Development of mouse kidney models on a nephron scale and influence of non-uniform activity distribution on preclinical renal dosimetry

Introduction: Nephrotoxicity is often the dose-limiting factor in Targeted Radionuclide Therapy (TRT) due to the clearance of radiopharmaceuticals through the kidneys. Small radiolabeled peptides are often reabsorbed in the proximal tubules (PT), leading to a heterogeneous dose distribution in nephrons and even within nephron sub-compartments (Glomerulus (GL) , PT, Distal Tubule and Loop of Henle) [1]. In order to investigate factors affecting nephrotoxicity in a controlled manner, preclinical investigations are of great importance. This study investigated the influence of nephron type and morphology on murine nephron dosimetry, as well as the effect of heterogeneous activity distribution in nephrons on kidney tissue dosimetry by developing a 3D multi-nephron anatomical model for dosimetric calculations.

Methods: Two realistic computational murine kidney models have been considered. Investigating the influence of nephron type on dosimetry, a model of three single nephrons with their respective sub-compartments (GL, PT, DT and loop of Henle) was developed. The nephrons represent each type present in murine kidneys: a superficial (small GL located in the outermost region of the renal cortex and straight, less convoluted PT), a mid-cortical (intermediate) and a juxtamedullary nephron (large GL close to the medullary border and long, convoluted PT). The second model currently being finalized is a multi-nephron kidney model of more than 420 nephrons representing different kidney tissues (renal cortex, outer- and inner stripe of outer medulla and inner tissues), enabling more realistic dose estimations considering cross-irradiation between nephron types and substructures. Both models were developed from 3D multiphoton microscopy images of murine kidney tissues [2]. S-values and energy absorbed fractions (φ) were calculated for various Auger-electron, beta- and alpha-emitting radionuclides (¹⁷⁷Lu, ¹⁶¹Tb, ²¹¹At), considering a uniform source in each nephron PT or GL in the first model, and will be performed on the multi-nephron model once finalized. Monte Carlo simulations were performed with GATE v9.2.

Results: For the influence of nephron type on dosimetry, the three single nephrons were considered. With PT as source region, the φ for both self- and cross-irradiation was higher in the juxtamedullary nephron for all radionuclides. For self-irradiation, the φ differed with a factor of 1.4 for ¹⁷⁷Lu and 1.2 for ¹⁶¹Tb for Auger- and internal conversion electrons, and 1.7 for betas of both radionuclides compared to the superficial nephron. For ²¹¹At, the difference in φ was by a factor of 1.8 for alphas. The difference in φ for the mid-cortical nephron was less pronounced (approximately 1.2 times higher for all particles of all radionuclides). For cross-irradiation to GL, the mid-cortical nephron had the lowest total φ by a factor of 0.5 for ²¹¹At and 0.7 for ¹⁶¹Tb compared to the juxtamedullary nephron. In contrast, the superficial nephron had the lowest φ for ¹⁷⁷Lu, with a factor of 0.6 compared to the juxtamedullary nephron. However, for all radionuclides, the S-values were considerably higher for the superficial nephron for self- and cross-dose (with a factor of approximately 2 compared to the juxtamedullary), as the superficial PT mass is 0.3 and 0.5 times lower than the mid-cortical and juxtamedullary PT.

Conclusions: Nephron type and morphology significantly affects microscopic dosimetry with a non-uniform activity distribution in murine kidneys. This influence is being investigated on a larger, multi-nephron scale for accurate renal dosimetry in support of preclinical nephrotoxicity investigations. By taking the complexity of renal activity retention into account at a nephron level, accurate dosimetry on a relevant scale can be applied in preclinical investigations of the dose-response for nephrotoxicity in TRT.

[1] EJNMMI 2005;32(10):1136-43.

[2] Kidney International 2021;99(3):632-45.