Weir M R, Klassen D K, Shen S Y, Sullivan D, Buddemeyer E U, Handwerger B S
Department of Medicine, University of Maryland Hospital, Baltimore 21201.
Transplantation. 1990 Jan;49(1):41-7. doi: 10.1097/00007890-199001000-00009.
The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of 99m TcDTPA and 131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6 +/- 24.9 ml/min during the control infusion and 463.3 +/- 12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8 +/- 2.5 ml/min, vs. cyclosporine, 91.1 +/- 2.2 ml/min, P less than .01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2 during cyclosporine administration was markedly increased in all patients, being 39.9 +/- 8.2 ng/hr in the control period and 85.8 +/- 22.3 ng/hr during cyclosporine infusion (P less than .05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin F1a or prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P less than .05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion.(ABSTRACT TRUNCATED AT 400 WORDS)
与环孢素相关的急性肾衰竭可能源于肾内小动脉的血管收缩。为评估环孢素诱导肾毒性的机制，我们对8名血压和肾功能正常的健康女性志愿者急性给予环孢素。将250 ml含5%葡萄糖的水溶液（D5W）中的环孢素（4 mg/kg）以稳定静脉输注的方式在6小时内给予。在输注的最后3小时期间，分别通过99m锝-二乙三胺五乙酸（99mTcDTPA）的血清清除率和131碘-马尿酸（131I hippuran）来测量肾小球滤过率和肾血浆流量。在环孢素输注前的不同日期给患者输注D5W以获取对照数据。输注期间每小时测量收缩压和舒张压，环孢素给药期间肾血管阻力略有升高，但升高无统计学意义。肾血浆流量不受环孢素影响，对照输注期间为479.6±24.9 ml/分钟，环孢素输注期间为463.3±12.7 ml/分钟。然而，除1名无明显变化的患者外，所有患者的肾小球滤过率均因环孢素而降低（对照，108.8±2.5 ml/分钟，vs环孢素，91.1±2.2 ml/分钟，P＜0.01）。环孢素给药期间所有患者血栓素B2的尿排泄量均显著增加，对照期为39.9±8.2 ng/小时，环孢素输注期间为85.8±22.3 ng/小时（P＜0.05），但该名肾小球滤过率未降低的患者除外。环孢素输注期间6-酮-前列腺素F1α或前列腺素E的尿排泄率无显著变化。与对照相比，环孢素给药期间外周肾素活性、血管紧张素II和醛固酮的血清平均水平未改变。所有患者在环孢素输注当天24小时尿钠和钾排泄量均减少。缓释维拉帕米（在环孢素输注前7天每日240 mg）未能逆转环孢素诱导的肾小球滤过率降低；然而，与单独使用环孢素相比，志愿者同时接受维拉帕米和环孢素治疗时，肾血管阻力显著降低，肾血浆流量增加（P＜0.05）。静脉输注溶解环孢素的溶媒聚氧乙烯蓖麻油（Cremophor EL）对血压、肾血流动力学或尿前列腺素排泄无显著影响。（摘要截短至400字）
