Pathophysiological Aspects of Nephropathy Caused by Non

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Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs Aspectos fisiopatológicos da nefropatia por anti-inflamatórios não esteroidais

Authors Abstract Resumo Guillherme Nobre Cavalcanti Lucas1 Non-steroidal anti-inflammatory drugs Os anti-inflamatórios não esteroidais (AI- Ana Carla Carneiro Leitão1 (NSAIDs) are commonly used medica- NEs) são medicamentos comumente utiliza- Renan Lima Alencar1 tions associated with nephrotoxicity, es- dos, associados à nefrotoxicidade, sobretudo Rosa Malena Fagundes Xavier1,2,3 pecially when used chronically. Factors quando utilizados cronicamente. Fatores such as advanced age and comorbidities, como idade avançada e comorbidades, que Elizabeth De Francesco Daher4 which in themselves already lead to a por si só já levam à diminuição da taxa de Geraldo Bezerra da Silva Junior1 decrease in glomerular filtration rate, in- filtração glomerular, aumentam o risco de crease the risk of NSAID-related nephro- nefrotoxicidade dos AINEs. O principal

1 Universidade de Fortaleza, toxicity. The main mechanism of NSAID mecanismo de ação dos AINEs é a inibição Programa de Pós-Graduação action is cyclooxygenase (COX) enzyme da enzima ciclooxigenase (COX), interfer- em Saúde Coletiva, Centro de inhibition, interfering on arachidonic acid indo na conversão do ácido araquidônico em Ciências da Saúde, Fortaleza, conversion into E2 prostaglandins E2, prostaglandinas E2, prostaciclinas e trom- CE, Brasil. prostacyclins and thromboxanes. Within boxanos. Nos rins, as prostaglandinas atuam 2 Universidade do Estado da Bahia, Curso de Farmácia, the kidneys, prostaglandins act as vaso- como vasodilatadoras, aumentando a per- Salvador, BA, Brasil. dilators, increasing renal perfusion. This fusão renal. Essa vasodilatação atua como 3 Universidade Federal da Bahia, vasodilatation is a counter regulation of uma contrarregulação de mecanismos, como Instituto de Saúde Coletiva, mechanisms, such as the renin-angioten- a atuação do sistema renina-angiotensina- Salvador, BA, Brasil. sin-aldosterone system works and that of aldosterona e do sistema nervoso simpático, 4 Universidade Federal do Ceará, Faculdade de Medicina, the sympathetic nervous system, culmina- culminando com uma compensação para as- Departamento de Medicina ting with compensation to ensure adequa- segurar o fluxo adequado ao órgão. O uso Clínica, Fortaleza, CE, Brasil. te flow to the organ. NSAIDs inhibit this de AINEs inibe esse mecanismo, podendo mechanism and can lead to acute kidney causar lesão renal aguda (LRA). Altas doses injury (AKI). High doses of NSAIDs have de AINEs têm sido implicadas como causas been implicated as causes of AKI, espe- de LRA, especialmente em idosos. A princi- cially in the elderly. The main form of AKI pal forma de LRA por AINEs é a hemodin- by NSAIDs is hemodynamically mediated. amicamente mediada. A segunda forma de The second form of NSAID-induced AKI apresentação da LRA induzida por AINES is acute interstitial nephritis, which may é a nefrite intersticial aguda, que pode se manifest as nephrotic proteinuria. Long- manifestar com proteinúria nefrótica. O uso -term NSAID use can lead to chronic kid- de AINEs em longo prazo pode ocasionar ney disease (CKD). In patients without doença renal crônica (DRC). Nos pacientes renal diseases, young and without comor- sem doenças renais, jovens e sem comorbidities, NSAIDs are not greatly harmful. bidades, os AINEs não apresentam grandes However, because of its dose-dependent malefícios. Entretanto, por seu efeito dose- effect, caution should be exercised in dependente, deve-se ter grande cautela no chronic use, since it increases the risk of uso crônico, por aumentar risco de desen- developing nephrotoxicity. volver nefrotoxicidade. Keywords: Anti-Inflammatory Agents; Palavras-chave: Anti-Inflamatórios; Efeitos Submitted on: 05/17/2018. Drug-Related Side Effects and Adverse Colaterais e Reações Adversas Relacionados Approved on: 08/05/2018. Reactions; Toxicity; Physiopathology; a Medicamentos; Toxicidade; Fisiopatologia; Review. Revisão. Correspondence to: Geraldo Bezerra da Silva Junior. E-mail: [email protected]

DOI: 10.1590/2175-8239-JBN-2018-0107

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INTRODUCTION Based on the classification of these enzymes, NSAIDs can be classified into non-target NSAIDs Non-steroidal anti-inflammatory drugs (NSAIDs), (ketoprofen, aspirin, naproxen, flunixin, meglumine often prescribed in medical practice as analgesic, and others), COX-2 preferential inhibitors (meloxi- antipyretic and anti-inflammatory agent, are among can, etodolac, nimesulide) and highly selective COX- the most widely used drug classes worldwide. Recent 2 inhibitors (coxib). Most of the side effects are rela- studies point to NSAIDs as the most effective dru- ted to COX-1 inhibition, due to its action in several gs, for example, for the treatment of pain associated systems associated with cell cleansing. In the kidneys, with renal calculi, being better even than opioids.1 they are in greater quantities acting in glomerular The main consumers of this group of drugs are indi- filtration maintenance. Therefore, studies indicate viduals afflicted by chronic pain, usually associated that individuals with previously compromised renal with rheumatologic diseases, including rheumatoid function are the most affected by the time-dependent arthritis, osteoarthritis and other musculoskeletal di- use of non-selective NSAIDs. The action of COX-2 sorders.2,3,4 The pharmacological action of NSAIDs is associated with water and electrolytic maintenance depends on the dose and duration of use, which pre- in the renal environment, which worsens its effects disposes the involvement of specific organs, and the under dehydration, low renal perfusion or previously second one most affected are the kidney. Therefore, existing renal damage.7 it is one of the drugs that, if used in the long term, increases morbidity, especially for the elderly, since PHYSIOPATHOLOGY OF NSAID-RELAT- they use several other medications (antihypertensives, ED KIDNEY INJURY antidepressants, anticoagulants) that may cause inte- ractions. These patients are likely to develop kidney The kidneys are important organs for the excre- injury, which may be transitory or not. However, tho- tory function of the body because they receive about 1 se exposed by a prolonged use of drugs are those with 25% of all cardiac output. In order to adequately chronic kidney disease, with a 3 to 4-fold increase in perform their filtration function, these organs have regulatory mechanisms, such as prostaglandin syn- risks of adverse effects.5 thesis, which will maintain glomerular filtration rate In addition to renal complications, NSAIDs can (GFR) and renal homeostasis.9 cause gastrointestinal (gastric perforation and ulcera- NSAIDs inhibit the cascade of arachidonic acid, tion), hepatic (cirrhosis), cardiovascular and platelet selectively or not, causing a nonpermissive effect on (thrombotic events) alterations, requiring caution and the formation of prostaglandins.10 In the kidneys, proper indications in its prescription.6 prostaglandins - mainly prostacyclins, PGE2, PGD2 - MECHANISM OF ACTION OF NSAIDS will act as vasodilators in the afferent arteriole, increasing renal perfusion, with distribution of the cortex The main mechanism of NSAID action is the flow to the nephrons in the renal medullary region. cyclooxygenase (COX) enzyme inhibition, both cen- This vasodilatation acts as a negative feedback on the trally and peripherally, thus interfering with the con- mechanisms, such as the performance of the renin- version of arachidonic acid into E2 prostaglandins, -angiotensin-aldosterone system and the sympathetic prostacyclins and thromboxanes. Prostaglandins have nervous system, culminating with compensation to a vasodilatation effect, which is extremely important ensure adequate flow to the organ. NSAIDs inhibit for preglomerular resistance maintenance, maintai- this mechanism and may result in acute vasoconstric- ning glomerular filtration rate and preserving renal tion and spinal cord ischemia, which can lead to acute blood flow.7 renal injury.2,9,10 Enzymes related to the action of NSAIDs can be In addition to the vasodilatation action, throu- divided into COX-1 and COX-2, acting in different gh the stimulation of tubular receptors PGE2 will regions. COX-1 is the one that occurs in most cells, inhibit the transport of sodium and chloride in even fetal and amniotic fluid, and participates in phy- the ascending loop of Henle and in the collecting siological effects, such as regulatory and protective ducts, by means of stimulating of the EP1 recep- effects. COX-2 is activated by inflammation and pro- tor, leading to natriuresis. In addition, PGE2 exerts -inflammatory cytokines.8 an antagonistic action on the antidiuretic hormone

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(ADH) receptors, also promoting diuresis.9,11,12 The same applies to comorbidities that lead to a NSAIDs may also cause higher sodium and water decrease in effective arterial volume, such as nephro- retention by inhibiting PGE2 production, leading tic syndrome with a high level of proteinuria, liver to the formation of edema, which is often subcli- cirrhosis, especially in those with ascites, heart failu- nical.8 Clinical trials comparing different NSAIDs re and lupus nephritis. Patients with these conditions show the development of hypertension, especially using NSAIDs have an inhibition of the kidney-com- when using high doses and for a prolonged time, pensation mechanism, as it happens in hypertensive with ibuprofen being more involved.13 patients, which contributes to renal damage.2,3,8,14 In addition to its actions in the kidneys, prostaglandins perform several functions related to ho- NSAIDs AND HYDROELETROLYTIC DIS- meostasis, such as protection of the gastrointestinal ORDERS mucosa, platelet activation, inflammation, broncho- As already explained above, prostaglandins (PGs) 2 dilation, and others. play an important role in maintaining renal activity. Figure 1 shows the pathophysiology of renal in- Renal vasodilatation induced by PGs is critical for jury induced by NSAIDs. maintenance of adequate kidney perfusion by PGE2 and PGI2. The main hydroelectrolytic and acid-basic RISK FACTORS changes caused by this class of drugs are sodium re- Kidney damage caused by the use of NSAIDs is tention (causing edema and hypertension), hyperkale- not common, especially when it comes to individu- mia and metabolic acidosis due to the lower activity als who are previously healthy and who do not use of COX-1 and COX-2.4,15 abusive or high doses of these drugs. Some factors, The inhibition of prostaglandin-mediated vaso- such as advanced age and comorbidities, which in dilatation (PGE-2) prevents adequate renal perfu- themselves already lead to a decrease in GFR, in- sion. In circulating arterial volume dysregulation crease the risk of NSAID-related nephrotoxicity, situations, in which there is higher RAAS stimula- contributing to the development of side effects. tion, there is a high production of prostaglandins One of the risk factors is systemic arterial hyper- (PGE-2, PGI-2) by the afferent arteriole endothe- tension, which causes an even higher activation of lium. These prostaglandins are a self-regulating the renin-angiotensin-aldosterone system (RAAS) mechanism in cases of decreased renal perfusion, and the sympathetic nervous system, leading to such as heart failure, hypovolemia, and as com- vasoconstriction; and the inhibition of prostaglan- pensatory vasodilatation of the afferent arteriole din synthesis causes the loss of the compensatory mediated by PGE2, that occurs in response to no- mechanism of renal vasodilation.14 repinephrine or angiotensin II action.2,6

Figure 1. NSAID-induced kidney injury pathophysiology

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There is an increased synthesis in glomerular di- low.2,4,11,12,15,17 It has been suggested that the acu- sease, renal failure (GFR <60mL/minute/1.73m2), te sodium retention caused by NSAIDs in healthy hyperkalemia, heart failure, cirrhosis and hypovo- elderly is mediated by COX-2 inhibition, whi- lemic shock, states of circulating arterial volume le the sudden decrease in GFR is due to COX-1 reduction, which implies a greater stimulus for inhibition.4 PG synthesis. If production is reduced, it is on- Thus, NSAIDs with little or no effect on COX- ly natural for plasma retention to occur due to 2, such as aspirin, rarely cause obvious sodium re- afferent arteriolar vasoconstriction, leading to tention and hypertension.18 In the SUCCESS VI and hydroelectrolytic and acid-base disturbances, es- VII trials, there was a significant increase in the num- pecially water retention (resulting from increased ber of patients with high blood pressure in an elder- sodium reabsorption) and hyperkalemia. Thus, ly population (> 65 years), using coxibs, especially patients with such conditions associated with the rofecoxib.19,20 use of NSAIDs are more vulnerable to developing Hyponatremia induced by NSAIDs is possibly nephrotoxicity.2,14,16 correlated with the lower release of PGE2 and NSAIDs may reduce response to diuretics by PGI2, which antagonize the action of vasopressin about 20%, especially loop diuretics, and such in water absorption in collecting tubules, although effect may be more commonly expressed in chro- there is a negative feedback NSAID mechanism of nic sodium retainers, such as those with congestive sodium retention by prostanoid inhibition, which heart failure. is the main cause of the overfilling effect due to Aldosterone is able to increase potassium excre- arterial hypertension and edema. It is suggested tion. Since prostaglandin PGI2 stimulates renal jux- that sodium retention by NSAIDs is mediated by taglomerular cells to release renin and, consequen- COX-2.12,15,17 tly, aldosterone (a state of hypoaldosteronism), Several statements regarding the renal effects of inhibition of the production of this molecule by NSAIDs have been proven in experimental animal NSAIDs can cause less distal tubular flow, resul- studies. In rats with volume depletion by oral ad- ting in hyperkalemia, as well as metabolic acido- ministration of furosemide, the use of indometha- sis. Recent evidence from case-control and retros- cin (non-selective inhibitor) and flosulide (selective pective studies suggest that there is no correlation COX-2 inhibitor) caused renal hypoperfusion and between a higher incidence of hyperkalemia with decreased GFR, in addition to the expected decrease selective COX-2 inhibitors (the coxibs), as already in urinary prostaglandins, indicating that NSAIDs described in clinical trials of the 1980s, and thus and non-COX-2 inhibitors alter renal function in 21 the incidence of hypokalemia with any class of hypovolemic animals. Another study demonstra- NSAIDs.4,9,14,17 ted a correlation between the effects of both classes COX-1 acts primarily in the control of renal (COX-1 and COX-2 inhibitors) causing low rennin 10 GFR, while COX-2 plays a role in sodium and levels in cats. Burukoglu et al. ratified these results water excretion. Blocking both enzymes prevents with the use of meloxican in rats. Hypomagnesemia PGE2 production. This enzyme regulates the reab- and hypophosphatemia can be established wi- sorption of sodium and water in the renal tubules thin one to two days after an episode of excessive 22 (diuretic and natriuretic effect), besides optimi- NSAIDs intake. zing blood perfusion to the renal medulla, which contributes to this effect. PGE2 is considered NSAID AND ACUTE RENAL INJURY a tubular PG, while PGI2 is vascular. However, Acute kidney injury comprises a syndrome in physiological situations, such enzymes are not characterized by abrupt GFR reduction, leading primary components of the hydroelectrolytic ho- to retention of urea, creatinine, and other nitro- meostasis generated in the kidneys, since the base- gen waste substances that are normally cleared by line production rate of prostaglandins is relatively the kidneys. This condition is clinically defined

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when patients increase creatinine levels within a derivatives, activating T-lymphocytes, resulting in few days (or it is 1.5 times higher in relation to a interstitial infiltration, leading to the onset of mini- recent or presumed outcome) or who develop oli- mal lesion disease (MLD), with nephrotic syndro- guria/anuria, justifying high morbidity and morta- me (edema, oliguria, proteinuria) a few days after lity in the emergency room. Virtually all NSAIDs treatment onset. Renal function is usually restored can be associated with AKI.23,24 Arterial blood after drug interruption.4 gas sampling is often the essential admission test Therapeutic doses of NSAIDs in susceptible pa- if the patient has uremic syndrome signs, such as tients can cause acute renal injury. The explana- progressive decline in mental status and seizures, tion for this comes from the same mechanism pre- or signs of acute kidney injury (such as oliguria), viously explained: biosynthesis inhibition of the leading to metabolic acidosis caused by excessive prostanoids involved in the maintenance of renal intake of NSAIDs.22 High doses of NSAIDs have blood flow, specifically PGE2 and PGI2. The risk been implicated as cause for AKI, especially in the is higher in neonates and the elderly, as well as in elderly.12 However, NSAID-mediated AKI is a rare patients with some cardiovascular, liver, kidney, or condition.24 chronic disease, or with reduced circulating blood The main form of acute kidney injury caused volume, such as patients using NSAIDs combined by NSAIDs is hemodynamically mediated. In con- with diuretics and RAAS inhibitors.5,12 Dreischulte trast, in situations of chronic kidney disease, heart et al.,28 in a case-control study with almost 80,000 failure, liver failure, hypovolemic shock and other users on prolonged use of NSAIDs associated wi- conditions that reduce circulating arterial volume, th diuretics and/or angiotensin converting enzyme the secretion of these hormones increases in order (ACE) inhibitors, showed a strong relationship. It to preserve renal perfusion and GFR. The breakdo- was reported that combined therapy compared to wn of this process by NSAIDs results in reduction of NSAID monotherapy was responsible for an ab- intramedullary renal perfusion and ischemia, increa- solute increase in the risk of community-acquired sing the risk of acute tubular necrosis (ATN). Some AKI in one year of use, despite the high rate of evidence suggests a lower nephrotoxic potential in AKI caused by the exclusive use of anti-inflamma- low dose non-selective COX drugs, such as ASA tory drugs, being the main drug class causing renal and ibuprofen, in comparison to selective COX-2 dysfunction.28 agents.25,26 The second form of presentation of NSAID- NSAID-INDUCED CHRONIC RENAL DIS- induced AKI is acute interstitial nephritis (AIN) EASE with nephrotic syndrome. Nephrotic proteinuria There are not many studies yet showing the long- is reported in about 80% of patients, more often -term effects of NSAIDs on the development of chro- associated with phenoprofen, naproxen and ibu- nic kidney disease (CKD). However, it has been sho- profen.27 AIN may also happen without nephrotic wn that daily use for more than one year increases the syndrome. The exact mechanisms of the patho- risk of developing CKD.14 physiology of NIAs triggered by NSAIDs are not There may be progression in patients who do not yet known and have been attributed to a delayed discontinue NSAIDs when they develop acute inters- hypersensitivity reaction, with the main factors titial nephritis and interstitial fibrosis.5 A recent stu- that point to this mechanism being: need for pro- dy in the elderly population shows that regardless of longed exposure to NSAIDs, low frequency of the the class of this medication, whether selective or not, classic signs of hypersensitivity and interstitial in- both high doses and longer half-lives significantly in- filtrate with predominance of T-lymphocytes.27 It is crease the risk of CKD development.11,29 also described a deviation of the arachidonic acid The main effects of NSAIDs on renal function are metabolism for the formation of leukotrienes and summarized in Table 1.

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Table 1 Main NSAID effects on kidney function

Mechanisms Risk factors Prevention/Treatment Water and electrolyte disorders -Sodium retention -Hyperkalemia PGE2 and PG12-induced NSAID use (most common kidney vasodilatation Discontinue NSAID use -Hyponatremia nephrotoxic effects inhibition; RAAS activation -Metabolic acidosis -Lower response to diuretics (especially loop diuretics) Liver diseases; Kidney Avoid in high-risk patients Hemodynamic alterations/ Acute kidney injury diseases; Heart failure; (patients with comorbidities); Kidney perfusion reduction Dehydration; advanced age Discontinue NSAID Prolonged NSAID exposure; some specific NSAIDs Acute interstitial nephritis Hypersensitivity reaction Discontinue NSAID use (Phenoprofen, Naproxen, Ibuprofen) Avoid use in high- risk patients (those Chronic kidney disease Hemodynamic alterations Chronic use of NSAIDS with comorbidities and advanced age); Discontinue NSAID use Phenacetine abuse; Aspirin Discontinue NSAID use Papillary necrosis Direct toxicity and acetaminophen and avoid chronic use of combination analgesics *PGE2: prostaglandins; PGI2: prostacyclins; RAAS: Renin-angiotensin-aldosterone system; NSAIDs: Non-steroidal anti-inflammatory drugs. Adapted from: Melgaço et al.14

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