Long-term toxicity of [177Lu-DOTA0,Tyr3]octreotate in rats

Purpose and methods: 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 [Lu-177-DOTA(0), Tyr(3)] octreotate and the effects of dose fractionation and lysine co-injection in two tumour-bearing rat models. Results: 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 [Lu-177-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 2 x 278 MBq groups. Three doses of 185 MBq [(177)LuDOTA(0), Tyr3] octreotate with intervals of a day, a week or a month significantly influenced serum creatinine ( 469 +/- 18, 134 +/- 70 and 65 +/- 15 mu mol/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. Conclusion: Injection of high doses of [Lu-177- DOTA(0), Tyr3] 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.