NSAIDs - Acute Kidney Injury - UpToDate

6/27/23, 9:24 AM NSAIDs: Acute kidney injury - UpToDate
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NSAIDs: Acute kidney injury

AUTHORS: Randy Luciano, MD, PhD, Mark A Perazella, MD, FACP
SECTION EDITOR: Paul M Palevsky, MD
DEPUTY EDITOR: Eric N Taylor, MD, MSc, FASN
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2023.

This topic last updated: Jan 18, 2023.
INTRODUCTION
Nonsteroidal antiinflammatory drugs (NSAIDs) are a class of medications used for analgesic
and antiinflammatory 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".)

● (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease".)
● (See "NSAIDs: Electrolyte complications".)
The mechanism of action, therapeutic action, and non-kidney-related adverse effects of

NSAIDs are also discussed elsewhere:
● (See "NSAIDs: Pharmacology and mechanism of action".)

● (See "NSAIDs: Therapeutic use and variability of response in adults".)
● (See "Nonselective NSAIDs: Overview of adverse effects".)
● (See "NSAIDs: Adverse cardiovascular effects".)
EPIDEMIOLOGY
Prevalence and relative risk — Adverse kidney events occur in approximately 1 to 5 percent

of all patients using NSAIDs [1]. Because of the large number of patients who take NSAIDs
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(estimates of more than 70 million prescriptions and 30 billion over-the-counter doses

annually in the United States), this translates to upwards of 2.5 million patients experiencing a
nephrotoxic event annually [2].
Use of NSAIDs increases the risk of AKI by nearly twofold [3], and the risk diminishes after
cessation of the drug [4]. AKI can occur with any class of traditional, nonselective NSAID or
cyclooxygenase (COX) 2-specific NSAIDs [5-10]. As an example, in a nested, case-control study
that included 121,722 older patients, an increased risk of hospitalization for AKI within 30
days was associated with initiation of naproxen, other nonselective NSAIDs, rofecoxib, and
celecoxib with relative risks (RRs) of 2.4, 2.3, 2.3, and 1.5, respectively, compared with
unexposed individuals [10]. 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 [9].
Risk factors — There are numerous risk factors for NSAID-mediated AKI ( table 2):
● Chronic kidney disease – Chronic kidney disease (CKD), especially stage 3 or worse (ie,
estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), is a major risk factor
for NSAID-induced AKI. The important role of preexisting CKD in the relationship
between NSAID use and GFR was illustrated by an observational study of 1522 patients
with CKD stages 3, 4, and 5 that quantified increases in mean eGFR after NSAID
discontinuation [11]. In this study, implementation of mandatory reporting of eGFR to
clinicians was accompanied by a 10 percent reduction in NSAID prescriptions, which in
turn was associated with increases in mean eGFR. The improvements in eGFR were
greatest for those with more severe CKD at baseline (from 46 to 47 among patients with
eGFRs of 30 to 59, from 24 to 27 among patients with eGFRs of 15 to 29, and from 12 to
26 among patients with eGFRs of <15 mL/min/1.73 m2).
● Volume depletion – Volume depletion, such as after aggressive diuresis, vomiting, or

diarrhea, increases the risk of NSAID-associated AKI [12].
● Effective arterial volume depletion – Patients with effective arterial volume depletion
due to heart failure, nephrotic syndrome, or cirrhosis are also at higher risk for NSAID-
induced AKI. In a nested, case-controlled study of 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 (RRs of 7.63 and 3.34, respectively) [13]. NSAID use
in patients with cirrhosis can result in large decreases in GFR ( figure 1).
● Medications and radiocontrast – Certain medications are associated with an increased

risk of NSAID-associated AKI when coadministered.
• Diuretics, ACE inhibitors, or ARBs – These 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), with the highest risk within the first 30
days of therapy (OR 1.82) [14]. The use of NSAIDS, diuretics, angiotensin-converting
enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs) alone did not result
in significant AKI.
• Calcineurin inhibitors – The risk for AKI is also elevated when NSAIDs are combined
with maintenance calcineurin inhibitor (CNI) therapy in recipients of solid organ or
hematopoietic cell transplants. AKI occurred in 5 of 41 patients exposed to CNIs and
NSAIDs compared with 7 of 126 transplant recipients only given CNIs (12 versus 6
percent) [15]. An increase in serum creatinine above baseline was also more frequent
among patients exposed to both CNIs and NSAIDs (80 versus 56 percent).
• Other nephrotoxic agents – NSAIDs 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
[16,17]. As an example, a retrospective study showed that, among 38 patients
without heart failure who developed contrast-associated AKI, 8 percent were
prescribed NSAIDs prior to contrast exposure [18].
Theoretical concerns have been raised about the concomitant use of sodium-glucose
cotransporter 2 (SGLT2) inhibitors and NSAIDs [19]; however, there are no convincing
human data suggesting that SGLT2 inhibitors increase the risk of NSAID-mediated
AKI.
● Older age – Older age, especially >65 years, is a risk factor for NSAID-induced AKI [3,20].
In a cohort study of individuals aged ≥66 years, increasing age was a predictor of NSAID-
associated AKI, independent of eGFR and the use of medications such as diuretics, ACE
inhibitors, or ARBs [20].
● Hypercalcemia – Case reports suggest that patients with severe hypercalcemia (and
associated renal arteriolar vasoconstriction) who use NSAIDs are at high risk of severe
AKI [21,22].
MECHANISM OF ACUTE KIDNEY INJURY
NSAID inhibition of cyclooxygenase (COX) enzymes with subsequent reduction in

prostaglandin (PG) synthesis can lead to reversible kidney ischemia, a decline in glomerular
hydraulic pressure (the major driving force for glomerular filtration), and AKI [6,7,13]. The
details of PG synthesis, and the NSAID-mediated reduction in same, are presented elsewhere
( figure 2). (See "NSAIDs: Pharmacology and mechanism of action".)

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 [23] and other
physiologic challenges. The tubules predominantly synthesize PGE2, while the glomeruli
synthesize both PGE2 and PGI2 [24].
Kidney PGs are primarily local vasodilators. In the setting of hypotension and reduced kidney
perfusion from vasoconstriction stimulated by angiotensin II, norepinephrine, vasopressin, or
endothelin, PG synthesis is increased to maintain kidney perfusion and minimize ischemia
[25-28]. In addition to modulating renal hemodynamics, PGs also increase renin secretion
[29,30], antagonize the water-retentive effects of arginine vasopressin [28,31], and enhance
sodium excretion [32,33]. (See "NSAIDs: Electrolyte complications".)
Hemodynamically mediated AKI due to NSAIDs occurs via attenuation of PG-mediated 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 conditions associated
with NSAID-induced AKI ( table 2) [6,7,34] (see 'Risk factors' above). 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 [35].
Both nonselective NSAID and COX-2-specific NSAIDs affect renal hemodynamics and can
decrease GFR [8-10,36-38]. In a randomized controlled study of older patients, indomethacin
and rofecoxib decreased GFR (as measured by inulin or iothalamate clearance) to a similar
degree [39].
CLINICAL PRESENTATION
Patients with hemodynamically mediated AKI due to NSAIDs 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 NSAID use, which is the time required for attainment of
steady-state drug levels and therefore maximum inhibition of prostaglandin (PG) synthesis
[40]. However, the increase in plasma creatinine may occur at any point.
The degree of NSAID-induced AKI is variable. AKI can be severe, especially among patients
who use higher doses of NSAIDs and have multiple risk factors. (See 'Risk factors' above.)

Urinalysis is usually negative for hematuria, pyuria, and proteinuria. Although low-level
proteinuria (<500 mg/day) may be observed, significant proteinuria (ie, >1 g/day) is
uncommon. The urine sediment may contain hyaline casts and, if acute tubular necrosis (ATN)
has developed, renal tubular epithelial cells, renal tubular epithelial cell casts, or muddy
brown granular casts.
DIAGNOSIS
Evaluation — NSAID-mediated AKI should be suspected in any patient with AKI and a history
of recent NSAID use. Among such patients, the objective of the initial evaluation is to establish
whether NSAID use is the likely cause of AKI and, if so, to assess the type of NSAID-induced
AKI. In patients who present with an increased plasma creatinine in the setting of NSAID use,
hemodynamically mediated AKI is the most common cause. However, AKI can be caused by or
complicate other NSAID-associated kidney lesions such as acute interstitial nephritis (AIN),
membranous nephropathy, or minimal change disease.
● Assess for other causes of AKI – Because AKI is not always due to NSAIDs, patients
should be evaluated thoroughly for other potential causes of AKI using the same
approach as that for patients without NSAID exposure. For example, a history should
assess for potential exposure to other nephrotoxins and for any recent volume-
depleting illness, and a physical examination should determine current volume status.
This is discussed in detail elsewhere. (See "Diagnostic approach to adult patients with
subacute kidney injury in an outpatient setting".)
● Evaluate timing of NSAID use and AKI – It is important to establish the chronicity of
NSAID use and the duration of the increased plasma creatinine, if possible. For
individuals who have been on a stable dose of NSAIDs and have not developed a recent
condition predisposing to AKI, hemodynamically mediated AKI is less likely than AIN.
Hemodynamically mediated AKI due to NSAIDs is acute, whereas AIN may present with a
more subacute, or even chronic, course.
● Urinalysis – The urinalysis may distinguish between NSAID-induced hemodynamically

mediated AKI and other causes of NSAID-related AKI. Whereas the urine sediment is
generally bland among patients with hemodynamically mediated AKI, urine white blood
cells (WBCs) and WBC casts are suggestive of AIN. A urinalysis also may identify a
superimposed acute tubular necrosis (ATN). Among patients with ATN, the sediment may
contain renal tubular epithelial cells, renal tubular epithelial cell casts, or muddy brown
granular casts.
● Urine protein quantification – Quantification of urine protein excretion may

differentiate between hemodynamically mediated AKI and an NSAID-induced

glomerular lesion such as membranous nephropathy or minimal change disease.

Proteinuria is absent or modest among patients with hemodynamically mediated AKI
and generally >1 g/day among patients with glomerular lesions.
● Kidney ultrasound – We usually obtain a kidney ultrasound to exclude possible urinary

tract obstruction as an alternate cause of AKI. (See "Clinical manifestations and
diagnosis of urinary tract obstruction (UTO) and hydronephrosis", section on
'Diagnosis'.)
If the history unequivocally documents recent NSAID use and if urinary findings are
consistent with hemodynamically mediated AKI, we generally avoid other costly tests during
the initial evaluation.
A kidney biopsy is generally reserved for patients whose kidney disease violates the natural
history of NSAID-induced AKI or for patients who have features of AIN or a glomerular lesion,
such as nephrotic-range proteinuria, hematuria with dysmorphic red blood cells, and/or red
blood cell casts. (See 'Differential diagnosis' below.)
Establishing the diagnosis — The diagnosis of hemodynamically mediated AKI due to

NSAIDs is suggested by the history of recent NSAID use, the absence of significant proteinuria
(<500 mg/day), and a bland urine sediment. The diagnosis is confirmed when recovery of
kidney function occurs after NSAIDs are discontinued.
The time course to recovery can be dependent on underlying kidney disease and any
additional confounding kidney injury (such as ATN). If AKI 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 suggests an alternate diagnosis.
The diagnoses of other NSAID-associated lesions such as AIN, membranous nephropathy, or

minimal change disease are discussed in detail elsewhere. (See "Clinical manifestations and
diagnosis of acute interstitial nephritis", section on 'NSAID-induced AIN and nephrotic
syndrome' and "Membranous nephropathy: Clinical manifestations and diagnosis", section on
'Diagnosis' and "Minimal change disease: Etiology, clinical features, and diagnosis in adults",
section on 'Diagnosis'.)
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'.)
NSAID USE IN AT-RISK PATIENTS
Decisions about whether and how to use NSAIDs in patients at risk for NSAID-induced
hemodynamically mediated AKI should be individualized. Our approach is outlined below:
Patients with kidney disease
Nephrotic syndrome — We avoid NSAIDs in patients with nephrotic syndrome regardless of

glomerular filtration rate (GFR) because the reduced effective arterial volume in such patients
is a major risk factor for hemodynamically mediated AKI. In addition, the nephrotic syndrome
of some patients with membranous nephropathy or minimal change disease may have been
caused by NSAIDs.
Chronic kidney disease — Although NSAIDs should generally be avoided in patients with

chronic kidney disease (CKD), in some patients with CKD, other analgesic agents such as
opioids may be associated with more adverse effects than NSAIDs [41].
● Stages 1 and 2 CKD – Use of NSAIDs in patients with stages 1 and 2 CKD (ie, CKD with
estimated GFR [eGFR] ≥ 60 mL/min/1.73 m2) depends on whether they have other risk
factors for NSAID-induced AKI ( table 2).
• For those who have no other risk factors, NSAIDs can be used in the same way as in
the general population.
• For patients with stages 1 and 2 CKD who have volume depletion, heart failure, or
cirrhosis, we avoid NSAIDs. These high prostaglandin (PG) states are especially strong
risk factors for hemodynamically mediated AKI.
• For patients with stages 1 and 2 CKD who have other risk factors for NSAID-induced
AKI, short-acting NSAIDs used at the lowest effective dose for up to seven days are a
reasonable pain management strategy. Longer-term therapy may be employed in
patients cognizant of those conditions (vomiting, diarrhea, volume depletion, etc)
that should prompt immediate NSAID discontinuation [12]. In patients starting long-
term NSAID therapy, a serum creatinine should be checked two to three weeks after
starting NSAIDs, and then every three months afterward. An increase in creatinine
should prompt NSAID discontinuation.
● Stage 3 CKD – For patients with stage 3 CKD (ie, eGFR 30 to 59 mL/min/1.73 m2) and no
other risk factors for AKI ( table 2), short-acting NSAIDs used at the lowest effective
dose for up to seven days are a reasonable pain management strategy.
Use of NSAIDs for a longer course depends on the eGFR:
• For patients with stage 3a CKD (ie, eGFR 45 to 59 mL/min/1.73 m2) and no other risk
factors for AKI, a longer course of NSAIDs may be acceptable. Such patients should
receive instruction about conditions that require immediate NSAID discontinuation
(eg, vomiting, diarrhea, and volume depletion). In patients with stage 3a CKD starting
long-term NSAID therapy, a serum creatinine and electrolytes should be checked 7 to
10 days after starting NSAIDs, in one month, and then every three months.
Electrolytes should be followed since the risk of NSAID-induced hyperkalemia is

elevated in stage 3 CKD compared with earlier stages of CKD.
• For patients with stage 3b CKD (ie, eGFR of 30 to 44 mL/min/1.73 m2), we avoid long-
term NSAID use.
● Stage 4 CKD – NSAIDs should be avoided, if possible, among patients with stage 4 CKD
(ie, eGFR 15 to 29 mL/min/1.73 m2). No "safe" dose or duration of NSAID has been
defined among patients with stage 4 CKD.
However, for patients with stage 4 CKD (eGFR 15 to 29 mL/min/1.73 m2) 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), short half-life NSAIDs used at the
lowest effective dose for ≤5 days may be employed provided the following:
• The patient is without volume depletion, heart failure, cirrhosis, or a history of

hyperkalemia.
• The serum creatinine and electrolytes are checked two days after starting therapy.
● Stage 5 CKD – Nephrotoxic drugs, including NSAIDs, should never be used in patients
with stage 5 CKD (eGFR <15 mL/min/1.73 m2), unless the primary goal is comfort and
palliation.
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) [42]. Awareness of having CKD did not appear
to alter NSAID use in this study.
Acute kidney injury — Nephrotoxic drugs, including NSAIDs, should never be used in

patients with AKI, unless the primary goal is comfort and palliation.
Dialysis and kidney transplant
● Dialysis – Patients on maintenance dialysis may use NSAIDs if they are anuric. The
treating nephrologist should be consulted before patients on dialysis who still make
urine take NSAIDs since preservation of residual kidney function may be of benefit. If
preserving function is an important objective, NSAIDs should be avoided completely.
(See "Residual kidney function in kidney failure", section on 'Clinical importance of
residual kidney function'.)
● Kidney transplant – In general, NSAIDs should be avoided in patients with a functioning

kidney transplant, regardless of GFR. Patients with a kidney allograft may be at an

especially high risk of NSAID-associated AKI [43] and often have other comorbidities that
place them at higher risk for non-kidney NSAID-related adverse events.
Patients without kidney disease — In individuals without kidney disease, NSAIDs should
generally be avoided in those with volume depletion, heart failure, cirrhosis, and/or
hypercalcemia. These high PG states are especially strong risk factors for hemodynamically
mediated AKI.
In those without kidney disease who have other risk factors for NSAID-induced AKI
( table 2), NSAIDs should be used with caution. If such patients take NSAIDs long term (ie, ≥
seven days), a serum creatinine should be checked two to three weeks after starting NSAIDs
and then every three months afterward. An increase in creatinine should prompt NSAID
discontinuation.
Clinicians and patients also need to be aware of medications that may increase the risk of AKI
when used concomitantly with NSAIDs. Patients should not take NSAIDs prior to the
administration of other nephrotoxic drugs or before procedures involving radiocontrast. In
one retrospective observational study, a large number of patients who developed contrast-
associated AKI had been taking NSAIDs prior to contrast exposure [18]. (See 'Risk factors'
above.)
Topical NSAIDs — Topical NSAIDs are a reasonable option for the treatment of

musculoskeletal or arthritic pain in patients who should not take oral NSAIDs because of an
elevated risk of NSAID-mediated AKI. The exceptions are for patients with nephrotic
syndrome or for those with a history of NSAID-induced acute interstitial nephritis (AIN); in
such patients, we avoid all formulations of NSAIDs. (See 'Nephrotic syndrome' above and
"Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'NSAID-
induced AIN and nephrotic syndrome'.)
For patients who have stages 4 and 5 CKD, volume depletion, heart failure, cirrhosis, or
hypercalcemia, we monitor serum creatinine and electrolytes closely after the initiation of
topical NSAID therapy. If these laboratory parameters remain stable after several weeks of
topical NSAID use, monitoring can return to the usual interval.
Topical NSAID formulations are safer than oral NSAIDs for patients with CKD and other risk
factors for hemodynamically mediated AKI because only approximately 1 to 2 percent of
topical NSAIDs are systemically absorbed [44]. However, cases of AKI have been reported
after topical NSAID use [45,46]. Furthermore, in a population-based cohort study of older
patients (mean age 74 years) with high rates of CKD and diuretic and ACE inhibitor/ARB use,
AKI occurred at higher rates in topical NSAID users compared with nonusers (approximately
15 versus 10 percent) [47].

TREATMENT
Treatment of NSAID-associated hemodynamically mediated AKI is no different than that of

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. Kidney 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.
RISK OF CHRONIC KIDNEY DISEASE
In addition to hemodynamically mediated AKI, it has been proposed that long-term, regular
NSAID use may be associated with an increased risk of developing chronic kidney disease
(CKD), perhaps due to papillary necrosis or chronic interstitial nephritis similar to that seen
with other analgesics.
Long-term NSAID use also may accelerate the progression of preexisting CKD. 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 [48].
The relationship between NSAIDs and the development of CKD is discussed in detail
elsewhere. (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
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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
● Types of kidney disease associated with NSAIDs– Nonsteroidal antiinflammatory

drugs (NSAIDs) are a class of medications used for analgesic and antiinflammatory
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). (See 'Introduction' above.)
● Risk factors for hemodynamically mediated AKI – All nonselective NSAIDs or

cyclooxygenase (COX) 2-specific NSAIDs may cause AKI via the attenuation of renal
vasodilation. Higher doses of NSAIDs are associated with a greater risk of AKI. Additional
risk factors 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; a variety of medications and radiocontrast;
older age; and hypercalcemia ( table 2). (See 'Mechanism of acute kidney injury' above
and 'Risk factors' above.)
● Clinical presentation – Patients generally present with an incidentally detected increase

in the plasma creatinine. Urinalysis is usually negative for hematuria, pyuria, 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. (See 'Clinical presentation' above.)
● Diagnosis – Among all patients with AKI, we generally obtain a kidney ultrasound to
exclude possible urinary tract obstruction. If the history is overwhelmingly consistent
with NSAID initiation or subacute or chronic use, we avoid other costly tests as generally
the diagnosis of hemodynamically mediated AKI 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 warrants a biopsy. Kidney 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.)
● NSAID use in at-risk patients – We avoid systemic NSAIDs for pain or inflammation in
patients with the following:
• Volume depletion
• Nephrotic syndrome
• Heart failure
• Cirrhosis
• Hypercalcemia
For other patients, our approach to short- or long-term NSAID use depends on the type
and severity of preexisting kidney disease, if present, as well as other risk factors for AKI.
(See 'NSAID use in at-risk patients' above.)
● Treatment – 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. Kidney 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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Topic 7230 Version 32.0

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
NSAID: nonsteroidal antiinflammatory drug.
Source: Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 1984;
310:563.
Graphic 90018 Version 2.0

Conditions associated with NSAID-induced acute kidney injury
Volume depletion: Emesis, diarrhea, sepsis, hemorrhage
Medications: Diuretics, ACE inhibitors, ARBs, calcineurin inhibitors
Cirrhosis
Congestive heart failure
Nephrotic syndrome
Hypercalcemia (severe)
Chronic kidney disease
Renal artery stenosis
Older age
ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker.
Courtesy of Randy Luciano, MD, PhD, and Mark A Perazella, MD, FACP.

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 an NSAID (indomethacin or ibuprofen) to 12 patients with
stable hepatic cirrhosis and ascites. Urinary prostaglandin E2 excretion was
initially elevated and then fell markedly following therapy.
NSAID: nonsteroidal anti-inflammatory drug.
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. https://academic.oup.com/jcem. Copyright © 1979 The Endocrine Society.

Prostaglandin and thromboxane synthesis
Schematic representation of prostaglandin 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.

NSAIDs block the vasodilatory effect of prostaglandins on

the afferent arteriole and reduce GFR
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 antiinflammatory drugs; COX: cyclooxygenase.
Courtesy of Randy Luciano, MD, PhD, and Mark A Perazella, MD, FACP.

Contributor Disclosures
Randy Luciano, MD, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Mark A Perazella, MD, FACP No relevant financial relationship(s) with ineligible companies to
disclose. Paul M Palevsky, MD Consultant/Advisory Boards: Janssen Research & Development [AKI trial
design]. All of the relevant financial relationships listed have been mitigated. Eric N Taylor, MD, MSc,
FASN No relevant financial relationship(s) with ineligible companies 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 UpToDate standards of evidence.
Conflict of interest policy

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6/27/23, 9:24 AM NSAIDs: Acute kidney injury - UpToDate

Official reprint from UpToDate®

NSAIDs: Acute kidney injury

Literature review current through: May 2023.

● (See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

The mechanism of action, therapeutic action, and non-kidney-related adverse effects of

● (See "NSAIDs: Pharmacology and mechanism of action".)

Prevalence and relative risk — Adverse kidney events occur in approximately 1 to 5 percent

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150&… 1/22

(estimates of more than 70 million prescriptions and 30 billion over-the-counter doses

● Volume depletion – Volume depletion, such as after aggressive diuresis, vomiting, or

● Medications and radiocontrast – Certain medications are associated with an increased

MECHANISM OF ACUTE KIDNEY INJURY

NSAID inhibition of cyclooxygenase (COX) enzymes with subsequent reduction in

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150&… 3/22

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150&… 4/22

● Urinalysis – The urinalysis may distinguish between NSAID-induced hemodynamically

● Urine protein quantification – Quantification of urine protein excretion may

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150&… 5/22

glomerular lesion such as membranous nephropathy or minimal change disease.

● Kidney ultrasound – We usually obtain a kidney ultrasound to exclude possible urinary

Establishing the diagnosis — The diagnosis of hemodynamically mediated AKI due to

The diagnoses of other NSAID-associated lesions such as AIN, membranous nephropathy, or

Differential diagnosis — The differential diagnosis of AKI is broad and is discussed

NSAID USE IN AT-RISK PATIENTS

Patients with kidney disease

Nephrotic syndrome — We avoid NSAIDs in patients with nephrotic syndrome regardless of

Chronic kidney disease — Although NSAIDs should generally be avoided in patients with

Use of NSAIDs for a longer course depends on the eGFR:

Electrolytes should be followed since the risk of NSAID-induced hyperkalemia is

• The patient is without volume depletion, heart failure, cirrhosis, or a history of

Acute kidney injury — Nephrotoxic drugs, including NSAIDs, should never be used in

Dialysis and kidney transplant

● Kidney transplant – In general, NSAIDs should be avoided in patients with a functioning

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150&… 8/22

Topical NSAIDs — Topical NSAIDs are a reasonable option for the treatment of

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150&… 9/22

Treatment of NSAID-associated hemodynamically mediated AKI is no different than that of

RISK OF CHRONIC KIDNEY DISEASE

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

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SUMMARY AND RECOMMENDATIONS

● Types of kidney disease associated with NSAIDs– Nonsteroidal antiinflammatory

● Risk factors for hemodynamically mediated AKI – All nonselective NSAIDs or

● Clinical presentation – Patients generally present with an incidentally detected increase

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150… 11/22

● Treatment – Treatment of NSAID-induced AKI is similar to that of other forms of AKI.

Use of UpToDate is subject to the Terms of Use.

1. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic

3. Zhang X, Donnan PT, Bell S, Guthrie B. Non-steroidal anti-inflammatory drug induced

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150… 12/22

7. Patrono C, Dunn MJ. The clinical significance of inhibition of renal prostaglandin

13. Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150… 13/22

Clin Proc 2011; 86:e1.

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150… 14/22

https://www.uptodate.com/contents/nsaids-acute-kidney-injury/print?search=nsaids: ACUTE KIDNEY INJURY&source=search_result&selectedTitle=1~150… 15/22

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)

Hyperkalemia/type 4 renal tubular acidosis