NSAIDs in CKD: Are They Safe?

  • Megan Baker
    Department of Medicine, Yale University School of Medicine, New Haven, CT
    Search for articles by this author
  • Mark A. Perazella
    Address for Correspondence: Mark A. Perazella, MD, Section of Nephrology, Department of Medicine, Yale University School of Medicine, BB114, 330 Cedar St, New Haven, CT 06410.
    Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, CT

    Department of Medicine, Veterans Affairs Medical Center, West Haven, CT
    Search for articles by this author
      The management of pain in patients with chronic kidney disease (CKD) is challenging for many reasons. These patients have increased susceptibility to adverse drug effects due to altered drug metabolism and excretion, and there are limited safety data for use in this population despite a high pain burden. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been regarded as dangerous for use in patients with CKD because of their risk for nephrotoxicity and thus alternative classes of analgesics, including opioids, have become more commonly used for pain control in this population. Given the well-established risks that opioids and other analgesics pose, further characterization of the risk posed by NSAIDs in patients with CKD is warranted. NSAID use has been associated with acute kidney injury, progressive loss of glomerular filtration rate in CKD, electrolyte derangements, and hypervolemia with worsening of heart failure and hypertension. The risk for these nephrotoxicity syndromes is modified by many comorbid conditions, risk factors, and characteristics of use, and in patients with CKD, the risk differs between levels of glomerular filtration rate. In this review, we offer recommendations for the cautious use of NSAIDs in the CKD population after careful consideration of these risk factors on an individualized basis.

      Index Words

      To read this article in full you will need to make a payment


      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wu J.
        • Ginsberg J.S.
        • Zhan M.
        • et al.
        Chronic pain and analgesic use in CKD: implications for patient safety.
        Clin J Am Soc Nephrol. 2015; 10: 35-442
        • Bilge U.
        • Sahin G.
        • Unluoglu I.
        • Ipek M.
        • Durdu M.
        • Keskin A.
        Inappropriate use of nonsteroidal anti-inflammatory drugs and other drugs in chronic kidney disease patients without renal replacement therapy.
        Ren Fail. 2013; 35: 906-910
        • Koncicki H.M.
        • Unruh M.
        • Schell J.O.
        Pain management in CKD: a guide for nephrology providers.
        Am J Kidney Dis. 2017; 69: 451-460
        • By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel
        American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.
        J Am Geriatr Soc. 2019; 67: 674-694
        • Clive D.M.
        • Stoff J.S.
        Renal syndromes associated with nonsteroidal antiinflammatory drugs.
        N Engl J Med. 1984; 310: 563-572
        • Nath K.A.
        • Chmielewski D.H.
        • Hostetter T.H.
        Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.
        Am J Physiol. 1987; 252: F829-F837
        • Hull S.
        • Mathur R.
        • Dreyer G.
        • Yaqoob M.M.
        Evaluating ethnic differences in the prescription of NSAIDs for chronic kidney disease: a cross-sectional survey of patients in general practice.
        Br J Gen Pract. 2014; 64: e448-e455
        • Patel K.
        • Diamantidis C.
        • Zhan M.
        • et al.
        Influence of creatinine versus glomerular filtration rate on non-steroidal anti-inflammatory drug prescriptions in chronic kidney disease.
        Am J Nephrol. 2012; 36: 19-26
        • Davison S.N.
        Clinical pharmacology considerations in pain management in patients with advanced kidney failure.
        Clin J Am Soc Nephrol. 2019; 14: 917-931
        • Zhan M.
        • St Peter W.L.
        • Doerfler R.M.
        • et al.
        Patterns of NSAIDs use and their association with other analgesic use in CKD.
        Clin J Am Soc Nephrol. 2017; 12: 1778-1786
        • Eras J.
        • Perazella M.A.
        NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
        Am J Med Sci. 2001; 321: 181-190
        • Cooper C.
        • Chapurlat R.
        • Al-Daghri N.
        • et al.
        Safety of oral non-selective non-steroidal anti-inflammatory drugs in osteoarthritis: what does the literature say?.
        Drugs Aging. 2019; 36: 15-24
        • Hao C.M.
        • Kömhoff M.
        • Guan Y.
        • Redha R.
        • Breyer M.D.
        Selective targeting of cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival.
        Am J Physiol. 1999; 277: F352-F359
        • Nørregaard R.
        • Kwon T.-H.
        • Frøkiær J.
        Physiology and pathophysiology of cyclooxygenase-2 and prostaglandin E2 in the kidney.
        Kidney Res Clin Pract. 2015; 34: 194-200
        • Ferreri N.R.
        • Escalante B.A.
        • Zhao Y.
        • An S.J.
        • McGiff J.C.
        Angiotensin II induces TNF production by the thick ascending limb: functional implications.
        Am J Physiol. 1998; 274: F148-F155
        • Ferreri N.R.
        • An S.J.
        • McGiff J.C.
        Cyclooxygenase-2 expression and function in the medullary thick ascending limb.
        Am J Physiol. 1999; 277: F360-F368
        • Ohnaka K.
        • Numaguchi K.
        • Yamakawa T.
        • Inagami T.
        Induction of cyclooxygenase-2 by angiotensin II in cultured rat vascular smooth muscle cells.
        Hypertension. 2000; 35: 68-75
        • Kester M.
        • Coroneos E.
        • Thomas P.J.
        • Dunn M.J.
        Endothelin stimulates prostaglandin endoperoxide synthase-2 mRNA expression and protein synthesis through a tyrosine kinase-signaling pathway in rat mesangial cells.
        J Biol Chem. 1994; 269: 22574-22580
        • Gambaro G.
        • Perazella M.A.
        Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors.
        J Intern Med. 2003; 253: 643-652
        • Smith W.L.
        Prostanoid biosynthesis and mechanisms of action.
        Am J Physiol. 1992; 263: F181-F191
        • Palmer B.F.
        • Henrich W.L.
        Clinical acute renal failure with nonsteroidal anti-inflammatory drugs.
        Semin Nephrol. 1995; 15: 214-227
        • Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
        KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
        Kidney Int Suppl. 2013; 3: 1-150
        • Inker L.A.
        • Astor B.C.
        • Fox C.H.
        • et al.
        KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
        Am J Kidney Dis. 2014; 63: 713-735
        • Launay-Vacher V.
        • Karie S.
        • Fau J.-B.
        • Izzedine H.
        • Deray G.
        Treatment of pain in patients with renal insufficiency: the World Health Organization three-step ladder adapted.
        J Pain. 2005; 6: 137-148
        • Bennett W.M.
        • DeBroe M.E.
        Analgesic nephropathy--a preventable renal disease.
        N Engl J Med. 1989; 320: 1269-1271
        • Sriperumbuduri S.
        • Hiremath S.
        The case for cautious consumption: NSAIDs in chronic kidney disease.
        Curr Opin Nephrol Hypertens. 2019; 28: 163-170
        • Gertz B.J.
        • Krupa D.
        • Bolognese J.A.
        • Sperling R.S.
        • Reicin A.
        A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents.
        Curr Med Res Opin. 2002; 18: 82-91
        • Patrono C.
        • Dunn M.J.
        The clinical significance of inhibition of renal prostaglandin synthesis.
        Kidney Int. 1987; 32: 1-12
        • Kurth T.
        • Glynn R.J.
        • Walker A.M.
        • et al.
        Analgesic use and change in kidney function in apparently healthy men.
        Am J Kidney Dis. 2003; 42: 234-244
        • Curhan G.C.
        • Knight E.L.
        • Rosner B.
        • Hankinson S.E.
        • Stampfer M.J.
        Lifetime nonnarcotic analgesic use and decline in renal function in women.
        Arch Intern Med. 2004; 164: 1519-1524
        • Agodoa L.Y.
        • Francis M.E.
        • Eggers P.W.
        Association of analgesic use with prevalence of albuminuria and reduced GFR in US adults.
        Am J Kidney Dis. 2008; 51: 573-583
        • Perazella M.A.
        • Buller G.K.
        Can ibuprofen cause acute renal failure in a normal individual? A case of acute overdose.
        Am J Kidney Dis. 1991; 18: 600-602
        • Brewster U.C.
        • Perazella M.A.
        Acute tubulointerstitial nephritis associated with celecoxib.
        Nephrol Dial Transplant. 2004; 19: 1017-1918
        • Perazella M.A.
        • Tray K.
        Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs.
        Am J Med. 2001; 111: 64-67
        • Zhang X.
        • Donnan P.T.
        • 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: 256
        • Brater D.C.
        Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2–selective inhibition.
        Am J Med. 1999; 107: 65-70
        • Lipman G.S.
        • Shea K.
        • Christensen M.
        • et al.
        Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial.
        Emerg Med J. 2017; 34: 637-642
        • Blackshear J.L.
        • Davidman M.
        • Stillman M.T.
        Identification of risk for renal insufficiency from nonsteroidal anti-inflammatory drugs.
        Arch Intern Med. 1983; 143: 1130-1134
        • Griffin M.R.
        • Yared A.
        • Ray W.A.
        Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.
        Am J Epidemiol. 2000; 151: 488-496
        • Dreischulte T.
        • Morales D.R.
        • Bell S.
        • Guthrie B.
        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; 88: 396-403
        • Nash D.M.
        • Markle-Reid M.
        • Brimble K.S.
        • et al.
        Nonsteroidal anti-inflammatory drug use and risk of acute kidney injury and hyperkalemia in older adults: a population-based study.
        Nephrol Dial Transplant. 2019; 34: 1145-1154
        • Bouck Z.
        • Mecredy G.C.
        • Ivers N.M.
        • et al.
        Frequency and associations of prescription nonsteroidal anti-inflammatory drug use among patients with a musculoskeletal disorder and hypertension, heart failure, or chronic kidney disease.
        JAMA Intern Med. 2018; 178: 1516-1525
        • Joseph Hwang Y.
        • Shariff S.Z.
        • Gandhi S.
        • et al.
        Validity of the International Classification of Diseases, Tenth Revision code for acute kidney injury in elderly patients at presentation to the emergency department and at hospital admission.
        BMJ Open. 2012; 2e001821
        • Fleet J.L.
        • Shariff S.Z.
        • Gandhi S.
        • Weir M.A.
        • Jain A.K.
        • Garg A.X.
        Validity of the International Classification of Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to an emergency department and at hospital admission.
        BMJ Open. 2012; 2e002011
        • Lapi F.
        • Azoulay L.
        • Yin H.
        • Nessim S.J.
        • Suissa S.
        Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study.
        BMJ. 2013; 346e8525
        • Cheng H.F.
        • Wang J.L.
        • Zhang M.Z.
        • et al.
        Angiotensin II attenuates renal cortical cyclooxygenase-2 expression.
        J Clin Invest. 1999; 103: 953-961
        • Chiasson J.M.
        • Fominaya C.E.
        • Gebregziabher M.
        • Taber D.J.
        Long-term assessment of NSAID prescriptions and potential nephrotoxicity risk in adult kidney transplant recipients.
        Transplantation. 2019; 103: 2675-2681
        • Delzer L.M.
        • Golightly L.K.
        • Kiser T.H.
        • Biggins S.W.
        • Lewis V.J.
        • Kim I.I.
        Calcineurin inhibitor and nonsteroidal anti-inflammatory drug interaction: implications of changes in renal function associated with concurrent use.
        J Clin Pharmacol. 2018; 58: 1443-1451
        • Curtis E.
        • Fuggle N.
        • Shaw S.
        • et al.
        Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis.
        Drugs Aging. 2019; 36: 25-44
        • McGettigan P.
        • Han P.
        • Jones L.
        • Whitaker D.
        • Henry D.
        Selective COX-2 inhibitors, NSAIDs and congestive heart failure: differences between new and recurrent cases.
        Br J Clin Pharmacol. 2008; 65: 927-934
        • Hudson M.
        • Rahme E.
        • Richard H.
        • Pilote L.
        Risk of congestive heart failure with nonsteroidal antiinflammatory drugs and selective cyclooxygenase 2 inhibitors: a class effect?.
        Arthritis Rheum. 2007; 57: 516-523
        • Arfè A.
        • Scotti L.
        • Varas-Lorenzo C.
        • et al.
        Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study.
        BMJ. 2016; 354: i4857
        • Soi V.
        • Yee J.
        Sodium homeostasis in chronic kidney disease.
        Adv Chronic Kidney Dis. 2017; 24: 325-331
        • Perazella M.A.
        COX-2 selective inhibitors: analysis of the renal effects.
        Expert Opin Drug Saf. 2002; 1: 53-64
        • Kim S.
        • Joo K.W.
        Electrolyte and acid-base disturbances associated with non-steroidal anti-inflammatory drugs.
        Electrolyte Blood Press. 2007; 5: 116-125
        • Wharam P.C.
        • Speedy D.B.
        • Noakes T.D.
        • Thompson J.M.D.
        • Reid S.A.
        • Holtzhausen L.-M.
        NSAID use increases the risk of developing hyponatremia during an Ironman triathlon.
        Med Sci Sports Exerc. 2006; 38: 618-622
        • Clark B.A.
        • Shannon R.P.
        • Rosa R.M.
        • Epstein F.H.
        Increased susceptibility to thiazide-induced hyponatremia in the elderly.
        J Am Soc Nephrol. 1994; 5: 1106-1111
        • Roche C.
        • Ragot C.
        • Moalic J.-L.
        • Simon F.
        • Oliver M.
        Ibuprofen can induce syndrome of inappropriate diuresis in healthy young patients.
        Case Rep Med. 2013; 2013: 167267
        • Artom N.
        • Oddo S.
        • Pende A.
        • Ottonello L.
        • Giusti M.
        • Dallegri F.
        Syndrome of inappropriate antidiuretic hormone secretion and ibuprofen, a rare association to be considered: role of tolvaptan.
        Case Rep Endocrinol. 2013; 2013: 818259
        • Meijer E.
        • Boertien W.E.
        • Zietse R.
        • Gansevoort R.T.
        Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease.
        Kidney Blood Press Res. 2011; 34: 235-244
        • Jacob P.
        • Dow C.
        • Lasker S.S.
        • Drake W.M.
        • Chowdhury T.A.
        Hyponatraemia in primary care.
        BMJ. 2019; 365: l1774
        • Perazella M.A.
        Drug-induced hyperkalemia: old culprits and new offenders.
        Am J Med. 2000; 109: 307-314
        • Ling B.N.
        • Webster C.L.
        • Eaton D.C.
        Eicosanoids modulate apical Ca (2+)-dependent K+ channels in cultured rabbit principal cells.
        Am J Physiol. 1992; 263: F116-F126
        • Lafrance J.-P.
        • Miller D.R.
        Dispensed selective and nonselective nonsteroidal anti-inflammatory drugs and the risk of moderate to severe hyperkalemia: a nested case-control study.
        Am J Kidney Dis. 2012; 60: 82-89
        • Michel A.
        • Martín-Pérez M.
        • Ruigómez A.
        • García Rodríguez L.A.
        Risk factors for hyperkalaemia in a cohort of patients with newly diagnosed heart failure: a nested case--control study in UK general practice.
        Eur J Heart Fail. 2015; 17: 205-213
        • Pope J.E.
        • Anderson J.J.
        • Felson D.T.
        A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure.
        Arch Intern Med. 1993; 153: 477-484
        • Johnson A.G.
        • Nguyen T.V.
        • Day R.O.
        Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.
        Ann Intern Med. 1994; 121: 289-300
        • Kalafutova S.
        • Juraskova B.
        • Vlcek J.
        The impact of combinations of non-steroidal anti-inflammatory drugs and anti-hypertensive agents on blood pressure.
        Adv Clin Exp Med. 2014; 23: 993-1000
        • Whelton A.
        Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications.
        Am J Med. 1999; 106: 13S-24S
        • Pavlicevic I.
        • Kuzmanic M.
        • Rumboldt M.
        • Rumboldt Z.
        Interaction between antihypertensives and NSAIDS in primary care: a controlled trial.
        Can J Clin Pharmacol. 2008; 15: e372-e382
        • Ruschitzka F.
        • Borer J.S.
        • Krum H.
        • et al.
        Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial.
        Eur Heart J. 2017; 38: 3282-3292
        • Collins R.
        • Peto R.
        • MacMahon S.
        • et al.
        Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context.
        Lancet. 1990; 335: 827-838
        • Wilson S.L.
        • Poulter N.R.
        The effect of non-steroidal anti-inflammatory drugs and other commonly used non-narcotic analgesics on blood pressure level in adults.
        J Hypertens. 2006; 24: 1457-1469
        • Leonard C.E.
        • Freeman C.P.
        • Newcomb C.W.
        • et al.
        Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury.
        Pharmacoepidemiol Drug Saf. 2012; 21: 1155-1172
        • Nawaz F.A.
        • Larsen C.P.
        • Troxell M.L.
        Membranous nephropathy and nonsteroidal anti-inflammatory agents.
        Am J Kidney Dis. 2013; 62: 1012-1017
        • Mérida E.
        • Praga M.
        NSAIDs and nephrotic syndrome.
        Clin J Am Soc Nephrol. 2019; 14: 1280-1282
        • Bakhriansyah M.
        • Souverein P.C.
        • van den Hoogen M.W.F.
        • de Boer A.
        • Klungel O.H.
        Risk of nephrotic syndrome for non-steroidal anti-inflammatory drug users.
        Clin J Am Soc Nephrol. 2019; 14: 1355-1362
        • Whelton A.
        • Hamilton C.W.
        Nonsteroidal anti-inflammatory drugs: effects on kidney function.
        J Clin Pharmacol. 1991; 31: 588-598
        • Perneger T.V.
        • Whelton P.K.
        • Klag M.J.
        Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs.
        N Engl J Med. 1994; 331: 1675-1679
        • Sandler D.P.
        • Burr F.R.
        • Weinberg C.R.
        Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease.
        Ann Intern Med. 1991; 115: 165-172
        • Rexrode K.M.
        • Buring J.E.
        • Glynn R.J.
        • Stampfer M.J.
        • Youngman L.D.
        • Gaziano J.M.
        Analgesic use and renal function in men.
        JAMA. 2001; 286: 315-321
        • Gooch K.
        • Culleton B.F.
        • Manns B.J.
        • et al.
        NSAID use and progression of chronic kidney disease.
        Am J Med. 2007; 120 (280.e1-e7)
        • Nissen S.E.
        • Yeomans N.D.
        • Solomon D.H.
        • et al.
        Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.
        N Engl J Med. 2016; 375: 2519-2529
        • Murray M.D.
        • Craig Brater D.
        • Tierney W.M.
        • Hui S.L.
        • McDonald C.J.
        Ibuprofen-associated renal impairment in a large general internal medicine practice.
        Am J Med Sci. 1990; 299: 222-229
        • Möller B.
        • Pruijm M.
        • Adler S.
        • et al.
        Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study.
        Ann Rheum Dis. 2015; 74: 718-723
        • Nderitu P.
        • Doos L.
        • Jones P.W.
        • Davies S.J.
        • Kadam U.T.
        Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review.
        Fam Pract. 2013; 30: 247-255
        • Nelson D.A.
        • Marks E.S.
        • Deuster P.A.
        • O’Connor F.G.
        • Kurina L.M.
        Association of nonsteroidal anti-inflammatory drug prescriptions with kidney disease among active young and middle-aged adults.
        JAMA Netw Open. 2019; 2e187896
        • Pham P.C.
        • Khaing K.
        • Sievers T.M.
        • et al.
        2017 Update on pain management in patients with chronic kidney disease.
        Clin Kidney J. 2017; 10: 688-697
        • Perazella M.A.
        • Buller G.K.
        NSAID nephrotoxicity revisited: acute renal failure due to parenteral ketorolac.
        South Med J. 1993; 86: 1421-1424
        • McPherson M.L.
        • Cimino N.M.
        Topical NSAID formulations.
        Pain Med. 2013; 14: S35-S39
        • Simon L.S.
        • Grierson L.M.
        • Naseer Z.
        • Bookman A.A.M.
        • Zev Shainhouse J.
        Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis.
        Pain. 2009; 143: 238-245
        • Tugwell P.S.
        • Wells G.A.
        • Shainhouse J.Z.
        Equivalence study of a topical diclofenac solution (Pennsaid) compared with oral diclofenac in symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial.
        J Rheumatol. 2004; 31: 2002-2012