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Pathophysiological Aspects of Nephropathy Caused by Non UPDATE ARTICLE | ARTIGO DE ATUALIZAÇÃO 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 comor- bidities, 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 124 NSAID Nephropathy 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, incre- asing 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 125 Braz. J. Nephrol. (J. Bras. Nefrol.) 2019;41(1):124-130 NSAID Nephropathy (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
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