Kidney physiology and pathophysiology during heat stress and the modification by exercise, dehydration, heat acclimation and aging

Abstract

The kidneys' integrative responses to heat stress aid thermoregulation, cardiovascular control, and water and electrolyte regulation. Recent evidence suggests the kidneys are at increased risk of pathological events during heat stress, namely acute kidney injury (AKI), and that this risk is compounded by dehydration and exercise. This heat stress related AKI is believed to contribute to the epidemic of chronic kidney disease (CKD) occurring in occupational settings. It is estimated that AKI and CKD affect upwards of 45 million individuals in the global workforce. Water and electrolyte disturbances and AKI, both of which are representative of kidney-related pathology, are the two leading causes of hospitalizations during heat waves in older adults. Structural and physiological alterations in aging kidneys likely contribute to this increased risk. With this background, this comprehensive narrative review will provide the first aggregation of research into the integrative physiological response of the kidneys to heat stress. While the focus of this review is on the human kidneys, we will utilize both human and animal data to describe these responses to passive and exercise heat stress, and how they are altered with heat acclimation. Additionally, we will discuss recent studies that indicate an increased risk of AKI due to exercise in the heat. Lastly, we will introduce the emerging public health crisis of older adults during extreme heat events and how the aging kidneys may be more susceptible to injury during heat stress.

Keywords: AKI; Renal physiology; aged; hyperthermia; hypohydration; kidney function; older adults; physical work.

Figure 1.

Examples of common methods of studying heat stress in a laboratory setting delineated by internal (left) or external (right) validity. Abbreviations – METS: metabolic equivalents

Figure 2.

Simplified anatomy of the vascular system of the human kidney and the human nephron

Figure 3.

Example of how increases in urinary biomarkers of acute kidney injury can be used to identify the relative risk of tubular injury, the location of this potential injury, and the etiology that may be underlying the risk of tubular injury. Abbreviations – [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, IL-18: interleukin-18, L-FABP: liver-type fatty acid binding protein

Figure 4.

Continuous upper body cooling and drinking to replace sweat losses to minimize dehydration (Cool+Drink), which attenuated the rise in core temperature and reductions in body weight during 2 hours of exercise in the heat (A), attenuates peak urinary [IGFBP7•TIMP-2] compared to cooling alone (Cool), drinking alone (Drinking) or a condition where drinking or cooling were not permitted (Control) (B). This observation is mostly explained by higher peak urinary IGFBP7 concentrations in the Control trial compared to all other conditions (C) and not differential increases in peak urinary TIMP-2 (D). Data are presented as mean (SD). *indicates different from Control (P<0.05), ⁺ indicates different from Cooling (P≤0.03). B-D: Data were reanalyzed from Chapman et al. [63]. Data are presented as box and whisker plots. Data were analyzed using a one-way repeated measures (RM) analysis of variance (ANOVA) with actual p-values reported accordingly. Pairwise comparisons were made using two tailed least significant difference post hoc tests. P-values are shown for differences from Control. Abbreviations – Δ: change, [IGFBP7•TIMP-2]: the product of insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor metalloproteinase-2 (TIMP-2)

Figure 5.

Pearson correlation between the change (Δ) in core temperature evoked by exercise in the heat and the change in plasma neutrophil gelatinase-associated lipocalin (NGAL), a marker of the potential for renal ischemia. Raw data were obtained across three published studies from our laboratory [62-64]. Inset box: Pearson correlations were also conducted separately for trials in which subjects were dehydrated and euhydrated. The resulting correlation coefficients were compared via the methods of Meng et al. [336]. *indicates that the change in core temperature explained more variance in the change in plasma NGAL when subjects were dehydrated compared to when euhydrated (P=0.03)

Figure 6.

Potential mechanisms by which exercise, increases in core temperature and/or dehydration may increase the risk of acute kidney injury (AKI) while also promoting fluid conservation. Dashed lines indicate known beneficial physiological responses. Solid lines indicate potential pathogenic processes. Abbreviations – RAAS: renin-angiotensin-aldosterone system, RSNA: renal sympathetic nerve activity, PO₂: partial pressure of oxygen, ATP: adenosine triphosphate

Figure 7.

Potential beneficial (on left) and deleterious (on right) adaptations with heat acclimation that may modify the risk of acute kidney injury during heat stress

Figure 8.

Factors that may exacerbate the risk of acute kidney injury during heat stress in older adults