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This week we'll conclude with a discussion of pharmacologic interventions to prevent or treat acute renal failure.

1.What agents have been used to prevent and treat acute renal failure (ARF)?
2.What possible mechanisms exist for a beneficial effect of loop diuretics in preventing renal dysfunction?
3.What possible mechanisms exist for a beneficial effect of atrial natriueretic peptide (ANP) in preventing renal dysfunction?
4.What future medications or modalities may prove useful in preventing or treating ARF?

1 哪些药物曾用于预防和治疗急性肾功衰竭?
2 袢利尿剂预防肾功失调的可能机制是什么?
3 心房利钠肽预防肾功失调的可能机制是什么?
4 将来能有效预防和治疗急性肾功衰竭药物有哪些?

1 哪些药物曾用于预防和治疗急性肾功衰竭?
很多药物曾被用于试图预防性减少术后急性肾功衰竭发生率。除交感神经系统胺类物质外，其他的包括多陪沙明和非诺多泮等也曾被用于预防性术后急性肾功衰竭。此外也曾应用促钠排泄药（速尿、甘露醇、心房利钠肽）、钙通道拮抗剂（地尔硫卓、硝苯地平）和其他新药物（内皮素拮抗剂、生长因子、腺苷拮抗剂）。迄今为止，没有任何一种药物可被证明对急性肾功衰竭有持续或绝对预防或治疗作用。
2 袢利尿剂预防肾功失调的可能机制是什么?
实验资料证明如速尿类排钠型利尿药物可能通过以下机制改善肾功能：
•减少主动转运，从而减少肾脏氧需
•增加坏死细胞碎片的清除，从而减少肾小管阻塞
遗憾的是，这些资料更像根据实际肾功改善现象的假想理论，在两个前瞻性、随机、双盲、安慰剂对照研究中，患者随机接受小剂量多巴胺、甘露醇、或袢利尿剂或者安慰剂，在无透析生存率上总体无差异。一个有意思的观察是，患者由少尿状态转为非少尿状态后肾衰程度和死亡率减少。早期的一些研究也曾观察到此种非少尿性肾衰患者死亡率降低现象。
3 心房利钠肽预防肾功失调的可能机制是什么?
心房利钠肽是心房合成的一种激素，实验证明其可改善肾功能。其作用的某些机制已被阐明，包括：
•扩张入球小动脉进而增加肾小球滤过率
•抑制肾小管对钠和氯的重吸收
•髓质肾血流重分布
•阻断内皮素对肾血管的效应
然而，临床上心房利钠肽的有益效应甚微。虽然早期研究表明对少尿型肾衰患者进行心房利钠肽输注有改善作用（增加非透析生存率或减少透析）。然而，最近对照良好的研究结果与上述结果不同。早期和近期研究结果表明心房利钠肽对非少尿性急性肾衰无有益作用。
4 将来能有效预防和治疗急性肾功衰竭药物有哪些?
在实验模型和临床试验中曾证明，钙拮抗剂、激活β-受体阻断剂的内皮型一氧化氮合酶？（endothelial NO synthase-activating beta-blockers）、和胰岛素样生长因子对急性肾功衰患者有改善作用。值得一提的是，胰岛素样生长因子可与肾脏特异性受体（可能位于近球小管）结合，从而诱导受损细胞增殖和再生。未来工作将致力于寻找在肾衰发生时阻止肾损伤和促进肾修复的方法，并进行结果测量方法明确的临床研究。

英文参考答案：
1 What agents have been used to prevent and treat acute renal failure (ARF)?
A number of agents have attempted to prophylactically reduce the incidence of postoperative acute renal failure. In addition to this sympathetic amine, others, including dopexamine and fenoldopam, have been used. Moreover, natriuretics (furosemide, mannitol, atrial natriuretic peptide), calcium channel antagonists (diltiazem, nifedipine), and other newer agents (endothelin antagonists, growth factors, adenosine antagonists) have been used. To date, no agent has been consistently nor conclusively proven to be of value in preventing or treating ARF (1).
2 What possible mechanisms exist for a beneficial effect of loop diuretics in preventing renal dysfunction?
Experimental data suggests that naturetics like furosemide may improve renal function by:
•decreasing active transport, and thus reducing renal oxygen demand
•increasing clearance of necrotic cellular debris, thus reducing tubular obstruction
Unfortunately, these data appear to be theoretical in terms of actual improvement in renal function. In two prospective, randomized, double blind, placebo controlled studies (2,3), patients randomized to low dose dopamine, mannitol, and either loop diuretics or placebo, had no overall change in incidence of dialysis free survival. One interesting observation, however, was that the patients who converted from oliguric to nonoliguric states did have a decrease in their overall severity renal failure and experienced a decrease in mortality. This reduction in mortality in nonoliguric renal failure has been observed in some earlier studies (4).
3 What possible mechanisms exist for a beneficial effect of atrial natriueretic peptide (ANP) in preventing renal dysfunction?
A hormone synthesized in the cardiac atria, atrial natriuretic peptide (ANP) has been noted experimentally to improve renal function. Several mechanisms for its actions have been demonstrated, including:
•dilating afferent arterioles and consequently increasing glomerular filtration rates (GFR)
•inhibiting tubular reabsorption of sodium and chloride
•redistributing medullary blood flow
•blocking the effects of endothelin on the renal vasculature
Clinically, however, ANP appears less beneficial. Although earlier studies suggested a benefit (as defined increased dialysis free survival or reduction in dialysis) with ANP infusions for patients with oliguric ARF (5), more recent, better controlled work has not corroborated this findings . In both earlier and more recent studies, no benefit has been observed in patients with nonoliguric ARF.
4 What future medications or modalities may prove useful in preventing or treating ARF?In experimental models and some clinical trials, calcium channel antagonists (7), endothelial NO synthase-activating beta-blockers (7), and insulin-like growth factors  have been noted to produce favorable renal results in patients with acute renal dysfunction. Of particular interest, the insulin-like growth factors may bind specific receptors in kidney (most likely within the proximal tubule) and initiate proliferative and regenerative responses in damaged cells. Future work may find ways to prevent damage and promote kidney repair in the event of renal failure and well conducted clinical studies with relevant outcome measures are clearly warranted.

References:
1.Dishart MK, Kellum JA An evaluation of pharmacological strategies for the prevention and treatment of acute renal failure. Drugs 2000;59(1):79-91
2.Shilliday IR, Quinn KJ, Allison ME. Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study. Nephrol Dial Transplant. 1997;12(12):2592-6.
3.Hager B, Betschart M, Krapf R. Effect of postoperative intravenous loop diuretic on renal function after major surgery. Schweiz Med Wochenschr. 1996;126(16):666-73.
4.Dixon BS, Anderson RJ. Nonoliguric acute renal failure. Am J Kidney Dis 1985;6(2):71-80
5.Allgren RL, Marbury TC, Rahman SN, et al. Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med. 1997;336(12):828-34.
6.Lewis J, Salem MM, Chertow GM, et al. Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis 2000;36(4):767-74.
7.Kakoki M, Hirata Y, Hayakawa H, et al. Effects of vasodilatory antihypertensive agents on endothelial dysfunction in rats with ischemic acute renal failure. Hypertens Res 2000;23(5):527-33.
8.Nishiki M, Murakami Y, Kawaguchi M, et al. Renal expression of insulin-like growth factor-l in acute renal failure: a preliminary report. Clin Nephrol 1999;52(3):148-51.