Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’
Abstract Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given thes...
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| Format: | Article |
| Language: | English |
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Wiley
2022-10-01
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| Series: | Physiological Reports |
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| Online Access: | https://doi.org/10.14814/phy2.15507 |
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| author | Richard A. Zager |
| author_facet | Richard A. Zager |
| author_sort | Richard A. Zager |
| collection | DOAJ |
| description | Abstract Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given these facts, a multitude of experimental studies have addressed potential methods for inducing AKI prevention in high‐risk patients. However, successful clinical translation of promising experimental data has remained elusive. Over the past decade, our laboratory has focused on developing a method for safely triggering AKI protection by inducing “kidney preconditioning” in mice by the intravenous administration of a combination of Fe sucrose (FeS) + tin protoporphyrin (SnPP). These agents induce mild, but short lived, ‘oxidant stress’ which synergistically activate a number of kidney ‘self‐defense’ pathways (e.g., Nrf2, ferritin, IL‐10). Within 18–24 h of Fe/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS/SnPP‐mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called “organ cross talk” phenomenon. Given these promising experimental data, three phase 1b clinical trials were undertaken in healthy subjects and patients with stage 3 or 4 CKD. These studies demonstrated that FeS/SnPP were well tolerated and that they up‐regulated the cytoprotective Nrf2, ferritin, and IL‐10 pathways. Two subsequent phase 2 trials, conducted in patients undergoing ‘on‐pump’ cardiovascular surgery or in patients hospitalized with COVID 19, confirmed FeS/SnPP safety. Furthermore, interim data analyses revealed statistically significant improvements in several clinical parameters. The goals of this review are to: (i) briefly discuss the historical background of renal “preconditioning”; (ii) present the experimental data that support the concept of FeS/SnPP‐ induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an ‘oxidant preconditioning’ strategy. |
| first_indexed | 2024-03-09T01:04:36Z |
| format | Article |
| id | doaj.art-48491c9313ca40208c56179e94b443ce |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-09T01:04:36Z |
| publishDate | 2022-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-48491c9313ca40208c56179e94b443ce2023-12-11T10:47:17ZengWileyPhysiological Reports2051-817X2022-10-011020n/an/a10.14814/phy2.15507Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’Richard A. Zager0Department of Medicine University of Washington Seattle Washington USAAbstract Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given these facts, a multitude of experimental studies have addressed potential methods for inducing AKI prevention in high‐risk patients. However, successful clinical translation of promising experimental data has remained elusive. Over the past decade, our laboratory has focused on developing a method for safely triggering AKI protection by inducing “kidney preconditioning” in mice by the intravenous administration of a combination of Fe sucrose (FeS) + tin protoporphyrin (SnPP). These agents induce mild, but short lived, ‘oxidant stress’ which synergistically activate a number of kidney ‘self‐defense’ pathways (e.g., Nrf2, ferritin, IL‐10). Within 18–24 h of Fe/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS/SnPP‐mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called “organ cross talk” phenomenon. Given these promising experimental data, three phase 1b clinical trials were undertaken in healthy subjects and patients with stage 3 or 4 CKD. These studies demonstrated that FeS/SnPP were well tolerated and that they up‐regulated the cytoprotective Nrf2, ferritin, and IL‐10 pathways. Two subsequent phase 2 trials, conducted in patients undergoing ‘on‐pump’ cardiovascular surgery or in patients hospitalized with COVID 19, confirmed FeS/SnPP safety. Furthermore, interim data analyses revealed statistically significant improvements in several clinical parameters. The goals of this review are to: (i) briefly discuss the historical background of renal “preconditioning”; (ii) present the experimental data that support the concept of FeS/SnPP‐ induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an ‘oxidant preconditioning’ strategy.https://doi.org/10.14814/phy2.15507ferritinIL‐10iron sucroseNrf2tin protoporphyrin heme oxygenase 1 |
| spellingShingle | Richard A. Zager Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’ Physiological Reports ferritin IL‐10 iron sucrose Nrf2 tin protoporphyrin heme oxygenase 1 |
| title | Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’ |
| title_full | Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’ |
| title_fullStr | Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’ |
| title_full_unstemmed | Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’ |
| title_short | Oxidant‐ induced preconditioning: A pharmacologic approach for triggering renal ‘self defense’ |
| title_sort | oxidant induced preconditioning a pharmacologic approach for triggering renal self defense |
| topic | ferritin IL‐10 iron sucrose Nrf2 tin protoporphyrin heme oxygenase 1 |
| url | https://doi.org/10.14814/phy2.15507 |
| work_keys_str_mv | AT richardazager oxidantinducedpreconditioningapharmacologicapproachfortriggeringrenalselfdefense |