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NSAIDs: Acute kidney injury (acute renal failure)

Authors: Randy Luciano, MD, PhD, Mark A Perazella, MD, FACP

Section Editor: Paul M Palevsky, MD
Deputy Editor: John P Forman, MD, MSc

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2018. | This topic last updated: Mar 01, 2017.

INTRODUCTION — Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications used for analgesic
and anti-inflammatory benefits. NSAIDs can induce several different forms of kidney injury including
hemodynamically mediated acute kidney injury (AKI); electrolyte and acid-base disorders; acute interstitial
nephritis (AIN), which may be accompanied by the nephrotic syndrome; and papillary necrosis (table 1).

This topic reviews hemodynamically mediated AKI. The roles of NSAIDs in AIN, chronic kidney disease (CKD),
and electrolyte disorders are discussed elsewhere. (See "Clinical manifestations and diagnosis of acute
interstitial nephritis" and "Epidemiology and pathogenesis of analgesic-related chronic kidney disease" and
"NSAIDs: Electrolyte complications".)

The mechanism of action, therapeutic action, and non-renal-related adverse effects of NSAIDs are also
discussed elsewhere. (See "NSAIDs: Pharmacology and mechanism of action" and "NSAIDs: Therapeutic use and
variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects" and "Nonselective
NSAIDs: Adverse cardiovascular effects".)

EPIDEMIOLOGY — Adverse renal events occur in approximately 1 to 5 percent of all patients using NSAIDs [1].
Because of the large number of patients that take NSAIDs (estimates of more than 70 million prescriptions and
30 billion over-the-counter doses annually), this translates to upwards of 2.5 million patients experiencing a
nephrotoxic event annually [2].

AKI can occur with any class of traditional, nonselective NSAID or cyclooxygenase-2 (COX-2)-specific NSAIDs [3-
8]. As an example, in a nested, case-control study that included 121,722 older patients, an increased risk of
hospitalization within 30 days was associated with initiation of nonselective NSAIDs (other than naproxen),
naproxen, rofecoxib, and celecoxib with relative risks (RRs) of 2.3, 2.4, 2.3, and 1.5, respectively, compared with
unexposed individuals [8].

The selective COX-2 inhibitors also decrease renal clearance [6-11]. In a randomized, controlled study,
indomethacin and rofecoxib decreased glomerular filtration rate (GFR; as measured by inulin or iothalamate
clearance) to a similar degree among older patients [12]. Case reports and case series also show that the
selective COX-2 inhibitors have a nephrotoxicity profile similar to traditional NSAIDs, causing AKI, edema, and
electrolyte disorders [7].

RISK FACTORS — Risk factors for NSAID-induced AKI include chronic kidney disease (CKD); volume depletion
from aggressive diuresis, vomiting or diarrhea, or effective arterial volume depletion due to heart failure,
nephrotic syndrome, or cirrhosis; and severe hypercalcemia (figure 1). Certain medications, including diuretics
and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), may increase the
risk of NSAID-induced AKI.

Among older patients with CKD, NSAID users are more likely to have deterioration of kidney function over time
compared with patients who do not use NSAIDs chronically, and higher doses of NSAIDs are associated with a
greater risk of a decline in kidney function [13]. It is not known whether the decline in kidney function among
such patients is related to episodes of AKI, however. (See "Epidemiology and pathogenesis of analgesic-related
chronic kidney disease".)

An observational study reported an increase in mean estimated glomerular filtration rate (eGFR) among 1522
patients who had NSAIDs discontinued [14]. This study analyzed NSAID prescribing patterns and eGFR among
1522 patients with CKD stage 3, 4, and 5 before and after implementation of mandatory reporting of eGFR to
clinicians. A 10.2 percent reduction in NSAID prescriptions followed reporting of eGFR. The mean eGFR
increased from 45.9 to 46.9, 23.9 to 27.1, and 12.4 to 26.4 mL/min/1.73 m2 among patients with eGFRs of 30 to
59, 15 to 29, and <15 mL/min/1.73 m2, respectively, after reporting of the eGFR.

Patients with effective arterial volume depletion due to a condition such as heart failure are also at higher risk for
NSAID-induced AKI. This was shown in a nested, case-controlled study that showed that, among 386,916
patients, those who used NSAIDs and had heart failure had a higher risk of AKI compared with those who used
NSAIDs but did not have heart failure and compared with those who did not use NSAIDs (relative risks [RRs] of
7.63, 3.34, and 2.82, respectively) [15].

Diuretics, ACE inhibitors, or ARBs may increase the risk of NSAID-induced hemodynamically mediated AKI. This
was suggested in a nested, case-control cohort study in which the concomitant use of such medications was
associated with an increased rate of AKI (odds ratio [OR] 1.31, 95% CI 1.12-1.53), with the highest risk within the
first 30 days of therapy (OR 1.82, 95% CI 1.35-2.46) [16]. The use of NSAIDS, diuretics, ACE inhibitors, or ARBs
alone did not result in significant AKI.

RENAL PROSTAGLANDIN EXPRESSION AND FUNCTION — Prostaglandins (PGs) are lipids synthesized from cell
membrane phospholipids (figure 2). Through the enzymatic activity of phospholipase A2, lipids are converted to
arachidonic acid (AA), which is converted to a PG or leukotriene precursor in the presence of cyclooxygenase
(COX) or lipoxygenase enzymes, respectively. The enzymes responsible for conversion of AA to PG precursors
are COX-1 and COX-2. NSAIDs inhibit the activity of both COX-1 and COX-2 enzymes (although there is enzyme-
specific preference amongst traditional NSAIDS and there are specific COX-2 inhibitors). There are five PGs
(PGD2, PGE2, PGF2, PGI2, and thromboxane A2) that are synthesized from a common precursor by PG-specific
synthases.

In the kidney, COXs are locally produced at many sites, including glomerular and vascular endothelium, the
medullary and cortical collecting tubules, and medullary interstitial cells. COX-1 is expressed ubiquitously in most
tissues, while COX-2 expression is low at basal levels but increases with stimulation in the setting of acute or
chronic inflammation [17] and other physiologic challenges. The tubules predominantly synthesize PGE2, while
the glomeruli synthesize both PGE2 and PGI2 [18].

Renal PGs are primarily vasodilators in the kidneys. Under basal conditions, PGs have no significant role in the
regulation of renal perfusion. However, in the setting of hypotension and reduced renal perfusion from
vasoconstriction stimulated by angiotensin II, norepinephrine, vasopressin, or endothelin, PG synthesis is
increased to maintain renal perfusion and minimize ischemia [19-22].

In addition to modulating renal hemodynamics, PGs also increase renin secretion [23,24], antagonize the water-
retentive effects of arginine vasopressin [22,25], and enhance sodium excretion [26,27].
MECHANISM OF ACUTE KIDNEY INJURY — NSAID inhibition of cyclooxygenase (COX) enzymes with subsequent
reduction in prostaglandin (PG) synthesis can lead to reversible renal ischemia, a decline in glomerular hydraulic
pressure (the major driving force for glomerular filtration), and AKI [4,5,15].

This occurs via an NSAID-induced attenuation of renal vasodilation. In healthy patients, PGs play little role in
renal hemodynamics. However, PG synthesis is increased in the setting of prolonged renal vasoconstriction,
which serves to protect the glomerular filtration rate (GFR). PG synthesis is increased in the following conditions
(table 2) [4,5,28]:

● Chronic kidney disease (CKD), especially stage 3 or worse (ie, estimated GFR [eGFR] <60 mL/min/1.73 m2)

● Volume depletion from aggressive diuresis, vomiting, or diarrhea

● Effective arterial volume depletion due to heart failure, nephrotic syndrome, or cirrhosis

● Older age

● Severe hypercalcemia with associated renal arteriolar vasoconstriction

In these settings, PGs act to preserve renal blood flow and GFR by decreasing preglomerular resistance (figure
3). This differs from PG function in the setting of glomerular disease, where increased PG production maintains
GFR in the presence of a significant reduction in glomerular capillary permeability [29].

NSAID-induced inhibition of PG-mediated afferent vasodilation and reduction in peritubular blood flow may also
increase the risk of ischemic acute tubular necrosis (ATN) or other nephrotoxin-induced tubular injury from drugs
such as aminoglycosides, amphotericin B, hydroxyethyl starch, and radiocontrast material [30,31]. As an
example, a retrospective study showed that, among 38 patients without heart failure who developed contrast
nephropathy, 8 percent were prescribed NSAIDs prior to contrast exposure [32].

PREVENTION — NSAID-induced hemodynamically mediated AKI may be prevented by avoiding NSAIDs among

high-risk patients (such as those with chronic kidney disease [CKD], volume depletion, heart failure, or
hypercalcemia). (See 'Risk factors' above.)

NSAID use should be limited among patients at high risk for NSAID-induced AKI, including those with reduced
estimated glomerular filtration rate (eGFR), volume depletion, heart failure, nephrotic syndrome, cirrhosis, and
hypercalcemia.

We suggest that the chronic use of NSAIDs be avoided, if at all possible, among all patients with a reduced eGFR
(ie, eGFR <60 mL/min/1.73 m2) and suggest cautious use in patients with even mild reduction (ie, eGFR 60 to 89
mL/min/1.73 m2) and other comorbid conditions or risk factors, including heart failure, cirrhosis, or nephrotic
syndrome.

Even the episodic use of NSAIDs may confer a risk of AKI among patients with reduced eGFR, and no "safe" dose
or duration of NSAID has been defined. For patients with reduced eGFR in whom limited NSAID use is
unavoidable (such as those with significant pain or mobility issues in whom other pain medications are
significantly less effective), the patient should be advised of the risk, and the creatinine should be followed
closely when receiving NSAIDs.

Despite efforts to minimize use in at-risk patients, many patients with CKD continue to use NSAIDs. In a cross-
sectional study of 12,065 adults, chronic NSAID use (as defined as nearly every day for 30 days or longer) was
reported among 5 percent of patients with moderate to severe CKD (eGFR of 15 to 59 mL/min/1.73 m2) [33].
Awareness of having CKD did not appear to alter NSAID use in this study.
Clinicians and patients also need to be aware of medications that may increase the risk of hemodynamically
mediated AKI when used concomitantly with NSAIDs. (See 'Risk factors' above.)

Patients should not receive NSAIDs prior to procedures involving radiocontrast  or other nephrotoxic drug
administration. In a study cited above, a large number of patients who developed contrast nephropathy had been
taking NSAIDs prior to contrast exposure [32]. (See 'Mechanism of acute kidney injury' above.)

CLINICAL MANIFESTATIONS — Patients generally present with an increase in the plasma creatinine that is
usually detected incidentally during an evaluation of an unrelated problem. The increase in the plasma creatinine
concentration usually occurs within the first three to seven days of therapy, which is the time required for
attainment of steady-state drug levels and therefore maximum inhibition of prostaglandin synthesis [34].
However, the increase in creatinine may occur at any point.

Urinalysis is usually negative for hematuria and proteinuria. Although low-level proteinuria (<500 mg/day) may be
observed, significant proteinuria (ie, >1 g/day) is uncommon and suggests an NSAID-induced glomerular lesion
(minimal change disease or membranous nephropathy) rather than hemodynamically mediated AKI.

The urine sediment may contain hyaline casts and, if acute tubular necrosis (ATN) has developed, renal tubular
epithelial cell casts, renal tubular epithelial cells, or granular casts. White blood cells (WBCs) and WBC casts are
not seen in hemodynamically mediated AKI and suggest acute interstitial nephritis (AIN). (See 'Differential
diagnosis' below.)

DIAGNOSIS — The diagnosis of hemodynamically mediated AKI associated with NSAIDs is similar to other forms
of AKI (see "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting", section
on 'Major causes and pathogenesis of kidney disease'). The diagnosis is suggested by the history of recent
NSAID use, the absence of significant proteinuria (<500 mg/day), and hematuria and the bland urine sediment.

Among all patients with AKI, we generally obtain a renal ultrasound to exclude possible obstruction. If the history
is overwhelmingly consistent with NSAID initiation or subacute or chronic use, we avoid other costly tests as
generally the diagnosis is made when recovery of kidney function occurs after the NSAID is discontinued. The
time course to recovery can be dependent on underlying kidney disease and any additional confounding renal
injury (such as acute tubular necrosis [ATN]). If injury is truly hemodynamic in nature and due to NSAID use,
recovery should begin within 24 to 72 hours. Failure to recover or progression despite removal of NSAIDs should
warrant a biopsy within three to seven days, depending on the clinical course. A biopsy may also be done in
patients who have features of acute interstitial nephritis (AIN) or a glomerular lesion, such as nephrotic-range
proteinuria, hematuria with dysmorphic red blood cells, and/or red blood cell casts.

Differential diagnosis — The differential diagnosis of AKI is broad and is discussed elsewhere (see "Diagnostic
approach to adult patients with subacute kidney injury in an outpatient setting", section on 'Major causes and
pathogenesis of kidney disease'). Among patients who present with an increased creatinine in the setting of
NSAID use, other NSAID-associated lesions, such as AIN, or an NSAID-related glomerular lesion are among the
differential diagnoses. It is important to establish the chronicity of NSAID use and the duration of the increased
creatinine, if possible. This is necessary to distinguish between AKI and the more subacute to chronic AIN, which
may occur with or without features of nephrotic syndrome.

The urinalysis and quantitation of proteinuria may distinguish between hemodynamically mediated AKI and AIN.
Whereas the urine sediment is generally bland among patients with hemodynamically mediated AKI, urine white
blood cells (WBCs) and WBC casts are often observed among patients with AIN. (See 'Clinical manifestations'
above.)

Quantitation of urine protein excretion may differentiate between hemodynamically mediated AKI and an NSAID-
induced glomerular lesion such as membranous nephropathy or minimal change disease. As noted above,
proteinuria is absent or modest among patients with hemodynamically mediated AKI and generally >1 g/day
among patients with a glomerular lesion.

The urinalysis will also identify patients who have ATN. Among patients with ATN, the sediment may contain
renal tubular epithelial cells, renal tubular epithelial cell casts, or muddy brown granular casts.

TREATMENT — Treatment of NSAID-associated hemodynamically mediated AKI is no different than other forms

of AKI. The offending agent needs to be stopped immediately. Volume resuscitation should be provided in states
of hypovolemia and continued based on reassessment of volume status including blood pressure/pulse, urine
output, and other parameters. Renal replacement therapy is rarely required but may be needed initially when
severe AKI has occurred and there are serious electrolyte and acid-base disturbances present.

CHRONIC KIDNEY DISEASE — In addition to hemodynamically mediated AKI, it has been proposed that daily
NSAID use for a prolonged period of time may be associated with an increased risk of chronic kidney disease
(CKD), perhaps due to papillary necrosis or chronic interstitial nephritis similar to that seen with other analgesics.
This issue is discussed separately. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney
disease".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries
and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in
adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Acute kidney injury (The Basics)" and "Patient education: Nonsteroidal
antiinflammatory drugs (NSAIDs) (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of medications used for analgesic and anti-
inflammatory benefits. NSAIDs can induce several different forms of kidney injury including
hemodynamically mediated acute kidney injury (AKI); electrolyte and acid-base disorders and acute
interstitial nephritis (AIN), which may be accompanied by the nephrotic syndrome; and papillary necrosis.
(See 'Introduction' above.)

● All nonselective NSAIDs or cyclooxygenase (COX)-2-specific NSAIDs may cause AKI via the attenuation of
renal vasodilation. Risk factors for NSAID-induced AKI include chronic kidney disease (CKD); volume
depletion from aggressive diuresis, vomiting or diarrhea, or effective arterial volume depletion due to heart
failure, nephrotic syndrome, or cirrhosis; and severe hypercalcemia. Medications including diuretics and
angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may increase the
risk of NSAID-induced AKI. Higher doses of NSAIDs are associated with a greater risk of AKI. (See 'Risk
factors' above and 'Mechanism of acute kidney injury' above.)
● NSAID-induced AKI may be prevented by avoiding NSAIDs among high-risk patients. NSAID use should be
limited among patients with reduced estimated glomerular filtration rate (eGFR), volume depletion, heart
failure, nephrotic syndrome, cirrhosis, and hypercalcemia. The chronic use of NSAIDs should be avoided if at
all possible among patients with a reduced eGFR (eGFR <60 mL/min/1.73 m2) and used cautiously, even if
the reduction is mild (ie, eGFR 60 to 89 mL/min/1.73 m2). For patients with reduced eGFR in whom limited
NSAID use is unavoidable (such as those with significant pain or mobility issues in whom other pain
medications are significantly less effective), the patient should be advised of the risk, and the creatinine
should be followed closely when receiving NSAIDs. (See 'Prevention' above.)

● Patients generally present with an incidentally detected increase in the plasma creatinine. Urinalysis is
usually negative for hematuria and proteinuria. The urine sediment may contain hyaline casts and, if acute
tubular necrosis (ATN) has developed, renal tubular epithelial cell casts, renal tubular epithelial cells, or
granular casts. White blood cells (WBCs) and WBC casts are not seen in hemodynamically mediated AKI and
suggest acute interstitial nephritis (AIN). (See 'Diagnosis' above.)

● Among all patients with AKI, we generally obtain a renal ultrasound to exclude possible obstruction. If the
history is overwhelmingly consistent with NSAID initiation or subacute or chronic use, we avoid other costly
tests as generally the diagnosis is made when recovery of kidney function occurs after the NSAID is
discontinued. Failure to recover within three to seven days or progression despite removal of NSAIDs should
warrant a biopsy. A biopsy may also be done in patients who have features of AIN or a glomerular lesion,
such as nephrotic-range proteinuria or hematuria with dysmorphic red blood cells or red blood cell casts.
(See 'Diagnosis' above.)

● Treatment of NSAID-induced AKI is similar to that of other forms of AKI. The NSAID should be stopped
immediately. Volume resuscitation should be provided in states of hypovolemia and continued based on
reassessment of volume status including blood pressure/pulse, urine output, and other parameters. Renal
replacement therapy is rarely required but may be needed initially when severe AKI has occurred and there
are serious electrolyte and acid-base disturbances present. (See 'Treatment' above.)

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angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury:
nested case-control study. BMJ 2013; 346:e8525.
17. Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J 1998; 12:1063.
18. Bonvalet JP, Pradelles P, Farman N. Segmental synthesis and actions of prostaglandins along the nephron.
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25. Hébert RL, Jacobson HR, Breyer MD. PGE2 inhibits AVP-induced water flow in cortical collecting ducts by
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basolateral prostaglandin E2 is modulated by protein kinase C. J Clin Invest 1992; 90:1328.
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Topic 7230 Version 20.0

GRAPHICS

Renal syndromes associated with NSAID use

Acute kidney injury (hemodynamically-mediated or acute tubular necrosis)

Acute interstitial nephritis

Nephrotic syndrome (minimal change disease or membranous nephropathy)

Hyponatremia

Hyperkalemia/type 4 renal tubular acidosis

Hypertension/edema

Acute papillary necrosis

Chronic tubulointerstitial nephritis/analgesic nephropathy

Uroepithelial malignancy

Source: Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984; 310:563.

Graphic 90018 Version 1.0

Graph showing reduction in creatinine clearance after NSAIDs in patients with
hepatic cirrhosis

Reduction in glomerular filtration rate, as estimated from the creatinine clearance, from a mean of 73
mL/min down to 32 mL/min, after the administration of a nonsteroidal antiinflammatory drug (indomethacin
or ibuprofen) to 12 patients with stable hepatic cirrhosis and ascites. Urinary prostaglandin E 2 excretion was
initially elevated and then fell markedly following therapy.

Reproduced with permission from: Zipser RD, Hoefs JC, Speckhart PF, et al. Prostaglandins: modulators of renal
function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab 1979; 48:895-900.
http://press.endocrine.org/journal/jcem. Copyright © 1979 The Endocrine Society.

Graphic 89932 Version 2.0

Prostaglandin and thromboxane synthesis

Schematic representation of prostaglangin synthesis pathways with enzymes that catalyze

specific reactions. Of note, platelets only express cyclooxygenase (COX)-1. Refer to
UpToDate topics on nonsteroidal antiinflammatory drugs (NSAIDs), antiplatelet drugs, COX
inhibitors, and specific disease states for further details.

PG: prostaglandin; Tx: thromboxane.

Graphic 66146 Version 8.0

Conditions associated with NSAID-induced acute kidney injury

Volume depletion: emesis, diarrhea, sepsis, hemorrhage

Medications: diuretics, ACE-I, ARB, calcineurin inhibitors

Cirrhosis

Congestive heart failure

Nephrotic syndrome

Hypercalcemia (severe)

Chronic kidney disease

Renal artery stenosis

Older age

Angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB)

Courtesy of Randy Luciano, MD, PhD, and Mark A Perazella, MD, FACP.

Graphic 90019 Version 1.0

NSAIDs block the vasodilatory effect of prostaglandins on the afferent arteriole and
reduce glomerular filtration rate

Certain conditions that promote renal vasoconstriction and renal hypoperfusion require prostaglandins to
vasodilate the afferent arteriole and blunt vasoconstriction to maintain a normal GFR (left). However in the
presence of NSAIDs, which reduced prostaglandin production, afferent arteriole vasoconstriction dominates
and reduces GFR (right).

GFR: glomerular filtration rate; PGs: prostaglandins; Ang II: angiotensin II; NSAIDs: nonsteroidal anti-inflammatory
drugs; COX: cyclooxygenase.

Courtesy of Randy Luciano, MD, PhD, and Mark A Perazella, MD, FACP.

Graphic 89933 Version 1.0

Contributor Disclosures
Randy Luciano, MD, PhD Nothing to disclose Mark A Perazella, MD, FACP Nothing to disclose Paul M Palevsky,
MD Grant/Research/Clinical Trial Support: Spectral Medical [Sepsis (Endotoxin assay)]; BioPorto [Biomarker for
AKI]. Consultant/Advisory Boards: Baxter [Dialysis (Hemodialysis equipment, peritoneal dialysis equipment and
supplies, continuous renal replacement therapy equipment and solutions)]; Durect [Potential agent for AKI];
HealthSpan Dx [Novel diagnostic test for prediction of AKI]; GE Healthcare [Radiocontrast agents and
equipment]; Novartis [Potential agent for AKI]. John P Forman, MD, MSc Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform to
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