Fig. 10.1
Metabolism of purines and uric acid. AMP adenosine monophosphate, GMP guanosine monophosphate, IMP inosine monophosphate, XO xanthine oxidase
Uric acid is mainly excreted by the kidney, while the remainder is disposed of by intestinal bacteria. In the glomerulus, UA is freely filtered prior to being reabsorbed in the proximal tubule. While some secretion does occur in the distal tubule, the overall effect is retention of the majority of UA in the blood [4].
Etiology of Uric Acid Nephrolithiasis
Uric acid nephrolithiasis is a condition long linked to prosperity and dietary excess, and a Western-type diet appears to promote its onset [7]. Metabolic syndrome is a major culprit in the development of UA stones [8–11], and it has recently been demonstrated that total body fat and truncal obesity are strongly associated with 24-h urinary pH and UA supersaturation index [12]. Other clinical states conferring a higher risk of UA stones include chronic diarrhea, inflammatory bowel disease, and having an ileostomy [13, 14], all of which lead to a combination of fluid and bicarbonate loss in the stool and an acidic environment favoring UA precipitation.
The three main urinary risk factors for UA stones are low urine pH , insufficient urine volume, and elevated urinary uric acid. Low urine pH is by far the most important of these [15] because it increases the level of undissociated uric acid in the urine. Low urine pH can result from two mechanisms, reduced renal ammonium (RA) excretion and increased net acid excretion (NAE) [1, 3]. Obesity, DM, and metabolic syndrome are states of caloric imbalance wherein caloric intake exceeds caloric expenditure resulting in fat deposition in non-adipose tissue, including the kidney. Fat deposition in the kidney is thought to cause renal lipotoxicity [16, 17], and proximal renal tubule cells, which are the major contributors to the synthesis and secretion of ammonium [18], are injured, leading to impaired ammonium excretion [19]. Reduction in ammonium levels then requires buffering of secreted H+ by titratable acid, thereby increasing the acidity of the urine and promoting uric acid precipitation.
In addition to impaired ammonium excretion , high net acid excretion also causes acidic urine and leads to increased risk of UA stones. Patients with UA stones have been shown to be similar in this regard to patients with type 2 DM, in terms of having significantly increased NAE [20]. The pathophysiology of this derangement has not yet been established but may involve net GI losses of alkali due to alterations in pancreatic exocrine function induced by pancreatic lipotoxicity or changes in the intestinal microbiome or increased colonic transit time that promote organic acid production via fermentation [20].
Nutritional Strategies to Address the Risk Factors for Uric Acid Lithiasis
The three proximate factors leading to uric acid stone formation are inadequate urine volume, hyperuricosuria, and low urine pH, and all three must be addressed in a nutritional plan. Additional consideration should be given to fructose consumption.
Low Urine Volume
Adequate daily fluid intake is equally important for uric acid stone formers as it is for patients with other stone compositions. Generating a daily urine output of over 2 liters (L) is the goal and typically cannot be achieved unless patients consume at least 3 L of fluid per 24-h period. While not complicated, this can be difficult to achieve. Initial dietary screening should include obtaining a history of estimated daily fluid intake (often overestimated by patients) as well as identification of barriers to hydration. These can include factors ranging from work schedules that do not allow the patient to drink enough or have sufficient access to a toilet to daily work or recreational activities that lead to inordinate fluid losses such as working in a hot environment. Older patients with overactive bladder or prostatism may restrict their fluid intake to control symptoms of these syndromes. Systemic conditions leading to fluid loss such as chronic diarrhea or ileostomy status should be noted. A 24-h urine volume should be obtained to guide individual recommendations.
Counseling on fluid intake largely involves educating the patient on the role of fluid in preventing stones and on strategies to achieve a satisfactory amount of fluid, as well as which ones are desirable and which ones should be avoided. Tracking fluid intake is of paramount importance. This can be done by using a container of known volume or by advising the patient on the volumes of commonly used single-serve containers. In the United States, the latter include 16.9 oz (500 mL) bottles and 12 oz (354 mL) cans. Many patients find it easier to keep track if they know their daily goal of 3 L can be achieved by consuming six 16 oz bottles of water per day. The same can be achieved by drinking an 8 oz (236 ml) glass of water at the beginning and end of each meal and two glasses each in midmorning, midafternoon, and evening. Choices of fluid can include tap, bottled, and sparkling water, unsweetened lemonade, and nonsugar carbonated beverages, although noncaloric artificial sweeteners have recently been found to induce glucose intolerance by altering gut microflora [21]. Juices, sports or energy drinks, and sugared carbonated beverages should be avoided due to their carbohydrate load. Additionally, a recent analysis of data from the National Health and Nutrition Examination Survey found a 23% higher risk of kidney stone development in participants consuming sugar-sweetened cola, a 33% higher risk in those reporting intake of sugar-sweetened non-cola, and an 18% increased risk for those frequently consuming punch [22].
Hyperuricosuria and Low Urine pH
Nutritional strategies geared to lowering urinary uric acid and raising urine pH overlap and will be considered together.
Due to high levels of purines, animal protein consumed in excess has long been known to confer an increased risk of both uric acid and calcium oxalate stones. Diets high in animal protein have been shown to increase net acid excretion – thus lowering urine pH – and also to contribute to hyperuricosuria and hypocitraturia. A short-term increase in dietary animal protein of 34 g/day, yielding 11 mmol of purine nitrogen/day, caused a 48% increase in uric acid excretion in normal male subjects [23], while in a comparison of serum and urine chemistry between omnivorous and vegetarian women, the former were found to have a significantly higher level of urinary titratable acid [24]. Similarly, urinary net acid excretion rose in a progressive manner in a cohort of healthy adults consuming 75 g protein/day derived from vegetarian, ovo-vegetarian, or animal protein sources [25].
A study of recurrent stone formers fed high and low animal protein diets for 2 weeks showed a 200% increase in urinary uric acid and reduction of urine pH by 0.9 in the former. This was accompanied by a significant increase in urinary uric acid supersaturation and an increased risk of forming uric acid crystals or stones in the urine [26]. All of these studies were relatively balanced in terms of nutrient composition other than protein. The effects of a high protein diet combined with carbohydrate restriction (the so-called Atkins diet ) were shown to include significant decreases in urine pH and doubling of urinary ammonium, titratable acidity, net acid excretion , and sulfate in both the initial “induction” phase and the maintenance phase. The level of undissociated uric acid also doubled [27]. A recent randomized, crossover metabolic study comparing the effect of different animal protein sources found that fish raised urinary uric acid and titratable acidity levels significantly higher than did beef or chicken [28]. Patients often have heard that they should lower their intake of red meat for health reasons, and patients with high urinary uric acid should be made aware of the effects of both chicken and fish on uric acid levels.
Given the effects of animal protein intake on urinary stone risk factors, limiting its intake may be a strategy to lower the risk of uric acid lithiasis. A study on the effects of moderate dietary protein restriction on idiopathic hypercalciuria and calcium nephrolithiasis demonstrated a significant reduction in 24-h urinary uric acid in addition to beneficial changes in urinary calcium, although urine pH levels were not reported [29]. Conversely, an increase in the proportion of dietary protein, when combined with a reduction in calories and carbohydrates, and replacement of refined carbohydrates with complex carbohydrates can lead to clinically significant reduction in serum uric acid, as well as weight loss [30]. Such a diet may be more palatable and therefore easier to comply with than a protein restricted diet.
Fructose
Fructose has been implicated in the development of metabolic syndrome , obesity, and hypertension [31], and, as previously mentioned, high levels of fructose intake can stimulate uric acid production [6]. High fructose corn syrup (HFCS ) has been shown to adversely affect lipid risk factors for cardiovascular disease such as postprandial triglyceride and fasting low density lipoprotein levels in a dose-dependent manner [32]. The same study also demonstrated an increase in serum uric acid level in men and women whose ad-lib diets were supplemented with HFCS-sweetened beverages at up to 25% daily energy requirement [32]. More provocatively, it has been demonstrated that mice fed a combination high-fructose/high-sodium diet had two- to fourfold increases in urinary uric acid, accompanied by substantial decreases in urinary stone inhibitors citrate and magnesium, when compared to standard diet [33]. Analysis of data from the Nurses’ Health Studies I and II and the Health Professionals Follow-Up Study suggests that fructose intake is associated with an increased risk of kidney stones independent of age, body size, and other dietary factors [34].
Specific Dietary Advice
In addition to maintaining a satisfactory fluid intake and avoiding HCFS-sweetened items, patients with high urinary uric acid can benefit from knowledge of the purine levels of various foods in order to design a meal plan. In a 2014 review, Kaneko and associates analyzed, tabulated, and published the purine content of over 270 common foods and calculated the amount of uric acid produced by ingestion of each item [35]. They classified the amount of total purines (as mg uric acid generated per 100 g of food item) into five groups (very low <50, low 50–100, moderate 100–200, high 200–300, and very high >300) (Table 10.1). For example, eggs, dairy, and fruit (banana and strawberry) contained almost no purine and were classified in the very low group. Seventy percent of the 38 vegetables analyzed were also classified in the very low group. Examples of vegetables with significant purine content were broccoli sprouts (moderate – 153 mg/100 g) and parsley (very high – 341 mg/100 g), although the latter is typically eaten in small quantities. Most cuts of beef, chicken, and pork, as well as fish, fell into the moderate category, whereas organ meats, particularly the liver, were typically high in purine. Interestingly, previous investigations have shown that all purines do not have equal effects on serum and urinary uric acid concentration, with hypoxanthine having the strongest effect [36] and guanine having negligible effects [36, 37]. They found that so-called “metallic” oily fishes , which have also been found to be beneficial in decreasing cardiovascular risk, had a high proportion of guanine and thus would not need to be limited in a low-purine diet .
Food item | Group | Exception | Group |
|---|---|---|---|
Cereals | 1–2 | ||
Beans | 1–2 | ||
Soybean products | 1–2 | Dried soybean, fermented soybean | 3 |
Eggs | 1 | ||
Dairy products | 1 | ||
Mushrooms | 1–2 | Dried shiitake | 4 |
Fruits | 1 | ||
Vegetables
Related posts: Dietary Assessment of Patients Who Form Kidney Stones
Health-Related Quality of Life and Urolithiasis
Malabsorptive Disorders and Inflammatory Bowel Disease: Assessing and Improving Nutritional Stone Risk
Therapeutic Nutritional Strategies When No Risk Factors Are Apparent
 Low Urine Citrate/Magnesium/Potassium
 Chronic Kidney Disease: Balancing Nutritional Needs with Nutrition Prevention of Kidney Stones
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