The Effect of Lemonade and Diet Lemonade Upon Urinary Parameters Affecting Calcium Urinary Stone Formation

Introduction

Kidney stones affect 9% of the US population ¹ and the incidence of kidney stones continues to rise. ² In addition to surgery, medical therapy can contribute to the management of nephrolithiasis. Although increased fluid consumption and dietary modifications may lower the risk of kidney stone formation, metabolic testing is recommended by the American Urological Association to identify and manage high-risk stone formers. ³ Among factors identified on metabolic testing, hypercalciuria, hyperuricosuria, and hypocitraturia have been shown to predispose patients to nephrolithiasis. ⁴

Citrate (2-hydroxy-1,2,3-propanetricarboxylic acid) is an established stone inhibitor ^5,6 and is recommended for patients with low urinary citrate to reduce the risk of recurrent calcium nephrolithiasis. ³ Although pharmacological therapy with potassium citrate increases urine citrate and pH ⁷ and lowers the risk of recurrent calcium nephrolithiasis, ⁸ it can be limited by medication side effects and cost. ^9,10 Studies evaluating the efficacy of lemonade therapy have demonstrated conflicting results, where some studies demonstrate that lemonade increases urinary citrate, ^{11 –14} whereas other studies have shown no benefit. ^15,16 Furthermore, calorie and sugar intake from these beverages can contribute to weight gain, obesity, and diabetes mellitus, which can further increase the risk of kidney stone formation. ^17,18 Although the citrate content of various beverages and diet sodas have been evaluated, ^{19 –21} the effect of low-calorie beverages upon urine parameters is limited in the literature. The purpose of this study was to compare the effects of regular and diet lemonade upon urinary parameters affecting kidney stone formation.

Materials and Methods

This prospective blinded randomized controlled crossover study was approved by our Institutional Review Board. Fourteen healthy adult health care professionals (seven men and seven women) were recruited. Serum chemistry was obtained to rule out renal insufficiency (glomerular filtration rate <60 mL/min/1.73 m ² ), abnormal electrolyte levels, and metabolic acid–base disorders. Exclusion criteria included renal insufficiency, history of urinary tract obstruction, recurrent or active urinary tract infection, hematuria, pregnancy, and conditions with a risk of metabolic derangements, such as renal tubular acidosis, hyperparathyroidism, chronic diarrhea, other gastrointestinal disease, gout, hypercalcemia, and hyperkalemia. No medication use or prior stone history was reported by participants. One female participant became pregnant and one male participant withdrew. Twelve subjects ultimately completed the study.

A controlled low-oxalate diet, including 100–150 mEq sodium/day, 800–1200 mg calcium/day, and 1–1.2 g protein/kg body weight/day, was prepared by a professional dietician (G.H.). The food was prepared in the hospital cafeteria and delivered to participants for baseline, regular, and diet lemonade phases. Participants received an identical menu in all three phases and did not take any vitamins or supplements during the study period. Participants were able to consume water ad lib but no other beverages (soda, coffee, or alcohol). After baseline measurements on the controlled diet with ad lib water consumption, participants were randomized to consume either 2 L of regular lemonade (Minute Maid^®, Sugar Land, TX) or 2 L of diet lemonade (Minute Maid Light^®) daily for 5 days (Fig. 1) while on the same controlled diet. The volume of lemonade intake was set at 2 L as this was consistent with previous studies evaluating lemonade therapy. ^11,13 Consumption of 2 L of regular or diet lemonade (3% lemon juice in each beverage) was equivalent to 60 mL of lemon juice (1–2 medium-sized lemons). Two 24-hour urine collections (Litholink Corporation, Chicago, IL) were obtained on days 4 and 5 on the controlled diet and for the regular and diet lemonade study phases for a total of six urine collections per participant. There was a 1-week washout period between study phases.

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FIG. 1.

After baseline measurements on days 4 and 5 of the controlled diet, patients were randomized in a two-phase crossover study design to consume regular lemonade and diet lemonade. Urine was tested on days 4 and 5 of the study phases.

Primary outcomes were urine citrate, pH, and volume determined by 24-hour urine collections. Secondary outcomes included supersaturation of calcium oxalate, calcium phosphate, and uric acid. Additional measurements included the pH of beverages, content of citrate, malate, alkali, calorie, and sugar, and cost for 2 L of each beverage. Citrate and malate contents were measured by ion chromatography (Dionex Corporation, Sunnyvale, CA) using potassium hydroxide as the eluent, an AS11 column, and a conductivity detector. Beverage pH was measured using a pH electrode. Total alkali of each beverage was calculated from these measured values and the pKa for the organic acids (3.14, 4.77, and 6.39 for citric acid ²² and 3.40 and 5.11 for malic acid ²² ). Calorie and sugar content were provided by nutrition labels for both beverages (Appendix Fig. 1) and calculated by volume.

The Friedman test was used to compare 24-hour urine parameters at baseline and with regular and diet lemonade consumption. A p-value <0.05 was considered significant. Post hoc analysis was performed for parameters with significant differences using the Wilcoxon test to compare differences between baseline and regular lemonade, baseline and diet lemonade, and regular and diet lemonade. For pairwise comparisons, a p-value <0.05 on post hoc analysis was considered statistically significant.

Results

Demographics and creatinine excretion of participants are reported in Table 1. The validity of 24-hour urine collections was confirmed by creatinine excretion demonstrating <10% variation between study phases. Consistent with previous studies, ^{11 –13} regular and diet lemonade were both well tolerated with no significant adverse effects. All subjects reported strict compliance with their controlled diet and beverage intake.

Measurements from 24-hour urine collections at baseline, with regular lemonade, and with diet lemonade are listed in Table 2. Participants did not exhibit metabolic abnormalities at baseline. Urine volume significantly increased from baseline 1.9L to 2.6L with regular lemonade (p = 0.006) and 2.8 L with diet lemonade (p = 0.002). Urinary citrate was significantly higher with diet lemonade than regular lemonade (diet 761 vs regular 581 mg; p = 0.005). Urinary citrate with diet lemonade consumption was significantly increased (104 mg) from baseline values (diet 761 vs baseline 657 mg; p = 0.041) but decreased with regular lemonade consumption (baseline 657 vs regular 581 mg; p = 0.041). No significant changes were observed in urinary pH, calcium, oxalate, phosphate, uric acid, magnesium, sodium, or chloride.

The supersaturations of calcium oxalate, calcium phosphate, and uric acid are given in Table 3. The supersaturation of calcium oxalate significantly decreased from baseline with diet lemonade only (baseline 4.1 vs diet 2.7; p = 0.006). Supersaturation of calcium phosphate significantly decreased from baseline with both regular lemonade (baseline 1.1 vs regular 0.6; p = 0.005) and diet lemonade (baseline 1.1 vs diet 0.6; p = 0.008). There were no significant changes in the supersaturation of uric acid for either beverage (baseline 0.5 vs regular 0.6 vs diet 0.4; p = 0.37).

The pH as well as citrate, malate, and alkali contents of both beverages are listed in Table 4. Daily consumption of 2 L of regular lemonade and diet lemonade resulted in a respective intake of 55.2 mmol (168.4 mEq) and 55.8 mmol (170.2 mEq) of citrate and 12.2 and 16.0 mEq of total alkali content. The citrate and alkali content of regular lemonade in our study was consistent with that reported in the literature. ^{19 –21} Compared with diet lemonade, regular lemonade had a daily excess of 805 calories and 225 g of sugar. Regular lemonade has a daily total of 833 calories and 225 g of sugar consumed with 2 L. In contrast, diet lemonade has a daily total of 28 calories and 0 g of sugar consumed with 2 L. The cost of a 2 L bottle of either regular lemonade or diet lemonade was $1.99.

Discussion

Urinary citrate inhibits nephrolithiasis by forming a soluble complex with urinary calcium. This lowers the supersaturation of calcium oxalate and calcium phosphate by binding to the surface of crystals and acting as a direct inhibitor of crystal growth and aggregation. ^5,6 Lower levels of this urinary stone inhibitor can be a significant risk factor for recurrent calcium nephrolithiasis and has been identified in 44.3% of stone formers. ⁴ Medical management for hypocitraturia includes increased fluid intake, dietary modifications, and pharmacological therapy. ³

Pharmacological therapy with potassium citrate has been shown to significantly increase urinary citrate and pH ⁷ and decrease the risk of kidney stone recurrence. ⁸ A Cochrane review of potassium citrate, potassium–sodium citrate, and potassium–magnesium citrate in the management of calcium stones demonstrated that citrate therapy can significantly increase urinary citrate levels and decrease stone formation and growth. ⁹ Pharmacological therapy with potassium citrate, however, can be limited by a cumbersome regimen, medication side effects, and financial burden. Potassium citrate is administered in the form of multiple tablets, crystal packets for dilution, or an oral solution that needs to be consumed 3–4 times daily. Although adverse events are limited to upper gastrointestinal disturbance in the form of stomach pain, nausea, and bloating, they have nevertheless resulted in a higher dropout rate than placebo. ⁹ The financial burden of potassium citrate can also contribute to noncompliance. As medication coverage can vary with insurance companies, the retail cost of potassium citrate (Urocit-K; Mission Pharmacal Company, San Antonio, TX) is quoted to be $231.88 for 100 tablets of 10 mEq. ¹⁰ For 60 mEq daily dosing, patients would need to consume six tablets for a daily cost of $13.91 and an annual cost of up to $5078.17 without sales tax. In contrast, regular or diet lemonade therapy has a substantially lower cost of $726.35 without sales tax annually. Furthermore, periodic blood testing with pharmacological therapy may be necessary to monitor for hyperkalemia in patients treated with potassium citrate. ³ Hyperkalemia can be of particular concern in patients with renal dysfunction.

Although previous studies have demonstrated the potential efficacy of lemonade or lemon juice therapy as an alternative means of increasing urinary citrate, ^{11 –14} other studies showed no benefit ^15,16 and the effect of regular lemonade may be limited. However, variations in the amount, formulation, concentration, and preparation of different lemon juice-based therapies ^{11 –16} make a comprehensive understanding of the isolated effects of lemonade difficult. Although there was a decrease in calcium phosphate supersaturation with regular lemonade consumption in our study, this may be partially attributed to the significant increase in urine volume. Furthermore, urinary citrate and supersaturation of calcium oxalate did not improve with consumption of regular lemonade in our study. This may be attributed to lemonade delivering citrate in the form of citric acid as opposed to a citrate salt. Despite high citrate levels in regular and diet lemonade, urinary citrate levels cannot be solely attributed to the amount of citrate content that is consumed from each beverage.

The amount of urine citrate excretion ultimately depends on both plasma citrate levels and reabsorption of citrate at the proximal tubule, influenced by acid–base status (Fig. 2). ²³ Although a small amount of dietary citrate directly increases plasma citrate levels, the majority of dietary citrate absorbed from the gastrointestinal tract undergoes oxidation in the liver to form bicarbonate. ²⁴ The systemic alkaline load from this reaction depends on whether citrate is consumed as an acid or a salt. Citrate consumed in the form of citric acid, such as in lemonade, is accompanied by protons that neutralize the bicarbonate formed in the liver and negates systemic alkalinization. ²⁵ In contrast, citrate in the form of potassium or sodium salts enables systemic alkalinization through oxidation into bicarbonate without a neutralizing proton. The resultant alkalosis decreases citrate reabsorption at the proximal tubule and allows for more citrate excretion in the urine, ²³ and systemic alkalinization is more influential than direct increases in plasma citrate in determining renal citrate excretion. ²⁶ Malate content in a beverage also contributes to citraturia in a similar manner with regard to providing a systemic alkaline load when consumed as a salt. ²⁶ In our study, there was a modest and similar contribution of malate to the alkali content of both regular and diet lemonade.

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FIG. 2.

Factors that affect urinary citrate excretion after consumption of dietary citrate and the potential neutralizing effect of delivering citrate in the form of citric acid.

A randomized crossover comparison between lemonade and orange juice demonstrated a limited increase in urinary citrate after lemonade consumption. ¹⁶ Despite equal levels of beverage citrate, orange juice consumption resulted in a greater increase in urinary citrate and pH that was attributed to its higher pH and, therefore, alkali load. ¹⁶ As commercially available orange juice also exhibits high levels of citrate, ^19,20 orange juice consumption has been similarly associated with increased urinary citrate and an increase in urine pH comparable with that of potassium citrate. ^16,27,28 These improvements may be counteracted by an increase in urinary oxalate, ^16,28 however, as high levels of ascorbic acid in orange juice can contribute as precursors to oxalate formation.

Although diet lemonade also delivers citrate as citric acid, diet lemonade consumption nevertheless increased urine volume and citrate and decreased the supersaturation of both calcium oxalate and calcium phosphate in our study. As there was no significant difference in urine volume between regular and diet lemonade, the reduction in the supersaturation of calcium oxalate with diet lemonade only cannot be solely attributed to an increase in urine volume or the marginally higher citrate content in diet lemonade. Similar to orange juice, the increased citraturic effect and subsequently decreased calcium oxalate supersaturation from diet lemonade may be, in part, because of its slightly higher pH and alkali content as this may contribute to systemic alkalinization and citrate excretion at the proximal tubule.

Consumption of 2 L of diet lemonade also reduced daily calorie intake by 805 calories and sugar intake by 225 g compared with regular lemonade, which would avoid an annual excess of 293,825 calories consumed that could contribute to substantial weight gain. Furthermore, epidemiological studies have demonstrated a risk of nephrolithiasis associated with high fructose consumption. ²⁹ Other low-calorie beverages may provide alternative options for patients with hypocitraturia. Lemon-flavored Crystal Light^® is another low-calorie beverage that may lower the risk of kidney stone formation as its citrate concentration appears to be comparable with that of lemonade. ²⁰ Similar to diet lemonade, this beverage can also provide a low-calorie alternative for patients as it only contains five calories per serving. However, the alkali content and effect of this beverage on urine parameters has yet to be evaluated in healthy subjects or stone formers. Evaluation of the citrate content of diet sodas demonstrated high citrate and alkali content in citrus-based sodas, such as Diet 7-Up^®, Diet Sunkist^®, or Sierra Mist Free^®. ²¹ The potential benefit of diet sodas on urine parameters has yet to be demonstrated as Caffeine-Free Diet Coke^®, Fresca^®, and Diet Sunkist^® were not found to significantly improve urinary citrate in healthy subjects. ^30,31 To our knowledge, this is the first study that prospectively demonstrates improvements in 24-hour urinary parameters after consumption of a low-calorie beverage.

As the ideal beverage for the prevention of recurrent nephrolithiasis remains to be elucidated, diet lemonade therapy exhibits potential clinical benefit through its effects upon urinary parameters. Despite the improvement in urinary volume and supersaturation of calcium phosphate, consumption of regular lemonade does not appear to improve urinary citrate levels and may have a limited role in the risk of kidney stone formation. This finding is consistent with those of previous studies. ^15,16 As consumption of diet lemonade demonstrated significant improvements in urine volume, citrate, and supersaturation of calcium oxalate and phosphate in our study, diet lemonade may provide an alternative to regular lemonade therapy that also drastically reduces overall calorie and sugar intake. Diet lemonade therapy may be particularly appropriate in the subset of patients who dislike water.

Our study has some limitations. Our findings are limited to a short-term period and additional studies are needed to evaluate the long-term effect of diet lemonade therapy on urine parameters. This study was also conducted on a small group of healthy individuals and not stone formers to evaluate the physiological impact of different beverages in subjects without metabolic derangements. Additional studies are needed to assess the potential benefit of diet lemonade in hypocitraturic patients as well as the potential risks of consuming beverages with artificial sweeteners as these agents may result in physiological responses and metabolic changes that have yet to be completely elucidated. ³²

Conclusion

Diet lemonade may be a moderately effective low-calorie cost-effective option for decreasing the risk of calcium nephrolithiasis through an increase in urine volume and urinary citrate in addition to a reduction in the supersaturation of calcium oxalate and calcium phosphate. In contrast, regular lemonade does not appear to significantly improve citrate or calcium oxalate supersaturation.