{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:25:55Z","timestamp":1786926355052,"version":"build-2736575974"},"reference-count":73,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005895","name":"Fred Hutchinson Cancer Research Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005895","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK38532"],"award-info":[{"award-number":["DK38532"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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\u2010risk 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 \u201ckidney preconditioning\u201d in mice by the intravenous administration of a combination of Fe sucrose (FeS)\u2009+\u2009tin protoporphyrin (SnPP). These agents induce mild, but short lived, \u2018oxidant stress\u2019 which synergistically activate a number of kidney \u2018self\u2010defense\u2019 pathways (e.g., Nrf2, ferritin, IL\u201010). Within 18\u201324\u2009h of Fe\/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS\/SnPP\u2010mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called \u201corgan cross talk\u201d 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\u2010regulated the cytoprotective Nrf2, ferritin, and IL\u201010 pathways. Two subsequent phase 2 trials, conducted in patients undergoing \u2018on\u2010pump\u2019 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 \u201cpreconditioning\u201d; (ii) present the experimental data that support the concept of FeS\/SnPP\u2010 induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an \u2018oxidant preconditioning\u2019 strategy.<\/jats:p>","DOI":"10.14814\/phy2.15507","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T13:26:36Z","timestamp":1666963596000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Oxidant\u2010 induced preconditioning: A pharmacologic approach for triggering renal \u2018self defense\u2019"],"prefix":"10.14814","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4530-5612","authenticated-orcid":false,"given":"Richard A.","family":"Zager","sequence":"first","affiliation":[{"name":"Department of Medicine University of Washington  Seattle Washington USA"},{"name":"Fred Hutchinson Cancer Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015070740"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00025.2012"},{"key":"e_1_2_13_4_1","first-page":"327","article-title":"Tissue distribution and disposition of tin\u2010protoporphyrin, a potent competitive inhibitor of heme oxygenase","volume":"288","author":"Anderson K. E.","year":"1984","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-017-1389-9"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c110041"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2016.10.037"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000102069"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.21411"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186941"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2000.00996.x"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5674"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(02)01295-9"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3700205"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2015.11.019"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22042009"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.133050"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1089\/104454902753759726"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1987.136"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-010-9266-4"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00248.2010"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00307.2019"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2017.05.005"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfy029"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.2003.00882.x"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxh196"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40360-015-0040-y"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-5097fje"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2016.6659"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.804685"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.157"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.357"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.3071"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)68467-4"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5001565"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mnh.0000437613.88158.d3"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115847"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.23876\/j.krcp.20.091"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.328"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2018.05.011"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/9372182"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2011.11.010"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11030555"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014101037"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00615"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2011.16"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2019.05.013"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2009.11.004"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22661"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1159\/000490808"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11923"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1978.87"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2015.01.010"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122772"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1177\/09603271211047915"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.12994"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.49.3.411"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.102170"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.678914"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1995.80"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1996.48"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gft101"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2015.06.004"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1984.204"},{"issue":"72","key":"e_1_2_13_65_1","first-page":"592","article-title":"Postischemic proximal tubular resistance to oxidant stress and Ca2+ ionophore\u2010induced attack. Implications for reperfusion injury","volume":"1995","author":"Zager R. A.","year":"1995","journal-title":"Laboratory Investigation; a Journal of Technical Methods and Pathology"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523-1755.1999.00745.x"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1994.229"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00378.2014"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2016.01.022"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00716.x"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.14566"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.15951219"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfaa348"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0000000000000504"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.15507","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.14814\/phy2.15507","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.15507","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T10:54:03Z","timestamp":1704884043000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.15507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10]]},"references-count":73,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2022,10]]}},"alternative-id":["10.14814\/phy2.15507"],"URL":"https:\/\/doi.org\/10.14814\/phy2.15507","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10]]},"assertion":[{"value":"2022-09-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e15507"}}