Drukker Alfred
Division of Paediatric Nephrology, Centre Hôpitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Paediatr Child Health. 2002 Oct;7(8):538-43. doi: 10.1093/pch/7.8.538.
To summarize experimental animal data and to provide a limited literature review on the adverse renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the developing fetus and the maturing newborn.
The experimental data were obtained from anesthetized, ventilated, six- to eight-day-old rabbits that received an intravenous bolus of either acetylsalicylic acid (ASA), ibuprofen (IBU) or indomethacin (INDO). In one set of experiments, ASA was also tested in 12-week-old (young adult) rabbits. Renal function was monitored with inulin and para-aminohippuric acid clearances measuring glomerular filtration rate (GFR) and renal blood flow. The renal vascular resistance was calculated. All three nonspecific cyclo-oxygenase-1 or -2 (COX-1/2) inhibitors caused remarkably similar reversible, oliguric, acute renal failure (ARF). In young adult animals, the side effects were attenuated. The underlying pathophysiology is related to the carefully maintained low GFR of the fetus and the newborn, dependent on a delicate interplay between vasoconstriction (angiotensin II) and vasodilation (prostaglandins [PGs]). When PG-synthesis is inhibited, the vasoconstriction is relatively unopposed, causing ARF.
The renal effects of fetal exposure to NSAIDs are discussed, as are new insights into the role of COX-1/2 for a normal nephrogenesis. COX-nil or COX-inhibited animals have long lasting renal structural injury. Fetuses exposed in utero to significant amounts of NSAIDs have at birth various degrees of renal insufficiency and structural renal defects with a very high mortality.
All NSAIDs, both specific and nonspecific COX inhibitors, have renal side effects in the immediate post-natal period and should, therefore, be given with the utmost caution. NSAIDs given during pregnancy for the prevention of toxemia, polyhydramnios and premature labour may affect fetal renal function and structure. In animal experiments, IBU was not less nephrotoxic than INDO, as suggested recently by human premature neonates.
总结实验动物数据，并对非甾体抗炎药（NSAIDs）对发育中的胎儿和成熟新生儿的肾脏不良影响进行有限的文献综述。
实验数据来自麻醉、通气的6至8日龄兔子，这些兔子静脉推注乙酰水杨酸（ASA）、布洛芬（IBU）或吲哚美辛（INDO）。在一组实验中，还对12周龄（年轻成年）兔子进行了ASA测试。用菊粉和对氨基马尿酸清除率监测肾功能，以测量肾小球滤过率（GFR）和肾血流量。计算肾血管阻力。所有三种非特异性环氧化酶-1或-2（COX-1/2）抑制剂均导致明显相似的可逆性、少尿性急性肾衰竭（ARF）。在年轻成年动物中，副作用有所减轻。潜在的病理生理学与胎儿和新生儿精心维持的低GFR有关，这取决于血管收缩（血管紧张素II）和血管舒张（前列腺素[PGs]）之间的微妙相互作用。当PG合成受到抑制时，血管收缩相对不受抑制，从而导致ARF。
讨论了胎儿接触NSAIDs对肾脏的影响，以及对COX-1/2在正常肾发生中的作用的新见解。COX基因敲除或COX抑制的动物有持久的肾脏结构损伤。子宫内接触大量NSAIDs的胎儿出生时会有不同程度的肾功能不全和肾脏结构缺陷，死亡率很高。
所有NSAIDs，无论是特异性还是非特异性COX抑制剂，在出生后即刻都有肾脏副作用，因此应极其谨慎地使用。孕期使用NSAIDs预防子痫、羊水过多和早产可能会影响胎儿肾功能和结构。在动物实验中，正如最近人类早产新生儿所表明的那样，IBU的肾毒性并不比INDO小。
