Impact of Beverage Content on Health and the Kidneys : Nutrition Today

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Impact of Beverage Content on Health and the Kidneys

Johnson, Richard J. MD; Thomas, Jeffrey MD; Lanaspa, Miguel A. PhD

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Nutrition Today 47(4):p S22-S26, July/August 2012. | DOI: 10.1097/NT.0b013e3182626640
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An increase in the prevalence of obesity, hypertension, diabetes, and chronic kidney disease has been observed worldwide.1–4 Although genetic contributions are likely, the rapidity with which these epidemics are increasing strongly suggests that there must be an environmental stimulus.

Although it is acknowledged that numerous factors can contribute to obesity and thus to health issues,5–7 the link between obesity and increased total energy intake concurrent with decreased energy expenditure is widely accepted.8,9 One potential source of the increased energy is from sugar intake, particularly from soft drinks,10–12 with some studies suggesting the risk stems primarily from the fructose content in sugar.13–16 The intake of fructose, particularly from sugar, has increased markedly in the last 2 centuries and parallels the rise in obesity and diabetes.13,14 One of the strongest associations of obesity and insulin resistance is with the intake of sugary soft drinks.10,17 Sugar (or fructose) intake has also been found to predict the development of high blood pressure18 and albuminuria.19

Although fructose simply as an additional caloric source may contribute to the increasing prevalence of these disorders, experimental literature shows that fructose (or sucrose) may also encourage energy intake via a variety of mechanisms.18,19 Despite lack of support from evidence-based reviews in obese as well as normal-weight individuals,20–22 there is mounting animal-based evidence that fructose (or sucrose) may induce features of metabolic syndrome independent of excessive energy intake.

In this short article, we review the current evidence for sugar (and fructose) as a contributory etiologic factor for these conditions, as well as present some of the counteracting arguments to recent articles that have tried to challenge this work. For a comprehensive review of many of the themes presented in this article, see Johnson et al.14


Sucrose, or table sugar, is derived primarily from sugarcane or sugar beets and is the primary sweetener used in most countries. Sucrose consists of a disaccharide of glucose and fructose and following ingestion is degraded by sucrase in the gut, releasing the fructose and glucose, which are then absorbed. A similar sweetener, which is used commonly in the United States, is high-fructose corn syrup, which is composed of free fructose and glucose mixed in varying ratios, but for which a ratio of 55:45 fructose-glucose is commonly used in soft drinks.

Once absorbed, fructose is taken up primarily in the liver, where it is initially metabolized by fructokinase (KHK). Fructokinase uses adenosine triphosphate (ATP) to phosphorylate fructose to fructose-1-phosphate, which is then degraded stepwise, generating glucose, glycogen, triglycerides, and other products. However, this initial phosphorylation step is very rapid and can lead to transient intracellular phosphate and ATP depletion.23,24 This is not observed when glucose is phosphorylated as glucokinase has a negative feedback system to prevent excessive phosphorylation. For fructokinase, however, phosphate and ATP depletion are common, and this results in the activation of AMP deaminase and the stepwise reduction of AMP to uric acid (Figure 1). Indeed, concentrations of 1 mM of fructose are sufficient to induce transient ATP depletion in many cell types.25 In turn, serum uric acid levels increase in the circulation within minutes.26–28 If fructose is given chronically, even fasting uric acid levels will rise,29,30 in part because fructose also stimulates de novo uric acid synthesis.31

Figure 1:
Schema of fructose metabolism. Abbreviations: ADP, adenosine diphosphate; AMP, adenosine monophosphate; AMPD, adenosine monophosphate deaminase; ATP, adenosine triphosphatel; IMP, inosine monophosphate; KHK, fructokinase.


Sugar (or fructose) intake has been found to predict the development of high blood pressure32 and albuminuria in humans.33 Also, studies in laboratory animals have shown that fructose can induce all features of metabolic syndrome, including insulin resistance, elevated serum triglycerides, low high-density lipoprotein cholesterol, visceral fat accumulation, and fatty liver, leptin resistance, oxidative stress, endothelial dysfunction, and systemic inflammation (reviewed in Johnson et al14). Most importantly, the studies in animals show that the effect of fructose to induce metabolic syndrome is not related to caloric intake. Specifically, when rats are pair-fed so that they receive identical energy intake, only the fructose-fed (or sucrose-fed) rats develop metabolic syndrome, whereas the glucose- or starch-fed rats do not.34–36 Moreover, rats can even be dietary restricted, but if their diet is high in sucrose, they will develop fatty liver and, in some cases, type 2 diabetes.37 Studies such as these show that the mechanism(s) by which fructose induces metabolic syndrome, and obesity may not simply involve the ingestion of excessive energy from leptin resistance38,39 or central nervous system effects,40 but also can occur in the absence of excessive energy intake.

Exactly how fructose causes metabolic syndrome has been an area of extensive research for many groups. However, our research suggests that a key aspect is the ATP depletion that occurs with the initial metabolism of fructose by fructokinase. In particular, studies using fructokinase knockout mice strongly suggest that the fructokinase C isoform, which phosphorylates fructose rapidly and causes transient ATP depletion, is key for the metabolic phenotype.41 In contrast, fructokinase A metabolizes fructose slowly, resulting in minimal ATP consumption, and may actually protect animals from fructose-induced metabolic syndrome. Indeed, when fructose is administered to fructokinase A knockout mice, they develop even greater fatty liver and worse insulin resistance than do wild-type mice, even though energy intake is the same.41

The importance of ATP depletion in the induction of the metabolic phenotype may relate to the fact that the intracellular phosphate depletion that occurs with fructose results in the degradation of AMP to generate uric acid and other purine metabolites.42 Our unpublished studies suggest that the uric acid that is generated intracellularly affects cellular energetics in the mitochondria to drive the metabolic phenotype. Indeed, treatments aimed at reducing the intracellular uric acid generation from fructose appear to improve various features of metabolic syndrome in laboratory studies, including improvement in weight, fatty liver, blood pressure, insulin resistance, and dyslipidemia.35,36,43 Pilot studies in humans also support a role for uric acid as a contributory and modifiable risk factor for various features of the metabolic syndrome, especially elevated blood pressure.44,45 Although clearly more studies are needed, the possibility that fructose may contribute to the pathogenesis of metabolic syndrome through uric acid–dependent and –independent pathways appears increasingly evident.


Dietary management of patients with chronic kidney disease, regardless of etiology, includes low-salt diet, modest protein intake, and adequate hydration as subjects with chronic kidney disease often have urinary concentration defects. Historically, there have been minimal or no recommendations relating to the intake of sugar. However, there is increasing evidence that sugar intake may have adverse consequences on kidney health. An association between the intake of sugary soft drinks and albuminuria was observed in the National Health and Nutrition Examination Survey, 1999–2004.33 In addition, there is increasing evidence from laboratory studies that excessive intake of fructose (60% fructose diet) can both induce and accelerate kidney disease (Figure 2).34,46,47 For example, rats administered high concentrations of fructose develop hypertrophy of the kidney with evidence for proximal tubular injury and intrarenal inflammation.46 The mechanism may relate to the uptake of fructose by the proximal tubule, which, like the liver, expresses fructokinase.25 Studies in cell culture show that fructose can induce injury in proximal tubular cells via a mechanism that involves local ATP depletion, uric acid generation, and oxidative stress.

Figure 2:
Potential mechanisms by which fructose may cause renal disease. Abbreviation: ATP, adenosine triphosphate.

Feeding fructose, but not glucose, can also accelerate established renal disease in laboratory animals.34 For example, in rats with chronic kidney disease due to renal ablation, fructose was associated with worse proteinuria, worse renal function (creatinine clearance), and more glomerulosclerosis and tubulointerstitial fibrosis than in controls that received either normal diet or a glucose-based diet.34 Some of these effects may relate to the ability of fructose to raise uric acid, which can then induce renal microvascular disease, altered renal autoregulation, and glomerular hypertension.47,48


Some authors have suggested that sucrose (or fructose) may induce metabolic syndrome, and there is indeed evidence that sugar may increase total energy intake via effects on the mesolimbic dopamine system and hippocampus and by inducing leptin resistance in laboratory animals; fructose ingestion has also been reported to be relatively ineffective at stimulating leptin in humans.18,38,40,49 However, the experimental evidence showing that fructose effects can occur independent of energy intake suggests that energy intake alone cannot account for the metabolic effects of fructose.34,35,37,50

Human studies argue that short-term fructose intake does not affect body weight, blood pressure, insulin resistance, or uric acid levels,51–55 but the study design of these reports was such that fructose would not be expected to have any effects. For example, a meta-analysis that concluded that fructose does not appear to affect body weight54 primarily involved studies in which both groups were given isocaloric diets. Because body weight is driven largely by energy intake, no significant weight difference would be expected in short-term trials.56 Another meta-analysis, by the same authors, investigating the effects of fructose on blood pressure55 included measurements of blood pressure after fasting, when both experimental and human data show that the effects of fructose are to initially raise blood pressure during ingestion.28,57

Another problem is that studies on fructose often include studies in which natural fruits are administered as the fructose source. However, fruits contain substances such as ascorbate and other antioxidants that block the fructose-mediated metabolic changes, so including studies such as these would be like studying the role of high-salt diet in blood pressure in the presence of a diuretic.58


Although the authors concede that the evidence to date is inconclusive, they believe that there is sufficient evidence to recommend a general reduction in sugar intake for the prevention and management of obesity and metabolic syndrome.59 Recent studies suggest benefits of diets low in fructose, especially from added sugars, in both obese subjects and subjects with chronic kidney disease.60–62 Given the concerns for sucrose- or fructose-based drinks as a means for rapidly inducing ATP depletion and activating fructose-dependent mechanisms, leading to inflammation and insulin resistance, our primary recommendation is to specifically reduce sugary drinks as a primary goal. It is our hope that such public health measures may have long-reaching benefits to slow the current obesity and diabetes epidemics.


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