A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry.

Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the human and murine models. The renal cortex and medulla S-values were also calculated and the results compared to traditional absorbed fraction calculations. The nephron model enables a more optimal implementation of treatment and is a critical step in understanding toxicity for human translation of targeted α-particle therapy. The S-values established here will enable a MIRD-type application of α-particle dosimetry for α-emitters, i.e. measuring the TIA in the kidney (or renal cortex) will provide meaningful and accurate nephron-level dosimetry.

In vitro and in vivo expression of endothelial von Willebrand factor and leukocyte accumulation after fractionated irradiation.

Previous investigations have demonstrated an increased release of von Willebrand factor (VWF; also known as vWF) in endothelial cells after high single-dose irradiation in vitro. We have also found increased levels of Vwf protein in mouse glomeruli after a high single dose of renal irradiation in vivo. In addition, increased numbers of leukocytes were observed in the renal cortex after irradiation in vivo. The aim of the present study was to investigate and quantify these biological processes after clinically relevant fractionated irradiation and to relate them to changes in renal function. A significantly greater increase in release of VWF was observed in cultured human umbilical vein endothelial cells (HUVECs) after fractionated irradiation (20 x 1.0 Gy) than after a single dose of 20 Gy (147% compared to 115% of control, respectively, P < 0.0005). In contrast with the in vitro observations, glomerular Vwf staining was lower after fractionated irradiation in vivo (20 x 2.0 Gy or 10 x 1.6 Gy +/- re-irradiation) than after a single dose of 16 Gy. The number of leukocytes accumulating in the renal cortex was also lower after fractionated in vivo irradiation than after a single radiation dose. The onset of these events preceded renal functional and histopathological changes by approximately 10 weeks. These data indicate that radiation-induced changes in endothelial VWF expression after in vivo irradiation may be distinct from the in vitro observations. Increased VWF expression may reflect pivotal processes in the pathogenesis of late radiation nephropathy and provide a clue to appropriate timing of pharmacological intervention.

Progression rate of radiation damage to the mouse kidney: a quantitative analysis of experimental data using a simple mathematical model of the nephron.

Mouse kidneys were irradiated bilaterally with a range of single or fractionated X-ray doses. After an interval of 2 weeks or 26 weeks, the animals were reirradiated with a range of single X-ray doses. The rate of development of functional kidney damage was assessed repeatedly by the 51Cr-EDTA clearance assay. The rate at which the damage is expressed was found to depend on the primary dose, on the interval between primary treatment and retreatment, and on the retreatment dose. A subset of the data was analysed using a mathematical model of nephron function. In the model, the residual activity of 51Cr-EDTA depends on the glomerular filtration rate (GFR). The GFR is related to the cellularities of three target cell populations. The filtration capacity of the glomerulus is assumed to depend on the numbers of glomerular endothelial cells and mesangial cells. The reabsorption capacity of the tubule is related to the number of tubular epithelial cells. The impact of tubulo-glomerular feedback and the reserve capacity of the kidney on residual activity is considered. The target cell populations are assumed to be of a flexible type, i.e. to consist of cells which are all both functional and self-renewing. Free parameters of the model were optimized by minimizing the residual sum of squares. With the optimized parameter values, the measured and the model-predicted rates of progression of the functional damage correspond well for a wide range of irradiation schedules. The model analysis suggests a pronounced role of tubulo-glomerular feedback in the development of functional injury in the kidney. It is concluded that the model represents a good starting point for quantitative studies of the cellular basis of radiation nephropathy.