The Potential for Renal Injury Elicited by Physical Work in the Heat

Abstract

An epidemic of chronic kidney disease (CKD) is occurring in laborers who undertake physical work in hot conditions. Rodent data indicate that heat exposure causes kidney injury, and when this injury is regularly repeated it can elicit CKD. Studies in humans demonstrate that a single bout of exercise in the heat increases biomarkers of acute kidney injury (AKI). Elevations in AKI biomarkers in this context likely reflect an increased susceptibility of the kidneys to AKI. Data largely derived from animal models indicate that the mechanism(s) by which exercise in the heat may increase the risk of AKI is multifactorial. For instance, heat-related reductions in renal blood flow may provoke heterogenous intrarenal blood flow. This can promote localized ischemia, hypoxemia and ATP depletion in renal tubular cells, which could be exacerbated by increased sodium reabsorption. Heightened fructokinase pathway activity likely exacerbates ATP depletion occurring secondary to intrarenal fructose production and hyperuricemia. Collectively, these responses can promote inflammation and oxidative stress, thereby increasing the risk of AKI. Equivalent mechanistic evidence in humans is lacking. Such an understanding could inform the development of countermeasures to safeguard the renal health of laborers who regularly engage in physical work in hot environments.

Keywords: acute kidney injury; chronic kidney disease; dehydration; exercise; heat stress.

Figure 1

Top: Anatomical locations for biomarkers indicative of an increased risk of acute kidney injury (AKI) and common clinically relevant measures indicative of overall kidney function. Bottom: Potential etiology underlying increases in AKI biomarkers. Abbreviations—NGAL: Neutrophil gelatinase-associated lipocalin, [IGFBP7•TIMP-2]: the product of Insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor metalloproteinase 2 (TIMP-2), KIM-1: Kidney injury molecule-1, L-FABP: Liver-type fatty acid binding protein, IL-18: Interleukin-18. Please refer to text for references.

Figure 2

Proposed method for determining the relative risk of developing acute kidney injury (AKI) during exercise in the heat based on changes in kidney function and AKI biomarkers. A decrease in kidney function without increases in AKI biomarkers may be indicative of a relatively mild risk for AKI because the renal changes are unlikely to be pathological (bottom-left). Increases in AKI biomarkers without a change in kidney function may be interpreted as a slightly higher (i.e., moderate) risk of AKI, owing to the presence of potential pathological processes (top-right). The highest risk of AKI may occur when kidney function is reduced alongside increases in AKI biomarkers (bottom-right). AKI risk could be further delineated based on the magnitude of the reductions in kidney function and/or increases in AKI biomarkers.

Figure 3

During the longer of two bouts of exercise in the heat (LONG vs. SHORT), greater heat strain (A) and dehydration (B) resulted in greater changes (Δ) in serum creatinine (C), which were sufficient to satisfy the criteria for Stage 1 acute kidney injury (AKI) in ~30% of the subjects (D), and greater increases in plasma neutrophil gelatinase-associated lipocalin (NGAL) (E). * different from SHORT (p < 0.05), Mean ± SD, n = 29. From Schlader et al. [29] with permission.

Figure 4

Despite no differences in core temperature or changes in body weight (data not shown), drinking a high fructose soft drink compared to water during and following 4 h of exercise in the heat resulted in greater changes (Δ) in serum creatinine (A), meeting the criteria for Stage 1 acute kidney injury (AKI) at Post exercise in ~60% of the subjects (B). During the overnight period (defined as the time from leaving the laboratory immediately after post-exercise data collection until returning to the laboratory 24 h following pre-exercise (~18 h following post-exercise)), drinking a soft drink reduced urine flow rate (despite drinking ~347 mL more fluid during the overnight period) (C) and elevated urinary neutrophil gelatinase-associated lipocalin (NGAL) (D). These changes in indices in kidney function and biomarkers of AKI in the soft drink trial were paralleled by greater elevations in serum uric acid (E) and plasma copeptin (F), a stable surrogate for vasopressin. * different from Water (p < 0.05), Mean ± SD or individual values, n = 12. From Chapman et al. [30] with permission.

Figure 5

Potential mechanisms by which exercise in the heat and the subsequent development of heat strain (i.e., increases in core body temperature) and dehydration (a hypovolemic, hyperosmotic state) may increase the risk of acute kidney injury (AKI) while simultaneously promoting fluid conservation. Red arrows indicate potential pathophysiological pathways. Blue arrows indicate known beneficial physiological responses. Abbreviations—RAAS: Renin–angiotensin–aldosterone system, RSNA: Renal sympathetic nerve activity, ATP: adenosine triphosphate. Please refer to text for references.