A Realistic Multi-region Mouse Kidney Dosimetry Model to Support the Preclinical Evaluation of Potential Nephrotoxicity of Radiopharmaceutical Therapy.

Sub-organ absorbed dose estimates in mouse kidneys are crucial to support preclinical nephrotoxicity analyses of alpha- and beta-particle emitting radioligands exhibiting a heterogeneous activity distribution in kidney. This is however limited by the scarcity of reference dose factors (S values) available in the literature for specific mouse kidney tissues. Methods: A computational multi-region model of a mouse kidney was developed based on high-resolution magnetic resonance imaging data from a healthy mouse kidney. The model was used to calculate S values for 5 kidney tissues (cortex, outer and inner stripes of outer medulla, inner medulla, and papilla and pelvis) for a wide range of beta or alpha emitting radionuclides (45 in total) interesting for radiopharmaceutical therapy, using Monte Carlo calculations. Additionally, the application of regional S values was demonstrated for a 131 I-labelled single-domain antibody fragment with predominant retention in the renal outer stripe. Results: The heterogeneous activity distribution in kidneys of considered alpha and low to medium energy beta emitters considerably affected the absorbed dose estimation in specific sub-organ regions. The sub-organ tissue doses resulting from the non-uniform distribution of the 131 I-labelled single-domain antibody largely deviate (from -40% to 57%) from the mean kidney dose resulting from an assumed uniform activity distribution throughout the whole kidney. The absorbed dose in the renal outer stripe was about 2.0 times higher than in the cortex and in the inner stripe, and about 2.6 times higher than in inner tissues. Conclusion: The use of kidney regional S values allows a more realistic estimation of the absorbed dose in different renal tissues from therapeutic radioligands with a heterogeneous uptake in kidneys. This constitutes an improvement from the simplistic (less accurate) renal dose estimates assuming a uniform distribution of activity throughout kidney tissues. Such improvement in dosimetry is expected to support preclinical studies essential for a better understanding of nephrotoxicity in humans. The dosimetric database represents an added value in the development of new molecular vectors for radiopharmaceutical therapy.