Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis

Menna R Clatworthy, Mikko I Kettunen, De-En Hu, Rebeccah J Mathews, Timothy H Witney, Brett W C Kennedy, Sarah E Bohndiek, Ferdia A Gallagher, Lorna B Jarvis, Kenneth G C Smith, Kevin M Brindle

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Abstract

Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.
Original languageEnglish
Pages (from-to)13374-13379
Number of pages6
JournalPNAS
Volume109
Issue number33
DOIs
Publication statusPublished - 14 Aug 2012

Fingerprint

Fumarates
Necrosis
Magnetic Resonance Imaging
Kidney
Glomerulonephritis
Pyruvic Acid
Acute Kidney Injury
Morbidity
Lupus Nephritis
Dialysis
Lactic Acid
Differential Diagnosis
Biomarkers
Inflammation
Costs and Cost Analysis
Mortality
Therapeutics

Keywords

  • animals
  • carbon isotopes
  • early diagnosis
  • folic acid
  • fumarates
  • humans
  • kidney
  • kidney tubular necrosis, acute
  • kinetics
  • lupus nephritis
  • magnetic resonance imaging
  • malates
  • mice
  • mice, inbred C57BL
  • pyruvic acid

Cite this

Clatworthy, M. R., Kettunen, M. I., Hu, D-E., Mathews, R. J., Witney, T. H., Kennedy, B. W. C., ... Brindle, K. M. (2012). Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis. PNAS, 109(33), 13374-13379. https://doi.org/10.1073/pnas.1205539109

Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis. / Clatworthy, Menna R; Kettunen, Mikko I; Hu, De-En; Mathews, Rebeccah J; Witney, Timothy H; Kennedy, Brett W C; Bohndiek, Sarah E; Gallagher, Ferdia A; Jarvis, Lorna B; Smith, Kenneth G C; Brindle, Kevin M.

In: PNAS, Vol. 109, No. 33, 14.08.2012, p. 13374-13379.

Research output: Contribution to journalArticle

Clatworthy, MR, Kettunen, MI, Hu, D-E, Mathews, RJ, Witney, TH, Kennedy, BWC, Bohndiek, SE, Gallagher, FA, Jarvis, LB, Smith, KGC & Brindle, KM 2012, 'Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis', PNAS, vol. 109, no. 33, pp. 13374-13379. https://doi.org/10.1073/pnas.1205539109
Clatworthy MR, Kettunen MI, Hu D-E, Mathews RJ, Witney TH, Kennedy BWC et al. Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis. PNAS. 2012 Aug 14;109(33):13374-13379. https://doi.org/10.1073/pnas.1205539109
Clatworthy, Menna R ; Kettunen, Mikko I ; Hu, De-En ; Mathews, Rebeccah J ; Witney, Timothy H ; Kennedy, Brett W C ; Bohndiek, Sarah E ; Gallagher, Ferdia A ; Jarvis, Lorna B ; Smith, Kenneth G C ; Brindle, Kevin M. / Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis. In: PNAS. 2012 ; Vol. 109, No. 33. pp. 13374-13379.
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AU - Mathews, Rebeccah J

AU - Witney, Timothy H

AU - Kennedy, Brett W C

AU - Bohndiek, Sarah E

AU - Gallagher, Ferdia A

AU - Jarvis, Lorna B

AU - Smith, Kenneth G C

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AB - Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.

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KW - early diagnosis

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KW - fumarates

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KW - kinetics

KW - lupus nephritis

KW - magnetic resonance imaging

KW - malates

KW - mice

KW - mice, inbred C57BL

KW - pyruvic acid

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