We are grateful to Kleinsasser and Burtscher ( 1 ) for their interest and insightful commentary on our publication "Comparing integrative ventilatory and renal acid-base acclimatization in lowlanders and Tibetan highlanders during ascent to 4,300 m" ( 2 ). Briefly, we demonstrated enhanced ventilatory acclimatization and renal compensation of blood acid-base homeostasis in age-and sex-matched Tibetan highlanders (TH), compared to ancestral lowlanders (LL) following ascent to 4,300 m ( 2 ). A key strength of our study was the recruitment of unacclimatized participants at 1,400 m, who then followed an identical ascent profile up to 4,300 m over 5-d, where we repeated measures on days 8 to 9. This protocol design allowed us to compare participants to their own unacclimatized baseline variables prior to ascent, as opposed to the more common protocol of recruiting a convenience sample of already-acclimatized participants at high altitude (e.g., refs. 3 -6 ).

First, as Kleinsasser and Burtscher ( 1 ) point out, the TH participants had differential respiratory and acid-base variables in Kathmandu (1,400 m) compared to LL, prior to ascent. Specifically, PCO 2 , [bicarbonate], TCO 2 , and base excess (BE) were all significantly lower in TH ( 2 ). They assert that these differences between groups were the result of prior acclimatization to 1,400 m (P ATM ~650 mmHg; PO 2 ~137 mmHg) in TH, who resided there for 6 mo to 1 y. Conversely, our lowlander participants arrived at 1,400 m from destinations varying between sea level to 1,100 m (P ATM ~760 to 665 mmHg; PO 2 ~160 to 140 mmHg) before being tested ~3+ d after arrival. However, a number of observations suggest that the LL participants were likely acclimatized to 1,400 m by the time we tested them: a) ventilatory acclimatization is complete within 3-d of exposure to 3,800 m (e.g., ref. Second, the assertion that BE, a clinical metric reported by blood gas machines, may have limited utility in the context of high-altitude ascent is well-taken, in part because reduced

[bicarbonate] levels with renal compensation during/following ascent may be better described as a "base deficit." In addition, whether calculating BE using the original Van Slyke equation, or applying a modified metric of titratable hydrogen ion difference (THID) advanced by Zubieta-Calleja et al. ( 10 ), these calculations assume a) normative textbook values of PCO 2 , [bicarbonate] and pH prior to ascent, and b) that participants achieve fully compensated pH at any altitude ( 10 ). Our study ( 2 ) demonstrates that neither of these assumptions are correct, corroborated by reports of a) large interindividual variability in blood acid-base variables, both at baseline and in response to high-altitude exposure (e.g., refs. 2 , 9 , and 11 ) and b) the inability of lowlanders to fully compensate over any known time-course of exposure over ~4,000 m (e.g., refs. 2 , 11 , and 12 ). These facts highlight the importance of comparing within-individual responses, where possible, as opposed to applying metrics that assume normative mean values.

Our demonstration that TH are fully compensated from a pH and [H + ] perspective (the variables of importance biochemically) after exposure to 4,300 m is remarkable and sets the stage for future comparisons of integrated acute physiological responses, acclimatization, and genetic adaptation between groups ascending to and residing at high altitude (e.g., ref. 13 ).