The hypoxanthine-xanthine oxidase axis is not involved in the initial phase of clinical transplantation-related ischemia-reperfusion injury
Copyright © 2017 the American Physiological Society..
The hypoxanthine-xanthine oxidase (XO) axis is considered to be a key driver of transplantation-related ischemia-reperfusion (I/R) injury. Whereas interference with this axis effectively quenches I/R injury in preclinical models, there is limited efficacy of XO inhibitors in clinical trials. In this context, we considered clinical evaluation of a role for the hypoxanthine-XO axis in human I/R to be relevant. Patients undergoing renal allograft transplantation were included (n = 40) and classified based on duration of ischemia (short, intermediate, and prolonged). Purine metabolites excreted by the reperfused kidney (arteriovenous differences) were analyzed by the ultra performance liquid chromatography-tandem mass spectrometer (UPLCMS/MS) method and tissue XO activity was assessed by in situ enzymography. We confirmed progressive hypoxanthine accumulation (P < 0.006) during ischemia, using kidney transplantation as a clinical model of I/R. Yet, arteriovenous concentration differences of uric acid and in situ enzymography of XO did not indicate significant XO activity in ischemic and reperfused kidney grafts. Furthermore, we tested a putative association between hypoxanthine accumulation and renal oxidative stress by assessing renal malondialdehyde and isoprostane levels and allantoin formation during the reperfusion period. Absent release of these markers is not consistent with an association between ischemic hypoxanthine accumulation and postreperfusion oxidative stress. On basis of these data for the human kidney we hypothesize that the role for the hypoxanthine-XO axis in clinical I/R injury is less than commonly thought, and as such the data provide an explanation for the apparent limited clinical efficacy of XO inhibitors.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:312 |
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| Enthalten in: |
American journal of physiology. Renal physiology - 312(2017), 3 vom: 01. März, Seite F457-F464 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wijermars, Leonie G M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 10.07.2017 Date Revised 09.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1152/ajprenal.00214.2016 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM267535813 |
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| 245 | 1 | 4 | |a The hypoxanthine-xanthine oxidase axis is not involved in the initial phase of clinical transplantation-related ischemia-reperfusion injury |
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| 520 | |a Copyright © 2017 the American Physiological Society. | ||
| 520 | |a The hypoxanthine-xanthine oxidase (XO) axis is considered to be a key driver of transplantation-related ischemia-reperfusion (I/R) injury. Whereas interference with this axis effectively quenches I/R injury in preclinical models, there is limited efficacy of XO inhibitors in clinical trials. In this context, we considered clinical evaluation of a role for the hypoxanthine-XO axis in human I/R to be relevant. Patients undergoing renal allograft transplantation were included (n = 40) and classified based on duration of ischemia (short, intermediate, and prolonged). Purine metabolites excreted by the reperfused kidney (arteriovenous differences) were analyzed by the ultra performance liquid chromatography-tandem mass spectrometer (UPLCMS/MS) method and tissue XO activity was assessed by in situ enzymography. We confirmed progressive hypoxanthine accumulation (P < 0.006) during ischemia, using kidney transplantation as a clinical model of I/R. Yet, arteriovenous concentration differences of uric acid and in situ enzymography of XO did not indicate significant XO activity in ischemic and reperfused kidney grafts. Furthermore, we tested a putative association between hypoxanthine accumulation and renal oxidative stress by assessing renal malondialdehyde and isoprostane levels and allantoin formation during the reperfusion period. Absent release of these markers is not consistent with an association between ischemic hypoxanthine accumulation and postreperfusion oxidative stress. On basis of these data for the human kidney we hypothesize that the role for the hypoxanthine-XO axis in clinical I/R injury is less than commonly thought, and as such the data provide an explanation for the apparent limited clinical efficacy of XO inhibitors | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a de Vries, Dorottya K |e verfasserin |4 aut | |
| 700 | 1 | |a van Noorden, Cornelis J F |e verfasserin |4 aut | |
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| 700 | 1 | |a Schaapherder, Alexander F |e verfasserin |4 aut | |
| 700 | 1 | |a Lindeman, Jan H N |e verfasserin |4 aut | |
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