Stillman I E, Andoh T F, Burdmann E A, Bennett W M, Rosen S
Department of Pathology, Beth Israel Hospital, Boston, Massachusetts, USA.
Lab Invest. 1995 Dec;73(6):794-803.
FK506 is a useful agent in the prevention of allograft rejection but has recently been shown to be nephrotoxic.
Sprague-Dawley rats (n = 40) were divided into four groups: control (C); low-salt (LS); FK506, 3 mg/kg daily by gavage (FK); and FK506-low-salt (FK-LS). After 6 weeks, the animals underwent physiologic studies and were sacrificed with perfusion fixation of the kidneys. Semiquantitative analysis of morphologic injury was performed as well as grading of juxtaglomerular apparatus (JGA) granularity (1-micron plastic sections). Computer-assisted morphometry was used to measure medullary thick ascending limb (mTAL) size within the inner stripe.
Serum creatinine and plasma renin activity were significantly elevated only in the FK-LS group, but both FK groups had significantly increased fractional excretion of Mg. Tubular atrophy and fibrosis involving medullary rays and inner stripe (areas of low oxygen availability) was minimally present in FK, but prominent in FK-LS (P < 0.001). Injury correlated with decreased function (P < 0.001). Variance of mTAL size, an expression of co-existent tubular atrophy and hypertrophy was significantly greater in FK-LS and correlated with decreased renal function and urine osmolality (P < 0.001). JGA granularity was increased by FK506 (P < 0.006) with the highest values in FK-LS (P < 0.001), and strongly correlated with injury (P < 0.001). JGA granularity did not correlate with circulating renin activity levels, suggesting local activation of a renin-angiotensin system.
FK506 compromises renal parenchymal zones which are known to have limited oxygen availability (medullary ray and inner stripe), a pattern that has been observed with other nephrotoxins. The injury is potentiated by salt depletion and may be mediated by the renin-angiotensin system. Furthermore, these findings illustrate the close correlation between the medullary injury that was observed and the impaired function that was documented.
FK506是预防同种异体移植排斥反应的有效药物，但最近已证明其具有肾毒性。
将40只Sprague-Dawley大鼠分为四组：对照组（C）；低盐组（LS）；FK506组，每天经口灌胃3mg/kg（FK）；FK506-低盐组（FK-LS）。6周后，对动物进行生理学研究，然后通过肾脏灌注固定处死。对形态学损伤进行半定量分析，并对肾小球旁器（JGA）颗粒度进行分级（1微米塑料切片）。使用计算机辅助形态测量法测量内带髓质厚升支（mTAL）的大小。
仅FK-LS组血清肌酐和血浆肾素活性显著升高，但两个FK组的镁排泄分数均显著增加。FK组中涉及髓放线和内带（低氧区域）的肾小管萎缩和纤维化轻微存在，但在FK-LS组中明显（P<0.001）。损伤与功能降低相关（P<0.001）。FK-LS组中mTAL大小的变化（共存的肾小管萎缩和肥大的表现）显著更大，并且与肾功能和尿渗透压降低相关（P<0.001）。FK506增加了JGA颗粒度（P<0.006），FK-LS组中最高（P<0.001），并且与损伤密切相关（P<0.001）。JGA颗粒度与循环肾素活性水平无关，提示肾素-血管紧张素系统的局部激活。
FK506损害了已知氧供应有限的肾实质区域（髓放线和内带），这种模式在其他肾毒素中也有观察到。盐缺乏会加剧损伤，并且可能由肾素-血管紧张素系统介导。此外，这些发现说明了观察到的髓质损伤与记录的功能受损之间的密切相关性。
