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Nuklearmedizin 2018; 57(06): 224-233
DOI: 10.3413/Nukmed-0999-18-09
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Normal Values of Renal Function measured with 99mTechnetium Mercaptoacetyltriglycine SPECT in Mice with Respect to Age, Sex and Circadian Rhythm

Normwerte für die Nieren-SPECT mit 99mTechnetium Mercaptoacetyltriglycin bei der Maus in Abhängigkeit von Alter, Geschlecht und circadianem Rhythmus
Kai Huang
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
,
Mathias Lukas
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
,
Ingo G. Steffen
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
,
Catharina Lange
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
,
Eleonore L. Huang
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
,
Viktoria Dorau
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
2   Department of Internal Medicine, Military Hospital Hamburg, Germany
,
Winfried Brenner
1   Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Germany
,
Nicola Beindorff
3   Berlin Experimental Radionuclide Imaging Center (BERIC), Charité – Universitätsmedizin
› Author AffiliationsThis work was supported in part by the Technologiestiftung Berlin (TSB) for SPECT/CT use. This manuscript is based in parts on the results of the doctoral thesis of Kai Huang.
Further Information

Publication History

received: 10 September 2018

accepted: 02 November 2018

Publication Date:
18 December 2018 (online)

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Summary

Aim: The aim of this study is to present normal values for 99mtechnetium mercaptoacetyltriglycine renal uptake kinetics as a function of age, sex and circadian rhythm in mice using multi-pinhole SPECT.

Methods: Dynamic multi-pinhole SPECT semistationary acquisitions consisting of 10 20 s frames followed by 25 50 s frames began prior to intravenous injection of 50 MBq in 12 female (F) and 12 male (M) C57BL/6N mice. Each mouse had follow-up imaging at 1, 3, 6, 12 and 22 months of age. To assess physiological changes related to circadian rhythm, animals were imaged during light (sleeping phase, SP) and dark conditions (awake phase, AP). Renal excretion time activity curves were analysed to determine maximum time to peak uptake (Tmax).

Results: There was an age-related effect on renal Tmax. In one-month-old mice median Tmax (1.8 min) occurred later than in 3-month-old mice (1.7 min; p = 0.035). Thereafter, mice showed continuously increasing time to renal Tmax up to an age of 22 months (2.3 min; p < 0.001). Female mice showed a significantly later renal Tmax than males (F 2.1 min, M 1.7 min; p < 0.001) from 3 months onwards. An effect of circadian rhythm on renal uptake was also observed with borderline relevance. Pooled results for all animals showed that renal Tmax appeared at a later timepoint after injection during SP (2.0 min) than during AP (1.8 min; p = 0.019), while in age and sex matched animal groups no significant differences were observed.

Conclusion: This study showed that kidney function in mice is dependent on age and sex, whereas circadian rhythm does not cause a significant effect. Therefore, age and sex should be considered as important study design considerations for renal scintigraphy in mice, while the impact of circadian rhythm seems negligible.

Zusammenfassung

Ziel: Ziel dieser Studie war die Erhebung von Normwerten für die Nieren-Uptake-Kinetik von 99mTechnetium-Mercaptoacetyltriglycin Multipinhole SPECT in Abhängigkeit von Alter, Geschlecht und circadianem Rhythmus bei der Maus.

Methoden: Bei 12 weiblichen (F) und 12 männlichen (M) C57BL/6N Mäusen wurden unmittelbar vor intravenöser Injektion von 50 MBq 99mTc-MAG3 dynamische semistationäre Multipinhole-SPECT-Akquisitionen von 10 Frames à 20 s gefolgt von 25 Frames à 50 s gestartet. Jede Maus wurde im Altersverlauf mit 1, 3, 6, 12 und 22 Monaten untersucht. Um physiologische Veränderungen bezüglich des circadianen Rhythmus zu erfassen, wurden die Tiere während der Hellphase (Schlafphase, SP) sowie der Dunkelphase (Wachphase, AP) untersucht. Die Nierenfunktion ist als Zeit-Aktivitäts-Kurve dargestellt und die Zeit bis zum Maximum (Tmax) als Median in Minuten aufgeführt.

Ergebnisse: Generell zeigte sich ein altersabhängiger Einfluss auf Tmax. Bei 1 Mo alten Tieren erfolgte Tmax (1,8 min) später als mit 3 Mo (1,7 min; p = 0,035). Im weiteren Altersverlauf zeigten die Mäuse einen kontinuierlich späteren Zeitpunkt von Tmax bis 22 Mo (2,3 min; p < 0,001). Weibchen zeigten ein signifikant späteres Tmax als Männchen (F = 2,1 min, M = 1,7 min; p < 0,001) ab einem Alter von 3 Monaten. Für den circadianen Rhythmus wurde ein nicht eindeutiger Effekt beobachtet. Wenn alle Tiere zusammengefasst wurden, erfolgte Tmax während der SP (2,0 min) später als während der AP (1,8 min; p = 0,019) während sich in den alters- und geschlechtsgetrennten Gruppen keine signifikanten Unterschiede nachweisen ließen.

Schlussfolgerung: Diese Studie zeigte einen deutlichen Einfluss von Alter und Geschlecht auf die Nierenfunktion bei der Maus während der circadiane Rhythmus keinen eindeutigen Effekt aufwies. Deshalb sollten bei Nierenstudien mit Mäusen die Faktoren Alter und Geschlecht berücksichtigt werden, während der circadiane Rhythmus vernachlässigbar erscheint.

Keywords

Renal function - 99mTc-MAG3 - SPECT - age - sex - circadian rhythm - mouse

Schlüsselwörter

Nierenfunktion - 99mTc-MAG3 - SPECT - Alter - Geschlecht - circadianer Rhythmus - Maus
 

  • References

  • 1 Achong DM, Tenorio LE. Abnormal MAG3 renal scintigraphy resulting from dehydration. Clin Nucl Med 2003; 28 (08) 683-684.
    CrossrefPubMedSearch in Google Scholar
  • 2 Ahmadzadehfar H, Eppard E, Kurpig S. et al. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget 2016; 07 (11) 12477-12488.
    Search in Google Scholar
  • 3 Armbruster H, Vetter W, Uhlschmid G. et al. Circadian rhythm of plasma renin activity and plasma aldosterone in normal man and in renal allograft recipients. Proc Eur Dial Transplant Assoc 1975; 11: 268-276.
    PubMedSearch in Google Scholar
  • 4 Bares R, Muller-Schauenburg W. [Nuclear medicine diagnosis of the kidneys]. Radiologe 2000; 40 (10) 938-945.
    CrossrefPubMedSearch in Google Scholar
  • 5 Barnes S, Shih WJ, Saylor M. Intestinal activity on Tc-99m MAG3 scintigraphy in a patient after renal transplant may interfere with interpretation. Clin Nucl Med 2000; 25 (08) 643-644.
    CrossrefPubMedSearch in Google Scholar
  • 6 Beierle I, Meibohm B, Derendorf H. Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999; 37 (11) 529-547.
    PubMedSearch in Google Scholar
  • 7 Beindorff N, Bartelheimer A, Huang K. et al. Normal Values of Thyroid Uptake of 99mTechnetium Pertechnetate SPECT in Mice with Respect to Age, Sex, and Circadian Rhythm. Nuklearmedizin 2018; 57 (05) 181-189.
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Bonny O, Firsov D. Circadian regulation of renal function and potential role in hypertension. Curr Opin Nephrol Hypertens 2013; 22 (04) 439-444.
    CrossrefPubMedSearch in Google Scholar
  • 9 Boyd JD, Morgan LA, Blum A. The use of radioisotopes in the clinical study of renal function. South Med J 1959; 52 (01) 1-6.
    CrossrefPubMedSearch in Google Scholar
  • 10 Bridges CC, Zalups RK. The aging kidney and the nephrotoxic effects of mercury. J Toxicol Environ Health B Crit Rev 2017; 20 (02) 55-80.
    CrossrefPubMedSearch in Google Scholar
  • 11 Brolin G, Edenbrandt L, Granerus G. et al. The accuracy of quantitative parameters in 99mTc-MAG3 dynamic renography: a national audit based on virtual image data. Clin Physiol Funct Imaging 2016; 36 (02) 146-154.
    CrossrefPubMedSearch in Google Scholar
  • 12 Dahal A, Bellows BK, Sonpavde G. et al. Incidence of Severe Nephrotoxicity With Cisplatin Based on Renal Function Eligibility Criteria: Indirect Comparison Meta-analysis. Am J Clin Oncol 2016; 39 (05) 497-506.
    CrossrefPubMedSearch in Google Scholar
  • 13 Farmelant MH, Burrows BA. The renogram: physiologic basis and current clinical use. Semin Nucl Med 1974; 04 (01) 61-73.
    CrossrefPubMedSearch in Google Scholar
  • 14 Filss C, Heinzel A, Miiller B. et al. Relevant tumor sink effect in prostate cancer patients receiving 177Lu-PSMA-617 radioligand therapy. Nuklearmedizin 2018; 57 (01) 19-25.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Forrer F, Valkema R, Bernard B. et al. In vivo radionuclide uptake quantification using a multi-pinhole SPECT system to predict renal function in small animals. Eur J Nucl Med Mol Imaging 2006; 33 (10) 1214-1217.
    CrossrefPubMedSearch in Google Scholar
  • 16 Gates GF. Split renal function testing using Tc-99m DTPA. A rapid technique for determining differential glomerular filtration. Clin Nucl Med 1983; 08 (09) 400-407.
    CrossrefPubMedSearch in Google Scholar
  • 17 Hoffmann D, Adler M, Vaidya VS. et al. Performance of novel kidney biomarkers in preclinical toxicity studies. Toxicol Sci 2010; 116 (01) 8-22.
    CrossrefPubMedSearch in Google Scholar
  • 18 Hofman MS, Hicks RJ. Gallium-68 EDTA PET/CT for Renal Imaging. Semin Nucl Med 2016; 46 (05) 448-461.
    CrossrefPubMedSearch in Google Scholar
  • 19 Islamian JP, Azazrm A, Mahmoudian B. et al. Advances in pinhole and multi-pinhole collimators for single photon emission computed tomography imaging. World J Nucl Med 2015; 14 (01) 3-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Itoh K. 99mTc-MAG3: review of pharmacokinetics, clinical application to renal diseases and quantification of renal function. Ann Nucl Med 2001; 15 (03) 179-190.
    CrossrefPubMedSearch in Google Scholar
  • 21 Jafri RA, Britton KE, Nimmon CC. et al. Technetium-99m MAG3, a comparison with iodine-123 and iodine-131 orthoiodohippurate, in patients with renal disorders. J Nucl Med 1988; 29 (02) 147-158.
    PubMedSearch in Google Scholar
  • 22 Kade H, Meredith Jr. OM, Taplin GV. et al. The radioisotope renogram: an external test for individual kidney function and upper urinary tract patency. J Lab Clin Med 1956; 48 (06) 886-901.
    PubMedSearch in Google Scholar
  • 23 Khalil MM, Tremoleda JL, Bayomy TB. et al. Molecular SPECT Imaging: An Overview. Int J Mol Imaging 2011; 2011: 796025.
    PubMedSearch in Google Scholar
  • 24 Klingensmith 3rd WC, Briggs DE, Smith WI. Technetium-99m-MAG3 renal studies: normal range and reproducibility of physiologic parameters as a function of age and sex. J Nucl Med 1994; 35 (10) 1612-1617.
    PubMedSearch in Google Scholar
  • 25 Koopman MG, Koomen GC, Krediet RT. et al. Circadian rhythm of glomerular filtration rate in normal individuals. Clin Sci (Lond) 1989; 77 (01) 105-111.
    CrossrefPubMedSearch in Google Scholar
  • 26 Kunikowska J, Krolicki L, Sowa-Staszczak A. et al. Nephrotoxicity after PRRT – still a serious clinical problem? Renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATATE and 90Y/177Lu-DOTATATE. Endokrynol Pol 2013; 64 (01) 13-20.
    PubMedSearch in Google Scholar
  • 27 Kunin CM. Nephrotoxicity of antibiotics. JAMA 1967; 202 (03) 204-208.
    CrossrefPubMedSearch in Google Scholar
  • 28 Lange C, Apostolova I, Lukas M. et al. Performance evaluation of stationary and semi-stationary acquisition with a non-stationary small animal multi-pinhole SPECT system. Mol Imaging Biol 2014; 16 (03) 311-316.
    CrossrefPubMedSearch in Google Scholar
  • 29 Lapides J, Zierdt D. Compatibility of normal renal function with aging. JAMA 1967; 201 (10) 778-779.
    CrossrefPubMedSearch in Google Scholar
  • 30 Levey AS, Perrone RD, Madias NE. Serum creatinine and renal function. Annu Rev Med 1988; 39: 465-490.
    CrossrefPubMedSearch in Google Scholar
  • 31 Lipowska M, Jarkas N, Voll RJ. et al. Re(CO)3([(18)F]FEDA), a novel (18)F PET renal tracer: Radiosynthesis and preclinical evaluation. Nucl Med Biol 2018; 58: 42-50.
    CrossrefPubMedSearch in Google Scholar
  • 32 Luippold G, Pech B, Schneider S. et al. Age dependency of renal function in CD-1 mice. American Journal of Physiology-Renal Physiology 2002; 282 (05) F886-F890.
    Search in Google Scholar
  • 33 Lythgoe MF, Gordon I, Anderson PJ. Effect of renal maturation on the clearance of technetium-99m mercaptoacetyltriglycine. Eur J Nucl Med 1994; 21 (12) 1333-1337.
    CrossrefPubMedSearch in Google Scholar
  • 34 Meikle SR, Kench P, Kassiou M. et al. Small animal SPECT and its place in the matrix of molecular imaging technologies. Phys Med Biol 2005; 50 (22) R45-61.
    CrossrefPubMedSearch in Google Scholar
  • 35 Melis M, de Swart J, de Visser M. et al. Dynamic and static small-animal SPECT in rats for monitoring renal function after 177Lu-labeled Tyr3-octreotate radionuclide therapy. J Nucl Med 2010; 51 (12) 1962-1968.
    CrossrefPubMedSearch in Google Scholar
  • 36 Neugarten J, Silbiger SR. Effects of sex hormones on mesangial cells. Am J Kidney Dis 1995; 26 (01) 147-151.
    CrossrefPubMedSearch in Google Scholar
  • 37 Newman DJ, Thakkar H, Edwards RG. et al. Serum cystatin C measured by automated immunoassay: a more sensitive marker of changes in GFR than serum creatinine. Kidney Int 1995; 47 (01) 312-318.
    CrossrefPubMedSearch in Google Scholar
  • 38 Nuyts J, Vunckx K, Defrise M. et al. Small animal imaging with multi-pinhole SPECT. Methods 2009; 48 (02) 83-91.
    CrossrefPubMedSearch in Google Scholar
  • 39 Peremans K, Cornelissen B, Van Den Bossche B. et al. A review of small animal imaging planar and pinhole spect Gamma camera imaging. Vet Radiol Ultrasound 2005; 46 (02) 162-170.
    CrossrefPubMedSearch in Google Scholar
  • 40 Rane A, Wilson JT. Clinical pharmacokinetics in infants and children. Clin Pharmacokinet 1976; 01 (01) 2-24.
    CrossrefPubMedSearch in Google Scholar
  • 41 Sakemi T, Baba N. Castration attenuates proteinuria and glomerular injury in hyperlipidemic male Imai rats. Nephron 1993; 64 (03) 429-435.
    CrossrefPubMedSearch in Google Scholar
  • 42 Sakemi T, Toyoshima H, Morito F. Testosterone eliminates the attenuating effect of castration on the progressive glomerular injury in hypercholesterolemic male Imai rats. Nephron 1994; 67 (04) 469-476.
    CrossrefPubMedSearch in Google Scholar
  • 43 Sakemi T, Toyoshima H, Shouno Y. et al. Estrogen attenuates progressive glomerular injury in hypercholesterolemic male Imai rats. Nephron 1995; 69 (02) 159-165.
    CrossrefPubMedSearch in Google Scholar
  • 44 Sanchez J, Friedman S, Kempf J. et al. Gallbladder activity appearing 6 minutes after the intravenous injection of Tc99m MAG3 simulating a picture of obstructive uropathy of the right kidney. Clin Nucl Med 1993; 18 (01) 30-34.
    CrossrefPubMedSearch in Google Scholar
  • 45 Sathekge M, Bruchertseifer F, Knoesen O. et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2018 doi: 10.1007/s00259–018–4167–0. Epub ahead of print.
    PubMedSearch in Google Scholar
  • 46 Shattuck LA, Eshima D, Taylor Jr AT. et al. Evaluation of the hepatobiliary excretion of technetium-99m-MAG3 and reconstitution factors affecting radiochemical purity. J Nucl Med 1994; 35 (02) 349-355.
    PubMedSearch in Google Scholar
  • 47 Silbiger SR, Neugarten J. The impact of gender on the progression of chronic renal disease. Am J Kidney Dis 1995; 25 (04) 515-533.
    CrossrefPubMedSearch in Google Scholar
  • 48 Sulemanji M, Vakili K. Neonatal renal physiology. Semin Pediatr Surg 2013; 22 (04) 195-198.
    CrossrefPubMedSearch in Google Scholar
  • 49 Swedko PJ, Clark HD, Paramsothy K. et al. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med 2003; 163 (03) 356-360.
    CrossrefPubMedSearch in Google Scholar
  • 50 Taylor A. Radionuclide renography: a personal approach. Semin Nucl Med 1999; 29 (02) 102-127.
    CrossrefPubMedSearch in Google Scholar
  • 51 Taylor AT. Radionuclides in nephrourology, part 1: Radiopharmaceuticals, quality control, and quantitative indices. J Nucl Med 2014; 55 (04) 608-615.
    CrossrefPubMedSearch in Google Scholar
  • 52 Wakabayashi H, Werner RA, Hayakawa N. et al. Initial Preclinical Evaluation of 18F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent. J Nucl Med 2016; 57 (10) 1625-1628.
    CrossrefPubMedSearch in Google Scholar
  • 53 Winter CC. A clinical study of a new renal function test: the radioactive diodrast renogram. J Urol 1956; 76 (02) 182-196.
    CrossrefPubMedSearch in Google Scholar