The Role of Volume Regulation and Thermoregulation in AKI during Marathon Running

Discussion

In this prospective study, we interrogated the role of volume and thermoregulatory responses in runners with and without AKI to further advance our prior findings that transient ischemic AKI is common after running (4). We found that copeptin, sweat volume, and sweat sodium were significantly different between runners with and without AKI but that core body temperature was not significantly different. Our study highlights that there are hemodynamic differences in runners with and without AKI and provides insights for future research to assess if adequate sodium and fluid replenishment during the race may optimize hemodynamics and reduce the incidence of runners’ AKI.

The release of copeptin in marathon runners is likely multifactorial, secondary to both osmolar and nonosmolar stimuli (19,20). In our study, we were not able to capture any significant differences in serum osmolality between runners with and without AKI. However, systolic BP was lower among runners with AKI and could have contributed to copeptin production secondary to decrease in blood flow. Additionally, given the net negative fluid balance that most runners experienced during the race as well as the substantial shunting of blood away from main organs, such as the heart and the kidneys, to enhance blood flow to the musculoskeletal system (7), it is likely that dehydration and reduction in blood flow were the driving components of copeptin release. Elevated concentrations of copeptin are prognostic markers in many clinical conditions, such as septic shock, pneumonia, cardiovascular disease, and diabetes (21–23). Furthermore, copeptin is elevated in CKD and proteinuria (24,25). Although this association could be attributed to decreased filtration by the kidneys, it has been shown that kidney clearance is not a main determinant of copeptin concentrations, because levels were unchanged in living kidney donors despite reduction in eGFR (26). In our study, it is difficult to identify if increases in copeptin preceded creatinine rise, because both measurements were done simultaneously, but there are several speculated mechanisms that could explain the potential adverse effects of copeptin on kidney function. As copeptin increases, there is an increase in urine osmolality and reduction in urinary flow, which could lead to granular cast accumulation and an inflammatory kidney state (27,28). Vasopressin, for which copeptin is a surrogate marker, also activates the renin-angiotensin-aldosterone system, which leads to significant kidney vasoconstriction and further sustained reduction in blood flow to the kidneys, potentially leading to ischemic damage (29,30). Finally, administration of vasopressin has shown to exert a dose-dependent increase in kidney oxygen consumption, which may predispose to kidney hypoxia (31).

Similar to copeptin, core body temperature, sweat volume, and sweat sodium showed substantial deviations from normal resting physiology. Sweat sodium and volume losses were substantially higher in runners with AKI, but in contrast, core body temperature did not differentiate between runners with and without AKI. However, our sample size was small, and modest associations may still exist. Nonetheless, given the mild ambient temperatures during the race in Hartford, Connecticut (with an average ambient temperature of 18°C and average humidity of 84%), it is possible that core body temperature did not rise to critical levels that would play a role in AKI. Therefore, an association may still exist in hotter ambient temperatures.

We have also shown that novel biomarkers of injury and repair increase secondary to marathon running, validating our prior findings (4) and confirming the increased inflammatory state during marathon running (32). Some novel biomarkers on day of race were significantly higher in runners with AKI compared with runners without AKI, suggesting that the sustained physical stress imposed by marathon running leads to an acute inflammatory response that can distinguish between runners with and without AKI.

Our study is the first to investigate the possible mechanisms of AKI in marathon runners by testing markers of both volume and thermoregulatory processes. Furthermore, we are first to measure copeptin concentrations in the setting of marathon running and AKI. We have previously shown that AKI in runners is secondary to ischemic injury given findings of granular casts on microscopy as well as increase in biomarkers of tubular injury. In this study, we have identified that the cause of this ischemic injury is likely hypoperfusion secondary to hypovolemic changes during the race as evidenced by higher sweat losses and copeptin concentrations in runners with AKI. This study provides a layer of knowledge to aid in the understanding of runner AKI for future studies.

Additionally, most runners had a net negative sodium and fluid balance, highlighting the lack of adequate hydration and salt intake throughout the race. This raises an important clinical question regarding the role of volume regulatory parameters to guide personalized rehydration as calculated by sweat losses and copeptin release to possibly prevent runners’ AKI. Other studies have also shown that runners are inadequately hydrating during the race, and >70% of runners feel that dehydration plays a role in their race performance (33,34). Guidelines regarding hydration during a marathon are limited, because most studies rely on subjective data (33), and there are no randomized, controlled trials to help guide hydration protocols (35). Our study provides a more detailed understanding of the hemodynamic state of runners throughout the race by the measurement of objective volume-regulatory markers. These markers may be used in future research to more accurately guide adequate hydration protocols in runners and other endurance athletes. Our study also identified that runners with AKI had more years of running experience and more participation in marathons as well as more extensive training. Although a prospective longitudinal study of runners is needed, these data are suggestive that, with more marathon exposure, there may be a higher risk of AKI and that experienced runners are a potential target group for future studies. However, it is important to note that the assessment of kidney injury in runners requires a multifaceted approach involving many factors, such as change in kidney injury biomarkers and urine microscopy along with a rise in serum creatinine, to determine true injury.

We also acknowledge the limitations of our study, which include small sample size, and hence, our results are subject to confounding. We did not capture any long-term outcomes due to our short follow-up time of 3 days. Additionally, our total sweat sodium and volume measurements were calculated from the 5-mile mark measurements, which presume constant sweat and fluid losses throughout the race and may not be accurate. It is likely that sweat and fluid losses increase with increasing intensity and pace of running, and hence, our calculations may have underestimated the actual sweat and fluid losses throughout the race, which would bias our results toward the null. Our net fluid and sodium balance values were calculated via information from a postsurvey questionnaire, and the accuracy of the data may be subject to recall bias. We were also unable to quantify the urine output of runners in our study. The generalizability of our study is limited to moderate ambient temperatures and may not apply to races performed in hotter temperatures. Furthermore, our cohort consisted of experienced runners, and our findings may not apply to runners with limited running experience. However, our study did find that, among experienced runners, there was a higher incidence of AKI in those with longer history of running. It is possible that experienced runners had more years of training as well as more exposure to marathons with faster pace of running compared with less experienced runners. There could be cumulative subclinical recurring kidney injury in experienced runners, leading to less kidney reserve and higher risk of reinsult with additional marathons. The metabolic demands are heightened during a marathon, and with a faster pace of running, there is likely a further increase in metabolic demands and hemodynamic shifts, leading to higher risk of AKI. Furthermore, many studies have shown that marathon runners and endurance athletes have cardiac fibrosis (36–39), and it is plausible that kidney fibrosis also occurs with frequent marathon running. Future research needs to focus on the long-term kidney effects of marathon running to better determine how marathon participation affects long-term kidney function, which our study did not address. Lastly, the strength of inference testing in our study may be affected by lack of adjustment for multiple comparisons in the context of multiple planned analyses.

To conclude, our study shows that core body temperature, sweat volume, sodium losses, and copeptin concentrations are significantly affected during marathon running but that only sweat sodium, volume losses, and copeptin concentrations differed between runners with and without AKI. We have identified hemodynamic differences as measured by these regulatory markers between runners with and without AKI, which provide the building blocks for future research to assess if adequate hydration and optimization of hemodynamics will reduce the incidence of AKI in runners. Whether these markers play a causative role in AKI or are simply markers of injury in marathon runners with AKI warrants additional investigation.