Oxidative Stress and Inflammation Contribute to Kidney Injury Risk During Prolonged Passive Extreme Heat Exposure

Abstract

IntroductionKidney injury is a top cause of hospitalization during extreme heat events. Currently, wet bulb temperatures (Twet) during extreme heat events rarely exceed 31°C. However, it is predicted that Twet during future extreme heat events will exceed 34˚C, the limit of compensability in humans. We previously reported that, compared to a Twet of 31˚C, an 8 h resting exposure to a Twet of 34˚C elevated the risk of kidney injury risk, as quantified via the FDA‐approved kidney injury risk biomarker – the product of urine insulin‐like growth factor binding‐protein 7 and urine tissue inhibitor of metalloproteinases 2 ([IGFBP7·TIMP‐2]). This kidney injury risk is likely of tubular origin, and while the mechanisms underlying this extreme heat mediated tubular injury are unknown, an inflammatory etiology occurring secondary to oxidative stress has been speculated.PurposeTest the hypothesis that kidney injury risk during prolonged passive extreme heat exposure is contributed to by oxidative stress and inflammation.MethodsFifteen healthy men underwent 8 h resting exposures in Twet of 31°C and 34°C. Blood and urine samples were collected at 0 and 8 h. Following observations of elevations in [IGFBP7·TIMP‐2] in 34°C vs. 31°C (p<0.01), assays were conducted for urine liver‐type fatty acid binding‐protein (uL‐FABP ‐ a marker of tubular injury caused by oxidative stress), urine thiobarbituric acid reactive substances (uTBARS ‐ a marker of renal oxidative stress), urine interleukin‐18 (uIL‐18 ‐ a marker of tubular injury and inflammation), and plasma interleukin‐17a (pIL‐17a ‐ a circulating marker of inflammation, n=10). Serum TBARS (sTBARS) was measured to assess systemic oxidative stress. Data are reported as a change from 0 h (mean ± SD). Urine markers were normalized to urine flow rate.ResultsuL‐FABP increased in 34°C (+42 ± 64 ng/min, p<0.01) but not 31°C (+11 ± 20 ng/min, p=0.75) and was different between trials at 8 h (p<0.01). uTBARS increased in 34°C (+43 ± 37 nmol/min, p<0.01) but not 31°C (+14 ± 13 nmol/min, p=0.27) and was different between trials at 8 h (p<0.01). sTBARS did not change in 34°C (+1.2 ± 4.0 nmol/mL, p=0.08) nor 31°C (+0.3 ± 2.9 nmol/mL, p=0.92) and did not differ between trials at 8 h (p=0.16). uIL‐18 increased in 34°C (+27 ± 19 pg/min, p<0.01) and 31°C (+20 ± 25 pg/min, p<0.01) and was higher in 34°C at 8 h (p=0.05). pIL‐17a increased in 34°C (+199 ± 90 fg/dL, p<0.01) but not 31°C (+9 ± 96 fg/dL, p=0.94) and was different between trials at 8 h (p<0.01).ConclusionIncreases in uL‐FABP and uTBARS, in the absence of differences in sTBARS, support that renal tubular injury in 34°C is likely due to oxidative stress. pIL‐17a is selectively elevated in ischemic kidney injury. Thus, elevations in pIL‐17a in 34°C indicates inflammation of renal origins and this was translated to greater increases in uIL‐18 in 34°C. These findings support that kidney injury risk during prolonged passive extreme heat exposure is contributed to by oxidative stress and inflammation.