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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–base 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–base acclimatization (PCO₂, [HCO₃⁻], 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 PCO₂(P<0.0001) and [HCO₃⁻] (P<0.0001), and higher pH (P= 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO₂(P< 0.0001) and [HCO₃⁻] (P< 0.0001), but unchanged pH (P= 0.1), suggesting full renal compensation, with significantly lower PCO₂(P= 0.01), [HCO₃⁻] (P< 0.0001) and pH (P= 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory–renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization. 

High altitude native populations exhibit physiological adaptations to environmental hypoxia. It has been hypothesized that two of these populations, Andeans and Tibetans, demonstrate distinct adaptive modes with the former characterized by increased blood oxygen content, and the latter characterized by increased blood flow. To investigate this hypothesis, we recruited two groups of healthy adults (ages 18-35) with highland ancestry who were born and currently reside at high altitude. The groups were: Andean Quechuas recruited in Cerro de Pasco, Peru (AND, n = 301) and Tibetan Sherpas recruited in Pheriche, Nepal (SHP, n = 64). Participants were tested in field laboratories using identical equipment and protocols, at nearly identical altitudes (4,330m and 4,371m, respectively). We assessed a wide variety of physiological variables at rest, submaximal exercise, and maximal exercise. We found that although some phenotypes aligned with the above hypothesis, the majority did not. For example, as predicted, AND displayed significantly lower (p<0.001) ventilatory equivalents for oxygen (VE/VO2) at rest. However, this trend reversed at maximal exercise, with AND displaying significantly higher (p<0.001) VE/VO2 than SHP. Further, contrary to the above hypothesis, we found no statistically significant differences in flow-mediated dilation between the groups. These results suggest that the adaptive modes of these populations are perhaps not as distinct as previously supposed. Given that this hypothesis was formulated on the basis of data taken at rest, our data highlights the importance of assessing physiology both at rest and exercise, to gain a more complete understanding of adaptation to high altitude.