A Computational Multinephron Model for Small-Scale Preclinical Renal Dosimetry in Radiopharmaceutical Therapy

Nonuniform radiopharmaceutical uptake in kidney tissues leads to substructure-level absorbed dose heterogeneity, confounding the establishment of absorbed dose-effect relationships for nephrotoxicity in radiopharmaceutical therapy. We developed a model to enable nephron-level dosimetry. Methods: A multinephron computational model was developed on the basis of 3-dimensional multiphoton microscopy data, including different nephron types (superficial, midcortical, and juxtamedullary) and their main substructures (glomerulus, proximal tubule [PT], and distal tubule) in kidney tissues. Nephron-level S values were determined using Monte Carlo calculations for several β^-- and α-emitting radionuclides. The multinephron dosimetry framework was applied to nonuniform kidney tissue uptake data on ²²⁵Ac, located primarily in midcortical and juxtamedullary PTs. Results: A nonuniform substructure activity distribution resulted in pronounced absorbed dose heterogeneities. S values varied substantially among nephron types, with the largest in juxtamedullary substructures. The self-dose to PTs was 7.6-15 times higher than the S value of superficial PTs for the α-emitters considered. The cross dose to juxtamedullary glomeruli was on average 20% higher than to superficial glomeruli. The case study revealed substantial absorbed dose heterogeneity, with the absorbed dose to the different PTs being 40%-73% higher than to their respective glomeruli. Additionally, the contribution of free ²¹³Bi to the total absorbed dose differed from that of ²²⁵Ac. Conclusion: The developed multinephron framework enables nephron-level dosimetry, allowing quantification of absorbed dose heterogeneity within renal tissues. Such insights enable establishing critical nephron substructures for nephrotoxicity in radiopharmaceutical therapy, supporting nephroprotective strategies during clinical translation of novel radiopharmaceuticals.