Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy

Mengshi Li; Claudia Robles-Planells; Dijie Liu; Stephen A Graves; Gabriela Vasquez-Martinez; Gabriel Mayoral-Andrade; Dongyoul Lee; Prerna Rastogi; Brenna M Marks; Edwin A Sagastume; Robert M Weiss; Sarah C Linn-Peirano; Frances L Johnson; Michael K Schultz; Diana Zepeda-Orozco

doi:10.1007/s00259-023-06559-9

Back

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy

Journal article

Open access

Peer reviewed

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy

Mengshi Li, Claudia Robles-Planells, Dijie Liu, Stephen A Graves, Gabriela Vasquez-Martinez, Gabriel Mayoral-Andrade, Dongyoul Lee, Prerna Rastogi, Brenna M Marks, Edwin A Sagastume, …

European journal of nuclear medicine and molecular imaging, Vol.51(5), pp.1395-1408

04/2024

DOI: 10.1007/s00259-023-06559-9

PMCID: PMC10957612

PMID: 38095674

Files and links (1)

url

https://doi.org/10.1007/s00259-023-06559-9View

Published (Version of record) Open Access

Abstract

Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [ Pb]Pb-MC1L, was used for [ Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [ Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Biodistribution analysis identified [ Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [ Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [ Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Biomarkers

Dosimetry

NGAL

Radiopeptide ligand therapies

Nephrotoxicity

Alpha-emitter

Details

Title: Subtitle: Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy
Creators: Mengshi Li - Viewpoint Molecular Targeting (United States)
Claudia Robles-Planells - Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH, USA
Dijie Liu - Viewpoint Molecular Targeting (United States)
Stephen A Graves - University of Iowa
Gabriela Vasquez-Martinez - Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH, USA
Gabriel Mayoral-Andrade - Kidney and Urinary Tract Center, Abigail Wexner Research Institute at Nationwide Children's, Columbus, OH, USA
Dongyoul Lee - Department of Physics and Chemistry, Korea Military Academy, Seoul, Republic of Korea
Prerna Rastogi - University of Iowa
Brenna M Marks - Viewpoint Molecular Targeting (United States)
Edwin A Sagastume - Viewpoint Molecular Targeting (United States)
Robert M Weiss - University of Iowa
Sarah C Linn-Peirano - The Ohio State University
Frances L Johnson - Viewpoint Molecular Targeting (United States)
Michael K Schultz - University of Iowa
Diana Zepeda-Orozco - Nationwide Children's Hospital
Resource Type: Journal article
Publication Details: European journal of nuclear medicine and molecular imaging, Vol.51(5), pp.1395-1408
DOI: 10.1007/s00259-023-06559-9
PMID: 38095674
PMCID: PMC10957612
NLM abbreviation: Eur J Nucl Med Mol Imaging
eISSN: 1619-7089
Grant note: R44CA254613 / NCI NIH HHS R44CA203430 / NCI NIH HHS
Language: English
Electronic publication date: 12/14/2023
Date published: 04/2024
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Stead Family Department of Pediatrics; Pathology; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
Record Identifier: 9984528111902771

Metrics

3 Record Views

5 Times Cited - Web of Science