NSAIDs: Acute kidney injury

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 (including aspirin): 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 (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 (including aspirin): 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 5^th to 6^th 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 10^th to 12^th 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.)