- Email: [email protected]
The Characteristics of the Stone and Urine Composition in Chinese Stone Formers: Primary Report of a Single-center Results
Endourology and Stones The Characteristics of the Stone and Urine Composition in Chinese Stone Formers: Primary Report of a Single-center Results €ran Tiselius, Lili Ou, Yeping Liang, Hanliang Zhu, Shujue Li, Wenqi Wu, Dong Yang, Hans-Go and Guohua Zeng OBJECTIVE METHODS
RESULTS
CONCLUSION
To assess urine composition in Chinese patients with urolithiasis. Five hundred seven Chinese patients with urolithiasis from our center in southern China were included in this study. Analysis of stone composition was performed using infrared spectrometry. From all patients, 24-hour urine samples were collected for analysis of urinary variables. Some ion activity product risk indices were also calculated. The major stone constituents in the 507 analyzed stones were as follows: calcium oxalate (78.3%), infection stone components (14.6%), uric acid (3.6%), and calcium phosphate (3.4%). Only 1 stone was composed of cystine (0.2%). Of all patients, 504 (99.4%) had 1 or several urinary metabolic abnormalities. Hypocitraturia was recorded in 93.9%, high sodium excretion in 58.6%, small urine volume in 45.6%, hyperoxaluria in 31.0%, hypercalciuria in 26.0%, hyperuricosuria in 19.3%, and hyperphosphaturia in 2.8%. Moreover, high sodium excretion was more frequent in men than women (59.2% vs 49.3%, P ¼ .027), whereas hypercalciuria was more common in women (34.5% vs 20.4%, P <.001). High levels of urine sodium (187.7 86.9 vs 179.8 107.7 mmol/24h, P ¼ .038) and phosphate (18.26 8.36 vs 15.69 11.14 mmol/24h, P <.001) were found in men than in women. Infection stones were significantly (P <.004) more common in women. Compared with noninfection stone formers, the occurrence of hypomagnesuria (P ¼ .040) was more common in patients with infection stones. The results of urinary risk factors for stone formation in this study might serve as a basis for design of recurrence prevention. It is of interest to note that some of the demonstrated abnormalities differ from that in reports from other countries. UROLOGY 83: 732e737, 2014. 2014 Elsevier Inc.
U
rolithiasis is a disease with prevalence of 5%-15%, and in view of its high risk of recurrences with a relapse rate of 50% within 5-10 years and 75% in 20 years, it is one of the most common abnormalities of the urinary tract.1 Surgical treatment has become the mainstay for treatment of patients with urolithiasis. However, such procedures do not address the high recurrence risk. In contrast, medical and dietary treatment can effectively prevent recurrent stone Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This work was financed by a grant from Science and Technology Education Department of the Ministry of Health, China (No. 201002010). From the Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou, China; and the Division of Urology, Department of Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Reprint requests: Wenqi Wu, M.D., Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou 510230, China. E-mail: [email protected] Reprint requests: Guohua Zeng, M.D., Ph.D., Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou 510230, China. E-mail: gzgyzgh@ vip.tom.com Submitted: July 23, 2013, accepted (with revisions): November 13, 2013
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ª 2014 Elsevier Inc. All Rights Reserved
formation. Previous studies have confirmed the important role of metabolic evaluation for the identification of risk factors and rational recurrence preventive measures.2,3 Accordingly, underlying metabolic abnormalities can often be demonstrated in these patients. An elaborate metabolic evaluation can thus be helpful for understanding the reason for stone formation in the individual patient and for designing an appropriate recurrence preventive regime. In the European Association of Urology and American Urological Association guidelines, analysis of 24-hour urine and stone composition are recommended as the first step in the process of recurrence prevention. However, so far, the importance of the evaluation of 24-hour urine and stone analysis has not been recognized in China. To our knowledge, there is only 1 article addressing 24-hour urine analysis in Chinese patients with urolithiasis, and that article was just recently published.4 Several studies have shown that 24-hour urine composition might differ among patients from different countries and with different racial origin.1,5,6 Dietary habits, exposure to a hot climate, and racial factors in 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.11.012
Table 1. Percentage of urinary abnormalities in all patients, men and women, noninfection and infection stone patients Metabolic Abnormality Low urine volume Hypercalciuria High urine sodium Hypomagnesuria Hypocitraturia Hyperuricosuria Hyperoxaluria Hyperphosphaturia
Overall (n ¼ 507), %
Men (n ¼ 304), %
Women (n ¼ 203), %
Noninfection Stone Patient (n ¼ 432), %
Infection Stone Patients (n ¼ 74), %
45.60 26.00 58.60 13.80 93.90 19.30 31.00 2.80
43.80 20.40* 59.20y 13.50 93.10 19.10 32.90 1.40
48.30 34.5* 49.3y 14.30 95.10 19.70 28.60 1.40
46.30 25.00 58.40 13.00z 93.50 18.30 32.10 3.30
41.90 29.70 60.30 21.6z 94.60 21.60 27.00 5.40
*P <.001, yP ¼ .027, zP ¼ .040.
southern China might be important for explaining a risk situation that might be different from that in other parts of the world. A different therapeutic approach might thus be necessary, and for that purpose findings in 24-hour urine composition appear essential. The objective of the present study was to analyze metabolic risk factors and to determine the characteristics of stone patients in a Chinese population. In addition, we were interested to look at possible differences between men and women.
following definitions: hypercalciuria >250 mg (>6.25 mmol) of calcium for men and >200 mg (>5.0 mmol) for women; hyperoxaluria >40 mg (>0.44 mmol) of oxalate for both genders; hypocitraturia <450 mg (<2.3 mmol) of citrate for men and <550 mg (<2.9 mmol) for women; high sodium excretion >3.45 g (>150 mmol) for both genders; hyperuricosuria >800 mg (>4.8 mmol) of urate for men and >750 mg (>4.5 mmol) for women. Both men and women were considered hypomagnesuric when urine magnesium was <30 mg (<1.25 mmol) and hyperphosphaturic with >1200 mg (>38.7 mmol) of phosphate. A low 24-hour urine volume was defined as <2000 mL for both genders.7
MATERIALS AND METHODS Patients Between March 2003 and December 2012, a total of 583 Chinese patients with urolithiasis completed a 24-hour urine collection and had a stone analysis carried out. This information was retrospectively reviewed. Pediatric patients younger than 18 years (n ¼ 45) and those with obviously inappropriate urine collections (n ¼ 31) were excluded. The 24-hour urine collection was considered complete when creatinine excretion was >800 mg (>7.1 mmol) for men and >600 mg (>5.1 mmol) for women. It was thus possible to include 507 patients in the analysis: 304 men and 203 women.
Collection and Analysis of Urine and Stones Only one 24-hour urine was collected from all 507 inpatients before stone removal. All patients were on their habitual and self-selected diet. Urine biochemical variables including urine volume, calcium, magnesium, sodium, urate, phosphate, oxalate, citrate, and creatinine were measured. Urine oxalate and citrate were measured using ion exchange chromatography (Metrohm, Switzerland). Urine creatinine, phosphate, and urate were analyzed using standard chemical methods (Rayto, China). Urine calcium, magnesium, and sodium levels were determined using atomic absorption spectrophotometry (Shimadzu, Japan). Stone composition was analyzed using Fourier Transform-Infrared Spectrometry (Thermo) in our own laboratory. Patients were classified according to the chemical stone composition as suggested in the European Association of Urology guidelines. Calculi with magnesium ammonium phosphate, carbonate apatite, and ammonium urate were considered as infection stones; calculi with calcium oxalate, calcium phosphate, and uric acid as noninfection stones.
Ion Activity Product Risk Indices Approximate estimates of ion activity products of calcium oxalate and calcium phosphate were expressed in terms of AP(CaOx) index, AP(CaOx) indexs, and AP(CaP) indexs according to the formulas given in the following section.8 In the calculations, 24-hour calcium, oxalate, citrate, magnesium, and phosphate were expressed in millimole and the volume in liters.9 APðCaOxÞindex ¼
1:9,Calcium0:84 ,Oxalate Citrate0:22 ,Magnesium0:12 ,Volume1:03
APðCaOxÞindexs ¼
1:9,Calcium0:84 ,Oxalate Citrate0:22 ,Magnesium0:12 ,1:51:03
APðCaPÞindexs ¼ 2:7,103 ,Calcium1:07 ,Phospate0:70 ,ð7:0 4:5Þ6:8 Citrate0:20 ,1:51:31
Statistical Analysis Statistical analysis was made with SPSS statistical software version 13.0. All continuous variables were expressed as mean standard deviation. Independent-sample t test and MannWhitney U test were used for group comparison. Chi-square test was used to compare group frequency and gender differences. Spearman correlation coefficient was used for monovariate analysis. A P-value of <.05 was considered statistically significant.
Reference Standard
RESULTS
Standard laboratory 24-hour urine normal values were used according to those applied by Litholink (Chicago, IL) with the
Analysis of the chemical composition of the 507 stones disclosed 397 (78.3%) calcium oxalate stones, 74
UROLOGY 83 (4), 2014
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Table 2. Gender distribution, mean standard deviation age and 24-h urine variables in all patients, men and women, noninfection and infection stone patients Parameter Gender (male/female) Age (y) Volume (L) Calcium (mmol) Urate (mmol) Sodium (mmol) Oxalate (mmol) Citrate (mmol) Magnesium (mmol) Phosphate (mmol) AP(CaOx) index AP (CaOx) indexs AP (CaP) indexs
Overall (n ¼ 507) 47.3 2.18 4.40 3.69 182.6 0.44 1.05 3.29 17.2 1.13 1.66 28.70
13.1 0.93 2.75 2.27 95.7 0.43 0.92 2.67 39.7 1.89 1.15 11.81
Men (n ¼ 304) 47.0 2.22 4.43 3.68 187.7 0.46 1.01 3.35 18.26 1.16 1.73 30.27
13.0 0.90 2.57 1.70 86.9* 0.46 0.87 2.71 8.36y 1.95 1.15 10.10
Women (n ¼ 203)
Noninfection Stones (n ¼ 432)
Infection Stones (n ¼ 74)
271/161z 47.3 13.0 2.17 0.90 4.40 2.79 3.69 2.33 185.2 96.5 0.46 0.46 1.06 0.91 3.32 2.65 17.15 9.33 1.17 2.07 1.71 1.24 28.46 11.78
33/41z 47.3 13.0 2.27 1.01 4.53 2.50 3.62 1.87 180.1 93.1 0.36 0.24 0.96 0.84 3.15 2.84 17.78 11.42 0.92 0.89 1.41 0.59 30.72 12.24
47.8 2.13 4.37 3.69 179.8 0.42 1.12 3.22 15.69 1.07 1.54 26.22
13.1 0.96 2.99 2.92 107.7* 0.40 0.99 2.62 11.14y 1.78 1.13 14.10
*P ¼ .038, yP <.001, zP ¼ .004.
(14.6%) infection stones, 18 (3.6%) uric acid stones, 17 (3.4%) calcium phosphate stones, and 1 (0.2%) cystine stone. The average patient age was 47.3 13.1 years (range, 19-81). Urinary abnormalities were surprisingly common. One single abnormality was recorded in 22 (4.3%) patients, but as many as 482 (95.1%) had 2 or more abnormalities. In only 3 (0.6%) patients were all urine variables within the normal range. The most common abnormality was hypocitraturia, recorded in 93.9% of the patients. Excessive sodium excretion was recorded in 297 patients (58.6%) and low urine volumes in 231(45.6%). Hyperoxaluria was observed in 158 patients (31.0%), hypercalciuria in 132 (26.0%), hyperuricosuria in 98 (19.3%), hypomagnesuria in 70 (13.8%), and hyperphosphaturia in 14 patients (2.8%). There was a male predominance in our material with 304 men (60.0%) and 203 women (40.0%). A comparison between the genders disclosed that hyperexcretion of sodium was most frequent in men (59.2% vs 49.3%, P ¼ .027), whereas hypercalciuria was most frequent in women (34.5% vs 20.4%, P <.001). The various urinary abnormalities are summarized in Tables 1 and 2. The 24-hour urinary excretion of sodium (P ¼ .038) and phosphate (P <.001) was significantly higher in men than in women. Also AP(CaP) indexs was significantly higher in men than in women (P ¼ .003). All other urine variables in Table 2, including calcium, oxalate, citrate, magnesium, and volume, were not significantly different between the 2 genders. Because of different etiology between infection stones and noninfection stones, the 24-hour urine composition was also separately compared between these 2 patient groups. The results of this analysis (Tables 1 and 2) showed that infection stones were more common in women than in men (P ¼ .004). The frequency of hypomagnesuria in patients with infection stones was significantly higher than that in noninfection stone patients (21.6% vs 13.0%, P ¼ .040). There were, however, no statistically significant differences between the 2
734
Table 3. Percentage of urinary abnormalities in patients stratified according to stone composition Metabolic Abnormality Low urine volume Hypercalciuria High urine sodium Hypomagnesuria Hypocitraturia Hyperuricosuria Hyperoxaluria Hyperphosphaturia
CaOx, CaP, Uric Acid, n ¼ 397, n ¼ 17, n ¼ 18, % % P Value % 46.3 25.4 57.6 12.3 93.5 18.6 31.7 2.3
35.3 35.3 58.8 11.8 94.1 23.5 58.8 5.9
55.6 11.1 55.6 27.8 94.4 11.1 22.2 0
.665 .244 .568 .392 .981 .412 .042* .060
*P <.05 was considered statistically significant.
groups in terms of frequencies of low urine volume, hypercalciuria, high sodium excretion, hypomagnesuria, hypocitraturia, hyperuricosuria, or hyperoxaluria. Neither were there any differences when the individual urine variables were considered (Table 2). In Table 3, the recorded abnormalities are stratified according to stone composition in patients with calcium oxalate, calcium phosphate, and uric acid stones. The incidence of hyperoxaluria among the 3 types of stone composition was significantly different, but all other urine variables did not differ significantly (P >.05). Spearman correlation coefficients between sodium and calcium, sodium and citrate in noninfection stone patients are shown in Figure 1. There was as expected a pronounced relationship between sodium and calcium and between sodium and citrate (P <.001).
COMMENT To get an appropriate basis for decisions on the rational prevention of recurrent stone formation, a 24-hour urine analysis is generally considered useful. Despite a high prevalence and incidence of stone disease, analysis of risk factors for stone formation has not been a common part of the evaluation of Chinese patients with stone disease.
UROLOGY 83 (4), 2014
Figure 1. Correlations in urine from patients with noninfection stones; between urine sodium and citrate and between sodium and calcium (A and B) in all patients, in men (C and D) and in women (E and F). (Color version available online.)
Only recently was there a report on urine composition in a relatively small number of calcium oxalate and cystine stone-forming patients.4 The intention of our study was to review data from a larger group of stone-forming patients, and in that group, as many as 397 patients had produced calcium oxalate stones and 17 calcium phosphate stones. When all 507 patients were considered, biochemically abnormal values were encountered in 99.4%. That finding is thus in good agreement with the referred report.10 Although differences in patient selection might have influenced the outcome, the occurrence of abnormalities is striking. UROLOGY 83 (4), 2014
Highly interesting is the common occurrence of hypocitraturia, encountered in almost 94% of the patients. This is a frequency that is higher than that reported by Shen et al4 and also much higher than that commonly observed in international analyses of urine from stoneforming patients. The normally reported occurrence of hypocitraturia is in the range of 20%-60%,11 but both higher and lower frequencies have been reported. The excretion of citrate in the patients was 1.05 0.92 mmol/24h and accordingly similar to the level reported in the previous Chinese study,4 but very lower compared with other citrate levels in the literature.5,12-15 735
Citrate has a fundamental role in calcium stone formation. In addition to complex formation with calcium, citrate counteracts growth and aggregation/agglomeration of CaOx and CaP crystals and inhibits growth of CaOx on CaP.16 It has also been shown that citrate protects cells from CaOx crystal induced injury by preventing lipid peroxidation.17 Moreover, urinary citrate reflects the tubular acid base status and with the exception of patients with distal renal tubular acidosis.18 A low citrate is usually associated with low pH in tubular cells11 and low urine pH. In this preliminary examination of urine composition, we cannot explain why hypocitraturia is such a common abnormality among Chinese stone formers. Unfortunately the collection conditions did not allow us to reliably measure urine pH. It is, however, likely that the low citrate excretion in most patients was associated with low urine pH. The simultaneous occurrence of high APCaOx and low pH has been suggested as a particular risk for CaP-induced precipitation of CaOx.16 Excessive intake of animal protein is one cause of hypocitraturia and low pH, and such a diet might also result in high levels of urinary oxalate,19 which was recorded in 31% of the patients. It is also possible that genetic factors have contributed to the low citrate excretion.20 The calcium excretion was lower than in several international studies.12,14,20 The most likely explanation for that is that Chinese people have lower intake of calcium than is the case in western countries. Dairy products are not a common constituent of the everyday diet. A low intake of calcium will indirectly result in increased urinary oxalate as a result of excessive intestinal absorption. Consumption of oxalate-rich products such as tea and vegetables and low calcium intake might explain the relatively high urinary oxalate levels.21 High dietary calcium intake for a long time has been considered a risk factor for stone formation. However, recent studies22-24 have shown that dietary calcium intake is inversely associated with the risk of calcium oxalate stones, because low calcium intake allows free oxalate in the intestinal lumen to be absorbed and excreted in urine. A small increment in oxalate excretion has a pronounced effect on the activity product of calcium oxalate.23 Urine oxalate is considered more important than urine calcium as a determinant of calcium oxalate supersaturation. These findings have led to the conclusion that calcium restriction should not be recommended for calcium oxalate stone-forming patients.21 Although AP(CaOx) index had a relatively low value with a mean of 1.13, it is of note that that AP(CaOx) indexs calculated for a 24-hour urine volume of 1500 mL was approximately 1.7, a level in which the risk of heterogeneous crystallization of CaOx is assumed to start.25 An AP(CaOx) indexs >1.7 was present in 41.6% and a value >2.0 in 35.3% of the patients in our study. That low urine volumes were recorded in 46% of the patients needs to be considered in view of the definition used (<2000 mL). Nevertheless, our patients had higher urinary volumes than those other reported foreign patients.5,6,20 736
The mean urine volume of 2.18 L is also much higher than that seen, for instance, in Swedish male stone-forming patients in whom the mean volume was 1.6 L.13 It is, however, a common clinical problem that people tend to drink more when they collect urine, probably because they have been told of the value of drinking and they want to deliver a “good” sample. Excretion of urinary phosphate has been regarded as a risk factor for stone formation and recurrence. It was significantly higher in men in the study. This is also in line with previous studies.12,26 The combined effects of calcium, phosphate, and citrate at standardized urine volume of 1.5 L and a pH of 7 (AP [CaP] indexs) showed a slightly higher numerical level in men than in women. It is difficult to know if this is of importance because we have no nonestone-forming patients to compare with. A value >50 as used to indicate an increased risk of forming a urine supersaturated with CaP27 was found in 18.1%; 20.4% of men and 14.8% of women. It can, however, be assumed that a high risk of forming a urine supersaturated with CaP during a period of the 24-hour period is reflected in high AP(CaOx) indexs and indicates a risk of CaP precipitation and development of CaP deposits as a primary step in CaOx stone formation.16 In comparison with findings in normal urine from a group of Chinese people,4 it is of note that the patients in this series had lower urinary citrate and higher urate excretion. As discussed previously, the 24-hour urine volume was significantly higher. In terms of calcium and oxalate, no differences were recorded. Early study revealed that high sodium intake is associated with a high rate of nephrolithiasis and can promote crystallization of calcium salts by reducing concentrations of citrate.1 We found that the incidence of high sodium excretion and mean urinary sodium excretion was significant higher in men than in women in our study. Urine sodium is a good indicator for dietary sodium intake.28 Although the value of urine sodium is similar compared with other published data,12,15,20 it supports the clinical practice of advising local stone formers in reducing their salt intake, which would reduce the risk of stone formation. Urine calcium, oxalate, sodium, and citrate have been demonstrated to play main roles in the process of noninfection stone formation. Concerning the relationship between urine sodium and calcium, a study found that participants with the high urinary sodium excreted more urinary calcium than those with low urinary sodium.29 The positive correlation between urine sodium and calcium excretion was also found in the present study. Because there are differences in etiology and mechanism between infection stone and noninfection stone formation, the 24-hour urinary evaluation was compared between patients with infection stones and those with noninfection stones. A significant discrepancy in gender was shown. The probable reason is that urinary tract infection is more frequent in women. We also found that hypomagnesuria was more common in infection stone UROLOGY 83 (4), 2014
formers. Although daily magnesium output decreased in calcium oxalate stone formers,30 the underlying reason for hypomagnesuria was not possible to elucidate in this study. There were no statistically significant differences regarding other urine variables. There are several findings in this preliminary analysis of urine composition that can be used to improve future analyses in Chinese patients. We are aware of some shortcomings that need to be addressed in future studies. First, it seems important to measure the body weight so that a comparison with urinary creatinine can be used to assess the correctness of the samples. Measurement of urine pH in one or several urine samples seems to be particularly important in view of what has been found. Moreover, after drawing a sample for urate analysis, rapid acidification should be carried out to maintain calcium salts in solution and to prevent oxidation of ascorbate. There are some other limitations of our study that might be noted. We did not rule out other diseases, which might influence urine parameters, such as hypertension and gout. It needs to be emphasized, however, that information on stone composition was available for all patients in this analysis.
CONCLUSION Until additional information can be gained, it appears reasonable to assume that a majority of Chinese stoneforming patients would benefit from recurrence prevention with potassium citrate. References 1. Moe OW. Kidney stones: pathophysiology and medical management. Lancet. 2006;367:333-344. 2. Norman RW. Metabolic evaluation of stone disease patients: a practical approach. Curr Opin Urol. 2001;11:347-351. 3. Hesse A, Straub M. Rational evaluation of urinary stone disease. Urol Res. 2006;34:126-130. 4. Shen L, Sun X, Zhu H, et al. Comparison of renal function and metabolic abnormalities of cystine stone patients and calcium oxalate stone patients in China. World J Urol. 2013;31:1219-1223. 5. Hong YH, Dublin N, Razack AH, et al. Urinary metabolic evaluation of stone formers-a Malaysian perspective. Urology. 2012;80: 529-534. 6. Taylor EN, Curhan GC. Differences in 24-hour urine composition between black and white women. J Am Soc Nephrol. 2007;18: 654-659. 7. Battino BS, DeFOOR W, Coe F, et al. Metabolic evaluation of children with urolithiasis: are adult references for supersaturation appropriate? J Urol. 2002;168:2568-2571. 8. Tiselius HG. Medical evaluation of nephrolithiasis. Endocrinol Metab Clin North Am. 2002;31:1031-1050. 9. Tiselius HG. A simplified estimate of the ion-activity product of calcium phosphate in urine. Eur Urol. 1984;10:191-195. 10. Amaro CR, Goldberg J, Amaro JL, et al. Metabolic assessment in patients with urinary lithiasis. Int Braz J Urol. 2005;31:29-33.
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11. Zuckerman JM, Assimos DG. Hypocitraturia: pathophysiology and medical management. Rev Urol. 2009;11:134-144. 12. Curhan GC, Willett WC, Speizer FE, et al. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298. 13. Tiselius HG. Solution chemistry of supersaturation. In: Coe FL, Favus MJ, Pak CYC, et al., eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott Raven Publishers; 1996: 33-64. 14. Park KJ, Jeon SS, Han DH, et al. Clinical and metabolic evaluation of Korean patients with urolithiasis. Scand J Clin Lab Invest. 2011; 71:481-485. 15. Stitchantrakul W, Kochakarn W, Ruangraksa C, et al. Urinary risk factors for recurrent calcium stone formation in Thai stone formers. J Med Assoc Thai. 2007;90:688-698. 16. Tiselius HG. A hypothesis of calcium stone formation: an interpretation of stone research during the past decades. Urol Res. 2011; 39:231-243. 17. Byer K, Khan SR. Citrate provides protection against oxalate and calcium oxalate crystal induced oxidative damage to renal epithelium. J Urol. 2005;173:640-646. 18. Hamm LL, Hering-Smith KS. Pathophysiology of hypocitraturic nephrolithiasis. Endocrinol Metab Clin North Am. 2002;31:885-893. 19. Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clin Cases Miner Bone Metab. 2008;5:135-141. 20. Eisner BH, Porten SP, Bechis SK, et al. The role of race in determining 24-hour urine composition in white and Asian/Pacific Islander stone formers. J Urol. 2010;183:1407-1411. 21. Martini LA, Heilberg IP. Stop dietary calcium restriction in kidney stone-forming patients. Nutr Rev. 2002;60:212-214. 22. Menon M. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. J Urol. 1993;150: 563-564. 23. Martini LA, Wood RJ. Should dietary calcium and protein be restricted in patients with nephrolithiasis? Nutr Rev. 2000;58: 111-117. 24. Goldfarb DS. Reconsideration of the 1988 NIH consensus statement on prevention and treatment of kidney stones: are the recommendations out of date? Rev Urol. 2002;4:53-60. 25. Tiselius HG. Metabolic evaluation of patients with stone disease. Urol Int. 1997;59:131-141. 26. Heller HJ, Sakhaee K, Moe OW, et al. Etiological role of estrogen status in renal stone formation. J Urol. 2002;168:1923-1927. 27. Tiselius HG, Lindbäck B, Fornander AM, et al. Studies on the role of calcium phosphate in the process of calcium oxalate crystal formation. Urol Res. 2009;37:181-192. 28. Pak CY, Odvina CV, Pearle MS, et al. Effect of dietary modification on urinary stone risk factors. Kidney Int. 2005;68:2264-2273. 29. Taylor EN, Curhan GC. Demographic, dietary, and urinary factors and 24-h urinary calcium excretion. Clin J Am Soc Nephrol. 2009;4: 1980-1987. 30. Trinchieri A, Mandressi A, Luongo P, et al. Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones. Scand J Urol Nephrol. 1992;26:379-386.
APPENDIX SUPPLEMENTARY DATA
Supplementary associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2013.11.012.
737
RESULTS
CONCLUSION
To assess urine composition in Chinese patients with urolithiasis. Five hundred seven Chinese patients with urolithiasis from our center in southern China were included in this study. Analysis of stone composition was performed using infrared spectrometry. From all patients, 24-hour urine samples were collected for analysis of urinary variables. Some ion activity product risk indices were also calculated. The major stone constituents in the 507 analyzed stones were as follows: calcium oxalate (78.3%), infection stone components (14.6%), uric acid (3.6%), and calcium phosphate (3.4%). Only 1 stone was composed of cystine (0.2%). Of all patients, 504 (99.4%) had 1 or several urinary metabolic abnormalities. Hypocitraturia was recorded in 93.9%, high sodium excretion in 58.6%, small urine volume in 45.6%, hyperoxaluria in 31.0%, hypercalciuria in 26.0%, hyperuricosuria in 19.3%, and hyperphosphaturia in 2.8%. Moreover, high sodium excretion was more frequent in men than women (59.2% vs 49.3%, P ¼ .027), whereas hypercalciuria was more common in women (34.5% vs 20.4%, P <.001). High levels of urine sodium (187.7 86.9 vs 179.8 107.7 mmol/24h, P ¼ .038) and phosphate (18.26 8.36 vs 15.69 11.14 mmol/24h, P <.001) were found in men than in women. Infection stones were significantly (P <.004) more common in women. Compared with noninfection stone formers, the occurrence of hypomagnesuria (P ¼ .040) was more common in patients with infection stones. The results of urinary risk factors for stone formation in this study might serve as a basis for design of recurrence prevention. It is of interest to note that some of the demonstrated abnormalities differ from that in reports from other countries. UROLOGY 83: 732e737, 2014. 2014 Elsevier Inc.
U
rolithiasis is a disease with prevalence of 5%-15%, and in view of its high risk of recurrences with a relapse rate of 50% within 5-10 years and 75% in 20 years, it is one of the most common abnormalities of the urinary tract.1 Surgical treatment has become the mainstay for treatment of patients with urolithiasis. However, such procedures do not address the high recurrence risk. In contrast, medical and dietary treatment can effectively prevent recurrent stone Financial Disclosure: The authors declare that they have no relevant financial interests. Funding Support: This work was financed by a grant from Science and Technology Education Department of the Ministry of Health, China (No. 201002010). From the Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou, China; and the Division of Urology, Department of Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden Reprint requests: Wenqi Wu, M.D., Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou 510230, China. E-mail: [email protected] Reprint requests: Guohua Zeng, M.D., Ph.D., Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangdong Key Laboratory of Urology, Guangzhou 510230, China. E-mail: gzgyzgh@ vip.tom.com Submitted: July 23, 2013, accepted (with revisions): November 13, 2013
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formation. Previous studies have confirmed the important role of metabolic evaluation for the identification of risk factors and rational recurrence preventive measures.2,3 Accordingly, underlying metabolic abnormalities can often be demonstrated in these patients. An elaborate metabolic evaluation can thus be helpful for understanding the reason for stone formation in the individual patient and for designing an appropriate recurrence preventive regime. In the European Association of Urology and American Urological Association guidelines, analysis of 24-hour urine and stone composition are recommended as the first step in the process of recurrence prevention. However, so far, the importance of the evaluation of 24-hour urine and stone analysis has not been recognized in China. To our knowledge, there is only 1 article addressing 24-hour urine analysis in Chinese patients with urolithiasis, and that article was just recently published.4 Several studies have shown that 24-hour urine composition might differ among patients from different countries and with different racial origin.1,5,6 Dietary habits, exposure to a hot climate, and racial factors in 0090-4295/14/$36.00 http://dx.doi.org/10.1016/j.urology.2013.11.012
Table 1. Percentage of urinary abnormalities in all patients, men and women, noninfection and infection stone patients Metabolic Abnormality Low urine volume Hypercalciuria High urine sodium Hypomagnesuria Hypocitraturia Hyperuricosuria Hyperoxaluria Hyperphosphaturia
Overall (n ¼ 507), %
Men (n ¼ 304), %
Women (n ¼ 203), %
Noninfection Stone Patient (n ¼ 432), %
Infection Stone Patients (n ¼ 74), %
45.60 26.00 58.60 13.80 93.90 19.30 31.00 2.80
43.80 20.40* 59.20y 13.50 93.10 19.10 32.90 1.40
48.30 34.5* 49.3y 14.30 95.10 19.70 28.60 1.40
46.30 25.00 58.40 13.00z 93.50 18.30 32.10 3.30
41.90 29.70 60.30 21.6z 94.60 21.60 27.00 5.40
*P <.001, yP ¼ .027, zP ¼ .040.
southern China might be important for explaining a risk situation that might be different from that in other parts of the world. A different therapeutic approach might thus be necessary, and for that purpose findings in 24-hour urine composition appear essential. The objective of the present study was to analyze metabolic risk factors and to determine the characteristics of stone patients in a Chinese population. In addition, we were interested to look at possible differences between men and women.
following definitions: hypercalciuria >250 mg (>6.25 mmol) of calcium for men and >200 mg (>5.0 mmol) for women; hyperoxaluria >40 mg (>0.44 mmol) of oxalate for both genders; hypocitraturia <450 mg (<2.3 mmol) of citrate for men and <550 mg (<2.9 mmol) for women; high sodium excretion >3.45 g (>150 mmol) for both genders; hyperuricosuria >800 mg (>4.8 mmol) of urate for men and >750 mg (>4.5 mmol) for women. Both men and women were considered hypomagnesuric when urine magnesium was <30 mg (<1.25 mmol) and hyperphosphaturic with >1200 mg (>38.7 mmol) of phosphate. A low 24-hour urine volume was defined as <2000 mL for both genders.7
MATERIALS AND METHODS Patients Between March 2003 and December 2012, a total of 583 Chinese patients with urolithiasis completed a 24-hour urine collection and had a stone analysis carried out. This information was retrospectively reviewed. Pediatric patients younger than 18 years (n ¼ 45) and those with obviously inappropriate urine collections (n ¼ 31) were excluded. The 24-hour urine collection was considered complete when creatinine excretion was >800 mg (>7.1 mmol) for men and >600 mg (>5.1 mmol) for women. It was thus possible to include 507 patients in the analysis: 304 men and 203 women.
Collection and Analysis of Urine and Stones Only one 24-hour urine was collected from all 507 inpatients before stone removal. All patients were on their habitual and self-selected diet. Urine biochemical variables including urine volume, calcium, magnesium, sodium, urate, phosphate, oxalate, citrate, and creatinine were measured. Urine oxalate and citrate were measured using ion exchange chromatography (Metrohm, Switzerland). Urine creatinine, phosphate, and urate were analyzed using standard chemical methods (Rayto, China). Urine calcium, magnesium, and sodium levels were determined using atomic absorption spectrophotometry (Shimadzu, Japan). Stone composition was analyzed using Fourier Transform-Infrared Spectrometry (Thermo) in our own laboratory. Patients were classified according to the chemical stone composition as suggested in the European Association of Urology guidelines. Calculi with magnesium ammonium phosphate, carbonate apatite, and ammonium urate were considered as infection stones; calculi with calcium oxalate, calcium phosphate, and uric acid as noninfection stones.
Ion Activity Product Risk Indices Approximate estimates of ion activity products of calcium oxalate and calcium phosphate were expressed in terms of AP(CaOx) index, AP(CaOx) indexs, and AP(CaP) indexs according to the formulas given in the following section.8 In the calculations, 24-hour calcium, oxalate, citrate, magnesium, and phosphate were expressed in millimole and the volume in liters.9 APðCaOxÞindex ¼
1:9,Calcium0:84 ,Oxalate Citrate0:22 ,Magnesium0:12 ,Volume1:03
APðCaOxÞindexs ¼
1:9,Calcium0:84 ,Oxalate Citrate0:22 ,Magnesium0:12 ,1:51:03
APðCaPÞindexs ¼ 2:7,103 ,Calcium1:07 ,Phospate0:70 ,ð7:0 4:5Þ6:8 Citrate0:20 ,1:51:31
Statistical Analysis Statistical analysis was made with SPSS statistical software version 13.0. All continuous variables were expressed as mean standard deviation. Independent-sample t test and MannWhitney U test were used for group comparison. Chi-square test was used to compare group frequency and gender differences. Spearman correlation coefficient was used for monovariate analysis. A P-value of <.05 was considered statistically significant.
Reference Standard
RESULTS
Standard laboratory 24-hour urine normal values were used according to those applied by Litholink (Chicago, IL) with the
Analysis of the chemical composition of the 507 stones disclosed 397 (78.3%) calcium oxalate stones, 74
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Table 2. Gender distribution, mean standard deviation age and 24-h urine variables in all patients, men and women, noninfection and infection stone patients Parameter Gender (male/female) Age (y) Volume (L) Calcium (mmol) Urate (mmol) Sodium (mmol) Oxalate (mmol) Citrate (mmol) Magnesium (mmol) Phosphate (mmol) AP(CaOx) index AP (CaOx) indexs AP (CaP) indexs
Overall (n ¼ 507) 47.3 2.18 4.40 3.69 182.6 0.44 1.05 3.29 17.2 1.13 1.66 28.70
13.1 0.93 2.75 2.27 95.7 0.43 0.92 2.67 39.7 1.89 1.15 11.81
Men (n ¼ 304) 47.0 2.22 4.43 3.68 187.7 0.46 1.01 3.35 18.26 1.16 1.73 30.27
13.0 0.90 2.57 1.70 86.9* 0.46 0.87 2.71 8.36y 1.95 1.15 10.10
Women (n ¼ 203)
Noninfection Stones (n ¼ 432)
Infection Stones (n ¼ 74)
271/161z 47.3 13.0 2.17 0.90 4.40 2.79 3.69 2.33 185.2 96.5 0.46 0.46 1.06 0.91 3.32 2.65 17.15 9.33 1.17 2.07 1.71 1.24 28.46 11.78
33/41z 47.3 13.0 2.27 1.01 4.53 2.50 3.62 1.87 180.1 93.1 0.36 0.24 0.96 0.84 3.15 2.84 17.78 11.42 0.92 0.89 1.41 0.59 30.72 12.24
47.8 2.13 4.37 3.69 179.8 0.42 1.12 3.22 15.69 1.07 1.54 26.22
13.1 0.96 2.99 2.92 107.7* 0.40 0.99 2.62 11.14y 1.78 1.13 14.10
*P ¼ .038, yP <.001, zP ¼ .004.
(14.6%) infection stones, 18 (3.6%) uric acid stones, 17 (3.4%) calcium phosphate stones, and 1 (0.2%) cystine stone. The average patient age was 47.3 13.1 years (range, 19-81). Urinary abnormalities were surprisingly common. One single abnormality was recorded in 22 (4.3%) patients, but as many as 482 (95.1%) had 2 or more abnormalities. In only 3 (0.6%) patients were all urine variables within the normal range. The most common abnormality was hypocitraturia, recorded in 93.9% of the patients. Excessive sodium excretion was recorded in 297 patients (58.6%) and low urine volumes in 231(45.6%). Hyperoxaluria was observed in 158 patients (31.0%), hypercalciuria in 132 (26.0%), hyperuricosuria in 98 (19.3%), hypomagnesuria in 70 (13.8%), and hyperphosphaturia in 14 patients (2.8%). There was a male predominance in our material with 304 men (60.0%) and 203 women (40.0%). A comparison between the genders disclosed that hyperexcretion of sodium was most frequent in men (59.2% vs 49.3%, P ¼ .027), whereas hypercalciuria was most frequent in women (34.5% vs 20.4%, P <.001). The various urinary abnormalities are summarized in Tables 1 and 2. The 24-hour urinary excretion of sodium (P ¼ .038) and phosphate (P <.001) was significantly higher in men than in women. Also AP(CaP) indexs was significantly higher in men than in women (P ¼ .003). All other urine variables in Table 2, including calcium, oxalate, citrate, magnesium, and volume, were not significantly different between the 2 genders. Because of different etiology between infection stones and noninfection stones, the 24-hour urine composition was also separately compared between these 2 patient groups. The results of this analysis (Tables 1 and 2) showed that infection stones were more common in women than in men (P ¼ .004). The frequency of hypomagnesuria in patients with infection stones was significantly higher than that in noninfection stone patients (21.6% vs 13.0%, P ¼ .040). There were, however, no statistically significant differences between the 2
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Table 3. Percentage of urinary abnormalities in patients stratified according to stone composition Metabolic Abnormality Low urine volume Hypercalciuria High urine sodium Hypomagnesuria Hypocitraturia Hyperuricosuria Hyperoxaluria Hyperphosphaturia
CaOx, CaP, Uric Acid, n ¼ 397, n ¼ 17, n ¼ 18, % % P Value % 46.3 25.4 57.6 12.3 93.5 18.6 31.7 2.3
35.3 35.3 58.8 11.8 94.1 23.5 58.8 5.9
55.6 11.1 55.6 27.8 94.4 11.1 22.2 0
.665 .244 .568 .392 .981 .412 .042* .060
*P <.05 was considered statistically significant.
groups in terms of frequencies of low urine volume, hypercalciuria, high sodium excretion, hypomagnesuria, hypocitraturia, hyperuricosuria, or hyperoxaluria. Neither were there any differences when the individual urine variables were considered (Table 2). In Table 3, the recorded abnormalities are stratified according to stone composition in patients with calcium oxalate, calcium phosphate, and uric acid stones. The incidence of hyperoxaluria among the 3 types of stone composition was significantly different, but all other urine variables did not differ significantly (P >.05). Spearman correlation coefficients between sodium and calcium, sodium and citrate in noninfection stone patients are shown in Figure 1. There was as expected a pronounced relationship between sodium and calcium and between sodium and citrate (P <.001).
COMMENT To get an appropriate basis for decisions on the rational prevention of recurrent stone formation, a 24-hour urine analysis is generally considered useful. Despite a high prevalence and incidence of stone disease, analysis of risk factors for stone formation has not been a common part of the evaluation of Chinese patients with stone disease.
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Figure 1. Correlations in urine from patients with noninfection stones; between urine sodium and citrate and between sodium and calcium (A and B) in all patients, in men (C and D) and in women (E and F). (Color version available online.)
Only recently was there a report on urine composition in a relatively small number of calcium oxalate and cystine stone-forming patients.4 The intention of our study was to review data from a larger group of stone-forming patients, and in that group, as many as 397 patients had produced calcium oxalate stones and 17 calcium phosphate stones. When all 507 patients were considered, biochemically abnormal values were encountered in 99.4%. That finding is thus in good agreement with the referred report.10 Although differences in patient selection might have influenced the outcome, the occurrence of abnormalities is striking. UROLOGY 83 (4), 2014
Highly interesting is the common occurrence of hypocitraturia, encountered in almost 94% of the patients. This is a frequency that is higher than that reported by Shen et al4 and also much higher than that commonly observed in international analyses of urine from stoneforming patients. The normally reported occurrence of hypocitraturia is in the range of 20%-60%,11 but both higher and lower frequencies have been reported. The excretion of citrate in the patients was 1.05 0.92 mmol/24h and accordingly similar to the level reported in the previous Chinese study,4 but very lower compared with other citrate levels in the literature.5,12-15 735
Citrate has a fundamental role in calcium stone formation. In addition to complex formation with calcium, citrate counteracts growth and aggregation/agglomeration of CaOx and CaP crystals and inhibits growth of CaOx on CaP.16 It has also been shown that citrate protects cells from CaOx crystal induced injury by preventing lipid peroxidation.17 Moreover, urinary citrate reflects the tubular acid base status and with the exception of patients with distal renal tubular acidosis.18 A low citrate is usually associated with low pH in tubular cells11 and low urine pH. In this preliminary examination of urine composition, we cannot explain why hypocitraturia is such a common abnormality among Chinese stone formers. Unfortunately the collection conditions did not allow us to reliably measure urine pH. It is, however, likely that the low citrate excretion in most patients was associated with low urine pH. The simultaneous occurrence of high APCaOx and low pH has been suggested as a particular risk for CaP-induced precipitation of CaOx.16 Excessive intake of animal protein is one cause of hypocitraturia and low pH, and such a diet might also result in high levels of urinary oxalate,19 which was recorded in 31% of the patients. It is also possible that genetic factors have contributed to the low citrate excretion.20 The calcium excretion was lower than in several international studies.12,14,20 The most likely explanation for that is that Chinese people have lower intake of calcium than is the case in western countries. Dairy products are not a common constituent of the everyday diet. A low intake of calcium will indirectly result in increased urinary oxalate as a result of excessive intestinal absorption. Consumption of oxalate-rich products such as tea and vegetables and low calcium intake might explain the relatively high urinary oxalate levels.21 High dietary calcium intake for a long time has been considered a risk factor for stone formation. However, recent studies22-24 have shown that dietary calcium intake is inversely associated with the risk of calcium oxalate stones, because low calcium intake allows free oxalate in the intestinal lumen to be absorbed and excreted in urine. A small increment in oxalate excretion has a pronounced effect on the activity product of calcium oxalate.23 Urine oxalate is considered more important than urine calcium as a determinant of calcium oxalate supersaturation. These findings have led to the conclusion that calcium restriction should not be recommended for calcium oxalate stone-forming patients.21 Although AP(CaOx) index had a relatively low value with a mean of 1.13, it is of note that that AP(CaOx) indexs calculated for a 24-hour urine volume of 1500 mL was approximately 1.7, a level in which the risk of heterogeneous crystallization of CaOx is assumed to start.25 An AP(CaOx) indexs >1.7 was present in 41.6% and a value >2.0 in 35.3% of the patients in our study. That low urine volumes were recorded in 46% of the patients needs to be considered in view of the definition used (<2000 mL). Nevertheless, our patients had higher urinary volumes than those other reported foreign patients.5,6,20 736
The mean urine volume of 2.18 L is also much higher than that seen, for instance, in Swedish male stone-forming patients in whom the mean volume was 1.6 L.13 It is, however, a common clinical problem that people tend to drink more when they collect urine, probably because they have been told of the value of drinking and they want to deliver a “good” sample. Excretion of urinary phosphate has been regarded as a risk factor for stone formation and recurrence. It was significantly higher in men in the study. This is also in line with previous studies.12,26 The combined effects of calcium, phosphate, and citrate at standardized urine volume of 1.5 L and a pH of 7 (AP [CaP] indexs) showed a slightly higher numerical level in men than in women. It is difficult to know if this is of importance because we have no nonestone-forming patients to compare with. A value >50 as used to indicate an increased risk of forming a urine supersaturated with CaP27 was found in 18.1%; 20.4% of men and 14.8% of women. It can, however, be assumed that a high risk of forming a urine supersaturated with CaP during a period of the 24-hour period is reflected in high AP(CaOx) indexs and indicates a risk of CaP precipitation and development of CaP deposits as a primary step in CaOx stone formation.16 In comparison with findings in normal urine from a group of Chinese people,4 it is of note that the patients in this series had lower urinary citrate and higher urate excretion. As discussed previously, the 24-hour urine volume was significantly higher. In terms of calcium and oxalate, no differences were recorded. Early study revealed that high sodium intake is associated with a high rate of nephrolithiasis and can promote crystallization of calcium salts by reducing concentrations of citrate.1 We found that the incidence of high sodium excretion and mean urinary sodium excretion was significant higher in men than in women in our study. Urine sodium is a good indicator for dietary sodium intake.28 Although the value of urine sodium is similar compared with other published data,12,15,20 it supports the clinical practice of advising local stone formers in reducing their salt intake, which would reduce the risk of stone formation. Urine calcium, oxalate, sodium, and citrate have been demonstrated to play main roles in the process of noninfection stone formation. Concerning the relationship between urine sodium and calcium, a study found that participants with the high urinary sodium excreted more urinary calcium than those with low urinary sodium.29 The positive correlation between urine sodium and calcium excretion was also found in the present study. Because there are differences in etiology and mechanism between infection stone and noninfection stone formation, the 24-hour urinary evaluation was compared between patients with infection stones and those with noninfection stones. A significant discrepancy in gender was shown. The probable reason is that urinary tract infection is more frequent in women. We also found that hypomagnesuria was more common in infection stone UROLOGY 83 (4), 2014
formers. Although daily magnesium output decreased in calcium oxalate stone formers,30 the underlying reason for hypomagnesuria was not possible to elucidate in this study. There were no statistically significant differences regarding other urine variables. There are several findings in this preliminary analysis of urine composition that can be used to improve future analyses in Chinese patients. We are aware of some shortcomings that need to be addressed in future studies. First, it seems important to measure the body weight so that a comparison with urinary creatinine can be used to assess the correctness of the samples. Measurement of urine pH in one or several urine samples seems to be particularly important in view of what has been found. Moreover, after drawing a sample for urate analysis, rapid acidification should be carried out to maintain calcium salts in solution and to prevent oxidation of ascorbate. There are some other limitations of our study that might be noted. We did not rule out other diseases, which might influence urine parameters, such as hypertension and gout. It needs to be emphasized, however, that information on stone composition was available for all patients in this analysis.
CONCLUSION Until additional information can be gained, it appears reasonable to assume that a majority of Chinese stoneforming patients would benefit from recurrence prevention with potassium citrate. References 1. Moe OW. Kidney stones: pathophysiology and medical management. Lancet. 2006;367:333-344. 2. Norman RW. Metabolic evaluation of stone disease patients: a practical approach. Curr Opin Urol. 2001;11:347-351. 3. Hesse A, Straub M. Rational evaluation of urinary stone disease. Urol Res. 2006;34:126-130. 4. Shen L, Sun X, Zhu H, et al. Comparison of renal function and metabolic abnormalities of cystine stone patients and calcium oxalate stone patients in China. World J Urol. 2013;31:1219-1223. 5. Hong YH, Dublin N, Razack AH, et al. Urinary metabolic evaluation of stone formers-a Malaysian perspective. Urology. 2012;80: 529-534. 6. Taylor EN, Curhan GC. Differences in 24-hour urine composition between black and white women. J Am Soc Nephrol. 2007;18: 654-659. 7. Battino BS, DeFOOR W, Coe F, et al. Metabolic evaluation of children with urolithiasis: are adult references for supersaturation appropriate? J Urol. 2002;168:2568-2571. 8. Tiselius HG. Medical evaluation of nephrolithiasis. Endocrinol Metab Clin North Am. 2002;31:1031-1050. 9. Tiselius HG. A simplified estimate of the ion-activity product of calcium phosphate in urine. Eur Urol. 1984;10:191-195. 10. Amaro CR, Goldberg J, Amaro JL, et al. Metabolic assessment in patients with urinary lithiasis. Int Braz J Urol. 2005;31:29-33.
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11. Zuckerman JM, Assimos DG. Hypocitraturia: pathophysiology and medical management. Rev Urol. 2009;11:134-144. 12. Curhan GC, Willett WC, Speizer FE, et al. Twenty-four-hour urine chemistries and the risk of kidney stones among women and men. Kidney Int. 2001;59:2290-2298. 13. Tiselius HG. Solution chemistry of supersaturation. In: Coe FL, Favus MJ, Pak CYC, et al., eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott Raven Publishers; 1996: 33-64. 14. Park KJ, Jeon SS, Han DH, et al. Clinical and metabolic evaluation of Korean patients with urolithiasis. Scand J Clin Lab Invest. 2011; 71:481-485. 15. Stitchantrakul W, Kochakarn W, Ruangraksa C, et al. Urinary risk factors for recurrent calcium stone formation in Thai stone formers. J Med Assoc Thai. 2007;90:688-698. 16. Tiselius HG. A hypothesis of calcium stone formation: an interpretation of stone research during the past decades. Urol Res. 2011; 39:231-243. 17. Byer K, Khan SR. Citrate provides protection against oxalate and calcium oxalate crystal induced oxidative damage to renal epithelium. J Urol. 2005;173:640-646. 18. Hamm LL, Hering-Smith KS. Pathophysiology of hypocitraturic nephrolithiasis. Endocrinol Metab Clin North Am. 2002;31:885-893. 19. Nouvenne A, Meschi T, Guerra A, et al. Dietary treatment of nephrolithiasis. Clin Cases Miner Bone Metab. 2008;5:135-141. 20. Eisner BH, Porten SP, Bechis SK, et al. The role of race in determining 24-hour urine composition in white and Asian/Pacific Islander stone formers. J Urol. 2010;183:1407-1411. 21. Martini LA, Heilberg IP. Stop dietary calcium restriction in kidney stone-forming patients. Nutr Rev. 2002;60:212-214. 22. Menon M. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. J Urol. 1993;150: 563-564. 23. Martini LA, Wood RJ. Should dietary calcium and protein be restricted in patients with nephrolithiasis? Nutr Rev. 2000;58: 111-117. 24. Goldfarb DS. Reconsideration of the 1988 NIH consensus statement on prevention and treatment of kidney stones: are the recommendations out of date? Rev Urol. 2002;4:53-60. 25. Tiselius HG. Metabolic evaluation of patients with stone disease. Urol Int. 1997;59:131-141. 26. Heller HJ, Sakhaee K, Moe OW, et al. Etiological role of estrogen status in renal stone formation. J Urol. 2002;168:1923-1927. 27. Tiselius HG, Lindbäck B, Fornander AM, et al. Studies on the role of calcium phosphate in the process of calcium oxalate crystal formation. Urol Res. 2009;37:181-192. 28. Pak CY, Odvina CV, Pearle MS, et al. Effect of dietary modification on urinary stone risk factors. Kidney Int. 2005;68:2264-2273. 29. Taylor EN, Curhan GC. Demographic, dietary, and urinary factors and 24-h urinary calcium excretion. Clin J Am Soc Nephrol. 2009;4: 1980-1987. 30. Trinchieri A, Mandressi A, Luongo P, et al. Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones. Scand J Urol Nephrol. 1992;26:379-386.
APPENDIX SUPPLEMENTARY DATA
Supplementary associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.urology. 2013.11.012.
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