What NSAIDs are the least damaging to kidneys? What NSAID are safe use in CKD Stage 3A?

Comment by InpharmD Researcher

Available evidence does not identify a single oral nonsteroidal anti-inflammatory drug (NSAID) as least nephrotoxic or establish any NSAID as universally safe in chronic kidney disease (CKD) stage 3A. Comparative findings were inconsistent, with moderate-dose celecoxib producing fewer renal events than high-dose ibuprofen but not naproxen in a randomized trial, whereas a large retrospective cohort of patients without baseline CKD found ibuprofen had the lowest risk of kidney function decline among individual NSAIDs, although its risk remained elevated versus no NSAID use. Reviews and observational studies generally reported increased acute kidney injury (AKI) risk across NSAIDs, with higher CKD risk observed with prolonged oxicam exposure and ketorolac. Overall, in stable stage 3 CKD with minimized risk factors, one review considered short-term NSAID use for up to 5 days acceptable with risk-factor optimization and follow-up laboratory monitoring; short-acting agents were preferred, and topical NSAIDs were described as viable alternatives because of lower systemic exposure and fewer kidney-related adverse effects.
Background

A 2015 meta-analysis of 5 observational studies, encompassing 28,992 patients with AKI, evaluated AKI risk associated with individual NSAIDs compared with nonuse. Most traditional NSAIDs were associated with a statistically significant increase in AKI risk, with pooled risk ratios ranging from 1.58 to 2.11; however, no statistically significant differences were identified between individual NSAIDs. Diclofenac, meloxicam, rofecoxib, and celecoxib were also associated with elevated AKI risk, although these findings were not statistically significant, and their pooled risk ratios were comparable to those of other traditional NSAIDs. Overall, the authors recommended using the minimum NSAID amount for the shortest possible duration; however, the analysis evaluated AKI rather than CKD or CKD progression and therefore does not identify a least nephrotoxic NSAID or establish any NSAID as safe for patients with CKD stage 3A. [1]

A 2020 narrative review reported that the risk of NSAID-associated acute kidney injury was relatively similar among commonly used agents, although rofecoxib demonstrated the greatest risk, and that selective cyclooxygenase-2 inhibitors produce adverse kidney effects at a rate and severity comparable to nonselective NSAIDs; therefore, the authors did not identify a specific oral NSAID as least nephrotoxic. In patients with stable stage 3 chronic kidney disease in whom predisposing risk factors have been minimized, the authors considered short-term NSAID use for up to 5 days an acceptable pain-management strategy with acceptably low nephrotoxic risk, followed by routine laboratory testing and clinical follow-up within 2 to 3 weeks. Short-acting agents were preferred over long-acting agents, with adjustment of the dosing interval for reduced elimination, optimization of volume status and cardiac function, and avoidance in patients with true or effective circulating volume depletion, cirrhosis, congestive heart failure, nephrotic syndrome, or other risk factors for NSAID nephrotoxicity. Topical NSAIDs, which achieve peak systemic concentrations no greater than 1.5% of oral formulations and have demonstrated significantly fewer kidney-related adverse effects than oral formulations, were described as a viable alternative or adjunct for musculoskeletal and arthritic pain in patients with CKD. [2]

A review on the renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) states COX-2 selective inhibitors may have the same risk of adverse renal events as COX-nonselective NSAIDs because both isoenzymes are found within the kidney. High-dose NSAIDs are typically implicated in acute renal failure, with no specific agents standing out as a particularly higher risk. A 2009 case-control study found the risk of acute kidney injury (AKI) with new NSAID use generally decreased with COX-2 selectivity, with celecoxib (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.63 to 1.47) and meloxicam (OR 1.13; 95% CI 0.63 to 2.05) being the most favorable and ibuprofen (OR 2.25; 95% CI 2.04 to 2.49) and ketorolac (OR 2.07; 95% CI 1.78 to 2.41) showing the highest risk. Even though this study found a trend suggesting COX selectivity may be safer for AKI, the authors of the review state that selective agents may still precipitate renal injury via different mechanisms. [3], [4]

A 2013 review on NSAIDs discusses renal adverse effects in 1-5% of users as acute and chronic effects. The authors state there is not enough comparative data to rank NSAIDs based on renal side effects and it can not be assumed that any NSAID is free of acute renal failure. Celecoxib appears to have no significant effect on glomerular filtration rate. Renal adverse effects are dose-dependent and rare if patients avoid high therapeutic doses. [5]

A 2017 meta-analysis evaluated NSAID-induced AKI in patients with CKD. Pooled results of NSAIDs with varying COX-2 selectivity found there was a trend showing lower AKI risk with increasing COX-2 selectivity; however, this was not statistically significant. Drugs with no COX selectivity, low COX-2 selectivity, and high COX-2 selectivity all showed statistically significant odds ratios for AKI. This study found that the odds of developing AKI increased by over 50% in people who were exposed to NSAIDs in the general population and in people with CKD, and in older people, the odds of developing AKI doubled. [6]

Background References: [1] Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015;26(4):285-291. doi:10.1016/j.ejim.2015.03.008
[2] Baker M, Perazella MA. NSAIDs in CKD: are they safe? Am J Kidney Dis. 2020;76(4):546-557. doi:10.1053/j.ajkd.2020.03.023
[3] Hörl WH. Nonsteroidal Anti-Inflammatory Drugs and the Kidney. Pharmaceuticals (Basel). 2010;3(7):2291–2321.
[4] Lafrance JP, Miller DR. Selective and non-selective non-steroidal anti-inflammatory drugs and the risk of acute kidney injury. Pharmacoepidemiol Drug Saf. 2009;18(10):923-31.
[5] Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2013;16(5):821-47.
[6] Zhang X, Donnan PT, Bell S, Guthrie B. Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol. 2017;18(1):256.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What NSAIDs are the least damaging to kidneys? What NSAID are safe use in CKD Stage 3A?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-2 for your response.

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis
Design

Randomized, multicenter, double-blind, noninferiority trial

N= 24,081
Objective

To assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke compared to ibuprofen or naproxen
Study Groups

Celecoxib group (n= 8072)

Naproxen group (n= 7969)

Ibuprofen group (n= 8040)
Inclusion Criteria

Patients 18 years or older requiring daily NSAIDs for arthritis pain with established cardiovascular disease or increased cardiovascular risk
Exclusion Criteria

Patients whose arthritis pain was managed adequately with acetaminophen
Methods

Patients were randomized 1:1:1, stratified by arthritis diagnosis, aspirin use, and geographic region, to celecoxib 100 mg twice daily, naproxen 375 mg twice daily, or ibuprofen 600 mg three times daily with matching placebo. For rheumatoid arthritis, doses could be increased to celecoxib 200 mg twice daily, naproxen 500 mg twice daily, or ibuprofen 800 mg three times daily; naproxen and ibuprofen, but not celecoxib, could be increased for osteoarthritis because of regulatory dosing restrictions. All patients received esomeprazole 20 to 40 mg for gastric protection, and low-dose aspirin ≤325 mg/day was permitted. Renal events were independently adjudicated by specialists unaware of treatment assignments; the definition was provided in the Supplementary Appendix rather than the article. Mean daily doses were celecoxib 209 ± 37 mg, naproxen 852 ± 103 mg, and ibuprofen 2,045 ± 246 mg.
Duration

Mean treatment duration: 20.3 ± 16.0 months

Mean follow-up period: 34.1 ± 13.4 months
Outcome Measures

Primary: First occurrence of an adverse event meeting APTC criteria (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke)

Secondary: Major adverse cardiovascular events, clinically significant gastrointestinal events, renal events, hospitalization for heart failure or hypertension
Baseline Characteristics   Celecoxib Group (N= 8072)

Naproxen Group (N= 7969)

 Ibuprofen Group (N= 8040)
Age, years 63.0 ± 9.5 63.3 ± 9.4

63.2 ± 9.4
Female 64.1% 63.9%

64.4%
White

75.0%

 74.4% 74.5%
Body-mass index

32.7 ± 7.3

 32.6 ± 7.3 32.5 ± 7.4
Osteoarthritis

89.9%

 90.1% 89.7%
Rheumatoid arthritis

10.1%

 9.9% 10.3%
Current aspirin use

45.8%

 45.8% 46.2%
History of diabetes

35.2%

 34.7% 35.9%
History of hypertension

78.0%

 77.1% 78.4%
Baseline serum creatinine, mg/dL

0.9 ± 0.23

 0.9 ± 0.22 0.9 ± 0.22
Results Intention-to-Treat Analysis Celecoxib (n= 8072) Naproxen (n= 7969)

Ibuprofen (n= 8040)

 Celecoxib vs. Naproxen aHR (95% CI) Celecoxib vs. Ibuprofen aHR (95% CI)

Primary APTC end point

 188 (2.3%)

201 (2.5%)

 218 (2.7%) 0.93 (0.76–1.13) 0.85 (0.70–1.04)

Major adverse cardiovascular events

 337 (4.2%)

346 (4.3%)

 384 (4.8%) 0.97 (0.83–1.12) 0.87 (0.75–1.01)

Composite of serious gastrointestinal events

 86 (1.1%)

119 (1.5%)

 130 (1.6%) 0.71 (0.54–0.93) 0.65 (0.50–0.85)

Renal events

 57 (0.7%)

71 (0.9%)

 92 (1.1%) 0.79 (0.56–1.12) 0.61 (0.44–0.85)

On-Treatment Analysis

 Celecoxib (n=8,030)

Naproxen (n=7,933)

 Ibuprofen (n=7,990) Celecoxib vs Naproxen Celecoxib vs Ibuprofen

Renal events

 42 (0.5%)

62 (0.8%)

 73 (0.9%)

HR 0.66 (95% CI, 0.44–0.97)

 HR 0.54 (95% CI, 0.37–0.80)

The ibuprofen-versus-naproxen hazard ratio for renal events was 1.29 (95% CI 0.95–1.76; p= 0.10). P-values were not reported for on-treatment superiority comparisons because these analyses were considered exploratory.

Abbreviations: APTC, Antiplatelet Trialists Collaboration; aHR, adjusted hazard ratio; CI, confidence interval.
Adverse Events

The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen or ibuprofen. The risk of renal events was significantly lower with celecoxib than with ibuprofen but not significantly lower than with naproxen.
Study Author Conclusions

At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. Celecoxib also resulted in lower rates of gastrointestinal and renal adverse events compared to ibuprofen.

The rates of renal adverse events and hospitalization for hypertension were also significantly lower in the celecoxib group than in the ibuprofen group, although they did not differ significantly between the celecoxib group and the naproxen group. The current results reflect the relative safety of only the doses of celecoxib, ibuprofen, and naproxen studied.
Critique

The large, randomized, double-blind design and independent adjudication provide comparatively strong evidence that moderate-dose celecoxib produced fewer renal events than high-dose ibuprofen, while the difference between celecoxib and naproxen was not statistically significant. However, the cohort had a mean baseline serum creatinine of 0.9 mg/dL, CKD stage 3A was not separately evaluated, the renal outcome definition was not presented in the article, and treatment discontinuation was high; therefore, the study compares relative renal safety but does not establish that any evaluated NSAID is safe specifically in CKD stage 3A.
Table 1 References:
[7] Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519-2529. doi:10.1056/NEJMoa1611593

Comparative Risks of Nonsteroidal Anti-Inflammatory Drugs on CKD
Design

Retrospective cohort study

N= 1,982,488
Objective

To evaluate the association between nonsteroidal anti-inflammatory drug exposure and the risk of incident eGFR <60 ml/min per 1.73m2 and compare the risks between nonsteroidal anti-inflammatory drug (NSAID) subtypes in the Chinese population
Study Groups

No NSAID (n= 1,734,701)

Celecoxib (n= 1,274)

Etoricoxib (n= 1,030)

Diclofenac (n= 90,829)

Ibuprofen (n= 15,169)

Indomethacin (n= 5,199)

Mefenamic acid (n= 10,697)

Naproxen (n= 28,966)

Piroxicam (n= 1,308)

Sulindac (n= 519)
Inclusion Criteria

Individuals aged 18 years or older with baseline eGFR ≥60 ml/min per 1.73m2 between January 1, 2008 and December 31, 2017
Exclusion Criteria

Not specified
Methods

Demographics, diagnoses, prescriptions, laboratory results, and comorbidities were extracted from the Hong Kong Hospital Authority database. Exposure to 9 oral NSAIDs was defined as prescribing for ≥28 days/month and modeled as a time-varying variable. Fine-stratification propensity-score weighting and multivariable Cox regression were used to evaluate kidney outcomes while adjusting for baseline clinical characteristics and medication use. Missing data were handled using multiple imputation, and 8 sensitivity analyses assessed the robustness of the findings.
Duration

January 1, 2008 to December 31, 2017
Outcome Measures

Primary: Incident eGFR <60 ml/min per 1.73m2

Secondary: eGFR decline ≥30%
Baseline Characteristics  

No NSAID (n= 1,734,701)

 Any NSAID  (n= 154,991)
Men

811,803 (47%)

 76,236 (49%)
Age, years

55 ± 17

 55 ± 16
Current smoker

51,890 (3%)

 4813 (3%)
Systolic BP, mm Hg

132 ± 20

 131 ± 20
Diastolic BP, mm Hg

76 ± 12

 76 ± 12
Fasting glucose, mg/dl

102 ± 26

 103 ± 27
BMI, kg/m2

24.5 ± 4.0

 24.7 ± 4.0
LDL cholesterol, mg/dl

117 ± 35

 117 ± 35
eGFR, ml/min per 1.73 m2

113 ± 28

 114 ± 27
Charlson comorbidity index

2.4 ± 1.9

 2.4 ± 1.8

Abbreviations: BP, blood pressure; BMI, body mass index; LDL, low-density lipoprotein; eGFR, estimated glomerular filtration rate.
Results

After a median follow-up of 6.3 years, incident eGFR <60 mL/min/1.73 m² occurred in 271,848 patients (14%), and an eGFR decline ≥30% occurred in 388,386 (21%).

Compared with no NSAID use, any NSAID exposure was associated with higher risks of incident eGFR <60 mL/min/1.73 m² (adjusted hazard ratio [HR] 1.71; 95% confidence interval [CI] 1.67 to 1.75), eGFR decline ≥30% (HR 1.93; 95% CI 1.89 to 1.96), and the composite outcome (HR 1.88; 95% CI 1.85 to 1.91).

Among the individual NSAIDs, ibuprofen had the lowest adjusted risks of incident eGFR <60 mL/min/1.73 m² (HR 1.12; 95% CI 1.02–1.23), eGFR decline ≥30% (HR 1.32; 95% CI 1.23 to 1.41), and the composite outcome (HR 1.34; 95% CI 1.25 to 1.43), whereas etoricoxib had the highest corresponding risks (HR 3.12; 95% CI 2.69 to 3.62; HR 3.11; 95% CI 2.78 to 3.48; and HR 3.13; 95% CI 2.80 to 3.49, respectively).
Adverse Events

Not specified
Study Author Conclusions

Nonsteroidal anti-inflammatory drug exposure was associated with higher risks of incident eGFR <60 ml/min per 1.73 m2 and eGFR decline ≥30%. Highest risk was observed in etoricoxib users, and lowest risk was with ibuprofen.
Critique

The large population, long follow-up, prescription-based exposure ascertainment, time-varying exposure modeling, extensive adjustment, and consistent sensitivity analyses strengthen the comparative findings; however, the retrospective design remains susceptible to residual confounding, and NSAID dose, indication, adherence, and over-the-counter use were unavailable. Ibuprofen had the lowest adjusted kidney risk among the evaluated NSAIDs but remained associated with increased risk versus no NSAID use; because all participants had baseline eGFR ≥60 mL/min/1.73 m², this study does not establish ibuprofen or any other NSAID as safe in patients with CKD stage 3A.
Table 2 References:
[8] Wan EYF, Yu EYT, Chan L, et al. Comparative risks of nonsteroidal anti-inflammatory drugs on CKD. Clin J Am Soc Nephrol. 2021;16(6):898-907. doi:10.2215/CJN.18501120