Antioxidants and Self-Reported History of Kidney Stones: The National Health and Nutrition Examination Survey

Abstract

Background and Purpose:

Animal studies have demonstrated the likely role of oxidative tissue damage in the pathophysiology of stone disease; however, the effect of antioxidants on stone formation in the human population is unknown. We evaluated the association between serum antioxidant levels and the self-reported prevalence of kidney stones in a large cross-sectional population in a retrospective cohort study.

Materials and Methods:

Serum levels of antioxidants among adult participants in the National Health and Nutrition Examination Survey (NHANES III) 1988–1994 were compared between those with and without a self-reported history of kidney stones, adjusting for covariates of age, sex, body mass index (BMI), race/ethnicity, diabetes, and hypertension.

Results:

The prevalence of kidney stones was 5.25% (95% confidence interval: 4.60%, 5.90%). The prevalence of kidney stones was higher in males, white/non-Hispanics, diabetics, and those with hypertension. The prevalence of kidney stones increased with BMI. After adjusting for covariates, mean levels of alpha-carotene, beta-carotene, and beta-cryptoxanthin were significantly lower in those with kidney stones (-9.36%, −10.79%, and −8.48%, respectively). When analyzed by quartile, higher serum levels of beta-carotene and beta-cryptoxanthin,, trended toward a decreasing prevalence of stones (P=0.007 and P=0.03, respectively), indicating that the highest levels of these antioxidants may protect against the formation of kidney stones.

Conclusions:

Lower levels of alpha-carotene, beta-carotene, and beta-cryptoxanthin are associated with a history of kidney stones and may indicate a role for these antioxidants in preventing stone formation.

Introduction

T he increasing prevalence of nephrolithiasis in the United States is likely occurring for several reasons, including changes in diet as well as climate.^1,2 While several dietary factors, including increased protein intake and decreased fluid intake, have been linked previously to the formation of stones,^3,4 the role of several other nutritional components, including antioxidants, remains ill defined. Because of their ability to prevent oxidative tissue damage, antioxidants have been postulated to have preventive effects for multiple diseases, including prostate cancer⁵ and coronary artery disease.⁶ Given that nephrolithiasis has been associated with high oxidative stress and damage to renal tubular cells in humans,⁷ it is postulated that antioxidants may play a role in the prevention of urolithiasis.

Several studies have previously evaluated the potential role of oxidative stress in the animal model by demonstrating increased markers of lipid peroxidation and oxygen-free radicals in in vivo models of nephrolithiasis in rat,⁸ canine, and porcine models.⁹ Furthermore, recent evaluation of N-acetylcysteine found that this potent antioxidant neutralized the cytotoxic effects of calcium oxalate monohydrate crystals on porcine renal tubular cells.¹⁰

To further evaluate the results of these animal studies in a human population, we sought to evaluate the effect of various antioxidants on the prevalence of stone disease in a large cross-sectional portion of the population.

Materials and Methods

Study population

We evaluated data from the Third National Health and Nutrition Examination Survey NHANES III), conducted from 1988 to 1994 on a nationwide probability sample of 33,994 perspms aged 2 months and older.¹¹ Briefly, NHANES III was conducted by the National Center for Health Statistics, Centers for Disease Control and Prevention. The survey was a stratified probability sample of the civilian, noninstitutionalized U.S. population with oversampling of African-Americans, Mexican-Americans, and the elderly to provide more accurate estimates of their characteristics within their respective populations and the population as a whole.

Each respondent was assigned a weight based on geographic and demographic characteristics to allow the calculation of population-based estimates. An adult in-home questionnaire was administered to sampled subjects ≥18 years of age and physical examinations and blood sample evaluations were subsequently conducted on those subjects who were ambulatory and consented to the examination.

NHANES data

The current analysis relied on the 17,695 adults who responded to the survey question “have you ever had kidney stones?” These patients were then evaluated for baseline characteristics, including age, sex, body mass index (BMI), ethnicity, blood pressure, geographic location, waist circumference, serum triglycerides, serum high-density lipoprotein, serum glucose, and the presence of hypertension and diabetes. During NHANES III, patients also underwent venipuncture as previously described, including serum measurements of eight antioxidants: Alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene, retinyl esters, vitamin A, and vitamin E.¹¹

Statistical analysis

Mean antioxidant levels were compared between subjects with and without a self-reported history of kidney stones, adjusting for covariates and reported as the percentage difference. Logistic regression for kidney stones with antioxidant level (quartiles) in the blood as an independent variable, adjusting for age (<30, 30–44, 45–64, ≥65), sex, race/ethnicity, BMI (<20, 20–24, 25–29, ≥30), hypertension, and diabetes. All analyses calculations were performed using SAS (version 9.2; Cary, NC) procedures SURVEYFREQ, SURVEYREG, and SURVEYLOGISTIC.

Results

Of the 17,695 adult subjects, the overall prevalence of kidney stones was 5.25% (6.48% in men and 4.13% in women). An increasing prevalence of kidney stones was observed with increasing BMI, waist circumference, and triglycerides, or with the presence of diabetes, hypertension, male sex, or white non-Hispanic ethnicity (data published previously). The mean age of those with kidney stones was 54 vs a mean age of 43 in those without kidney stones. Of those with kidney stones, the mean waist circumference was 97.8 cm, while those without kidney stones had a mean waist circumference of 90.9 cm. Of subjects with kidney stones, 9.2% had diabetes, while only 5.0% of those without kidney stones had diabetes.

Table 1 lists mean antioxidant levels for those with and without a history of kidney stones. On univariate analysis, beta-cryptoxanthin levels were significantly lower in subjects with kidney stones while vitamins A and E levels were significantly higher in those with kidney stones. After adjusting for age, sex, BMI, ethnicity, hypertension, and diabetes, levels of beta-cryptoxanthin remained significantly lower in those with kidney stones, while patients with higher alpha- and beta-carotene levels were also significantly less likely to report a history of kidney stones than those with lower levels.

Table 1.

Comparison of Mean (Standard Error) Antioxidant Levels (μg/dL) of those with and without Kidney Stones

				Adjusted for covariates^*
Antioxidant	With kidney stones (n=754)	No kidney stones (n=15,904)	No covariates P value	% difference with-without	P value
Alpha-carotene	3.48 (0.14)	3.56 (0.07)	0.56	-9.36 (2.61)	0.010
Beta-carotene	14.40 (0.58)	14.87 (0.21)	0.36	-10.79 (2.78)	0.001
Beta-cryptoxanthin	7.02 (0.20)	7.78 (0.12)	0.0002	-8.48 (1.98)	0.0005
Lutein/zeaxanthin	19.67 (0.56)	19.25 (0.25)	0.43	-1.68 (2.51)	0.53
Lycopene	19.65 (0.64)	20.65 (0.27)	0.10	3.37 (2.98)	0.27
Retinyl esters	4.997 (0.193)	5.008 (0.058)	0.95	-5.10 (2.74)	0.14
Vitamin A	60.66 (0.75)	56.06 (0.33)	<0.0001	0.90 (1.30)	0.49
Vitamin E	1175 (19.5)	1063 (8.4)	<0.0001	-0.71 (1.46)	0.63

Age, sex, Bbody mass index, race/ethnicity, diabetes, hypertension.

To further characterize the effects of alpha-carotene, beta-carotene, and beta-cryptoxanthin, logistic regression analysis was used to analyze the prevalence of kidney stones by antioxidant level quartiles (Tables 2a –c). With all three antioxidants, a trend of increasing prevalence of stones with decreasing levels of individual antioxidant was observed. This trend was statistically significant for beta-carotene (P=0.007) and beta-cryptoxanthin (P=0.03). These trends were not observed for the other antioxidants in this study (Table 3).

Table 2A.

Adjusted Odds Ratio of Kidney Stones for Alpha-Carotene

	Prevalence kidney stones						Adjusted for covariates^*
	Male			Female
Antioxidant (quartiles)	n	Percent	95% CI for percent	n	Percent	95% CI for percent	Odds ratio (95% CI)	P value
Alpha-carotene								(0.146)
0–1	2227	5.87	(4.17, 7.56)	1896	4.32	(2.67, 5.97)	1.38 (1.04, 1.84)	0.026
2–3	2064	6.38	(4.67, 8.10)	2155	3.57	(2.36, 4.79)	1.09 (0.80, 1.48)	0.598
4–5	1962	7.19	(5.41, 8.98)	2232	4.77	(3.63, 5.90)	1.17 (0.92, 1.49)	0.207
≥6	1584	6.84	(4.75, 8.93)	2538	4.30	(3.27, 5.33)	-ref-	–
Since OR for 2–3 and 4–5 are similar, refit model combining these two categories
								(0.078)
0–1	2227	5.87	(4.17, 7.56)	1896	4.32	(2.67, 5.97)	1.38 (1.04, 1.84)	0.025
2–5	4026	6.78	(5.72, 7.84)	4387	4.21	(3.39, 5.03)	1.13 (0.90, 1.42)	0.287
≥6	1584	6.84	(4.75, 8.93)	2538	4.30	(3.27, 5.33)	-ref-	–

Age, sex, body mass index, race/ethnicity, diabetes, hypertension.

CI=confidence interval; OR=odds ratio.

Table 2B.

Adjusted Odds Ratio of Kidney Stones for Beta-Carotene

	Prevalence kidney stones						Adjusted for covariates^*
	Male			Female
Antioxidant (quartiles)	n	Percent	95% CI for percent	n	Percent	95% CI for percent	Odds ratio (95% CI)	P value
Beta-carotene								(0.007)
0–9	2951	6.08	(4.45, 7.72)	2306	4.22	(2.90, 5.53)	1.33 (1.03, 1.72)	0.03
10–14	1607	7.07	(5.03, 9.10)	1675	4.21	(2.95, 5.48)	1.24 (0.91, 1.70)	0.176
15–22	1612	6.89	(5.36, 8.42)	2045	3.50	(2.11, 4.88)	0.98 (0.71, 1.36)	0.917
≥23	1667	6.50	(4.27, 8.73)	2795	4.84	(3.66, 6.01)	-ref-	–
Since OR for 0–9 and 10–14 are similar, and 15–22 not different from ≥23, refit model with beta-carotene as two categories, below the median (0–14) and above the median (≥15)
0–14	4558	6.44	(5.07, 7.80)	3981	2.13	(3.40, 5.03)	1.27 (1.07, 1.50)	0.006
≥15	3279	6.70	(5.33, 8.06)	4840	2.94	(3.56, 5.02)	-ref-	–

Age, gender, BMI, race/ethnicity, diabetes, hypertension.

CI=confidence interval; OR=odds ratio.

Table 2C.

Adjusted Odds Ratio of Kidney Stones for Beta-Cryptoxanthin

	Prevalence kidney stones						Adjusted for covariates^*
	Male			Female
Antioxidant (quartiles)	n	Percent	95% CI for percent	n	Percent	95% CI for percent	Odds ratio (95% CI)	P value
Beta-cryptoxanthin								(0.030)
0–6	2987	7.79	(6.20, 9.38)	2991	4.23	(3.19, 5.27)	1.66 (1.13, 2.44)	0.010
7–9	1758	5.96	(4.19, 7.72)	2003	4.88	(3.45, 6.30)	1.53 (0.98, 2.41)	0.062
10–14	1656	6.03	(3.98, 8.07)	2023	3.86	(2.43, 5.30)	1.31 (0.79, 2.16)	0.298
≥15	1436	3.90	(1.30, 6.50)	1803	3.89	(2.26, 5.53)	-ref-	–
Since OR for 0–6 and 7–9 are similar, refit model combining these two categories
								(0.020)
0–9	4745	5.87	(5.78, 8.49)	4994	4.47	(3.68, 5.26)	1.60 (1.08, 2.37)	0.018
10–14	1656	6.03	(3.98, 8.07)	2023	3.86	(2.43, 5.30)	1.32 (0.80, 2.18)	0.282
≥15	1436	3.90	(1.30, 6.50)	1803	3.89	(2.26, 5.53)	-ref-	–

Age, gender, BMI, race/ethnicity, diabetes, hypertension.

CI=confidence interval; OR=odds ratio.

Table 3.

Adjusted Odds Ratio of Kidney Stones for Each Level of Antioxidant

	Prevalence kidney stones						Adjusted for covariates^*
	Male			Female
Antioxidant (quartiles)	n	Percent	95% CI for percent	n	Percent	95% CI for percent	Odds ratio (95% CI)	P value
Lutein/zeaxanthin								(0.213)
0–14	1844	6.34	(4.16, 8.51)	2245	4.82	(3.45, 6.20)	1.17 (0.83, 1.66)	0.377
15–20	2054	5.59	(4.06, 7.13)	2408	4.18	(2.89, 5.48)	0.89 (0.66, 1.22)	0.475
21–27	1859	6.63	(5.01, 8.25)	1995	3.38	(2.01, 4.75)	0.84 (0.59, 1.20)	0.330
>28	2080	8.02	(5.99, 10.04)	2173	4.52	(3.10, 5.94)	-ref-	–
Lycopene								-0.354
0–14	2172	8.26	(6.19, 10.33)	2595	3.99	(2.85, 5.12)	-ref-	–
15–21	1890	6.85	(5.26, 8.43)	2433	4.88	(3.57, 6.18)	1.27 (0.97, 1.67)	0.087
22–29	1820	6.21	(4.59, 7.83)	2008	3.29	(1.90, 4.68)	1.07 (0.80, 1.42)	0.653
>30	1955	5.48	(3.90, 7.05)	1785	4.88	(3.43, 6.33)	1.20 (0.85, 1.70)	0.299
Retinyl esters								(0.684)
0–3	2361	6.61	(4.87, 8.35)	2707	4.07	(2.92, 5.22)	1.19 (0.87, 1.64)	0.279
4–5	2241	6.84	(5.00, 8.68)	2454	3.90	(2.66, 5.15)	1.18 (0.88, 1.57)	0.269
6–7	1708	5.95	(4.41, 7.49)	1871	4.56	(3.21, 5.91)	1.12 (0.81, 1.53)	0.495
>8	1527	6.72	(5.05, 8.38)	1788	4.60	(3.16, 6.03)	-ref-	–
Vitamin A								(0.841)
<40	477	6.82	(1.89, 11.75)	1673	2.40	(0.97, 3.85)	1.10 (0.68, 1.78)	0.704
40–49	1434	4.98	(3.07, 6.89)	2393	4.02	(2.79, 5.24)	0.96 (0.54, 1.72)	0.894
50–62	2856	5.43	(4.12, 6.73)	2594	4.82	(3.68, 5.95)	1.00 (0.57, 1.75)	0.996
>63	3070	7.97	(6.22, 9.72)	2161	4.87	(3.71, 6.03)	-ref-	–
								(0.764)
≥1174	1316	3.03	(1.53, 4.52)	1363	2.58	(1.49, 3.67)	1.05 (0.72, 1.53)	0.793
	1731	4.63	(2.88, 6.38)	1493	3.31	(2.09, 4.53)	1.11 (0.69, 1.78)	0.676
	2340	7.34	(5.35, 9.33)	2493	4.32	(3.28, 5.35)	1.18 (0.80, 1.76)	0.396918–1173
	2450	8.65	(6.49, 10.81)	3022	5.37	(4.30, 6.43)	-ref-	–

Age, gender, BMI, race/ethnicity, diabetes, hypertension.

Discussion

There have been very few recent developments in the medical or nutritional prevention of nephrolithiasis.¹² While animal studies have demonstrated the likely role of oxidative tissue damage in the pathophysiology of stone disease, the effect of antioxidants on stone formation in the human population is unknown. In this large cross-sectional study of a representative sample of the U.S. population, we report the first population-based evidence of an inverse relationship between various serum antioxidant levels and the self-reported prevalence of kidney stones, with higher levels of these antioxidants correlated with a decreased risk in the prevalence of stones. Although these are statistically significant associations, this study does not show a direct causal relationship.

Previous studies have demonstrated associations between kidney stones and obesity, diabetes, hypertension, sex, and ethnicity,^13

–16 which may lead to an increased risk of nephrolithiasis by association with a variety of metabolic factors including a diet rich in sodium and protein, insulin resistance, and metabolic acidosis with a resultant hypocitraturia and acidic urine.^17,18 Using data from NHANES III, West and associates¹⁹ demonstrated a relationship between the components of the metabolic syndrome and the prevalence of kidney stones. To address this association, the effect of antioxidants on stone formation in the current study was evaluated using multivariate analysis, including male sex, white ethnicity, increased BMI, diabetes, and hypertension. After considering these confounding variables, serum levels of alpha-carotene, beta-carotene, and beta-cryptoxanthin independently predicted the prevalence of nephrolithiasis.

There is emerging evidence that oxidative stress, in addition to dietary factors, may be involved in the pathogenesis of kidney stones. In vitro studies have shown that calcium oxalate monohydrate is cytotoxic to renal tubular epithelial cells because of oxidative stress.¹⁰ Furthermore, free radical scavengers have been found to have a protective effect on these cells.⁹ In vivo studies in rats have shown that antioxidants have a protective effect on ethylene glycol-induced crystal deposition in renal tubular cells and papillary calcifications.^20,21

Oxidative stress also appears to play a role in the pathogenesis of nephrolithiasis in humans. Tungsanga and colleagues⁷ demonstrated that a cohort of patients who were scheduled for surgical stone removal had higher levels of blood lipid peroxidation products and a decreased antioxidant status compared with healthy nonstone formers.⁷ In addition, Boonla and coworkers²² showed elevated urinary 8-hydroxydeoxyguanosine excretion in nephrolithiasis patients indicating increased oxidative DNA damage. The current study, however, is the first to show a link between serum antioxidant levels and nephrolithiasis.

While many studies have shown a possible role for oxidative stress in stone pathogenesis, a diet-controlled study on the effects of variable oxalate load in human subjects failed to show increased levels of N-acetyl-ß-glucosaminidase and γ-glutamyl transpeptidase, markers of renal tubular injury.²³ While this study, consisting of 12 patients (6 stone formers and 6 nonstone formers), failed to show renal tubular injury from high oxalate loads, it did not evaluate the overall role of oxidative stress (ie, factors not associated with oxalate intake), nor did it have histologic data on renal tubules proving no tubular damage. In addition, because this was an acute response study in patients receiving a single oxalate load in a controlled setting with vigorous hydration, it is difficult to project these results to patients who may be chronically exposed to high oxalate intake in the setting of dehydration (an arguably more common scenario in the typical stone patient).

Our hypothesis is inherently different than that of Knight and colleagues,²³ in that we believe the oxidative stress involved in the pathogenesis of stone formation may be the end result of a systemic disorder (such as a manifestation of the metabolic syndrome, vascular disease, hypertension, etc.) rather than a process localized exclusively to the nephron. Because of the relatively low level of oxygen saturation in the renal medulla and medullary collecting duct, which borders on ischemia,²⁴ it is possible that factors influencing oxidative stress may have a more profound effect in this portion of the body. Because these sites within the nephron correspond to the sites of Randall plaque formation, it may be that early oxidative damage to tubular endothelial cells is one of the first inciting events in the pathogenesis of stone disease.

There are several limitations of our study. The self-reported history of kidney stones may not represent the true prevalence of nephrolithiasis because some study subjects may not be aware that they have received this diagnosis while others may have mistakenly believed they carry this diagnosis. While this study was performed in a nationally representative sample of women and men in the United States, it was not designed to specifically evaluate nephrolithiasis; therefore, we were not able to determine several important factors, such as number of stone episodes, size of stones, or stone composition. Nevertheless, similar evaluation of this population using NHANES data has identified several risks factors for stone formation that have later been proven in detailed prospective studies, validating its use as an accurate tool for evaluating general dietary measures in regard to risk of stone formation.^18,19,25,26

Cross-sectional studies, such as NHANES, as opposed to cohort studies, leave uncertainty regarding the temporal sequence of exposure and outcomes and are vulnerable to recall bias. For instance, if some participants increased their vegetable intake because of dietary counseling after a stone episode, it may lead to an increase in the level of serum antioxidants because antioxidants tend to be more abundant in vegetable sources. This change would then lead to an underestimation of the association between serum antioxidants and stone disease, making our findings conservative. Alternatively, it is possible that serum antioxidant levels are merely a surrogate marker for vegetable intake and that their effect on nephrolithiasis is simply because of higher vegetable intake (and lower protein intake), which has proven to lower the overall risk of stones.²⁷ If serum antioxidant levels were elevated solely because of vegetable intake, however, one would expect that all serum antioxidants would be significantly associated with stone disease, rather than only the three of eight antioxidants we evaluated.

The limited sampling of serum antioxidants in this study prevents evaluation of a broader spectrum of antioxidants and their effect on nephrolithiasis. For instance, polyphenols and ellagitannins, which are found in abundance in pomegranate juice, were not measured in the NHANES patient cohort. Because pomegranate juice has shown promise in reducing stone formation in the animal model,²⁰ it is likely that the current analysis may have not evaluated some of the important antioxidants associated with nephrolithiasis.

There are several key points regarding the antioxidants that were evaluated in this study that were linked to a reduced prevalence of nephrolithiasis. Alpha-carotene, beta-carotene, and beta-cryptoxanthin are all carotenoids that are converted to the active form of vitamin A—retinol. Retinol is esterified to retinyl esters and stored primarily in the liver. While direct measurement of retinyl esters themselves did not show significance in regard to stone prevalence (P=0.14), the fact that all three significant antioxidants are from the same family strengthens the argument that they play a true role in the reduction of nephrolithiasis. Many of these antioxidants have shown significant activity in other disease processes that are closely linked to nephrolithiasis. Beta-cryptoxanthin, which showed the strongest influence on stone disease, is a powerful antioxidant that has previously been associated with a decreased risk of myocardial infarction.²⁸ Beta-carotene has been associated with a decreased risk of development of microalbuminuria²⁹ and decreased arterial stiffness in hypertensive patients with type 2 diabetes.³⁰

Conclusions

In this cross-sectional study representing the U.S. population, we identified a significant association between lower levels of alpha-carotene, beta-carotene, and beta-cryptoxanthin and the prevalence of kidney stones. Further prospective studies in stone formers are necessary to determine whether various antioxidants may be useful in the treatment of recurrent nephrolithiasis.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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