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The study population was from the initial wave of CNHBM (2017–2018) [26, 27]. The CNHBM uses a multi-stage stratified sampling method to select a nationally representative sample of the general Chinese population between the ages of 3 and 79 years. Totally 152 districts/counties were selected nationwide as monitoring sites, and 3 villages/communities (units) were selected from each site using the probability-proportional-to-size sampling method to represent the approximate urban/rural participant ratio of the site. In each unit, 48 participants were selected according to the age and gender categories (3–5, 6–11, 12–18, 19–39, 40–59, and 60–79 years; male and female). Finally, a total of 21,888 participants (i.e., 152 sites × 3 units × 2 genders × 6 age groups × 4 persons) were selected. The data collected from each participant included detailed questionnaire information on demographic characteristics, behavior patterns, diet, and health, and a thorough physical examination was also conducted. Random spot urine and fasting blood samples were also collected. The study was approved by the Ethical Review Committee of National Institute of Environmental Health (NIEH), Chinese Center for Disease Control and Prevention (CDC) (No. 201701). All participants and/or their relatives provided written informed consent.
A total of 21,746 participants completed the questionnaire and biospecimen collection in the CNHBM (2017–2018). In the present cross-sectional study, we excluded participants without Ucr data (n = 59) or those missing relevant explanatory variables (n = 520), resulting in a final analytic sample of 21,167 participants. The participants in this study had similar characteristics with those who were excluded because of missing data (see Supplementary Table S1 available in www.besjournal.com).
Table S1. Comparison of characteristics between participants included and excluded from the analysis
Characteristics Included (n = 21,167) Excluded (n = 579) P n % (SE) n % (SE) Age (years) 3–5 3,516 10.29 (0.28) 102 11.1 (2.55) 0.304 6–11 3,535 12.46 (0.19) 81 9.09 (2.59) 12–18 3,540 12.05 (0.23) 69 8.46 (1.59) 19–39 3,507 22.01 (0.49) 124 27.56 (3.16) 40–59 3,535 25.26 (0.4) 102 25.38 (3.15) 60–79 3,534 17.93 (0.31) 101 18.40 (2.57) Gender Male 10,582 49.79 (1.79) 281 50.52 (5.52) 0.896 Female 10,585 50.21 (1.79) 298 49.48 (5.52) Residential area Urban 11,613 60.58 (2.77) 296 60.43 (9.07) 0.987 Rural 9,554 39.42 (2.77) 283 39.57 (9.07) BMI (kg/m2), means ± SD 21,167 22.21 ± 0.11 322 22.62 ± 0.57 0.476 -
Fasting blood (4–16 mL) and spot urine (50–80 mL) were collected from each participant. All the samples were processed locally within 4 hours after collection. Sample aliquots were held at 2–8 °C during processing and stored at –20 °C for no longer than 7 days. The Aliquot of urine samples for Ucr measurement were transported at 2–8 °C within 2 hours of collection to the local county-level CDC. Other aliquots of urine, serum, whole blood and blood clots were transported at –80 °C by a commercial courier to the Biobank of NIEH, China CDC and stored in ultra-low temperature refrigerators at –80 °C for future measurement. The Ucr measurements were performed immediately at the chemistry laboratories of the local county-level CDC using the Spectrophotometric method [28]. Ucr was reported in g/L. The limit of quantitation (LOQ) was 0.1 g/L with 0.87% of study participants having Ucr concentrations below the LOQ. For participants with Ucr concentrations below the LOQ, a level equal to the LOQ divided by the square root of 2 was imputed.
The Ucr assay had very stable quality-control measures throughout the study. The correlation coefficient of the standard curve was required to be > 0.998. Two blank samples containing no analyte were tested within each batch with the absorbance values of these two samples needing to be < 0.002. More than 10% of parallel samples were tested within each batch and the relative error of testing results for these parallel samples were required to be < 10%. The samples were diluted and re-measured if the testing results were out of the linear range. The limit of detection (LOD) and LOQ were estimated by measuring 20 replicates of a blank sample and calculating the mean and standard deviation (SD). LOD was calculated as the mean +3 SD and LOQ was calculated as the mean +10 SD.
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The explanatory variables included age, gender, residential area, red meat intake, smoking status, alcohol consumption, BMI, hypertension, diabetes, dyslipidemia, hyperthyroidism, alanine aminotransferase (ALT) elevation, and chronic kidney disease (CKD). The residential area was categorized as urban or rural according to the type of unit. Villages were classified as rural and communities were classified as urban. Data on dietary intake during the past year, self-reported smoking status, and self-reported alcohol consumption were obtained by the questionnaire. The frequency of red meat intake over the past year was calculated as the average number of times each week. Smoking status was categorized as current or non-current, with the latter category including both former smokers and those who had never smoked. Self-reported frequency of alcohol consumption in the past year was categorized as never, less than four times per month, or four or more times per month.
Blood pressure was measured in those aged over 12 years. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured three times in each participant, and the mean value of the three measurements were calculated. The blood biochemical analysis were determined by Dian Diagnostics (Dian Diagnostics Group Co., Ltd., Hangzhou, Zhejiang, China). Fasting blood glucose, serum lipids, serum thyroxine (T4), serum triiodothyronine (T3), and serum ALT concentrations were measured in participants aged over 18 years. BMI was calculated as weight divided by height squared (kg/m2). Cases with extreme values of BMI (< 5 kg/m2 or > 50 kg/m2) were excluded from the analysis. The cut-off points for BMI for overweight and obesity between 3 and 79 years are summarized in Supplementary Table S2 (available in www.besjournal.com). The definition for overweight and obesity for participants aged 3 to 5 years used cut off values recommended by the International Obesity Task Force [29], while for participants aged 6 years and older the screening guidelines issued by National Health Commission of People's Republic of China were used [30]. To evaluate kidney function, glomerular filtration rate (GFR) was calculated using the CKD epidemiology collaboration equation, which incorporates age, gender, and serum creatinine concentration [31]. The definitions for the health status of individuals are summarized in Supplementary Table S3 (available in www.besjournal.com).
Table S2. Cut off points for BMI for overweight and obesity by gender between 3 and 79 years (kg/m2)
Age (years) Males Females Overweight Obesity Overweight Obesity 3– 17.9 19.6 17.6 19.4 3.5– 17.7 19.4 17.4 19.2 4– 17.6 19.3 17.3 192 4.5– 17.5 19.3 17.2 19.1 5– 17.4 19.3 17.2 19.2 5.5– 17.5 19.5 17.2 19.3 6.0– 16.4 17.7 16.2 17.5 6.5– 16.7 18.1 16.5 18.0 7.0– 17.0 18.7 16.8 18.5 7.5– 17.4 19.2 17.2 19.0 8.0– 17.8 19.7 17.6 19.4 8.5– 18.1 20.3 18.1 19.9 9.0– 18.5 20.8 18.5 20.4 9.5– 18.9 21.4 19.0 21.0 10.0– 19.2 21.9 19.5 21.5 10.5– 19.6 22.5 20.0 22.1 11.0– 19.9 23.0 20.5 22.7 11.5– 20.3 23.6 21.1 23.3 12.0– 20.7 24.1 21.5 23.9 12.5– 21.0 24.7 21.9 24.5 13.0– 21.4 25.2 22.2 25.0 13.5– 21.9 25.7 22.6 25.6 14.0– 22.3 26.1 22.8 25.9 14.5– 22.6 26.4 23.0 26.3 15.0– 22.9 26.6 23.2 26.6 15.5– 23.1 26.9 23.4 26.9 16.0– 23.3 27.1 23.6 27.1 16.5– 23.5 27.4 23.7 27.4 17.0– 23.7 27.6 23.8 27.6 17.5– 23.8 27.8 23.9 27.8 18.0– 24.0 28.0 24.0 28.0 Table S3. Definitions of the health status of participants in CNHBM (2017–2018)
Health status Definitions Hypertension Systolic blood pressures > 140 mmHg and/or diastolic blood pressures > 90 mmHg; or self-reported diagnosis by a physician; or self-reported use of antihypertensive medication in the 24 h before the survey[1]. Diabetes Blood glucose ≥ 7.0 mmol/L; or self-reported diagnosis by a physician; or self-reported use of insulin or oral hypoglycemic agents in the 24 h before the survey[2]. Dyslipidemia Triglyceride ≥ 2.26 mmol/L, or cholesterol ≥ 6.22 mmol/L, or low-density lipoprotein ≥ 4.14 mmol/L, or high-density lipoprotein ≤ 1.04 mmol/L; or self-reported diagnosis by a physician; or self-reported use of anti-dyslipidemia medications in the 24 h before the survey. Hyperthyroidisma T4 > 161.25 nmol/L or T3 > 2.79 nmol/L; or self-reported diagnosis by a physician. ALT elevationa Male: ALT > 41 U/L; Female: ALT > 33 U/L. Chronic kidney disease Glomerular filtration rate < 60 mL·min−1·1.73 m−2; or self-reported diagnosis by a physician. Note. aCut-off levels for T4, T3 and ALT were according to laboratory-verified reference ranges. [1] Writing Group of 2018 Chinese Guidelines for the Management of Hypertension. Chin J Cardiovasc Med, 2018; 24, 24-56. [2] Chinese Diabetes Society. Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition). Chin J Diabetes Mellitus, 2018; 10, 4-67. -
The CNHBM used a complex sampling methodology that made it possible to derive national estimates from the data of the survey participants. We used strata, primary sampling units, and sampling weights to obtain point estimates and standard errors. The standard errors were estimated using the Taylor series linearization method. All statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at P < 0.05 (two-sided) for all analyses.
The Ucr data showed a positively skewed distribution and was natural log (ln) transformed in the analysis. The geometric mean (GM), selected percentiles and coefficient of variation (CV) of Ucr concentrations were calculated. The percentage of individuals with a Ucr concentration outside the WHO's recommended creatinine limit of 0.3–3.0 g/L was calculated, grouped by gender and age category. Age- and gender-adjusted GM of Ucr concentrations grouped by demographics, dietary intake, behavior patterns, and health status were calculated and compared using linear mixed-effects models. To evaluate the associations of explanatory variables with Ucr, uni- and multivariable regression analysis were performed with ln transformed Ucr as the dependent variable. Geometric mean ratios (GMR) of Ucr concentrations were estimated using mixed linear models. A two-level mixed linear model using the restricted maximum likelihood method was fitted, in which individuals were included as a fixed effect for level 1, and sites were included as a random effect for level 2. Because information on behavior patterns and health status were not available for all participants, the associations between these variables and Ucr were analyzed only for participants aged 19 to 79 years. We next explored the functional form of BMI, blood pressure, GFR and serum biochemical indexes with Ucr concentrations using generalized linear models to fit restricted cubic spline functions. The extreme 1% of these variables were excluded to avoid implausible extrapolations of the functional form caused by the extremes of the data distribution.
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A total of 21,746 participants were included in the study, of which 10,591 were aged 3 to 18 years and 10,576 aged 19 to 79 years. The characteristics of the participants were presented in Table 1, including age, gender, residential area and red meat intake for participants aged 3 to 79 years, and behavior patterns and health status for participants aged 19 to 79 years. In the 21,167 study participants, the weighted mean age (sx) was 34.45 (0.26) years, and 49.79% were male. Of the 10,576 participants aged 19 to 79 years, 38.38% were diagnosed with hypertension, and the prevalence of CKD was 4.56%.
Table 1. Characteristics of the study population
Variables No. % (sx) Age (years) 3–5 3,516 10.29 (0.28) 6–11 3,535 12.46 (0.19) 12–18 3,540 12.05 (0.23) 19–39 3,507 22.00 (0.49) 40–59 3,535 25.26 (0.40) 60–79 3,534 17.94 (0.31) Gender Female 10,585 50.21 (1.79) Male 10,582 49.79 (1.79) Residential area Rural 9,554 39.42 (2.77) Urban 11,613 60.58 (2.77) Smoking statusa Non-current 7,477 66.15 (1.19) Current 3,099 33.85 (1.19) Alcohol consumption in the past yeara Never 5,993 48.91 (1.76) < 4 drinks per week 3,577 39.44 (1.54) ≥ 4 drinks per week 1,006 11.65 (0.66) Red meat intake (times per week) ≤ 1 3,778 17.67 (0.87) > 1 to 7 11,874 57.46 (0.96) > 7 5,515 24.87 (0.98) BMI (kg/m2) Normal and underweight 13,743 58.04 (1.06) Overweight 4,822 27.88 (0.73) Obesity 1,632 14.08 (0.56) Hypertensiona No 6,591 61.62 (1.35) Yes 3,985 38.38 (1.35) Diabetesa No 9,473 89.19 (0.60) Yes 1,103 10.81 (0.60) Dyslipidemiaa No 6,453 58.62 (1.12) Yes 4,123 41.38 (1.12) Hyperthyroidisma No 10,379 98.07 (0.31) Yes 197 1.93 (0.31) ALT elevationa No 10,053 94.51 (0.45) Yes 523 5.49 (0.45) CKDa No 9,991 95.44 (0.52) Yes 585 4.56 (0.52) Note. All data were weighted to account for the complex sampling design; ALT, alanine aminotransferase; BMI, body mass index; CKD, chronic kidney disease; No., number of the participants; sx, standard error. aAnalyses limited to participants aged 19 to 79 years. -
The weighted Ucr concentrations of the total participants by age and gender are shown in Table 2, and Figure 1 showed the unweighted results. The GM of Ucr concentration was 0.90 g/L and the median was 1.01 g/L. The central 90% interval (5th-95th percentile) was 0.24–2.30 g/L. Median urinary creatinine was significantly higher in males [1.23 (IQR: 0.77, 1.69) g/L] compared with that in female [0.82 (IQR: 0.49, 1.26) g/L]. Children and elderly participants were more likely to have lower Ucr concentrations than adults. The coefficient of variation of Ucr concentrations of all the participants was 73.76%, that ranged in each age group by gender from 63.69% to 96.49%.
Table 2. Ucr concentrations (g/L) in each demographic group in the population of CNHBM 2017–2018
Groups No. GM (95% CI) M (IQR) 5th (95% CI) 95th (95% CI) CV (%) Overall All 21,167 0.90 (0.86, 0.95) 1.01 (0.59, 1.49) 0.24 (0.21, 0.27) 2.30 (2.15, 2.46) 73.76 3–5 3,516 0.52 (0.48, 0.55) 0.55 (0.32, 0.88) 0.13 (0.10, 0.16) 1.63 (1.45, 1.82) 93.10 6–11 3,535 0.70 (0.66, 0.74) 0.75 (0.47, 1.14) 0.19 (0.15, 0.23) 1.87 (1.70, 2.04) 72.51 12–18 3,540 1.00 (0.94, 1.06) 1.11 (0.68, 1.62) 0.27 (0.22, 0.31) 2.55 (2.36, 2.73) 71.37 19–39 3,507 1.08 (1.01, 1.15) 1.23 (0.77, 1.70) 0.29 (0.23, 0.34) 2.49 (2.27, 2.71) 70.75 40–59 3,535 1.03 (0.98, 1.09) 1.16 (0.72, 1.60) 0.31 (0.24, 0.37) 2.39 (2.21, 2.56) 68.19 60–79 3,534 0.92 (0.87, 0.98) 1.00 (0.63, 1.46) 0.28 (0.23, 0.33) 2.23 (2.04, 2.42) 66.20 Male All 10,582 1.09 (1.03, 1.16) 1.23 (0.77, 1.69) 0.33 (0.26, 0.39) 2.47 (2.29, 2.65) 74.68 3–5 1,757 0.59 (0.54, 0.64) 0.62 (0.42, 0.94) 0.18 (0.15, 0.21) 1.57 (1.34, 1.79) 96.49 6–11 1,768 0.79 (0.73, 0.85) 0.83 (0.57, 1.19) 0.25 (0.17, 0.33) 1.88 (1.52, 2.24) 72.16 12–18 1,771 1.15 (1.07, 1.23) 1.28 (0.80, 1.77) 0.34 (0.25, 0.43) 2.61 (2.30, 2.93) 72.51 19–39 1,757 1.22 (1.13, 1.31) 1.38 (0.87, 1.80) 0.35 (0.25, 0.44) 2.60 (2.29, 2.91) 66.81 40–59 1,763 1.16 (1.09, 1.24) 1.29 (0.86, 1.71) 0.37 (0.28, 0.46) 2.51 (2.32, 2.70) 68.06 60–79 1,766 1.08 (1.00, 1.15) 1.21 (0.79, 1.63) 0.35 (0.28, 0.42) 2.37 (2.20, 2.53) 64.14 Female All 10,585 0.75 (0.71, 0.79) 0.82 (0.49, 1.26) 0.20 (0.17, 0.22) 2.03 (1.88, 2.18) 69.18 3–5 1,759 0.50 (0.47, 0.54) 0.54 (0.30, 0.86) 0.13 (0.10, 0.15) 1.63 (1.45, 1.82) 79.35 6–11 1,767 0.66 (0.62, 0.70) 0.70 (0.43, 1.12) 0.17 (0.14, 0.20) 1.81 (1.67, 1.95) 71.96 12–18 1,769 0.94 (0.88, 0.99) 1.02 (0.64, 1.53) 0.24 (0.19, 0.29) 2.51 (2.29, 2.73) 67.68 19–39 1,750 0.88 (0.83, 0.94) 0.99 (0.61, 1.42) 0.25 (0.21, 0.29) 2.18 (1.97, 2.39) 69.63 40–59 1,772 0.82 (0.77, 0.87) 0.88 (0.57, 1.30) 0.24 (0.21, 0.27) 2.00 (1.77, 2.23) 65.78 60–79 1,768 0.77 (0.73, 0.82) 0.83 (0.53, 1.20) 0.24 (0.21, 0.27) 1.90 (1.73, 2.07) 63.69 Note. All data were weighted to account for the complex sampling design; CI, confidence interval; CV, coefficient of variation; GM, geometric mean; IQR, interquartile range; M, median. -
Among all the participants with a random spot urine sample collection, 9.36% were outside the creatinine limits (0.3–3.0 g/L), including 7.83% whose samples were too dilute (< 0.3 g/L) and 1.53% whose samples were too concentrated (> 3.0 g/L). In all age groups, extremely dilute urine was more prevalent than overly concentrated urine. More samples from female participants than from male participants were considered invalid. Invalid urinary samples were also more common in children than in adults. The percentage of urine samples outside the limit range was much higher in those aged 3–5 years (23%) than in the other age groups (Table 3).
Table 3. Percentage of samples with Ucr concentrations outside the WHO guideline range (0.3–3.0 g/L) in each demographic group, in population of CNHBM 2017–2018
Groups Overall Male Female < 0.3 g/L, % (sx) > 3.0 g/L, % (sx) < 0.3 g/L, % (sx) > 3.0 g/L, % (sx) < 0.3 g/L, % (sx) > 3.0 g/L, % (sx) All 7.83 (0.89) 1.53 (0.57) 4.53 (0.93) 2.00 (0.77) 11.11 (0.94) 1.06 (0.39) 3–5 22.56 (0.17) 0.53 (0.04) 15.00 (0.08) 0.33 (0.01) 24.38 (0.26) 0.57 (0.07) 6–11 11.30 (0.15) 0.54 (0.04) 7.00 (0.12) 0.59 (0.04) 13.39 (0.22) 0.51 (0.04) 12–18 6.06 (0.12) 2.53 (0.08) 4.51 (0.07) 2.88 (0.07) 6.74 (0.18) 2.38 (0.11) 19–39 5.25 (0.22) 2.32 (0.15) 4.03 (0.33) 2.94 (0.25) 7.26 (0.18) 1.31 (0.08) 40–59 4.83 (0.23) 1.59 (0.17) 3.44 (0.34) 1.93 (0.27) 7.62 (0.17) 0.90 (0.08) 60–79 5.55 (0.16) 1.05 (0.12) 3.91 (0.19) 1.37 (0.17) 7.41 (0.16) 0.68 (0.07) Note. All data were weighted to account for the complex sampling design; sx, standard error. -
In participants age 19 to 79 years, after adjusting for age and gender, Ucr concentrations varied significantly according to smoking status (P = 0.038), frequency of red meat intake (P = 0.027), BMI (P = 0.001), and kidney function (P = 0.002) (Table 4). Ucr concentrations were 0.03 g/L higher in current smokers than those who had never smoked or were former smokers. Participants with more than 7 times per week of red meat intake had 0.05 g/L higher Ucr concentration than individuals who ate red meat less than or equal to one times per week. Compared with participants classified as underweight and normal weight, individuals defined as overweight and obesity had 0.03 g/L and 0.06 g/L higher Ucr concentration, respectively. Participants with CKD had 0.08 g/L higher Ucr concentration than those without CKD. In the multivariable-adjusted models restricted to participants aged 19 years and older, age group, gender, smoking status, red meat intake, BMI, and CKD were found to be associated significantly with Ucr concentrations (Table 4).
Table 4. Age and gender adjusted geometric mean (95% CI) and fully adjusted geometric mean ratio (95% CI) of Ucr concentrations (g/L) by explanatory variables in CNHBM participants aged 19 to 79 years
Characteristics No. (%) GMa F P GMRb P Age (years) 54.01 < 0.001 19–39 3,507 (33.16) 1.04 (0.99, 1.10) 1.00 40–59 3,535 (33.42) 0.97 (0.92, 1.02) 0.93 (0.91, 0.96) < 0.001 60–79 3,534 (33.42) 0.90 (0.86, 0.95) 0.87 (0.85, 0.89) < 0.001 Gender 947.53 < 0.001 Female 5,290 (50.02) 0.82 (0.78, 0.86) 1.00 Male 5,286 (49.98) 1.15 (1.09, 1.21) 1.38 (1.34, 1.42) < 0.001 Residential area 0.37 0.543 Rural 4,746 (44.88) 0.97 (0.92, 1.02) 1.00 Urban 5,830 (55.12) 0.97 (0.92, 1.03) 0.99 (0.96, 1.02) 0.629 Smoking status 4.33 0.038 Non-current 7,477 (70.70) 0.96 (0.91, 1.01) 1.00 Current 3,099 (29.30) 0.99 (0.94, 1.05) 1.04 (1.01, 1.07) 0.017 Alcohol consumption in the past year 0.49 0.611 Never 5,993 (56.67) 0.97 (0.92, 1.02) 1.00 < 4 drinks per week 3,577 (33.82) 0.97 (0.92, 1.03) 1.00 (0.97, 1.03) 0.982 ≥ 4 drinks per week 1,006 (9.51) 0.95 (0.90, 1.02) 0.98 (0.94, 1.02) 0.313 Red meat intake (times per week) 3.62 0.027 ≤ 1 2,082 (19.69) 0.94 (0.89, 1.00) 1.00 1 to 7 5,922 (55.99) 0.97 (0.92, 1.02) 1.03 (1.00, 1.06) 0.052 > 7 2,572 (24.32) 0.99 (0.94, 1.05) 1.06 (1.01, 1.09) 0.010 BMI (kg/m2) 6.81 0.001 Normal and underweight 5,275 (49.88) 0.95 (0.90, 1.00) 1.00 Overweight 3,669 (34.69) 0.98 (0.93, 1.03) 1.03 (1.00, 1.06) 0.023 Obesity 1,632 (15.43) 1.01 (0.95, 1.07) 1.06 (1.03, 1.10) < 0.001 Hypertension 1.03 0.31 No 6,591 (62.32) 0.98 (0.93, 1.03) 1.00 Yes 3,985 (37.68) 0.96 (0.91, 1.01) 0.98 (0.95, 1.00) 0.088 Diabetes 0.01 0.924 No 9,473 (89.57) 0.97 (0.92, 1.02) 1.00 Yes 1,103 (10.43) 0.97 (0.91, 1.03) 0.99 (0.96, 1.03) 0.706 Dyslipidemia 0.08 0.784 No 6,453 (61.02) 0.97 (0.92, 1.02) 1.00 Yes 4,123 (38.98) 0.97 (0.92, 1.02) 0.98 (0.96, 1.01) 0.182 Hyperthyroidism 0.01 0.933 No 10,379 (98.14) 0.97 (0.92, 1.02) 1.00 Yes 197 (1.86) 0.97 (0.88, 1.06) 0.99 (0.91, 1.08) 0.884 ALT elevation 2.72 0.099 No 10,053 (95.05) 0.97 (0.92, 1.02) 1.00 Yes 523 (4.95) 1.01 (0.94, 1.08) 1.03 (0.98, 1.08) 0.252 CKD 9.59 0.002 No 9,991 (94.47) 0.97 (0.92, 1.02) 1.00 Yes 585 (5.53) 1.05 (0.98, 1.12) 1.08 (1.03, 1.14) 0.002 Note. ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; GM, geometric mean; GMR, Geometric mean ratio; No., number of the participants. aModels are adjusted for age group and gender. bModels are shown as geometric mean ratio, adjusted for age group, gender, residential area, smoking status, alcohol consumption in the past year, red meat intake, and BMI. A final multivariable mixed linear model that included age group, gender, residential area, red meat intake, and BMI was performed in participants aged 3 to 79 years (Table 5). In the final model, participants with CKD were excluded. As shown in Table 5, age group, gender, and BMI were significantly associated with Ucr in a model that included all ages. Compared with participants aged 3 to 5 years, Ucr concentrations were 29% higher (95% CI: 26%, 33%) in individuals aged 6 to 11 years, 85% higher (95% CI: 79%, 90%) in individuals aged 12 to 18 years, 85% higher (95% CI: 80%, 91%) in individuals aged 19 to 39 years, 72% higher (95% CI: 67%, 77%) in individuals aged 40 to 59 years, and 60% higher (95% CI: 55%, 65%) in individuals aged 60 to 79 years. Males had 30% higher (95% CI: 28%, 38%) Ucr concentration than females. Ucr concentrations were 3% higher (95% CI: 1%, 5%) and 6% higher (95% CI: 4%, 9%) in individuals defined as overweight or obesity than in participants classified as underweight and normal weight, respectively.
Table 5. Geometric mean ratio (95% CI) of Ucr concentrations (g/L) by explanatory variables from multiple mixed linear models for CNHBM participants aged 3 to 79 years
Characteristics GMRa P Age (years) 3–5 1.00 6–11 1.29 (1.26, 1.33) < 0.001 12–18 1.85 (1.79, 1.90) < 0.001 19–39 1.85 (1.80, 1.91) < 0.001 40–59 1.72 (1.67, 1.77) < 0.001 60–79 1.60 (1.55, 1.65) < 0.001 Gender (male vs. female) 1.30 (1.28, 1.33) < 0.001 Residential area (rural vs. urban) 0.99 (0.96, 1.01) 0.297 Red meat intake (times per week) ≤ 1 1.00 1 to 7 1.00 (0.98, 1.03) 0.732 > 7 1.02 (0.99, 1.05) 0.150 BMI (kg/m2) Normal and underweight 1.00 Overweight 1.03 (1.01, 1.05) 0.008 Obesity 1.06 (1.04, 1.09) < 0.001 Note. BMI, body mass index; CI, confidence interval; GMR, Geometric mean ratio. aModels are shown as geometric mean ratio, adjusted for age group, gender, residential area, red meat intake and BMI. Participants aged 19 years and older and diagnosed with chronic kidney disease were not included in the analysis. Restricted cubic splines showed significant positive and linear associations between BMI and Ucr concentrations in participants aged 3 to 79 years after adjustment for demographics, diet and behavioral patterns. In models based on restricted cubic splines, after further adjusting for BMI, a significant inversely and linear association were observed between Ucr and SBP (P < 0.001), DBP (P = 0.006), triglyceride (P = 0.003), and GFR (P < 0.001) in participants aged 19 to 79 years. The association between T3 and Ucr was significant but non-linear, with a P value for the overall association of 0.003 and for the non-linear association a P value of 0.016 (Figure 2).
doi: 10.3967/bes2022.117
Urinary Creatinine Concentrations and Its Explanatory Variables in General Chinese Population: Implications for Creatinine Limits and Creatinine Adjustment
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Abstract:
Objective The study aimed to analyze the applicability of the World Health Organization's exclusionary guidelines for Urinary creatinine (Ucr) in the general Chinese population, and to identify Ucr related factors. Methods We conduct a cross-sectional study using baseline data from 21,167 participants in the China National Human Biomonitoring Program. Mixed linear models and restricted cubic splines (RCS) were used to analyze the associations between explanatory variables and Ucr concentration. Results The geometric mean and median concentrations of Ucr in the general Chinese population were 0.90 g/L and 1.01 g/L, respectively. And 9.36% samples were outside 0.3–3.0 g/L, including 7.83% below the lower limit and 1.53% above the upper limit. Middle age, male, obesity, smoking, higher frequency of red meat consumption and chronic kidney disease were associated significantly with higher concentrations of Ucr. Results of the RCS showed Ucr was positively and linearly associated with body mass index, inversely and linearly associated with systolic blood pressure, diastolic blood pressure, triglycerides level, and glomerular filtration rate, and were non-linearly associated with triiodothyronine. Conclusion The age- and gender-specific cut-off values of Ucr that determine the validity of urine samples in the general Chinese population were recommended. To avoid introducing bias into epidemiologic associations, the potential predictors of Ucr observed in the current study should be considered when using Ucr to adjust for variations in urine dilution. -
Key words:
- Biomonitoring /
- Urine /
- Hydration correction /
- Creatinine
注释: -
Figure 1. Urinary creatinine concentrations (g/L) for each gender by age group.
The plus signs represent the unweighted means. The whisker plots represent between the 5% and 95% unweighted percentiles, and the box displays the 25th, 50th and 75th unweighted percentiles, respectively. Abbreviation: Ucr, urinary creatinine.
Figure 2. Change in Ucr concentrations according to explanatory variables based on restricted cubic splines.
The red lines represent the beta coefficients of ln transformed Ucr concentrations based on restricted cubic splines with knots at the 10th, 50th, and 90th percentiles, while the dotted lines represent the 95% CIs. The reference value was set at the 50th percentile. Models fitting restricted cubic spline functions were adjusted for age group, gender, residential area, smoking status, alcohol consumption in the past year, red meat intake, and BMI (except BMI model) among participants aged 19 years and older. An exception was made for the model estimating the association between BMI and Ucr, in which participants aged 3 to 79 years were included. The extreme 1% of explanatory variables were excluded to avoid implausible extrapolation caused by the extremes of the data. ALT, alanine aminotransferase; BMI, body mass index; DBP, diastolic blood pressure; GFR, glomerular filtration rate; SBP, systolic blood pressure; T4, thyroxine; T3, triiodothyronine; Ucr, urinary creatinine.
S1. Comparison of characteristics between participants included and excluded from the analysis
Characteristics Included (n = 21,167) Excluded (n = 579) P n % (SE) n % (SE) Age (years) 3–5 3,516 10.29 (0.28) 102 11.1 (2.55) 0.304 6–11 3,535 12.46 (0.19) 81 9.09 (2.59) 12–18 3,540 12.05 (0.23) 69 8.46 (1.59) 19–39 3,507 22.01 (0.49) 124 27.56 (3.16) 40–59 3,535 25.26 (0.4) 102 25.38 (3.15) 60–79 3,534 17.93 (0.31) 101 18.40 (2.57) Gender Male 10,582 49.79 (1.79) 281 50.52 (5.52) 0.896 Female 10,585 50.21 (1.79) 298 49.48 (5.52) Residential area Urban 11,613 60.58 (2.77) 296 60.43 (9.07) 0.987 Rural 9,554 39.42 (2.77) 283 39.57 (9.07) BMI (kg/m2), means ± SD 21,167 22.21 ± 0.11 322 22.62 ± 0.57 0.476 S2. Cut off points for BMI for overweight and obesity by gender between 3 and 79 years (kg/m2)
Age (years) Males Females Overweight Obesity Overweight Obesity 3– 17.9 19.6 17.6 19.4 3.5– 17.7 19.4 17.4 19.2 4– 17.6 19.3 17.3 192 4.5– 17.5 19.3 17.2 19.1 5– 17.4 19.3 17.2 19.2 5.5– 17.5 19.5 17.2 19.3 6.0– 16.4 17.7 16.2 17.5 6.5– 16.7 18.1 16.5 18.0 7.0– 17.0 18.7 16.8 18.5 7.5– 17.4 19.2 17.2 19.0 8.0– 17.8 19.7 17.6 19.4 8.5– 18.1 20.3 18.1 19.9 9.0– 18.5 20.8 18.5 20.4 9.5– 18.9 21.4 19.0 21.0 10.0– 19.2 21.9 19.5 21.5 10.5– 19.6 22.5 20.0 22.1 11.0– 19.9 23.0 20.5 22.7 11.5– 20.3 23.6 21.1 23.3 12.0– 20.7 24.1 21.5 23.9 12.5– 21.0 24.7 21.9 24.5 13.0– 21.4 25.2 22.2 25.0 13.5– 21.9 25.7 22.6 25.6 14.0– 22.3 26.1 22.8 25.9 14.5– 22.6 26.4 23.0 26.3 15.0– 22.9 26.6 23.2 26.6 15.5– 23.1 26.9 23.4 26.9 16.0– 23.3 27.1 23.6 27.1 16.5– 23.5 27.4 23.7 27.4 17.0– 23.7 27.6 23.8 27.6 17.5– 23.8 27.8 23.9 27.8 18.0– 24.0 28.0 24.0 28.0 S3. Definitions of the health status of participants in CNHBM (2017–2018)
Health status Definitions Hypertension Systolic blood pressures > 140 mmHg and/or diastolic blood pressures > 90 mmHg; or self-reported diagnosis by a physician; or self-reported use of antihypertensive medication in the 24 h before the survey[1]. Diabetes Blood glucose ≥ 7.0 mmol/L; or self-reported diagnosis by a physician; or self-reported use of insulin or oral hypoglycemic agents in the 24 h before the survey[2]. Dyslipidemia Triglyceride ≥ 2.26 mmol/L, or cholesterol ≥ 6.22 mmol/L, or low-density lipoprotein ≥ 4.14 mmol/L, or high-density lipoprotein ≤ 1.04 mmol/L; or self-reported diagnosis by a physician; or self-reported use of anti-dyslipidemia medications in the 24 h before the survey. Hyperthyroidisma T4 > 161.25 nmol/L or T3 > 2.79 nmol/L; or self-reported diagnosis by a physician. ALT elevationa Male: ALT > 41 U/L; Female: ALT > 33 U/L. Chronic kidney disease Glomerular filtration rate < 60 mL·min−1·1.73 m−2; or self-reported diagnosis by a physician. Note. aCut-off levels for T4, T3 and ALT were according to laboratory-verified reference ranges. [1] Writing Group of 2018 Chinese Guidelines for the Management of Hypertension. Chin J Cardiovasc Med, 2018; 24, 24-56. [2] Chinese Diabetes Society. Guidelines for the prevention and control of type 2 diabetes in China (2017 Edition). Chin J Diabetes Mellitus, 2018; 10, 4-67. Table 1. Characteristics of the study population
Variables No. % (sx) Age (years) 3–5 3,516 10.29 (0.28) 6–11 3,535 12.46 (0.19) 12–18 3,540 12.05 (0.23) 19–39 3,507 22.00 (0.49) 40–59 3,535 25.26 (0.40) 60–79 3,534 17.94 (0.31) Gender Female 10,585 50.21 (1.79) Male 10,582 49.79 (1.79) Residential area Rural 9,554 39.42 (2.77) Urban 11,613 60.58 (2.77) Smoking statusa Non-current 7,477 66.15 (1.19) Current 3,099 33.85 (1.19) Alcohol consumption in the past yeara Never 5,993 48.91 (1.76) < 4 drinks per week 3,577 39.44 (1.54) ≥ 4 drinks per week 1,006 11.65 (0.66) Red meat intake (times per week) ≤ 1 3,778 17.67 (0.87) > 1 to 7 11,874 57.46 (0.96) > 7 5,515 24.87 (0.98) BMI (kg/m2) Normal and underweight 13,743 58.04 (1.06) Overweight 4,822 27.88 (0.73) Obesity 1,632 14.08 (0.56) Hypertensiona No 6,591 61.62 (1.35) Yes 3,985 38.38 (1.35) Diabetesa No 9,473 89.19 (0.60) Yes 1,103 10.81 (0.60) Dyslipidemiaa No 6,453 58.62 (1.12) Yes 4,123 41.38 (1.12) Hyperthyroidisma No 10,379 98.07 (0.31) Yes 197 1.93 (0.31) ALT elevationa No 10,053 94.51 (0.45) Yes 523 5.49 (0.45) CKDa No 9,991 95.44 (0.52) Yes 585 4.56 (0.52) Note. All data were weighted to account for the complex sampling design; ALT, alanine aminotransferase; BMI, body mass index; CKD, chronic kidney disease; No., number of the participants; sx, standard error. aAnalyses limited to participants aged 19 to 79 years. Table 2. Ucr concentrations (g/L) in each demographic group in the population of CNHBM 2017–2018
Groups No. GM (95% CI) M (IQR) 5th (95% CI) 95th (95% CI) CV (%) Overall All 21,167 0.90 (0.86, 0.95) 1.01 (0.59, 1.49) 0.24 (0.21, 0.27) 2.30 (2.15, 2.46) 73.76 3–5 3,516 0.52 (0.48, 0.55) 0.55 (0.32, 0.88) 0.13 (0.10, 0.16) 1.63 (1.45, 1.82) 93.10 6–11 3,535 0.70 (0.66, 0.74) 0.75 (0.47, 1.14) 0.19 (0.15, 0.23) 1.87 (1.70, 2.04) 72.51 12–18 3,540 1.00 (0.94, 1.06) 1.11 (0.68, 1.62) 0.27 (0.22, 0.31) 2.55 (2.36, 2.73) 71.37 19–39 3,507 1.08 (1.01, 1.15) 1.23 (0.77, 1.70) 0.29 (0.23, 0.34) 2.49 (2.27, 2.71) 70.75 40–59 3,535 1.03 (0.98, 1.09) 1.16 (0.72, 1.60) 0.31 (0.24, 0.37) 2.39 (2.21, 2.56) 68.19 60–79 3,534 0.92 (0.87, 0.98) 1.00 (0.63, 1.46) 0.28 (0.23, 0.33) 2.23 (2.04, 2.42) 66.20 Male All 10,582 1.09 (1.03, 1.16) 1.23 (0.77, 1.69) 0.33 (0.26, 0.39) 2.47 (2.29, 2.65) 74.68 3–5 1,757 0.59 (0.54, 0.64) 0.62 (0.42, 0.94) 0.18 (0.15, 0.21) 1.57 (1.34, 1.79) 96.49 6–11 1,768 0.79 (0.73, 0.85) 0.83 (0.57, 1.19) 0.25 (0.17, 0.33) 1.88 (1.52, 2.24) 72.16 12–18 1,771 1.15 (1.07, 1.23) 1.28 (0.80, 1.77) 0.34 (0.25, 0.43) 2.61 (2.30, 2.93) 72.51 19–39 1,757 1.22 (1.13, 1.31) 1.38 (0.87, 1.80) 0.35 (0.25, 0.44) 2.60 (2.29, 2.91) 66.81 40–59 1,763 1.16 (1.09, 1.24) 1.29 (0.86, 1.71) 0.37 (0.28, 0.46) 2.51 (2.32, 2.70) 68.06 60–79 1,766 1.08 (1.00, 1.15) 1.21 (0.79, 1.63) 0.35 (0.28, 0.42) 2.37 (2.20, 2.53) 64.14 Female All 10,585 0.75 (0.71, 0.79) 0.82 (0.49, 1.26) 0.20 (0.17, 0.22) 2.03 (1.88, 2.18) 69.18 3–5 1,759 0.50 (0.47, 0.54) 0.54 (0.30, 0.86) 0.13 (0.10, 0.15) 1.63 (1.45, 1.82) 79.35 6–11 1,767 0.66 (0.62, 0.70) 0.70 (0.43, 1.12) 0.17 (0.14, 0.20) 1.81 (1.67, 1.95) 71.96 12–18 1,769 0.94 (0.88, 0.99) 1.02 (0.64, 1.53) 0.24 (0.19, 0.29) 2.51 (2.29, 2.73) 67.68 19–39 1,750 0.88 (0.83, 0.94) 0.99 (0.61, 1.42) 0.25 (0.21, 0.29) 2.18 (1.97, 2.39) 69.63 40–59 1,772 0.82 (0.77, 0.87) 0.88 (0.57, 1.30) 0.24 (0.21, 0.27) 2.00 (1.77, 2.23) 65.78 60–79 1,768 0.77 (0.73, 0.82) 0.83 (0.53, 1.20) 0.24 (0.21, 0.27) 1.90 (1.73, 2.07) 63.69 Note. All data were weighted to account for the complex sampling design; CI, confidence interval; CV, coefficient of variation; GM, geometric mean; IQR, interquartile range; M, median. Table 3. Percentage of samples with Ucr concentrations outside the WHO guideline range (0.3–3.0 g/L) in each demographic group, in population of CNHBM 2017–2018
Groups Overall Male Female < 0.3 g/L, % (sx) > 3.0 g/L, % (sx) < 0.3 g/L, % (sx) > 3.0 g/L, % (sx) < 0.3 g/L, % (sx) > 3.0 g/L, % (sx) All 7.83 (0.89) 1.53 (0.57) 4.53 (0.93) 2.00 (0.77) 11.11 (0.94) 1.06 (0.39) 3–5 22.56 (0.17) 0.53 (0.04) 15.00 (0.08) 0.33 (0.01) 24.38 (0.26) 0.57 (0.07) 6–11 11.30 (0.15) 0.54 (0.04) 7.00 (0.12) 0.59 (0.04) 13.39 (0.22) 0.51 (0.04) 12–18 6.06 (0.12) 2.53 (0.08) 4.51 (0.07) 2.88 (0.07) 6.74 (0.18) 2.38 (0.11) 19–39 5.25 (0.22) 2.32 (0.15) 4.03 (0.33) 2.94 (0.25) 7.26 (0.18) 1.31 (0.08) 40–59 4.83 (0.23) 1.59 (0.17) 3.44 (0.34) 1.93 (0.27) 7.62 (0.17) 0.90 (0.08) 60–79 5.55 (0.16) 1.05 (0.12) 3.91 (0.19) 1.37 (0.17) 7.41 (0.16) 0.68 (0.07) Note. All data were weighted to account for the complex sampling design; sx, standard error. Table 4. Age and gender adjusted geometric mean (95% CI) and fully adjusted geometric mean ratio (95% CI) of Ucr concentrations (g/L) by explanatory variables in CNHBM participants aged 19 to 79 years
Characteristics No. (%) GMa F P GMRb P Age (years) 54.01 < 0.001 19–39 3,507 (33.16) 1.04 (0.99, 1.10) 1.00 40–59 3,535 (33.42) 0.97 (0.92, 1.02) 0.93 (0.91, 0.96) < 0.001 60–79 3,534 (33.42) 0.90 (0.86, 0.95) 0.87 (0.85, 0.89) < 0.001 Gender 947.53 < 0.001 Female 5,290 (50.02) 0.82 (0.78, 0.86) 1.00 Male 5,286 (49.98) 1.15 (1.09, 1.21) 1.38 (1.34, 1.42) < 0.001 Residential area 0.37 0.543 Rural 4,746 (44.88) 0.97 (0.92, 1.02) 1.00 Urban 5,830 (55.12) 0.97 (0.92, 1.03) 0.99 (0.96, 1.02) 0.629 Smoking status 4.33 0.038 Non-current 7,477 (70.70) 0.96 (0.91, 1.01) 1.00 Current 3,099 (29.30) 0.99 (0.94, 1.05) 1.04 (1.01, 1.07) 0.017 Alcohol consumption in the past year 0.49 0.611 Never 5,993 (56.67) 0.97 (0.92, 1.02) 1.00 < 4 drinks per week 3,577 (33.82) 0.97 (0.92, 1.03) 1.00 (0.97, 1.03) 0.982 ≥ 4 drinks per week 1,006 (9.51) 0.95 (0.90, 1.02) 0.98 (0.94, 1.02) 0.313 Red meat intake (times per week) 3.62 0.027 ≤ 1 2,082 (19.69) 0.94 (0.89, 1.00) 1.00 1 to 7 5,922 (55.99) 0.97 (0.92, 1.02) 1.03 (1.00, 1.06) 0.052 > 7 2,572 (24.32) 0.99 (0.94, 1.05) 1.06 (1.01, 1.09) 0.010 BMI (kg/m2) 6.81 0.001 Normal and underweight 5,275 (49.88) 0.95 (0.90, 1.00) 1.00 Overweight 3,669 (34.69) 0.98 (0.93, 1.03) 1.03 (1.00, 1.06) 0.023 Obesity 1,632 (15.43) 1.01 (0.95, 1.07) 1.06 (1.03, 1.10) < 0.001 Hypertension 1.03 0.31 No 6,591 (62.32) 0.98 (0.93, 1.03) 1.00 Yes 3,985 (37.68) 0.96 (0.91, 1.01) 0.98 (0.95, 1.00) 0.088 Diabetes 0.01 0.924 No 9,473 (89.57) 0.97 (0.92, 1.02) 1.00 Yes 1,103 (10.43) 0.97 (0.91, 1.03) 0.99 (0.96, 1.03) 0.706 Dyslipidemia 0.08 0.784 No 6,453 (61.02) 0.97 (0.92, 1.02) 1.00 Yes 4,123 (38.98) 0.97 (0.92, 1.02) 0.98 (0.96, 1.01) 0.182 Hyperthyroidism 0.01 0.933 No 10,379 (98.14) 0.97 (0.92, 1.02) 1.00 Yes 197 (1.86) 0.97 (0.88, 1.06) 0.99 (0.91, 1.08) 0.884 ALT elevation 2.72 0.099 No 10,053 (95.05) 0.97 (0.92, 1.02) 1.00 Yes 523 (4.95) 1.01 (0.94, 1.08) 1.03 (0.98, 1.08) 0.252 CKD 9.59 0.002 No 9,991 (94.47) 0.97 (0.92, 1.02) 1.00 Yes 585 (5.53) 1.05 (0.98, 1.12) 1.08 (1.03, 1.14) 0.002 Note. ALT, alanine aminotransferase; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; GM, geometric mean; GMR, Geometric mean ratio; No., number of the participants. aModels are adjusted for age group and gender. bModels are shown as geometric mean ratio, adjusted for age group, gender, residential area, smoking status, alcohol consumption in the past year, red meat intake, and BMI. Table 5. Geometric mean ratio (95% CI) of Ucr concentrations (g/L) by explanatory variables from multiple mixed linear models for CNHBM participants aged 3 to 79 years
Characteristics GMRa P Age (years) 3–5 1.00 6–11 1.29 (1.26, 1.33) < 0.001 12–18 1.85 (1.79, 1.90) < 0.001 19–39 1.85 (1.80, 1.91) < 0.001 40–59 1.72 (1.67, 1.77) < 0.001 60–79 1.60 (1.55, 1.65) < 0.001 Gender (male vs. female) 1.30 (1.28, 1.33) < 0.001 Residential area (rural vs. urban) 0.99 (0.96, 1.01) 0.297 Red meat intake (times per week) ≤ 1 1.00 1 to 7 1.00 (0.98, 1.03) 0.732 > 7 1.02 (0.99, 1.05) 0.150 BMI (kg/m2) Normal and underweight 1.00 Overweight 1.03 (1.01, 1.05) 0.008 Obesity 1.06 (1.04, 1.09) < 0.001 Note. BMI, body mass index; CI, confidence interval; GMR, Geometric mean ratio. aModels are shown as geometric mean ratio, adjusted for age group, gender, residential area, red meat intake and BMI. Participants aged 19 years and older and diagnosed with chronic kidney disease were not included in the analysis. -
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22036Supplementary Materials.pdf