- Email: [email protected]
Pacific Islander Stone Formers
Urolithiasis/Endourology
The Role of Race in Determining 24-Hour Urine Composition in White and Asian/Pacific Islander Stone Formers Brian H. Eisner,*,† Sima P. Porten, Seth K. Bechis and Marshall L. Stoller‡ From the Department of Urology, Massachusetts General Hospital, Boston, Massachusetts
Purpose: We examined differences in 24-hour urine composition between white and Asian/Pacific Islander stone formers. Materials and Methods: We retrospectively reviewed the 24-hour urinalysis database at a metabolic stone clinic. We identified and included in the study patients 18 years old or older who presented for the initial metabolic stone evaluation when race was marked as white or Asian/Pacific Islander in the electronic medical record. Univariate analysis was done to compare 24-hour urine composition between white and Asian/Pacific Islander stone formers. We performed multivariate linear regression adjusted for possible confounders, including age, gender, body mass index, hypertension, diabetes mellitus, thiazide use, potassium citrate use and 24-hour urine chemistry (volume, pH, calcium, citrate, creatinine, oxalate, magnesium, phosphate, potassium, sodium, sulfate and uric acid). Results: Included in analysis were 371 white and 91 Asian/Pacific Islander patients. On univariate analysis Asian/Pacific Islander patients excreted significantly greater uric acid, and significantly less citrate, magnesium, phosphate and creatinine than white patients. On multivariate analysis Asian/Pacific Islander patients excreted significantly greater uric acid, and significantly less urine citrate, phosphate, creatinine and volume than white patients. Conclusions: Significant differences exist in 24-hour urine chemistry between white and Asian/PI stone formers. Knowledge of these differences would be useful to evaluate and treat these patients, and prevent stone recurrence.
Abbreviations and Acronyms BMI ⫽ body mass index PI ⫽ Pacific Islander Submitted for publication August 18, 2009. Study received institutional review board approval. * Correspondence: Department of Urology, GRB 1102, Massachusetts General Hospital, 55 Fruit St., Boston, Massachusetts 02114 (telephone: 617-726-3512; FAX: 617-726-6131; e-mail: [email protected]). † Financial interest and/or other relationship with Boston Scientific, PercSys and Ravine Group. ‡ Financial interest and/or other relationship with PercSys and Ravine Group.
Key Words: urinary calculi, urine, Oceanic ancestry group, European continental ancestry group, Asian continental ancestry group SEVERAL early studies of the relationship between race and nephrolithiasis showed little difference in the incidence of stone disease1 and 24-hour urine abnormalities based on race.2 However, a recent study demonstrated considerable differences in the nephrolithiasis risk and urine composition among ethnic groups in North America, including patients of European, Arabic, West Indian, East and West Asian, and Latin American descent.3 Of nonstone
formers black women excrete significantly less calcium and more citrate, and have higher urine pH than white women, suggesting that race impacts 24-hour urine composition.4 If race has a role in determining 24hour urine chemistry, certain treatments and dietary recommendations for nephrolithiasis may be more appropriate in patients of 1 racial group compared with another. We examined differences in 24-hour urine chemistry
0022-5347/10/1834-1407/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 183, 1407-1411, April 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.12.033
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RESEARCH, INC.
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RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
between white and Asian/Pacific Islander stone forming patients evaluated at a metabolic stone clinic.
MATERIALS AND METHODS Study Design We retrospectively reviewed the 24-hour urinalysis database at the metabolic stone clinic of a tertiary care academic medical center. Patients 18 years old or older who presented for the initial metabolic stone evaluation were identified and included in the study when race was marked as white or Asian/PI in the electronic medical record. Outpatient clinic and hospital records, and 24hour urine composition data were analyzed. BMI was calculated in kg/m2 from self-reported patient height and weight. Electronic medical records were reviewed to determine patient demographic information (self-reported race and gender), medical history (ie diabetes mellitus and hypertension) and medication use (ie thiazide diuretics and potassium citrate). Patients were excluded from study when BMI or medical history could not be obtained or 24-hour urine collections were deemed to be inadequate, including 24-hour urine creatinine less than 800 mg in men and less than 600 mg in women. Our standard practice in a new patient with stones is to perform the initial clinic evaluation, provide dietary guidelines and then perform 24-hour urine chemistry at least 1 month after the patient has adjusted to the dietary recommendations. Our dietary guidelines include adequate fluid intake to ensure 2.0 l urine output daily, low salt diet using potassium salt substitute and low sodium soy sauce substitute with salt limited when shopping and/or cooking, and a limited animal protein intake of 2 meals and no more than 8 ounces daily.
Urine Collection Patients who presented to our clinic for metabolic stone evaluation underwent 24-hour urinalysis. Self-reported height and weight were recorded at urine collection. Standard urinary parameters were evaluated, including sodium, calcium, citrate, creatinine, uric acid, oxalate, potassium, phosphorus, magnesium, sulfate, pH and urine volume. The supersaturation ratio of calcium oxalate, calcium phosphate and uric acid were calculated using the iterative computer program EQUIL 2.
Statistical Analysis In our analysis we included only a single 24-hour urinalysis. In patients with more than a single 24-hour urinalysis available only the first urinalysis was used. Univariate analysis was done to compare 24-hour urine composition between white and Asian/PI stone formers. Multivariate linear regression was adjusted for possible confounders, including age, gender, BMI, hypertension, diabetes mellitus, thiazide use, potassium citrate use and 24-hour urine chemistry (volume, pH, calcium, citrate, creatinine, oxalate, magnesium, oxalate, phosphate, potassium, sodium, sulfate and uric acid). All tests were 2-sided with significance considered at p ⬍0.05. The 95% CI was calculated for all regression coefficients. All analysis was done using JMP® 8.0.
RESULTS Included in analysis were 371 white and 91 Asian/PI patients. Compared to white patients Asian/PI patients were older (mean ⫾ SD age 55.1 ⫾ 14.2 vs 51.2 ⫾ 13.0 years, p ⫽ 0.02) and had lower BMI (24.6 ⫾ 3.4 vs 27.5 ⫾ 6.2 kg/m2, p ⬍0.001). Asian/PI patients were also more likely to have hypertension (44.0% vs 26.7%, p ⫽ 0.002) and diabetes mellitus (19.8% vs 7.6%, p ⫽ 0.001) than white patients. There was no significant difference between Asian/PI and white patients in the use of thiazide (5.5% vs 11.6%, p ⫽ 0.07) or potassium citrate (8.8% vs 10.0%, p not significant). Mean unadjusted 24-hour urine composition values are shown in table 1. Asian/PI patients excreted significantly greater uric acid and significantly lower citrate, magnesium, phosphate and creatinine than white patients. There was no significant difference in 24-hour urine volume, pH, or excretion of calcium, oxalate, potassium, sodium or sulfate between the 2 groups (table 1). Multivariate linear regression results comparing differences in urinary factors by race was adjusted for possible confounders, including age, gender, BMI, hypertension, diabetes, thiazide use, potassium use and 24-hour urine constituents (calcium, oxalate, citrate, uric acid, sodium, potassium, magnesium, phosphate, sulfate, creatinine, pH and volume). Compared with white patients Asian/PI patients excreted significantly greater uric acid and significantly less citrate, phosphate, creatinine and volume daily (table 2). There was no difference in 24-hour urine pH, or excretion of calcium, oxalate, potassium, sodium or sulfate between the 2 groups (table 2).
Table 1. Univariate analysis of 24-hour urine chemistry by race
Calcium (mg) Oxalate (mg) Citrate (mg) Uric acid (gm) Sodium (mmol) Potassium (mEq) Magnesium (mg) Phosphate (gm) Sulfate (mmol) Creatinine (mg) pH Vol (l) Supersaturation: Calcium oxalate Calcium phosphate Uric acid
Mean ⫾ SD White
Mean ⫾ SD Asian/PI
p Value
211.2 ⫾ 114.0 42.6 ⫾ 17.3 604.1 ⫾ 371.8 0.68 ⫾ 0.22 170.3 ⫾ 73.4 69.3 ⫾ 27.5 110.0 ⫾ 43.1 1.02 ⫾ 0.36 44.6 ⫾ 16.5 1588.1 ⫾ 480.1 6.04 ⫾ 0.54 2.1 ⫾ 1.0
211.8 ⫾ 135.8 43.2 ⫾ 22.1 438.6 ⫾ 303.1 0.77 ⫾ 0.27 180.5 ⫾ 83.9 62.9 ⫾ 40.9 97.2 ⫾ 39.0 0.85 ⫾ 0.31 46.5 ⫾ 18.2 1380.0 ⫾ 422.3 6.12 ⫾ 0.54 2.2 ⫾ 1.1
0.97 0.81 ⬍0.001 0.009 0.29 0.16 0.004 ⬍0.001 0.37 ⬍0.001 0.18 0.29
7.1 ⫾ 1.1 ⫾ 1.0 ⫾
4.1 1.0 1.0
6.7 ⫾ 1.1 ⫾ 0.9 ⫾
3.9 1.0 0.8
0.50 0.48 0.13
RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
Table 2. Multivariate adjusted differences in 24-hour urine composition in white vs Asian/PI stone formers Parameter
Difference (95% CI)*
Calcium (mg) Oxalate (mg) Citrate (mg) Uric acid (gm) Sodium (mmol) Potassium (mEq) Magnesium (mg) Phosphate (gm) Sulfate (mmol) Creatinine (mg) pH Volume (l) Supersaturation: Calcium oxalate Calcium phosphate Uric acid
18.5 (⫺2.9–43.6) 1.7 (⫺2.3–5.7) ⫺119.0 (⫺201.7– ⫺36.2) 0.11 (0.07–0.15) 13.8 (⫺0.4–28.0) ⫺2.1 (⫺7.7–3.4) ⫺7.8 (⫺16.4–0.7) ⫺0.07 (⫺0.12– ⫺0.01) 2.5 (⫺0.2–5.2) ⫺97.6 (⫺158.3– ⫺137.0) 0.02 (⫺0.09–0.12) ⫺0.2 (⫺0.4– ⫺0.04) 0.61 0.11 0.09
(⫺0.14–1.36) (⫺0.07–0.28) (⫺0.05–0.2)
* Referent is white race.
DISCUSSION Recent evidence suggests that race may have a significant role in determining the nephrolithiasis risk and 24-hour urine composition.3,4 Mente et al reported that of the inhabitants of Canada the nephrolithiasis risk in European individuals was lower than in those of Arabic, West Indian, West Asian and Latin American descent but greater than in East Asian and African individuals.3 In a study of 24-hour urine chemistry in black and white nonstone forming women Taylor and Curhan observed various racial differences, that is black women excreted significantly less calcium, more citrate and had higher urine pH than white women.4 They conjectured that these findings may in part be responsible for the differences in the nephrolithiasis rate between these 2 racial groups.4 A recent study of the relationship between race, urine calcium and sodium intake in black and white female adolescents showed that race affects urine calcium and the calciuric effect of increased sodium intake.5 These studies contradict the earlier study by Maloney et al of the role of race in nephrolithiasis showing that nonwhite patients, ie those who were black, Asian or Hispanic, had a lower rate of hypercalciuria than white patients but there were no significant differences in the rate of hypocitraturia, hyperoxaluria, low urine pH or low urine volume between white and nonwhite patients.2 They concluded that the underlying metabolic abnormality rate was remarkably similar in all racial groups, suggesting that dietary and environmental factors may be as important as ethnicity for stone disease etiology. Given the low number of nonwhite patients in that study (fewer than 1,000 white vs 44 black, 8 Asian and 8 Hispanic patients), it may have been under powered to detect significant differences.
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We examined whether race has a role in determining 24-hour urine composition in white and Asian/PI stone formers evaluated at a metabolic stone clinic. On univariate analysis Asian/PI patients excreted significantly greater uric acid but significantly less citrate, magnesium and phosphate than white patients. We then performed multivariate analysis controlled for several known risk factors for nephrolithiasis, including BMI, hypertension and diabetes mellitus, as well as 24-hour urine constituents. On multivariate analysis 24-hour urine constituents are commonly included to differentiate dietary from other contributors to 24-hour urine composition.6 On multivariate analysis the relationship between race and citrate, uric acid and phosphate persisted but that of magnesium did not since Asian/PI patients excreted significantly greater uric acid, and significantly less citrate and phosphate than white patients. On multivariate analysis Asian/PI patients also voided 200 cc less fluid daily than white patients. The fact that differences in urinary magnesium were significant on univariate analysis with Asian/PI patients excreting significantly less magnesium but not on multivariate analysis suggests that dietary differences between white and Asian/PI patients may explain this difference. To define the role of race in determining 24-hour urine chemistry in white and Asian/PI stone formers our multivariate analysis was also controlled for known risk factors for stone disease, ie BMI, diabetes mellitus and hypertension.7–10 This differentiates our methodology from that in a previous report of the same ethnic groups that used a case-control study design rather than multivariate regression due to smaller numbers.3 Our findings are also notable since all patients received similar dietary counseling at least 30 days before 24-hour urine collection. As described, our standard practice in a new patient with stones is to perform the initial clinic evaluation, provide dietary guidelines and then perform 24-hour urine chemistry at least 1 month after the patient has adjusted to the dietary recommendations. Our dietary guidelines include adequate fluid intake to ensure 2.0 l urine output daily day, a low salt diet (using potassium salt substitute, low sodium soy sauce substitute and limited salt when cooking, and choosing low sodium foods when shopping), limited animal protein intake at each meal and limited eating at restaurants to the extent possible. That these differences persisted despite uniform dietary recommendations in all patients further emphasizes the role of race in determining 24-hour urine constituents. Our findings are consistent with a significant role of genetics in nephrolithiasis. We assume that Asian/PI patients, who share a similar region of
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RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
origin, may share certain genes that predispose them to unique urine chemistry compared to that of white patients. This hypothesis is consistent with previously published genetic studies of stone disease. One series in 7,500 twin pairs revealed a significantly greater nephrolithiasis concordance rate in monozygotic than in dizygotic twins, suggesting a strong genetic contribution to nephrolithiasis.11 Using tetrachoric analysis that group estimated a 56% heritability risk of stones. We studied 24-hour chemistry in stone formers and not the stone disease incidence but our finding could be a plausible explanation for the results of Mente et al that the incidence of calcium nephrolithiasis is significantly increased in West Asian compared with European (ie white) patients while the incidence in Filipino and South Asian patients is greater than in European patients, although not statistically significant so.3 Our findings have important implications in the care of white and Asian/PI patients with stone disease. Studies show that while patient interest in metabolic evaluation, willingness to change diet and receive medical therapy for stone disease is greater than 90%, patients with nephrolithiasis are offered metabolic evaluation less than 50% of the time, including 46% for recurrent and 30% for first time stone formers.12,13 More than 25 years ago Hosking et al described the stone clinic effect, that is encouraging high fluid intake and avoiding certain dietary excesses has a beneficial impact on 24-hour urine chemistry in patients with nephrolithiasis.14 When 24-hour urinalysis is not done, it may be beneficial to focus on race specific dietary interventions in Asian/PI patients. In our study Asian/PI patients excreted lower volumes, less citrate and more uric acid than white patients. Thus, they may benefit more than their white counterparts from increased fluid intake, which is
known to prevent recurrent nephrolithiasis,15 beverages that increase urinary citrate16 or empirical treatment with potassium citrate17 and animal protein restriction. The limitations of our study deserve mention. It is retrospective in nature and, thus, subject to the limitations of a nonprospective study. Patients were stone formers only so results may not be generalizable to the population at large. Since height and weight were self-reported, reporting errors could potentially have confounded our results. However, the accuracy of self-reported height and weight was previously validated in the adult population.18 Also, we routinely measure patient height and weight at the clinic visit, ie 1 to 2 months before 24-hour urinalysis with self-reported height and weight, and inform them of the results. We also did not include stone analysis information in our study. We assume that based on previous studies greater than 85% of stones in the United States are composed of calcium oxalate and, thus, our findings are generalizable to most with urinary stone disease.19 Finally, we used a single 24-hour urinalysis. Although this is considered acceptable for metabolic evaluation of stone disease, some practitioners routinely perform 2, 24hour urinalyses for the initial stone disease metabolic evaluation.20 Finally, we analyzed patients classified in the electronic medical record as Asian/PI as a group. In the future a more detailed analysis using country of origin may yield data more specific to individuals.
CONCLUSIONS Significant differences exist in 24-hour urine chemistry between white and Asian/PI stone formers. Knowledge of these differences would be useful to evaluate and treat these patients, and prevent stone recurrence, given the racial diversity encountered by many physicians who treat urinary stone disease.
REFERENCES 1. Pak CY, Resnick MI and Preminger GM: Ethnic and geographic diversity of stone disease. Urology 1997; 50: 504. 2. Maloney ME, Springhart WP, Ekeruo WO et al: Ethnic background has minimal impact on the etiology of nephrolithiasis. J Urol 2005; 173: 2001.
5. Wigertz K, Palacios C, Jackman LA et al: Racial differences in calcium retention in response to dietary salt in adolescent girls. Am J Clin Nutr 2005; 81: 845. 6. Taylor EN and Curhan GC: Body size and 24-hour urine composition. Am J Kidney Dis 2006; 48: 905.
3. Mente A, Honey RJ, McLaughlin JR et al: Ethnic differences in relative risk of idiopathic calcium nephrolithiasis in North America. J Urol 2007; 178: 1992.
7. Madore F, Stampfer MJ, Rimm EB et al: Nephrolithiasis and risk of hypertension. Am J Hypertens 1998; 11: 46.
4. Taylor EN and Curhan GC: Differences in 24-hour urine composition between black and white women. J Am Soc Nephrol 2007; 18: 654.
8. Madore F, Stampfer MJ, Willett WC et al: Nephrolithiasis and risk of hypertension in women. Am J Kidney Dis 1998; 32: 802.
9. Taylor EN, Stampfer MJ and Curhan GC: Obesity, weight gain, and the risk of kidney stones. JAMA 2005; 293: 455. 10. Taylor EN, Stampfer MJ and Curhan GC: Diabetes mellitus and the risk of nephrolithiasis. Kidney Int 2005; 68: 1230. 11. Goldfarb DS, Fischer ME, Keich Y et al: A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry. Kidney Int 2005; 67: 1053. 12. Chandhoke PS: Evaluation of the recurrent stone former. Urol Clin North Am 2007; 34: 315. 13. Grampsas SA, Moore M and Chandhoke PS: 10Year experience with extracorporeal shockwave
RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
lithotripsy in the state of Colorado. J Endourol 2000; 14: 711.
hypocitraturic calcium nephrolithiasis. J Urol 1996; 156: 907.
14. Hosking DH, Erickson SB, Van den Berg CJ et al: The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1983; 130: 1115.
17. Pak CY, Fuller C, Sakhaee K et al: Long-term treatment of calcium nephrolithiasis with potassium citrate. J Urol 1985; 134: 11.
15. Borghi L, Meschi T, Amato F et al: Urinary volume, water and recurrences in idiopathic calcium nephrolithiasis: a 5-year randomized prospective study. J Urol 1996; 155: 839.
18. Rimm EB, Stampfer MJ, Colditz GA et al: Validity of self-reported waist and hip circumferences in men and women. Epidemiology 1990; 1: 466.
16. Seltzer MA, Low RK, McDonald M et al: Dietary manipulation with lemonade to treat
19. Pearle MS, Calhoun EA and Curhana GC: Urolithiasis. In: Urologic Disease in America Interim
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Compendium, April 2004. Edited by MS Litwin and CS Saigal. United States Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Publication 04.5512. Washington, D. C.: United States Government Printing Office 2004; pp 3– 42. 20. Pak CY, Britton F, Peterson R et al: Ambulatory evaluation of nephrolithiasis. Classification, clinical presentation and diagnostic criteria. Am J Med 1980; 69: 19.
The Role of Race in Determining 24-Hour Urine Composition in White and Asian/Pacific Islander Stone Formers Brian H. Eisner,*,† Sima P. Porten, Seth K. Bechis and Marshall L. Stoller‡ From the Department of Urology, Massachusetts General Hospital, Boston, Massachusetts
Purpose: We examined differences in 24-hour urine composition between white and Asian/Pacific Islander stone formers. Materials and Methods: We retrospectively reviewed the 24-hour urinalysis database at a metabolic stone clinic. We identified and included in the study patients 18 years old or older who presented for the initial metabolic stone evaluation when race was marked as white or Asian/Pacific Islander in the electronic medical record. Univariate analysis was done to compare 24-hour urine composition between white and Asian/Pacific Islander stone formers. We performed multivariate linear regression adjusted for possible confounders, including age, gender, body mass index, hypertension, diabetes mellitus, thiazide use, potassium citrate use and 24-hour urine chemistry (volume, pH, calcium, citrate, creatinine, oxalate, magnesium, phosphate, potassium, sodium, sulfate and uric acid). Results: Included in analysis were 371 white and 91 Asian/Pacific Islander patients. On univariate analysis Asian/Pacific Islander patients excreted significantly greater uric acid, and significantly less citrate, magnesium, phosphate and creatinine than white patients. On multivariate analysis Asian/Pacific Islander patients excreted significantly greater uric acid, and significantly less urine citrate, phosphate, creatinine and volume than white patients. Conclusions: Significant differences exist in 24-hour urine chemistry between white and Asian/PI stone formers. Knowledge of these differences would be useful to evaluate and treat these patients, and prevent stone recurrence.
Abbreviations and Acronyms BMI ⫽ body mass index PI ⫽ Pacific Islander Submitted for publication August 18, 2009. Study received institutional review board approval. * Correspondence: Department of Urology, GRB 1102, Massachusetts General Hospital, 55 Fruit St., Boston, Massachusetts 02114 (telephone: 617-726-3512; FAX: 617-726-6131; e-mail: [email protected]). † Financial interest and/or other relationship with Boston Scientific, PercSys and Ravine Group. ‡ Financial interest and/or other relationship with PercSys and Ravine Group.
Key Words: urinary calculi, urine, Oceanic ancestry group, European continental ancestry group, Asian continental ancestry group SEVERAL early studies of the relationship between race and nephrolithiasis showed little difference in the incidence of stone disease1 and 24-hour urine abnormalities based on race.2 However, a recent study demonstrated considerable differences in the nephrolithiasis risk and urine composition among ethnic groups in North America, including patients of European, Arabic, West Indian, East and West Asian, and Latin American descent.3 Of nonstone
formers black women excrete significantly less calcium and more citrate, and have higher urine pH than white women, suggesting that race impacts 24-hour urine composition.4 If race has a role in determining 24hour urine chemistry, certain treatments and dietary recommendations for nephrolithiasis may be more appropriate in patients of 1 racial group compared with another. We examined differences in 24-hour urine chemistry
0022-5347/10/1834-1407/0 THE JOURNAL OF UROLOGY® © 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 183, 1407-1411, April 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.12.033
AND
RESEARCH, INC.
www.jurology.com
1407
1408
RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
between white and Asian/Pacific Islander stone forming patients evaluated at a metabolic stone clinic.
MATERIALS AND METHODS Study Design We retrospectively reviewed the 24-hour urinalysis database at the metabolic stone clinic of a tertiary care academic medical center. Patients 18 years old or older who presented for the initial metabolic stone evaluation were identified and included in the study when race was marked as white or Asian/PI in the electronic medical record. Outpatient clinic and hospital records, and 24hour urine composition data were analyzed. BMI was calculated in kg/m2 from self-reported patient height and weight. Electronic medical records were reviewed to determine patient demographic information (self-reported race and gender), medical history (ie diabetes mellitus and hypertension) and medication use (ie thiazide diuretics and potassium citrate). Patients were excluded from study when BMI or medical history could not be obtained or 24-hour urine collections were deemed to be inadequate, including 24-hour urine creatinine less than 800 mg in men and less than 600 mg in women. Our standard practice in a new patient with stones is to perform the initial clinic evaluation, provide dietary guidelines and then perform 24-hour urine chemistry at least 1 month after the patient has adjusted to the dietary recommendations. Our dietary guidelines include adequate fluid intake to ensure 2.0 l urine output daily, low salt diet using potassium salt substitute and low sodium soy sauce substitute with salt limited when shopping and/or cooking, and a limited animal protein intake of 2 meals and no more than 8 ounces daily.
Urine Collection Patients who presented to our clinic for metabolic stone evaluation underwent 24-hour urinalysis. Self-reported height and weight were recorded at urine collection. Standard urinary parameters were evaluated, including sodium, calcium, citrate, creatinine, uric acid, oxalate, potassium, phosphorus, magnesium, sulfate, pH and urine volume. The supersaturation ratio of calcium oxalate, calcium phosphate and uric acid were calculated using the iterative computer program EQUIL 2.
Statistical Analysis In our analysis we included only a single 24-hour urinalysis. In patients with more than a single 24-hour urinalysis available only the first urinalysis was used. Univariate analysis was done to compare 24-hour urine composition between white and Asian/PI stone formers. Multivariate linear regression was adjusted for possible confounders, including age, gender, BMI, hypertension, diabetes mellitus, thiazide use, potassium citrate use and 24-hour urine chemistry (volume, pH, calcium, citrate, creatinine, oxalate, magnesium, oxalate, phosphate, potassium, sodium, sulfate and uric acid). All tests were 2-sided with significance considered at p ⬍0.05. The 95% CI was calculated for all regression coefficients. All analysis was done using JMP® 8.0.
RESULTS Included in analysis were 371 white and 91 Asian/PI patients. Compared to white patients Asian/PI patients were older (mean ⫾ SD age 55.1 ⫾ 14.2 vs 51.2 ⫾ 13.0 years, p ⫽ 0.02) and had lower BMI (24.6 ⫾ 3.4 vs 27.5 ⫾ 6.2 kg/m2, p ⬍0.001). Asian/PI patients were also more likely to have hypertension (44.0% vs 26.7%, p ⫽ 0.002) and diabetes mellitus (19.8% vs 7.6%, p ⫽ 0.001) than white patients. There was no significant difference between Asian/PI and white patients in the use of thiazide (5.5% vs 11.6%, p ⫽ 0.07) or potassium citrate (8.8% vs 10.0%, p not significant). Mean unadjusted 24-hour urine composition values are shown in table 1. Asian/PI patients excreted significantly greater uric acid and significantly lower citrate, magnesium, phosphate and creatinine than white patients. There was no significant difference in 24-hour urine volume, pH, or excretion of calcium, oxalate, potassium, sodium or sulfate between the 2 groups (table 1). Multivariate linear regression results comparing differences in urinary factors by race was adjusted for possible confounders, including age, gender, BMI, hypertension, diabetes, thiazide use, potassium use and 24-hour urine constituents (calcium, oxalate, citrate, uric acid, sodium, potassium, magnesium, phosphate, sulfate, creatinine, pH and volume). Compared with white patients Asian/PI patients excreted significantly greater uric acid and significantly less citrate, phosphate, creatinine and volume daily (table 2). There was no difference in 24-hour urine pH, or excretion of calcium, oxalate, potassium, sodium or sulfate between the 2 groups (table 2).
Table 1. Univariate analysis of 24-hour urine chemistry by race
Calcium (mg) Oxalate (mg) Citrate (mg) Uric acid (gm) Sodium (mmol) Potassium (mEq) Magnesium (mg) Phosphate (gm) Sulfate (mmol) Creatinine (mg) pH Vol (l) Supersaturation: Calcium oxalate Calcium phosphate Uric acid
Mean ⫾ SD White
Mean ⫾ SD Asian/PI
p Value
211.2 ⫾ 114.0 42.6 ⫾ 17.3 604.1 ⫾ 371.8 0.68 ⫾ 0.22 170.3 ⫾ 73.4 69.3 ⫾ 27.5 110.0 ⫾ 43.1 1.02 ⫾ 0.36 44.6 ⫾ 16.5 1588.1 ⫾ 480.1 6.04 ⫾ 0.54 2.1 ⫾ 1.0
211.8 ⫾ 135.8 43.2 ⫾ 22.1 438.6 ⫾ 303.1 0.77 ⫾ 0.27 180.5 ⫾ 83.9 62.9 ⫾ 40.9 97.2 ⫾ 39.0 0.85 ⫾ 0.31 46.5 ⫾ 18.2 1380.0 ⫾ 422.3 6.12 ⫾ 0.54 2.2 ⫾ 1.1
0.97 0.81 ⬍0.001 0.009 0.29 0.16 0.004 ⬍0.001 0.37 ⬍0.001 0.18 0.29
7.1 ⫾ 1.1 ⫾ 1.0 ⫾
4.1 1.0 1.0
6.7 ⫾ 1.1 ⫾ 0.9 ⫾
3.9 1.0 0.8
0.50 0.48 0.13
RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
Table 2. Multivariate adjusted differences in 24-hour urine composition in white vs Asian/PI stone formers Parameter
Difference (95% CI)*
Calcium (mg) Oxalate (mg) Citrate (mg) Uric acid (gm) Sodium (mmol) Potassium (mEq) Magnesium (mg) Phosphate (gm) Sulfate (mmol) Creatinine (mg) pH Volume (l) Supersaturation: Calcium oxalate Calcium phosphate Uric acid
18.5 (⫺2.9–43.6) 1.7 (⫺2.3–5.7) ⫺119.0 (⫺201.7– ⫺36.2) 0.11 (0.07–0.15) 13.8 (⫺0.4–28.0) ⫺2.1 (⫺7.7–3.4) ⫺7.8 (⫺16.4–0.7) ⫺0.07 (⫺0.12– ⫺0.01) 2.5 (⫺0.2–5.2) ⫺97.6 (⫺158.3– ⫺137.0) 0.02 (⫺0.09–0.12) ⫺0.2 (⫺0.4– ⫺0.04) 0.61 0.11 0.09
(⫺0.14–1.36) (⫺0.07–0.28) (⫺0.05–0.2)
* Referent is white race.
DISCUSSION Recent evidence suggests that race may have a significant role in determining the nephrolithiasis risk and 24-hour urine composition.3,4 Mente et al reported that of the inhabitants of Canada the nephrolithiasis risk in European individuals was lower than in those of Arabic, West Indian, West Asian and Latin American descent but greater than in East Asian and African individuals.3 In a study of 24-hour urine chemistry in black and white nonstone forming women Taylor and Curhan observed various racial differences, that is black women excreted significantly less calcium, more citrate and had higher urine pH than white women.4 They conjectured that these findings may in part be responsible for the differences in the nephrolithiasis rate between these 2 racial groups.4 A recent study of the relationship between race, urine calcium and sodium intake in black and white female adolescents showed that race affects urine calcium and the calciuric effect of increased sodium intake.5 These studies contradict the earlier study by Maloney et al of the role of race in nephrolithiasis showing that nonwhite patients, ie those who were black, Asian or Hispanic, had a lower rate of hypercalciuria than white patients but there were no significant differences in the rate of hypocitraturia, hyperoxaluria, low urine pH or low urine volume between white and nonwhite patients.2 They concluded that the underlying metabolic abnormality rate was remarkably similar in all racial groups, suggesting that dietary and environmental factors may be as important as ethnicity for stone disease etiology. Given the low number of nonwhite patients in that study (fewer than 1,000 white vs 44 black, 8 Asian and 8 Hispanic patients), it may have been under powered to detect significant differences.
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We examined whether race has a role in determining 24-hour urine composition in white and Asian/PI stone formers evaluated at a metabolic stone clinic. On univariate analysis Asian/PI patients excreted significantly greater uric acid but significantly less citrate, magnesium and phosphate than white patients. We then performed multivariate analysis controlled for several known risk factors for nephrolithiasis, including BMI, hypertension and diabetes mellitus, as well as 24-hour urine constituents. On multivariate analysis 24-hour urine constituents are commonly included to differentiate dietary from other contributors to 24-hour urine composition.6 On multivariate analysis the relationship between race and citrate, uric acid and phosphate persisted but that of magnesium did not since Asian/PI patients excreted significantly greater uric acid, and significantly less citrate and phosphate than white patients. On multivariate analysis Asian/PI patients also voided 200 cc less fluid daily than white patients. The fact that differences in urinary magnesium were significant on univariate analysis with Asian/PI patients excreting significantly less magnesium but not on multivariate analysis suggests that dietary differences between white and Asian/PI patients may explain this difference. To define the role of race in determining 24-hour urine chemistry in white and Asian/PI stone formers our multivariate analysis was also controlled for known risk factors for stone disease, ie BMI, diabetes mellitus and hypertension.7–10 This differentiates our methodology from that in a previous report of the same ethnic groups that used a case-control study design rather than multivariate regression due to smaller numbers.3 Our findings are also notable since all patients received similar dietary counseling at least 30 days before 24-hour urine collection. As described, our standard practice in a new patient with stones is to perform the initial clinic evaluation, provide dietary guidelines and then perform 24-hour urine chemistry at least 1 month after the patient has adjusted to the dietary recommendations. Our dietary guidelines include adequate fluid intake to ensure 2.0 l urine output daily day, a low salt diet (using potassium salt substitute, low sodium soy sauce substitute and limited salt when cooking, and choosing low sodium foods when shopping), limited animal protein intake at each meal and limited eating at restaurants to the extent possible. That these differences persisted despite uniform dietary recommendations in all patients further emphasizes the role of race in determining 24-hour urine constituents. Our findings are consistent with a significant role of genetics in nephrolithiasis. We assume that Asian/PI patients, who share a similar region of
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RACE AND 24-HOUR URINE COMPOSITION IN STONE FORMERS
origin, may share certain genes that predispose them to unique urine chemistry compared to that of white patients. This hypothesis is consistent with previously published genetic studies of stone disease. One series in 7,500 twin pairs revealed a significantly greater nephrolithiasis concordance rate in monozygotic than in dizygotic twins, suggesting a strong genetic contribution to nephrolithiasis.11 Using tetrachoric analysis that group estimated a 56% heritability risk of stones. We studied 24-hour chemistry in stone formers and not the stone disease incidence but our finding could be a plausible explanation for the results of Mente et al that the incidence of calcium nephrolithiasis is significantly increased in West Asian compared with European (ie white) patients while the incidence in Filipino and South Asian patients is greater than in European patients, although not statistically significant so.3 Our findings have important implications in the care of white and Asian/PI patients with stone disease. Studies show that while patient interest in metabolic evaluation, willingness to change diet and receive medical therapy for stone disease is greater than 90%, patients with nephrolithiasis are offered metabolic evaluation less than 50% of the time, including 46% for recurrent and 30% for first time stone formers.12,13 More than 25 years ago Hosking et al described the stone clinic effect, that is encouraging high fluid intake and avoiding certain dietary excesses has a beneficial impact on 24-hour urine chemistry in patients with nephrolithiasis.14 When 24-hour urinalysis is not done, it may be beneficial to focus on race specific dietary interventions in Asian/PI patients. In our study Asian/PI patients excreted lower volumes, less citrate and more uric acid than white patients. Thus, they may benefit more than their white counterparts from increased fluid intake, which is
known to prevent recurrent nephrolithiasis,15 beverages that increase urinary citrate16 or empirical treatment with potassium citrate17 and animal protein restriction. The limitations of our study deserve mention. It is retrospective in nature and, thus, subject to the limitations of a nonprospective study. Patients were stone formers only so results may not be generalizable to the population at large. Since height and weight were self-reported, reporting errors could potentially have confounded our results. However, the accuracy of self-reported height and weight was previously validated in the adult population.18 Also, we routinely measure patient height and weight at the clinic visit, ie 1 to 2 months before 24-hour urinalysis with self-reported height and weight, and inform them of the results. We also did not include stone analysis information in our study. We assume that based on previous studies greater than 85% of stones in the United States are composed of calcium oxalate and, thus, our findings are generalizable to most with urinary stone disease.19 Finally, we used a single 24-hour urinalysis. Although this is considered acceptable for metabolic evaluation of stone disease, some practitioners routinely perform 2, 24hour urinalyses for the initial stone disease metabolic evaluation.20 Finally, we analyzed patients classified in the electronic medical record as Asian/PI as a group. In the future a more detailed analysis using country of origin may yield data more specific to individuals.
CONCLUSIONS Significant differences exist in 24-hour urine chemistry between white and Asian/PI stone formers. Knowledge of these differences would be useful to evaluate and treat these patients, and prevent stone recurrence, given the racial diversity encountered by many physicians who treat urinary stone disease.
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5. Wigertz K, Palacios C, Jackman LA et al: Racial differences in calcium retention in response to dietary salt in adolescent girls. Am J Clin Nutr 2005; 81: 845. 6. Taylor EN and Curhan GC: Body size and 24-hour urine composition. Am J Kidney Dis 2006; 48: 905.
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