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The perils of rehydrating with soft drinks following heat and exercise.

Intake of sugary beverages, and especially soft drinks, increases the risk of obesity and diabetes. But they are now emerging as a major risk factor for kidney disease. Sugary beverages contain ~11% sugar content, either as sucrose (a disaccharide of fructose and glucose) or as high-fructose corn syrup (HFCS), the latter a mixture of fructose and glucose monosaccharides in a 55-to-45 relative ratio. Intake of soft drinks increased markedly over the last century but has been steadily decreasing in the United States since 2005. However, this has been partially compensated by increased intake of other sugary beverages, including energy drinks, sports drinks, and juices. Today ~5 to 7% of the overall energy intake comes from sugary beverages. Epidemiological studies have linked soft drink intake with kidney disease. The first major association noted was with kidney stones (16). The fructose present in soft drinks generates uric acid during its metabolism, resulting in acute uricosuria with a fall in urine pH (10). Urate crystalluria may result, which can result in urate stones as well as acting as a nidus for calcium-based kidney stones. Soft drinks are also known to result in urinary concentration and volume contraction, which is thought to be due to slowed gastric emptying and a loss of fluid into the gut (12). The urinary concentration that results may result in an increased risk of kidney stones. Indeed, it has been reported that reducing soft drink intake can lead to a reduction in the rate of recurrence of kidney stones (15). Soft drink intake has also been reported to increase the risk for chronic kidney disease (CKD) in some but not all studies (3). However, a recent meta-analysis provided evidence that, overall, it is a risk factor for CKD (3). Most evidence suggests that the risk is greater for sugary soft drinks as opposed to diet soft drinks. Several mechanisms may account for this association. First, while low concentrations of fructose are metabolized by the gut, higher concentrations, such as present in soft drinks, reach the liver and kidney (9). Fructose filtered by the glomeruli is taken up by the proximal tubule where it is metabolized rapidly by the enzyme fructokinase, resulting in intracellular phosphate depletion, uric acid generation, the development of oxidative stress, and the release of inflammatory chemotactic factors (4). This may result in acute proximal tubular injury and over time may lead to interstitial fibrosis and inflammasome-associated intrarenal inflammation, as demonstrated in animal models (6, 11). Fructose metabolism can also result in uricosuria in the absence of stones that may lead to tubular injury. Indeed, in a study in diabetics, the abolition of glucose-induced urate crystalluria with oral bicarbonate resulted in a decrease in urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL, a biomarker of kidney disease) (1). In addition, soft drinks may contain other substances that may increase the risk of kidney disease. Thus, colas contain high concentrations of phosphate, which may chelate with calcium in vivo and increase the risk for acute kidney injury, especially in subjects with underlying CKD (5). Some evidence indicates increased risk of CKD in subjects drinking phosphate-rich colas as opposed to other soft drinks (14). Thus both fructose-dependent and fructose-independent mechanisms for kidney disease have been proposed. Recently there has been interest in the role of fructose in mediating kidney injury associated with heat stress. In this regard, epidemics of CKD have been recognized in several regions of the world in which a major risk factor appears to be heat stress. One of the primary areas is in Central America where epidemics of CKD have been reported among sugarcane workers. The results of several studies suggest that these individuals are developing repeated acute kidney injury in association with heat stress and dehydration, and there is limited evidence that this may increase the risk for CKD over time (8, 17). Experimental studies suggests that the renal damage may be mediated by recurrent dehydration that leads to activation of the aldose reductase (polyol) pathway in the kidney, resulting in endogenous fructose production (13), as well as by chronic effects of vasopressin (7). The local metabolism of fructose, coupled with the effects of vasopressin, are thought to mediate kidney injury that over time may increase the risk for CKD. In this setting, the intake of soft drinks might exacerbate kidney injury several ways. First, it could provide an exogenous source of fructose that could accelerate kidney disease. In addition, recent reports indicate that fructose also stimulates vasopressin release that could potentiate vasopressin-mediated renal injury (7, 18). Indeed, in an experimental study, rehydration with fructose-containing solutions in heat-stressed rats resulted in higher serum levels of vasopressin (copeptin), higher intrarenal fructokinase expression, greater intrarenal oxidative stress, increased tubular injury, and worse renal function compared with water-hydrated rats (6). However, until now there has been little or no evidence that rehydration with soft drinks has potentially deliterious effects in humans. In this issue, Chapman et al. (2) describe an evaluation of the effects of soft drink rehydration in heat-stressed humans. Specifically, young healthy individuals were subjected to 4 h of heat (35°C, 61% humidity) during which they exercised for 4 h (split Address for reprint requests and other correspondence: L. G. SanchezLozada, Laboratory of Renal Physiopathology, Dept. of Nephrology. INC Ignacio Chávez, Juan Badiano 1, 14080 Tlalpan, Mexico City, Mexico (e-mail: lgsanchezlozada@gmail.com). Am J Physiol Regul Integr Comp Physiol 316: R187–R188, 2019; doi:10.1152/ajpregu.00007.2019.