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Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes
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Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes Jinhua He a,b, Xianghai Zhou a,⁎ a b
Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China Shijiazhuang Second Hospital, Hebei, Shijiazhuang 050000, China
a r t i c l e
i n f o
Article history: Received 14 August 2019 Received in revised form 26 November 2019 Accepted 26 November 2019 Available online xxxx Keywords: Diabetes mellitus type 2 Proteinuria 24-h urine sodium Renal tubular injury
a b s t r a c t Aims: This study used estimated sodium intake from 24-h urine sodium (24hUNa) to explore the relationship of sodium intake with proteinuria among hospitalized patients with type 2 diabetes and with renal tubular injury markers [retinol-binding protein (RBP), beta 2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG)]. Methods: Hospitalized patients with type 2 diabetes (N = 269) were divided into two groups according to the median (0.08 g/day) 24-h urinary protein (24hUpro) level. Logistic regression was used to analyze the association between 24hUNa and 24hUpro ≥ 0.08 g/L; scatter plots were used to analyze the association of RBP, β2-MG, and NAG with 24hUNa. Results: Overall, 269 patients with type 2 diabetes mellitus were enrolled (average age, 56 ± 12 years; men, 61.3%). Multivariate logistic regression analysis revealed a positive correlation between 24hUNa and 24hUpro ≥ 0.08 g/L; every 10 mmol of 24hUNa had an increased risk of 24hUpro elevation [odds ratio (OR) (95% confidence interval [CI]: 1.06 (1.01–1.11)]. Compared with the lowest quartile of 24hUNa, the highest quartile had an increased risk of 24hUpro elevation [OR (95% CI): 2.76 (1.25–6.05)]; 24hUNa did not correlate with RBP, β2-MG, or NAG. Conclusions: In hospitalized patients with type 2 diabetes, 24hUNa was independently related to 24hUpro ≥ 0.08 g/day. However, no correlation of 24hUNa with RBP, β2-MG, or NAG was found. © 2019 Elsevier Inc. All rights reserved.
1. Introduction Diabetic nephropathy is a microvascular complication that affects millions of patients with diabetes worldwide. In China, the incidence of diabetic nephropathy has surpassed that of glomerulonephritis as the leading cause of end-stage renal disease.1 Control of blood glucose, use of an angiotensin-converting enzyme inhibitor (ACE\\I), or use of ▲ an angiotensin receptor blocker (ARB) can significantly reduce the risk of diabetic nephropathy development; however, the presence of residual urinary albumin still predicts the adverse outcome of nephropathy.2 Studies in hypertensive3,4 and general populations5,6 show that a high‑sodium diet is associated with impaired kidney function. Sodium restriction can effectively improve renal function in patients with hypertension,3,7 and when combined with ACE-I drugs, a synergistic effect is exerted to decrease urinary protein levels.3 However, there have been inconsistent findings regarding the association between sodium intake and kidney function in type 2 diabetes. Some studies have shown that a high‑sodium intake is positively correlated with increased urinary protein8 and decreased serum creatinine clearance9; in contrast,
Q4
Conflict of interest: The authors have no conflicts of interest to disclose. ⁎ Corresponding author. E-mail address: [email protected] (X. Zhou).
some studies have shown a positive correlation between low sodium intake and increased urinary protein level,10 and some have shown no correlation between sodium intake and increased urinary protein, as well as a reduced estimated glomerular filtration rate (eGFR).11 Previously, it was believed that diabetic nephropathy-related renal damage primarily occurred in the glomerulus; however, recent studies revealed that renal tubular damage occurs during the early stage of diabetic nephropathy, prior to glomerular damage.12,13 However, the relationship between high‑sodium intake and renal tubular damage in patients with type 2 diabetes is unclear. This study aimed to investigate the relationship between 24hUNa and urinary protein as well as that between 24hUNa and retinol-binding protein (RBP), beta 2-microglobulin (β2-MG), and N-acetyl-beta-D-glucosaminidase (NAG) in consecutive inpatients with type 2 diabetes mellitus. 2. Materials and methods 2.1. Study design and patients This was a cross-sectional study. The clinical data of 370 patients with type 2 diabetes admitted to the Department of Endocrinology, Peking University People's Hospital from May to September 2018
https://doi.org/10.1016/j.jdiacomp.2019.107498 1056-8727/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498
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were collected. To reduce the influence of factors on urinary sodium and urinary protein, we excluded 3 cases of type 2 diabetes mellitus complicated with pregnancy, 21 cases of type 2 diabetic ketosis, 20 cases of chronic nephropathy or an eGFR of b60 mL/min*1.73 m2, 1 case of primary aldosteronism, 14 cases of diuretic use, and 42 cases in which the 24hUNa data were not detected. Finally, the data of 269 patients were included in this study. 2.2. Measurements Clinical data on the day of admission were collected. The diagnosis of diabetes mellitus was based on a patient's self-reported history of diabetes mellitus, judgment made by our outpatient physicians, or on the ongoing treatment of diabetes mellitus. The diagnosis of hypertension was based on each patient's systolic blood pressure (N140 mmHg), diastolic blood pressure (N90 mmHg),14 or ongoing treatment with the administration of antihypertensive drugs. A patient was identified as a smoker based on their smoking pattern, i.e., smoking more than a cigarette a day or having quit for b1 year. The height, weight, and blood pressure of the patients were measured on admission day; blood glucose, triglyceride, cholesterol, low-density lipoprotein cholesterol (LDL-C), creatinine, and glycated hemoglobin (HbA1c) levels were measured under fasting conditions on the next day. Twenty-fourhour urine samples were collected to measure the levels of 24hUNa, 24h urine protein (24hUpro), and creatinine, whereas morning urine samples were collected to measure RBP, β2-MG, and NAG levels. The urinary albumin/creatinine ratio (ACR) was measured three times on successive days from the 2nd to the 4th day of admission, the average ACR value was then calculated and used in our analysis; ACR was measured only twice in 15 patients，once in 2 patients, and the ACR was not obtained in one patient. The 24hUpro level was detected by chemical colorimetry; 24hUNa level was detected using a membrane electrode; RBP, β2-MG, and NAG levels were detected by immunoturbidimetry. For both sexes, eGFR was estimated based on their respective collaborative epidemiological formulae for chronic kidney disease (CKD-EPI) as follows.15 Female patients: if serum creatinine was ≤0.7 mg/dL, then eGFR = 144 × (serum creatinine/0.7)−0.329 × 0.993age, and if serum creatinine was N0.7 mg/dL, then eGFR = 144 × (serum creatinine/0.7)−1.209 × 0.993age. Male patents: if serum creatinine was ≤0.9 mg/dL, then eGFR = 141 × (serum creatinine /0.9)−0.411 × 0.993age, and if serum creatinine was N0.9 mg/dL, then eGFR = 141 × (serum creatinine/0.9)−1.209 × 0.993age. Conversion of serum creatinine units can be performed as follows: 1 mg/dL = 88.4 μmol/L. 2.3. Statistical analysis Data were analyzed using the IBM SPSS 25.0 statistical software. The continuous variables of the normal distribution were expressed as mean ± standard deviation (x ± s), and an independent sample t-test was used to compare between groups. Continuous variables of the non-normal distribution were expressed as the median values (25th, 75th percentile), and the rank-sum test was performed for making inter-group comparisons. Categorical data were expressed as n (%), and the chi-squared test was used for making comparisons between groups. Logistic regression analysis and scatter plots were used for correlation analysis. All statistical tests were two-sided, and a P-value b.05 was considered statistically significant. 3. Results 3.1. Comparison of clinical data of patients The average age of the 269 patients with type 2 diabetes mellitus was 56 ± 12 years, and 61.3% were men. The patients were divided
into two groups according to the 24hUpro median of 0.08 g/day. Compared with the 24hUpro b 0.08 g/day group, the 24hUpro ≥ 0.08 g/day group had higher blood pressure, 24hUNa, RBP, β2-MG, and NAG levels. With an increase in 24hUNa level, the proportion of 24hUpro ≥ 0.08 g/day showed an upward trend. There was no significant difference in fasting blood sugar and HbA1c levels between the two groups (Table 1). According to the median ACR value (8.66 mg/g), the median values for 24hUNa level in the two groups were 158.6 and 149.7 mmol/day, respectively, without any statistically significant difference (Z = −0.900, P N .05). 3.2. Correlation between 24hUNa and 24hUpro ≥ 0.08 g/day Logistic regression analysis was conducted after adjusting for age, sex, smoking, systolic blood pressure, body mass index, duration of diabetes, HbA1c, LDL-C, eGFR, and use of ACE-I or ARB antihypertensive drugs to analyze the changes in 24hUpro ≥ 0.08 g/L for every 10-mmol increase in 24hUNa and revealed that the odds ratio and 95% confidence interval [OR (95% CI)] for 24hUpro ≥ 0.08 g/day was 1.06 (1.01–1.11). Compared with the minimum quartile of the 24hUNa group, the OR (95% CI) for 24hUpro ≥ 0.08 g/day in the highest quartile group was 2.76 (1.25–6.05) (Table 2). 3.3. Correlation between 24hUNa and ACR, RBP, β2-MG, and NAG 24hUNa did not correlate with ACR (Fig. 1a), RBP (Fig. 1b), β2-MG (Fig. 1c), or NAG (Fig. 1d). 3.4. Correlation between RBP, β2-MG, NAG, and 24hUpro ≥ 0.08 g/day NAG was positively correlated with 24hUpro ≥ 0.08 g/day, with an OR (95% CI) of 1.09 (1.02–1.16); RBP and β2-MG/10 were not correlated with 24hUpro ≥ 0.08 g/day, with ORs (95% CI) of 0.96 (0.73–1.25) and 1.01 (1.00–1.01), respectively (Table 3). 4. Discussion This study found that 24hUNa and renal tubular markers levels were positively associated with urinary protein levels, whereas no association was found between 24hUNa and renal tubular injury markers, suggesting that a high‑sodium diet was a risk factor for proteinuria while a high‑sodium diet-induced proteinuria was not related to renal tubular injury. Few previous studies have assessed and reported inconsistent results for the relationship between sodium intake and nephropathy in type 2 diabetes mellitus. Cross-sectional studies conducted in Japan showed that a high‑sodium diet positively correlated with an increased urinary protein level8 or decreased serum creatinine clearance rate9 in patients with type 2 diabetes, suggesting that a high‑sodium diet was a factor related to the prevalence or progression of diabetic nephropathy. These conclusions support the results of our study. However, contrary to the findings of this study, a cross-sectional study of Japanese patients with type 2 diabetes who did not receive antihypertensive drugs demonstrated that a low-sodium diet was associated with albuminuria; the study used a single-point urinary sodium concentration to assess sodium intake.10 Another global multicenter large cohort study did not find a correlation between sodium intake and increased urinary protein levels or decreased eGFR in patients with type 2 diabetes, and in that study, dietary questionnaires were used to assess sodium intake.11 The reasons for the inconsistency may be related to different research groups and different methods used for the assessment of sodium intake. Under the condition of stable dietary intake, the extent of sodium intake and excretion are equivalent; hence, 24hUNa is the gold standard for estimating sodium intake.16 Compared with the abovementioned studies, this study adopted the more accurate 24hUNa estimation method for measuring sodium intake. However, in
Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498
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Table 1 Clinical features of patients with type 2 diabetes grouped according to median 24hUpro.
Number Age (years) Male (%) Duration of diabetes (years) History of hypertension (%) ACEI or ARB (%) ▲ Smoke (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Body mass index (kg/m2) Fasting serum glucose (mmol/L) HbA1c (%) Cholesterol (mmol/L) Triglycerides (mmol/L) LDL cholesterol (mmol/L) serum creatinine (μmol/L) eGFR (mL/min*1.73 m2) ACR (mg/g) 24hUNa (mmol/day) Quantile of 24hUNa (mmol/day) b115.4 115.5–152.7 152.8–205.3 ≥205.4 24-h urinary creatinine (mmol/day) Male Female RBP (mg/L) β2-MG (μg/L) NAG (U/L)
All patients
24hUpro ≥ 0.08 g/day
24hUpro b 0.08 g/day
269 56 ± 12 165 (61.3) 10.0 (5.0, 17.0) 128 (47.6) 46 (17.1) 79 (29.4) 132 ± 17 76 ± 11 26.5 ± 4.0 7.23 ± 2.69 9.3 ± 2.0 4.26 ± 1.15 1.45 (1.10, 2.18) 2.73 (2.16, 3.34) 63 ± 16 101.53 ± 15.88 8.66 (4.69, 24.01) 152.8 (115.4, 205.4)
136 56 ± 12 91 (66.9) 10.0 (5.0, 18.0) 73 (53.7) 21 (15.4) 45 (33.1) 135 ± 17 77 ± 11 26.8 ± 4.2 7.47 ± 2.60 9.4 ± 1.9 4.31 ± 1.18 1.56 (1.10, 2.31) 2.77 (2.17, 3.31) 65 ± 17 100.71 ± 17.00 15.59 (5.70, 75.25) 167.4 (123.7, 223.3)
133 56 ± 11 74 (55.6) 10.0 (4.0,16.5) 55 (41.4)*** 25 (18.8) 34 (25.6) 128 ± 17** 74 ± 11*** 26.3 ± 3.8 6.98 ± 2.76 9.2 ± 2.0 4.21 ± 1.12 1.38 (1.08, 2.07) 2.67 (2.13, 3.38) 62 ± 14 102.39 ± 14.65 6.92 (4.02, 10.03)* 143.7 (106.5, 192.0)**
67 (24.9) 66 (24.5) 69 (25.7) 67 (24.9)
26 (19.1) 30 (22.1) 37 (27.2) 43 (31.6)
41 (30.8)*** 36 (27.1) 32 (24.1) 24 (18.0)
11.40 ± 3.44 7.56 ± 2.71 0.27 (0.20, 0.36) 200.00 (141.70, 307.20) 11.40 (9.60, 14.70)
12.09 ± 3.75 8.15 ± 3.52 0.30 (0.21, 0.42) 213.80 (141.70, 395.70) 12.30 (10.05, 15.85)
10.53 ± 2.80** 7.12 ± 1.81 0.25 (0.18, 0.33)** 194.75 (144.33, 242.60)*** 10.60 (9.20, 12.00)*
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HbA1c, glycosylated hemoglobin; eGFR, estimated glomerular filtration rate; ACR, ▲ urinary albumin/creatinine ratio; LDL, low-density lipoprotein; 24hUpro, 24-h urinary protein; 24hUNa, 24-h urinary sodium; RBP, retinol-binding protein; β2-MG, beta 2-microglobulin; NAG, N-acetyl-beta-D-glucosaminidase. Normally distributed continuous variables are expressed as mean ± standard deviation (x ± s), continuous variables exhibiting a non-normal distribution are expressed as median values (25th, 75th), and categorical data are expressed as percentages (%). An independent sample t-test and rank-sum test were performed to detect differences between the two groups; a chi-squared test was used to compare categorical variables. Compared with 24hUpro b 0.08 g/day group, *P b .001, **P b .01, ***P b .05.
this study, no difference in 24hUNa was found between the two groups according to the median ACR value, which may be related to a greater variability of random urine ACR determined according to exercise, sex, and other factors. High-sodium intake may cause proteinuria through a variety of mechanisms. Animal experiments have shown that high-sodium intake can lead to increased intraglomerular pressure and glomerular volume,17 as well as cause interlobular artery wall thickening, macrophage infiltration, and increased renal vascular resistance in rats.18 Clinical studies have also found that a high-sodium diet can induce glomerular hyperfiltration, increase glomerular filtration rate and cystic pressure,19 cause oxidative stress,20 and activate the renin–angiotensin–aldosterone system.3,21,22 Animal studies have revealed that high-sodium intake can result in renal tubular epithelial damage and tubulointerstitial fibrosis,23,24 but clinical trials regarding this have not been conducted to date. Table 2 Logistic regression analysis between 24hUNa and 24hUpro ≥ 0.08 g/day [OR (95% CI)].
24hUNa/10 (mmol/day) Quantile of 24hUNa (mmol/day) b115.4 115.4–152.7 152.8–205.3 ≥205.4
Model 1
Model 2
1.06 (1.01–1.11)
1.06 (1.01–1.11)
1 1.36 (0.65–2.85) 2.02 (0.95–4.27) 2.80 (1.28–6.15)
1 1.36 (0.65–2.85) 1.98 (0.94–4.20) 2.76 (1.25–6.05)
Abbreviations: 24hUpro, 24-h urinary protein; 24hUNa, 24-h urinary sodium, CI, confidence interval, OR, odds ratio. Model 1: adjusted for age, sex, smoking, systolic blood pressure, body mass index, course of diabetes, HbA1c, low-density lipoprotein cholesterol, and eGFR. Model 2: adjusted for the use of ACEI/ARB antihypertensive drugs on the basis of model 1. Values ▲ for 24hUNa/10, quantile of 24hUNa were entered into the two models separately.
Recent studies have shown that diabetic nephropathy causes tubular damage before glomerulopathy.12,13 RBP, β2-MG, and NAG are markers of proximal tubular injury, which can occur in the early stage of nephropathy.13,25–27 Here, 24hUpro ≥ 0.08 g/day was found to correlate with NAG but not with RBP and β2-MG, which may be due to the higher sensitivity of NAG; therefore, the highly sensitive NAG suggests early renal injury and predicts albuminuria.28,29 However, the relationship between high-sodium intake and renal tubular injury is not clear. To our knowledge, the present study is the first to explore the relationship between high-sodium intake and renal tubular injury clinically; however, no correlation was found between 24hUNa and RBP, β2-MG, or NAG. Some limitations were noted for this study. First, it had a crosssectional design; hence, a causal relationship between 24hUNa and urinary protein could not be examined. A large number of prospective studies are needed to confirm the relationship between 24hUNa and urinary protein in type 2 diabetes. Second, although this study involved a more accurate sodium intake estimation method of detecting the 24hUNa levels, the 24-h urine sample was collected only once, which may have been influenced by patients' daytime activities and blood pressure fluctuations. Additionally, patients receiving diabetic meals after hospitalization may achieve varying sodium intake reductions based on their individual characteristics, which in turn weakens the correlation between 24hUNa and urinary protein level. Third, although this is the first clinical study to explore the relationship between highsodium diet and renal tubular injury, the sample size was relatively small. More clinical studies are needed, and more sensitive indicators of early renal tubular injury need to be further validated. In conclusion, this study showed that sodium intake was independently related to an increase in urinary protein in inpatients with type
Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498
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J. He, X. Zhou / Journal of Diabetes and Its Complications xxx (xxxx) xxx
r = -0.049
r = -0.047
P = 0.425
P = 0.475
(a) Scatter plots of 24hUNa and ACR
(b) Scatter plots of 24hUNa and RBP
r = 0.078
r = -0.115
P = 0.235
P = 0.080
(c) Scatter plots of 24hUNa and β2-MG
(d) Scatter plots of 24hUNa and NAG
Fig. 1. Correlation of 24hUNa with ACR, RBP, β2-MG, and NAG. (a) Scatter plots of 24hUNa and ACR (b) Scatter plots of 24hUNa and RBP. (c) Scatter plots of 24hUNa and β2-MG (d) Scatter plots of 24hUNa and NAG. Abbreviations: 24hUNa, 24-h urinary sodium; ACR, urinary albumin/creatinine ratio; RBP, retinol-binding protein; β2-MG, beta2-microglobulin; NAG, N-acetyl-beta-Dglucosaminidase.
2 diabetes, but no correlation was found between sodium intake and renal tubular injury markers.
Funding information This work is supported by grants 2016YFC1305600 and 2016YFC1305603 from the Major Chronic Non-communicable Disease Prevention and Control Research, National Key Research and Development Program of China.
Acknowledgements None.
References Table 3 Logistic regression analysis between RBP, β2-MG, NAG and 24hUpro ≥ 0.08 g/day [OR (95% CI)].
RBP (mg/L) β2-MG/10 (μg/L) NAG (U/L)
Model 1
Model 2
0.96 (0.73–1.26) 1.01 (1.00–1.01) 1.08 (1.01–1.16)
0.96 (0.73–1.25) 1.01 (1.00–1.01) 1.09 (1.02–1.16)
Abbreviations: RBP, retinol-binding protein; β2-MG, beta2-microglobulin; NAG, N-acetylbeta-D-glucosaminidase; 24hUpro, 24-h urinary protein; CI, confidence interval, OR, odds ratio. Model 1: adjusted for age, sex, smoking, systolic blood pressure, body mass index, course of diabetes, HbA1c, low-density lipoprotein cholesterol, and eGFR. Model 2: adjusted for the use of ACEI/ARB antihypertensive drugs on the basis of model 1. ▲ Values for RBP, β2-MG/10, and NAG were entered into the two models separately.
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Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes Jinhua He a,b, Xianghai Zhou a,⁎ a b
Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China Shijiazhuang Second Hospital, Hebei, Shijiazhuang 050000, China
a r t i c l e
i n f o
Article history: Received 14 August 2019 Received in revised form 26 November 2019 Accepted 26 November 2019 Available online xxxx Keywords: Diabetes mellitus type 2 Proteinuria 24-h urine sodium Renal tubular injury
a b s t r a c t Aims: This study used estimated sodium intake from 24-h urine sodium (24hUNa) to explore the relationship of sodium intake with proteinuria among hospitalized patients with type 2 diabetes and with renal tubular injury markers [retinol-binding protein (RBP), beta 2-microglobulin (β2-MG), N-acetyl-beta-D-glucosaminidase (NAG)]. Methods: Hospitalized patients with type 2 diabetes (N = 269) were divided into two groups according to the median (0.08 g/day) 24-h urinary protein (24hUpro) level. Logistic regression was used to analyze the association between 24hUNa and 24hUpro ≥ 0.08 g/L; scatter plots were used to analyze the association of RBP, β2-MG, and NAG with 24hUNa. Results: Overall, 269 patients with type 2 diabetes mellitus were enrolled (average age, 56 ± 12 years; men, 61.3%). Multivariate logistic regression analysis revealed a positive correlation between 24hUNa and 24hUpro ≥ 0.08 g/L; every 10 mmol of 24hUNa had an increased risk of 24hUpro elevation [odds ratio (OR) (95% confidence interval [CI]: 1.06 (1.01–1.11)]. Compared with the lowest quartile of 24hUNa, the highest quartile had an increased risk of 24hUpro elevation [OR (95% CI): 2.76 (1.25–6.05)]; 24hUNa did not correlate with RBP, β2-MG, or NAG. Conclusions: In hospitalized patients with type 2 diabetes, 24hUNa was independently related to 24hUpro ≥ 0.08 g/day. However, no correlation of 24hUNa with RBP, β2-MG, or NAG was found. © 2019 Elsevier Inc. All rights reserved.
1. Introduction Diabetic nephropathy is a microvascular complication that affects millions of patients with diabetes worldwide. In China, the incidence of diabetic nephropathy has surpassed that of glomerulonephritis as the leading cause of end-stage renal disease.1 Control of blood glucose, use of an angiotensin-converting enzyme inhibitor (ACE\\I), or use of ▲ an angiotensin receptor blocker (ARB) can significantly reduce the risk of diabetic nephropathy development; however, the presence of residual urinary albumin still predicts the adverse outcome of nephropathy.2 Studies in hypertensive3,4 and general populations5,6 show that a high‑sodium diet is associated with impaired kidney function. Sodium restriction can effectively improve renal function in patients with hypertension,3,7 and when combined with ACE-I drugs, a synergistic effect is exerted to decrease urinary protein levels.3 However, there have been inconsistent findings regarding the association between sodium intake and kidney function in type 2 diabetes. Some studies have shown that a high‑sodium intake is positively correlated with increased urinary protein8 and decreased serum creatinine clearance9; in contrast,
Q4
Conflict of interest: The authors have no conflicts of interest to disclose. ⁎ Corresponding author. E-mail address: [email protected] (X. Zhou).
some studies have shown a positive correlation between low sodium intake and increased urinary protein level,10 and some have shown no correlation between sodium intake and increased urinary protein, as well as a reduced estimated glomerular filtration rate (eGFR).11 Previously, it was believed that diabetic nephropathy-related renal damage primarily occurred in the glomerulus; however, recent studies revealed that renal tubular damage occurs during the early stage of diabetic nephropathy, prior to glomerular damage.12,13 However, the relationship between high‑sodium intake and renal tubular damage in patients with type 2 diabetes is unclear. This study aimed to investigate the relationship between 24hUNa and urinary protein as well as that between 24hUNa and retinol-binding protein (RBP), beta 2-microglobulin (β2-MG), and N-acetyl-beta-D-glucosaminidase (NAG) in consecutive inpatients with type 2 diabetes mellitus. 2. Materials and methods 2.1. Study design and patients This was a cross-sectional study. The clinical data of 370 patients with type 2 diabetes admitted to the Department of Endocrinology, Peking University People's Hospital from May to September 2018
https://doi.org/10.1016/j.jdiacomp.2019.107498 1056-8727/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498
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were collected. To reduce the influence of factors on urinary sodium and urinary protein, we excluded 3 cases of type 2 diabetes mellitus complicated with pregnancy, 21 cases of type 2 diabetic ketosis, 20 cases of chronic nephropathy or an eGFR of b60 mL/min*1.73 m2, 1 case of primary aldosteronism, 14 cases of diuretic use, and 42 cases in which the 24hUNa data were not detected. Finally, the data of 269 patients were included in this study. 2.2. Measurements Clinical data on the day of admission were collected. The diagnosis of diabetes mellitus was based on a patient's self-reported history of diabetes mellitus, judgment made by our outpatient physicians, or on the ongoing treatment of diabetes mellitus. The diagnosis of hypertension was based on each patient's systolic blood pressure (N140 mmHg), diastolic blood pressure (N90 mmHg),14 or ongoing treatment with the administration of antihypertensive drugs. A patient was identified as a smoker based on their smoking pattern, i.e., smoking more than a cigarette a day or having quit for b1 year. The height, weight, and blood pressure of the patients were measured on admission day; blood glucose, triglyceride, cholesterol, low-density lipoprotein cholesterol (LDL-C), creatinine, and glycated hemoglobin (HbA1c) levels were measured under fasting conditions on the next day. Twenty-fourhour urine samples were collected to measure the levels of 24hUNa, 24h urine protein (24hUpro), and creatinine, whereas morning urine samples were collected to measure RBP, β2-MG, and NAG levels. The urinary albumin/creatinine ratio (ACR) was measured three times on successive days from the 2nd to the 4th day of admission, the average ACR value was then calculated and used in our analysis; ACR was measured only twice in 15 patients，once in 2 patients, and the ACR was not obtained in one patient. The 24hUpro level was detected by chemical colorimetry; 24hUNa level was detected using a membrane electrode; RBP, β2-MG, and NAG levels were detected by immunoturbidimetry. For both sexes, eGFR was estimated based on their respective collaborative epidemiological formulae for chronic kidney disease (CKD-EPI) as follows.15 Female patients: if serum creatinine was ≤0.7 mg/dL, then eGFR = 144 × (serum creatinine/0.7)−0.329 × 0.993age, and if serum creatinine was N0.7 mg/dL, then eGFR = 144 × (serum creatinine/0.7)−1.209 × 0.993age. Male patents: if serum creatinine was ≤0.9 mg/dL, then eGFR = 141 × (serum creatinine /0.9)−0.411 × 0.993age, and if serum creatinine was N0.9 mg/dL, then eGFR = 141 × (serum creatinine/0.9)−1.209 × 0.993age. Conversion of serum creatinine units can be performed as follows: 1 mg/dL = 88.4 μmol/L. 2.3. Statistical analysis Data were analyzed using the IBM SPSS 25.0 statistical software. The continuous variables of the normal distribution were expressed as mean ± standard deviation (x ± s), and an independent sample t-test was used to compare between groups. Continuous variables of the non-normal distribution were expressed as the median values (25th, 75th percentile), and the rank-sum test was performed for making inter-group comparisons. Categorical data were expressed as n (%), and the chi-squared test was used for making comparisons between groups. Logistic regression analysis and scatter plots were used for correlation analysis. All statistical tests were two-sided, and a P-value b.05 was considered statistically significant. 3. Results 3.1. Comparison of clinical data of patients The average age of the 269 patients with type 2 diabetes mellitus was 56 ± 12 years, and 61.3% were men. The patients were divided
into two groups according to the 24hUpro median of 0.08 g/day. Compared with the 24hUpro b 0.08 g/day group, the 24hUpro ≥ 0.08 g/day group had higher blood pressure, 24hUNa, RBP, β2-MG, and NAG levels. With an increase in 24hUNa level, the proportion of 24hUpro ≥ 0.08 g/day showed an upward trend. There was no significant difference in fasting blood sugar and HbA1c levels between the two groups (Table 1). According to the median ACR value (8.66 mg/g), the median values for 24hUNa level in the two groups were 158.6 and 149.7 mmol/day, respectively, without any statistically significant difference (Z = −0.900, P N .05). 3.2. Correlation between 24hUNa and 24hUpro ≥ 0.08 g/day Logistic regression analysis was conducted after adjusting for age, sex, smoking, systolic blood pressure, body mass index, duration of diabetes, HbA1c, LDL-C, eGFR, and use of ACE-I or ARB antihypertensive drugs to analyze the changes in 24hUpro ≥ 0.08 g/L for every 10-mmol increase in 24hUNa and revealed that the odds ratio and 95% confidence interval [OR (95% CI)] for 24hUpro ≥ 0.08 g/day was 1.06 (1.01–1.11). Compared with the minimum quartile of the 24hUNa group, the OR (95% CI) for 24hUpro ≥ 0.08 g/day in the highest quartile group was 2.76 (1.25–6.05) (Table 2). 3.3. Correlation between 24hUNa and ACR, RBP, β2-MG, and NAG 24hUNa did not correlate with ACR (Fig. 1a), RBP (Fig. 1b), β2-MG (Fig. 1c), or NAG (Fig. 1d). 3.4. Correlation between RBP, β2-MG, NAG, and 24hUpro ≥ 0.08 g/day NAG was positively correlated with 24hUpro ≥ 0.08 g/day, with an OR (95% CI) of 1.09 (1.02–1.16); RBP and β2-MG/10 were not correlated with 24hUpro ≥ 0.08 g/day, with ORs (95% CI) of 0.96 (0.73–1.25) and 1.01 (1.00–1.01), respectively (Table 3). 4. Discussion This study found that 24hUNa and renal tubular markers levels were positively associated with urinary protein levels, whereas no association was found between 24hUNa and renal tubular injury markers, suggesting that a high‑sodium diet was a risk factor for proteinuria while a high‑sodium diet-induced proteinuria was not related to renal tubular injury. Few previous studies have assessed and reported inconsistent results for the relationship between sodium intake and nephropathy in type 2 diabetes mellitus. Cross-sectional studies conducted in Japan showed that a high‑sodium diet positively correlated with an increased urinary protein level8 or decreased serum creatinine clearance rate9 in patients with type 2 diabetes, suggesting that a high‑sodium diet was a factor related to the prevalence or progression of diabetic nephropathy. These conclusions support the results of our study. However, contrary to the findings of this study, a cross-sectional study of Japanese patients with type 2 diabetes who did not receive antihypertensive drugs demonstrated that a low-sodium diet was associated with albuminuria; the study used a single-point urinary sodium concentration to assess sodium intake.10 Another global multicenter large cohort study did not find a correlation between sodium intake and increased urinary protein levels or decreased eGFR in patients with type 2 diabetes, and in that study, dietary questionnaires were used to assess sodium intake.11 The reasons for the inconsistency may be related to different research groups and different methods used for the assessment of sodium intake. Under the condition of stable dietary intake, the extent of sodium intake and excretion are equivalent; hence, 24hUNa is the gold standard for estimating sodium intake.16 Compared with the abovementioned studies, this study adopted the more accurate 24hUNa estimation method for measuring sodium intake. However, in
Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498
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Table 1 Clinical features of patients with type 2 diabetes grouped according to median 24hUpro.
Number Age (years) Male (%) Duration of diabetes (years) History of hypertension (%) ACEI or ARB (%) ▲ Smoke (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Body mass index (kg/m2) Fasting serum glucose (mmol/L) HbA1c (%) Cholesterol (mmol/L) Triglycerides (mmol/L) LDL cholesterol (mmol/L) serum creatinine (μmol/L) eGFR (mL/min*1.73 m2) ACR (mg/g) 24hUNa (mmol/day) Quantile of 24hUNa (mmol/day) b115.4 115.5–152.7 152.8–205.3 ≥205.4 24-h urinary creatinine (mmol/day) Male Female RBP (mg/L) β2-MG (μg/L) NAG (U/L)
All patients
24hUpro ≥ 0.08 g/day
24hUpro b 0.08 g/day
269 56 ± 12 165 (61.3) 10.0 (5.0, 17.0) 128 (47.6) 46 (17.1) 79 (29.4) 132 ± 17 76 ± 11 26.5 ± 4.0 7.23 ± 2.69 9.3 ± 2.0 4.26 ± 1.15 1.45 (1.10, 2.18) 2.73 (2.16, 3.34) 63 ± 16 101.53 ± 15.88 8.66 (4.69, 24.01) 152.8 (115.4, 205.4)
136 56 ± 12 91 (66.9) 10.0 (5.0, 18.0) 73 (53.7) 21 (15.4) 45 (33.1) 135 ± 17 77 ± 11 26.8 ± 4.2 7.47 ± 2.60 9.4 ± 1.9 4.31 ± 1.18 1.56 (1.10, 2.31) 2.77 (2.17, 3.31) 65 ± 17 100.71 ± 17.00 15.59 (5.70, 75.25) 167.4 (123.7, 223.3)
133 56 ± 11 74 (55.6) 10.0 (4.0,16.5) 55 (41.4)*** 25 (18.8) 34 (25.6) 128 ± 17** 74 ± 11*** 26.3 ± 3.8 6.98 ± 2.76 9.2 ± 2.0 4.21 ± 1.12 1.38 (1.08, 2.07) 2.67 (2.13, 3.38) 62 ± 14 102.39 ± 14.65 6.92 (4.02, 10.03)* 143.7 (106.5, 192.0)**
67 (24.9) 66 (24.5) 69 (25.7) 67 (24.9)
26 (19.1) 30 (22.1) 37 (27.2) 43 (31.6)
41 (30.8)*** 36 (27.1) 32 (24.1) 24 (18.0)
11.40 ± 3.44 7.56 ± 2.71 0.27 (0.20, 0.36) 200.00 (141.70, 307.20) 11.40 (9.60, 14.70)
12.09 ± 3.75 8.15 ± 3.52 0.30 (0.21, 0.42) 213.80 (141.70, 395.70) 12.30 (10.05, 15.85)
10.53 ± 2.80** 7.12 ± 1.81 0.25 (0.18, 0.33)** 194.75 (144.33, 242.60)*** 10.60 (9.20, 12.00)*
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; HbA1c, glycosylated hemoglobin; eGFR, estimated glomerular filtration rate; ACR, ▲ urinary albumin/creatinine ratio; LDL, low-density lipoprotein; 24hUpro, 24-h urinary protein; 24hUNa, 24-h urinary sodium; RBP, retinol-binding protein; β2-MG, beta 2-microglobulin; NAG, N-acetyl-beta-D-glucosaminidase. Normally distributed continuous variables are expressed as mean ± standard deviation (x ± s), continuous variables exhibiting a non-normal distribution are expressed as median values (25th, 75th), and categorical data are expressed as percentages (%). An independent sample t-test and rank-sum test were performed to detect differences between the two groups; a chi-squared test was used to compare categorical variables. Compared with 24hUpro b 0.08 g/day group, *P b .001, **P b .01, ***P b .05.
this study, no difference in 24hUNa was found between the two groups according to the median ACR value, which may be related to a greater variability of random urine ACR determined according to exercise, sex, and other factors. High-sodium intake may cause proteinuria through a variety of mechanisms. Animal experiments have shown that high-sodium intake can lead to increased intraglomerular pressure and glomerular volume,17 as well as cause interlobular artery wall thickening, macrophage infiltration, and increased renal vascular resistance in rats.18 Clinical studies have also found that a high-sodium diet can induce glomerular hyperfiltration, increase glomerular filtration rate and cystic pressure,19 cause oxidative stress,20 and activate the renin–angiotensin–aldosterone system.3,21,22 Animal studies have revealed that high-sodium intake can result in renal tubular epithelial damage and tubulointerstitial fibrosis,23,24 but clinical trials regarding this have not been conducted to date. Table 2 Logistic regression analysis between 24hUNa and 24hUpro ≥ 0.08 g/day [OR (95% CI)].
24hUNa/10 (mmol/day) Quantile of 24hUNa (mmol/day) b115.4 115.4–152.7 152.8–205.3 ≥205.4
Model 1
Model 2
1.06 (1.01–1.11)
1.06 (1.01–1.11)
1 1.36 (0.65–2.85) 2.02 (0.95–4.27) 2.80 (1.28–6.15)
1 1.36 (0.65–2.85) 1.98 (0.94–4.20) 2.76 (1.25–6.05)
Abbreviations: 24hUpro, 24-h urinary protein; 24hUNa, 24-h urinary sodium, CI, confidence interval, OR, odds ratio. Model 1: adjusted for age, sex, smoking, systolic blood pressure, body mass index, course of diabetes, HbA1c, low-density lipoprotein cholesterol, and eGFR. Model 2: adjusted for the use of ACEI/ARB antihypertensive drugs on the basis of model 1. Values ▲ for 24hUNa/10, quantile of 24hUNa were entered into the two models separately.
Recent studies have shown that diabetic nephropathy causes tubular damage before glomerulopathy.12,13 RBP, β2-MG, and NAG are markers of proximal tubular injury, which can occur in the early stage of nephropathy.13,25–27 Here, 24hUpro ≥ 0.08 g/day was found to correlate with NAG but not with RBP and β2-MG, which may be due to the higher sensitivity of NAG; therefore, the highly sensitive NAG suggests early renal injury and predicts albuminuria.28,29 However, the relationship between high-sodium intake and renal tubular injury is not clear. To our knowledge, the present study is the first to explore the relationship between high-sodium intake and renal tubular injury clinically; however, no correlation was found between 24hUNa and RBP, β2-MG, or NAG. Some limitations were noted for this study. First, it had a crosssectional design; hence, a causal relationship between 24hUNa and urinary protein could not be examined. A large number of prospective studies are needed to confirm the relationship between 24hUNa and urinary protein in type 2 diabetes. Second, although this study involved a more accurate sodium intake estimation method of detecting the 24hUNa levels, the 24-h urine sample was collected only once, which may have been influenced by patients' daytime activities and blood pressure fluctuations. Additionally, patients receiving diabetic meals after hospitalization may achieve varying sodium intake reductions based on their individual characteristics, which in turn weakens the correlation between 24hUNa and urinary protein level. Third, although this is the first clinical study to explore the relationship between highsodium diet and renal tubular injury, the sample size was relatively small. More clinical studies are needed, and more sensitive indicators of early renal tubular injury need to be further validated. In conclusion, this study showed that sodium intake was independently related to an increase in urinary protein in inpatients with type
Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498
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J. He, X. Zhou / Journal of Diabetes and Its Complications xxx (xxxx) xxx
r = -0.049
r = -0.047
P = 0.425
P = 0.475
(a) Scatter plots of 24hUNa and ACR
(b) Scatter plots of 24hUNa and RBP
r = 0.078
r = -0.115
P = 0.235
P = 0.080
(c) Scatter plots of 24hUNa and β2-MG
(d) Scatter plots of 24hUNa and NAG
Fig. 1. Correlation of 24hUNa with ACR, RBP, β2-MG, and NAG. (a) Scatter plots of 24hUNa and ACR (b) Scatter plots of 24hUNa and RBP. (c) Scatter plots of 24hUNa and β2-MG (d) Scatter plots of 24hUNa and NAG. Abbreviations: 24hUNa, 24-h urinary sodium; ACR, urinary albumin/creatinine ratio; RBP, retinol-binding protein; β2-MG, beta2-microglobulin; NAG, N-acetyl-beta-Dglucosaminidase.
2 diabetes, but no correlation was found between sodium intake and renal tubular injury markers.
Funding information This work is supported by grants 2016YFC1305600 and 2016YFC1305603 from the Major Chronic Non-communicable Disease Prevention and Control Research, National Key Research and Development Program of China.
Acknowledgements None.
References Table 3 Logistic regression analysis between RBP, β2-MG, NAG and 24hUpro ≥ 0.08 g/day [OR (95% CI)].
RBP (mg/L) β2-MG/10 (μg/L) NAG (U/L)
Model 1
Model 2
0.96 (0.73–1.26) 1.01 (1.00–1.01) 1.08 (1.01–1.16)
0.96 (0.73–1.25) 1.01 (1.00–1.01) 1.09 (1.02–1.16)
Abbreviations: RBP, retinol-binding protein; β2-MG, beta2-microglobulin; NAG, N-acetylbeta-D-glucosaminidase; 24hUpro, 24-h urinary protein; CI, confidence interval, OR, odds ratio. Model 1: adjusted for age, sex, smoking, systolic blood pressure, body mass index, course of diabetes, HbA1c, low-density lipoprotein cholesterol, and eGFR. Model 2: adjusted for the use of ACEI/ARB antihypertensive drugs on the basis of model 1. ▲ Values for RBP, β2-MG/10, and NAG were entered into the two models separately.
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Please cite this article as: J. He and X. Zhou, Association between 24-h urine sodium and proteinuria among hospitalized patients with type 2 diabetes, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2019.107498