Pathophysiological Mechanisms by which Heat Stress Potentially Induces Kidney Inflammation and Chronic Kidney Disease in Sugarcane Workers

Abstract

Background: Chronic kidney disease of non-traditional origin (CKDnt) is common among Mesoamerican sugarcane workers. Recurrent heat stress and dehydration is a leading hypothesis. Evidence indicate a key role of inflammation.

Methods: Starting in sports and heat pathophysiology literature, we develop a theoretical framework of how strenuous work in heat could induce kidney inflammation. We describe the release of pro-inflammatory substances from a leaky gut and/or injured muscle, alone or in combination with tubular fructose and uric acid, aggravation by reduced renal blood flow and increased tubular metabolic demands. Then, we analyze longitudinal data from >800 sugarcane cutters followed across harvest and review the CKDnt literature to assess empirical support of the theoretical framework.

Results: Inflammation (CRP elevation and fever) and hyperuricemia was tightly linked to kidney injury. Rehydrating with sugary liquids and NSAID intake increased the risk of kidney injury, whereas electrolyte solution consumption was protective. Hypokalemia and hypomagnesemia were associated with kidney injury.

Discussion: Heat stress, muscle injury, reduced renal blood flow and fructose metabolism may induce kidney inflammation, the successful resolution of which may be impaired by daily repeating pro-inflammatory triggers. We outline further descriptive, experimental and intervention studies addressing the factors identified in this study.

Keywords: acute kidney injury; heat; heat stress; hydration; inflammation; kidney; occupation.

Figure 1

Schematic summary of potential pro-inflammatory stimuli in the sugarcane worker nephron. Red = blood vessels. Yellow = tubular lumen. White boxes = tubulointerstitial cells. RBF = renal blood flow. NSAID = non-steroidal anti-inflammatory drug. SNS = sympathetic nervous system. BF = blood flow. RAAS = renin–angiotensin–aldosterone system. EPO = erythropoietin. Heavy work in heat leads to loss of volume and electrolytes triggering RAAS activation and vasopressin release, reducing renal blood flow, as well as increasing sodium absorption and potassium excretion. Heavy exercise and work decreases renal and gut blood flow through direct competition over the cardiac output and through sympathetic neural pathways. NSAID used to treat musculoskeletal pain from heavy work inhibits afferent arteriolar dilation, further decreasing renal blood flow, while also increasing intestinal permeability. Increased gut permeability enables endotoxins to enter the blood stream and trigger cytokine release systemically and in the tubuli, activating an inflammatory response. This inflammatory response in the tubuli can be further promoted by muscle cell breakdown products such as uric acid and tubular fructose metabolism, which also lead to uric acid production. Inflammation and relative hypoxia in the tubuli cause tubular cell injury, leading to further loss of potassium and decreased EPO synthesis, which in turn further impair tubular oxygen delivery.