Summary
Background and objectives
Lower urinary citrate excretion is a risk factor for nephrolithiasis and associated with metabolic acidosis and higher prevalence of hypertension and insulin resistance. This study sought to quantify the independent predictors of urinary citrate excretion in population-based cohorts.
Design, setting, participants, & measurements
A cross-sectional study of 2561 individuals from the Health Professionals Follow-Up Study and Nurses’ Health Studies I and II who provided two 24-hour urine collections was conducted. Dietary data were ascertained from the semiquantitative food frequency questionnaire. Lifestyle and disease data were derived from responses to biennial questionnaires. Multivariable linear regression was used to quantify the predictors of urinary citrate excretion.
Results
After adjusting for age, urinary creatinine, dietary, and other factors, higher intake of nondairy animal protein (per 10 g/d; −20 mg/d; 95% confidence interval [−29 to −11]), higher body mass index (per 1 kg/m2; −4 mg/d; [−6 to −2]), and history of nephrolithiasis (−57 mg/d; [−79 to −36]), hypertension (−95 mg/d; [−119 to −71]), gout (−104 mg/d; [−155 to −54]), and thiazide use (−34 mg/d; [−68 to −1]) were independently associated with lower 24-hour urinary citrate excretion. Higher intake of potassium (per 1000 mg/d; 53 mg/d; [33 to 74]), higher urinary sodium (per 100 mEq/d; 56 mg/d; [31 to 80]), and history of diabetes (61 mg/d; [21 to 100]) were independently associated with higher citrate excretion.
Conclusions
Several dietary and lifestyle factors and medical conditions are independently associated with urinary citrate excretion.
Introduction
Lower urinary citrate excretion is a known modifiable risk factor for calcium oxalate nephrolithiasis (1,2) and associated with both prevalent hypertension (3) and greater insulin resistance (4). However, the independent associations of several dietary and lifestyle factors and medical conditions with urinary citrate excretion are unclear.
Citrate is filtered and then reabsorbed in the proximal tubule through a sodium-dependent dicarboxylate (NaDC1) transporter with greatest affinity for the divalent citrate molecule (5,6). As such, citrate reabsorption is pH-dependent, with low intracellular and low luminal pH leading to greater concentration and consequently, greater reabsorption of the divalent form of citrate (5,6). Intracellular acidosis also leads to increased expression of NaDC1 at the apical membrane by both increased trafficking and increased synthesis, thereby enhancing citrate reabsorption (7). Factors associated with lower intracellular and urine pH, such as metabolic acidosis or hypokalemia, therefore lead to decreased citrate excretion (5,6).
Because citrate is metabolized to bicarbonate, the major buffer in blood, modification of urinary citrate excretion is an adaptive physiologic response to alterations in acid–base balance. The major determinant of acid–base balance in the steady state is net endogenous acid production, resulting from a combination of dietary acid intake, dietary alkali intake, and incomplete metabolism of organic acids (8). The major dietary sources of alkali are the conjugate bases of potassium salts that serve as bicarbonate precursors, often found in fruits and vegetables (9,10). The major dietary sources of acid intake are proteins containing amino acids with sulfur moieties, largely found in nondairy animal protein including meat, poultry, fish, and eggs (8). Lower dietary nondairy animal protein intake has been shown to lead to higher urinary citrate excretion in small interventional trials (11). However, these associations have yet to be explored on the population level. Furthermore, numerous other dietary and lifestyle factors and medical conditions are known to be associated with low urine pH, including obesity (12), diabetes mellitus (4,13–15), and gout (16,17). However, the independent associations between these factors and urinary citrate excretion have not yet been reported.
To examine the independent relations between specific dietary and lifestyle factors and medical conditions and the 24-hour urinary excretion of citrate, we conducted a cross-sectional study of 2561 individuals with and without a history of kidney stones from three cohorts: the Health Professionals Follow-up Study (HPFS), the Nurses’ Health Study (NHS I), and the Nurses’ Health Study II (NHS II).
Materials and Methods
Study Population
NHS I.
In 1976, 121,700 registered nurses (all women) ages 30–55 years enrolled in NHS I by completing and returning an initial questionnaire that provided detailed information on medical history, lifestyle, and certain medications.
NHS II.
In 1989, 116,430 registered nurses (all women) ages 25–42 years enrolled in NHS II by completing and returning an initial questionnaire that provided detailed information on medical history, lifestyle, and certain medications.
HPFS.
In 1986, 51,529 dentists, optometrists, osteopaths, pharmacists, podiatrists, and veterinarians (all men) ages 40–75 years enrolled in HPFS by completing and returning an initial questionnaire that provided detailed information on medical history, lifestyle, and certain medications.
NHS I, NHS II, and HPFS participants have been followed by biennial mailed questionnaires that ask about lifestyle practices and other exposures of interest as well as newly diagnosed diseases. The follow-up for eligible person-time in all three cohorts exceeds 90%.
Ascertainment of Diet
A semiquantitative food frequency questionnaire (FFQ), querying about the average intake of foods and beverages during the previous year, was mailed to participants every 4 years. Intake of specific dietary factors was computed from the reported frequency of consumption of each specified unit of food and US Department of Agriculture data on the content of the relevant nutrient in specified portions. The reproducibility and validity of the FFQs have been documented (18,19). To determine the nutrient composition of the diet independent of the total amount of food eaten, nutrient values were adjusted for total caloric intake by the residual method (20). For each individual, we used the dietary data from the FFQ closest to completion of the first urine collection.
Ascertainment of Other Factors
Information on age and weight was obtained on the baseline questionnaire. Self-reported weight was updated every 2 years and has been validated (21). Body mass index (BMI) was calculated as the weight in kilograms divided by the square of height in meters. Information on cigarette smoking, menopausal status, and use of postmenopausal hormones (PMH) was obtained and physical activity (metabolic equivalent tasks) was calculated from the biennial questionnaires. Physical activity assessment has been validated previously (22,23). History of kidney stones, hypertension, diabetes mellitus, gout, or thiazide use was obtained from the biennial questionnaires. The validity of self-reported history of kidney stones, hypertension, diabetes mellitus, and gout has been documented previously (24–31).
Urine Collections and Exclusion Criteria
As part of previously described studies of urinary risk factors for stone formation (1,32), two 24-hour urine collections were performed by 2920 individuals (1749 stone-formers [SFs] and 1171 randomly selected nonstone-formers [NSFs]; NHS I: 666 SFs, 390 NSFs; NHS II: 599 SFs, 522 NSFs; HPFS: 484 SFs, 259 NSFs) and comprise the eligible participants for this study. The rates of participation and completion among SFs and NSFs in each cohort have been reported previously; the demographic characteristics and dietary intake of participants who collected urine and participants who did not were similar (1). Participants collected the 24-hour urine samples using the system provided by Mission Pharmacal (San Antonio, TX). In addition to the exclusion criteria of the initial subcohort (age>75 years and history of cancer other than nonmelanoma skin cancer), we excluded those individuals with missing information on diet or BMI and those individuals with 24-hour urinary creatinine excretion in the bottom 1% or top 1% of the urinary creatinine distribution of NSFs in each cohort, leaving a total of 2561 individuals: 960 NHS I, 927 NHS II, and 674 HPFS participants.
Urine Measurements
Urine creatinine and citrate were measured by a Cobas centrifugal analyzer. Sodium and potassium were determined directly by flame emission photometry. Blinded split samples were sent previously to assess reproducibility; the intra-assay coefficients of variation for all factors analyzed were less than 10%. For urinary citrate, the coefficient of variation comparing the first with the second urine collection was 17% in HPFS, 16% in NHS I, and 17% in NHS II participants. For all analyses, the arithmetic mean of individual urinary values from the two collections was used.
Statistical Analyses
We compared baseline characteristics of participants using t tests, Wilcoxon rank sum tests, or χ2 tests. To examine the independent relations between dietary and lifestyle factors and medical conditions and urinary citrate excretion, we constructed multivariable linear regression models with 24-hour urinary citrate as the dependent variable. Independent variables considered were age (continuous); BMI (continuous); smoking (never, past, or current); physical activity (continuous as metabolic equivalents per week); history of hypertension (yes or no), diabetes mellitus (yes or no), nephrolithiasis (yes or no), or gout (yes or no); 24-hour urinary creatinine (continuous); 24-hour urinary sodium (continuous); dietary intakes of nondairy animal protein, dairy protein, vegetable protein, carbohydrate, total fat, and potassium (continuous and in quintiles by cohort according to the distribution in NSFs); alcohol intake (0, 0.1–5.0, 5.1–10.0, 10.1–15.0, 15.1–30.0, 30.1–50.0, and ≥50.0 g/d); and total vitamin C intake (continuously per 250 mg/d and in categories as <90, 90–249, 250–499, 500–999, and ≥1000 mg/d). Secondary analyses included examining age (groups of 5 years) and BMI (<25, 25–29.9, and ≥30) in categories, substituting urinary potassium (continuous) for dietary potassium intake and controlling for menopausal status and PMH use (premenopausal, postmenopausal never used PMH, past PMH use, and current PMH use) among women. We also examined possible effect modification by history of nephrolithiasis. All P values are two-tailed. We calculated 95% confidence intervals for all estimates. Data were analyzed using SAS software, version 9.2 (SAS Institute Inc., Cary, NC). The research protocol for this study was approved by the institutional review board of Brigham and Women’s Hospital in accordance with the Declaration of Helsinki. Return of completed questionnaires was deemed to constitute informed consent.
Results
Characteristics of included men (HPFS), older women (NHS I), and younger women (NHS II) are reported in Tables 1–3. The majority of individuals had a history of kidney stones resulting from the design of the original study. A history of hypertension or gout was more common among men and older women, whereas the percentage with a history of diabetes was slightly higher among older women. Men had higher levels of activity, higher vitamin C intake, and higher urinary sodium excretion than women. Urinary creatinine excretion was highest among men and lowest among older women. Overall mean (SD) urinary citrate excretion was 701 (298) mg/d.
Table 1.
Baseline characteristics of the participants in Health Professionals Follow-up Study (HPFS)
| Characteristic | Stone-Formers (n=431) | Nonstone-Formers (n=243) | P Value |
|---|---|---|---|
| Age at collection, yr | 67.0 (7.3) | 65.5 (5.1) | 0.002 |
| Body mass index, kg/m2 | 26.3 (3.5) | 26.0 (3.7) | 0.36 |
| Activity, mets/wk | 28.6 [14.7, 52.9] | 39.6 [21.5, 64.1] | <0.001 |
| Smoking status | |||
| Never smoked, % | 55 | 54 | 0.08 |
| Past smoker, % | 36 | 36 | |
| Current smoker, % | 3 | 6 | |
| Alcohol intake, gm/d | 6.0 [0.8, 15.7] | 9.8 [2.5, 21.2] | 0.002 |
| Estimated net endogenous acid production, mEq/d | 42.9 [37.2, 49.7] | 42.0 [36.0, 46.7] | 0.06 |
| Nondairy animal protein intake, g/d | 39.3 [30.7, 50.1] | 41.0 [31.7, 49.0] | 0.67 |
| Dairy protein intake, g/d | 12.9 [9.1, 18.7] | 14.0 [9.1, 20.3] | 0.15 |
| Vegetable protein intake, g/d | 27.7 [24.3, 31.8] | 28.1 [24.2, 33.2] | 0.47 |
| Potassium intake, mg/d | 3356 [2952, 3782] | 3523 [3093, 3957] | <0.001 |
| Total fat intake, g/d | 69.2 [60.3, 77.8] | 66.3 [58.5, 74.9] | 0.02 |
| Carbohydrate intake, g/d | 254 [226, 281] | 249 [223, 275] | 0.17 |
| Dietary vitamin C intake, mg/d | 136 [101, 179] | 139 [109, 184] | 0.54 |
| Total vitamin C intake, mg/d | 234 [154, 559] | 264 [145, 674] | 0.36 |
| History of hypertension, % | 50 | 40 | 0.01 |
| History of diabetes mellitus, % | 8 | 6 | 0.22 |
| History of gout, % | 12 | 5 | 0.005 |
| Thiazide use, % | 7 | 8 | 0.68 |
| Urinary creatinine, mg/d | 1667 (333) | 1649 (312) | 0.47 |
| Urinary sodium, mEq/24 h | 181 (56) | 171 (54) | 0.02 |
| Urinary citrate, mg/d | 687 (289) | 758 (291) | 0.003 |
Values are means (SD), median [interquartile range], or percentages. Percentages may not add up to 100% because of individuals with missing values.
Table 3.
Baseline characteristics of the participants in the Nurses’ Health Study II (NHS II)
| Characteristic | Stone-Formers (n=436) | Nonstone-Formers (n=491) | P Value |
|---|---|---|---|
| Age at collection, yr | 49.5 (5.1) | 51.7 (4.5) | <0.001 |
| Body mass index, kg/m2 | 27.5 (6.9) | 27.2 (6.4) | 0.53 |
| Activity, mets/wk | 10.4 [3.6, 25.7] | 14.0 [5.6, 27.6] | 0.01 |
| Smoking status | |||
| Never smoked, % | 70 | 70 | 0.58 |
| Past smoker, % | 24 | 25 | |
| Current smoker, % | 6 | 5 | |
| Alcohol intake, gm/d | 0.7 [0.0, 3.6] | 1.8 [0.0, 5.7] | <0.001 |
| Estimated net endogenous acid production, mEq/d | 46.7 [39.9, 54.5] | 44.4 [37.5, 51.8] | <0.001 |
| Nondairy animal protein intake, g/d | 37.1 [27.6, 46.8] | 35.4 [27.7, 44.8] | 0.39 |
| Dairy protein intake, g/d | 15.5 [10.4, 21.9] | 14.7 [9.5, 20.4] | 0.07 |
| Vegetable protein intake, g/d | 24.7 [21.3, 28.9] | 25.7 [21.8, 30.1] | 0.02 |
| Potassium intake, mg/d | 2961 [2587, 3339] | 3094 [2700, 3510] | <0.001 |
| Total fat intake, g/d | 65.2 [57.3, 76.0] | 63.7 [56.6, 72.9] | 0.05 |
| Carbohydrate intake, g/d | 227 [200, 251] | 231 [202, 250] | 0.44 |
| Dietary vitamin C intake, mg/d | 105 [73, 139] | 116 [82, 154] | 0.005 |
| Total vitamin C intake, mg/d | 160 [103, 270] | 183 [116, 348] | <0.001 |
| History of hypertension, % | 30 | 29 | 0.74 |
| History of diabetes mellitus, % | 6 | 5 | 0.39 |
| History of gout, % | 2 | 1 | 0.16 |
| Thiazide use, % | 9 | 11 | 0.35 |
| Urinary creatinine, mg/d | 1238 (246) | 1251 (232) | 0.41 |
| Urinary sodium, mEq/24 h | 152 (52) | 150 (49) | 0.57 |
| Urinary citrate, mg/d | 732 (300) | 807 (283) | <0.001 |
Values are means (SD), median [interquartile range], or percentages. Percentages may not add up to 100% because of individuals with missing values.
Table 2.
Baseline characteristics of the participants in the Nurses’ Health Study (NHS I)
| Characteristic | Stone-Formers (n=601) | Nonstone-Formers (n=359) | P Value |
|---|---|---|---|
| Age at collection, yr | 68.7 (6.4) | 66.8 (4.7) | <0.001 |
| Body mass index, kg/m2 | 27.4 (5.4) | 26.8 (5.0) | 0.06 |
| Activity, mets/wk | 15.2 [5.3, 25.4] | 15.7 [7.9, 33.3] | 0.06 |
| Smoking status | |||
| Never smoked, % | 48 | 50 | 0.68 |
| Past smoker, % | 44 | 44 | |
| Current smoker, % | 8 | 6 | |
| Alcohol intake, gm/d | 0.8 [0.0, 5.4] | 0.7 [0.0, 4.4] | 0.57 |
| Estimated net endogenous acid production, mEq/d | 40.5 [34.8, 48.1] | 39.1 [33.0, 46.1] | 0.01 |
| Nondairy animal protein intake, g/d | 30.1 [24.2, 37.4] | 30.5 [24.6, 39.5] | 0.50 |
| Dairy protein intake, g/d | 13.3 [9.0, 19.0] | 11.6 [6.8, 18.5] | <0.001 |
| Vegetable protein intake, g/d | 22.5 [19.4, 26.2] | 22.9 [19.9, 26.9] | 0.06 |
| Potassium intake, mg/d | 2868 [2553, 3281] | 3004 [2596, 3360] | 0.03 |
| Total fat intake, g/d | 55.4 [47.4, 62.9] | 53.5 [45.9, 61.0] | 0.02 |
| Carbohydrate intake, g/d | 208 [187, 231] | 214 [191, 238] | 0.01 |
| Dietary vitamin C intake, mg/d | 117 [84, 156] | 125 [90, 165] | 0.01 |
| Total vitamin C intake, mg/d | 200 [127, 382] | 243 [152, 609] | <0.001 |
| History of hypertension, % | 59 | 57 | 0.64 |
| History of diabetes mellitus, % | 13 | 10 | 0.20 |
| History of gout, % | 5 | 2 | 0.008 |
| Thiazide use, % | 17 | 21 | 0.15 |
| Urinary creatinine, mg/d | 1059 (204) | 1120 (214) | <0.001 |
| Urinary sodium, mEq/24 h | 139 (47) | 135 (46) | 0.21 |
| Urinary citrate, mg/d | 602 (289) | 672 (286) | <0.001 |
Values are means (SD), median [interquartile range], or percentages. Percentages may not add up to 100% because of individuals with missing values.
With the exception of potassium intake, there was no effect modification by history of nephrolithiasis (all P values>0.05). Because the findings were similar between the cohorts and among those participants with and without a history of nephrolithiasis, we combined all participants while controlling for cohort membership and history of nephrolithiasis. Multivariable-adjusted differences in 24-hour urinary citrate excretion by specific dietary and lifestyle factors and medical conditions are reported in Table 4.
Table 4.
Multivariable-adjusted differences in 24-hour urinary citrate excretion by dietary factor, lifestyle factor, or medical condition
| Factor | Difference (95% Confidence Interval) in Urinary Citrate Excretion (mg/d) | |||
|---|---|---|---|---|
| HPFS (n=674) | NHS I (n=960) | NHS II (n=927) | All Cohorts (n=2561) | |
| Nondairy animal protein (per 10 g/d) | −27 (−43 to −11) | −15 (−33 to 2) | −20 (−35 to −4) | −20 (−29 to −11) |
| Potassium (per 1000 mg/d) | 62 (24 to 100) | 54 (17 to 90) | 45 (10 to 79) | 53 (33 to 74) |
| Vitamin C (per 250 mg/d) | −15 (−27 to −4) | 7 (−4 to 19) | −5 (−17 to 6) | −5 (−12 to 1) |
| Urinary sodium (per 100 mEq/d) | 82 (39 to 125) | 60 (18 to 102) | 33 (−8 to 74) | 56 (31 to 80) |
| Age (per 5 years) | 15 (−2 to 31) | −18 (−34 to −2) | −21 (−41 to −2) | −6 (−15 to 4) |
| Body mass index (per kg/m2) | −8 (−15 to −2) | −6 (−10 to −3) | −2 (−5 to 1) | −4 (−6 to −2) |
| Smoking | ||||
| Nonsmoker | Referent | Referent | Referent | Referent |
| Past smoker | −19 (−63 to 25) | −47 (−81 to −12) | −27 (−68 to 15) | −35 (−57 to −12) |
| Current smoker | −70 (−176 to 36) | −64 (−131 to 4) | −27 (−107 to 52) | −50 (−96 to −4) |
| Hypertension | −66 (−109 to −22) | −110 (−148 to −72) | −96 (−140 to −53) | −95 (−119 to −71) |
| Nephrolithiasis | −77 (−119 to −34) | −29 (−65 to 7) | −75 (−112 to −39) | −57 (−79 to −36) |
| Gout | −87 (−156 to −19) | −119 (−204 to −34) | −130 (−278 to 18) | −104 (−155 to −54) |
| Diabetes mellitus | 133 (53 to 213) | −5 (−60 to 49) | 131 (50 to 212) | 61 (21 to 100) |
| Thiazide use | −43 (−123 to 37) | −42 (−89 to 4) | −16 (−79 to 47) | −34 (−68 to −1) |
Adjusted for all presented factors as well as dietary intakes of dairy protein, total fat, and carbohydrates (all in quintiles), total caloric intake, and urinary creatinine (continuous per 100 mg/d). The model combining all cohorts was additionally adjusted for cohort membership.
Dietary Factors
Nondairy animal protein intake was associated with lower (per 10 g/d; −20 mg/d; 95% confidence interval [−29 to −11]; P<0.001) urinary citrate excretion. Dairy and vegetable protein intakes were not associated with urinary citrate, nor were intakes of total fat or carbohydrate.
With each 1000 mg/d increase in potassium intake, urinary citrate was higher by 53 mg/d ([33 to 74]; P<0.001). Substituting urinary potassium excretion for dietary potassium intake yielded a greater magnitude urinary citrate (per 1000 mg/d; 99 mg/d; [84 to 114]; P<0.001). After stratifying on history of nephrolithiasis, each 1000 mg/d dietary potassium intake was associated with 28 mg/d ([−3.00 to 59.00]; P=0.08) higher urinary citrate among NSFs and 75 mg/d ([47 to 103]; P<0.001) higher urinary citrate among SFs.
Urinary sodium excretion, a measure of sodium intake, was associated with higher urinary citrate (per 100 mEq/d; 56 mg/d; [31 to 80]; P<0.001). After controlling for urinary potassium excretion instead of dietary potassium, the urinary sodium finding was attenuated (31 mg/d; [7 to 55]; P=0.01).
Vitamin C intake was not associated with urinary citrate among women, but among men, it was associated with lower (per 250 mg/d; −15 mg/d; [−27 to −4]; P=0.007) urinary citrate. Men with vitamin C intake of 1000 mg/d or more had lower (−139 mg/d; [−237 to −40; P=0.006) urinary citrate than those men consuming less than 90 mg/d.
Demographic and Lifestyle Factors
Older age (per 5 years) was associated with lower urinary citrate in women but not men (Table 4). Higher BMI was associated with lower (per 1 kg/m2; −4 mg/d; [−6 to −2]; P<0.001) urinary citrate. Past smoking (−35 mg/d; [−57 to −12]; P=0.003) and current smoking (−50 mg/d; [−96 to −4]; P=0.03) were associated with lower urinary citrate. Alcohol intake and physical activity were not independently associated with urinary citrate.
We examined menopausal status and use of PMH in women. Urinary citrate was lower (−43 mg/d; [−80 to −6]; P=0.02) among current PMH users compared with postmenopausal women who had never used PMH. Neither past PMH use nor premenopausal status was associated with urinary citrate.
Medical Conditions
Hypertension (−95 mg/d; [−119 to −71]; P<0.001), nephrolithiasis (−57 mg/d; [−79 to −36]; P<0.001), and gout (−104 mg/d; [−155 to −54]; P<0.001) were associated with lower urinary citrate, whereas diabetes was associated with higher urinary citrate (61 mg/d; [21 to 100]; P=0.003). Thiazide use was associated with lower urinary citrate (−34 mg/d; [−68 to −1]; P=0.05).
Discussion
This study is the first population-based study of factors associated with urinary citrate excretion. Although the associations for nondairy animal protein, as the major source of dietary acid, and potassium, a marker of intake of base precursors, were consistent across all three cohorts, some factors were associated with citrate excretion in men, women, or older individuals only. These nuances emphasize the complex nature of urinary citrate handling and excretion and highlight several important avenues for additional exploration.
Higher total vitamin C was associated with lower urinary citrate in older men. Two plausible mechanisms could explain an association between vitamin C intake and lower urinary citrate. First, gut absorption of citrate and vitamin C may occur through the same transporter (33), such that the presence of vitamin C may competitively inhibit the absorption of dietary citrate, leading to decreased serum and therefore, urinary levels of citrate. Second, ascorbic acid may lower urine pH (34), which in turn, may lead to increased reabsorption of urinary citrate. However, it is not clear why the association would be present in men and not women. In a small study of vitamin C supplementation and urine composition in SFs and NSFs administered 1 or 2 g vitamin C, Baxmann et al. (35) and Traxer et al. (36) reported that vitamin C supplementation yielded no significant change in urinary citrate excretion. However, both studies were small, included both men and women, and did not stratify on sex. Our finding of an association between total vitamin C intake and urinary citrate excretion in a larger study of older men, therefore, requires additional exploration.
Higher urinary sodium excretion was associated with higher urinary citrate excretion in our study. In contrast, Sakhaee et al. (37) found that healthy volunteers given a high-salt diet over 10 days had lower urinary citrate excretion than when given a more sodium-restrictive diet. More recently, Stoller et al. (38) conducted a small interventional study, in which eight hypocitraturic but not hypercalciuric kidney SFs were given a daily 3-g sodium chloride supplement for 7 days in addition to their usual intake and found no difference in urinary citrate excretion. The different findings may be explained by the different basal sodium intakes, smaller sample sizes, different relevant periods of exposure, and younger populations enrolled in these trials compared with our larger population-based study. The mechanism underlying our finding of an association between higher urinary sodium excretion and higher urinary citrate excretion is unclear.
Older age was associated with lower urinary citrate in women independent of diet. Additional adjustment for menopausal status and PMH use only slightly attenuated the association, suggesting that the explanation is elsewhere. Previous cross-sectional studies of PMH use and urinary citrate excretion found either higher urinary citrate excretion among individuals using PMH or no difference (39,40). In both studies, PMH nonusers were older than users, which may partially explain the findings. Our finding that current use of PMH was associated with lower urinary citrate excretion requires additional exploration.
Obesity has been associated with higher net endogenous acid production (41) as well as impaired ammonia production (42) and lower urine pH (43). The fact that higher BMI, which can be interpreted as adiposity given adjustment for urinary creatinine, was associated with lower urinary citrate excretion is consistent with these findings.
Smoking, both past and current, was associated with lower urinary citrate excretion. This finding raises the possibility that smoking may alter acid–base balance or renal acid–base handling.
Previous studies have shown that moderate physical activity is associated with lower urinary citrate excretion when replenishment of fluids and electrolytes is withheld, suggesting that exercise may increase net acid production (44). Our finding that physical activity was not associated with urinary citrate excretion suggests that, when free access to fluid and electrolyte repletion is available, exercise may have no effect on net acid production. However, the range of exercise in our cohort limits the ability to draw conclusions regarding acid–base balance, citrate excretion, and intense exercise.
Among medical conditions, gout was associated with lower urinary citrate excretion across all three cohorts. Gout (16,17) and urinary citrate excretion (4) have been associated with the metabolic syndrome and insulin resistance, and the association between gout and urinary citrate may, therefore, reflect this common association. Alternatively, because the association between gout and citrate excretion was independent of BMI, history of hypertension, and history of diabetes, there may be alternative explanations, such as systemic acid–base changes associated with gout. Thiazide use was associated with lower urinary citrate excretion. This finding may be explained by thiazide-induced hypokalemia leading to lower urinary citrate excretion.
Diabetes was surprisingly associated with higher urinary citrate excretion in men and younger women. Several studies have shown an association between metabolic acidosis and diabetes mellitus. In a study of 61 young calcium SFs, Cupisti et al. (4) showed an association between insulin resistance and lower urinary citrate excretion. However, our study included an older population of both SFs and NSFs and considered prevalent diabetes rather than measures of insulin resistance. Mechanistically, our findings may be explained in two possible ways. First, because proximal tubular reabsorption of most organic molecules occurs through sodium cotransport, excess filtered glucose may compete with other substrates, such as citrate, for reabsorption through this pathway. Second, it is possible that altered renal citrate handling leading to citrate wasting, like alterations in renal net acid excretion (14), is another manifestation of altered renal acid–base handling in diabetes.
The identified associations with urinary citrate excretion may have important implications for current approaches to kidney stone prevention. Dietary animal protein restriction and increased intake of fruits and vegetables (major sources of dietary potassium) are generally recommended to individuals with nephrolithiasis and hypocitraturia (45). Our study shows that higher nondairy animal protein intake and lower potassium intake are independently associated with lower urinary citrate excretion at the population level and supports the simultaneous implementation of both dietary animal protein restriction and increased intake of fruits and vegetables for SFs with lower urinary citrate. In previous studies, we reported an increased risk of nephrolithiasis among men with higher vitamin C intake, which was proposed to result from higher vitamin C intake leading to higher urinary oxalate excretion (46). The fact that vitamin C is associated with low urinary citrate excretion in men may represent an alternative explanation for the observed increased risk of stone formation. Finally, obesity is associated with higher risk of nephrolithiasis (47,48), and the findings of this study suggest that lower urinary citrate excretion, a known risk factor for nephrolithiasis, may partially underlie this association.
Our study has limitations. The cross-sectional design precludes drawing inferences about causation and does not show that alterations in any of the proposed determinants of urinary citrate excretion will alter urinary citrate excretion. We used the FFQ to ascertain long-term dietary intake, whereas 24-hour urine values more likely reflect short-term intake, although the average of two 24-hour urine collections should partially mitigate this limitation. Nevertheless, the magnitudes of the associations between dietary factors and urinary citrate excretion may be underestimated. Furthermore, we do not have data on citrate supplementation prescribed for prevention of stone formation among those individuals with a history of nephrolithiasis. Finally, the generalizability of our results may be limited, because we did not have urine collections from younger men and our cohorts were composed predominantly of white individuals.
In conclusion, our population-based study identifies several dietary and nondietary factors that were independently associated with urinary citrate excretion. Intakes of nondairy animal protein and in men, vitamin C as well as older age, BMI, smoking, and use of PMH in postmenopausal women are associated with lower urinary citrate excretion, whereas intakes of potassium and sodium are associated with higher urinary citrate excretion. Our study confirms previously reported inverse associations between hypertension, nephrolithiasis, and urinary citrate excretion, and it also identifies previously unreported inverse associations between gout, diabetes, and urinary citrate excretion as well as a positive association between diabetes and urinary citrate excretion. Additional research to confirm these findings in different populations and elucidate the mechanisms underlying these associations with urinary citrate excretion is warranted.
Disclosures
E.I.M. discloses research support from the American Kidney Fund Clinical Scientist in Nephrology Program. E.N.T. has no disclosures. G.C.C. discloses financial involvement in UpToDate, Inc. (author, section editor) and the American Society of Nephrology (CJASN, Editor-in-Chief).
Acknowledgment
Support for this study was provided by the American Kidney Fund Clinical Scientist in Nephrology Program and National Institutes of Health (NIH) Grants CA055075, CA50385, CA87969, DK007527, DK59583, DK70756, and DK91417.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
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