Rolleman Edgar J, Krenning Eric P, Bernard Bert F, de Visser Monique, Bijster Magda, Visser Theo J, Vermeij Marcel, Lindemans Jan, de Jong Marion
Department of Nuclear Medicine, Erasmus MC Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Eur J Nucl Med Mol Imaging. 2007 Feb;34(2):219-27. doi: 10.1007/s00259-006-0232-1. Epub 2006 Sep 22.
Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models.
Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2x278 MBq groups. Three doses of 185 MBq [(177)Lu-DOTA(0),Tyr(3)]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469+/-18, 134+/-70 and 65+/-15 micromol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria.
Injection of high doses of [(177)Lu-DOTA(0),Tyr(3)]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.
使用放射性标记的生长抑素类似物进行肽受体放射性核素治疗（PRRT）的研究在肿瘤控制方面显示出了有前景的结果。PRRT的疗效受到肾脏近端小管摄取和滞留的限制，这可能导致放射性肾病。我们在两种荷瘤大鼠模型中研究了不同剂量的[(177)Lu-DOTA(0),Tyr(3)]奥曲肽后的长期肾脏毒性以及剂量分割和赖氨酸共同注射的影响。
治疗开始100天后检测到显著的肾脏毒性，表现为血清肌酐升高和蛋白尿。显微镜下，肾小管强烈扩张，上皮扁平，含有蛋白管型。555 MBq [(177)Lu-DOTA(0),Tyr(3)]奥曲肽后肌酐水平显著升高，但278 MBq（单次注射）或每周两次278 MBq后显著降低。肾脏损伤评分在555 MBq后最高，在278和2x278 MBq组中显著降低。间隔一天、一周或一个月给予三次185 MBq [(177)Lu-DOTA(0),Tyr(3)]奥曲肽对血清肌酐有显著影响（分别为469±18、134±70和65±15 μmol/l；p<0.001）。肾脏组织学损伤评分不受剂量分割的显著影响。赖氨酸与每周三次185 MBq治疗共同给药显著降低了血清肌酐和蛋白尿。
注射高剂量的[(177)Lu-DOTA(0),Tyr(3)]奥曲肽导致大鼠出现严重的肾脏损伤，表现为蛋白尿、血清肌酐升高和组织学损伤。这种损伤是剂量依赖性的，在治疗后100至200天之间明显出现。剂量分割对肾功能有显著的有益影响。此外，赖氨酸共同注射成功预防了功能损伤。
