Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.

摘要 非甾体抗炎药（Non-steroidal anti-inflammatory drugs, NSAIDs）为临床常用药物，与肾毒性存在明确关联，长期用药时该风险尤为突出。高龄、合并症等本身可导致肾小球滤过率下降的因素，会进一步升高NSAIDs相关肾毒性的发生概率。NSAIDs的核心作用机制为抑制环氧合酶（cyclooxygenase, COX），干扰花生四烯酸向前列腺素E2、前列腺环素及血栓素的转化过程。在肾脏组织中，前列腺素可充当血管舒张因子，提升肾灌注水平。该血管舒张效应是对肾素-血管紧张素-醛固酮系统、交感神经系统等调控通路的代偿性调节，最终保障肾脏的充足血流灌注。NSAIDs会抑制这一代偿机制，进而可能诱发急性肾损伤（acute kidney injury, AKI）。大剂量使用NSAIDs已被证实可引发AKI，在老年群体中该现象尤为显著。NSAIDs诱导的AKI主要类型为血流动力学介导型；第二类为急性间质性肾炎，临床表现可包括肾病性蛋白尿。长期使用NSAIDs还可进展为慢性肾脏病（chronic kidney disease, CKD）。对于无基础肾脏疾病、年轻且无合并症的人群，NSAIDs的危害性相对有限。但由于其肾毒性存在剂量依赖性，长期用药时仍需保持谨慎，因其会显著提升肾毒性的发生风险。