
==== Front
Kidney360
Kidney360
KIDNEY
Kidney360
Kidney360
2641-7650
American Society of Nephrology

39012708
K360-2024-000239
10.34067/KID.0000000000000508
00015
3
Clinical Research
Nephrolithiasis
Chronic Fructose and Sucrose Intake and 24-Hour Urine Composition
https://orcid.org/0000-0001-9207-5971
Prochaska Megan 1
https://orcid.org/0000-0002-1379-022X
Ferraro Pietro Manuel 2
Taylor Eric 3 4
https://orcid.org/0000-0001-7386-6305
Curhan Gary 3
1 Department of Medicine, University of Chicago, Chicago, Illinois
2 Section of Nephrology, Department of Medicine, Università degli Studi di Verona, Verona, Italy
3 Channing Division of Network Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts
4 Tufts University School of Medicine, Boston, Massachusetts
Correspondence: Dr. Megan Prochaska, email: mprocha2@bsd.uchicago.edu
8 2024
16 7 2024
5 8 11671177
26 3 2024
8 7 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Visual Abstract

Key Points

Higher dietary intakes of fructose and sucrose are associated with lower 24-hour urine calcium.

Higher dietary intakes of fructose and sucrose are associated with other modest changes in 24-hour urine composition.

Background

Consumption of sugar, including fructose and sucrose, is associated with higher risk of kidney stones. The association is believed to be because of an acute rise in urine calcium after sugar intake. However, the association between chronic sugar intake and urine composition is not known.

Methods

We conducted a cross-sectional analysis of dietary intake from a food frequency questionnaire and 24-hour urine collections from 6457 kidney stone- and non–stone-former participants from the Nurses' Health Study I (1,297), Nurses' Health Study II (4,053), and Health Professionals Follow-up Study (1,107). We used multivariate adjusted linear regression to examine the association between long-term intake of free fructose, total fructose, and sucrose and 24-hour urine composition.

Results

Higher free and total fructose and sucrose intakes were each associated with lower 24-hour urine calcium. Comparing the highest versus lowest quintiles, mean urine calcium was 23 (31–15) mg/d lower for free fructose (P-trend <0.001), 26 (34–18) mg/d for total fructose (P-trend <0.001), and 8 (17–1) mg/d for sucrose (P-trend 0.03). Higher total fructose intake was associated with slightly higher calcium phosphate supersaturation (P-trend 0.002), and higher sucrose intake was associated with higher calcium oxalate (P-trend 0.03) and calcium phosphate (P-trend <0.001) supersaturations. Differences in 24-hour urine calcium were similar between kidney stone- and non–stone-former participants.

Conclusions

In contrast to the acute rise in urine calcium previously seen in short-term studies, higher long-term intake of free and total fructose and sucrose was associated with lower 24-hour urine calcium excretion in those with and without a history of kidney stones. Other modest differences in urine composition were noted for each sugar. Future studies should test potential mechanisms for the observed lower 24-hour urine calcium with chronic sugar intake.

calcium
kidney stones
National Institute of Diabetes and Digestive and Kidney DiseasesDK127252 Megan ProchaskaNational Institutes of HealthCA186107 Gary CurhanNational Institutes of HealthCA176726 Gary CurhanNational Institutes of HealthCA167552 Gary CurhanNational Institute of Diabetes and Digestive and Kidney DiseasesDK127252 National Institutes of HealthCA186107 National Institutes of HealthCA176726 National Institutes of HealthCA167552 OPEN-ACCESSTRUE
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pmcIntroduction

Kidney stones are common and increasing in prevalence.1,2 Important clinical risk factors of kidney stones include diabetes mellitus and higher body mass index (BMI).3–6 Diet is also critical for kidney stone risk, and many important dietary risk factors have been well described.7–13

Sugars, including fructose and sucrose, have been associated with higher risk of kidney stones.8,9,12,14 For example, higher fructose intake has been associated with higher incident kidney stone risk in the Nurses' Health Study I (NHS I), Nurses' Health Study II (NHS II), and Health Professionals Follow-up Study (HPFS).9,12 In these three cohorts, the highest intake of sugar-sweetened non-cola beverages (with fructose) had a pooled multivariate (MV) adjusted relative risk of 1.89 compared with the lowest intake group.9 Similarly, higher dietary sucrose intake was associated with higher risk of stones in NHS I11 and NHS II8; however, sucrose intake was not associated with kidney stone risk in HPFS.15

The association between higher sugar intake and risk of calcium-containing kidney stones has been believed to be related to changes in urine composition, such as an increase in urine calcium, with sugar intake. Higher urine calcium is associated with higher kidney stone risk,16 and multiple investigators have observed an acute rise in urine calcium and other urine stone risk factors (e.g., magnesium, where higher levels are associated with lower stone risk, and phosphorus, where higher levels are associated with higher stone risk), following an oral glucose, sucrose, or galactose load.17–20

However, information on the change in urine composition with chronic sugar intake is limited. One small cross-over study of 16 men, eight of whom had diabetes mellitus, examined changes in 24-hour urine composition after 2–4 weeks of isocaloric diets containing either high-fat, high complex carbohydrate, or high simple carbohydrate proportions.21 At the end of the study, there were no differences in urine calcium between the two diet patterns and very minimal other changes in urine composition. However, this study only examined a duration of 2–4 weeks of the diet patterns and did not include women or patients with kidney stone.

Knowledge of the changes in urine composition and urine calcium levels with chronic sugar intake may be important for understanding mechanisms contributing to stone risk. This may also have important implications for bone health as glucose ingestion in the absence of dietary calcium may reduce bone mineral stores.17 Therefore, we examined the association between long-term fructose and sucrose intake and 24-hour urine composition in 6457 kidney stone formers and non–stone-forming participants from the NHS I, NHS II, and HPFS.

Methods

Study Participants

Female registered nurses from the NHS I and NHS II and male health professionals from the HPFS completed 24-hour urine collections that were analyzed for this study.22 Every 2 years, participants also completed questionnaires to update information on lifestyle, medications, and medical diagnoses.

Free Fructose, Total Fructose, and Sucrose Intake Ascertainment

Each participant completed a semiquantitative food frequency questionnaire (FFQ) reporting information on dietary intake of more than 130 foods and beverages during the previous year. Participants completed a FFQ every 4 years. For this study, dietary intake was assessed from the FFQ data that were closest to and predating the urine collection. Free fructose (monosaccharide form) and sucrose (disaccharide of glucose and fructose) intake was computed using data from the US Department of Agriculture and energy adjusted to determine intake independent of the total caloric intake.23 Total fructose was calculated by adding intake of free fructose to one half the intake of sucrose. Validity and reproducibility of the FFQ data have been previously reported.24–27

Covariate Ascertainment

Information on age, BMI, diabetes mellitus, and hypertension were obtained from biennial questionnaires from the cohort. Kidney stone history was obtained from a biennial questionnaire and confirmed with a supplemental questionnaire. Validation of these methods has been previously reported.10,25

Twenty-Four-Hour Urine Collections

There were four major cycles of 24-hour urine collections, three of which have been previously described.16,28–30 In short, the first cycle included both kidney stone formers and non–stone formers who were younger than 65 years (NHS I) or 70 years (HPFS) and had no history of cancer or cardiovascular disease. The second cycle included additional kidney stone formers and non–stone formers who were younger than 75 years and had no history of cancer. In the third cycle, largely non–stone-forming NHS II participants without a history of hypertension were included. During the fourth cycle, urine collections were performed in 2020–2021 by 457 NHS II participants with and without a history of kidney stone disease and no history of cancer (except non-melanoma skin cancer) who also participated in the Microbiome Among Nurses stool collection project.31 Non–stone formers were matched to stone formers by age (within 5 years), race, and calendar time of receipt of the stool sample (±2 weeks). Urine collection procedures for the first two cycles were performed using Mission Pharmacal (San Antonio, TX), and the third and fourth cycles were performed using Litholink Corporation (Itasca, IL). Urine supersaturations for calcium oxalate, calcium phosphate, and uric acid were calculated using EQUIL2.32

Participants who provided at least 1 urine collection were included in this study. If a participant had provided more than 1 collection, the first one was used. Participants were excluded for missing dietary data or if their 24-hour urine creatinine was in the top or bottom 1% to reduce the likelihood of including those with under- or overcollections. After exclusions, there were a total of 1107 HPFS participants, 1297 NHS I participants, and 4053 NHS II participants.

Statistical Analyses

MV linear regression models were used to examine the association between free fructose, total fructose, and sucrose intake (cohort-specific quintiles) and 24-hour excretion of urinary factors. In separate models, urinary calcium, magnesium, pH, potassium, phosphate, sodium, oxalate, volume, and calcium oxalate and calcium phosphate supersaturations were the dependent variables. MV analyses were adjusted for age (continuous), cohort, race, BMI (five categories), history of kidney stones, history of gout, history of hypertension, history of diabetes, history of osteoporosis, thiazide use, and furosemide use. Models were also adjusted for dietary intakes of calcium, phosphorus, sodium, potassium, magnesium, oxalate, animal protein, total fluid intake, vitamin D, vitamin C (all quintiles), and supplemental calcium (quartiles), as well as sucrose (quintiles) and free fructose (quintiles) for our models examining free fructose intake and sucrose intake, respectively. Models were also simultaneously adjusted for urine creatinine (continuous). Additional models stratified by kidney stone status were also performed.

Data were analyzed using SAS software, version 9.4 (SAS Institute Inc., Cary, NC). The research protocol for this study was approved by the institutional review board at Mass General Brigham.

Results

The characteristics of study participants by cohort and by free fructose intake are presented in Table 1 and Supplemental Table 1, respectively. Participants in the highest quintile of free fructose intake had slightly lower BMI in all three cohorts and lower rates of diabetes in HPFS and NHS I. This same relationship has been seen previously.12 Hypertension was similar across the quintiles for NHS I and II but lower in the highest quintile for HPFS. The 24-hour urine results by cohort and free fructose intake are presented in Table 2 and Supplemental Table 2, respectively. Characteristics by sucrose intake are presented in Supplemental Table 3. Participants in the highest quintile of sucrose intake had lower rates of diabetes in all three cohorts (Supplemental Table 3).

Table 1 Characteristics of study participants closest to the time of urine collection by free fructose intake (mg/d) (N=6457)

HPFS	Quintile 1 (n=221)	Quintile 3 (n=221)	Quintile 5 (n=221)	
Age, yra	63 (8)	63 (8)	64 (8)	
White, %	93	94	94	
BMI, kg/m2	27 (4)	26 (3)	26 (3)	
Dietary calcium intake, mg/d	807 (335)	860 (295)	800 (286)	
Supplemental calcium intake, mg/d	149 (337)	169 (290)	183 (328)	
Animal protein intake, g/d	67 (18)	59 (15)	50 (15)	
Phosphorus intake, mg/d	1475 (268)	1480 (245)	1352 (239)	
Potassium intake, mg/d	3196 (498)	3510 (586)	3530 (752)	
Sodium intake, mg/d	2326 (520)	2209 (428)	2064 (453)	
Magnesium intake, mg/d	383 (112)	412 (107)	393 (115)	
Oxalate intake, mg/d	179 (76)	211 (93)	206 (104)	
Vitamin C intake, mg/d	346 (441)	435 (412)	518 (512)	
Vitamin D intake, IU/d	455 (305)	498 (293)	448 (275)	
Total fluid intake, ml/d	1886 (749)	1812 (710)	1737 (694)	
Free fructose intake, mg/da	14 (3)	25 (1)	43 (9)	
Total fructose intake, mg/da	30 (9)	48 (8)	71 (14)	
Sucrose intake, mg/da	32 (15)	47 (15)	56 (19)	
History of hypertension, %	45	36	39	
History of diabetes, %	9	6	5	
History of gout, %	10	4	8	
History of osteoporosis, %	1	3	1	
Thiazide use, %	9	5	4	
Furosemide use, %	1	2	1	
NHS I	Quintile 1 (n=259)	Quintile 3 (n=259)	Quintile 5 (n=259)	
Age, yra	64 (6)	65 (7)	67 (7)	
White, %	97	96	93	
BMI, kg/m2	28 (6)	26 (5)	26 (5)	
Dietary calcium intake, mg/d	738 (341)	779 (296)	812 (329)	
Supplemental calcium intake, mg/d	437 (491)	452 (487)	498 (476)	
Animal protein intake, g/d	53 (17)	49 (13)	43 (13)	
Phosphorus intake, mg/d	1214 (287)	1225 (253)	1183 (254)	
Potassium intake, mg/d	2677 (580)	3060 (548)	3195 (693)	
Sodium intake, mg/d	1991 (461)	1909 (385)	1713 (350)	
Magnesium intake, mg/d	318 (97)	355 (108)	356 (113)	
Oxalate intake, mg/d	147 (71)	173 (79)	166 (81)	
Vitamin C intake, mg/d	297 (369)	351 (346)	432 (416)	
Vitamin D intake, IU/d	441 (296)	483 (311)	518 (355)	
Total fluid intake, ml/d	1757 (747)	1818 (651)	1939 (760)	
Free fructose intake, mg/da	11 (2)	20 (1)	34 (7)	
Total fructose intake, mg/da	27 (8)	39 (7)	58 (12)	
Sucrose intake, mg/da	31 (15)	37 (12)	47 (16)	
History of hypertension, %	52	56	55	
History of diabetes, %	12	11	9	
History of gout, %	3	2	4	
History of osteoporosis, %	24	27	35	
Thiazide use, %	10	15	12	
Furosemide use, %	6	5	8	
NHS II	Quintile 1 (n=811)	Quintile 3 (n=811)	Quintile 5 (n=811)	
Age, yra	53 (7)	54 (7)	54 (7)	
White, %	97	97	96	
BMI, kg/m2	27 (6)	26 (5)	25 (5)	
Dietary calcium intake, mg/d	909 (352)	948 (322)	943 (351)	
Supplemental calcium intake, mg/d	455 (519)	462 (495)	539 (526)	
Animal protein intake, g/d	59 (18)	53 (14)	48 (16)	
Phosphorus intake, mg/d	1413 (260)	1399 (246)	1340 (264)	
Potassium intake, mg/d	2940 (521)	3210 (541)	3305 (750)	
Sodium intake, mg/d	2156 (450)	2099 (411)	1934 (416)	
Magnesium intake, mg/d	378 (126)	393 (110)	399 (138)	
Oxalate intake, mg/d	185 (94)	202 (106)	199 (138)	
Vitamin C intake, mg/d	249 (379)	287 (341)	354 (365)	
Vitamin D intake, IU/d	685 (769)	756 (807)	784 (935)	
Total fluid intake, ml/d	1754 (749)	1771 (745)	1719 (710)	
Free fructose intake, mg/da	11 (2)	20 (2)	35 (9)	
Total fructose intake, mg/da	27 (9)	39 (7)	58 (14)	
Sucrose intake, mg/da	34 (16)	39 (13)	46 (18)	
History of hypertension, %	15	14	13	
History of diabetes, %	3	4	3	
History of gout, %	0.7	1.1	0.7	
History of osteoporosis, %	17	18	19	
Thiazide use, %	3	4	2	
Furosemide use, %	0.4	0.6	0.4	
Values of polytomous variables may not sum to 100% because of rounding. BMI, body mass index; HPFS, Health Professionals Follow-Up Study; NHS I, Nurses' Health Study I; NHS II, Nurses' Health Study II.

Quintiles 2 and 4 not shown. See Supplemental Table 1 for details with all quintiles.

a Values are mean (SD) or percent and are standardized to the age distribution of the study population (except age, free fructose intake, total fructose intake, and sucrose intake).

Table 2 Urinary composition by cohort and quintiles of free fructose intake (mg/d) (N=6457)

HPFS	Quintile 1 (n=221)	Quintile 3 (n=221)	Quintile 5 (n=221)	
Calcium, mg/d	216 (110)	204 (108)	175 (98)	
Oxalate, mg/d	39 (12)	41 (14)	39 (12)	
Citrate, mg/d	669 (325)	714 (286)	699 (299)	
Sodium, mEq/d	201 (77)	175 (64)	175 (69)	
Potassium, mEq/d	75 (26)	78 (23)	75 (27)	
Magnesium, mg/d	121 (44)	126 (45)	121 (44.9)	
Phosphorus, mg/d	1121 (333)	1038 (293)	1013 (316)	
pH	5.8 (0.5)	5.9 (0.5)	5.9 (0.5)	
Uric acid, mg/d	632 (263)	640 (217)	580 (213)	
Ammonium, mEq/d	37 (11.3)	34 (8.5)	35 (8.9)	
Sulfate, mmol/d	25 (9.1)	24 (7.8)	22 (8.2)	
Creatinine, mg/d	1724 (397)	1630 (354)	1575 (370)	
Calcium oxalate supersaturation	8.3 (4.6)	9.1 (5.3)	8.2 (4.8)	
Calcium phosphate supersaturation	1.7 (1.4)	2.1 (1.8)	2 (1.8)	
NHS I	Quintile 1 (n=259)	Quintile 3 (n=259)	Quintile 5 (n=259)	
Calcium, mg/d	208 (102)	195 (99)	187 (105)	
Oxalate, mg/d	29 (10)	29 (10)	30 (11)	
Citrate, mg/d	628 (311)	638 (298)	627 (303)	
Sodium, mEq/d	148 (57)	139 (62)	134 (55)	
Potassium, mEq/d	58 (19)	62 (22)	62 (22)	
Magnesium, mg/d	104 (43)	97 (35)	102 (40)	
Phosphorus, mg/d	801 (225)	744.6 (234)	736 (257)	
pH	5.9 (0.5)	6.1 (0.5)	6 (0.6)	
Uric acid, mg/d	461 (147)	447 (160)	439 (176)	
Ammonium, mEq/d	28 (7)	28 (7.5)	27 (7)	
Sulfate, mmol/d	18 (6.1)	16 (6.1)	16 (6.3)	
Creatinine, mg/d	1075 (216)	1015 (213)	1038 (240)	
Calcium oxalate supersaturation	7.7 (4.5)	7 (4.4)	6.8 (4.1)	
Calcium phosphate supersaturation	1.9 (1.8)	1.8 (1.5)	1.8 (1.7)	
NHS II	Quintile 1 (n=811)	Quintile 3 (n=811)	Quintile 5 (n=811)	
Calcium, mg/d	212 (97)	201 (96)	187 (88)	
Oxalate, mg/d	29 (12)	30 (11)	31 (13)	
Citrate, mg/d	740 (282)	779 (310)	762 (285)	
Sodium, mEq/d	146 (58)	138 (57)	131 (55)	
Potassium, mEq/d	60 (20)	63 (20)	61 (22)	
Magnesium, mg/d	104 (40)	103 (37)	102 (42)	
Phosphorus, mg/d	870 (270)	815 (253)	764 (248)	
pH	6.1 (0.5)	6.2 (0.5)	6.2 (0.5)	
Uric acid, mg/d	548 (144)	537 (146)	520 (147)	
Ammonium, mEq/d	30 (9)	29 (9)	27 (9)	
Sulfate, mmol/d	32 (14)	31 (14)	29 (13)	
Creatinine, mg/d	1220 (229)	1207 (234)	1174 (233)	
Calcium oxalate supersaturation	5.8 (4.0)	5.8 (3.6)	6.1 (3.9)	
Calcium phosphate supersaturation	1.4 (1.4)	1.4 (1.3)	1.5 (1.3)	
Values are means (SD) and are standardized to the age distribution of the study population. HPFS, Health Professionals Follow-up Study; NHS I, Nurses' Health Study I; NHS II, Nurses' Health Study II.

Quintiles 2 and 4 not shown. See Supplemental Table 2 for details with all quintiles.

Free and Total Fructose and Urine Composition

For individuals in the highest quintile of free fructose intake compared with those in the lowest, mean (95% confidence interval) 24-hour urine values were lower for calcium (−23 [−31 to −15] mg/d, P-trend <0.001), magnesium (−4 [−8 to −1] mg/d, P-trend 0.01), phosphate (−39 [−58 to −20] mg/d, P-trend 0.002), and volume (−0.05 [−0.11 to 0.01], P-trend 0.04) (Table 3). Urine oxalate was modestly higher (1.3 [0.4 to 2.3] mg/d, P-trend 0.03) in the highest free fructose group compared with the lowest. There were no statistically significant differences in urine potassium, sodium, pH, citrate, or calcium oxalate and phosphate supersaturations by intake of free fructose (Table 3). Results were largely similar for total fructose intake, except higher intake was associated with slightly lower potassium (−4 [−5 to −2] mg/d, P-trend <0.001) and higher pH (0.08 [0.04 to 0.13], P-trend 0.003) (Table 3).

Table 3 Multivariate differences in 24-hour urine variables per quintile of free fructose, total fructose, and sucrose intakes for Nurses' Health Study I, Nurses' Health Study II, and Health Professionals Follow-up Study (N=6457)

Urine Variable	Free Fructose (MV Adjusted Mean Difference, 95% CI)	Total Fructose (MV Adjusted Mean Difference, 95% CI)	Sucrose (MV Adjusted Mean Difference, 95% CI)	
Calcium (mg/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	−11 (−19 to −4)	−9 (−16 to −2)	−2 (−9 to 5)	
 Quintile 3	−10 (−17 to −2)	−15 (−22 to −7)	−8 (−16 to −1)	
 Quintile 4	−14 (−22 to −6)	−16 (−24 to −9)	−5 (−12 to 3)	
 Quintile 5	−23 (−31 to −15)	−26 (−34 to −18)	−8 (−17 to −1)	
 P-trend	<0.001	<0.001	0.03	
Potassium (mg/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	−1 (−3 to 0)	0 (−2 to 1)	−1 (−2 to 1)	
 Quintile 3	0 (−2 to 2)	−2 (−4 to −1)	−2 (−4 to −1)	
 Quintile 4	−1 (−2 to 1)	−1 (−3 to 0)	−3 (−4 to −1)	
 Quintile 5	−1 (−3 to 0)	−4 (−5 to −2)	−3 (−5 to −2)	
 P-trend	0.08	<0.001	<0.001	
Magnesium (mg/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	2 (−5 to 1)	−2 (−4 to 1)	−2 (−5 to 0)	
 Quintile 3	−3 (−6 to 0)	−3 (−6 to 0)	−3 (−6 to 0)	
 Quintile 4	−2 (−5 to 1)	−2 (−5 to 1)	0 (−4 to 3)	
 Quintile 5	−4 (−8 to −1)	−5 (−8 to −2)	−3 (−6 to 0)	
 P-trend	0.01	0.002	0.10	
Sodium (mEq/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	−3 (−8 to 1)	−4 (−8 to 0)	−7 (−11 to −3)	
 Quintile 3	−4 (−9 to 0)	−9 (−13 to −5)	−7 (−11 to −2)	
 Quintile 4	−5 (−10 to −1)	−7 (−12 to −3)	−6 (−11 to −2)	
 Quintile 5	3 (−7 to 2)	−7 (−11 to −2)	−7 (−11 to −2)	
 P-trend	0.49	0.05	0.10	
pH				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	0.00 (−0.04 to 0.03)	0.01 (−0.03 to 0.05)	0.01 (−0.02 to 0.05)	
 Quintile 3	0.02 (−0.02 to 0.07)	0.02 (−0.02 to 0.05)	0.00 (−0.03 to 0.04)	
 Quintile 4	0.00 (−0.04 to 0.04)	0.03 (−0.01 to 0.07)	0.04 (0 to 0.08)	
 Quintile 5	0.04 (0 to 0.08)	0.08 (0.04 to 0.13)	0.05 (0.01 to 0.10)	
 P-trend	0.22	0.003	0.03	
Phosphate (mg/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	−30 (−48 to −13)	−18 (−35 to −2)	−12 (−29 to 5)	
 Quintile 3	−32 (−50 to −15)	−43 (−60 to −26)	−16 (−33 to 1)	
 Quintile 4	−30 (−48 to −12)	−32 (−49 to −14)	−29 (−47 to −12)	
 Quintile 5	−39 (−58 to −20)	−58 (−77 to −40)	−39 (−58 to −21)	
 P-trend	0.002	<0.001	<0.001	
Oxalate (mg/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	0.3 (−0.6 to 1.2)	0.6 (−0.2 to 1.5)	0 (−0.8 to 0.9)	
 Quintile 3	0.7 (−0.2 to 1.5)	0.1 (−0.7 to 1.0)	0 (−0.9 to 0.9)	
 Quintile 4	1.0 (0.1 to 1.9)	0.8 (−0.1 to 1.7)	0 (−0.9 to 0.9)	
 Quintile 5	1.3 (0.4 to 2.3)	0.8 (−0.2 to 1.7)	−0.9 (−1.9 to 0.1)	
 P-trend	0.03	0.90	0.002	
Citrate (mg/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	7 (−15 to 28)	10 (−11 to 32)	21 (−1 to 43)	
 Quintile 3	23 (0 to 45)	29 (7 to 51)	10 (−12 to 33)	
 Quintile 4	10 (−13 to 34)	25 (3 to 48)	23 (0 to 47)	
 Quintile 5	10 (−15 to 34)	12 (−13 to 36)	13 (−11 to 38)	
 P-trend	0.51	0.28	0.31	
Total volume (L/d)				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	−0.06 (−0.12 to −0.01)	−0.07 (−0.12 to −0.01)	−0.09 (−0.15 to −0.04)	
 Quintile 3	−0.02 (−0.08 to 0.03)	−0.12 (−0.17 to −0.06)	−0.14 (−0.19 to −0.08)	
 Quintile 4	−0.04 (−0.10 to 0.02)	−0.08 (−0.14 to −0.03)	−0.12 (−0.18 to −0.06)	
 Quintile 5	−0.05 (−0.11 to 0.01)	−0.14 (−0.20 to −0.07)	−0.15 (−0.21 to −0.09)	
 P-trend	0.04	<0.001	<0.001	
Calcium oxalate supersaturation				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	0.01 (−0.30 to 0.32)	0.20 (−0.11 to 0.50)	0.34 (0.03 to 0.65)	
 Quintile 3	0.08 (−0.24 to 0.41)	0.27 (−0.05 to 0.58)	0.49 (0.17 to 0.81)	
 Quintile 4	0.05 (−0.29 to 0.38)	0.28 (−0.05 to 0.60)	0.36 (0.03 to 0.69)	
 Quintile 5	−0.09 (−0.45 to 0.26)	0.20 (−0.14 to 0.55)	0.45 (0.10 to 0.79)	
 P-trend	0.48	0.44	0.03	
Calcium phosphate supersaturation				
 Quintile 1	Referent	Referent	Referent	
 Quintile 2	−0.08 (−0.19 to 0.03)	0.03 (−0.08 to 0.14)	0.05 (−0.06 to 0.16)	
 Quintile 3	−0.01 (−0.13 to 0.10)	0.02 (−0.09 to 0.13)	0.08 (−0.03 0.19)	
 Quintile 4	−0.10 (−0.22 to 0.02)	0.02 (−0.09 to 0.13)	0.07 (−0.05 to 0.18)	
 Quintile 5	−0.07 (−0.19 to 0.06)	0.09 (−0.03 to 0.21)	0.16 (0.04 to 0.28)	
 P-trend	0.98	0.002	<0.001	
Multivariate models: All models include age; body mass index; race; hypertension; gout; thiazide use; furosemide use; osteoporosis; diabetes; cohort; and dietary intake of calcium, supplemental calcium, protein, phosphorus, potassium, sodium, magnesium, oxalate, vitamin C, vitamin D. Models are also adjusted for urinary creatinine. Free fructose quintiles are additionally adjusted for intake of sucrose and sucrose models adjusted for intakes of free fructose. CI, confidence interval; MV, multivariate.

Sucrose and Urine Composition

Urine factors that were lower for individuals in the highest quintile of sucrose intake compared with those in the lowest were calcium (−8 [−17 to −1] mg/d, P-trend 0.03), potassium (−3 [−5 to −2] mg/d, P-trend <0.001), phosphate (−39 [−58 to −21] mg/d, P-trend <0.001), oxalate (−0.9 [−1.9 to 0.1], P trend 0.002), and urine volume (−0.15 [−0.21 to 0.09], P-trend <0.001). Higher urine factors were pH (0.05 [0.01 to 0.10], P-trend 0.03), calcium oxalate supersaturation (0.45 [0.10 to 0.79], P-trend 0.03), and calcium phosphate supersaturation (0.16 [0.04 to 0.28], P-trend <0.001) (Table 3). There were no substantial differences in urine magnesium, sodium, or citrate by intake of sucrose (Table 3).

Kidney Stone Formers versus Non–Stone Formers

When stratified by stone forming status, there were minimal differences between the two groups (P values for interaction >0.05) (Table 4). In particular, there were no differences between the two groups in calcium oxalate or phosphate supersaturations by intakes of free fructose or sucrose (Tables 5 and 6).

Table 4 Multivariate adjusted difference in 24-hour urine calcium per quintiles of free fructose and sucrose intake presented by kidney stone status (N=6457)

Participant Type	Mean Difference in Urine Calcium (mg/d) (95% CI) with Free Fructose	Mean Difference in Urine Calcium (mg/d) (95% CI) with Sucrose	
Kidney stone participants (N=2622)			
 Quintile 1	Referent	Referent	
 Quintile 2	−12 (−25 to 0)	−1 (−14 to 12)	
 Quintile 3	−8 (−21 to 5)	−9 (−22 to 5)	
 Quintile 4	−15 (−29 to −2)	−4 (−18 to 10)	
 Quintile 5	−21 (−36 to −7)	−9 (−23 to 6)	
 P-trend	0.002	0.18	
Non–kidney stone participants (N=3835)			
 Quintile 1	Referent	Referent	
 Quintile 2	−9 (−18 to 0)	−3 (−12 to 5)	
 Quintile 3	−10 (−19 to 0)	−8 (−17 to 1)	
 Quintile 4	−13 (−22 to −3)	−6 (−16 to 3)	
 Quintile 5	−22 (−32 to −12)	−11 (−21 to 0)	
 P-trend	<0.001	0.04	
Multivariate model: All models include age; body mass index; race; hypertension; gout; thiazide use; furosemide use; osteoporosis; diabetes; cohort; and dietary intake of calcium, supplemental calcium, protein, phosphorus, potassium, sodium, magnesium, oxalate, vitamin C, vitamin D, and urinary creatinine. Free fructose quintiles are additionally adjusted for intake of sucrose and sucrose models adjusted for intakes of free fructose. P for interaction for kidney stone and free fructose 0.95. P for interaction for kidney stone and sucrose 0.53. CI, confidence interval.

Table 5 Multivariate adjusted difference in 24-hour urine calcium oxalate supersaturation per quintiles of free fructose and sucrose intake presented by kidney stone status (N=6457)

Participant Type	Mean Difference in Urine Calcium Oxalate Supersaturation (95% CI) with Free Fructose	Mean Difference in Urine Calcium Oxalate Supersaturation (95% CI) with Sucrose	
Kidney stone participants (N=2622)			
 Quintile 1	Referent	Referent	
 Quintile 2	−0.29 (−0.87 to 0.30)	0.17 (−0.43 to 0.78)	
 Quintile 3	0.04 (−0.58 to 0.66)	0.45 (−0.18 to 1.08)	
 Quintile 4	−0.31 (−0.96 to 0.33)	0.41 (−0.24 to 1.06)	
 Quintile 5	−0.58 (−1.25 to 0.10)	0.44 (−0.24 to 1.12)	
 P-trend	0.08	0.19	
Non–kidney stone participants (N=3835)			
 Quintile 1	Referent	Referent	
 Quintile 2	0.26 (−0.08 to 0.60)	0.42 (0.09 to 0.76)	
 Quintile 3	0.12 (−0.24 to 0.47)	0.52 (0.18 to 0.86)	
 Quintile 4	0.29 (−0.08 to 0.65)	0.33 (−0.02 to 0.68)	
 Quintile 5	0.18 (−0.20 to 0.56)	0.47 (0.09 to 0.84)	
 P-trend	0.44	0.06	
Multivariate model: All models include age; body mass index; race; hypertension; gout; thiazide use; furosemide use; osteoporosis; diabetes; cohort; and dietary intake of calcium, supplemental calcium, protein, phosphorus, potassium, sodium, magnesium, oxalate, vitamin C, vitamin D, and urinary creatinine. Free fructose quintiles are additionally adjusted for intake of sucrose and sucrose models adjusted for intakes of free fructose. P for interaction for kidney stone and free fructose 0.04. P for interaction for kidney stone and sucrose 0.43. CI, confidence interval.

Table 6 Multivariate adjusted difference 24-hour urine calcium phosphate supersaturation per quintiles of free fructose and sucrose intake presented by kidney stone status (N=6457)

Participant Type	Mean Difference in Urine Calcium Phosphate Supersaturation (95% CI) with Free Fructose	Mean Difference in Urine Calcium Phosphate Supersaturation (95% CI) with Sucrose	
Kidney stone participants (N=2622)			
 Quintile 1	Referent	Referent	
 Quintile 2	−0.13 (−0.35 to 0.08)	−0.08 (−0.30 to 0.15)	
 Quintile 3	−0.02 (−0.25 to 0.21)	0.04 (−0.20 to 0.27)	
 Quintile 4	−0.17 (−0.41 to 0.07)	0.03 (−0.21 to −0.27)	
 Quintile 5	−0.10 (−0.35 to 0.15)	0.18 (−0.07 to 0.43)	
 P-trend	0.72	0.02	
Non–kidney stone participants (N=3835)			
 Quintile 1	Referent	Referent	
 Quintile 2	−0.02 (−0.13 to 0.08)	0.14 (0.03 to 0.24)	
 Quintile 3	−0.01 (−0.12 to 0.10)	0.11 (0.00 to 0.21)	
 Quintile 4	−0.04 (−0.15 to 0.08)	0.10 (−0.01 to 0.21)	
 Quintile 5	−0.05 (−0.17 to 0.07)	0.14 (0.02 to 0.26)	
 P-trend	0.99	0.008	
Multivariate model: All models include age; body mass index; race; hypertension; gout; thiazide use; furosemide use; osteoporosis; diabetes; cohort; and dietary intake of calcium, supplemental calcium, protein, phosphorus, potassium, sodium, magnesium, oxalate, vitamin C, vitamin D, and urinary creatinine. Free fructose quintiles are additionally adjusted for intake of sucrose and sucrose models adjusted for intakes of free fructose. P for interaction for kidney stone and free fructose 0.84. P for interaction for kidney stone and sucrose 0.19. CI, confidence interval.

Discussion

After MV adjustment, 24-hour urinary calcium was lower for individuals with the highest chronic intake of free and total fructose and sucrose. We also found that urine magnesium, phosphate, and volume were lower with higher free and total fructose, and the latter two were also lower with higher sucrose intake. Urine pH and calcium oxalate supersaturation were higher for individuals in the highest intake of free fructose and sucrose. Participants with and without kidney stones had similar differences in urine calcium for both free fructose and sucrose.

This study is the first to examine chronic intake of individual sugars and the association with 24-hour excretion of calcium and other urine parameters. Our findings differ from prior short-term studies that have shown an acute increase in urine calcium after intake of different sugars.17,18,20 These prior studies used timed spot urine samples soon after a sugar load, but did not report 24-hour excretions. Notably, urine calcium rose within 1 hour and then returned to baseline within a few hours20; it is not known whether urine calcium would have further dropped before the next prandial period.

By contrast, 24-hour urine calcium was lower with higher intakes of free and total fructose and sucrose in this study. The 24-hour urine samples of this study did not capture the short-term peaks and troughs of urine calcium that correspond with typical episodic eating patterns and may be exaggerated with acute sugar intake. In a prior small study, Garg et al. placed eight healthy men on a high-carbohydrate diet prepared in a metabolic kitchen for 2 weeks, and there was no difference in 24-hour urine calcium.21 Our larger study differs from this previous work because our participants consumed free-choice diets at home. In addition, our models controlled for other potential differences in dietary patterns that occur with higher fructose or sucrose intake, such as potential differences in dietary calcium intake, thus other dietary differences would be unlikely to account for the lower 24-hour urine calcium.

One potential mechanism to explain the lower urine calcium with higher long-term free and total fructose and sucrose intake could be the effect of fructose or sucrose on gut absorption of calcium33 and calcium balance.34–37 Prior balance studies have found that overall calcium balance is less positive with fructose compared with starch or even sucrose.35–37 The fractional gut absorption of calcium with fructose in these studies was near typical absorption levels at 20%37–30%.36 However, even a small difference in calcium absorption could explain the observed difference in urine calcium in our study of around 8–26 mg/d. For this reason, it is possible that high fructose or sucrose intake can affect the homeostasis of minerals, such as calcium or phosphate, but it is not clear whether gut absorption has a substantial, if any, role in the association between fructose or sucrose intake and the observed lower 24-hour urine calcium.

A second potential mechanism is the effect of fructose and sucrose on bone metabolism. Consistent with this is that our study also found that higher intakes of fructose and sucrose were associated with slightly lower urine phosphate and magnesium, two minerals that are largely stored in bone. In a previous study, higher intake of sugar-sweetened beverages containing fructose was associated with higher risk of hip fracture.38 However, in that study, higher risk was also present in diet sodas, which do not contain fructose or sucrose. This raises the question as to whether bone fracture risk in these studies was mediated by something other than sugar intake. That prior study did not examine urine composition, which may have provided insight into underlying mechanisms or associated changes in calcium metabolism. By contrast, other studies have found no differences in bone disease or fracture risk on the basis of sugar intake. In a study of adults older than 65 years, there was no difference in bone mineral density or fracture risk on the basis of sugar intake at 4 years of follow-up.39 However, 4 years may not be not enough time to see substantial changes in bone mineral density. It is possible that this study reflects longer dietary patterns than measured because some individual dietary patterns likely remain stable over time, but it is not clear whether sugar intake remains stable. Further study is required to elucidate potential mechanisms mediating the association of long-term fructose and sucrose intake on urine calcium, magnesium, and phosphate.

We found that there was higher urine oxalate with higher free fructose intake and slightly lower urine oxalate with higher sucrose intake. A prior study similarly found that individuals in the highest fructose intake quartile excreted 1.5 mg/d (0.6–2.5 mg/d; P-trend=0.004)28 more oxalate compared with the lowest quartile. It has been hypothesized that fructose metabolism can lead to increased oxalate generation.40,41 However, in a study of controlled diets containing 4%, 13%, and 21% fructose, there were no differences in urine oxalate or calcium, and with carbon-labeled fructose, they concluded that the fructose was not metabolized to oxalate.42 The mechanism for the association between high free fructose intake and higher urine oxalate remains unknown. Given that sucrose is half fructose, it is not known why sucrose intake was associated with slightly lower urine oxalate. However, the differences are small, and it is possible that despite adjusting for dietary oxalate we were unable to sufficiently control for potential confounders.

We found higher urine pH for higher intakes of total fructose and sucrose, but there was no difference for free fructose. Previous work has shown that urine pH was lower acutely after glucose ingestion, although pH returned to baseline after approximately 2 hours.20 Our results may differ because we only measured 24-hour urine pH. Similarly, Garg et al. found no difference in 24-hour urine pH in healthy men after 2 weeks on a high-carbohydrate diet.21 It is also possible that different sugars have a different effect on acid–base balance.

Other modest differences in urine composition with higher intakes of total fructose and sucrose included lower urine potassium and lower urine volume. Our models included dietary intake of many nutrients, such as potassium, and therefore, these small differences are less likely due to differences in dietary patterns (i.e., fruit or vegetable intake). Some of these urine differences have been noted in previous studies of spot urine collections,19 but underlying mechanisms mediating these differences are not entirely elucidated.

Previous work has also shown that higher fructose and sucrose intake are associated with higher kidney stone risk.8,9,12 It has previously been believed that this higher risk is driven by acute increases in urine calcium after sugar ingestion. On the basis of this study, it is possible that the higher kidney stone risk is due to acute rises in urine calcium and supersaturation after meals that are not reflected in 24-hour collections. Crystals formed acutely during these periods would be expected to persist in the urinary space and contribute to ongoing stone risk, even after urine calcium and supersaturations have returned to baseline or even decreased below the baseline values.

Alternatively, the increase in stone risk may be mediated by changes in urine composition independent of changes in urine calcium, such as change in urine oxalate or volume or by something that was not measured in urine. Higher calcium oxalate and calcium phosphate supersaturations and higher urine oxalate are each independently associated with higher kidney stone risk,16,43 and in this study, we found modestly higher urine oxalate with higher free fructose intake, higher calcium phosphate supersaturation with total fructose intake, and higher calcium oxalate and calcium phosphate supersaturations with higher sucrose intake. The supersaturation changes were potentially mediated by the lower urine volume seen with higher intakes of all three. Finally, it is possible that there is an unmeasured promoter of stone formation that is increased in urine with sugar intake.

Our study has limitations. Most notably, we examined 24-hour urine composition and were unable to capture acute postprandial changes in any urine parameters, including urine calcium. We studied chronic intake of free and total fructose and sucrose in this study and did not measure dietary intake of participants on the day of urine collection. Stone composition information is not available for most participants with kidney stone, although a validation study in these cohorts found the majority are likely calcium oxalate.10 Finally, generalizability may be limited because our study participants were largely White.

In conclusion, higher free and total fructose and sucrose intakes were associated with lower 24-hour urine calcium excretion and higher sucrose intake was associated with higher calcium oxalate supersaturation. Total fructose and sucrose intakes were associated with higher calcium phosphate supersaturation. Given that the observed increase in stone risk is not explained by 24-hour urine calcium excretion, future studies should test potential mechanisms driving these urine composition changes to better understand the association between sugar intake and kidney stone risk.

Supplementary Material

Acknowledgments

Thank you to Elaine Coughlan-Gifford for programming support. Thank you to John Asplin, MD for encouraging us to do this work.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/A576.

Funding

M. Prochaska: National Institute of Diabetes and Digestive and Kidney Diseases (DK127252). G. Curhan: National Institutes of Health (CA186107, CA176726, and CA167552).

Author Contributions

Conceptualization: Gary Curhan, Megan Prochaska.

Formal analysis: Gary Curhan, Megan Prochaska.

Funding acquisition: Gary Curhan, Megan Prochaska.

Supervision: Gary Curhan.

Writing – original draft: Megan Prochaska.

Writing – review & editing: Gary Curhan, Pietro Manuel Ferraro, Megan Prochaska, Eric Taylor.

Data Sharing Statement

Partial restrictions to the data and/or materials apply. Data are stored in a repository, but investigators must apply to access it.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/KN9/A575.

Supplemental Table 1. Characteristics of study participants closest to the time of urine collection by quintile of free fructose intake (N=6457).

Supplemental Table 2. Urinary composition by cohort and quintiles of free fructose intake (mg/d) (N=6457).

Supplemental Table 3. Characteristics of study participants closest to the time of urine collection by cohort and quintiles of sucrose (mg/d) (N=6457).
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