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Protection of Kidney Function with Human Antioxidation Protein α 1 -Microglobulin in a Mouse 177 Lu-DOTATATE Radiation Therapy Model

Journal article
Authors A. Kristiansson
J. Ahlstedt
B. Holmqvist
A. Brinte
T. A. Tran
Eva Forssell-Aronsson
S. E. Strand
M. Gram
B. Akerström
Published in Antioxidants and Redox Signaling
Volume 30
Issue 14
Pages 1746-1759
ISSN 1523-0864
Publication year 2019
Published at Institute of Clinical Sciences, Department of Radiation Physics
Sahlgrenska Cancer Center
Pages 1746-1759
Language en
Links dx.doi.org/10.1089/ars.2018.7517
Keywords 177 Lu-DOTATATE, cancer, PRRT, radionuclide therapy, renal protection, α 1 -microglobulin, alpha 1 microglobulin, oxodotreotide lu 177, protective agent, animal experiment, animal model, animal tissue, apoptosis, Article, controlled study, double stranded DNA break, female, gene expression, histopathology, kidney cortex, kidney function, kidney injury, mouse, nonhuman, priority journal, proteinuria, radioisotope therapy, upregulation
Subject categories Radiology, Nuclear Medicine and Medical Imaging

Abstract

Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α 1 -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 ( 177 Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177 Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177 Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment. © Amanda Kristiansson et al. 2018; Published by Mary Ann Liebert, Inc.

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