Fructose: A New Variable to Consider in SIADH and the Hyponatremia Associated With Long-Distance Running?

Fructose has recently been proposed to stimulate vasopressin secretion in humans. Fructose-induced vasopressin secretion is not only postulated to result from ingestion of fructose-containing drinks but may also occur from endogenous fructose production via activation of the polyol pathway. This raises the question of whether fructose might be involved in some cases of vasopressin-induced hyponatremia, especially in situations where the cause is not fully known such as in the syndrome of inappropriate secretion of diuretic hormone (SIADH) and exercise-associated hyponatremia, which has been observed in marathon runners. Here we discuss the new science of fructose and vasopressin, and how it may play a role in some of these conditions, as well as in the complications associated with rapid treatment (such as the osmotic demyelination syndrome). Studies to test the role of fructose could provide new pathophysiologic insights as well as novel potential treatment strategies for these common conditions.

Allicin, an Emerging Treatment for Pulmonary Arterial Hypertension: An Experimental Study.

We assessed whether allicin, through its antihypertensive and antioxidant effects, relieves vascular remodeling, endothelial function, and oxidative stress (OS), thereby improving experimental pulmonary arterial hypertension (PAH). Allicin (16 mg/kg) was administered to rats with PAH (monocrotaline 60 mg/kg). Allicin encouraged body weight gain and survival rate, and medial wall thickness and the right ventricle (RV) hypertrophy were prevented. Also, angiotensin II concentrations in the lung (0.37 ± 0.01 vs. 0.47 ± 0.06 pmoles/mL, allicin and control, respectively) and plasma (0.57 ± 0.05 vs. 0.75 ± 0.064, allicin and control respectively) and the expressions of angiotensin-converting enzyme II and angiotensin II type 1 receptor in lung tissue were maintained at normal control levels with allicin. In PAH rats treated with allicin, nitric oxide (NO) (31.72 ± 1.22 and 51.4 ± 3.45 pmoles/mL), tetrahydrobiopterin (8.43 ± 0.33 and 10.14 ± 0.70 pmoles/mL), cyclic guanosine monophosphate (5.54 ± 0.42 and 5.64 ± 0.73 pmoles/mL), and Ang-(1-7) (0.88 ± 0.23 and 0.83 ± 0.056 pmoles/mL) concentrations increased in lung tissue and plasma, respectively. In contrast, dihydrobiopterin increase was prevented in both lung tissue and plasma (5.75 ± 0.3 and 5.64 ± 0.73 pmoles/mL); meanwhile, phosphodiesterase-5 was maintained at normal levels in lung tissue. OS in PAH was prevented with allicin through the increased expression of Nrf2 in the lung. Allicin prevented the lung response to hypoxia, preventing the overexpression of HIF-1α and VEGF. Allicin attenuated the vascular remodeling and RV hypertrophy in PAH through its effects on NO-dependent vasodilation, modulation of RAS, and amelioration of OS. Also, these effects could be associated with the modulation of HIF-1α and improved lung oxygenation. The global effects of allicin contribute to preventing endothelial dysfunction, remodeling of the pulmonary arteries, and RV hypertrophy, preventing heart failure, thus favoring survival. Although human studies are needed, the data suggest that, alone or in combination therapy, allicin may be an alternative in treating PAH if we consider that, similarly to current treatments, it improves lung vasodilation and increase survival. Allicin may be considered an option when there is a lack of efficacy, and where drug intolerance is observed, to enhance the efficacy of drugs, or when more than one pathogenic mechanism must be addressed.

Sirtuin deficiency and the adverse effects of fructose and uric acid synthesis.

Fructose metabolism and hyperuricemia have been shown to drive insulin resistance, metabolic syndrome, hepatic steatosis, hypertension, inflammation, and innate immune reactivity in experimental studies. We suggest that these adverse effects are at least in part the result of suppressed activity of sirtuins, particularly Sirtuin1. Deficiency of sirtuin deacetylations is a consequence of reduced bioavailability of its cofactor nicotinamide adenine dinucleotide (NAD+). Uric acid-induced inflammation and oxidative stress consume NAD+ and activation of the polyol pathway of fructose and uric acid synthesis also reduces the NAD+-to-NADH ratio. Variability in the compensatory regeneration of NAD+ could result in variable recovery of sirtuin activity that may explain the inconsistent benefits of treatments directed to reduce uric acid in clinical trials. Here, we review the pathogenesis of the metabolic dysregulation driven by hyperuricemia and their potential relationship with sirtuin deficiency. In addition, we discuss therapeutic options directed to increase NAD+ and sirtuins activity that may improve the adverse effects resulting from fructose and uric acid synthesis.

Cellular Mechanisms Underlying the Cardioprotective Role of Allicin on Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are a group of diseases in which the common denominator is the affection of blood vessels, heart tissue, and heart rhythm. The genesis of CVD is complex and multifactorial; therefore, approaches are often based on multidisciplinary management and more than one drug is used to achieve the optimal control of risk factors (dyslipidemia, hypertension, hypertrophy, oxidative stress, endothelial dysfunction, inflammation). In this context, allicin, a sulfur compound naturally derived from garlic, has shown beneficial effects on several cardiovascular risk factors through the modulation of cellular mechanisms and signaling pathways. Effective pharmacological treatments for CVD or its risk factors have not been developed or are unknown in clinical practice. Thus, this work aimed to review the cellular mechanisms through which allicin exerts its therapeutic effects and to show why it could be a therapeutic option for the prevention or treatment of CVD and its risk factors.

Role of Sulfur Compounds in Garlic as Potential Therapeutic Option for Inflammation and Oxidative Stress in Asthma.

Asthma is a chronic inflammatory disease in the airways with a multifactorial origin but with inflammation and oxidative stress as related pathogenic mechanisms. Garlic (Allium sativum) is a nutraceutical with different biological properties due to sulfur-containing natural compounds. Studies have shown that several compounds in garlic may have beneficial effects on cardiovascular diseases, including those related to the lungs. Therefore, it is possible to take advantage of the compounds from garlic as nutraceuticals for treating lung diseases. The objective of this article is to review the biological properties of the sulfur compounds present in garlic for the treatment of asthma, as well as the cellular mechanisms involved. Here, we discuss the potential therapeutic effects of garlic compounds in the modulation of inflammation and oxidative stress, as well as its antibiotic and antiviral activities for identifying and testing potential treatment options for asthma management.

Fructose Production and Metabolism in the Kidney.

Understanding fructose metabolism might provide insights to renal pathophysiology. To support systemic glucose concentration, the proximal tubular cells reabsorb fructose as a substrate for gluconeogenesis. However, in instances when fructose intake is excessive, fructose metabolism is costly, resulting in energy depletion, uric acid generation, inflammation, and fibrosis in the kidney. A recent scientific advance is the discovery that fructose can be endogenously produced from glucose under pathologic conditions, not only in kidney diseases, but also in diabetes, in cardiac hypertrophy, and with dehydration. Why humans have such a deleterious mechanism to produce fructose is unknown, but it may relate to an evolutionary benefit in the past. In this article, we aim to illuminate the roles of fructose as it relates to gluconeogenesis and fructoneogenesis in the kidney.

Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats.

Dietary, fructose-containing sugars have been strongly associated with the development of nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that fructose also can be produced via the polyol pathway in the liver, where it may induce hepatic fat accumulation. Moreover, fructose metabolism yields uric acid, which is highly associated with NAFLD. Here, using biochemical assays, reporter gene expression, and confocal fluorescence microscopy, we investigated whether uric acid regulates aldose reductase, a key enzyme in the polyol pathway. We evaluated whether soluble uric acid regulates aldose reductase expression both in cultured hepatocytes (HepG2 cells) and in the liver of hyperuricemic rats and whether this stimulation is associated with endogenous fructose production and fat accumulation. Uric acid dose-dependently stimulated aldose reductase expression in the HepG2 cells, and this stimulation was associated with endogenous fructose production and triglyceride accumulation. This stimulatory mechanism was mediated by uric acid-induced oxidative stress and stimulation of the transcription factor nuclear factor of activated T cells 5 (NFAT5). Uric acid also amplified the effects of elevated glucose levels to stimulate hepatocyte triglyceride accumulation. Hyperuricemic rats exhibited elevated hepatic aldose reductase expression, endogenous fructose accumulation, and fat buildup that was significantly reduced by co-administration of the xanthine oxidase inhibitor allopurinol. These results suggest that uric acid generated during fructose metabolism may act as a positive feedback mechanism that stimulates endogenous fructose production by stimulating aldose reductase in the polyol pathway. Our findings suggest an amplifying mechanism whereby soft drinks rich in glucose and fructose can induce NAFLD.

Increase of core temperature affected the progression of kidney injury by repeated heat stress exposure.

An epidemic of chronic kidney disease of unknown etiology (Mesoamerican nephropathy) has emerged in hot regions of Central America. We have demonstrated that dehydration associated with recurrent heat exposure causes chronic kidney disease in animal models. However, the independent influence of core body temperature on kidney injury has not been explored. In the present study, we tested the hypothesis that kidney injury could be accelerated by increasing body temperature independent of external temperature. Wild-type mice were exposed to heat (39.5°C, 30 min, 2 times daily) with or without the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) for 10 days. Core temperature, renal function, proteinuria, and renal histological and biochemical analyses were performed. Isolated mitochondria markers of oxidative stress were evaluated from kidney tissue. DNP increased body core temperature in response to heat by 1°C (42 vs. 41°C), which was transient. The mild increase in temperature correlated with worsening albuminuria (R = 0.715, P < 001), renal tubular injury, and interstitial infiltration of monocytes/macrophages. Tubular injury was marked in the outer medulla. This was associated with a reduction in kidney tissue ATP levels (nonheated control: 16.71 ± 1.33 nmol/mg and DNP + heat: 13.08 ± 1.12 nmol/mg, P < 0.01), reduced mitochondria, and evidence for mitochondrial oxidative stress. The results of the present study suggest that kidney injury in heat stress is markedly worsened by increasing core temperature. This is consistent with the hypothesis that clinical and subclinical heat stroke may play a role in Mesoamerican nephropathy.

Climate Change and the Kidney.

The worldwide increase in temperature has resulted in a marked increase in heat waves (heat extremes) that carries a markedly increased risk for morbidity and mortality. The kidney has a unique role not only in protecting the host from heat and dehydration but also is an important site of heat-associated disease. Here we review the potential impact of global warming and heat extremes on kidney diseases. High temperatures can result in increased core temperatures, dehydration, and blood hyperosmolality. Heatstroke (both clinical and subclinical whole-body hyperthermia) may have a major role in causing both acute kidney disease, leading to increased risk of acute kidney injury from rhabdomyolysis, or heat-induced inflammatory injury to the kidney. Recurrent heat and dehydration can result in chronic kidney disease (CKD) in animals and theoretically plays a role in epidemics of CKD developing in hot regions of the world where workers are exposed to extreme heat. Heat stress and dehydration also has a role in kidney stone formation, and poor hydration habits may increase the risk for recurrent urinary tract infections. The resultant social and economic consequences include disability and loss of productivity and employment. Given the rise in world temperatures, there is a major need to better understand how heat stress can induce kidney disease, how best to provide adequate hydration, and ways to reduce the negative effects of chronic heat exposure.

Fructose and sugar: A major mediator of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup [HFCS]) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.

Fructose increases risk for kidney stones: potential role in metabolic syndrome and heat stress.

BACKGROUND: Fructose intake, mainly as table sugar or high fructose corn syrup, has increased in recent decades and is associated with increased risk for kidney stones. We hypothesized that fructose intake alters serum and urinary components involved in stone formation. METHODS: We analyzed a previously published randomized controlled study that included 33 healthy male adults (40-65 years of age) who ingested 200 g of fructose (supplied in a 2-L volume of 10% fructose in water) daily for 2 weeks. Participants were evaluated at the Unit of Nephrology of the Mateo Orfila Hospital in Menorca. Changes in serum levels of magnesium, calcium, uric acid, phosphorus, vitamin D, and intact PTH levels were evaluated. Urine magnesium, calcium, uric acid, phosphorus, citrate, oxalate, sodium, potassium, as well as urinary pH, were measured. RESULTS: Ingestion of fructose was associated with an increased serum level of uric acid (p < 0.001), a decrease in serum ionized calcium (p = 0.003) with a mild increase in PTH (p < 0.05) and a drop in urinary pH (p = 0.02), an increase in urine oxalate (p = 0.016) and decrease in urinary magnesium (p = 0.003). CONCLUSIONS: Fructose appears to increase urinary stone formation in part via effects on urate metabolism and urinary pH, and also via effects on oxalate. Fructose may be a contributing factor for the development of kidney stones in subjects with metabolic syndrome and those suffering from heat stress. TRIAL REGISTRATION: ClinicalTrials.gov NCT00639756 March 20, 2008.

Rehydration with fructose worsens dehydration-induced renal damage.

BACKGROUND: Increasing evidence suggests heat stress induced chronic kidney disease (CKD) may be mediated by endogenous fructose generation and may be exacerbated by rehydration by fructose-containing solutions. We have recently reported a model of CKD induced by heat stress. Here we test the hypothesis that rehydration with fructose may induce worse kidney injury than rehydration with equal amounts of water, and we also test if this fructose-induced injury is associated with activation of inflammasomes in the kidney. METHODS: Mice were recurrently exposed to heat (39.5 C0 for 30 min/h, 5 times daily for 5 wks) with rehydration consisting of 6 ml each night of water (Heat, n = 7) or fructose (Heat+F, 10%, n = 7), and were compared to control mice on water (Control, n = 7) or fructose (Fructose, n = 7). Various markers of renal injury were assessed. RESULTS: Compared to control animals, there was a progressive worsening of renal injury (inflammation and fibrosis) with fructose alone, heat stress alone, and heat stress with fructose rehydration (P < 0.01 by ANOVA). The combination of heat stress with rehydration with fructose was associated with increased intrarenal expression of the inflammasome markers, NLRP3 and IL-18, compared to heat stress alone. In addition, heat stress with or without fructose was associated with increased expression of caspase - 3 and monocyte chemoattractant protein-1 levels. Fructose administration was also associated with an increase in serum copeptin levels (a biomarker of vasopressin) and elevated copeptin was also observed in mice undergoing heat stress alone. CONCLUSIONS: These studies suggest that heat stress may activate intrarenal inflammasomes leading to inflammation and renal injury, and provide evidence that rehydration with fructose may accelerate the renal injury and inflammatory response.

Effects of exogenous desmopressin on a model of heat stress nephropathy in mice.

Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway.

Metabolic and Kidney Diseases in the Setting of Climate Change, Water Shortage, and Survival Factors.

Climate change (global warming) is leading to an increase in heat extremes and coupled with increasing water shortage, provides a perfect storm for a new era of environmental crises and potentially, new diseases. We use a comparative physiologic approach to show that one of the primary mechanisms by which animals protect themselves against water shortage is to increase fat mass as a means for providing metabolic water. Strong evidence suggests that certain hormones (vasopressin), foods (fructose), and metabolic products (uric acid) function as survival signals to help reduce water loss and store fat (which also provides a source of metabolic water). These mechanisms are intricately linked with each other and stimulated by dehydration and hyperosmolarity. Although these mechanisms were protective in the setting of low sugar and low salt intake in our past, today, the combination of diets high in fructose and salty foods, increasing temperatures, and decreasing available water places these survival signals in overdrive and may be accelerating the obesity and diabetes epidemics. The recent discovery of multiple epidemics of CKD occurring in agricultural workers in hot and humid environments may represent harbingers of the detrimental consequences of the combination of climate change and overactivation of survival pathways.

Aging-associated renal disease in mice is fructokinase dependent.

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy.

Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.

Hyponatremia with Persistent Elevated Urinary Fractional Uric Acid Excretion: Evidence for Proximal Tubular Injury?

BACKGROUND/AIMS: Hyponatremia associated with high urinary fractional excretion of uric acid which persists after serum sodium is corrected is the cardinal feature of salt losing nephropathy (SLN). We hypothesize that low grade proximal tubular injury is present in SLN because the proximal tubule is the main site of uric acid and sodium transport. METHODS: Five subjects with SLN were compared to four subjects with recurrent hyponatremia and three healthy individuals. Urinary NGAL (neutrophil gelatinase associated lipocalin, a marker of tubular injury) and fasting urinary fructose levels (a marker of proximal tubular injury) were measured. RESULTS: Subjects with SLN (n=5) showed elevated fractional uric acid excretion (22 ± 6 vs 4 ± 2 percent, p<0.0001), elevated urinary NGAL levels (62 ± 37 vs 9 ± 7 ng/mg creatinine, p=0.001) and fasting urinary fructose levels compared with the 7 controls (383 ± 465 vs 60 ± 34µmole/µg creatinine, p <0.001). A strong correlation between urinary NGAL levels and urinary fructose levels was observed (r =0.87, p<0.001). CONCLUSION: High urinary fractional excretion of uric acid in SLN is associated with elevated NGAL and fasting urinary fructose levels suggesting that SLN may involve tubular injury.

Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice.

Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Fructose intake also causes features of metabolic syndrome in laboratory animals and humans. The first enzyme in fructose metabolism is fructokinase, which exists as two isoforms, A and C. Here we show that fructose-induced metabolic syndrome is prevented in mice lacking both isoforms but is exacerbated in mice lacking fructokinase A. Fructokinase C is expressed primarily in liver, intestine, and kidney and has high affinity for fructose, resulting in rapid metabolism and marked ATP depletion. In contrast, fructokinase A is widely distributed, has low affinity for fructose, and has less dramatic effects on ATP levels. By reducing the amount of fructose for metabolism in the liver, fructokinase A protects against fructokinase C-mediated metabolic syndrome. These studies provide insights into the mechanisms by which fructose causes obesity and metabolic syndrome.

Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy.

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.