high-risk group can be identified; for instance, NSAIDs apparently uniformly impair the renal function of people with renal disease or a reduced effective blood volume; but they don’t do so in healthy people. Clinical evidence of reduced liver function, congestive heart failure, renal disease, or any evidence of reduced blood volume identifies patients in whom renal function at the very least should be carefully monitored in case they have been prescribed NSAIDs. All patients with a high plasma rennin level that indicates some stress on renal perfusion are included in this group.


The incidence of transient renal impairment and acute tubular necrosis can be identified and then reduced with the help of further study of patients at risk. Although this requires more study, but it seems that one of the NSAIDs called sulindac may not have this adverse effect on renal function. There are reports of very small doses inducing renal impairment, so that whether the reductions in the glomnerular filtration rate induced by NSAIDs are dose related or not is still not clear. Even though there’s evidence suggesting that patients who exhibit renal injury due to phenylbutazone are more sensitive to further damage from other, chemically distinct NSAIDs, but it’s still not known whether patients receiving two or more NSAIDs are at increased risk. In treating musculoskeletal and rheumatic ailments, many people will continue to require and benefit from NSAIDs. But the possibility of renal impairment should always be considered, and after a few days of treatment, the renal function of patients whose function may already be stressed should be evaluated. Even though the adverse effects of NSAIDs on renal function are less clamant than the gastrointestinal effects, but they are probably as dangerous, potentially avoidable or reversible if care is taken, but less easily identified.


Prepared By: Dr. Mehyar Al-Khashroum
Edited By: Miss Araz Kahvedjian

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