591 Low kidney mass contributes to enhanced fractionated irradiation-induced renal hemodynamic dysfunction in mice

Abstract

Objectives/Goals: Radiation nephropathy results in morbidity and mortality in patients receiving cancer treatment. In addition, low birth weight and low nephron number are associated with increased risk for chronic kidney disease. This study examined the development and severity of radiation-induced renal hemodynamic dysfunction in a low renal mass mouse model. Methods/Study Population: Male mice (C57Bl/6, 8–12-weeks) were used to determine a suitable radiation dose regimen. Mice were subjected to fractionated bilateral kidney irradiation with 5–6 fractions of an X-ray dose of 0, 6, 8, and 10 Gy at 24-hr intervals using a CT-image-guided irradiator. Body weight and mortality were monitored for 5 weeks in mice. In a separate set of experiments, the low renal mouse model, ROP Os/+, and their normal counterpart, ROP +/+ mice were subjected to 5 fractionated bilateral kidney irradiations at 24-hr intervals with an X-ray dose of 6 Gy. Renal blood flow was assessed from renal artery resistive index (RRI) over 5 weeks post-irradiation using an ultrasound system. Transcutaneous measurement of FITC-sinistrin clearance was used to determine glomerular filtration rate (GFR). Results/Anticipated Results: The C57Bl/6 mice that received 5–6 fractions of 8 and 10 Gy had more than 50% mortality, while 100% of the mice exposed to 5 fractions of 6 Gy survived for 5 weeks. Body weight was also significantly decreased in mice exposed to 5 or 6 fractions of 8 or 10 but not 6 Gy radiation. Nonirradiated C57Bl/6, ROP +/+, and ROP Os/+ mice had similar baseline GFR and RRI. Irradiation of 5 fractions at 6 Gy decreased GFR and increased RRI in C57Bl/6 and ROP +/+ mice. Interestingly, following 5 fractions at 6 Gy irradiation ROP Os/+ mice had 25% lower GFR than wild-type ROP +/+ mice (946.3 ± 50.3 vs. 1232.9 ± 69.3 µL/min/100g BW, p Discussion/Significance of Impact: Our study determined a suitable fractionated bilateral kidney irradiation dose regimen to evaluate radiation nephropathy. Data demonstrated that fractionated bilateral kidney irradiation leads to decreased renal hemodynamics in mice. We also demonstrated that irradiation caused greater renal hemodynamic dysfunction in low renal mass mice.