Potential Biomarkers for Radiation-Induced Renal Toxicity following (177)Lu-Octreotate Administration in Mice

The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after (177)Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity. METHODS: C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq (177)Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using (99m)Tc-DTPA/(99m)Tc-DMSA scintigraphy. RESULTS: In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of (99m)Tc-DTPA after 150 MBq, an increased uptake of (99m)Tc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months. CONCLUSION: Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for (177)Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these genes as markers of radiation damage in kidney tissue.