{'fraction_non_alphanumeric': 0.03191340456305697, 'fraction_numerical': 0.024261652591797696, 'mean_word_length': 5.1187553525549525, 'pattern_counts': {'":': 0, '<': 9, '<?xml version=': 0, '>': 3, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Prevalence of depression and suicidal ideation increases proportionally with renal function decline, beginning from early stages of chronic kidney disease

Abstract Depression and suicidal ideation are prevalent mental health problems in patients with chronic kidney disease (CKD. However, the association between mental health problems and kidney disease has been investigated in severe cases only. Thus, this study evaluated the relationship between mental health problems and renal function in a community-based prospective cohort study comprising patients with mild to moderate kidney disease. A total of 44,938 participants who were participated in Korean National Health and Nutrition Examination Survey IV, V, and VI from 2007 to 2014 were enrolled. Estimated glomerular filtration rate (eGFR) was calculated using the CKD Epidemiology Collaboration equation. The study outcome was the prevalence of depression and suicidal ideations assessed by self-reporting surveys. Logistic regression analysis was performed to evaluate the relationship between renal function and outcomes. The mean age of the study subjects was 49.2 ± 16.6 years, and the mean eGFR was 94.0 mL/min/1.73 m2. The prevalence of depression and suicidal ideation increased with decreasing eGFR. Multivariate logistic regression analysis showed that the risk of depression increased in subjects with eGFR <45 mL/min/1.73 m2 [odds ratio (OR) 1.47; 95% confidence interval (CI) 1.09–1.98]. The risk of suicidal ideation gradually increased in groups with eGFR <90 mL/min/1.73 m2 (OR, 1.11; 95% CI, 1.03–1.20), even after adjustments for confounding variables. In conclusion, depression and suicidal ideation are related closely with renal dysfunction. The risk of having depression and suicidal ideation increased even in patient with mild renal dysfunction. Therefore, evaluation and management strategies regarding mental health problems should be taken into account throughout all stages of CKD.


Introduction
The number of patients with chronic kidney disease (CKD) is increasing at a rapid rate worldwide. [1][2][3] This has become a global health problem because CKD leads to a reduced quality of life and increased mortality rate. [4][5][6] Among the factors that affect quality of life and survival in patients with CKD are mental health problems that often develop in patients with reduced renal function. [7,8] Depression is a well-known independent risk factor for hospitalization or death in patients with impaired renal function. [9,10] The prevalence of depression in the general population ranges from 2% to 4%. [11,12] Depression is more common in patients with CKD and considerably affects the disease outcome. [9] In previous reports, depression was found in up to 20% of patients with severe CKD before dialysis initiation. [13,14] In addition, the prevalence of depression in patients undergoing dialysis are higher than in patients with CKD without dialysis (∼20%-30% of that of patients on dialysis), with investigations reporting rates as high as 47%. [15][16][17] On the other hand, suicide, one of the gravest results of depression, has also been known to be more common in patients with CKD than in the general population. In a recent study, 22% of patients treated with hemodialysis were reported to have had suicidal ideations. [18,19] Although the causes of this increased mental health problems in patients with CKD are uncertain, symptoms related to chronic comorbid conditions and the direct effect of uremic toxins have been suspected as contributing factors. [20] Considering that several uremic toxins are already increased in the early stages of CKD, the prevalence of mental health problems may begin to increase even in patients with mild impairment in renal function. However, most of the previous reports only investigated patients with severe CKD or patients on dialysis, and the associations of mental health problems and renal function in patients with early CKD is not well known.
Therefore, in this study, the relationship between renal function and mental health problems, including depression and suicidal ideations, was investigated in a community-based cohort comprising patients with early CKD.

Study subjects
This study was performed by using data from the Korean National Health and Nutrition Examination Survey (KNHANES IV, V, and VI 2007 to 2014). KNHANES has been conducted periodically to assess the health and nutritional status of the Korean civilian noninstitutionalized population. The sampling frame was developed on the basis of the 2005 population and housing census in Korea. Household units were selected by using a stratified multistage probability sampling design for the South Korean population. KNHANES IV, V, and VI were crosssectional, nationally representative surveys conducted by the Division of Chronic Disease Surveillance, Korea Centers for Disease Control and Prevention, among ∼260,000 primary sampling units, each of which included ∼60 households. A total of 65,973 subjects were screened. Patients younger than 18 years, with a diagnosis of end-stage renal disease, with estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m 2 , and with missing data were excluded. A total of 44,938 subjects were included in the final analysis (Fig. 1). This study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional review board of the Yonsei University Health System Clinical Trial Center (4-2016-0882).

Anthropometric and laboratory data
Anthropometric measurements were obtained by trained experts following standardized protocols. Body mass index (BMI) was calculated as weight (kg) divided by the square of height (m 2 ). Diabetes mellitus (DM) was defined as serum fasting blood glucose level ≥126 mg/dL, use of antidiabetic medication, or previous diagnosis by a physician. Hypertension (HTN) was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medications. Indicators of socioeconomic status, such as education (high school or lower/university or higher) and occupation (currently employed or not), were surveyed. Economic status was assessed as the total household income, and marital status was categorized as currently married or single. Health behaviors such as sleep duration, alcohol consumption, and smoking status were evaluated with questionnaires. According to smoking status, subjects were classified as current or past smokers versus nonsmokers. Sleeping hours were assessed with the question "How much time do you usually sleep per day?" Stress level was reported as none, mild, moderate, and severe during routine daily life.
Blood samples were collected after an at least 8 hours fast, and transported to a central laboratory within 24 hours. Serum creatinine was measured by using the colorimetric method. ADVIA 1650 (Siemens, Tarrytown, New York) was used for KNHANES 2007, and the Automatic Analyzer 7600 (Hitachi, Tokyo, Japan) was used for KNHANES 2008 to 2014. Blood hemoglobin levels were measured by using the impedance method for KNHANES 2007 and the sodium lauryl sulfate hemoglobin method for KNHANES 2008 to 2013. Proteinuria was defined as values ≥1+ determined by using the dipstick urine test.

Renal function estimation
Renal function was estimated by using the CKD Epidemiology Collaboration (CKD-EPI) equation, with serum creatinine levels calibrated to an isotope-dilution mass spectrometry traceable standard for KNHANES 2008 to 2014. [21] As measurements were not standardized for creatinine levels of KNHANES 2007, creatinine levels that were reduced by a calibration factor of 5% were used to calculate eGFR. [22] The accuracy of the CKD-EPI equation in estimating the glomerular filtration rate has previously been validated. [23] Patients were categorized into 6 groups according to eGFR. Patients with eGFR 45 to 30 mL/min/ 1.73 m 2 and those with eGFR 30 to 15 mL/min/1.73 m 2 were grouped together owing to the small number of patients allocated to these categories ( Fig. 1).

Mental health measures
Data on mental health were obtained from a self-reported questionnaire administered under the supervision of an investigator. Depressive symptoms were assessed with the question "Have you felt sadness or despair affecting your daily life for more than 2 weeks over the past year?" In addition, the question "are you currently diagnosed with depression?" was also asked. The participants answered these questions with a "yes" or "no" response. Subjects were defined as having depression when they reported having depressive symptoms or were currently diagnosed as having depression. Suicidal ideation was assessed by a positive answer to the question "in the last 12 months, did you think about committing suicide?" A "yes" or "no" response was also used to determine whether they had suicidal ideations. This indicator has been previously documented as a predictor of suicide in other surveys. [24]

Statistical analysis
All statistical analyses were performed by using SPSS for Windows version 21.0 (SPSS Inc., Chicago, IL). Continuous variables are expressed as mean ± standard deviation, and categorical variables as absolute numbers with percentages. Each variable was tested for normality before statistical analysis. Comparisons between the groups were made by using analysis of variance or Student t test for continuous variables and the x 2 test or Fisher exact test for categorical variables. The Kolmogorov-Smirnov test was performed to determine the normality of the distribution of parameters. If the resulting data did not show a normal distribution, geometric mean ± standard deviation was reported; the Mann-Whitney U test or Kruskal-Wallis test was used for multiple comparisons. Logistic regression analysis was conducted to evaluate the associations of depression and suicidal ideation with eGFR. Odds ratios (ORs) for depression and suicidal ideation were compared among groups of eGFR categories. Multivariable models were also constructed for logistic regression. Variables that showed statistical significance (P < .05) in the univariate analysis were included in the multivariable models. Variables that did not meet the statistical criteria were included if they were considered to have clinical significance. Colinearity was assessed by using Pearson correlation coefficients. P < .05 were considered statistically significant.

Baseline characteristics according to eGFR categories
The baseline characteristics of the study population are described in Table 1. The mean age of the subjects was 49.2 ± 16.6 years, and 43.1% were men. The mean eGFR of the subjects was 94.0 mL/ min/1.73 m 2 . A total of 6781 (15.1%) of subjects had depression, and suicidal ideation was reported in 5733 (12.8%) subjects. When comparisons were made among the eGFR category groups, subjects in the lower eGFR category groups tended to be older and were more likely to have a diagnosis of HTN or DM. The percentage of smokers increased in the lower eGFR category groups, whereas the proportion of drinkers decreased. Concerning socioeconomic status, subjects in the lower eGFR category groups were less educated and less likely to be employed. Laboratory data assessment revealed that the proportion of subjects with proteinuria increased, whereas blood hemoglobin levels decreased in category groups with lower eGFR.

Mental health problems
Experience of depression during the past year was reported in 14.0% of subjects in the eGFR > 90 mL/min/1.73 m 2 group. The Table 1 Baseline characteristics according to eGFR categories. proportion of subjects with depression gradually increased in category groups with lower eGFR, resulting in a rate of 23.1% in the eGFR 45 to 15 mL/min/1.73 m 2 category group (P < .001). A similar trend was found for suicidal ideation. The proportion of subjects with suicidal ideation gradually increased from 11.3% in the eGFR > 90 mL/min/1.73 m 2 category group to 24.4% in the eGFR 45 to 15 mL/min/1.73 m 2 category group (P < .001, Fig. 2).

Factors associated with depression and suicidal ideations
Logistic regression analysis revealed that older age, female sex, comorbidities including HTN and DM, and severe level of stress were significantly related with depression and suicidal ideation. On the other hand, current employment, having a higher household income, being college educated, and having longer sleeping hours were factors found to be protective against depression or suicidal ideations (Table 2).

Relationship of eGFR with depression and suicidal ideations
When the association between eGFR and depression was evaluated by using multivariate regression analysis, the ORs for depression was found to gradually increase as eGFR decreased in each category group. The OR for depression was significantly increased in the eGFR 15 to 45 mL/min/1.73 m 2 category group [OR, 1.47; 95% confidence interval (CI) 1.09-1.98; P = .01], after adjustments for confounding factors ( Table 3). The association between eGFR and suicidal ideations showed a similar trend. The OR for having suicidal ideation gradually increased as eGFR decreased in each category group. The OR for having suicidal ideations was significantly increased from the eGFR 75 to 90 mL/min/1.73 m 2 category group (OR, 1.11; 95% CI, 1.03-1.20; P = .01) through the eGFR 15 to 45 mL/min/1.73 m 2 category group (OR, 1.79; 95% CI, 1.35-2.39; P < .001), after adjustment for confounding factors (Table 4).
Moreover, when the associations of depression and suicidal ideations with eGFR as a continuous variable were assessed, the risks of depression (OR, 0.98; 95% CI, 0.97-0.99; P = .02) and   (Tables 3 and 4).

Discussion
In this study, we evaluated a community-based cohort comprising subjects with normal to moderately declined renal function. The prevalence of depression and suicidal ideations were found to increase with the decrease of eGFR. In addition, the association between mental health problems and renal function was found to be significant even in the relatively early stages of CKD. Depression and suicidal ideations have been considered as problems affecting patients with advanced stages of CKD. Previous reports have described the prevalence of depression in patients with moderate to severe CKD to be from 15% to 50%. In patients with advanced CKD with eGFR <30 mL/min/1.73 m 2 , the point prevalence of depression screened by using the Beck depression inventory was demonstrated to be as high as 54.8%. [13,25,26] A recent meta-analysis of 55,982 patients showed that 39.3% of patients undergoing dialysis had depression assessed with self-reported rating scales. [19] These reported prevalence of depression in predialysis patients with CKD and patients undergoing dialysis are much higher than the prevalence of depression in the general population, which is approximately 2% to 4%. [2,27] Similar to depression, suicidal ideations, and suicidal attempts are more frequent in patients with CKD. A recent investigation of a health insurance-based database revealed that the risk of committing suicide was 25% higher in patients with CKD and >30% higher in patients receiving dialysis than in those without CKD. [19] Although previous studies have repeatedly shown that depression and suicidal ideations are common problems in patients with CKD, the risk of developing these mental health problems in the early stages of CKD and the relationship with the degree of renal function decline have seldom been investigated. Compared with previous reports, the present study investigated nonhospitalized patients with CKD recruited through a community-based cohort, which enabled the evaluation of the full range of renal function.
The prevalence of depression was significantly increased in subjects with moderately decreased renal function. Moreover, the risk of having suicidal ideations clearly increased even in asymptomatic subjects with mild renal dysfunction. Interestingly, the prevalence of suicidal ideations increased as renal function further deteriorated. Mental health problems, especially depression and suicidal ideations, are more prevalent not only in patients with CKD but also among patients with other chronic medical conditions such as chronic obstructive pulmonary disease, coronary artery disease, DM, and cerebrovascular accidents. [28][29][30][31][32] This is believed to be caused by the decrease in the quality of life owing to symptoms resulting from the chronic diseases. However, considering that symptoms of uremia only begin to manifest in patients with severe renal dysfunction, the results of the present study suggest that factors other than impaired quality of life play a role in the development of these mental health problems. Table 3 Multivariate logistic regression analysis for depression according to eGFR categories.  Recent studies have found that systemic inflammation and oxidative stress may have direct effects on the central nervous system, resulting in a close relationship with depression and suicide. [33,34] Systemic inflammation and oxidative stress is known to be aggravated with mild reductions of renal function. [35] In addition, several uremic products are known to be elevated in patients with early CKD. Furthermore, the amino acid neurotransmitter milieu has been shown to be altered in uremic rats, suggesting that uremic toxins may act centrally and influence mental health and behavior. [36] Therefore, these factors may have a role in affecting mental health even in asymptomatic subjects whose renal function is only mildly decreased. Further investigations linking uremia-induced factors and mental health would be needed to confirm this hypothesis.
Comorbid conditions that precede renal function decline, such as DM and HTN, could also play a role in increasing the risk of depression and suicidal ideations. In this study, subjects in the lower eGFR group were more likely to be older, have HTN, or have been treated for DM, all of which are known factors that increase the risk for developing mental health problems such as depression and suicide. [37][38][39][40] Therefore, these factors may have increased the prevalence of depression and suicidal ideations among the subjects regardless of eGFR. However, eGFR was an independent risk factor for depression and suicidal ideations even after adjustments for confounding medical illnesses and behavior factors known to influence mental health. This implies that the decrease in eGFR itself may have influenced the development of depression and suicidal ideations.
Suicide is a growing medical and social problem in developing and developed countries. In Korea, the suicide rate has increased rapidly and steadily during recent years. The average rate of suicide was 9.8 per 100,000 persons in 1990, which increased to an average of 28.1 per 100,000 persons in 2012. [41,40] Along with socioeconomic factors, chronic diseases such as DM, [42] cardiovascular disease, [43] cancer, [44] and chronic obstructive pulmonary diseases are known to be risk factors for suicide. [45] Suicide is also well established as a prevalent mental health problem in patients on hemodialysis. [46,47] Sudden transition of lifestyle and deterioration of the quality of life have been implicated as factors responsible for this increased prevalence. However, little is known about the risk of suicidal ideation in patients with early CKD. Although the effect of proper management on improving the rate of suicide in patients with early CKD needs to be further investigated, the findings of this study suggest that evaluation and intervention for suicide would be needed beginning from the early stages of CKD.
This study has several limitations. First, mental health problems were assessed by using a single question, opening the possibility for misclassifications. However, single-question methods have been used as a rapid and reasonable alternative to more lengthy questionnaires in surveys involving large samples. In addition, the accuracy of detecting depression through a single-question method has been verified in a recent analysis of patients with cerebrovascular accidents. [48] Nevertheless, further investigations with more cognitive measures delineating depression in patients with CKD would be needed. Second, this study was composed of an Asian population of a developing country. The prevalence of depression and suicide has been reported to be largely dependent on ethnicity and socioeconomic environment. [49] Therefore, the findings may not be applicable to other communities. Despite these weak points, the data used in this study were obtained from a nationwide community-based cohort with a high response rate and therefore may provide information representative of the whole population. Moreover, the extensive data on potential confounders and large number of participants enabled statistical adjustments for multiple confounding factors, further strengthening the observed relationship between renal function and mental health problems.

Conclusions
In conclusion, decreased eGFR was significantly associated with depression and suicidal ideation. Furthermore, the prevalence of these mental health problems increased at a relatively early stage of CKD. Evaluation and management strategies for mental health issues should be provided throughout all stages of CKD.