Nephrotoxicity profiles and threshold dose values for [177Lu]-DOTATATE in nude mice

Introduction: In peptide receptor radionuclide therapy for neuroendocrine tumors the main dose-limiting tissue is found in the kidneys because of tubular reabsorption and retention of radioactivity. The aim of this study was to quantify late effects in renal cortex of nude mice exposed to high amounts of [177Lu]-DOTA-Tyr3-octreotate ([177Lu]-DOTATATE), and to determine whether a threshold dose value exists for these findings. Methods: Nude mice were exposed to 90, 120 or 150MBq of [177Lu]-DOTATATE. Renal toxicity was evaluated up to 6 months after injection. Blood samples were collected to examine renal functional markers, and after sacrifice at 6 months changes in renal morphology were explored. Tissue damage was estimated by quantifying the relative area of the different subunits in the renal cortex using point counting. Additional morphological signs of radiation damage were also noted. The absorbed doses to the kidneys were estimated by previously determined kidney pharmacokinetics and Monte Carlo simulations for different assumptions regarding the activity distribution. Results: Increased serum creatinine and urea values indicated long-term renal toxicity. The tissue area occupied by proximal tubules decreased with increasing doses of [177Lu]-DOTATATE, whereas the other subunits in cortex slightly increased. The mean absorbed dose in the renal cortex for [177Lu]-DOTATATE was estimated to be 35-58Gy for the different groups of animals. A dose-response relationship was observed for proximal tubular damage, and a threshold dose value of 24Gy (BED 37Gy) was determined. Conclusions: Selective morphological changes in kidney cortex of nude mice were quantified and appeared in a dose dependent manner after injection of high amounts of [177Lu]-DOTATATE.

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