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Metabolic Syndrome and the Genesis of Uric Acid Stones
REVIEW
Metabolic Syndrome and the Genesis of Uric Acid Stones Naim M. Maalouf, MD Uric acid stones are significantly more common among nephrolithiasis patients with type 2 diabetes, obesity, and/or the metabolic syndrome. The principal metabolic feature responsible for this association is an overly acidic urine, which leads to the precipitation of sparingly soluble uric acid crystals in urine and subsequent development of stones. The unduly acidic urine in uric acid stone formers is caused by a combination of excessive dietary intake of animal proteins and a defect in renal ammoniagenesis and/or excretion that leads to impaired buffering and amplifies the acidic urine caused by an increased acid excretion. Ó 2011 by the National Kidney Foundation, Inc. All rights reserved.
U
RIC ACID (UA) stones constitute a minority of all cases of nephrolithiasis, but are significantly more common among stone formers with the metabolic syndrome. Overly acidic urine is recognized as the major abnormality responsible for UA nephrolithiasis. This article reviews the epidemiology, pathogenesis, and management of UA stone disease, with a focus on its recent association with the metabolic syndrome and the underlying mechanisms.
Epidemiology UA nephrolithiasis comprises 8% to 10% of all kidney stones in the United States; 16% in Okinawa, Japan; and 25% in certain regions in Germany.1 Moreover, this prevalence is significantly higher in certain subsets of stones formers; stone formers with type-2 diabetes mellitus (T2DM) have UA stones as the main stone constitDepartment of Internal of Medicine and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas. Maalouf has no conflicts relevant to this publication. Address reprint requests to Naim Maalouf, MD, The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885. E-mail: naim.
[email protected] Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.10.015
128
uent more frequently than stone formers without diabetes.2–4 For example, in 1 retrospective study, UA stones constituted 34% of the stone burden in patients with T2DM as compared with 6% in stone-forming patients without diabetes.3 A higher prevalence of UA stones has also been described among obese stone formers.5,6 It also seems that greater body mass index and T2DM are independent risk factors for UA nephrolithiasis.4 The clustering of obesity and insulin resistance along with hypertension and dyslipidemia describes the metabolic syndrome. In recent studies, a large proportion of UA nephrolithiasis patients were found to be affected by various features of the metabolic syndrome.7,8 In summary, the metabolic syndrome and its individual features are linked with UA nephrolithiasis.
UA Metabolism and Physical Chemistry UA is the end product of purine metabolism in human beings who display serum and urinary UA concentrations significantly higher than other mammals. Because urinary excretion of UA in human beings generally exceeds 600 mg/day, the limited urinary UA solubility of 96 mg/L presents a great risk for UA precipitation. In urine, UA, a weak acid, is known to be in equilibrium with its base urate as follows: UA 4 H1 1 urate2. The pKa for this equilibrium is 5.35 at 37 C, which lies within the clinical Journal of Renal Nutrition, Vol 21, No 1 (January), 2011: pp 128–131
METABOLIC SYNDROME AND URIC ACID STONES
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range for urine pH, thus rendering urine pH an important determinant of urinary UA solubility. Unduly acidic urine (urine pH, #5.5) leads to precipitation of sparingly soluble UA, thereby increasing the predisposition to UA nephrolithiasis. Another important physicochemical property is that UA and sodium urate crystals in urine increase the propensity toward formation of mixed UA and calcium oxalate stones through the process of heterogeneous nucleation and epitaxial crystal growth.
Conditions that can contribute to acidic urine include chronic diarrhea and increased endogenous acid generation (which occurs with ingestion of an acidogenic diet11). However, the vast majority of UA stone formers lack these features, and are classified under the idiopathic UA nephrolithiasis (IUAN) group, previously termed ‘‘gouty diathesis.’’
Pathophysiology of UA Stone Formation
Patients with IUAN comprise the vast majority of UA stone formers.7 In this group, the most important and invariant feature is an overly acidic urine that increases the urinary content of undissociated UA and the propensity for UA precipitation. Dietary factors, primarily consumption of animal protein, could be responsible for this more acidic urine. However, dietary factors alone do not account for the overly acidic urine in IUAN because studies in subjects who consumed a fixed metabolic diet low in acid ash have shown greater acid excretion in patients with IUAN versus controls.7 The pathophysiologic mechanism(s) accounting for this increased acid excretion appears to be related to obesity and/or insulin resistance because patients with T2DM and without stones as well as those with IUAN seem to have
The pathogenetic mechanisms for UA stone formation are diverse, and may be congenital, acquired, or idiopathic.1 Three significant urinary abnormalities have been described in patients with UA nephrolithiasis as follows: low urinary volume, hyperuricosuria, and low urine pH.
Low Urine Volume A low urinary volume (,2 L/day) increases urinary saturation with respect to stone-forming constituents and contributes toward the development of all stone types, including UA stones. Hyperuricosuria Conditions associated with excessive UA excretion include dietary indiscretion (consumption of purine-rich diets),9 use of drugs that prevent renal proximal tubule reabsorption of UA (losartan, probenecid, and high doses of salicylates), and increased purine catabolism (myeloproliferative disorders, hemolytic diseases, and after chemotherapy).1 Several congenital disorders are also associated with UA overproduction and subsequent hyperuricemia and significant hyperuricosuria. The relatively infrequent occurrence of stone disease in inherited and acquired hyperuricosuric states underscores the importance of additional factor(s) in UA precipitation. In fact, unless present in massive amounts, hyperuricosuria per se without low urine pH is insufficient to cause UA nephrolithiasis. Low Urine pH Overly acidic urine is the overriding pathogenetic mechanism underlying UA nephrolithiasis. A low 24-hour urine pH (,5.5) is often observed in the vast majority of UA stone formers, many of whom exhibit normal urinary UA excretion.7,10
Metabolic Syndrome and the Genesis of UA Stones
Figure 1. Relationship between 24-hour urine pH and 24-hour urine sulfate (a marker of dietary animal protein intake) in subjects with (,) and without (-) the metabolic syndrome. Data from 148 non-stone forming volunteers. Subjects with the metabolic syndrome exhibited a significantly higher 24-hour urine sulfate, indicating greater consumption of acidogenic diet. The regression line for each group shows that 24-hour urine pH declines with increasing acid intake (24-hour urine sulfate). However, at any given 24-hour urine sulfate, 24-hour urine pH is significantly lower in subjects with the metabolic syndrome, suggesting that factors besides dietary acid intake contribute to the more acidic urine.
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greater acid excretion as compared with lean, insulin-sensitive controls without diabetes.12 In addition, obesity itself is associated with low urine pH in patients with nephrolithiasis.13 Finally, as compared with subjects without the metabolic syndrome, those with the metabolic syndrome exhibit low urine pH at any level of dietary acid intake (Fig. 1). Greater acid excretion alone is not sufficient to lower urine pH because the excess acid can be buffered in urine. However, when excess acid is not appropriately buffered, urine becomes unduly acidic. Ammonium is an important urinary buffer because of its high pK, and additionally, its renal production and excretion are regulated by acid– base status. Reduced ammonium excretion has been shown in subjects with IUAN and this defect was amplified by administration of an acute acid load.7 A similar finding was also demonstrated in non-stone forming patients with the metabolic syndrome.14 These findings are consistent with a defect in renal ammoniagenesis and/or excretion that leads to impaired buffering and amplifies the acidic urine caused by the increased acid excretion in patients with IUAN and the metabolic syndrome.
approximately 2 L/day. Compared with consumption of water, some fruit juices (such as orange juice) may provide an alkali load and raise urine pH in addition to raising urine volume.17 Correction of hyperuricosuria can be achieved with lifestyle changes (consumption of a balanced diet and avoiding food sources of purine16) and pharmacological therapy (allopurinol). Dissolution therapy is generally effective and most patients achieve durable results with lifelong alkali therapy. Urological intervention is infrequently used in the management of UA nephrolithiasis and is reserved for patients with prolonged obstruction, progressive renal insufficiency, intractable pain, and/or poor response to medical therapy.
Conclusions UA stone disease is primarily a disorder in which overly acidic urine results in the precipitation of UA in the urinary tract. Although it comprises a minority of all kidney stone diseases, it is significantly more common in stone formers with the metabolic syndrome. Treatment is primarily medical and relies on stone dissolution with alkalinization of urine.
Management of UA Stones— Nutritional and Pharmacological Approaches
References
The initial management of patients with UA nephrolithiasis consists of medical dissolution therapy, a noninvasive approach that has been successful in the vast majority of cases.15 Medical management is directed at correcting the underlying metabolic abnormalities that lead to stone formation including low urine volume, hyperuricosuria, and low urine pH. Correction of low urine pH is the cornerstone of therapy in UA nephrolithiasis. It results in the dissolution of existing stones and prevents recurrent stone formation. Reduction in dietary intake of animal proteins is helpful and should be recommended to all patients.16 However, pharmacological therapy with potassium citrate is most commonly used in this setting.15 Sodium salts (e.g., sodium bicarbonate) are used in patients who cannot tolerate or are poor candidates for potassium citrate (because of either hyperkalemia or renal insufficiency). Correction of low urine volume requires increasing fluid intake to maintain a urinary volume of
1. Maalouf NM, Cameron MA, Moe OW, et al: Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens 13:181-189, 2004 2. Lieske JC, de la Vega LS, Gettman MT, et al: Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. Am J Kidney Dis 48:897-904, 2006 3. Pak CY, Sakhaee K, Moe O, et al: Biochemical profile of stone-forming patients with diabetes mellitus. Urology 61: 523-527, 2003 4. Daudon M, Traxer O, Conort P, et al: Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol 17: 2026-2033, 2006 5. Ekeruo WO, Tan YH, Young MD, et al: Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol 172:159-163, 2004 6. Daudon M, Lacour B, Jungers P: Influence of body size on urinary stone composition in men and women. Urol Res 34: 193-199, 2006 7. Sakhaee K, Adams-Huet B, Moe OW, et al: Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int 62:971-979, 2002 8. Abate N, Chandalia M, Cabo-Chan AV Jr, et al: The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int 65:386-392, 2004
METABOLIC SYNDROME AND URIC ACID STONES 9. Fellstrom B, Danielson BG, Karlstrom B, et al: The influence of a high dietary intake of purine-rich animal protein on urinary urate excretion and supersaturation in renal stone disease. Clin Sci (Lond) 64:399-405, 1983 10. Pak CY, Sakhaee K, Peterson RD, et al: Biochemical profile of idiopathic uric acid nephrolithiasis. Kidney Int 60:757-761, 2001 11. Reddy ST, Wang CY, Sakhaee K, et al: Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism. Am J Kidney Dis 40:265-274, 2002 12. Cameron MA, Maalouf NM, Adams-Huet B, et al: Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol 17:1422-1428, 2006
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13. Maalouf NM, Sakhaee K, Parks JH, et al: Association of urinary pH with body weight in nephrolithiasis. Kidney Int 65: 1422-1425, 2004 14. Maalouf NM, Cameron MA, Moe OW, et al: Low urine pH: a novel feature of the metabolic syndrome. Clin J Am Soc Nephrol 2:883-888, 2007 15. Preminger GM: Pharmacologic treatment of uric acid calculi. Urol Clin North Am 14:335-338, 1987 16. Siener R, Hesse A: The effect of a vegetarian and different omnivorous diets on urinary risk factors for uric acid stone formation. Eur J Nutr 42:332-337, 2003 17. Odvina CV: Comparative value of orange juice versus lemonade in reducing stone-forming risk. Clin J Am Soc Nephrol 1:1269-1274, 2006
Metabolic Syndrome and the Genesis of Uric Acid Stones Naim M. Maalouf, MD Uric acid stones are significantly more common among nephrolithiasis patients with type 2 diabetes, obesity, and/or the metabolic syndrome. The principal metabolic feature responsible for this association is an overly acidic urine, which leads to the precipitation of sparingly soluble uric acid crystals in urine and subsequent development of stones. The unduly acidic urine in uric acid stone formers is caused by a combination of excessive dietary intake of animal proteins and a defect in renal ammoniagenesis and/or excretion that leads to impaired buffering and amplifies the acidic urine caused by an increased acid excretion. Ó 2011 by the National Kidney Foundation, Inc. All rights reserved.
U
RIC ACID (UA) stones constitute a minority of all cases of nephrolithiasis, but are significantly more common among stone formers with the metabolic syndrome. Overly acidic urine is recognized as the major abnormality responsible for UA nephrolithiasis. This article reviews the epidemiology, pathogenesis, and management of UA stone disease, with a focus on its recent association with the metabolic syndrome and the underlying mechanisms.
Epidemiology UA nephrolithiasis comprises 8% to 10% of all kidney stones in the United States; 16% in Okinawa, Japan; and 25% in certain regions in Germany.1 Moreover, this prevalence is significantly higher in certain subsets of stones formers; stone formers with type-2 diabetes mellitus (T2DM) have UA stones as the main stone constitDepartment of Internal of Medicine and Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas. Maalouf has no conflicts relevant to this publication. Address reprint requests to Naim Maalouf, MD, The Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885. E-mail: naim.
[email protected] Ó 2011 by the National Kidney Foundation, Inc. All rights reserved. 1051-2276/$36.00 doi:10.1053/j.jrn.2010.10.015
128
uent more frequently than stone formers without diabetes.2–4 For example, in 1 retrospective study, UA stones constituted 34% of the stone burden in patients with T2DM as compared with 6% in stone-forming patients without diabetes.3 A higher prevalence of UA stones has also been described among obese stone formers.5,6 It also seems that greater body mass index and T2DM are independent risk factors for UA nephrolithiasis.4 The clustering of obesity and insulin resistance along with hypertension and dyslipidemia describes the metabolic syndrome. In recent studies, a large proportion of UA nephrolithiasis patients were found to be affected by various features of the metabolic syndrome.7,8 In summary, the metabolic syndrome and its individual features are linked with UA nephrolithiasis.
UA Metabolism and Physical Chemistry UA is the end product of purine metabolism in human beings who display serum and urinary UA concentrations significantly higher than other mammals. Because urinary excretion of UA in human beings generally exceeds 600 mg/day, the limited urinary UA solubility of 96 mg/L presents a great risk for UA precipitation. In urine, UA, a weak acid, is known to be in equilibrium with its base urate as follows: UA 4 H1 1 urate2. The pKa for this equilibrium is 5.35 at 37 C, which lies within the clinical Journal of Renal Nutrition, Vol 21, No 1 (January), 2011: pp 128–131
METABOLIC SYNDROME AND URIC ACID STONES
129
range for urine pH, thus rendering urine pH an important determinant of urinary UA solubility. Unduly acidic urine (urine pH, #5.5) leads to precipitation of sparingly soluble UA, thereby increasing the predisposition to UA nephrolithiasis. Another important physicochemical property is that UA and sodium urate crystals in urine increase the propensity toward formation of mixed UA and calcium oxalate stones through the process of heterogeneous nucleation and epitaxial crystal growth.
Conditions that can contribute to acidic urine include chronic diarrhea and increased endogenous acid generation (which occurs with ingestion of an acidogenic diet11). However, the vast majority of UA stone formers lack these features, and are classified under the idiopathic UA nephrolithiasis (IUAN) group, previously termed ‘‘gouty diathesis.’’
Pathophysiology of UA Stone Formation
Patients with IUAN comprise the vast majority of UA stone formers.7 In this group, the most important and invariant feature is an overly acidic urine that increases the urinary content of undissociated UA and the propensity for UA precipitation. Dietary factors, primarily consumption of animal protein, could be responsible for this more acidic urine. However, dietary factors alone do not account for the overly acidic urine in IUAN because studies in subjects who consumed a fixed metabolic diet low in acid ash have shown greater acid excretion in patients with IUAN versus controls.7 The pathophysiologic mechanism(s) accounting for this increased acid excretion appears to be related to obesity and/or insulin resistance because patients with T2DM and without stones as well as those with IUAN seem to have
The pathogenetic mechanisms for UA stone formation are diverse, and may be congenital, acquired, or idiopathic.1 Three significant urinary abnormalities have been described in patients with UA nephrolithiasis as follows: low urinary volume, hyperuricosuria, and low urine pH.
Low Urine Volume A low urinary volume (,2 L/day) increases urinary saturation with respect to stone-forming constituents and contributes toward the development of all stone types, including UA stones. Hyperuricosuria Conditions associated with excessive UA excretion include dietary indiscretion (consumption of purine-rich diets),9 use of drugs that prevent renal proximal tubule reabsorption of UA (losartan, probenecid, and high doses of salicylates), and increased purine catabolism (myeloproliferative disorders, hemolytic diseases, and after chemotherapy).1 Several congenital disorders are also associated with UA overproduction and subsequent hyperuricemia and significant hyperuricosuria. The relatively infrequent occurrence of stone disease in inherited and acquired hyperuricosuric states underscores the importance of additional factor(s) in UA precipitation. In fact, unless present in massive amounts, hyperuricosuria per se without low urine pH is insufficient to cause UA nephrolithiasis. Low Urine pH Overly acidic urine is the overriding pathogenetic mechanism underlying UA nephrolithiasis. A low 24-hour urine pH (,5.5) is often observed in the vast majority of UA stone formers, many of whom exhibit normal urinary UA excretion.7,10
Metabolic Syndrome and the Genesis of UA Stones
Figure 1. Relationship between 24-hour urine pH and 24-hour urine sulfate (a marker of dietary animal protein intake) in subjects with (,) and without (-) the metabolic syndrome. Data from 148 non-stone forming volunteers. Subjects with the metabolic syndrome exhibited a significantly higher 24-hour urine sulfate, indicating greater consumption of acidogenic diet. The regression line for each group shows that 24-hour urine pH declines with increasing acid intake (24-hour urine sulfate). However, at any given 24-hour urine sulfate, 24-hour urine pH is significantly lower in subjects with the metabolic syndrome, suggesting that factors besides dietary acid intake contribute to the more acidic urine.
130
MAALOUF
greater acid excretion as compared with lean, insulin-sensitive controls without diabetes.12 In addition, obesity itself is associated with low urine pH in patients with nephrolithiasis.13 Finally, as compared with subjects without the metabolic syndrome, those with the metabolic syndrome exhibit low urine pH at any level of dietary acid intake (Fig. 1). Greater acid excretion alone is not sufficient to lower urine pH because the excess acid can be buffered in urine. However, when excess acid is not appropriately buffered, urine becomes unduly acidic. Ammonium is an important urinary buffer because of its high pK, and additionally, its renal production and excretion are regulated by acid– base status. Reduced ammonium excretion has been shown in subjects with IUAN and this defect was amplified by administration of an acute acid load.7 A similar finding was also demonstrated in non-stone forming patients with the metabolic syndrome.14 These findings are consistent with a defect in renal ammoniagenesis and/or excretion that leads to impaired buffering and amplifies the acidic urine caused by the increased acid excretion in patients with IUAN and the metabolic syndrome.
approximately 2 L/day. Compared with consumption of water, some fruit juices (such as orange juice) may provide an alkali load and raise urine pH in addition to raising urine volume.17 Correction of hyperuricosuria can be achieved with lifestyle changes (consumption of a balanced diet and avoiding food sources of purine16) and pharmacological therapy (allopurinol). Dissolution therapy is generally effective and most patients achieve durable results with lifelong alkali therapy. Urological intervention is infrequently used in the management of UA nephrolithiasis and is reserved for patients with prolonged obstruction, progressive renal insufficiency, intractable pain, and/or poor response to medical therapy.
Conclusions UA stone disease is primarily a disorder in which overly acidic urine results in the precipitation of UA in the urinary tract. Although it comprises a minority of all kidney stone diseases, it is significantly more common in stone formers with the metabolic syndrome. Treatment is primarily medical and relies on stone dissolution with alkalinization of urine.
Management of UA Stones— Nutritional and Pharmacological Approaches
References
The initial management of patients with UA nephrolithiasis consists of medical dissolution therapy, a noninvasive approach that has been successful in the vast majority of cases.15 Medical management is directed at correcting the underlying metabolic abnormalities that lead to stone formation including low urine volume, hyperuricosuria, and low urine pH. Correction of low urine pH is the cornerstone of therapy in UA nephrolithiasis. It results in the dissolution of existing stones and prevents recurrent stone formation. Reduction in dietary intake of animal proteins is helpful and should be recommended to all patients.16 However, pharmacological therapy with potassium citrate is most commonly used in this setting.15 Sodium salts (e.g., sodium bicarbonate) are used in patients who cannot tolerate or are poor candidates for potassium citrate (because of either hyperkalemia or renal insufficiency). Correction of low urine volume requires increasing fluid intake to maintain a urinary volume of
1. Maalouf NM, Cameron MA, Moe OW, et al: Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens 13:181-189, 2004 2. Lieske JC, de la Vega LS, Gettman MT, et al: Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. Am J Kidney Dis 48:897-904, 2006 3. Pak CY, Sakhaee K, Moe O, et al: Biochemical profile of stone-forming patients with diabetes mellitus. Urology 61: 523-527, 2003 4. Daudon M, Traxer O, Conort P, et al: Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol 17: 2026-2033, 2006 5. Ekeruo WO, Tan YH, Young MD, et al: Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol 172:159-163, 2004 6. Daudon M, Lacour B, Jungers P: Influence of body size on urinary stone composition in men and women. Urol Res 34: 193-199, 2006 7. Sakhaee K, Adams-Huet B, Moe OW, et al: Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int 62:971-979, 2002 8. Abate N, Chandalia M, Cabo-Chan AV Jr, et al: The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int 65:386-392, 2004
METABOLIC SYNDROME AND URIC ACID STONES 9. Fellstrom B, Danielson BG, Karlstrom B, et al: The influence of a high dietary intake of purine-rich animal protein on urinary urate excretion and supersaturation in renal stone disease. Clin Sci (Lond) 64:399-405, 1983 10. Pak CY, Sakhaee K, Peterson RD, et al: Biochemical profile of idiopathic uric acid nephrolithiasis. Kidney Int 60:757-761, 2001 11. Reddy ST, Wang CY, Sakhaee K, et al: Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism. Am J Kidney Dis 40:265-274, 2002 12. Cameron MA, Maalouf NM, Adams-Huet B, et al: Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol 17:1422-1428, 2006
131
13. Maalouf NM, Sakhaee K, Parks JH, et al: Association of urinary pH with body weight in nephrolithiasis. Kidney Int 65: 1422-1425, 2004 14. Maalouf NM, Cameron MA, Moe OW, et al: Low urine pH: a novel feature of the metabolic syndrome. Clin J Am Soc Nephrol 2:883-888, 2007 15. Preminger GM: Pharmacologic treatment of uric acid calculi. Urol Clin North Am 14:335-338, 1987 16. Siener R, Hesse A: The effect of a vegetarian and different omnivorous diets on urinary risk factors for uric acid stone formation. Eur J Nutr 42:332-337, 2003 17. Odvina CV: Comparative value of orange juice versus lemonade in reducing stone-forming risk. Clin J Am Soc Nephrol 1:1269-1274, 2006