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Original ArticlesChronic Kidney Disease
Open Access

Association of Depressive Symptoms with Rapid Kidney Function Decline in Adults with Normal Kidney Function

Zhuxian Zhang, Panpan He, Mengyi Liu, Chun Zhou, Chengzhang Liu, Huan Li, Yuanyuan Zhang, Qinqin Li, Ziliang Ye, Qimeng Wu, Guobao Wang, Min Liang and Xianhui Qin
CJASN June 2021, 16 (6) 889-897; DOI: https://doi.org/10.2215/CJN.18441120
Zhuxian Zhang
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Panpan He
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Mengyi Liu
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Chun Zhou
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Chengzhang Liu
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
2Institute of Biomedicine, Anhui Medical University, Hefei, China
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Huan Li
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Yuanyuan Zhang
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Qinqin Li
2Institute of Biomedicine, Anhui Medical University, Hefei, China
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Ziliang Ye
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Qimeng Wu
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Guobao Wang
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Min Liang
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Xianhui Qin
1National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Abstract

Background and objectives The relationship of depressive symptoms with kidney function remains poorly investigated. We aimed to evaluate the prospective association between depressive symptoms and rapid decline in kidney function in Chinese adults with normal kidney function.

Design, setting, participants, & measurements A total of 4763 participants with eGFR≥60 ml/min per 1.73 m2 at baseline were enrolled from the China Health and Retirement Longitudinal Study. Baseline depressive symptoms were determined using a ten-item Center for Epidemiologic Studies Depression scale with a cutoff score of greater than or equal to ten to define high depressive symptoms. The GFR was estimated by a combination of serum creatinine and cystatin C. The primary outcome was rapid decline in kidney function, defined as an annualized decline in eGFR of ≥5 ml/min per 1.73 m2. Secondary outcome was defined as an annualized decline in eGFR of ≥5 ml/min per 1.73 m2 and to a level of <60 ml/min per 1.73 m2 at the exit visit.

Results During a median follow-up of 4 years (interquartile range, 3.92–4.00), 260 (6%) participants developed rapid decline in kidney function. Overall, there was a significant positive association between baseline depressive symptoms and rapid decline in kidney function (per five-scores increment; adjusted odds ratio, 1.15; 95% confidence interval, 1.03 to 1.28) after adjustments for major demographic, clinical, or psychosocial covariates. Consistently, compared with participants with low depressive symptoms (total Center for Epidemiologic Studies Depression scale score less than ten), a significantly higher risk of rapid decline in kidney function was found among those with high depressive symptoms (total Center for Epidemiologic Studies Depression scale score greater than or equal to ten; adjusted odds ratio, 1.39; 95% confidence interval, 1.03 to 1.88). Similar results were found for the secondary outcome (per five-scores increment; adjusted odds ratio, 1.26; 95% confidence interval, 1.06 to 1.51).

Conclusions High depressive symptoms were significantly associated with a higher risk of rapid kidney function decline among Chinese adults with normal kidney function.

  • depressive symptom
  • depression
  • kidney function decline
  • chronic kidney disease
  • CHARLS

Introduction

CKD is a leading risk factor for cardiovascular disease, kidney failure, and mortality worldwide (1 ⇓–3). In 2012, the overall prevalence of CKD was 11% in Chinese adults. That is, the number of patients with CKD in China is estimated to be about 119.5 million (4,5). Therefore, the identification of more modifiable risk factors may possibly reduce the huge burden of CKD and its related complications by leading to early detection and primary prevention.

Depression is a common mental disorder in middle-aged and older adults (6,7), and it is reported to be prevalent in patients with CKD (8). Depressive symptoms may possibly lead to active inflammation and impaired immune response, resulting in poor clinical outcomes (9). Accordingly, several studies have assessed the relationship of depressive symptoms with faster eGFR decrease or progression to kidney failure and reported inconsistent results (10 ⇓ ⇓ ⇓–14). Of note, most of the previous studies (10 ⇓ ⇓–13) examined these relationships in patients living with CKD prior to maintenance dialysis initiation rather than in the general population. Moreover, although the eGFR on the basis of a combination of serum creatinine and cystatin C (eGFRcr-cys) has been reported to be more closely related to the measured GFR than eGFR on the basis of creatinine (eGFRcr) alone or eGFR on the basis of cystatin C (eGFRcys) alone (15), all of the previous studies (10 ⇓ ⇓ ⇓–14) assessed the kidney outcomes on the basis of eGFRcr or eGFRcys alone. Overall, although we speculated that high depressive symptoms may also be related to rapid decline in kidney function, especially on the basis of eGFRcr-cys, among the general population, to date, this hypothesis has not been evaluated in previous studies.

To address the above important knowledge gaps, our study aimed to evaluate the prospective association between depressive symptoms and rapid kidney function decline in the general population with normal kidney function, using data from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative, longitudinal study with measurements of both serum creatinine and cystatin C.

Materials and Methods

Study Design and Population

The detailed study design and methods of CHARLS have been reported previously (16). In brief, CHARLS is a nationally representative, longitudinal study of the middle-aged and elderly population of China designed to collect a range of information on demographic, socioeconomic, lifestyle, and health circumstances. The baseline survey included 17,708 participants aged 45 years and older from 450 villages within 28 provinces between June 2011 and March 2012, using a multistage, stratified, probability proportionate to size sampling method. All participants were assessed by one-to-one interviews with a structured questionnaire. Participants were followed up every 2 years with a face-to-face interview. Physical measurements were carried out at every follow-up, and blood sample collection was performed once in every two follow-up cycles (4 years).

We conducted a prospective, longitudinal analysis using data from the three waves of CHARLS for 2011, 2013, and 2015. A total of 4763 participants with complete measurements on baseline depressive symptoms, baseline and exit visit kidney outcomes, and an eGFR≥60 ml/min per 1.73 m2 at baseline were enrolled in this analysis (Supplemental Figure 1).

CHARLS was approved by the Biomedical Ethics Review Committee of Peking University, Beijing, China (IRB00001052–11015). All participants provided written informed consent. The data and study materials that support the findings of this study will be available at the CHARLS project website (http://charls.pku.edu.cn/).

Assessment of Depressive Symptoms

Depressive symptoms were measured using a ten-item Center for Epidemiologic Studies Depression (CES-D) scale included in the questionnaire. The ten-item CES-D has been suggested to provide excellent sensitivity and specificity (17,18), and it has been validated among Chinese older adults (19). Participants were asked to rate how often they experienced depressive symptoms in the past week from zero (rarely or none of the time [<1 day]) to three (most or all of the time [5–7 days]). The total score ranged from zero to 30, with a higher score indicating higher depressive symptoms. Participants with a cutoff score of ten or above were considered to have high depressive symptoms (20), and we further graded those with high depressive symptoms into two groups according to the scores: moderate (ten to <21) and higher (≥21) (21).

Assessment of Covariates

At baseline, information on age, sex, smoking and drinking status (no or yes), living residence (rural or others), marital status, and educational level were obtained from the questionnaires. Educational level was classified as illiteracy, literate, primary school, and middle school or above. Health-related factors included self-reported smoking and drinking status, self-reported physician-diagnosed diabetes and heart disease, and use of medications for diabetes. Marital status was classified into two groups: married and unmarried (never married, separated, divorced, and widowed). Height, weight, and BP were measured following a standard procedure with calibrated equipment. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Diabetes was defined as physician-diagnosed diabetes, use of glucose-lowering drugs, fasting glucose ≥126 mg/dl, random glucose ≥200 mg/dl, or hemoglobin A1c ≥7%.

Laboratory Assays

Venous blood was collected by trained staff members and transported to the local laboratory at 4°C. The blood samples were frozen at −20°C, transported to the Chinese Center for Disease Control and Prevention in Beijing within 2 weeks, and stored at −80°C until assayed at Capital Medical University laboratory. Serum glucose and lipids were measured using an enzymatic colorimetric test. Hemoglobin A1c was determined using boronated affinity high-performance liquid chromatography. Uric acid was obtained using a uric acid plus method. High-sensitivity C-reactive protein (CRP) was determined using an immunoturbidimetric assay. Serum creatinine and cystatin C were measured using a rate-blanked and compensated Jaffe creatinine method and particle-enhanced turbimetric assay, respectively. Of note, in CHARLS, blood sample collection was performed in 2011 and 2015 visits, and therefore, serum creatinine and cystatin C were only assessed at baseline (2011) and the exit visit (2015) in our study.

The eGFRcr-cys was calculated by a combination of both serum creatinine and cystatin C using the Chronic Kidney Disease Epidemiology Collaboration equation (22).

Study Outcome

The primary outcome was rapid decline in kidney function, defined as an annualized decline in eGFRcr-cys of 5 ml/min per 1.73 m2 or more (23). Annualized decline in eGFRcr-cys was estimated as (eGFRcr-cys at baseline − eGFRcr-cys at exit)/follow-up time.

Secondary outcome was progression to CKD, defined as an annualized decline in eGFRcr-cys of ≥5 ml/min per 1.73 m2 and to a level of <60 ml/min per 1.73 m2 at the exit visit.

Statistical Analyses

Baseline characteristics are presented as mean ± SD or median (interquartile range [IQR]) for continuous variables and proportions for categorical variables by depressive symptoms categories (low [total CES-D score less than ten] or high [total CES-D score greater than or equal to ten]). The differences in population characteristics were compared using two-sample t tests or chi-squared tests, accordingly.

Variables known as traditional or suspected risk factors for kidney function decline (24,25) or those that showed significant differences across different categories of depressive symptoms were selected as covariables. Because of the small fluctuation in the follow-up period (median, 4.00 years; IQR, 3.92–4.00) and the low incidence of study outcomes (<10%), the odds ratio (OR) derived from the logistic regression may be close to the risk ratio (26). Therefore, we used multivariable logistic regression models (ORs and 95% confidence intervals [95% CIs]) to evaluate the association between depressive symptoms and study outcomes with adjustments for baseline eGFRcr-cys in model 1 and age, sex, BMI, smoking status, living residence, systolic BP, diastolic BP, glucose, total cholesterol, triglycerides, HDL cholesterol, eGFRcr-cys, uric acid, and self-reported heart disease in model 2.

Furthermore, possible modifications of the relationship of depressive symptoms (high versus low) with rapid decline in kidney function were explored for the following variables: age (<65 versus ≥65 years), sex, BMI (<24 versus ≥24 kg/m2), smoking status (no versus yes), drinking status (no versus yes), marital status (married versus unmarried), educational level (illiteracy or literate versus primary school or above), diabetes (no versus yes), systolic BP (<140 versus ≥140 mm Hg), total cholesterol (<200 versus ≥200 mg/ml), uric acid (<4.2 mg/ml [median] versus ≥4.2 mg/ml), and high-sensitivity CRP (<1.0 mg/L [median] versus ≥1.0 mg/L) by stratified analyses and interaction testing.

The descriptive analyses were weighted to account for the complex, multistage design of the study and nonresponse in CHARLS. Previous studies using CHARLS data suggested that results from regression analyses with and without weighting are similar (27,28). Therefore, the regression analyses in our study were unweighted. A two-tailed P<0.05 was considered to be statistically significant in all analyses. R software (version 3.6.3; http://www.R-project.org) was used for all data analyses.

Results

Study Participants and Baseline Characteristics

As illustrated in the flow chart (Supplemental Figure 1), a total of 4763 participants with complete depressive symptoms measurements and eGFRcr-cys≥60 ml/min per 1.73 m2 at baseline from CHARLS were included in the final analysis. Baseline characteristics of those excluded from the analysis due to missing depressive symptoms or eGFRcr-cys measurements were similar to those who were included in the analysis (Supplemental Table 1).

The mean age of the study population was 59 (SD, 9) years, and 2161 (45%) of the participants were men. The average values of eGFRcr-cys were 89 (SD, 15) ml/min per 1.73 m2 at baseline and 92 (SD, 16) ml/min per 1.73 m2 at exit, and the mean annualized decline in eGFRcr-cys was −0.8 (SD, 3.5) ml/min per 1.73 m2. Of the 4763 participants, 1837 (39%) had high baseline depressive symptoms (total CES-D score greater than or equal to ten). Baseline characteristics of study participants by depressive symptoms categories (low or high) are shown in Table 1. Participants with high depressive symptoms were older; were less likely to be men and married; were more likely to be nonsmokers, nondrinkers, and farmers; had higher percentage of self-reported heart disease and HDL cholesterol levels; and had lower BMI, systolic BP, diastolic BP, uric acid, and education levels (Table 1).

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Table 1.

Population characteristics by depressive symptoms categories

Association between Depressive Symptoms and Study Outcomes

During a median follow-up of 4.00 years (IQR, 3.92–4.00), 260 (6%) and 83 (2%) participants developed rapid decline in kidney function and progression to CKD, respectively.

After adjustments for major demographic, clinical, or psychosocial covariates (model 2), there was a significant positive association between depressive symptoms and rapid decline in kidney function (per five-scores increment; adjusted OR, 1.15; 95% CI, 1.03 to 1.28) (Figure 1A, Table 2). Accordingly, participants with high depressive symptoms (total CES-D score greater than or equal to ten) had a significantly higher risk of rapid decline in kidney function (adjusted OR, 1.39; 95% CI, 1.03 to 1.88) than those with low depressive symptoms. When depressive symptoms were assessed as three categories, compared with those with low depressive symptoms (total CES-D score less than ten), the adjusted ORs for participants with moderate (total CES-D score ten to <21) and higher (total CES-D score ≥21) depressive symptoms were 1.24 (95% CI, 0.90 to 1.72) and 2.18 (95% CI, 1.32 to 3.62), respectively (Table 2). Consistently, when depressive symptoms were assessed as quintiles, a significantly higher risk of rapid decline in kidney function was found among participants in quintiles 4 and 5 (total CES-D score greater than or equal to nine; adjusted OR, 1.44; 95% CI, 1.07 to 1.93) compared with those in quintiles 1–3 (total CES-D score less than nine) (Supplemental Table 2). Similar results were found for the secondary outcome (per five-scores increment; adjusted OR, 1.26; 95% CI, 1.06 to 1.51) (Figure 1B, Table 2) in the log-binomial regression models that take into account follow-up time (Supplemental Table 3), and in the weighted regression analyses (Supplemental Table 4).

Figure 1.
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Figure 1.

Positive relation of  depressive symptoms with rapid decline in kidney function  and progression to CKD . (A) Log-OR for rapid kidney function decline; (B) Log-OR for progression to CKD. *Adjusted for age, sex, body mass index, smoking status, living residence, systolic BP, diastolic BP, glucose, total cholesterol, triglycerides, HDL cholesterol, eGFR, uric acid, and self-reported heart disease. Log-OR, log odds ratio. 

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Table 2.

The association between depressive symptoms and CKD outcomes

Moreover, further adjustment for LDL cholesterol (Supplemental Table 5), excluding participants with emotional, nervous, or psychiatric problems, or use of related medications at baseline (Supplemental Table 6) did not substantially change the results. Similar trends were also observed in the association between depressive symptoms and kidney outcomes defined by eGFRcr (Supplemental Table 7) or eGFRcys alone (Supplemental Table 8), although some of the comparisons were NS.

The associations of specific depressive symptoms and the risk of rapid decline in kidney function are presented in Supplemental Table 9. Although all of the ORs for the ten individual depressive symptoms were >1.00, only four symptoms (bothered by things: adjusted OR, 1.16; 95% CI, 1.02 to 1.32; had trouble concentrating: adjusted OR, 1.17; 95% CI, 1.03 to 1.33; felt everything was an effort: adjusted OR, 1.18; 95% CI, 1.04 to 1.33; and felt lonely: adjusted OR, 1.16; 95% CI, 1.00 to 1.34) were significantly associated with rapid kidney function decline (Supplemental Table 9).

Stratified Analyses by Potential Effect Modifiers

Stratified analyses were further performed to assess the association between depressive symptoms (high versus low) and rapid kidney function decline in various subgroups (Figure 2).

Figure 2.
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Figure 2.

Stratified analyses for the association between depressive symptoms (high versus low) and rapid decline in kidney function. *Adjusted, if not stratified, for age, sex, body mass index, smoking status, living residence, systolic BP, diastolic BP, glucose, total cholesterol, triglycerides, HDL cholesterol, eGFR, uric acid, and self-reported heart disease. 95% CI, 95% confidence interval; CRP, C-reactive protein; OR, odds ratio. 

None of the variables, including age, sex, BMI, smoking status, drinking status, marital status, educational level, diabetes, systolic BP, total cholesterol, uric acid, or high-sensitivity CRP, significantly modified the association between depressive symptoms and rapid kidney function decline (all P interactions values >0.05) (Figure 2).

Discussion

In this prospective, longitudinal, cohort study, we first demonstrated that the presence of high depressive symptoms was significantly associated with a 39% higher risk of rapid kidney function decline among Chinese adults with normal kidney function.

Depression is an important health concern in China. Previous studies have noticed the high prevalence of depressive symptoms among Chinese adults (7,29,30). The estimated prevalence of depressive symptoms among the Chinese adult population was 38% on the basis of a National Household Survey in 2012 (29). In addition, a study of rural elderly (aged ≥60) showed that the prevalence of depressive symptoms was 53% in central China (Anhui Province) (30). Consistent with our study (39%), another study from CHARLS also suggested the same high prevalence of depressive symptoms, which reached 37% (7). Considering the poor outcomes caused by depressive symptoms, the high prevalence of depressive symptoms in Chinese adults highlighted the importance of our study.

Several previous studies have found inconsistent results regarding the relationship between depressive symptoms and kidney function decline or CKD progression among individuals with CKD (10 ⇓ ⇓–13). A cohort of 262 patients living with CKD from Taiwan suggested that depressive symptoms contributed to a 2.25-fold higher risk for progression to dialysis during 3 years of follow-up (11). Tsai et al. (12) also found that depressive symptoms in CKD were independent predictors of faster eGFR decrease and progression to kidney failure. Moreover, a previous study of men veterans with CKD indicated that a major depressive episode was associated with a higher risk of dialysis initiation (hazard ratio, 3.51; 95% CI, 1.77, 6.97) (13). Nevertheless, Fischer et al. (10) reported that the presence of depressive symptoms was not associated with the risk of progression to kidney failure in Black individuals with hypertensive CKD over a 5-year follow-up period. At the same time, only one related study (14) was conducted in participants without baseline CKD. Findings from the Cardiovascular Health Study suggested that depressive symptoms were not significantly associated with rapid decline in eGFR (defined as eGFR decline ≥3 ml/min per 1.73 m2 per year) among those without CKD at baseline (n=3561) (14). The possible explanations for the null results in this study (14) may be that there were only two categories for the depressive symptoms (high versus low). For example, in our study, even when kidney outcomes were assessed on the basis of eGFRcr, although there was no significant association between depressive symptoms (high versus low) and rapid kidney function (OR, 1.20; 95% CI, 0.98 to 1.48) compared with those with low depressive symptoms (total CES-D score less than ten), a significantly higher risk of rapid kidney function decline was found among participants with higher depressive symptoms (total CES-D score ≥21; OR, 1.77; 95% CI, 1.24 to 2.53). Moreover, some important confounders, such as baseline eGFR levels, were not considered in the major analysis in this study (14). Overall, the above studies indicated that the relation of depressive symptoms with the risk of kidney function decline remains uncertain. Moreover, most of these studies focused on patients living with CKD, and the kidney outcomes in these studies were only assessed by eGFRcr or eGFRcys alone. The association between depressive symptoms and kidney outcomes defined by eGFRcr-cys has not been fully investigated in previous studies. With the measurements of both serum creatinine and cystatin C, CHARLS provides an opportunity to evaluate the dose-response association between depressive symptoms and rapid decline in kidney function among general population, with comprehensive adjustments for a large number of known covariables, and a series of subgroup analyses.

Our study provides some novel findings. We found that high depressive symptoms were related to a higher risk of rapid kidney function decline in general Chinese adults. This association persisted after adjusting for a number of potentially confounding factors and remained in various subgroups defined by major covariables. Moreover, we evaluated kidney outcomes by eGFRcr-cys, which is more precise than eGFRcr or eGFRcys alone (31). Creatinine-based eGFR was relatively imprecise, especially in older population, because creatinine may vary with muscle mass, diet, and physical activity (32). Serum cystatin C levels may also be altered by insulin resistance or inflammation (33,34). Therefore, adding the measurement of cystatin C to that of serum creatinine to determine eGFR can improve accuracy (35).

Furthermore, although there were no significant interactions, the stratified analyses showed stronger associations between depressive symptoms and rapid decline in kidney function in smokers, nondiabetic participants, and those with BMI<24 kg/m2 or systolic BP ≥140 mm Hg. However, these results may possibly not have significant clinical implications given multiple testing and similar directionality of most of the associations. On the other hand, it should be noted that at the existing sample size, the power for detecting a moderate interaction in the test is limited, and future studies with large sample sizes are necessary to confirm the absence of interaction.

The exact mechanisms underlying the relationship of depressive symptoms and kidney function decline remain to be further elucidated. We speculate that there are several potential mechanisms by which depressive symptoms would accelerate kidney function decline. First, previous studies have reported that patients with high depressive symptoms had higher circulating levels of inflammatory cytokines, such as IL-6 and TNF-α, which may activate autoimmune processes, contribute to endothelial dysfunction, promote kidney fibrosis, and accelerate kidney function decline (36 ⇓–38). However, in our study, there were similar levels of high-sensitivity CRP in participants with high versus low CES-D scores; therefore, we speculated that inflammation may not fully explain our findings. Second, the presence of depressive symptoms may decrease immune system sensitivity to glucocorticoid hormones and impair immune system via autonomic imbalance and activation of the hypothalamic pituitary adrenal axis (39 ⇓–41). Third, depression may be related to some health behaviors or health literacy, such as delayed health care seeking and unhealthy lifestyle choices, including poor nutrition, disruption of social interaction, and physical inactivity, which may also contribute to rapid decline in kidney function (42,43). Consistently, compared with those with low depressive symptoms, participants with high depressive symptoms had lower education levels in our study. Participants with lower education levels may be less able to adjust their emotions and have lower self-care awareness (30). Moreover, in our analysis, only four specific depressive symptoms (bothered by things, had trouble concentrating, felt everything was an effort, and felt lonely) were significantly associated with rapid kidney function decline. In addition, no significant association was observed between other individual depressive symptoms and rapid decline in kidney function, which may be due to the short follow-up period. Overall, our findings and the detailed mechanisms still need to be confirmed in further studies.

Several potential limitations need to be mentioned. First, this is an observational analysis. Although a series of confounders had been adjusted, residual confounding cannot be completely eliminated. Second, the kidney function was only assessed at baseline and the exit visit. More frequent kidney function assays would allow for a more accurate evaluation of its progression over time. Third, as urine protein or urine albumin was not measured in CHARLS, we could not evaluate the influence of proteinuria on the relationship between depressive symptoms and kidney function decline. Fourth, some of the participants were excluded from this analysis due to incomplete outcome data or depressive symptoms measurements. However, the participants included did not differ from those excluded in baseline characteristics (Supplemental Table 1). Moreover, most of these variables had been included in the regression models, and the stratified analysis further showed that none of the variables materially modified the results. Fifth, the information about diagnosis of major depression or any other mental health concern, such as anxiety disorder or bipolar disorder, and antidepressant treatment at baseline were unavailable in CHARLS. However, excluding participants with emotional, nervous, or psychiatric problems or use of related medications at baseline did not substantially change our findings. Finally, this study was performed in general Chinese participants aged 45 years and older; therefore, the results may not be fully generalized to younger or other populations. Overall, further confirmation of our findings in future studies is required.

In summary, our study demonstrated that high depressive symptoms were significantly associated with rapid decline in kidney function among Chinese adults with normal kidney function. If further confirmed, our data provide some evidence for depressive symptom screening and effective psychosocial intervention to improve primary prevention of CKD.

Disclosures

Q. Li reports employment with Anhui Medical University. M. Liang reports employment with Nanfang Hospital, Southern Medical University. M. Liu reports employment with Nanfang Hospital, Southern Medical University. X. Qin reports employment with Renal Division, Nanfang Hospital, Southern Medical University and the National Clinical Research Center for Kidney Disease and grants from the National Natural Science Foundation of China. G. Wang reports employment with the National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University. All remaining authors have nothing to disclose.

Funding

The study was supported by National Natural Science Foundation of China grants 81973133 and 81730019 (to X. Qin).

Acknowledgments

The authors thank the CHARLS research team and the field team for collecting and providing the data. The authors also thank all volunteers and staff involved in this research.

This analysis uses data from CHARLS.

P. He, X. Qin, and Z. Zhang designed and conducted the study; P. He, C. Liu, Z. Zhang performed the data analyses; X. Qin and Z. Zhang drafted the manuscript; and all authors read and approved the final manuscript.

Supplemental Material

This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.18441120/-/DCSupplemental.

Supplemental Figure 1. Flow chart of the participants.

Supplemental Table 1. Characteristics of the included and excluded participants.

Supplemental Table 2. The association between depressive symptoms and CKD outcomes by quintiles of depressive symptoms.

Supplemental Table 3. The association between depressive symptoms and CKD outcomes in log-binomial regression models.

Supplemental Table 4. The association between depressive symptoms and CKD outcomes in the weighted regression analyses.

Supplemental Table 5. The association between depressive symptoms and CKD outcomes with further adjustment for LDL cholesterol.

Supplemental Table 6. The association between depressive symptoms and CKD outcomes with exclusion of participants with emotional, nervous, or psychiatric problems or use of related medications at baseline.

Supplemental Table 7. The association between depressive symptoms and CKD outcomes defined by creatinine-based eGFR.

Supplemental Table 8. The association between depressive symptoms and CKD outcomes defined by cystatin C–based eGFR.

Supplemental Table 9. The association between specific depressive symptoms and rapid decline in kidney function.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related Patient Voice, “Depressive Symptoms and Rapid Kidney Function Decline,” on page 839

  • Received November 24, 2020.
  • Accepted February 25, 2021.
  • Copyright © 2021 by the American Society of Nephrology

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Clinical Journal of the American Society of Nephrology: 16 (6)
Clinical Journal of the American Society of Nephrology
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Association of Depressive Symptoms with Rapid Kidney Function Decline in Adults with Normal Kidney Function
Zhuxian Zhang, Panpan He, Mengyi Liu, Chun Zhou, Chengzhang Liu, Huan Li, Yuanyuan Zhang, Qinqin Li, Ziliang Ye, Qimeng Wu, Guobao Wang, Min Liang, Xianhui Qin
CJASN Jun 2021, 16 (6) 889-897; DOI: 10.2215/CJN.18441120

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Association of Depressive Symptoms with Rapid Kidney Function Decline in Adults with Normal Kidney Function
Zhuxian Zhang, Panpan He, Mengyi Liu, Chun Zhou, Chengzhang Liu, Huan Li, Yuanyuan Zhang, Qinqin Li, Ziliang Ye, Qimeng Wu, Guobao Wang, Min Liang, Xianhui Qin
CJASN Jun 2021, 16 (6) 889-897; DOI: 10.2215/CJN.18441120
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