ApoSense: a novel technology for functional molecular imaging of cell death in models of acute renal tubular necrosis.
OBJECTIVE
Acute renal tubular necrosis (ATN), a common cause of acute renal failure, is a dynamic, rapidly evolving clinical condition associated with apoptotic and necrotic tubular cell death. Its early identification is critical, but current detection methods relying upon clinical assessment, such as kidney biopsy and functional assays, are insufficient. We have developed a family of small molecule compounds, ApoSense, that is capable, upon systemic administration, of selectively targeting and accumulating within apoptotic/necrotic cells and is suitable for attachment of different markers for clinical imaging. The purpose of this study was to test the applicability of these molecules as a diagnostic imaging agent for the detection of renal tubular cell injury following renal ischemia.


METHODS
Using both fluorescent and radiolabeled derivatives of one of the ApoSense compounds, didansyl cystine, we evaluated cell death in three experimental, clinically relevant animal models of ATN: renal ischemia/reperfusion, radiocontrast-induced distal tubular necrosis, and cecal ligature and perforation-induced sepsis.


RESULTS
ApoSense showed high sensitivity and specificity in targeting injured renal tubular epithelial cells in vivo in all three models used. Uptake of ApoSense in the ischemic kidney was higher than in the non-ischemic one, and the specificity of ApoSense targeting was demonstrated by its localization to regions of apoptotic/necrotic cell death, detected morphologically and by TUNEL staining.


CONCLUSIONS
ApoSense technology should have significant clinical utility for real-time, noninvasive detection of renal parenchymal damage of various types and evaluation of its distribution and magnitude; it may facilitate the assessment of efficacy of therapeutic interventions in a broad spectrum of disease states.
Damianovich
Maya
M
NeuroSurvival Technologies (NST) Ltd., 5 Odem St., Kiryat Matalon, Petah Tikva 49170, Israel.
Ziv
Ilan
I
Heyman
Samuel N
SN
Rosen
Seymour
S
Shina
Ahuva
A
Kidron
Dvora
D
Aloya
Tali
T
Grimberg
Hagit
H
Levin
Galit
G
Reshef
Ayelet
A
Bentolila
Alfonso
A
Cohen
Avi
A
Shirvan
Anat
A
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001709:Biotechnology / Q000379:methods; D003553:Cystine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003619:Dansyl Compounds / Q000493:pharmacokinetics; D005456:Fluorescent Dyes; D006801:Humans; D019169:Jurkat Cells; D007673:Kidney Cortex Necrosis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D003619:Dansyl Compounds; D005456:Fluorescent Dyes; D019275:Radiopharmaceuticals; D014316:Tritium; C038494:di(dansyl)cystine; D003553:Cystine