, Introduction
Chronic kidney disease (CKD) is associated with multiple chronic conditions and poor outcomes [1]. High burden of comorbidities are drivers of adverse outcomes in CKD [2]. Mental health problems are increasing worldwide and exacerbating medical conditions, and contribute to increased morbidity and mortality [3–5]. The global rise in mental health disorders is associated with social, economic, and environmental problems [6]. During our lives, one in four will experience a mental health problem [7] and a meta-analysis of large-scale mental health surveys showed that the global prevalence estimate of mental disorders was 17.6% [8]. Among adults with CKD, mental health problems are prevalent but frequently underrecognized. Meta-analysis studies have reported that the prevalence of depression [9], insomnia [10], and anxiety [11] is approximately 21%, 48%, and 19% respectively in non-dialysis CKD. A cross-sectional study about mental health in 268 adults with CKD assessed by self-reported method showed that a total of 23.5% of participants had mental health problems with depression 14.5%, anxiety 14.2%, and experienced suicidal ideation 26.4% and mental health problems were associated with poorer health-related quality of life (HRQOL) [12]. The Taiwan national database reported that CKD and hemodialysis were associated with suicide [13]. A cross-sectional study of 70,079 Korean patients with ESKD reported that 28.3% of them had a mental illness, including 16.8% with depression and 20.0% with anxiety disorder according to data from the Korean National Health Insurance Services [14]. Mental health problems often coexist with non-dialysis CKD, but less is known about the effects of mental health problems on clinical outcomes in CKD [12,15].
Mental health problems of non-dialysis CKD are poorly understood and are difficult to manage for several reasons. The polythetic diagnostic criteria for mental disorders are theoretical and empirical, which contributes to heterogeneity in diagnosis [16]. Although many mental health assessment tools have been studied for their validity and reliability, there is heterogeneity and inconsistency [17]. Mental health problems such as depression, sleep disturbance, and anxiety are frequently comorbid [18] and their symptoms overlap with uremic symptoms [19]. Moreover, mental health is influenced by age, sex, socioeconomic status, and environmental factors, health care system, and which differ by various countries. Therefore, there are complicacy of mental health problems in CKD. There are a few studies of prospective observation between mental health problems and clinical outcomes in non-dialysis CKD.
Patient-reported outcome is any report of a patient’s health condition that comes directly from the patients. Patient-reported outcomes are increasingly used to inform patient-centered care and decision-making [20]. HRQOL is a questionnaire as subjective assessment of functioning and well-being across physical, psychological, and social domains. Mental disorders have been associated with reduced HRQOL [21]. To investigate the clinical importance of patient-reported mental health in adults with CKD, we analyzed a prospective cohort database from the KoreaN Cohort Study for Outcomes in Patients With CKD (KNOW-CKD). We identified patients with mental health problems using a patient-reported questionnaire that was developed and quality-controlled by the Korea National Health and Nutrition Examination Survey (KNHANES) [22]. To validate the clinical use of the KNHANES mental health questionnaire in CKD, we described the Kidney Disease Quality of Life Short Form (KDQOL-SF) score and differences according to mental health disorder. We hypothesized that poor mental health assessed by the mental health questionnaire of KNHANES can predict adverse clinical outcomes in non-dialysis CKD.
Methods
Ethics statement
This study was conducted by the principles of the Declaration of Helsinki and the study protocol was approved by the Institutional Review Board of the Kangbuk Samsung Hospital in Seoul, Korea (No. 2011-01-076-001). Written informed consents were acquired from all participants.
Study cohort
The KNOW-CKD is a prospective cohort study investigating the clinical outcomes of Koreans with non-dialysis CKD. The study design, methods, and protocol summary are detailed elsewhere [23,24]. This cohort enrolled 2,238 adults between the ages of 20 and 75 years with non-dialysis CKD stages G1 to G5 between 2011 and 2016. We excluded patients with any of the following: unwillingness to provide written consent, inability to fill in self-reported questionnaires, previous dialysis, heart failure (New York Heart Association class 3 or 4), liver cirrhosis, pregnancy, history of malignancy, or severe mental illness including schizophrenia, bipolar disorder, and major depressive disorder. We analyzed 1,879 participants from this cohort who underwent extensive laboratory tests, completed health questionnaires, and had available follow-up clinical outcomes data.
Clinical data and health-related quality of life
Baseline demographics and laboratory data were retrieved from the electronic data management system (Phacta X). Demographic characteristics, medical history, and lifestyle factors were collected from patient-reported questionnaires and a review of the medical records. Serum creatinine was measured at a central lab using an isotope dilution mass spectrometry-calibrated method. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation. Urinary albumin excretion was determined using the spot urine albumin-to-creatinine ratio (ACR). We collected the following characteristics through patient-reported questionnaires: educational level, marital status, current smoking, alcohol drinking, mental health, and physical activities using the International Physical Activity Questionnaire. HRQOL was measured using the KDQOL-SF, which is composed of 43 multidomain kidney disease component summary (KDCS) and generic 36-item health survey as physical component summary (PCS), and mental component summary (MCS) [25].
Assessment of exposure: patient-reported mental health problems
Data about mental health problems were obtained using a patient-reported mental health questionnaire from the KNHANES. We evaluated four indicators of mental health: sleep duration, perceived stress, depressive symptoms, and suicidal ideation [22]. Sleep duration was identified using the question, “How many hours do you sleep a day?” Sleep duration from 6 to 9 hours was deemed adequate, and short (5 hours) or long (≥9 hours) was deemed inadequate [26]. Perceived stress was assessed using the question, “How much stress do you feel in your daily life?” The subjective distress was those who answered “very much” or “much”; the unstressed was those who answered “a little” or “none.” Depressive symptoms were identified by a positive answer to the question, “Have you experienced sadness or despair severe enough to interfere with daily life for 2 consecutive weeks or longer in the last 12 months?” Suicidal ideation was assessed by a positive answer to the question, “Have you thought about wanting to die in the past 12 months?” We categorized the study participants into three groups by the numbers of mental health problems; adults of good, fair, and poor mental health had 0, 1, and 2 to 4 mental health problems of inadequate sleep duration, subjective distress, depressive symptom, or suicidal ideation.
Assessment of clinical outcomes: end-stage kidney disease and all-cause death
The primary outcomes of interest were incident ESKD and all-cause death during follow-up. ESKD was defined as CKD G5 requiring dialysis or kidney transplantation. The time of kidney replacement therapy and death were collected for a median follow-up of 6.4 years. Patients who reached the endpoints were reported by each center.
Statistical analysis
We described the distribution of each mental health problem by sex, age, and eGFR. KDQOL-SF is a self-reported measure developed for individuals with CKD and those on dialysis [25]. In addition, KDQOL-SF differences between groups of patients with different mental health problems were analyzed using the scaled effect size (ES) of Cohen’s d. The ES of KDQOL-SF domain differences according to the mental health groups was calculated using the following equation.
ES = (MeanKDQOL-SFgroup1 - MeanKDQOL-SFgroup2)/SDKDQOL-SFgroup1
We interpreted the ES as follows: 0.2 to 0.5 small, 0.5 to 0.8 moderate, and greater than 0.8 was considered large [27].
The cumulative event probabilities were estimated using a Kaplan-Meier analysis and log-rank tests. Cox proportional hazard models were used to investigate the association between mental health problems and clinical outcomes. The data were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Model 1 considered baseline age, sex, eGFR, and ACR. Model 2 added body mass index, serum albumin, a history of diabetes mellitus, hypertension, and cardiovascular disease. Model 3 added marital status, education status, employment, current smoking, current alcohol drinking, and health-enhancing physical activity. Because patient-reported mental health problems differed by age, sex, and eGFR, we evaluated the association between mental health, suicidal ideation, and clinical outcomes stratified by age, sex, and eGFR group. All analyses were performed using Stata version 17 (StataCorp LLC).
Results
Baseline characteristics of study participants
The baseline characteristics of the study participants are shown in Table 1 and Supplementary Table 1 (available online). All study participants are Koreans, the mean and standard deviation (SD) of age was 53 ± 12 years, 1,157 participants were males (61.6%), and the mean and SD of eGFR was 54 ± 31 mL/min/1.73 m2. The mental health problems of inadequate sleep duration (17.4%), subjective distress (27.3%), depression symptoms (13.2%), and suicidal ideation (16.8%) were common among non-dialysis CKD adults but were not well managed by psychiatric counseling (1.9%) and antidepressant therapy (2.8%). The prevalence of patient-reported mental health problems differed by sex, age, and eGFR categories (Fig. 1). Females had more mental health problems than males. Older adults (≥65 years) had fewer mental health problems than younger adults except for sleep duration. The J-shaped pattern of mental health problems was shown according to eGFR categories.
Characteristics of patient-reported mental health questionnaire
The meaningful clinical interpretation of measuring patient-reported mental health questionnaire differences between groups is to anchor those data to a relevant tool. The KDQOL-SF is a reliable and valid method for collecting individual well-being of health status in patients with CKD. We analyzed KDQOL-SF score differences between the mental health groups and the groups divided by each item using a scaled ES of Cohen’s d. Differences between good and poor mental health groups showed large ES (KDCS = 1.27, PCS = 1.13, and MCS = 1.64) (Supplementary Table 2, available online). Among the mental health items, suicidal ideation showed the largest ES (KDCS = 1.18, PCS = 1.00, and MCS = 1.33) (Supplementary Table 3, available online). Among the KDQOL-SF components, MCS showed the largest ES (Supplementary Table 4, available online). The box plot of the KDQOL-SF subscales scores shows the distributions of numeric data, which gradually decrease according to the mental health groups (Fig. 2). This suggested that the mental health questionnaire of this study was reflected in the clinical effect of mental well-being in non-dialysis CKD.
Age-specific mortality according to mental health and suicidal ideation
Crude mortality rates were 10.2 and 15.2 per 1,000 person/yr in adults with good and poor mental health, respectively, and 9.9 and 17.7 per 1,000 person/yr in adults without suicidal ideation and with suicidal ideation, respectively (Supplementary Table 5, available online). Among categories of cause of death, there was no suicide death in the study participants. The age-specific mortality rate according to mental health categories and the presence of suicidal ideation differed more in adults with younger ages than those with older ages.
Association between mental health and risk of end-stage kidney disease and death
The Kaplan-Meier curves revealed that the cumulative probabilities of ESKD and all-cause death during follow-up were higher in patients with poor mental health compared to those with good mental health (log-rank p < 0.05) (Fig. 3). Compared with the good mental health group, the adjusted HRs for ESKD were 1.03 (95% CI, 0.84–1.26) and 1.46 (95% CI, 1.18–1.80) respectively in fair and poor mental health group (model 3). The adjusted HRs for all-cause death were 0.94 (95% CI, 0.62–1.44) and 1.55 (95% CI, 1.04–2.32), respectively in fair and poor mental health group, compared with the good mental health group (model 3) (Table 2).
Association between each mental health indicator and the risk of end-stage kidney disease and death
Among the four indicators of mental health, suicidal ideation was significantly associated with adverse clinical outcomes. The Kaplan-Meier curves revealed that the cumulative probabilities of the ESKD and all-cause death were higher in adults with suicidal ideation than in adults without suicidal ideation (log-rank p < 0.05) (Fig. 3). The adjusted HRs for ESKD was 1.37 (95% CI, 1.11–1.69) in adults with suicidal ideation compared with adults without suicidal ideation (model 3). The adjusted HRs for all-cause death was 1.98 (95% CI, 1.34–2.92) in adults with suicidal ideation compared with adults without suicidal ideation (model 3) (Table 3). Investigating data linked with the national death registers to ascertain the direct causes of death in the death certification, there was no intentional self-harm in the study participants, but the uncertain cause of death showed a higher rate in adults with poor mental health than those with good mental health (Supplementary Table 6, available online).
Subgroup analysis by age, sex, and estimated glomerular filtration rate
Because mental health problems differed by age, sex, and eGFR groups, we further examined how modifying those factors affected the risk of ESKD and all-cause death. The association between poor mental health and risk of ESKD and all-cause death was higher in females and younger adults than in males and older adults (p for interaction < 0.001). The association between suicidal ideation and all-cause death was also higher in female and younger adults (p for interaction < 0.001). In the adults with advanced CKD (eGFR <45 mL/min/1.73 m2), the relationship between poor mental health or suicidal ideation and the risk of ESKD and all-cause death was consistent with that in the overall analysis (p < 0.001) (Fig. 4).
Discussion
This study has investigated the relationship of patient-reported mental health problems with clinical outcomes in adults with non-dialysis CKD. Mental health problems were prevalent and important to well-being in CKD. Poor mental health that had two or more mental health problems was associated with the risk of ESKD and death. After adjusting for confounders, those with poor mental health showed a consistent association with adverse clinical outcomes.
Mental disorders accumulate with chronic diseases [28] and mortality of comorbid chronic disease is associated with mental disorders [29]. Previous studies also reported that various psychiatric symptoms measured by heterogeneous questionnaires have been associated with poor clinical outcomes in CKD. In this study, we evaluated the mental health symptoms by four items of the KNHANES mental health questionnaire and showed the ES compared by KDQOL-SF score and predictive validity of clinical outcomes in prospective KNOW-CKD cohort. Among four items of the KNHANES questionnaire, a single question of suicidal ideation was associated with poor clinical outcomes in non-dialysis CKD.
A meta-analysis by Palmer et al. [9] showed that the prevalence of depression in patients with non-dialysis CKD was 26.5% evaluated by screening questionnaires and 21.4% by clinical interviews. Prevalence rates were similar when depression was diagnosed whether using questionnaires or clinical interviews. In this study, we assessed mental health using a patient-reported mental health questionnaire from KNHANES that inquired about sleep duration, perceived stress, depression symptoms, and suicidal ideation. A study using the KNHANES mental health questionnaire cross-sectionally showed poor mental health in chronic obstructive pulmonary disease [30], and several studies reported clinical validities in predicting clinical outcomes [31,32]. This study shows that the prevalence of poor mental health having multiple mental health problems was 19.7% and the prevalence of suicidal ideation was 16.8% (Fig. 1).
Mental disorders are chronically disabling in nature, adversely affect other medical conditions, and contribute to the burden of disease worldwide [5]. They are common and burdensome in patients with CKD. National Survey on Drug Use and Health of the United States reported that the prevalence of any mental illness in the past year was 27% in adults with CKD and only 21% of those with mental illness received any mental health treatment [33]. Despite adults with non-dialysis CKD having a high prevalence of mental health problems in this study, a small of them received psychiatric management (1.9% psychiatric counseling, 2.8% antidepressant medication). Mental health is influenced by sex and the stages of life. In the multivariable-adjusted model of demographic, socioeconomic, lifestyle factors, and comorbidities, poor mental health increased the risk of ESKD and all-cause death. Among females and young adults, poor mental health showed stronger associations with the risk of ESKD and death than among males and older adults.
Suicidality is a sensitive health problem and most people with suicidal thoughts do not attempt suicide [34]. However, suicidal ideation increases the risk of suicidal behavior. Several studies have suggested the use of Patient Health Questionnaire-9 (PHQ-9) item 9 as a universal screening instrument to identify suicide risk [35]. The PHQ-9 item 9 asks “Over the last 2 weeks, how often have you been bothered by thoughts that you would be better off dead or of hurting yourself in some way?” However, few studies have studied the effect of suicidal ideation on clinical outcomes in CKD. In our study, even though suicidal ideation was common, most of them were not managed by prevention strategies. In the multivariable adjustment model, suicidal ideation increased the risk of ESKD and all-cause. Females and young adults showed a stronger association with the risk of death than males and older adults. Mental health is influenced not only by individual factors and socioeconomic status but also by social circumstances. Risk exposures vary at all stages of life [36]. A recent study reported that elder adults are capable of resilience despite declining health [37]. We suggest that age could modify the association between clinical outcomes and mental health in subgroup analysis.
This study has several limitations. First, there are general limitations of patient-reported data, such as recall bias and nonresponse bias. Mental health problems and suicidality questions are sensitive and uncomfortable for patients. Nevertheless, computer-assisted patient-reported methods provide greater privacy to patients and 1,976 of the total participants (88.3%) responded to the questionnaire. Second, the KNHANES mental health questionnaire was just used in community-dwelling Korean adults and was not standardized and validated in CKD. In this study, we confirmed this mental health questionnaires had large ES in each item and were clinically meaningful methods for mental health in adults with CKD. Third, mental health is influenced by individual risk, socioeconomic determinants, and environmental factors. The causes of suicidal ideation are various and uncertain. Thus, this study contains unknown and unmeasured potential confounders such as personal life events, social relationships, inequality, and discrimination. Finally, the mental health care system has wide variation and different cultures across countries. It might thus be difficult to generalize our results to all patients with CKD.
Despite those limitations, our study has several strengths. We used comprehensive health history and clinical data from the KNOW-CKD cohort. We found that multiple mental health problems and suicidal ideation were common and that mental health was connected with clinical outcomes. The single question about suicidal ideation could predict the risk of ESKD and all-cause death in non-dialysis CKD. The mental health problems are often overlooked. Nephrology providers should be aware of the impact of mental health concerns and be prepared to screen their patients regularly for those concerns. More research is needed to evaluate comprehensive mental health, develop management strategies, and provide evidence for practical guidelines [38].
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