Robbins M E, Stephens L C, Thames H D, Gray K N, Peters L J, Ang K K
CRC Normal Tissue Radiobiology Research Group, Research Institute (University of Oxford), Churchill Hospital, UK.
Int J Radiat Oncol Biol Phys. 1994 Sep 30;30(2):347-54. doi: 10.1016/0360-3016(94)90014-0.
The long-term functional and morphologic responses of the hypertrophied monkey kidney after unilateral nephrectomy to fractionated irradiation were assessed.
The right kidney of 13 adult female rhesus monkeys was removed. Twelve weeks after unilateral nephrectomy (UN) the remaining kidney received fractionated doses of gamma-rays ranging from 35.2 Gy/16 fractions (F) up to 44 Gy/20 F. Glomerular filtration rate, effective renal plasma flow, blood urea nitrogen, serum creatinine, and hematocrit values were measured up to 107 weeks postirradiation (PI). The monkeys were killed and the remaining kidneys were removed 107 weeks PI or earlier when end-stage renal failure was exhibited. Glomeruli were scored for the presence/absence of several pathologic features including increased intercapillary eosinophilic material (ICE), ectatic capillaries, and thrombi. The relative proportion of renal cortex occupied by glomeruli, interstitium, normal tubules or abnormal tubules was determined using a Chalkley point grid. These quantal dose response data were analyzed using a logistic regression model.
Irradiation of the remaining kidney in UN monkeys resulted in a dose-dependent reduction in renal function and anemia. Glomerular dysfunction preceded tubular dysfunction. Animals receiving 44 Gy all manifested progressive clinical renal failure. Conversely, those receiving < or = 39.6 Gy showed stable, albeit impaired, renal function for the duration of the observation period of 107 weeks. Morphologically, the incidence of ICE, ectatic glomerular capillaries, thrombi, and periglomerular fibrosis was significantly dose-related (p < 0.005). A significant (p < 0.001) dose-related increase in the relative proportion of renal cortex occupied by abnormal tubules was indicative of tubular injury. A highly significant (p < 0.001) dose-dependent increase in the proportion of abnormal to normal tubules was also seen.
The pathogenesis of radiation nephropathy is difficult to fully understand because of the complex and dynamic interactions among all components of the nephron that make discrimination between primary radiation effects and secondary pathophysiological consequences very difficult. Notwithstanding, the current experiment shows that the functional and morphological expressions of radiation injury in the kidney are dose dependent. Renal failure occurs when both the glomeruli and tubules are dysfunctional. In monkeys following UN, a total dose of 44 Gy to the remaining kidney damages all components of the nephron and causes renal failure in less than 45 weeks. With lower doses, changes to the glomeruli predominate and the animals survive. Kidney doses of up to 39.6 Gy/18 fractions of 2.2 Gy are compatible with survival for at least 2 years in primates.
评估单侧肾切除术后肥大的猴肾对分次照射的长期功能和形态学反应。
切除13只成年雌性恒河猴的右肾。单侧肾切除（UN）12周后，对剩余肾脏给予分次γ射线照射，剂量范围从35.2 Gy/16次分割（F）至44 Gy/20 F。在照射后（PI）长达107周的时间内测量肾小球滤过率、有效肾血浆流量、血尿素氮、血清肌酐和血细胞比容值。在PI 107周或更早出现终末期肾衰竭时处死猴子并取出剩余肾脏。对肾小球进行评分，观察是否存在几种病理特征，包括毛细血管间嗜酸性物质增加（ICE）、扩张的毛细血管和血栓。使用Chalkley点网格确定肾小球、间质、正常肾小管或异常肾小管在肾皮质中所占的相对比例。使用逻辑回归模型分析这些定量剂量反应数据。
对UN猴子的剩余肾脏进行照射导致肾功能和贫血呈剂量依赖性降低。肾小球功能障碍先于肾小管功能障碍。接受44 Gy照射的动物均表现出进行性临床肾衰竭。相反，接受≤39.� Gy照射的动物在107周的观察期内肾功能虽受损但保持稳定。在形态学上，ICE、扩张的肾小球毛细血管、血栓和肾小球周围纤维化的发生率与剂量显著相关（p<0.005）。异常肾小管在肾皮质中所占相对比例显著（p<0.001）的剂量相关增加表明肾小管损伤。异常肾小管与正常肾小管比例也呈现出高度显著（p<0.001）的剂量依赖性增加。
由于肾单位所有组成部分之间复杂且动态的相互作用，使得区分原发性辐射效应和继发性病理生理后果非常困难，因此放射性肾病的发病机制难以完全理解。尽管如此，当前实验表明肾脏辐射损伤的功能和形态学表现是剂量依赖性的。当肾小球和肾小管均功能障碍时会发生肾衰竭。在UN后的猴子中，对剩余肾脏给予44 Gy的总剂量会损害肾单位的所有组成部分，并在不到45周内导致肾衰竭。较低剂量时，肾小球的变化占主导，动物存活。在灵长类动物中，肾脏剂量高达39.6 Gy/18次分割（每次2.2 Gy）与至少存活2年相符。
