Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria

Matthew P. Rubach, Haoyue Zhang, Salvatore M. Florence, Jackson P. Mukemba, Ayam R. Kalingonji, Nicholas M. Anstey, Tsin W. Yeo, Bert K. Lopansri, J. Will Thompson, Esther D. Mwaikambo, Sarah Young, David S. Millington, J. Brice Weinberg, Donald L. Granger

    Research output: Contribution to journalArticle

    Abstract

    The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n 61), children with cerebral falciparum malaria (CM; n 45), and healthy children (HC; n 109). We also administered primed infusions of L-arginine uniformly labeled with 13 C 6 and 15 N 4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 M (interquartile range [IQR], 400 to 508 M) in HC, 300 M (IQR, 256 to 365 M) in UM, and 257 M (IQR, 195 to 320 M) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 mol/h/kg of body weight (IQR, 84.4 to 129.3 mol/h/ kg) versus 88.0 mol/h/kg (IQR, 73.0 to 102.2 mol/h/kg) (P 0.247) by the two mass spectrometric methods in SM and 93.7 mol/h/kg (IQR, 79.1 to 117.8 mol/h/ kg) versus 81.0 mol/h/kg (IQR, 75.9 to 88.6 mol/h/kg) (P 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.

    Original languageEnglish
    Article numbere00655-18
    Pages (from-to)1-16
    Number of pages16
    JournalInfection and Immunity
    Volume87
    Issue number4
    Early online date25 Mar 2019
    DOIs
    Publication statusPublished - 1 Apr 2019

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    Falciparum Malaria
    Arginine
    Cross-Sectional Studies
    Pediatrics
    Glutamine
    Nitric Oxide
    Cerebral Malaria
    Amino Acids
    Citrulline
    Ornithine
    Proline
    Biological Availability
    Malaria
    Glutamic Acid
    Body Weight

    Cite this

    Rubach, M. P., Zhang, H., Florence, S. M., Mukemba, J. P., Kalingonji, A. R., Anstey, N. M., ... Granger, D. L. (2019). Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria. Infection and Immunity, 87(4), 1-16. [e00655-18]. https://doi.org/10.1128/IAI.00655-18
    Rubach, Matthew P. ; Zhang, Haoyue ; Florence, Salvatore M. ; Mukemba, Jackson P. ; Kalingonji, Ayam R. ; Anstey, Nicholas M. ; Yeo, Tsin W. ; Lopansri, Bert K. ; Thompson, J. Will ; Mwaikambo, Esther D. ; Young, Sarah ; Millington, David S. ; Weinberg, J. Brice ; Granger, Donald L. / Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria. In: Infection and Immunity. 2019 ; Vol. 87, No. 4. pp. 1-16.
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    abstract = "The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n 61), children with cerebral falciparum malaria (CM; n 45), and healthy children (HC; n 109). We also administered primed infusions of L-arginine uniformly labeled with 13 C 6 and 15 N 4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 M (interquartile range [IQR], 400 to 508 M) in HC, 300 M (IQR, 256 to 365 M) in UM, and 257 M (IQR, 195 to 320 M) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 mol/h/kg of body weight (IQR, 84.4 to 129.3 mol/h/ kg) versus 88.0 mol/h/kg (IQR, 73.0 to 102.2 mol/h/kg) (P 0.247) by the two mass spectrometric methods in SM and 93.7 mol/h/kg (IQR, 79.1 to 117.8 mol/h/ kg) versus 81.0 mol/h/kg (IQR, 75.9 to 88.6 mol/h/kg) (P 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.",
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    author = "Rubach, {Matthew P.} and Haoyue Zhang and Florence, {Salvatore M.} and Mukemba, {Jackson P.} and Kalingonji, {Ayam R.} and Anstey, {Nicholas M.} and Yeo, {Tsin W.} and Lopansri, {Bert K.} and Thompson, {J. Will} and Mwaikambo, {Esther D.} and Sarah Young and Millington, {David S.} and Weinberg, {J. Brice} and Granger, {Donald L.}",
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    Rubach, MP, Zhang, H, Florence, SM, Mukemba, JP, Kalingonji, AR, Anstey, NM, Yeo, TW, Lopansri, BK, Thompson, JW, Mwaikambo, ED, Young, S, Millington, DS, Weinberg, JB & Granger, DL 2019, 'Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria', Infection and Immunity, vol. 87, no. 4, e00655-18, pp. 1-16. https://doi.org/10.1128/IAI.00655-18

    Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria. / Rubach, Matthew P.; Zhang, Haoyue; Florence, Salvatore M.; Mukemba, Jackson P.; Kalingonji, Ayam R.; Anstey, Nicholas M.; Yeo, Tsin W.; Lopansri, Bert K.; Thompson, J. Will; Mwaikambo, Esther D.; Young, Sarah; Millington, David S.; Weinberg, J. Brice; Granger, Donald L.

    In: Infection and Immunity, Vol. 87, No. 4, e00655-18, 01.04.2019, p. 1-16.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Kinetic and cross-sectional studies on the genesis of hypoargininemia in severe pediatric Plasmodium falciparum malaria

    AU - Rubach, Matthew P.

    AU - Zhang, Haoyue

    AU - Florence, Salvatore M.

    AU - Mukemba, Jackson P.

    AU - Kalingonji, Ayam R.

    AU - Anstey, Nicholas M.

    AU - Yeo, Tsin W.

    AU - Lopansri, Bert K.

    AU - Thompson, J. Will

    AU - Mwaikambo, Esther D.

    AU - Young, Sarah

    AU - Millington, David S.

    AU - Weinberg, J. Brice

    AU - Granger, Donald L.

    PY - 2019/4/1

    Y1 - 2019/4/1

    N2 - The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n 61), children with cerebral falciparum malaria (CM; n 45), and healthy children (HC; n 109). We also administered primed infusions of L-arginine uniformly labeled with 13 C 6 and 15 N 4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 M (interquartile range [IQR], 400 to 508 M) in HC, 300 M (IQR, 256 to 365 M) in UM, and 257 M (IQR, 195 to 320 M) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 mol/h/kg of body weight (IQR, 84.4 to 129.3 mol/h/ kg) versus 88.0 mol/h/kg (IQR, 73.0 to 102.2 mol/h/kg) (P 0.247) by the two mass spectrometric methods in SM and 93.7 mol/h/kg (IQR, 79.1 to 117.8 mol/h/ kg) versus 81.0 mol/h/kg (IQR, 75.9 to 88.6 mol/h/kg) (P 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.

    AB - The low bioavailability of nitric oxide (NO) and its precursor, arginine, contributes to the microvascular pathophysiology of severe falciparum malaria. To better characterize the mechanisms underlying hypoargininemia in severe malaria, we measured the plasma concentrations of amino acids involved in de novo arginine synthesis in children with uncomplicated falciparum malaria (UM; n 61), children with cerebral falciparum malaria (CM; n 45), and healthy children (HC; n 109). We also administered primed infusions of L-arginine uniformly labeled with 13 C 6 and 15 N 4 to 8 children with severe falciparum malaria (SM; age range, 4 to 9 years) and 7 healthy children (HC; age range, 4 to 8 years) to measure the metabolic flux of arginine, hypothesizing that arginine flux is increased in SM. Using two different tandem mass spectrometric methods, we measured the isotopic enrichment of arginine in plasma obtained at 0, 60, 90, 120, 150, and 180 min during the infusion. The plasma concentrations of glutamine, glutamate, proline, ornithine, citrulline, and arginine were significantly lower in UM and CM than in HC (P 0.04 for all pairwise comparisons). Of these, glutamine concentrations were the most markedly decreased: median, 457 M (interquartile range [IQR], 400 to 508 M) in HC, 300 M (IQR, 256 to 365 M) in UM, and 257 M (IQR, 195 to 320 M) in CM. Arginine flux during steady state was not significantly different in SM than in HC by the respective mass spectrometric methods: 93.2 mol/h/kg of body weight (IQR, 84.4 to 129.3 mol/h/ kg) versus 88.0 mol/h/kg (IQR, 73.0 to 102.2 mol/h/kg) (P 0.247) by the two mass spectrometric methods in SM and 93.7 mol/h/kg (IQR, 79.1 to 117.8 mol/h/ kg) versus 81.0 mol/h/kg (IQR, 75.9 to 88.6 mol/h/kg) (P 0.165) by the two mass spectrometric methods in HC. A limited supply of amino acid precursors for arginine synthesis likely contributes to the hypoargininemia and NO insufficiency in falciparum malaria in children.

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