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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 8

Uric Acid: A Friend in the Past, a Foe in the Present


1 Division of Nephrology, University of Florida, Gainesville, FL, USA
2 Horizon Therapeutics, Lake Forest, IL, USA
3 Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA
4 Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO, USA
5 Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO; Division of Nephrology, Oregon Health Science University, Portland, OR, USA
6 Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center; Rocky Mountain VA Medical Center, Aurora, CO, USA

Date of Submission12-Apr-2022
Date of Decision28-May-2022
Date of Acceptance03-Jun-2022
Date of Web Publication26-Jul-2022

Correspondence Address:
Prof. Richard J Johnson
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, 12700 E 19th Ave., Box C-281, Aurora 80045, CO
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2773-0387.348714

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  Abstract 


The etiology of the epidemics of obesity and diabetes has commonly been attributed to the western diet rich in sugars and fat. More recent studies suggest that the epidemic may have evolutionary origins. Specifically, fructose appears to be a unique nutrient that acts to reduce ATP levels in the cell, creating an alarm signal that activates an orchestrated response that includes hunger, foraging, the stimulation of fat accumulation in the adipose, liver and blood, the development of insulin resistance, a rise in blood pressure, and systemic inflammation. This constellation of findings is similar to what is called as the metabolic syndrome, but is a protective system to aid survival in settings of food shortage. Uric acid generated from ATP depletion appears to be central in driving the biologic process. Here we discuss the role of uric acid in obesity, metabolic syndrome and chronic kidney disease. A key finding is that a mutation in uric acid metabolism occurring during our past that aided survival but that today is acting as an amplifier driving the obesity response to western diet. Uric acid is emerging as a key target in the mechanisms driving metabolic syndrome and kidney disease.

Keywords: Uric acid, fructose, metabolic syndrome, mitochondria, chronic kidney disease, gout


How to cite this article:
Ejaz AA, Antenor JA, Kumar V, Roncal C, Garcia GE, Andres-Hernando A, Lanaspa MA, Johnson RJ. Uric Acid: A Friend in the Past, a Foe in the Present. Integr Med Nephrol Androl 2022;9:8

How to cite this URL:
Ejaz AA, Antenor JA, Kumar V, Roncal C, Garcia GE, Andres-Hernando A, Lanaspa MA, Johnson RJ. Uric Acid: A Friend in the Past, a Foe in the Present. Integr Med Nephrol Androl [serial online] 2022 [cited 2022 Dec 3];9:8. Available from: https://journal-imna.com//text.asp?2022/9/1/8/348714



Uric acid is a circulating nitrogenous product generated during the metabolism of DNA, RNA, and ATP. It can also be synthesized from amino acid precursors. While it is eliminated by enzymatic degradation in many mammals by uricase, in humans there was a stepwise loss of uricase activity that primarily affected the promoter region during the Eocene and Oligocene, until it was finally silenced in an ancestral ape prior to the split of the lesser apes from the great apes/humans.[1],[2] While some uric acid can still be degraded when it reacts with oxidants and nitric oxide,[3],[4],[5] most uric acid must be eliminated through the kidney (two-thirds) or the gut (one-third). This mechanism is less efficient, and so baseline uric acid levels in apes lacking uricase tend to be two-fold greater than those in other mammals.[6] The loss of the mutation also resulted in uric acid levels being much more likely to be altered by diet or by a reduction in kidney function.


  Function of Uric Acid Top


Originally uric acid was viewed simply as a nitrogenous waste product and that it might have provided benefit to terrestrial animals, especially reptiles and birds, since it can be excreted as a solid chalky precipitate (guano) via the cloaca to minimize water loss.[7],[8] Indeed, it was observed that animals living in water often excrete nitrogenous wastes as ammonia (in which ammonia can be diluted to minimize irritation), while terrestrial mammals excrete most nitrogenous wastes as urea and birds and reptiles that need to conserve water even more are uricotelic as they lack uricase and thereby excrete uric acid.[8]

This argument did not explain why humans (and other apes) lack uricase as we use urea as our main way to excrete nitrogenous wastes. However, studies over the last two decades have shown that uric acid has many biologic functions, but particularly appears to have a role in the survival response that occurs when animals are starving, or are preparing for food shortage.[9],[10],[11],[12] Some have suggested that a rise in uric acid represents a sign of an intracellular energy crisis.[13] In particular, uric acid is produced during the metabolism of fructose, which appears to be relatively unique among nutrients in stimulating an orchestrated survival response[14] [Figure 1].
Figure 1: Fructose, uric acid and the survival response. While fructose intake from added sugars such as sucrose and high fructose corn syrup is a major source of fructose, recent studies document that fructose can be generated in the body via the polyol pathway, and that this can be stimulated by diets high in high glycemic carbohydrates, salt and alcohol. The fructose is then metabolized by fructokinase and subsequent steps, eventually producing CO2, water and ATP (caloric pathway). However, during its metabolism and energy depletion pathway is activated in which ATP is consumed, generating AMP that is removed by AMP deaminase to eventually generate uric acid. While many mammals will further degrade the uric acid to allantoin, humans lost the enzyme uricase and uric acid then accumulates. The uric acid has been shown to cause oxidative stress to the mitochondria that suppresses the mitochondrial function. A consequence of these effects is an alarm signal in the cell as intracellular ATP levels fall, that appears to activate an orchestrated survival response. While this is beneficial when fructose intake or generation is relatively low, when it is high the consequence is to induce features of metabolic syndrome, hypertension, obesity and kidney disease. AMP, adenosine monophosphate; BP, blood pressure.

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The production of uric acid has been shown to have multiple actions that aid this survival response. This includes causing the translocation of NADPH oxidase to the mitochondria where the oxidative stress blocks the Krebs (citric acid) cycle as well as β -fatty acid oxidation.[10],[15],[16],[17],[18],[19],[20] This suppresses mitochondrial ATP production which then acts to stimulate glycolysis by reducing the inhibition of phosphofructokinase.[21] This shift also reduces oxygen needs, thereby aiding the organism if hypoxia is present,[22],[23] while at the same time releasing citrate that can stimulate lipogenesis.[10] Fructose-induced hyperuricemia also increases blood pressure,[24] which is mediated by oxidative stress, a decrease in endothelial nitric oxide bioavailability, and a stimulation of the renin angiotensin system.[25],[26],[27] The uric acid also has a role in stimulating inflammatory responses, including the activation of NF-κB and stimulation of the inflammasome[28],[29],[30],[31] [Figure 1].

The timing of the silencing of the uricase mutation is not known with certainty, but likely occurred after the split of monkeys from apes (around 29 million years ago) but before the separation of the orangutan from the other great apes (around 12 million years ago).[2] It is of interest that during this time there was a period of global cooling that occurred around 14 to 15 million years ago (the Middle Miocene Disruption) that led to an extinction of 30 percent of all species. There is evidence that the climatic effects were more severe for apes in Eurasia, where it resulted in seasonal starvation during the colder months due to lack of fruit availability.[32],[33] The uricase mutation has been posited to increase the sensitivity of apes to the fattening effects of fructose, and thereby may have conferred a survival advantage.[1],[34]

While the evidence that the uricase mutation may have aided survival by enhancing the effect of dwindling amount of fruits to help maintain fat stores and blood pressure is strong, there is a commonly held hypothesis that uric acid may have actually functioned as an antioxidant that would help promote aging and block cancer.[35] This hypothesis has been proposed to explain why a high uric acid is epidemiologically associated with a lower risk for Parkinson’s disease,[36],[37] and also for some experimental and clinical studies in which administering uric acid appears to be protective, such as in acute ischemic stroke.[38],[39] However, experimental studies suggest it is not the antioxidant effect of uric acid that is protective, for ascorbate does not protect despite providing antioxidant effects.[40],[41] Rather, it appears that the infusion of uric acid blocks the blood brain barrier which is known to provide acute protection for these conditions.[40],[41] For example, the blood brain barrier can be blocked by inhibiting endothelial nitric oxide, leading to a protection in acute stroke, and this is one of the biological actions of uric acid.[42],[43] However, chronic effects of hyperuricemia are expected to cause progressive endothelial dysfunction and loss that may lead to a disruption of the blood brain barrier.[44],[45],[46]

Additional evidence against the anti-oxidant hypothesis is that uric acid, while being an antioxidant outside the cell, is a pro-oxidant inside the cell through its ability to stimulate NADPH oxidase.[16],[46],[47],[48] Furthermore, studies suggest high uric acid levels do not increasing longevity or protect from cancer, but rather mediate the reverse.[49],[50]


  From Thrifty Gene to Metabolic Syndrome and Kidney Disease Top


The loss of uricase resulted in a doubling of the serum uric acid, but levels remained in the 3 to 4 mg/dL range. However, this changed with the advent of the western diet and the dramatic increased intake of added sugars rich in fructose, such as table sugar (sucrose) and high fructose corn syrup (HFCS).[6] In addition, another source of fructose are fruit juices and fruit drinks.

While sugar and HFCS were the major sources of dietary fructose, some foods also activate aldose reductase, an enzyme in the polyol pathway, leading to increased fructose production from glucose. This includes high glycemic carbohydrates and salty foods, and while they do not necessarily increase serum uric acid, they do increase intracellular uric acid which is involved in how uric acid drives its metabolic effects.[51],[52]

In addition to sugar, uric acid is also generated following the ingestion of umami foods, such as from beer (which contains yeast extract), red meats (especially processed meats), organ meats, shellfish, and tomatoes.[53] Umami is primarily due to glutamate, which is an amino acid that is present in these foods especially following drying, curing, or cooking. Glutamate ingestion does result in uric acid production.[54] In addition, umami foods are often rich in nucleosides, such as inosine monophosphate (IMP) or adenosine monophosphate (AMP), and these substances can dramatically enhance the umami flavor. These substances are also broken down to uric acid, leading to the suggestion that the umami taste is primarily to seek foods that raise uric acid levels.[53],[54]

Today, serum uric acid levels have risen from around 3 or 4 mg/dL that was the average uric acid in the 1920s, to levels averaging 5 to 6 mg/dL in the general population.6 Furthermore, approximately 20 million people have uric acid levels greater than 6.8 mg/dL, which is defined as hyperuricemia.[55] The importance of this number is that above this level uric acid will crystallize when it is in water. These blood levels are five to 10 times what was present during the time when uricase was expressed, and the consequences on metabolic health are substantial.


  The Consequence of High Uric Acid on Cardio-Metabolic Diseases Top


One significant consequence of high uric acid levels is the risk for crystallization [Figure 2]. Urate crystals can activate toll-like receptor pathways leading to inflammasome-mediated inflammation.[29] One such consequence is the risk for gout, a type of arthritis associated with urate crystallization in the synovial fluid, especially in the big toe, but also with preference for the ankle, knees and wrists. Subcutaneous tophi containing uric acid crystals are also common among subjects with gout. However, recently it has been recognized that urate crystals can deposit in many other sites, including the spine, the skin, the eye, and even the kidney.[56] One particular site where urate deposits is in the atherosclerotic plaque.[57] While this was once thought to be relatively rare and insignificant, the use of the sensitive dual energy computed tomography (DECT) scan has documented the presence of urate crystals in the aorta and coronary arteries of approximately 80 percent of subjects with gout, and as many as 15 percent of those with hyperuricemia.[58] These findings are relevant to both meta-analyses and Mendelian randomization studies that have linked a high uric acid level with increased risk for cardiovascular mortality, especially in subjects with gout.[50],[59]
Figure 2: Multiple actions of uric acid in health and disease. A high uric acid can have multiple causes, including increased generation from intake of umami foods rich in glutamate and purines, from excess alcohol intake, or from the intake of sugary foods, especially sugary beverages. Uric acid generation can also result from cell turnover. The other major mechanism for raising uric acid levels is from reduced renal excretion (as well as the decreased degradation that occurred from the mutation in uricase). The consequence includes both crystalline and noncrystalline effects.

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While urate crystals remain a major potential mechanism for driving uric acid-related pathologies, there is also evidence that elevated serum uric acid is also a major predictor for obesity, diabetes, hypertension, fatty liver, and even cancer.[12],[60],[61] The mechanism may involve an overdrive of the fructose- uric acid survival pathway [Figure 2]. While Mendelian randomization studies have not always been able to find a link between serum uric acid and metabolic outcomes such as diabetes, the biology suggests it is the intrahepatic uric acid level that predicts metabolic events and this can be dissociated from serum uric acid. Indeed, genetic polymorphisms or deletions in urate transporters that increase portal vein uric acid levels are associated with features of metabolic syndrome in animals.[62],[63] Furthermore, pilot studies suggest lowering uric acid can reduce body weight gain, improve insulin resistance, and reduce blood pressure in humans.[64],[65],[66]

One complex aspect of uric acid is that it may be more involved in the initiation of disease than in the long-term progression. For example, experimental studies suggest that an elevation in uric acid causes a rise in blood pressure associated with renal vasoconstriction, but that over time there is the development of renal inflammation that causes persistent hypertension and renal vasoconstriction even if uric acid levels are normalized.[67] Likewise, some studies suggest that the effect of uric acid to cause oxidative stress to mitochondria may initially represent a reversible process, but that over time it may lead to a loss of mitochondria that resets the body weight to a higher level.[68] Uric acid is also a better predictor for the development of chronic kidney disease than for the progression of kidney disease, and this may reflect the effect of reduced kidney function to lead to the retention of salt and fluid.[69]


  Role of Uric Acid in Acute and Chronic Kidney Disease Top


The kidney has a major role in the excretion of uric acid, so that as kidney function falls, there is a passive rise in serum uric acid. This has led to the question of whether uric acid is simply passively elevated in acute kidney injury (AKI) or chronic kidney disease (CKD) or whether it is contributing to the reduction in function. Epidemiological studies suggest that serum uric acid can predict the development of AKI and CKD even in subjects with normal kidney function[69],[70], suggesting that it may have a causal role, while most Mendelian randomization studies have not been able to confirm such as association. Experimental studies have also linked both crystalline-dependent and -independent mechanisms by which uric acid may cause kidney disease [Figure 3].
Figure 3: Potential crystalline-dependent and crystalline-independent mechanisms by which uric acid may cause acute and chronic kidney disease. VSMC, vascular smooth muscle cell; GFR, glomerular filtration rate; RBF, renal blood flow.

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One way people have tried to sort this out is by clinical trial. In this regard, there have been over 20 pilot trials to evaluate the effect of lowering uric acid on CKD with mixed results.[71] One problem, however, is that many trials did not show any evidence for worsening of CKD in the control group, and since the premise is that the lowering of uric acid will slow progression (and not improved already diseased kidney), then those trials would be inadequate for determining if lowering uric acid has a protective role. When those studies are removed, the majority of published trials demonstrate a benefit from lowering uric acid.[71]

More recently, two large randomized, double blind clinical trials were published in which lowering uric acid demonstrated no benefit despite the fact that in both cases the control group showed evidence of progression.[72],[73] However, an important caveat is that neither study restricted subjects to those with hyperuricemia who would be the most likely to benefit, and also both trials excluded subjects with gout who might be the most likely to respond. We believe the assumption was that the subjects with gout would already be on a urate lowering drug, but the actuality is that as many as 30 or 40 percent of subjects with gout are not on urate-lowering therapy or are on inadequate therapy.

We therefore recommend clinical trials to determine if lowering uric acid is of benefit on chronic kidney disease in subjects who are either hyperuricemic or have gout. In addition, there is some evidence that the passive retention of uric acid may not necessarily reflect increased intracellular uric acid, as some studies suggest that raising extracellular uric acid will actually inhibit the transporters involved in taking uric acid up inside cells.[74] Thus, an alternative approach might be to measure plasma xanthine oxidase levels as a surrogate marker for intracellular uric acid production and levels.[75]


  Summary Top


In summary, uric acid is a biologically active molecule that is likely involved in survival pathways that aid animals at risk for food or water shortage. During our past we had a series of mutations that affected our ability to degrade uric acid, and the result is that our baseline uric acid levels are higher than most other mammals and we cannot regulate uric acid as well. The problem has been amplified by western diet, with foods rich in sugar, salt, and umami, that are acting together with the uric acid to drive metabolic and kidney diseases. While urate crystallization in extra-articular sites is one risk, there is also evidence that soluble, intracellular uric acid may also have a role in kidney disease as well as other metabolic disorders.

Conflicts of interest

Richard J Johnson and Miguel A. Lanaspa are members of Colorado Research Partners LLC, that is developing inhibitors of fructose metabolism. Richard J Johnson also has some shares with XORT therapeutics, which is a startup company developing novel xanthine oxidase inhibitors. Richard J Johnson has also received honoraria from Horizon Therapeutics. Jo Ann Antenor works for Horizon Therapeutics. All others have no conflicts of interest.



 
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