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American Journal of Kidney Diseases

NSAIDs in CKD: Are They Safe?

  • Megan Baker
    Affiliations
    Department of Medicine, Yale University School of Medicine, New Haven, CT
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  • Mark A. Perazella
    Correspondence
    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.
    Affiliations
    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

      Introduction

      Chronic pain is common in patients with chronic kidney disease (CKD), and its management is limited by drug-related adverse effects across analgesic classes.
      • Wu J.
      • Ginsberg J.S.
      • Zhan M.
      • et al.
      Chronic pain and analgesic use in CKD: implications for patient safety.
      Patients with reduced glomerular filtration rates (GFR) are at increased risk for drug-related toxicity due to impaired metabolism and excretion and increased accumulation of parent drugs and their metabolites.
      Medications that have adverse side effects specifically associated with their use in CKD are prescribed more frequently as patients progress to more severe stages of CKD.
      • 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.
      This is likely a reflection of both increasingly complex prescribing considerations with worsening GFR and polypharmacy related to advanced disease. For decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been at the top of the list of potentially harmful medications in patients with CKD, and this consensus continues to affect practice patterns today.
      • Koncicki H.M.
      • Unruh M.
      • Schell J.O.
      Pain management in CKD: a guide for nephrology providers.
      ,
      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.
      Concern for increasing risk for the classic “clinical renal syndromes” associated with NSAIDs (Box 1) in patients with CKD underlies this thought process.
      • Clive D.M.
      • Stoff J.S.
      Renal syndromes associated with nonsteroidal antiinflammatory drugs.
      Underlying CKD is considered a “prostaglandin-dependent” state, which makes NSAID use potentially more risky.
      • Nath K.A.
      • Chmielewski D.H.
      • Hostetter T.H.
      Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.
      Adverse Effects of NSAIDs on the Kidney
      • Acute kidney injury
        • Hemodynamic and acute tubular injury
      • Hyperkalemia ± metabolic acidosis
      • Hyponatremia
      • Hypervolemia and sodium avidity
        • Edema, congestive heart failure
        • Diuretic resistance
      • Exacerbation of hypertension
      • Acute interstitial nephritis
      • Nephrotic syndrome
        • Membranous nephropathy
        • Minimal change disease
      • Acute or chronic papillary necrosis
      • Progression of chronic kidney disease
      Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.
      Although patients with advancing CKD are exposed to more NSAIDs from combined over-the-counter and prescription use, health care provider prescribing of NSAIDs recently has been decreasing in a stepwise fashion with higher CKD stage in accordance with prescription guidance.
      • 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.
      ,
      • 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.
      NSAID avoidance has ultimately led to increased opioid administration and other adjuvant therapies to manage pain, often at excessive doses for the degree of GFR reduction.
      • Davison S.N.
      Clinical pharmacology considerations in pain management in patients with advanced kidney failure.
      ,
      • Zhan M.
      • St Peter W.L.
      • Doerfler R.M.
      • et al.
      Patterns of NSAIDs use and their association with other analgesic use in CKD.
      Opioid use poses many risks regardless of GFR, and data regarding the safety of even commonly used agents in patients with CKD are markedly limited.
      • Davison S.N.
      Clinical pharmacology considerations in pain management in patients with advanced kidney failure.
      A review of the evidence surrounding NSAID use in patients with CKD suggests a more nuanced approach encompassing CKD stage and other risk-enhancing comorbid conditions given the difficulty managing pain in this population.

      Prostaglandins and the Kidneys

      NSAIDs provide their analgesic, anti-inflammatory, and antipyretic actions through inhibition of cyclooxygenase (COX) enzymes. COX enzymes convert arachidonic acid, liberated from the cell membrane, to various eicosanoids, namely thromboxane and prostaglandins. These fatty acid derivatives act locally in a paracrine and autocrine manner, primarily as modulators of the effects of systemic hormones.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      Two isoforms of COX, COX-1 and COX-2, have separate but overlapping roles. COX-1 is expressed constitutively in many tissues and maintains baseline physiologic functions, including maintenance of kidney perfusion and function, regulation of platelet aggregation, and protection of gastric mucosa.
      • 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?.
      COX-2 expression is modified by growth factors, cytokines, and other external signals and is upregulated in response to inflammation.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      Although differences in their gene regulation lead to more constitutive expression of COX-1 and inducible expression of COX-2 in many tissues, COX-2 is also constitutively expressed in the kidneys.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      ,
      • 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.
      COX-2 is largely responsible for increased prostaglandin production under circumstances requiring augmentation of renal blood flow (RBF), including in cases of reduced effective circulating volume (ECV) and reduced GFR.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      The sites of COX-1 and COX-2 expression and prostaglandin action in human kidneys are shown in Figure 1.
      • Nørregaard R.
      • Kwon T.-H.
      • Frøkiær J.
      Physiology and pathophysiology of cyclooxygenase-2 and prostaglandin E2 in the kidney.
      COX-2 is upregulated in animal kidneys in response to volume contraction and circulating angiotensin II, which increases prostaglandin synthesis, leading to local adaptation.
      • 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.
      • Ferreri N.R.
      • An S.J.
      • McGiff J.C.
      Cyclooxygenase-2 expression and function in the medullary thick ascending limb.
      • Ohnaka K.
      • Numaguchi K.
      • Yamakawa T.
      • Inagami T.
      Induction of cyclooxygenase-2 by angiotensin II in cultured rat vascular smooth muscle cells.
      • 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.
      Although differences in COX-2 localization exist between humans and animals, the strategic locations of this enzyme and its upregulation under physiologic stress in both models suggest that COX-2 plays a critical role in adaptive renoprotective measures.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      Hence, NSAID inhibition of COX-2 is likely a major cause of the nephrotoxicity of this drug class.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      ,
      • Gambaro G.
      • Perazella M.A.
      Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors.
      Figure thumbnail gr1
      Figure 1Location of expression of cyclooxygenase (COX) isoforms in the kidney and the predominant prostaglandins (PGs) produced. Text in green denotes locations where COX-1 expressed; blue, COX-2; and black, locations of overlapping COX-1 and COX-2 expression. Abbreviations: TAL, thick ascending limb; TXA2, thromboxane A2.
      The primary eicosanoids in the kidney are prostaglandin I2 (PGI2), PGE2, thromboxane A2, and PGF.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.
      Prostaglandins play a significant role in modulating RBF and GFR (Table 1; Fig 2A). Vasodilating prostaglandins counteract vasoconstrictor effects to maintain RBF, GFR, and peritubular capillary perfusion.
      • Clive D.M.
      • Stoff J.S.
      Renal syndromes associated with nonsteroidal antiinflammatory drugs.
      ,
      • Smith W.L.
      Prostanoid biosynthesis and mechanisms of action.
      Prostaglandins also influence renal sodium, water, and potassium handling (Fig 2A).
      • Clive D.M.
      • Stoff J.S.
      Renal syndromes associated with nonsteroidal antiinflammatory drugs.
      ,
      • Smith W.L.
      Prostanoid biosynthesis and mechanisms of action.
      Their inhibition of sodium reabsorption and blunting of antidiuretic hormone (ADH) effects result in natriuresis and aquaresis, whereas prostaglandin stimulation of renin leads to aldosterone synthesis and potassium secretion.
      • Clive D.M.
      • Stoff J.S.
      Renal syndromes associated with nonsteroidal antiinflammatory drugs.
      ,
      • Smith W.L.
      Prostanoid biosynthesis and mechanisms of action.
      Unlike many systemic hormones that act unidirectionally to affect physiologic conditions, prostaglandins control a delicate balance, operating both under conditions requiring excretion and those calling for retention of sodium, water, and potassium and therefore their effects are complex and highly localized.
      Table 1Prostaglandins and the Kidney
      EicosanoidSiteActionEffect in the Kidney
      PGE2 and PGI2JGA of glomerulusActivation of RAASSodium and water retention by the PCT, and sodium retention and potassium wasting by the DCT through the effects of aldosterone
      Medulla, inner cortexArteriolar vasodilationAugmentation of postglomerular perfusion
      Inhibition of cAMP synthesisDecreased ADH effect and increase diuresis
      Loop of HenleDecreases transcellular transport of sodiumIncreased sodium excretion and decreased medullary osmotic gradient
      GlomerulusAttenuates podocyte cell contraction and arteriolar vasoconstriction induced by angiotensin II, endothelin, ADH, platelet activating factorAttenuation of podocyte cell contraction leads to preservation of glomerular surface area and GFR
      TXA2GlomerulusVasoconstriction and podocyte contractionDecreased renal blood flow, glomerular filtration, and perfusion pressure
      PGFMedullary interstitial and tubular cellsModulation of water reabsorption and transcellular transport of sodiumAdaptive sodium and water handling
      Abbreviations: ADH, antidiuretic hormone; cAMP, cyclic adenosine monophosphate; DCT, distal collecting tubule; GFR, glomerular filtration rate; JGA, juxtaglomerular apparatus; PCT, proximal convoluted tubule; PG, prostaglandin; RAAS, renin-angiotensin-aldosterone system; TXA2, thromboxane A2.
      Figure thumbnail gr2
      Figure 2Prostaglandins (PGs) and the kidney. (A) Prostaglandin production and downstream effects in the kidneys. Synthesis of various prostaglandins from arachidonic acid by cyclooxygenase (COX) enzymes has a number of effects in the kidneys. (B) Adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on kidney function. NSAID therapy causes a number of adverse effects in the kidney through inhibition of prostaglandin production. Abbreviations: AKI, acute kidney injury; ATI, acute tubular injury; CHF, congestive heart failure; GFR, glomerular filtration rate; HTN, hypertension; RTA, renal tubular acidosis.
      Under various circumstances of ECV depletion, prostaglandin production is increased to augment RBF, renin production, and sodium and water retention.
      • Palmer B.F.
      • Henrich W.L.
      Clinical acute renal failure with nonsteroidal anti-inflammatory drugs.
      Prostaglandin production is increased in CKD as a mechanism to improve the perfusion of remaining nephrons, even in the absence of volume depletion.
      • Nath K.A.
      • Chmielewski D.H.
      • Hostetter T.H.
      Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.
      This is important in maintaining baseline GFR even in the setting of modestly reduced glomerular filtration.
      • Eras J.
      • Perazella M.A.
      NSAIDs and the kidney revisited: are selective cyclooxygenase-2 inhibitors safe?.

      NSAIDs and the Kidneys

      Overview

      In the medical community, NSAIDs are regarded as harmful for patients with CKD. Clinical guidelines currently recommend the avoidance of prolonged NSAID use in CKD with GFR > 30 mL/min/1.73 m2 and complete avoidance with GFR < 30 mL/min/1.73 m2.
      Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      • 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.
      • 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.
      Concern for NSAID-associated nephrotoxicity in patients with CKD arose from an era of combination analgesics (a mixture of NSAIDs with phenacetin, paracetamol, or salicylamide and caffeine or codeine) and is founded physiologically on concern for lack of renal reserve in the “CKD kidney.”
      • Bennett W.M.
      • DeBroe M.E.
      Analgesic nephropathy--a preventable renal disease.
      Epidemiologic studies have suggested increased nephrotoxicity risk with noncombination NSAID use in patients with CKD. However, epidemiologic studies examining the risk for CKD progression from NSAIDs are tasked with comparing unique sets of populations that are defined by their use of NSAIDs. Knowledge about NSAID nephrotoxicity leads to altered drug use, leading to selection and confounding biases.
      • Sriperumbuduri S.
      • Hiremath S.
      The case for cautious consumption: NSAIDs in chronic kidney disease.
      Patients with CKD ingesting NSAIDs despite their well-publicized risk for nephrotoxicity represent a population that is inherently different than nonusers. Incompatible conclusions between many well-designed studies likely result from differences in study population, study design, study size, and methods used for attempting to adjust for confounders. These contradictory findings suggest a propensity for NSAIDs to cause nephrotoxicity in CKD, but also the presence of strong modifiers of this effect, such as severity of underlying health conditions, burden of chronic disease, and concomitant medication exposures (Box 2). Many studies also have lack of stratification by CKD stage or exclusion of advanced CKD (stages 4-5) altogether.
      Risk Factors for NSAID Nephrotoxicity

      Acute Kidney Injury

      • True circulating volume depletion
        • Exercise-induced, diarrhea, vomiting, excessive diuresis, poor oral intake
      • Effective circulating volume depletion
        • Nephrotic syndrome, cirrhosis, CHF, hypoalbuminemia
      • High cumulative dose exposure
      • Concurrent calcineurin inhibitors and other vasoconstrictors
      • Concurrent therapy with RAAS inhibitors, diuretics, or both

      Hyperkalemia

      • Concurrent use of medications promoting hyperkalemia
        • RAAS inhibitors, trimethoprim, heparin, other drugs
      • Exposure to radiocontrast with concomitant RAAS inhibitor
      • Age > 65 y
      • Hyporeninemic hypoaldosteronism
      • Type 4 RTA

      Hyponatremia

      • True or effective circulating volume depletion (outlined above)
      • Conditions associated with SIADH
      • Increased free water intake ± increased sodium losses (eg, with extreme exercise)
      • Thiazide use in elderly patients

      Hypervolemia

      • Underlying comorbid conditions promoting sodium avidity, including CHF, cirrhosis, and nephrotic syndrome

      Worsened hypertension

      • Underlying hypertension, including on effective treatment
      • Hyporeninemic states, as seen in elderly and diabetes mellitus

      Progression of CKD

      • Age > 65 y
      • High cumulative dose exposure
      • Coronary artery disease
      • Combination analgesics (banned)
      Note: Risk posed by kidney disease outlined in Figure 3; excluded from this table.
      Abbreviations: CHF, congestive heart failure; CKD, chronic kidney disease; NSAID, nonsteroidal anti-inflammatory drug; RAAS, renin-angiotensin-aldosterone system; RTA, renal tubular acidosis; SIADH, syndrome of inappropriate antidiuretic hormone secretion.
      Prescribing NSAIDs raises the concern for increased risk for the development of one of the serious “clinical renal syndromes.” The risk for each of these effects is discussed next.

      Acute Kidney Injury

      The major concern associated with NSAID use is acute kidney injury (AKI). Despite this, AKI and other adverse effects such as fluid and electrolyte derangements rarely develop in patients with few or no risk factors for injury (Box 2) with regular NSAID use.
      • 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.
      • Patrono C.
      • Dunn M.J.
      The clinical significance of inhibition of renal prostaglandin synthesis.
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      • et al.
      Analgesic use and change in kidney function in apparently healthy men.
      • 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.
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      • Francis M.E.
      • Eggers P.W.
      Association of analgesic use with prevalence of albuminuria and reduced GFR in US adults.
      • Perazella M.A.
      • Buller G.K.
      Can ibuprofen cause acute renal failure in a normal individual? A case of acute overdose.
      Pooled risk ratios for AKI events among individual NSAIDs for patients without CKD are reported to be within a range of 1.6 to 2.2.
      • 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?.
      Although the nephrotoxicity of individual NSAIDs may vary to a certain degree, a meta-analysis characterizing AKI risk with the use of many common agents demonstrated a relatively similar elevation in risk among all agents, though rofecoxib demonstrated the greatest risk.
      • Brewster U.C.
      • Perazella M.A.
      Acute tubulointerstitial nephritis associated with celecoxib.
      Importantly, selective COX-2 inhibitors cause adverse kidney effects at a rate and severity comparable to nonselective NSAIDs.
      • Gambaro G.
      • Perazella M.A.
      Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors.
      ,
      • Brewster U.C.
      • Perazella M.A.
      Acute tubulointerstitial nephritis associated with celecoxib.
      • Perazella M.A.
      • Tray K.
      Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to traditional nonsteroidal anti-inflammatory drugs.
      • 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.
      • Brater D.C.
      Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2–selective inhibition.
      NSAID-associated AKI is predominantly hemodynamically mediated, resulting in reversible reduction in GFR or ischemic tubular injury (Fig 2B). Patients at highest risk for AKI are those in whom kidney perfusion is dependent on prostaglandin-induced vasodilation to combat circulating systemic and local vasoconstrictors. In states of reduced ECV, angiotensin II and endothelin reduce GFR and postglomerular capillary perfusion, increasing risk for ischemic tubular injury. True volume depletion and reduced ECV as seen with congestive heart failure (CHF), nephrotic syndrome, and cirrhosis increase the risk for hemodynamic AKI with NSAIDs.
      • Lipman G.S.
      • Shea K.
      • Christensen M.
      • et al.
      Ibuprofen versus placebo effect on acute kidney injury in ultramarathons: a randomised controlled trial.
      ,
      • Blackshear J.L.
      • Davidman M.
      • Stillman M.T.
      Identification of risk for renal insufficiency from nonsteroidal anti-inflammatory drugs.
      Conditions associated with vascular dysfunction such as advancing age and hypertension are associated with increased AKI risk with NSAIDs, likely reflecting reduced vascular reserve due to atherosclerosis and narrowing of renal arterioles, effecting heavier reliance on prostaglandin for perfusion.
      • Nath K.A.
      • Chmielewski D.H.
      • Hostetter T.H.
      Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.
      ,
      • Griffin M.R.
      • Yared A.
      • Ray W.A.
      Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.
      ,
      • 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.
      ,
      • 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.
      The biological plausibility of CKD conferring an increased risk for NSAID-associated AKI is based on the concept of reduced renal reserve in CKD and increased prostaglandin dependence for perfusion of remnant nephrons.
      • Nath K.A.
      • Chmielewski D.H.
      • Hostetter T.H.
      Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons.
      ,
      • Griffin M.R.
      • Yared A.
      • Ray W.A.
      Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.
      ,
      • 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.
      Although overall studies show that NSAIDs confer AKI risk in patients with CKD, quantification of this risk varies greatly between studies examining populations with differing baseline characteristics and use patterns.
      A retrospective cohort study including more than 35,000 matched elderly patient pairs with hypertension, CKD, or CHF showed no difference in kidney complications between those exposed and not exposed to prescription NSAIDs.
      • 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.
      However, diagnosis codes were used to define these outcomes and CKD stages were not stratified.
      • 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.
      ,
      • 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.
      A systematic meta-analysis of high-quality observation-based population studies found that NSAID-related AKI risk in patients with CKD was similar to the general population. However, there was significant study heterogeneity, suggesting significant modifiers to the risk.
      • 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.
      Although informative for moderate (stage 3) CKD, many large trials and meta-analyses to date characterize CKD as a homogeneous group of patients with any GFR < 60 mL/min/1.73 m2 and therefore conclusions regarding NSAID risk based on these studies cannot be applied to patients with more advanced stage 4-5 CKD, who are often either excluded or vastly under-represented.
      The risk for NSAID-associated AKI appears higher in elderly patients with CKD, though elderly patients without CKD are also at increased risk, as previously mentioned. A large population-based study of an elderly cohort found no impact of baseline GFR on risk for NSAID-associated AKI. However, there was a trend toward higher absolute increase in AKI risk with lower baseline GFR.
      • 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.
      Another study demonstrated similar risk for reversible hemodynamic AKI between elderly patients with moderate CKD and without CKD using NSAIDs, but NSAIDs significantly increased the risk for intrinsic AKI only among patients with CKD.
      • Griffin M.R.
      • Yared A.
      • Ray W.A.
      Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.
      AKI risk with NSAIDs also increases with use alongside interacting medications. Concomitant NSAID use with renin-angiotensin-aldosterone system (RAAS) inhibitors, diuretics, or both has been associated with increased AKI risk, especially within the first 30 days of combined use.
      • 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.
      ,
      • 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.
      The AKI risk of double or triple therapy is suggested to be even more pronounced in patients with stages 1-3 CKD and is likely elevated in advanced stages as well.
      • 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.
      Prostaglandins attenuate angiotensin II–mediated afferent arteriole vasoconstriction, and COX-2 expression is upregulated with angiotensin-converting enzyme inhibitor use,
      • Cheng H.F.
      • Wang J.L.
      • Zhang M.Z.
      • et al.
      Angiotensin II attenuates renal cortical cyclooxygenase-2 expression.
      providing a physiologic model explaining why RAAS inhibitors increase NSAIDs’ AKI risk. Other prominent examples include calcineurin inhibitors, whose vasoconstrictive effects increase the risk for ischemic injury in transplant recipients.
      • 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.
      ,
      • 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.
      Although more advanced stages of CKD, older age, and specific medication coadministrations can lead to greater NSAID-related AKI risk, the multimorbidity of patients with CKD rather than CKD itself should be considered the greatest risk to NSAID therapy. The CKD population is a complex patient cohort with significant comorbid disease burden, and these comorbid conditions, their complications, and their management frequently lead to significant AKI risk factors.

      Hypervolemia

      NSAIDs also affect fluid and electrolyte balance. By preventing the natriuretic and aquaretic effects of prostaglandins, NSAIDs increase sodium and water retention, thereby promoting edema formation, exacerbating CHF, and worsening hypertension (Fig 2B).
      • Sriperumbuduri S.
      • Hiremath S.
      The case for cautious consumption: NSAIDs in chronic kidney disease.
      These effects are most pronounced in patients with underlying sodium- and water-avid states such as CHF, nephrotic syndrome, and cirrhosis (Box 2). A recent meta-analysis of randomized placebo-controlled trials found 70% increased risk for CHF and edema with selective COX-2 inhibitor use versus placebo, even when excluding particularly high-risk agents such as rofecoxib.
      • Curtis E.
      • Fuggle N.
      • Shaw S.
      • et al.
      Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis.
      Additionally, NSAIDs are associated with an increased dose-dependent risk for CHF hospitalization.
      • 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.
      • 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?.
      • 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.
      In the setting of CKD, increased ADH secretion and RAAS activation act to augment blood flow to hypoperfused nephrons though sodium and water retention.
      • Soi V.
      • Yee J.
      Sodium homeostasis in chronic kidney disease.
      NSAID-induced increased sodium avidity worsens this underlying process and its propensity for adverse effects, though specific data for this population are lacking. Epidemiologically, patients with CKD are at increased risk for hypervolemia even outside the physiology of their kidney disease because of their burden of comorbid conditions. Hypertension and diabetes mellitus are the 2 main causes of CKD in the United States and they are also 2 prominent risk factors for NSAID-associated hypervolemia and hypertension.

      Hyponatremia

      NSAID-associated hyponatremia occurs largely as a result of the mechanisms that lead to water and sodium retention. The antidiuretic effect of ADH is amplified in the absence of prostaglandins’ regulatory effect on this hormone, whereas intensification of the medullary interstitial osmotic gradient with prostaglandin inhibition enhances free-water absorption. Both these mechanisms produce conditions that promote net free-water absorption and hyponatremia.
      • Perazella M.A.
      COX-2 selective inhibitors: analysis of the renal effects.
      Patients with underlying conditions (Box 2) that promote water retention are at higher risk for hyponatremia with NSAID exposure. This includes cirrhosis, nephrotic syndrome, and CHF, as well as conditions associated with syndrome of inappropriate ADH secretion.
      • Kim S.
      • Joo K.W.
      Electrolyte and acid-base disturbances associated with non-steroidal anti-inflammatory drugs.
      NSAIDs blunt the inhibitory effects of prostaglandins on ADH and under circumstances of elevated ADH levels, the effect is further exacerbated. NSAIDs will also lower the threshold for the development of hyponatremia under conditions that promote non–ADH-mediated hyponatremia. Exercise-associated hyponatremia in endurance athletes can develop from increased free-water intake in combination with NSAIDs.
      • 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.
      NSAIDs may also increase the susceptibility of older adults to thiazide diuretic–induced hyponatremia.
      • Clark B.A.
      • Shannon R.P.
      • Rosa R.M.
      • Epstein F.H.
      Increased susceptibility to thiazide-induced hyponatremia in the elderly.
      Finally, several reports suggest an association between NSAID use and syndrome of inappropriate ADH secretion–mediated hyponatremia.
      • Roche C.
      • Ragot C.
      • Moalic J.-L.
      • Simon F.
      • Oliver M.
      Ibuprofen can induce syndrome of inappropriate diuresis in healthy young patients.
      ,
      • 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.
      ADH levels can be persistently elevated in patients with CKD, particularly in those with underlying diabetes mellitus.
      • 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.
      Individuals with CKD also have comorbid conditions such as CHF, nephrotic syndrome, and cirrhosis, which increase nonosmotic ADH production, predisposing to NSAID-induced hyponatremia. Similar to the literature on other NSAID adverse effects, studies performed to date that characterize hyponatremia with NSAIDs are confounded by these underlying predisposing factors. Although the incidence of NSAID-associated clinically symptomatic hyponatremia is likely low, even mild forms of hyponatremia are associated with increased mortality, longer hospitalizations, readmissions, falls, osteoporosis, and cognitive impairment.
      • Kim S.
      • Joo K.W.
      Electrolyte and acid-base disturbances associated with non-steroidal anti-inflammatory drugs.
      ,
      • Jacob P.
      • Dow C.
      • Lasker S.S.
      • Drake W.M.
      • Chowdhury T.A.
      Hyponatraemia in primary care.

      Hyperkalemia

      Because prostaglandins modulate renal potassium handling, their inhibition contributes to NSAID-associated hyperkalemia. Prostaglandin-mediated renin release facilitates aldosterone-driven potassium excretion in the distal nephron. Prostaglandin deficiency induces hypoaldosteronism, which leads to impaired principal cell potassium secretion, likely the primary driver of NSAID-induced hyperkalemia.
      • Perazella M.A.
      Drug-induced hyperkalemia: old culprits and new offenders.
      Decreased sodium chloride delivery to the distal tubule also reduces the electrochemical gradient for potassium secretion,
      • Perazella M.A.
      Drug-induced hyperkalemia: old culprits and new offenders.
      while reduced principal cell potassium channel activity also contributes.
      • Ling B.N.
      • Webster C.L.
      • Eaton D.C.
      Eicosanoids modulate apical Ca (2+)-dependent K+ channels in cultured rabbit principal cells.
      Finally, NSAID-associated AKI can further exacerbate hyperkalemia. However, under most circumstances, there is a low absolute risk for hyperkalemia with NSAIDs.
      • 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.
      Hyperkalemia with NSAID use in clinical practice is related to underlying comorbid conditions and exposure to medications that impair renal potassium handling (Box 2), and NSAIDs are rarely the sole cause of hyperkalemia in studies to date.
      • 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.
      A nested case-control study by Lafrance and Miller
      • 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.
      that quantified the risk for the development of hyperkalemia with potassium levels > 6.0 mEq/L imposed by NSAIDs alone in a patient population of veterans demonstrated no increased risk with either single or multiple NSAID use. However, certain individual agents were reported to have elevated risk unrelated to COX-2 selectivity, including rofecoxib (odds ratio, 1.37) and indomethacin (odds ratio, 1.36).
      • 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.
      The strongest risk factors for developing hyperkalemia include a prior episode of hyperkalemia, hospitalization within the past month, diabetes, and AKI.
      • 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.
      Heart failure also appears to increase the risk posed by NSAIDs.
      • 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.
      The combination of RAAS inhibitors and contrast media with NSAIDs has a positive additive risk.
      • 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.
      Unsurprisingly, combination therapy with multiple hyperkalemia-inducing medications such as RAAS inhibitors and trimethoprim is associated with significant hyperkalemia.
      • Perazella M.A.
      Drug-induced hyperkalemia: old culprits and new offenders.
      Thus, NSAIDs contribute to hyperkalemia in at-risk patients with CKD but rarely cause it in the absence of risk factors.
      Although CKD itself may be a risk factor for hyperkalemia, current evidence does not support that mild to moderate CKD increases hyperkalemia risk with NSAIDs. Lafrance and Miller
      • 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.
      found that the hyperkalemia risk with NSAIDs in patients with moderate CKD was less than the combined risks of NSAID use and CKD individually, suggesting that moderate CKD does not increase the risk for NSAID-associated hyperkalemia. A retrospective cohort study of elderly patients found no significant association between CKD and hyperkalemia with NSAIDs, though elderly age has been linked with a 50% increased risk for hyperkalemia with NSAID use compared with younger patients.
      • 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.
      Patients with CKD frequently develop hyperkalemia due to additional comorbid conditions such as hyporeninemic hypoaldosteronism, type 4 renal tubular acidosis, and advanced age or due to RAAS blockers or other drugs that impair renal potassium handling. However, moderate CKD alone does not appear to increase the risk for NSAID-associated hyperkalemia.

      Hypertension

      NSAIDs may worsen blood pressure (BP) control by approximately 3 to 6 mm Hg
      • Pope J.E.
      • Anderson J.J.
      • Felson D.T.
      A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure.
      ,
      • Johnson A.G.
      • Nguyen T.V.
      • Day R.O.
      Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.
      through renal sodium and water retention and increased peripheral vascular resistance.
      • Gambaro G.
      • Perazella M.A.
      Adverse renal effects of anti-inflammatory agents: evaluation of selective and nonselective cyclooxygenase inhibitors.
      In addition, NSAID-associated decreased renin production and increased sodium avidity appears to render several classes of antihypertensives less effective, particularly angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics.
      • Johnson A.G.
      • Nguyen T.V.
      • Day R.O.
      Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.
      • Kalafutova S.
      • Juraskova B.
      • Vlcek J.
      The impact of combinations of non-steroidal anti-inflammatory drugs and anti-hypertensive agents on blood pressure.
      • Whelton A.
      Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications.
      • Pavlicevic I.
      • Kuzmanic M.
      • Rumboldt M.
      • Rumboldt Z.
      Interaction between antihypertensives and NSAIDS in primary care: a controlled trial.
      A double-blinded randomized cardiovascular safety trial showed that 3% of patients using NSAIDs developed average systolic BPs 3 mm Hg higher than baseline after 4 months.
      • 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.
      Although single-digit BP elevations appear inconsequential for individual patients, from an epidemiologic standpoint, BP increases as low as 5 mm Hg increase cardiovascular morbidity.
      • 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.
      Patients with underlying hypertension and sodium-avid states are at higher risk for hypertension with NSAIDs (Box 2). A meta-analysis that included more than 1,200 patients found that the NSAIDs increased BP primarily in patients with underlying hypertension,
      • Pope J.E.
      • Anderson J.J.
      • Felson D.T.
      A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure.
      including patients on effective antihypertensive treatment.
      • Johnson A.G.
      • Nguyen T.V.
      • Day R.O.
      Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.
      Patients with advancing age, diabetes, and CKD also appear to be at increased risk for worsening hypertension with NSAIDs.
      • 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.

      Acute Interstitial Nephritis and Glomerulonephritis

      NSAIDs also cause kidney injury through idiosyncratic reactions, including acute interstitial nephritis (AIN). In this setting, AIN may occur in part due to shunting of arachidonic acid into the lipo-oxygenase pathway, leading to increased production of proinflammatory leukotrienes.
      • Whelton A.
      Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications.
      As a class, NSAIDs confer an approximate 2-fold increase in risk for AIN, though the absolute risk is very low.
      • 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.
      Proteinuria and nephrotic syndrome due to either membranous nephropathy or minimal change disease are other well-established but more infrequent complications of NSAIDs, which may occur alone or with AIN.
      • Nawaz F.A.
      • Larsen C.P.
      • Troxell M.L.
      Membranous nephropathy and nonsteroidal anti-inflammatory agents.
      • Mérida E.
      • Praga M.
      NSAIDs and nephrotic syndrome.
      • 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.
      These glomerulopathies occur weeks to months after initial NSAID exposure.
      • Clive D.M.
      • Stoff J.S.
      Renal syndromes associated with nonsteroidal antiinflammatory drugs.
      ,
      • Whelton A.
      • Hamilton C.W.
      Nonsteroidal anti-inflammatory drugs: effects on kidney function.

      Progression of CKD

      Concern about CKD progression has been another barrier to NSAID use in patients with CKD, and the literature on this subject is proportionally vast and filled with incompatible conclusions. Many early often-cited studies charted the correlation between patient-reported prior NSAID consumption and the presence of CKD.
      • Kurth T.
      • Glynn R.J.
      • Walker A.M.
      • et al.
      Analgesic use and change in kidney function in apparently healthy men.
      ,
      • 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.
      ,
      • Perneger T.V.
      • Whelton P.K.
      • Klag M.J.
      Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs.
      • Sandler D.P.
      • Burr F.R.
      • Weinberg C.R.
      Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease.
      • 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.
      These studies are highly subject to recall bias and also demonstrated conflicting findings.
      • Kurth T.
      • Glynn R.J.
      • Walker A.M.
      • et al.
      Analgesic use and change in kidney function in apparently healthy men.
      ,
      • 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.
      ,
      • Perneger T.V.
      • Whelton P.K.
      • Klag M.J.
      Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs.
      • Sandler D.P.
      • Burr F.R.
      • Weinberg C.R.
      Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease.
      • 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.
      A prospective observational study of 10,184 individuals older than 65 years with GFR > 60 mL/min/1.73 m2 reported that NSAID users had a small but significant risk for increased rate of CKD progression compared with nonusers.
      • Gooch K.
      • Culleton B.F.
      • Manns B.J.
      • et al.
      NSAID use and progression of chronic kidney disease.
      However, there was no association between NSAID use and CKD progression with GFR < 60 mL/min/1.73 m2.
      • Gooch K.
      • Culleton B.F.
      • Manns B.J.
      • et al.
      NSAID use and progression of chronic kidney disease.
      This and other similar studies are affected by the design’s inability to exclude a protopathic bias away from greater NSAID use in patients with CKD knowledgeable about NSAID risk, as well as under-representation of more advanced-stage CKD that renders such studies underpowered to detect an effect.
      To reduce confounding, some studies have examined the effect of NSAIDs in populations requiring long-term anti-inflammatory medications. A large randomized 3-year trial comparing the use of celecoxib, naproxen, and ibuprofen in more than 24,000 patients with arthritis and with early or no CKD showed a low incidence of composite acute and long-term decrease in GFRs with all 3 agents.
      • Nissen S.E.
      • Yeomans N.D.
      • Solomon D.H.
      • et al.
      Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis.
      However, this study was affected by drug discontinuation by 70% of patients at the time of follow-up. Using a controlled multivariable analysis, a retrospective cohort study of nearly 2,000 patients using ibuprofen and 4,000 using acetaminophen found that age of 65 years and older and coronary artery disease, but not underlying CKD, were risk factors for worsening kidney disease with ibuprofen use.
      • 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.
      Although CKD stage was not collected in this study, it demonstrated that ibuprofen does not cause CKD progression, at least in moderate CKD.
      • 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.
      Another prospective cohort study of more than 4,000 patients with rheumatoid arthritis showed no difference in the rate of GFR change between NSAID users and nonusers with CKD stages 1-3 at baseline. However, 17 NSAID-treated patients with CKD stages 4-5 developed a significantly steeper GFR decline.
      • 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.
      Similar to other nephrotoxic manifestations, the risk for CKD progression appears to be dose-dependent. A meta-analysis targeting the strength of the association between NSAID use and CKD progression in moderate to severe CKD showed no association with regular-dose NSAID use.
      • 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.
      At undefined higher doses, there was a statistically significant increase in risk for CKD progression, but the absolute risk was small.
      • 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.
      A retrospective longitudinal cohort study of US Army soldiers without pre-existing kidney disease demonstrated 20% greater risk for CKD progression among patients receiving more than 7 World Health Organization–defined daily doses per month of total NSAIDs compared with nonusers.
      • 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.
      Similarly, a case-control study found an association between stage 5 CKD development and NSAIDs only in users of the highest quantities.
      • Perneger T.V.
      • Whelton P.K.
      • Klag M.J.
      Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs.
      In summary, although the risk for CKD progression due to NSAID use is not insignificant, it appears to be small, related to cumulative dose, and modifiable by appropriate patient selection in patients with mild to moderate CKD.

      Recommendations

      Based on the somewhat incomplete data for NSAID nephrotoxicity in patients with advanced CKD, we make recommendations for cautious use of NSAIDs in patients with CKD under certain circumstances (Fig 3). It is most important to avoid causing potentially life-threatening NSAID-related complications such as AKI, hyperkalemia, and hypervolemia in at-risk patients with CKD. Worsening BP control and increasing CKD progression are other possible adverse effects to consider before NSAID therapy initiation.
      Figure thumbnail gr3
      Figure 3Summary of potential nonsteroidal anti-inflammatory drug (NSAID) nephrotoxicity in chronic kidney disease (CKD). ∗Outlines additional risk for each nephrotoxicity posed by CKD at different stages, as well as any risk factors (including those in ) that pose a greater risk in these populations. The burden of risk factors is high, especially with increasing CKD stage, and this must be considered in conjunction with the risk outlined in this table, which is reflected in these Recommendations. In the absence of other risk factors as noted in . ∗∗With minimization of risk factors outlined in , as able. Abbreviations: AKI, acute kidney injury; DM, diabetes mellitus; GFR, glomerular filtration rate; KRT, kidney replacement therapy; RAASi, renin-angiotensin-aldosterone system inhibitor.
      For stable patients with CKD stages 1 and 2 without predisposing risk factors, monitoring can be similar to that for patients without kidney disease. In patients with stage 3 CKD in whom predisposing risk factors have been minimized, short-term NSAID use for up to 5 days is an acceptable pain management strategy with an acceptably low nephrotoxic risk. Routine laboratory testing and follow-up within 2 to 3 weeks of use are adequate for surveillance for adverse effects. Long-term NSAID use in these patients carries more risk for adverse outcomes; however, this relates to a longer exposure period over which additional risk factors for NSAID toxicity may develop. Therefore, long-term therapy is acceptable in patients amenable to education regarding higher risk conditions that may arise under which NSAIDs should be withheld and to continued close follow up with medical care. Short-acting agents are preferred over long-acting agents (Table 2), along with optimization of volume status and cardiac function before and during treatment.
      • Pham P.C.
      • Khaing K.
      • Sievers T.M.
      • et al.
      2017 Update on pain management in patients with chronic kidney disease.
      Adjustment of the NSAID dosing interval should be made to account for reduced elimination of the drug with CKD.
      • Perazella M.A.
      • Buller G.K.
      NSAID nephrotoxicity revisited: acute renal failure due to parenteral ketorolac.
      NSAIDs should likely be avoided in those with prostaglandin-dependent RBF, including states of true and ECV depletion, cirrhosis, CHF, or nephrotic syndrome.
      • Clive D.M.
      • Stoff J.S.
      Renal syndromes associated with nonsteroidal antiinflammatory drugs.
      Additional caution with NSAID use should be undertaken in patients with CKD with potassium handling issues who are prescribed RAAS inhibitors, diuretics, and other hyperkalemia-promoting drugs such as mineralocorticoid inhibitors and trimethoprim.
      Table 2NSAID Dosing
      NSAID ClassTrade Namet1⁄2Total Dose/d (Dosing)
      Dosing in healthy patients.
      Recommendation for CKD Dosing
      GFR > 30 < 60mL/min, limited/no data for GFR < 30 mL/min.
      Carboxylic Acids
      SalsalateDisalcid1 h1.5-3.0 g (2×/d)Reduced dose 2×/d
      Choline Mg++ trisalicylateTrilisate0.25 h1.5-3.0 g (2-3×/d)Reduced dose 2×/d
      DiflunisalDolobid7.5-8 h0.5-1.5 g (2×/d)Reduced dose 1×/d
      Acetic Acids
      Indomethacin
      Biliary excretion of 30% to 40%.
      Indocin5-10 h75-150 mg (2-4×/d)Normal dose 1-2×/d
      TolmetinTolectin1 h400-2,400 mg (2-3×/d)Reduced dose 2×/d
      Sulindac
      Nabumetone and sulindac are metabolized to active metabolites.
      Clinoril16.4 h200-400 mg (2×/d)Reduced dose 1×/d
      Diclofenac
      Biliary excretion of 30% to 40%.
      Voltaren, Cataflam1-2 h100-150 mg (2×/d)Reduced dose 2×/d
      Arthrotec2 h100 mg (2×/d)Reduced dose 2×/d
      EtodolacLodine6.4 h400-1,200 mg (2-4×/d)Normal dose 1-2×/d
      KetorolacToradol5-6 hOral 40 mg (4×/d)Reduced dose 1-2×/d
      IV 60-120 mg (4×/d)Reduced dose 1-2×/d
      Propionic Acids
      IbuprofenMotrin, Rufen1.8-2 h800-3,200 mg (4×/d)Normal dose 2×/d
      NaproxenNaprosyn, Anaprox12-17 h500-1,000 mg (2×/d)Reduced dose 1×/d
      Aleve450 mg (2×/d)Reduced dose 1×/d
      KetoprofenOrudis2-4 h225 mg (3×/d)Reduced dose 1-2×/d
      FlurbiprofenAnsaid5-7 h200-300 mg (2-3×/d)Reduced dose 1×/d
      FenoprofenNalfon2.5-3 h1,200-2,400 mg (4×/d)Reduced dose 2×/d
      Oxaprozin
      Biliary excretion of 30% to 40%.
      Daypro38-44 h1,200 mg (1×/d)Avoid
      Enolic Acids
      Piroxicam
      Biliary excretion of 30% to 40%.
      Feldene45-50 h10-20 mg (1×/d)Avoid
      Fenamates
      Mefenamic acidPonstel2 h1,000 mg (4×/d)Reduced dose 2-3×/d
      Meclofenamate
      Biliary excretion of 30% to 40%.
      Meclomen1-5 h150-400 mg (3-4×/d)Reduced dose 1-2×/d
      Naphthylkanones
      Nabumetone
      Nabumetone and sulindac are metabolized to active metabolites.
      Relafen23-30 h1,000-1,500 mg (2-3×/d)Reduced dose 1-2×/d
      COX-2 Inhibitors
      CelecoxibCelebrex11 h100-400 mg (1-2×/d)Reduced dose 1-2×/d
      Note: NSAIDs undergo hepatic metabolism. Kidney excretion of inactive metabolites predominates for most.
      Abbreviations: CKD, chronic kidney disease; COX, cyclooxygenase; GFR, glomerular filtration rate; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug; t1⁄2, half-life.
      a Dosing in healthy patients.
      b GFR > 30 < 60 mL/min, limited/no data for GFR < 30 mL/min.
      c Biliary excretion of 30% to 40%.
      d Nabumetone and sulindac are metabolized to active metabolites.
      Patients with stage 4 CKD require a more judicious approach to NSAID therapy because the risk for nephrotoxicity has not been adequately studied in this cohort. Because many of these patients struggle with increased AKI events, electrolyte and acid-base abnormalities (particularly hyperkalemia and metabolic acidosis), and hypervolemia, an individualized approach to NSAID use is mandated. NSAID exposure will likely exacerbate all these problems in many patients with stages 4-5 CKD, especially in the setting of common comorbid conditions (CHF, nephrosis, cirrhosis, hypertension, and type 4 renal tubular acidosis) and concomitant medications (RAAS blockers, diuretics, and mineralocorticoid antagonists). If NSAIDs are to be used in patients with stable stage 4 CKD, low doses of short half-life preparations with an appropriate dosing interval for 5 or fewer days and close monitoring within the treatment period are required.
      Except under circumstances prioritizing palliation over prolongation of life, patients with stage 5 CKD should never receive these drugs because the risk for lethal renal complications is high despite the absence of data. The decision to avoid NSAIDs for pain management in patients receiving maintenance hemodialysis or peritoneal dialysis to preserve GFR (residual renal function) should be individualized but is outside the scope of this review. Similarly, the decision to use NSAIDs in patients with a kidney transplant should be individualized based on GFR and concomitant risk factors for adverse effects. Because these patients lack normal autoregulatory mechanisms to protect against reduced prostaglandin levels and are often using immunosuppressive agents that amplify the potential toxicity posed by NSAIDs, judicious use and close monitoring is mandated.
      Topical NSAID formulations have little systemic absorption, with peak concentrations no greater than 1.5% of oral NSAID formulations, and should be considered a viable alternative or adjunctive pain management strategy in all patients with CKD, particularly in addressing musculoskeletal and arthritic pain.
      • McPherson M.L.
      • Cimino N.M.
      Topical NSAID formulations.
      Although studies of topical formulations consistently demonstrate significantly reduced kidney-related adverse effects compared with oral formulations, use in patients with stages 4-5 CKD, especially those with other prostaglandin-dependent conditions, should be accompanied by close monitoring at the onset of use.
      • 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.
      ,
      • 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.

      Conclusion

      NSAIDs are associated with adverse renal outcomes, and their risk must be weighed against the benefit of improved pain control. An accurate risk assessment must be highly individualized based on CKD stage, age, comorbid conditions, and concomitant medication use. Although historically avoided in kidney disease, NSAIDs should be considered for use in this population alongside other therapies after appropriate patient selection.

      Article Information

      Authors’ Full Names and Academic Degrees

      Megan Baker, MD, and Mark A. Perazella, MD.

      Support

      None.

      Financial Disclosure

      The authors declare that they have no relevant financial interests.

      Peer Review

      Received January 2, 2020, in response to an invitation from the journal. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form March 18, 2020.

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