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Mechanisms of NSAID Induced Functional Renal Toxicity

By: James W.  Schurr & Stephen Argiro, PharmD Candidates c/o 2014

Patients frequently utilize non-steroidal anti-inflammatory drugs (NSAIDs) for a wide variety of conditions, including but not limited to arthritis, headaches, and generalized pain.  Despite an excellent safety profile, NSAIDs are associated with certain toxicities, including renal complications (particularly among at risk populations).1  Acute and chronic interstitial nephritis, glomerulopathy, and altered intraglomerular hemodynamics have been established as mechanisms by which NSAIDs induce nephrotoxicity.1  Patients at risk for these problems include those with age-related declines in glomerular filtration rate (GFR), hypovolemia, those concurrently on loop diuretic therapy (e.g. furosemide, torsemide), congestive heart failure (CHF), cirrhosis of the liver, underlying renal disease, and concurrent use of angiotensin converting enzyme inhibitors (ACEIs) (e.g. enalapril, ramipril) or angiotensin receptor blockers (ARBs) (e.g. valsartan, losartan).2

The renal mechanisms of toxicity include two overall categories of functional and inflammatory renal impairment.  Functional renal impairment involves the decrease of glomerular ultrafiltrate production or intraglomerular hydrostatic pressure, while inflammatory renal impairment involves an underlying hypersensitivity response with interstitial nephritis and glomerulopathy.1,3  Functional renal failure is a product of inadequate glomerular hydrostatic pressure caused by changes in the hemodynamics of the afferent and efferent arterioles.3  In abnormal renal physiology, the blood flow through these arterioles is altered, causing an imbalance in the normal pressure and leading to an ischemic state.3  Interstitial nephritits can be acute or chronic with NSAID use, and occurs as an idiosyncratic, non-dose-dependent, allergic response.1  Inflammation is noted by the presence of leukocytes found in the urine upon presentation.1,4  Interstitial nephritis leads to minimal change glomerulopathy (often manifesting as nephrotic syndrome), and is characterized by heavy proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria.4

      NSAIDs inhibit the cyclooxygenase (COX) enzymes, which are part of the arachidonic acid pathway.2  COX has two variant forms (i.e. COX-1, COX-2), each with its own particular inflammatory effect.2  COX-1 and COX-2 have anatomical and physiological overlap within the kidney, evidenced by their presence at the afferent arterioles, glomerulus, and efferent arterioles as denoted in Figure 1.2  However, their distributive differences dictate their varying functional roles in renal hematologic homeostasis.2 COX-2, unlike COX-1, can also be found in the Macula densa, the thick ascending limb of the Loop of Henle, and podocytes, leading to effects that vary from those caused by COX-1.2  COX-1 mainly works by controlling hemodynamics and GFR, while COX-2 exerts its effects on the excretion of salt and water.2  NSAIDs are classified into two groups, notably COX-2 selective (e.g. celecoxib) and non-selective (e.g. ibuprofen, naproxen, diclofenac).2  Because of the differences in the roles of COX-1 and COX-2 in the kidneys, non-selective and COX-2 selective inhibitors would theoretically have varying consequences related to renal function.2

In individuals with normal renal function and no predisposing hemodynamic insults to the kidney, glomerular filtration is not prostaglandin (PG) dependent.5  Therefore, NSAID use does not generally lead to functional renal toxicity in these individuals.5  The primary PG involved in renal hemodynamic homeostasis is prostacyclin (PGI2).6  PGI2 is necessary for maintaining normal renal homeostasis mechanisms, while PGE2 and PGD2 dilate the renal vascular bed, lower renal vascular resistance, and increase renal perfusion.2  Inhibition of PGI2 synthesis in the kidney specifically produces acute renal failure and hyperkalemia.2  Inhibition of PGE2 can lead to peripheral edema, blood pressure increases, weight gain, and CHF (rarely).2  COX-2 is located specifically on the thick ascending limb of the Loop of Henle (Figure 1) where it produces PGE2 and promotes diuresis and natriuresis by blocking reabsorption of water and sodium, respectively.2  Inhibition of COX-2 in this region is, therefore, a likely mechanism by which edema-related problems may occur from both, COX-2 selective and non-selective, NSAIDs.2

      It is also worth noting that during times of renal stress from poor perfusion, such as in hypovolemic states (dehydration, hemorrhage), CHF, or excessive diuresis, a greater emphasis is placed on PG mechanisms to maintain adequate renal blood flow.6  Angiotensin II, catecholamines, and vasopressin will be released to support glomerular filtration via vasoconstriction of the efferent arterioles, and PGI2 and PGE2 will be produced to dilate the afferent arterioles to support perfusion.6  In these circumstances, or when a patient is already renal impaired (creatinine clearance < 70mL/min/1.73m2), PG synthesis becomes a dependent mechanism for renal homeostatic maintenance.6 

Additional concerns exist in patients who are concurrently taking ACEIs or ARBs.  Angiotensin II receptors are primarily located on efferent arterioles, and, when activated, will cause vasoconstriction and increase the pressure inside of the glomerulus.6  When this mechanism is blocked by ACEIs or ARBs the intraglomerular pressure will decrease.6  If NSAIDs are added to this therapy, and the patient has PG dependent renal function, the afferent arterioles will be prohibited from dilating, causing further decreases in intraglomerular pressure and precipitating ischemia / acute renal failure.

Despite being considered safe medications and available to the public over-the-counter, NSAIDs have risks associated with use, especially in particular patient populations.  Age-related declines in renal function, conditions that develop PG dependent renal perfusion, anti-angiotensin therapy, and comorbid renal diseases are important considerations when initiating NSAID therapy.  Pharmacists are able to make excellent recommendations to patients and their physicians regarding NSAIDs, particularly considering patients’ comorbidities and concomitant therapies.


  1. Naughton CA.  Drug-induced nephrotoxicity.  Am Fam Physician.  2008;78(6):743-50.
  2. Weir M.  Renal effects of nonselective NSAIDs and coxibs.  Cleve Clin J Med.  2002;69 (Suppl 1): S153-S158
  3. Brophy DF.  Acute renal failure.  In: Koda-Kimble MA, Young LY, Alldredge BK, et al.  Applied Therapeutics: The clinical use of drugs 9th edition.  Baltimore, MD: Lippincott, Williams, & Wilkins; 2009: 30-2
  4. Jennette JC.  The Kidney.  In: Rubin’s Pathology: Clinicopathologic foundations of medicine 5th edition.  Baltimore, MD: Lippincott, Williams, & Wilkins; 2008: 698-730
  5. Black HE.  Renal Toxicity of Non-Steroidal Anti-Inflammatory Drugs.  Toxicologic Pathology.  1986;14(1):83-90.
  6. Murray MD, Brater DC.  Renal toxicity of the nonsteroidal anti-inflammatory drugs.  Annu Rev Pharmacol Toxicol.  1993;33:435-65.
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