{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T21:18:09Z","timestamp":1792876689989,"version":"4.5.0"},"reference-count":81,"publisher":"National Academy of Sciences","issue":"1","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000209","name":"NASEM | National Academy of Sciences","doi-asserted-by":"publisher","award":["2216548"],"award-info":[{"award-number":["2216548"]}],"id":[{"id":"10.13039\/100000209","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Canadian Government | Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2016-04915"],"award-info":[{"award-number":["RGPIN-2016-04915"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,1,7]]},"abstract":"<jats:p>\n                    With over 14 million people living above 3,500 m, the study of acclimatization and adaptation to high altitude in human populations is of increasing importance, where exposure to high altitude (HA) imposes a blood oxygenation and acid\u2013base challenge. A sustained and augmented hypoxic ventilatory response protects oxygenation through ventilatory acclimatization, but elicits hypocapnia and respiratory alkalosis. A subsequent renally mediated compensatory metabolic acidosis corrects pH toward baseline values, with a high degree of interindividual variability. Differential renal compensation between acclimatizing lowlanders (LL) and Tibetan highlanders (TH; Sherpa) with ascent was previously unknown. We assessed ventilatory and renal acclimatization between unacclimatized LL and TH during incremental ascent from 1,400 m to 4,300 m in age- and sex-matched groups of 15-LL (8F) and 14-TH (7F) of confirmed Tibetan ancestry. We compared respiratory and renally mediated blood acid\u2013base acclimatization (PCO\n                    <jats:sub>2<\/jats:sub>\n                    , [HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ], pH) in both groups before (1,400 m) and following day 8 to 9 of incremental ascent to 4,300 m. We found that following ascent to 4,300 m, LL had significantly lower PCO\n                    <jats:sub>2<\/jats:sub>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.0001) and [HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ] (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.0001), and higher pH (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO\n                    <jats:sub>2<\/jats:sub>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001) and [HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ] (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001), but unchanged pH (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.1), suggesting full renal compensation, with significantly lower PCO\n                    <jats:sub>2<\/jats:sub>\n                    (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.01), [HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ] (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001) and pH (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory\u2013renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2412561121","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T15:00:46Z","timestamp":1735570846000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Comparing integrative ventilatory and renal acid\u2013base acclimatization in lowlanders and Tibetan highlanders during ascent to 4,300 m"],"prefix":"10.1073","volume":"122","author":[{"given":"Nicole A.","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology, Mount Royal University","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Dickenson","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology, Mount Royal University","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin W.L.","family":"MacKenzie","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology, Mount Royal University","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodion","family":"Isakovich","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology, Mount Royal University","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7936-8025","authenticated-orcid":false,"given":"Anne","family":"Kalker","sequence":"additional","affiliation":[{"name":"Radboud University Medical Center","place":["Nijmegen, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne","family":"Bouten","sequence":"additional","affiliation":[{"name":"Department of Movement and Sports Sciences, Ghent University","place":["Ghent, Belgium"]},{"name":"Laboratory of Sport, Expertise and Performance, French Institute of Sport (INSEP)","place":["Paris, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4998-2300","authenticated-orcid":false,"given":"Nicholas D.J.","family":"Strzalkowski","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology, Mount Royal University","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor S.","family":"Harman","sequence":"additional","affiliation":[{"name":"Department of Exercise Science, Syracuse University","place":["Syracuse"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pontus","family":"Holmstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Mid Sweden University","place":["\u00d6stersund, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajaya J.","family":"Kunwar","sequence":"additional","affiliation":[{"name":"Kathmandu Center for Genomics and Research Laboratory, Global Hospital","place":["Lalitpur, Nepal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nilam","family":"Thakur","sequence":"additional","affiliation":[{"name":"Kathmandu Center for Genomics and Research Laboratory, Global Hospital","place":["Lalitpur, Nepal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Dhungel","sequence":"additional","affiliation":[{"name":"College of Medicine, Nepalese Army Institute of Health Sciences","place":["Kathmandu, Nepal"]},{"name":"Medical University of the Americas, Charlestown, Nevis, Saint Kitts and Nevis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nima","family":"Sherpa","sequence":"additional","affiliation":[{"name":"Glory of Nepal Travels and Tours","place":["Kathmandu, Nepal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-5844","authenticated-orcid":false,"given":"Abigail W.","family":"Bigham","sequence":"additional","affiliation":[{"name":"Department of Anthropology, University of Los Angeles","place":["Los Angeles, CA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom D.","family":"Brutsaert","sequence":"additional","affiliation":[{"name":"Department of Exercise Science, Syracuse University","place":["Syracuse"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7102-4235","authenticated-orcid":false,"given":"Trevor A.","family":"Day","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology, Mount Royal University","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2102463118"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat8824"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/ham.2010.1094"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag0357"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701985104"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00018.2014"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00146.2018"},{"key":"e_1_3_4_8_2","first-page":"201","article-title":"Tibetan and Andean patterns of adaptation to high-altitude hypoxia","volume":"72","author":"Beall C. M.","year":"2000","unstructured":"C. M. Beall, Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 72, 201\u2013228 (2000).","journal-title":"Hum Biol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.059188"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1580\/PR04-04.1"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mjafi.2018.03.008"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00757.2021"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199105163242003"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2013.05.020"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP276973"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00973.2020"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1993.74.1.303"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00012.2009"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1089\/ham.2021.0115"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021698"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(98)00026-7"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.10191"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2007.01.009"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1975.38.6.1067"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0801581"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1988.64.4.1309"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(67)90036-9"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-201X.1997.574342000.x"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP285341"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep16249"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1975.38.4.665"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1972.47"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00553.2007"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP284767"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2017.07.006"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1980.49.3.374"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(90)90015-Q"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(94)00110-L"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8644(199712)104:4<427::AID-AJPA1>3.0.CO;2-P"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1997.83.6.2098"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0034-5687(00)00133-X"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.185504"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-91137-3_2"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.15521"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1113\/EP088488"},{"key":"e_1_3_4_46_2","volume-title":"The ABC of Acid-Base Chemistry: The Elements of Physiological Blood-gas Chemistry for Medical Students and Physicians","author":"Davenport H. W.","year":"1974","unstructured":"H. W. Davenport, The ABC of Acid-Base Chemistry: The Elements of Physiological Blood-gas Chemistry for Medical Students and Physicians (University of Chicago Press, 1974)."},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.01126.2013"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2012010029"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1975.130"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.22435"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/0034-5687(69)90066-8"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-201X.2004.01361.x"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1089\/ham.2006.7.64"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00174.2010"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP277691"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00021.2023"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1002\/cphy.c100043"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00119.2019"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00605.2013"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1189406"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-011-1109-3"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1113\/EP085035"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1190371"},{"key":"e_1_3_4_64_2","first-page":"S61","article-title":"Physiology and molecular biology of renal carbonic anhydrase","volume":"15","author":"Schwartz G. J.","year":"2002","unstructured":"G. J. Schwartz, Physiology and molecular biology of renal carbonic anhydrase. J. Nephrol. 15, S61\u2013S74 (2002).","journal-title":"J. Nephrol."},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.310.6986.1071c"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1113\/JP281446"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0000000000003460"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.310.6971.24"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.310.6986.1072a"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2002.016261"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2006.07.002"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2012.08.025"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1080\/20018525.2019.1644892"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199711000-00032"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.jsm.0000171287.99174.b7"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.96.09020186"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resp.2010.05.017"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.1952.tb00847.x"},{"key":"e_1_3_4_79_2","first-page":"345","article-title":"A clinical method for assessing the ventilatory response to hypoxia","volume":"109","author":"Rebuck A. S.","year":"1974","unstructured":"A. S. Rebuck, E. J. Campbell, A clinical method for assessing the ventilatory response to hypoxia. Am. Rev. Respir Dis 109, 345\u2013350 (1974).","journal-title":"Am. Rev. Respir Dis"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2015.03.005"},{"key":"e_1_3_4_81_2","volume-title":"Physiology, Oxygen Transport in StatPearls","author":"Rhodes C. E.","year":"2024","unstructured":"C. E. Rhodes, D. Denault, M. Varacallo, Physiology, Oxygen Transport in StatPearls (StatPearls Publishing, 2024)."}],"updated-by":[{"DOI":"10.1073\/pnas.2505576122","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T00:00:00Z","timestamp":1743984000000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2412561121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T15:02:17Z","timestamp":1735570937000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2412561121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":81,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,7]]}},"alternative-id":["10.1073\/pnas.2412561121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2412561121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,30]]},"assertion":[{"value":"2024-08-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2412561121"}}