Journal of the American College of Nutrition, Vol. 19, No. 1, 16-22 (2000)
Published by the American College of Nutrition
Influence of Purine Intake on Uric Acid Excretion in Infants Fed Soy Infant Formulas
Matthew J. Kuchan, PhD,
Karin M. Ostrom, PhD,
Carla Smith, BS and
Peter E. Hu, PhD
Pediatric Clinical Nutrition Research, Medical and Regulatory Affairs (M.J.K., K.M.O., P.E.H.) Ross Products Division of Abbott Laboratories, Columbus, Ohio
Analytical Research and Development (C.S.), Ross Products Division of Abbott Laboratories, Columbus, Ohio
Address reprint requests to: Matthew J. Kuchan, PhD, Pediatric Clinical Nutrition Research, Medical and Regulatory Affairs, Dept. 105215/DN3, Ross Products Division of Abbott Laboratories, 625 Cleveland Avenue, Columbus, OH 43215-1724.
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ABSTRACT
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Objective: These studies tested the hypothesis that increasing intake of purines, delivered as RNA from soy protein-based infant formula, would increase urinary uric acid excretion in infants.
Methods: Study One examined the influence of feeding on serum uric acid in a total of 178 infants from four separate trials with infants fed commercial and experimental soy-based and milk-based infant formulas or human milk. Studies Two and Three compared the effect of a standard purine soy formula (STD Purine; 180 mg purines/L from RNA) and a reduced purine soy formula (Reduced Purine; 65 mg purines/L; 26 mg/L from RNA and 39 mg/L from ribonucleotides) on urinary uric acid excretion in infants. In Study Two, 11 infants ranging in age from 16 to 128 days of age were fed both formulas in a random crossover design. Complete 72-hour urine collections were done at the end of each 11-day feeding period. Urinary uric acid excretion was expressed as mmol/day. In Study Three, 33 infants were enrolled before eight days of age and randomized to one of the formulas one week later. Spot urine samples were collected at 28 and/or 56 days of age and urinary uric acid concentration was expressed as mmol/mmol creatinine.
Results: In Study One, each of the feedings resulted in mean serum uric acid levels within normal reference ranges. Soy formula led to higher serum uric acid levels than human milk, and human milk to levels indistinguishable from cow milk-based formulas. In Study Two, infants excreted significantly more uric acid in the urine when fed the STD Purine formula compared to the Reduced Purine formula (0.86±.04 vs. 0.57±.04 mmol/d) (p=0.006). In Study Three, infants fed the STD Purine formula had a significantly higher concentration of uric acid in their urine compared to those fed the Reduced Purine formula (2.1±0.2 vs. 1.4±0.1 mmol uric acid/mmol creatinine) (p=0.0001).
Conclusion: These data indicate that healthy infants can digest RNA and subsequently absorb the liberated purine ribonucleotides as determined by urinary uric acid concentration.
Key words: uric acid, purines, soy infant formula, RNA, urine
Abbreviations: mmol=millimole • NAD=nicotinamide adenine dinucleotide • oxidized • NADH=nicotinamide adenine dinucleotide • reduced • RNA=ribonucleic acid
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INTRODUCTION
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Compounds derived from the purine nitrogenous bases, adenine and guanine are essential to cellular metabolism and function. Whereas most mammals catabolize purines to uric acid, which is oxidized by uricase to urea and allantoin, humans and primates produce uric acid as the end product of purine catabolism due to the absence of uricase. This metabolic trait has been used as a diagnostic tool to determine if adult humans can absorb dietary purines.
Increased purine intake has been found to increase urinary excretion of uric acid in adults [1–6]. Recovery of supplemented purines as urinary uric acid was nearly quantitative [5] and a dose-response relationship was observed between urinary uric acid output and the intake of purines from either RNA or ribonucleotides [3, 5]. These observations provide compelling evidence that adults are capable of absorbing dietary purines fed as free ribonucleotides and as RNA, the polymeric form of ribonucleotides.
Infants consume significant concentrations of RNA from both human milk [7] and soy protein-based formula [8, 9]. Whether the RNA in human milk and soy formula is digested and the constituent ribonucleotides absorbed by infants is unknown. Soy protein-based formula typically contains about 300 mg nucleotides/L derived from RNA inherent to the protein isolate. Human milk contains on average 68–72 mg nucleotides/L and as much as 150 mg/L [7]. About half of the total nucleotide content of human milk is derived from RNA [7]. In animals and adult humans, dietary RNA is hydrolyzed to ribonucleotides and then to ribonucleosides, the predominant form absorbed in the intestinal mucosa [reviewed in 10]. Human milk contains ribonuclease capable of hydrolyzing RNA [11, 12], and in vitro data suggest that fetal intestine possesses the necessary enzymes to digest RNA and ribonucleotides to ribonucleosides [12]. However, there is no direct evidence that infants digest RNA and absorb the liberated ribonucleotides.
This study was designed to investigate whether infants consuming soy formulas differing in RNA and, therefore, purine content differentially excrete uric acid. If urinary uric acid excretion increased when infants consumed soy formulas containing more RNA, evidence would be provided that human infants can digest dietary RNA and absorb the resulting ribonucleotides and ribonucleosides.
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METHODS AND MATERIALS
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Study Design
In Study One, serum samples from 178 infants enrolled into four separate trials were analyzed for uric acid. Subjects were fed commercial soy protein and cow milk protein based infant formulas. In three of the four trials, subjects with a sufficient volume of serum remaining for uric acid analysis represented a subset of the original cohort (Table 1). Depending on the trial, subjects ranged from birth to 14 days of age at enrollment and blood samples were drawn at ages ranging from 14 to 112 days. Although group means were compared within trials, statistical comparisons were not made across the trials constituting Study One.
In Study Two, a blinded randomized crossover design was used to conduct metabolic balance studies with each of two study formulas in normal infants. The formulas were masked through the use of codes and were studied in a predetermined and random order. The interval between balance studies was at least 13 days, and study formula was fed for at least 13 days prior to collection of samples. At the end of each feeding period, urine was collected for 72 hours between fecal carmine markers using procedures described elsewhere [13]. An aliquot from the pooled urine collection was frozen at -20°C until analysis. Formula intake was determined by weighing prepared bottles of formula before and after each feeding. Intake of formulas other than the study formulas, or solid foods, was not allowed.
In Study Three, spot urine samples were collected from subjects enrolled into a randomized, parallel study. Infants were enrolled before eight days of age and were given Similac with Iron (prior to commercial supplementation with nucleotides). At 14 days of age, the subjects were randomly assigned to one of four masked formulas. The present analysis of Study Three is limited to two of the four formulas originally fed. The two formulas reported on here were the same as those used in Study Two. Only the assigned formula was consumed until 56 days of age. Spot urine samples, of at least 5 mL, were collected using urine bags on days 28 and 56. Urine samples were immediately frozen until analysis. Formula intake was estimated from daily intake diaries completed by each subject’s parents for 13 days before the 28-day visit and for six days before the 56-day visit. Intake of formulas other than the study formulas, or solid foods, was not allowed.
Subjects
The formulas fed in each of the trials constituting Study One and subject characteristics are summarized in Table 1.
Characteristics of the subjects enrolled into Study Two are shown in Table 2. No differences were detected between the feeding sequences for any of the measures shown.
In Study Three, at least one urine sample was collected from each of 33 subjects (Table 2). No differences were detected among the feeding groups for any of the measures shown. All of the subjects were propropriate for gestational age, with the exception of one large-for-gestational-age subject in the Reduced Purine formula group. That subject was judged to be healthy by the physician and was therefore included in the analysis.
Each of the study protocols was approved by Institutional Review Boards, and a parent/legal guardian of each subject granted informed consent.
Feedings
One of the following six formulas was fed in Study One: 1) Isomil® Soy Formula with Iron, 2) experimental soy formula supplemented with 72 mg nucleotides/L, 3) experimental Similac® with Iron (as marketed in 1997; supplemented with 72 mg nucleotides/L), 4) Similac® with Iron (as marketed from 1987 to 1991; not supplemented with nucleotides, 8–12 mg/L inherent), 5) experimental Similac supplemented with calcium (based on formula marketed from 1987 to 1991), 6) Enfamil® with Iron (as marketed in 1987 to 1988; not supplemented with nucleotides) or human milk. With the exception of Enfamil (Mead Johnson), each of the formulas was manufactured by Ross Products Division of Abbott Laboratories.
Subjects enrolled into Studies Two and Three consumed commercially available STD Purine formula (Isomil® Soy Formula with Iron) and/or an experimental Reduced Purine version of that formula. Study formula composition was similar except for purine content (Table 3). Ninety-eight percent of the purines in the STD Purine formula were derived from RNA, compared to 40% in the Reduced Purine formula. The remaining purines in the Reduced Purine formula were present as free ribonucleotides and ribonucleosides. Uric acid could not be detected in the soy protein isolates used to manufacture the Reduced Purine and STD Purine formulas. The difference in nitrogen concentration between the study formulas was approximately 0.022 g/L, consisting of only 0.8% of the total nitrogen concentration. Each of the formulas met or exceeded nutrient levels specified by the Infant Formula Act [14].
Measurement of uric acid and creatinine
Urinary concentration of uric acid was determined by the uricase-catalase-alcohol dehydrogenase coupled method described elsewhere [15, 16], using modified procedures specifically for the Abbott Spectrum Epx Clinical Chemistry Analyzer (Abbott Laboratories, North Chicago, IL). Briefly, the procedure is based on oxidation of uric acid to allantoin and hydrogen peroxide. Catalase then catalyzes the reaction of ethanol with hydrogen peroxide to yield acetaldehyde, which is reduced by alcohol dehydrogenase with the concomitant oxidation of NADH to NAD. The degree of NADH oxidation is proportional to the concentration of uric acid and is detected by the decrease in absorbance at 340 nm. The same methodology was applied to serum samples and to soy protein isolates (twice extracted with distilled water).
Urinary creatinine was determined by measuring the Jaffe reaction between creatinine and alkaline picrate [17] on an Abbott Spectrum EPx Clinical Chemistry Analyzer. Briefly, creatinine reacts with alkaline picrate to form a colored complex with an absorbance maximum at 516 nm. The change in color intensity is proportional to the concentration of creatinine.
Statistical Analyses
Serum uric acid concentrations resulting from the three feedings in Trial A (Study One) were compared using Analysis of Variance. Additionally, concentrations from the four feeding groups in Trial C (Study One) were also compared using Analysis of Variance. Formula intake and uric acid output from Study Two were analyzed by the Wilcoxon Exact test after adjustment for the period effect (p=0.073). As suggested by Senn [18], adjustment for a potential carry-over effect was not included in the model. Formula intake and urinary uric acid/creatinine data generated from Study Three were compared using Analysis of Variance. These analyses represent post hoc biochemical and statistical analysis of urine samples collected for a different purpose. Comparisons with a p-value less than 0.05 were considered statistically significant.
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RESULTS
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Mean serum uric acid concentrations in Study One were all within published, age-specific reference ranges. The reference range for serum uric acid is 1.4–5.3 mg/dL for infants from one to three months of age [19]. Infants fed Isomil with Iron soy formula or experimental soy formula had significantly higher serum uric acid concentrations than those fed human milk (Figure 1; Trial A). Serum uric acid concentrations in infants fed cow milk-based infant formulas without supplemental nucleotides were not different from those of infants fed human milk (Fig. 1; Trial C).
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Fig. 1. Serum uric acid concentration in infants fed different infant formulas or human milk. The data result from 4 separate trials as indicated by the shading. Trial A,  ; infants were enrolled from birth to 8 days of age (Isomil with Iron, experimental soy formula with supplemental nucleotides 72 mg/L, human milk; n=20/group). Trial B,  ; infants were enrolled from birth to 14 days of age and were fed Similac with Iron supplemented with nucleotides 72 mg/L (n=23). Trial C, ; infants were enrolled from birth to 2 days of age [human milk, n=19; Similac with Iron not supplemented with nucleotides, n1=20 and n2=18 (same formula supplemented with calcium), and Enfamil with Iron, n=20]. Trial D,  ; infants were enrolled between birth and 8 days of age and fed Similac with Iron not supplemented with nucleotides (n=22). Values represent mean ± SEM. Means values generated within trials were compared statistically, however, comparisons were not done across the trials constituting this Study. * No differences were detected between the groups in trial C.   Means from trial A with different symbols differed, p<0.0001. Dashed lines indicate reference standards for infants 1 to 3 months of age [19].
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In Study Two, mean urinary uric acid excretion was significantly lower when infants were fed the Reduced Purine formula than when fed the STD Purine formula (p=0.006) (Fig. 2). On average, urinary uric acid output increased 50% when the subjects were fed STD Purine compared to Reduced Purine. Urinary uric acid output was 0.6 mmol/day when the infants were fed Reduced Purine and 0.9 mmol/day when fed STD Purine. All of the subjects excreted more uric acid when fed the STD Purine formula; however, the change was small in one subject. That one subject consumed 228 g of green bean and 112 g of pear baby foods during the Reduced Purine urine collection period and 16 g of green bean and 339 g of pear baby foods during the STD Purine urine collection period. Since green beans contain high levels of purines and pears contain very low concentrations, these solid foods may have obscured the formula-dependent difference in uric acid output. Total urine volume during the 72-hour balance period was not affected by formula with 1.42±0.96 L and 1.42±1.08 L of urine collected when infants were fed the Reduced Purine and the STD Purine formulas, respectively. Total formula intake during the 72 hour balance period also was not different. Body weight did not differ between feeding sequences at the end of balance periods one and two.
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Fig. 2. Urinary uric acid output in infants fed the two study formulas. Complete 72 hour urine collections were analyzed for uric acid and the average output per 24 hours calculated. Each symbol indicates the result of one balance study with results in the same infant connected by lines. Output was higher (p=0.006) while subjects were fed the STD Purine formula compared to when the subjects were fed the Reduced Purine formula.
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In Study Three, mean urinary uric acid excretion was significantly lower in subjects fed the Reduced Purine formula compared to those fed the STD Purine formula (p=0.0001) (Fig. 3)W. Mean uric acid excretion (mean ± SEM) for the feeding groups was 1.36±0.16 and 2.13±0.05 mmol uric acid/mmol creatinine for the Reduced Purine and STD Purine formula groups, respectively. Formula intake recorded by parents did not differ between the feeding groups, with group means of 694 and 715 mL/day for days 15 to 27, for the Reduced Purine and STD Purine formulas, respectively. Likewise, parents reported similar intake for days 50 to 55, with group means of 841 and 872 mL/day, for the Reduced Purine and STD Purine formulas, respectively. Body weights were similar among the feeding groups at 56 days of age.
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Fig. 3. Urinary uric acid excretion in infants fed the two study formulas. Spot urine collections were done at 28 and/or 56 days of age and the average excretion as a ratio of creatinine concentration calculated. Each symbol represents a subject and at least one uric acid measurement. Bars indicate group means, which differed, p=0.0001.
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DISCUSSION
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Infants fed soy formula had higher serum uric acid concentrations than those fed human milk, and human milk and cow milk-based formulas led to indistinguishable levels. This latter observation is not surprising, as the range in purine intake represented by these feeding is small compared to blood uric acid pools. The soy formula effect, however, led us to hypothesize that infants have the ability to liberate and absorb ribonucleotides from soy RNA. Soy protein-based infant formula contains purine ribonucleotides, occurring almost exclusively as RNA, at concentrations (310 mg/L) [8, 9, 20] substantially higher than those in either human milk (68 to 72 mg/L) [7] or cow milk-based formulas (8 mg/L to 72 mg/L) [21]. The composition of the feedings in Study One differed in many ways including the concentration of sucrose, which is known to be uricosuric [22, 23]. Therefore, we measured urinary uric acid concentration in infants fed soy formulas differing only in purine concentration and the source of purines. The results of Studies Two and Three indicated urinary uric acid excretion was increased by higher purine intake predominantly in the form of soy RNA.
Formula intake and the content of non-purine uricosuric components of the formulas, including sucrose [22,23], protein [3] and fat [24], as well as free ribonucleotides [5, 6], can account for the difference observed. The higher free ribonucleotide concentrations in the Reduced Purine formula likely blunted the hypothesized RNA-dependent differences observed. Finally, we found negligible concentrations of uric acid in the soy protein isolates used to make the formulas studied despite the presence of uricase [25] in soybeans. Thus, formula composition and formula intake do not account for the difference observed in urinary uric acid excretion.
The most likely explanation for this observation is that infants are capable of digesting RNA and of absorbing the liberated ribonucleotides. Alternate explanations, including the differences being driven purely by decreased purines in the Reduced Purine formula, limited/absent absorption of free nucleotides and/or limited or absent hydrolysis of RNA hydrolysis, are inconsistent with the results obtained. Absorption and excretion of soy RNA-derived purines is consistent with previous reports [12], indicating fetal intestine possesses the necessary enzymes for RNA digestion. Pyrimidines have been shown to be well absorbed in animal studies using radiotracers [26, 27]. While similar studies have not been done in humans, the current data do not offer any reason that infants would not be capable of absorbing pyrimidines consumed as RNA.
When considered together, the serum and urine data indicate that increased purine intake from standard soy formula leads to small increases in serum uric acid concentration accompanied by measurable changes in urinary uric acid excretion. This observation suggests that the infant responds to increased purine intake by increasing excretion of catabolized purines. Data from radiotracer studies in adults are consistent with this speculation [28, 29].
The data reported here are consistent with those from previous studies with adults. Healthy adults fed a purine-free diet excreted more uric acid when given supplemental RNA [3, 6] or free purine ribonucleotides [5, 6]. The adult subjects studied by Griebsch and Zollner were fed 9 and 18 mg purine/kg/day, very similar to the 10 and 21 mg purine/kg/day fed to infants in the present studies. Approximate average daily excretions in the adults were 8 and 12 mg uric acid/kg/day, respectively [3–5]. Consistent with the literature [30], we observed higher weight-adjusted daily excretions in Study Two: 19 and 30 mg uric acid/kg/day.
The values from Study Three are consistent with the available literature. Kaufman et al. [31] studied 171 infants and found that uric acid excretion (mmol/mol creatinine) decreases from about 1.7 at birth (with a 2 standard deviation range from 0.2 to 2.9) to about 1.3 at one year of age (range from 0.6 to 2.2). A wide range exists within the literature values possibly related to age-dependent decrease in uric acid excretion. Van Acker et al. [32] reported a median urinary uric acid concentration of 3.03 mmol/mmol creatinine and a 97th percentile of 4.71 mmol/mmol creatinine in 510 healthy, mostly breastfed four day-old infants. In contrast, Grivna et al. [33] reported a mean urinary uric acid concentration of 0.3 mmol/mmol creatinine in infants from 2 to 12 months of age with a median age of 6.5 months. Study Three values fall within the age dependent range of Kaufman et al. [31] and are consistent with the data of Van Acker et al. [32], even when considering our subjects were fed formulas higher in purines than standard milk-based formulas or human milk.
Approximately half of the total ribonucleotides in human milk [7, 12] are present as RNA; this represents a substantial concentration of ribonucleotides [34, 7, 12]. While preterm infants fed human milk excrete 1.2 mmol uric acid/mmol creatinine, those fed standard milk-based infant formula excrete 0.8 mmol/mmol [35]. Differences in uric acid intake do not account for this difference as human milk contains only 10 to 20 µmol uric acid/100 mL [36, 37]. These reports likely overestimate human milk uric acid concentrations, since human milk contains enzymes capable of rapidly catabolizing purines to uric acid, unless immediately deactivated [12]. When the present data are taken together with these observations, the data show that infants are able to digest human milk or soy RNA and subsequently to absorb its constituent purine ribonucleotide monomers.
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CONCLUSION
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Overall, these data suggest that, like the adult, the infant responds to increased purine intake with increased uric acid excretion. The infant is capable of digesting RNA and of absorbing the resulting purine ribonucleotides.
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ACKNOWLEDGMENTS
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The authors wish to acknowledge Ekhard Ziegler, MD, and his research staff for the collection of the urine samples and Mike Montalto, PhD, for editorial assistance.
Received July 1, 1999.
Accepted November 1, 1999.
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ABSTRACT
INTRODUCTION
