Relationship of Renal Function in Mice to Strain, Sex and ¹⁷⁷Lutetium-Somatostatin Receptor Ligand Treatment

Abstract

Aim Aim of the study was to establish parameters for ^99mTc-MAG3 SPECT renal uptake kinetics in healthy SCID mice as a function of mouse strain and sex and to evaluate the feasibility of this method for detecting ¹⁷⁷Lu-somatostatin receptor ligand (¹⁷⁷Lu-SRL) treatment effects on kidney function.

Materials and Methods Dynamic semi-stationary SPECT acquisitions (68 frames, total duration 35 min) was started prior to i. v. injection of ^99mTc-MAG3 in 12 female and 12 male SCID mice. Additionally, 6 female SCID mice with neuroendocrine tumors were imaged 1–5 months after ¹⁷⁷Lu-SRL (5 DOTATOC, 1 DOTA-JR11) treatment. Kidney function is expressed as maximum time to peak (T_max), T₅₀ and T₂₅ in minutes (median [interquartile range]). Differences between groups were tested using the Mann-Whitney-U test, and SCID mouse parameters were compared with data for C57BL/6N mice from a recent publication.

Results Significant sex-based differences in T_max between strains were observed (females: C57BL/6N 1.6 [1.4–1.7], SCID 1.4 [1.3–1.5], p = 0.05; males: C57BL/6N 1.4 [1.3–1.4], SCID 1.6 [1.4–1.7], p = 0.04). In C57BL/6N mice, females showed a later T_max (p < 0.01) than males. SCID mice showed no difference (p = 0.14). Treated SCID mice showed no significant delay in T_max (2.0 [1.4–2.7], p = 0.15) but a significant delay in T₅₀ (p = 0.02) and T₂₅ (p = 0.01) compared to healthy untreated mice.

Conclusion This study demonstrated significant sex-related differences between SCID and C57BL/6N mouse strains in kidney function. Establishment of normal values for different strains and sexes therefore is important for experimental therapy studies. Renal SPECT imaging with ^99mTc-MAG3 was sufficiently sensitive to detect ¹⁷⁷Lu-SRL treatment toxic effects on kidney function in SCID mice.

Zusammenfassung

Ziel Ziel dieser Studie war es, Werte für die Nieren-Uptake-Kinetik von ^99mTc-MAG3-SPECT bei gesunden SCID-Mäusen in Abhängigkeit von Mausstamm und Geschlecht zu erheben sowie zu untersuchen, inwieweit mit dieser Methode Therapieeffekte von ¹⁷⁷Lutetium-Somatostatin-Rezeptor-Liganden (¹⁷⁷Lu-SRL) auf die Nierenfunktion messbar sind.

Methoden Bei 12 weiblichen und 12 männlichen SCID-Mäusen wurden unmittelbar vor intravenöser Injektion von ^99mTc-MAG3 dynamische semistationäre SPECT-Aufnahmen (68 Frames, insgesamt 35 min Dauer) gestartet. Zusätzlich wurden 6 weibliche SCID-Mäuse mit neuroendokrinen Tumoren 1–5 Monate nach ¹⁷⁷Lu-SRL-Therapie (5 DOTATOC, 1 DOTA-JR11) untersucht. Die Nierenfunktion ist als Zeit bis zum Maximum (T_max), T₅₀ und T₂₅ in Minuten (Median [Interquartilabstand]) aufgeführt. Gruppenunterschiede wurden mit dem Mann-Whitney-U-Test untersucht, und die Parameter der SCID-Mäuse wurden mit kürzlich publizierten Daten für C57BL/6N-Mäuse verglichen.

Ergebnisse Für T_max konnten signifikant geschlechtsabhängige Unterschiede zwischen den Mausstämmen beobachtet werden (Weibchen: C57BL/6N 1,6 [1,4–1,7], SCID 1,4 [1,3–1,5]; p = 0,05; Männchen: C57BL/6N 1,4 [1,3–1,4], SCID 1,6 [1,4–1,7]; p = 0,04). T_max trat bei weiblichen C57BL/6N später als bei männlichen Mäusen auf (p < 0,01). Dahingegen zeigten SCID-Mäuse keinen Unterschied (p = 0,14). Verglichen mit gesunden Mäusen zeigten therapierte Mäuse keine signifikante Veränderung von T_max (2,0 [1,4–2,7]; p = 0,15), jedoch erfolgten T₅₀ (p = 0,02) und T₂₅ (p = 0,01) signifikant später.

Schlussfolgerung Diese Studie zeigte signifikante geschlechtsabhängige Unterschiede in der Nierenfunktion zwischen SCID- und C57BL/6N-Mausstämmen. Für experimentelle Therapiestudien ist daher die Etablierung von Normwerten in Abhängigkeit von Mausstamm und Geschlecht wichtig. Die ^99mTc-MAG3-Nierenszintigrafie war zudem eine ausreichend sensitive Methode zum Nachweis toxischer Einflüsse von ¹⁷⁷Lu-SRL auf die Nierenfunktion bei SCID-Mäusen.

Key words

^99mTc-MAG3 - SPECT - sex - ¹⁷⁷Lu - PRRT - mouse

Schlüsselwörter

Nierenfunktion - ^99mTc-MAG3 - SPECT - Geschlecht - ¹⁷⁷Lu - PRRT - Maus

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