Effect of Renin-Angiotensin System Inhibitors on the Comparative Nephrotoxicity of NSAIDs and Opioids during Hospitalization
- PMID: 33163971
- PMCID: PMC7643868
- DOI: 10.34067/kid.0001432020
Effect of Renin-Angiotensin System Inhibitors on the Comparative Nephrotoxicity of NSAIDs and Opioids during Hospitalization
Abstract
Background: Nonsteroidal anti-inflammatory drugs (NSAIDS) are increasingly important alternatives to opioids for analgesia during hospitalization as health systems implement opioid-minimization initiatives. Increasing NSAID use may increase AKI rates, particularly in patients with predisposing risk factors. Inconclusive data in outpatient populations suggests that NSAID nephrotoxicity is magnified by renin-angiotensin system inhibitors (RAS-I). No studies have tested this in hospitalized patients.
Methods: Retrospective, active-comparator cohort study of patients admitted to four hospitals in Philadelphia, Pennsylvania. To minimize confounding by indication, NSAIDs were compared to oxycodone, and RAS-I were compared to amlodipine. We tested synergistic NSAID+RAS-I nephrotoxicity by comparing the difference in AKI rate between NSAID versus oxycodone in patients treated with RAS-I to the difference in AKI rate between NSAID versus oxycodone in patients treated with amlodipine. In a secondary analysis, we restricted the cohort to patients with baseline diuretic treatment. AKI rates were adjusted for 71 baseline characteristics with inverse probability of treatment-weighted Poisson regression.
Results: The analysis included 25,571 patients who received a median of 2.4 days of analgesia. The overall AKI rate was 23.6 per 1000 days. The rate difference (RD) for NSAID versus oxycodone in patients treated with amlodipine was 4.1 per 1000 days (95% CI, -2.8 to 11.1), and the rate difference for NSAID versus oxycodone in patients treated with RAS-I was 5.9 per 1000 days (95% CI, 1.9 to 10.1), resulting in a nonsignificant interaction estimate: 1.85 excess AKI events per 1000 days (95% CI, -6.23 to 9.92). Analysis in patients treated with diuretics produced a higher, albeit nonsignificant, interaction estimate: 9.89 excess AKI events per 1000 days (95% CI, -5.04 to 24.83).
Conclusions: Synergistic nephrotoxicity was not observed with short-term NSAID+RAS-I treatment in the absence of concomitant diuretics, suggesting that RAS-I treatment may not be a reason to choose opioids in lieu of NSAIDs in this population. Synergistic nephrotoxicity cannot be ruled out in patients treated with diuretics.
Conflict of interest statement
J. Brown has received consulting fees from Bracco Scientific. S. Hennessy has received consulting fees from the following companies: Braeburn Pharmaceuticals Inc, Esteve Pharmaceuticals LLC, Greenwich Biosciences Inc, Hoffman La Roche, Indivior Inc, Inspiron Delivery Sciences LLC, Janssen Research & Development LLC, Laboratoire HRA PHARMA, Lexicon Pharmaceuticals Inc, Lilly USA LLC, Mallincrodt Pharmaceuticals, Medulary Thyroid Cancer Consortium (AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, Novo Nordisk Inc, GlaxoSmithKline LLC), Merck Research Laboratories, Nektar Therapeutics Inc, NovoNordisk, Pacira Pharmaceuticals Inc, PTC Therapeutics Inc, Purdue Pharma LP, Sage Therapeutics, Sanofi US Services Inc, Shire Human Genetic Therapies Inc, and Transdermal Immediate Release Fentanyl REMS (BioDelivery Sciences International Inc, Insys Therapeutics Inc, Mylan Inc, Par Pharmaceutical Inc, Sentynl Therapeutics Inc, SpecGX LLC [a wholly owned subsidiary of Mallinckrodt Inc], Teva Pharmaceuticals USA Inc, West Therapeutic Development LLC). In addition, S. Hennessy leads the Center for Pharmacoepidemiology Research and Training, which has received support for pharmacoepidemiology training programs from Pfizer Inc. A. Zuppa has served on an advisory committee for Pfizer. All remaining authors have nothing to disclose.
Figures



Comment in
-
Renal Safety of Nonsteroidal Anti-Inflammatory Drugs and Opioids in Hospitalized Patients on Renin-Angiotensin System Inhibitors.Kidney360. 2020 Jul 20;1(7):586-587. doi: 10.34067/KID.0003682020. eCollection 2020 Jul 30. Kidney360. 2020. PMID: 35372946 Free PMC article. No abstract available.
Similar articles
-
Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study.Arch Gerontol Geriatr. 2024 Aug;123:105394. doi: 10.1016/j.archger.2024.105394. Epub 2024 Mar 26. Arch Gerontol Geriatr. 2024. PMID: 38537386
-
Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury.Kidney Int. 2015 Aug;88(2):396-403. doi: 10.1038/ki.2015.101. Epub 2015 Apr 15. Kidney Int. 2015. PMID: 25874600
-
Risk of acute kidney injury by initiation of non-steroidal anti-inflammatory drugs in hospitalised patients treated with diuretics and renin-angiotensin-aldosterone system inhibitors.Eur J Hosp Pharm. 2022 Nov;29(6):359-361. doi: 10.1136/ejhpharm-2020-002550. Epub 2021 Jan 21. Eur J Hosp Pharm. 2022. PMID: 33478983 Free PMC article.
-
Non-steroidal Anti-inflammatory Drugs: Clinical Implications, Renal Impairment Risks, and AKI.Adv Ther. 2023 May;40(5):2082-2096. doi: 10.1007/s12325-023-02481-6. Epub 2023 Mar 22. Adv Ther. 2023. PMID: 36947330 Review.
-
Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs.J Bras Nefrol. 2019 Jan-Mar;41(1):124-130. doi: 10.1590/2175-8239-JBN-2018-0107. Epub 2018 Sep 21. J Bras Nefrol. 2019. PMID: 30281062 Free PMC article. Review.
Cited by
-
Can NSAIDs be used safely for analgesia in patients with CKD?: PRO.Kidney360. 2020 Nov;1(11):1184-1188. doi: 10.34067/kid.0004582020. Kidney360. 2020. PMID: 34296195 Free PMC article. No abstract available.
-
Utility of suPAR and NGAL for AKI Risk Stratification and Early Optimization of Renal Risk Medications among Older Patients in the Emergency Department.Pharmaceuticals (Basel). 2021 Aug 25;14(9):843. doi: 10.3390/ph14090843. Pharmaceuticals (Basel). 2021. PMID: 34577543 Free PMC article.
-
Evaluation of Drug-Drug Interactions in Pharmacoepidemiologic Research.Pharmacoepidemiol Drug Saf. 2025 Jan;34(1):e70088. doi: 10.1002/pds.70088. Pharmacoepidemiol Drug Saf. 2025. PMID: 39805810 Review.
-
Nonopioid analgesic use in older patients admitted for orthopedic rehabilitation.PM R. 2024 Dec;16(12):1324-1333. doi: 10.1002/pmrj.13205. Epub 2024 Jun 7. PM R. 2024. PMID: 38847115 Free PMC article.
-
Robust causal inference of drug-drug interactions.Stat Med. 2023 Mar 30;42(7):970-992. doi: 10.1002/sim.9653. Epub 2023 Jan 10. Stat Med. 2023. PMID: 36627826 Free PMC article.
References
-
- Wu CL, King AB, Geiger TM, Grant MC, Grocott MPW, Gupta R, Hah JM, Miller TE, Shaw AD, Gan TJ, Thacker JKM, Mythen MG, McEvoy MD; Fourth Perioperative Quality Initiative Workgroup : American society for enhanced recovery and perioperative quality initiative joint consensus statement on perioperative opioid minimization in opioid-naïve patients. Anesth Analg 129: 567–577, 2019 - PMC - PubMed
-
- Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, Carter T, Cassidy CL, Chittenden EH, Degenhardt E, Griffith S, Manworren R, McCarberg B, Montgomery R, Murphy J, Perkal MF, Suresh S, Sluka K, Strassels S, Thirlby R, Viscusi E, Walco GA, Warner L, Weisman SJ, Wu CL: Management of postoperative pain: A clinical practice guideline from the American pain society, the American society of regional anesthesia and pain medicine, and the American society of anesthesiologists’ committee on regional anesthesia, executive committee, and administrative council [published correction appears in J Pain 17: 508–510, 2016]. J Pain 17: 131–157, 2016 - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Miscellaneous