https://orcid.org/0000-0002-9916-7390
Figures
Abstract
Short-term heat acclimation (HA) induces cardiovascular and fluid-regulatory adaptations, but it’s impact on markers of renal tubular injury and acute kidney injury risk (AKI) during exercise-heat stress remains unclear. Fourteen healthy endurance-trained male athletes were randomised to five days of isothermic HA (HOT; n = 7; 32 °C, 70% relative humidity; target core temperature ≥38.5 °C), or exercise in thermoneutral conditions (TEMP, n = 7). Heat stress tests (HST; 45 min cycling at 32 °C, 70% RH) were performed pre- and post-intervention. Blood biomarkers of kidney tubular stress (NGAL, KIM-1), fluid-regulation (copeptin, serum osmolality) and sympathetic activity (plasma normetanephrine) were measured at rest and immediately post-HST. HA reduced resting heart rate (−8 ± 5 bpm, p = 0.007, d = 1.0), increased plasma volume (+7.3 ± 5.1%, p = 0.022) and sweat loss (+500 ± 539 mL, p = 0.018, d = 1.1). Copeptin rose during the pre-intervention HST in both groups (HOT: + 11 ± 6; TEMP: + 12 ± 13 pmol·L ⁻ ¹, p < 0.05), but not post-intervention. NGAL increased only in TEMP during HST1 (+45 ± 29 μg·L ⁻ ¹, p = 0.030), while KIM-1 remained unchanged. No group x time interactions were observed for any biomarkers (p > 0.05). Five days of HA improved cardiovascular and thermoregulatory responses but did not alter renal stress markers or fluid-regulatory responses during exercise in the heat. These findings suggest short-term HA enhances heat tolerance but may not attenuate renal biomarker responses associated with early tubular stress under hot, humid conditions.
Citation: Snape D, Wainwright B, Parsons IT, Stacey MJ, Woods DR, O’Hara J (2026) Five days of heat acclimation improves cardiovascular and thermoregulatory responses without altering renal stress biomarkers in endurance athletes. PLoS One 21(8): e0345346. https://doi.org/10.1371/journal.pone.0345346
Editor: Hidenori Otani, Himeji Dokkyo University, JAPAN
Received: March 13, 2026; Accepted: July 27, 2026; Published: August 11, 2026
Copyright: © 2026 Snape et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Endurance athletes frequently train and compete in hot, humid environments where metabolic heat production and environmental heat stress impose significant thermal and cardiovascular strain. Inadequate heat dissipation elevates core temperature, impairing performance and increasing the risk of heat-related illness, including exertional heat stroke, which can lead to systemic inflammation and multi-organ dysfunction [1]. During exercise, redistribution of cardiac output to active muscle and skin reduces renal blood flow by 25–50% compared with rest, an effect exacerbated in the heat as skin blood flow and sweating rates increase [2]. Fluid loss through sweat and plasma volume contraction further diminishes renal perfusion, while neurohumoral activation via sympathetic outflow, catecholamine release, and arginine vasopressin (AVP) secretion acts to conserve fluid but simultaneously exacerbates renal vasoconstriction [3]. These responses increase tubular strain, induce transient renal dysfunction, reflected by elevated serum creatinine and reduced glomerular filtration rate consistent with AKI [4–6].
Significant rises in serum creatinine have been reported following endurance events, often exceeding the diagnostic threshold for stage I AKI after marathons, ultra-endurance races, and long-distance cycling [7,8]. Creatinine often rises 24−36 hours after injury and can be confounded by exercise due to haemoconcentration and muscle metabolism rather than kidney injury, complicating interpretation in athletic cohorts [9]. Therefore, collection of sensitive tubular stress biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) during exercise-heat stress, which rise before changes in creatinine, may offer a more responsive insight into renal strain [4,5]. In addition, collection of copeptin (a stable surrogate for AVP), plasma normetanephrine (reflecting sympathetic tone), and serum osmolality (a marker of hydration and osmotic stress) alongside NGAL and KIM-1 may provide an integrated view of systemic and renal responses to heat stress [10–12].
Recent work by [13] demonstrated that plasma NGAL and creatinine appear to be unaffected by acute heat stress before and after 10-days of fixed-intensity treadmill walking in a climatic chamber (40 °C). However, a strong correlation between serum creatinine and core body temperature was present at day 10, suggesting the kidneys have an increased sensitivity to hyperthermia in heat-acclimated individuals. Application of a fixed-intensity protocol may have limited the magnitude of heat adaptation stimulus – evidenced by no change in plasma volume in [13]. Controlled isothermic HA, which maintains core temperature ≥38.5 °C for 60–90 min per session, provides a potent and time-efficient stimulus for athletes and military personnel [14]. Five consecutive isothermic sessions have been shown to lower core body temperature, expand plasma volume, improve sweat efficiency, and lower exercising heart rate [15], with diminishing marginal returns thereafter [16]. While these adaptations enhance thermal tolerance, their influence on renal ischaemia and tubular stress remains unclear. Improved plasma volume and sympathetic modulation following HA may help reduce tubular injury and AKI risk during exercise in the heat, associated with better fluid regulation, reduced hyperthermia, and lower renal ischaemia [4].
Therefore, this study investigated whether a short-term (5-day, 90 min·day ⁻ ¹) isothermic HA protocol in endurance-trained individuals influences thermoregulatory, cardiovascular, renal, and neuroendocrine responses to exercise in the heat. We hypothesised that HA would reduce thermal and cardiovascular strain and attenuate biomarkers of renal tubular injury (NGAL, KIM-1), sympathetic activation (normetanephrine), and fluid-regulatory stress (copeptin and osmolality).
Methods
Ethics statement and participant population
The study protocol gained institutional ethical approval (Reference: 51919, Leeds Beckett University) and was conducted in line with the principles expressed in the Declaration of Helsinki, 2013. Data collection occurred between 12/12/2018–24/06/2019. Fourteen endurance-trained male athletes volunteered for the study (Table 1). All participants were healthy, had not been exposed to hot conditions (>25 °C) for a least 3-months, and provided written informed consent. All individuals completed a minimum of 5h aerobic exercise per week and according to classifications by [17] met the criteria for performance levels 2 or 3, see Table 1.
Design of study
A randomised, between-groups, pre-post design was employed. Participants completed five consecutive daily intervention sessions (HOT or TEMP). Heat stress tests (HSTs) were conducted exactly 48 hours before the first intervention session (HST1) and 48 hours after the final session (HST2). Randomisation to groups was performed using GraphPad Prism software. Testing occurred between 07:00–11:00am to control for circadian variation and participants arrived euhydrated (urine osmolality <700 mOsmol kg−1; urine specific gravity <1.020), avoiding caffeine <12 hours and alcohol intake <24 hours prior. Training temperatures were specifically chosen to mimic the conditions athletes were anticipated to face during the Tokyo 2020 games (30–35 °C and 70–90% RH) [18].
Preliminary testing
Participants’ stature (Seca, 220, Hamburg, Germany) and body mass (Seca, 770) were initially measured. A graded exercise test (GXT) was performed on a cycle ergometer (Wattbike, Trainer, Nottingham, UK) under temperate laboratory conditions (19.3 ± 1.6 °C, 46 ± 6% RH). Participants cycled at 150 W, increasing by 25 watts (W) every 4 min until blood lactate concentration exceeded 4.0 mmol L−1, measured on a biochemistry analyser (EKF, Biosen C-Line, Cardiff, UK). Following a 15-min recovery, participants cycled at 150 W and increased the power by 20 W min−1 until volitional exhaustion. Heart rate (HR) was recorded continuously via chest strap telemetry (V800, Polar, Kempele, Finland) and expired gases were measured using a calibrated online gas analysis system (Cortex, Metalyzer 3B, Leipzig, Germany). Maximal oxygen uptake (V̇O2max) was determined according to standard criteria of [19].
Heat stress test
HST’s involved 45 minutes cycling at 2.5 W.kg-1 within an environmental chamber (Sporting Edge, UK) set to hot-humid conditions (32.0 °C ± 0.2, 70.4 ± 0.8% RH), adapted from [20]. Gastrointestinal temperature (Tgi) was measured via a telemetric pill (e-Celsius, BodyCap, Caen, France), calibrated through water immersion. Skin temperature (Tskin) was measured via four iButton sensors (Maxim Integrated Products, DS1922L, CA, USA), and mean Tskin calculated using the equation by [21]. Sweat patches (3M, Tagaderm +Pad, Minnesota, USA) were applied to the forearm for the collection of localised sweat. During exercise HR was monitored continuously, Tgi at 2.5-min intervals, and perceived exertion (RPE; [22]), thermal sensation (TSS; [23]) and thermal comfort (TC; [24]) recorded at 5-min intervals. Sweat loss (mL) was estimated from nude body mass changes, corrected for urine output. Venous blood samples were collected pre- and immediately post-HST for analysis of NGAL, KIM-1, copeptin, normetanephrine, and serum osmolality. Capillary blood samples were analysed in triplicate for haemoglobin (Hb) and haematocrit (Hct) to calculate plasma volume (PV) changes.
Heat acclimation intervention (HOT)
Participants in the HOT group completed five consecutive 90-minute sessions in a hot-humid environment (32.2 ± 0.2 °C, 69.7 ± 1.8% RH) using the controlled hyperthermia methodology [25]. During exercise trials in the heat participants self-inserted a rectal thermistor probe (Variohm, 4492, 400 series) connected to a data logger (Grant,SQ2020 2F8) approximately 10 cm proximal of the anal sphincter for the measurement of rectal temperature. Participants initially exercised at 2.5 W·kg ⁻ ¹ to elevate rectal temperature to ≥38.5 °C. Once this threshold was achieved, exercise intensity was self-selected to maintain core temperature ≥38.5 °C for the remainder of the session. Passive recovery periods were permitted when core temperature exceeded 39.3 °C.Heart rate and perceptual measures (RPE, TSS, TC) were recorded throughout. Fluid intake was monitored, with bottle weight measured pre- to post-session to the nearest 0.1 g using weighing scales (Ohaus, C series, New Jersey, USA).
Temperate climate exercise intervention (TEMP)
Participants in the TEMP group completed five consecutive 90-minute sessions in a thermo-neutral environment (21.3 ± 1.3 °C, 37.3 ± 6.1% RH). Participants initially exercised at 2.5 W·kg ⁻ ¹ for approximately 30 minutes, after which exercise intensity was self-selected for the remainder of the session. Physiological and perceptual measures were recorded at similar intervals to the HOT group. Fluid intake was ad libitum and recorded to calculate sweat loss.
Analytical methods
Changes in plasma volume (∆PV) were calculated using [26] equation from measured Hct and Hb. Sweat Na+ concentration was measured using a flame photometer (Jenway, PFP7 Flame Photometer, IL, USA). Venous blood samples were processed in serum separator (Becton Dickinson, SSTTM II Advance, Franklin Lakes, NJ, USA) and EDTA tubes (32.332 Sarstedt, Akteingesellscaft & Co., Numbrecht, Germany), centrifuged at 2600 rpm for 15-minutes at 4 °C, and aliquots stored at −80 °C. Serum osmolality was measured in duplicate by a micro-osmometer (Advanced Model 3320, Advanced Instruments, USA; CV 1.1%). Normetanephrine was analysed via LC-MS/MS (CV: 4–12%), copeptin via immunoassay (Brahms, CT-proAVP Kryptor Compact Plus, USA; CV: 2–10%). KIM-1 and NGAL were analysed using commercially available ELISA kits (R & D systems Europe, Abingdon, Oxon) by a specialist biomarker laboratory (Affinity Biomarker Labs, London). Intra/inter assay variability for KIM-1 was (CV: 1.3–7.0%), and for NGAL (CV: 2.3–3.9%). The lower limit of detection was 1.31 ng. L-1, and 0.012 µg/L-1, respectively. Hormone concentrations presented are uncorrected for changes in plasma volume.
Statistical analysis
Prior to experimentation, an a-priori power calculation was performed using G*Power software (version 3.1) to determine the sample size required. Using previously reported data where the primary outcome variables were the same as the present study (i.e., gastrointestinal temperature, whole body sweat loss, heart rate), the minimum effect size reported to observe a difference was 0.50. A total number of 12 participants was deemed as being necessary based upon an alpha (α: 0.05) and beta (β: 0.80).
Statistical calculations were performed using GraphPad Prism (version 9.0). Data are reported as means ± standard deviation (SD) and significance set at P < 0.05. Normality was assessed using the Shapiro–Wilk test (P ≥ 0.05). Parametric data from the pre-intervention HST were analysed using an independent-samples t-test between groups (HOT and TEMP), while non-parametric perceptual data were analysed using a Wilcoxon signed-rank test. The effects of time (PRE or POST) and group (HOT or TEMP) on continuous variables were determined using a two-way ANOVA for repeated measures. Where data were non-parametric but log-transformed data were parametric, ANOVA was performed on the log values. If log transformation did not normalize data, ANOVA was applied only when the Browne-Forsythe test indicated equal variance. Significant interactions were followed by Bonferroni-corrected post-hoc tests (alpha = 0.05). Effect sizes (Cohen’s d) were calculated to assess the magnitude of differences [27], categorized as trivial (<0.2), small (>0.2), moderate (>0.6), large (>1.2), very large (>2.0), and extremely large (>4.0).
Results
Fourteen endurance-trained participants were randomised to HOT (n = 7) or the TEMP (n = 7). All completed the five-day intervention and both heat stress tests (HST1 and HST2), except one participant in the TEMP did not complete venous blood sampling due to trypanophobia. There were no significant differences (p > 0.05) in exercise duration or relative exercise PO (~2.5 W.kg-1) between groups, suggesting a similar training stress was induced across the study duration. However, the magnitude of cardiovascular strain was different between groups, evidenced by a higher HR percentage maximum in the HOT compared to the TEMP group (79 vs. 71%, p = 0.030, respectively).
Heat stress testing – physiological and perceptual adaptations
Baseline hydration indices did not differ between groups (urine osmolality: p = 0. 839, d = 0.1; urine specific gravity: p = 0.352, d = 0.6; serum osmolality: p = 0.369, d = 0.6). A summary of resting and peak physiological measures throughout each intervention are presented in Table 2. Resting HR showed a significant group × time interaction (P = 0.014) and main effect of time (P = 0.047). Post-hoc analysis revealed a moderate reduction in HOT (−8 ± 5 bpm, P = 0.007, d = 1.0), with no change in TEMP. Resting Tgi and Tskin were unchanged in both groups (P > 0.05). Plasma volume increased significantly in HOT (+7.3 ± 5.1%, P = 0.022) but not TEMP (+3.0 ± 6.4%, P = 0.393). Sweat loss demonstrated a significant interaction (P = 0.010), with HOT showing a moderate increase (+500 ± 539 mL, P = 0.017, d = 1.1). No interaction was observed for peak RPE, TSS, or TC (P > 0.05). However, time effects indicated improvements in HOT for peak RPE (−2 ± 2, P = 0.007, d = 1.0) and TC (−1 ± 1, P = 0.016, d = 1.3). TEMP showed no significant changes.
Renal and neuroendocrine blood biomarkers following intervention
There were no significant group × time interactions for any blood biomarker (P > 0.05; Fig 1),. Post-HST concentrations of NMET (−5.7%, P > 0.999, d = 0.2), copeptin (−21.5%, P = 0.314, d = 0.5), NGAL (−13.9%, P = 0.716, d = 0.7), and KIM-1 (+22.3%, P > 0.808, d = 0.2) were unchanged after HA. TEMP also showed no changes (P > 0.05).
Two-way ANOVA results for copeptin: Group (p = 0.794), Time (p = 0.030), Interaction (p = 0.672); NMET: Group (p = 0.664), Time (p = 0.585), Interaction (p = 0.679); NGAL: Group (p = 0.383), Time (p = 0.422), Interaction (p = 0.646); KIM-1: Group (p = 0.919), Time (p = 0.652), Interaction (p = 0.461). Pairwise comparisons shown above bars.
Acute response of blood biomarkers to exercise-heat stress
Plasma NMET increased significantly from PRE to POST in both groups during HST1 (HOT: + 990 ± 1025 pmol·L ⁻ ¹; TEMP: + 1106 ± 1156 pmol·L ⁻ ¹; P < 0.001) and HST2 (HOT: + 918 ± 965 pmol·L ⁻ ¹; TEMP: + 1035 ± 1062 pmol·L ⁻ ¹; P < 0.001). Copeptin rose during HST1 in both groups (HOT: + 11 ± 6 pmol·L ⁻ ¹, P = 0.015; TEMP: + 12 ± 13 pmol·L ⁻ ¹, P = 0.019) but not HST2 (P > 0.05). Serum osmolality was similar between groups at rest (HST1: HOT 295 ± 6 vs TEMP 293 ± 4 mOsm·kg ⁻ ¹; HST2: HOT 291 ± 4 vs TEMP 295 ± 5 mOsm·kg ⁻ ¹; P > 0.899). A significant increase occurred during HST2 in HOT (+10 ± 5 mOsm·kg ⁻ ¹, P = 0.010), with no changes during HST1. NGAL did not differ at rest (P > 0.05) but increased post-HST only in TEMP during HST1 (+45 ± 29 μg·L ⁻ ¹, P = 0.030). KIM-1 showed no within-trial changes in either group during HST1 or HST2 (P > 0.999).
Discussion
The primary aim of this study was to determine whether five days of isothermic HA could reduce thermal and cardiovascular strain and attenuate renal stress during exercise in the heat. The key finding of this study is that five days isothermic HA improved cardiovascular and thermoregulatory responses, evidenced by reductions in resting and peak heart rate, plasma volume expansion (+7.3%), and increased sweat loss (+500 mL). However, in the current study we did not observe detectable changes in neuroendocrine markers (copeptin, normetanephrine) or renal tubular stress markers (KIM-1, NGAL) during exercise in hot-humid conditions.
Cardiovascular adaptations in the current study are consistent with previous reports of short-term HA benefits but exceeded the mean plasma volume change (+4.3%) reported in earlier studies [28]. Cardiovascular improvements likely reflect enhanced stroke volume secondary to plasma volume expansion [29], although no change in sweat sodium concentration suggests mechanisms beyond aldosterone-mediated sodium retention, possibly involving isosmotic fluid shifts from the cutaneous vascular space [30]. Despite these thermoregulatory and cardiovascular benefits, markers of sympathetic activity (normetanephrine) and fluid-regulatory stress (copeptin) remained unchanged. This contrasts with earlier reports of reduced norepinephrine following HA [11,31], suggesting that heart rate reductions may reflect improved cardiac function rather than diminished sympathetic drive [32]. Evidence on neuroendocrine adaptation remains equivocal: [33] found no significant change in copeptin after 23 days of acclimatization despite reduced cardiovascular strain, indicating limited AVP-mediated fluid regulation. In contrast, [34] reported decreases in copeptin and normetanephrine after 7 days of mixed-method HA, highlighting protocol-specific effects.
Improvements in cardiovascular efficiency have often been associated with reductions in core temperature; however, resting Tgi did not change significantly in this study (−0.2 °C), which may reflect high inter-individual variability and independence of different HA indices [35]. Therefore, classifying whether a HA intervention has been successful should be done with reference to multiple specific indices of HA, rather than a global classification. Increased sweat loss observed here (+37%) was more pronounced than previous short-term HA studies (+5%) (Tyler et al., 2016), likely due to the high humidity (70% RH) reducing evaporative cooling and promoting greater sweat gland responsiveness [36].
To our knowledge this is the first study to examine these specific renal and neuroendocrine markers in the context of short-term isothermic HA. NGAL and KIM-1 remained unchanged, indicating that short-term HA may not alter biomarkers of early tubular stress during exercise in hot-humid conditions. These findings align with [13] who reported that 10 days of HA improved thermal tolerance but did not attenuate increases in serum creatinine or NGAL during exercise-heat stress, suggesting persistent renal sensitivity to hyperthermia. Furthermore, [37] observed that seven days of passive HA did not improve glomerular filtration rate during heat stress, although albuminuria incidence was reduced, suggesting better preservation of renal filtration integrity under thermal stress. Research by [5] also reported that six day’s HA did not reduce serum creatinine rise, though fewer participants met AKI thresholds post-HA. This aligns with [38] who demonstrated reductions in AKI risk with gradual acclimatisation, and a significant reduction in serum creatinine post-exercise by day 23, reinforcing that renal adaptation is gradual and protocol-dependent.
Collectively, these studies indicate that HA whether short-term, extended, or passive, may not fully protect renal function during heat stress, but may reduce the risk of developing AKI. In the current study, it was postulated that expanded PV may improve central haemodynamics, reducing sympathetic vasoconstrictor drive and blunting vasopressin release, evidence by a reduction in neurohumoral markers (copeptin, NMET). Thereby, improving renal blood flow and reducing the risk of damage to the kidneys filtering units. However, despite an increase in PV and reduced thermal strain in the current study, there was no change in copeptin or NMET, suggesting similar levels of renal perfusion and risk of tubular injury following acclimation within this population. Our findings, highlight that while short-term HA improves cardiovascular and thermoregulatory responses, extended HA protocols (≥10 days), combined with individual hydration plans or cooling interventions may be required to safeguard renal function during exercise in hot environments. This aligns with evidence from occupational settings, were prolonged work in the heat without adequate hydration or cooling increases the risk of kidney injury among workers in physically demanding roles [2].
This study has several limitations that should be considered when interpreting the findings. Firstly, we didn’t include direct measures of kidney function (e.g., serum creatinine or glomerular filtration rate). While this was intentional to focus on emerging early tubular injury markers (NGAL and KIM-1) and neuroendocrine indices (copeptin, NMET), it limits inferences about acute changes in filtration and the functional significance of any biomarker shifts. Second, kidney injury markers were assessed only in blood. Although circulating concentrations of NGAL and KIM-1 offer practical sampling during repeated exercise-heat exposures, they are not kidney-exclusive and may be influenced by extra renal sources and systemic inflammation. Future research should include a concurrent urinary biomarker panel to better understand tubular site specificity. The blood biomarker analysis was limited to a single time-point after the heat stress test, which may not have coincided with the peak response, specifically in NGAL and KIM-1. However, sampling immediately after exercise was chosen to capture peak physiological perturbations associated with heat stress, reflecting peak responses in copeptin, osmolality and NMET which rise rapidly with haemodynamic and osmotic stress on the kidney. Finally, while five days HA elicited physiological adaptations in the present study, high inter-individual variability in HST-induced responses combined with modest sample size may have reduced statistical power, increasing the risk of biomarker-specific false negatives. Thus, some “no change observed” outcomes may reflect an underpowered design rather than true absence of effect. This interpretation is supported by prior work [34], where even a short HA intervention (+2 days) induced measurable reductions in fluid-regulatory strain. Future studies should consider larger cohorts and/or extended HST protocols to improve sensitivity for detecting renal and neuroendocrine adaptations.
Conclusion
Five days isothermic HA was effective at evoking meaningful physiological and perceptual adaptations at rest and during exercise-heat stress but did not modify the response of surrogate markers of sympathetic activation, fluid regulation or renal stress. This HA protocol offers a time-efficient and effective strategy for endurance-trained individuals competing in a hot-humid environment. However, extended HA protocols (≥10 days), combined with individual hydration plans or cooling interventions may be required to safeguard renal function during exercise in hot environments in athletic and military populations.
Acknowledgments
The figures were created with GraphPad Prism (version 9) and are published with permission.
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