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Depressive Symptoms in Older Adults with Chronic Kidney Disease: Mortality, Quality of Life Outcomes, and Correlates
Depressive Symptoms in Older Adults with Chronic Kidney Disease: Mortality, Quality of Life Outcomes, and Correlates Liang Feng, Ph.D., Keng Bee Yap, M.Med., Tze Pin Ng, M.D.
Objective: Among patients with chronic kidney disease (CKD), we investigated the prevalence of depressive symptoms, their impact on mortality and quality of life, and correlates of depressive symptoms. Design: Prospective cohort study, followed up to 4 years. Setting: General community. Participants: A total of 362 older adults with CKD (Stages 3 and 4 assessed from estimated glomerular filtration rate [eGFR]) drawn from the Singapore Longitudinal Aging Study cohort. Measurements: Scores on the Geriatric Depression Scale (GDS) and the prevalence of depressive symptoms (GDS 5) and other variables were assessed at baseline, and SF-12 quality of life (QOL) (at 2 years) and mortality determined from 4 years of follow-up. Results: Depressive symptoms were present in 13% of the participants at baseline, and were associated with poorer SF-12 QOL scores (up to 30 percentage point differences). There was a significant association between depressive symptoms and increased mortality risk (odds ratio: 3.17; 95% confidence interval: 1.17e8.61; c2 ¼ 5.11; df ¼ 1; p ¼ 0.023), which was statistically significant in unadjusted analysis, but not in multivariate analysis that accounted for covariates (odds ratio: 2.62; 95% confidence interval: 0.77-8.89; c2 ¼ 2.37; df ¼ 1; p ¼ 0.13). Baseline cognitive impairment, functional disability, and other chronic illness were significantly associated with both increasing GDS scores and depressive symptoms. No relationship between eGFR and depressive symptoms was observed. Conclusion: Depression among individuals with CKD was significantly associated with poorer quality of life, but not with increased mortality in predialysis CKD patients. More prospective studies are needed to establish the effects of depression on adverse CKD outcomes in predialysis CKD patients. (Am J Geriatr Psychiatry 2013; 21:570e579) Key Words: Chronic kidney disease, cognitive impairment, depression, mortality, quality of life, risk factors
C
hronic Kidney disease (CKD) is an important public health problem in older populations. The prevalence of CKD increases with older age and
approximately half of all new cases of end-stage renal disease (ESRD) are older adults age 60 years and older.1,2 CKD is known to be associated with
Received November 16, 2010; revised November 27, 2011; accepted December 27, 2011. From the Gerontological Research Programme (LF, TPN) and Department of PsychologicalMedicine (LF, TPN), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Department of Geriatric Medicine, Alexandra Hospital, Singapore (KBY). Send correspondence and reprint requests to Tze-Pin Ng, M.D., Gerontological Research Programme, Department of Psychological Medicine, National University of Singapore, NUHS Tower Block, 9th Floor, 1E Kent Ridge Road, Singapore 119228. e-mail: [email protected] Ó 2013 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2012.12.020
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Feng et al. increased risks of mortality, cardiovascular event, and hospitalization.3 CKD is classified into 5 stages: Stage 1, kidney damage with normal or relatively high glomerular filtration rate (GFR) (90 mL/minute/1.73 m2); Stage 2, mild reduction in GFR (60e89 mL/minute/1.73 m2) with kidney damage; Stage 3, moderate reduction in GFR (30e59 mL/minute/1.73 m2); Stage 4, severe reduction in GFR (15-29 mL/minute/1.73 m2); and Stage 5, established kidney failure (GFR <15 mL/ minute/1.73 m2). Major depression or depressive symptoms is commonly associated with late-stage CKD. The reported point estimates varied from 15% to 45% for patients with ESRD or dialysis populations,4e7 and is highest in older patients. However, there are few published data on the prevalence of depressive symptoms in patients with earlier stage CKD before dialysis therapy initiation.8,9 Studies of patients with ESRD have shown that depression contributed to adverse outcomes including increased risks of mortality, hospitalization, cardiovascular events,10,11 peritonitis,4 and poor dialysis adherence.12,13 Physician-diagnosed depression or depressive symptoms was reportedly associated with poorer self-rated quality of life among both patients with ESRD and patients with CKD.14,15 The association between depression and poor outcomes in patients with CKD may be explained by biological factors such as altered autonomic tone16 and systemic inflammation.17 The risk factors and correlates of depression in CKD patients reportedly include younger age, female sex, low income, social support, marital satisfaction,4,13,18,19 and comorbid medical conditions including cardiac diseases, diabetes, and hypertension.4,6,20 In dialysis populations, depression has been reported to be correlated with low hemoglobin, low albumin, and C-reactive protein.7,21 The evidence for an association of the level of renal function measured by estimated glomerular filtration rate [eGFR] with depression is equivocal. A study of renal transplant patients22 reported that an increase in eGFR was associated with lower risk of depression, but other studies have failed to observe an association.8,23 No studies have investigated the association of cognitive impairment with depression in CKD patients, although this association is well studied in general populations of older adults.24
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The bulk of findings described earlier have been reported in studies of ESRD or dialysis patients. There is a dearth of population-based and longitudinal studies of older persons with earlier stage CKD not on dialysis therapy. A better understanding of the burden, correlates, and impact of depression in elderly populations with CKD has important implications for reducing morbidity and mortality, and improving quality of life. We conducted a population-based prospective study of 362 older adults with CKD (Stages 3 and 4) who were drawn from a cohort in the Singapore Longitudinal Aging Study. In this study population, we aimed to examine the baseline prevalence of depressive symptoms and its association with mortality and quality of life outcomes from 4 years of follow-up. We hypothesized that depressive symptoms among individuals with CKD would be associated with poorer quality of life and higher mortality risk. We also explored the significant correlates of depressive symptoms in older adults with CKD.
METHODS Study Population The participants in this study were drawn from cohort members in the Singapore Longitudinal Aging Study, a 4-year prospective study of aging and health among community-dwelling older adults resident in five districts in South East Region of Singapore. The baseline assessment began in 2004e2005, with subsequent interviews conducted at 2-yearly intervals. Details of the study design and subject recruitment have been published elsewhere.25 Briefly, the eligible population consisted of all persons age 55 years and older, who were Singaporean citizens or permanent residents. Individuals with serious physical or mental illnesses that rendered them incapable of participating were excluded. A total of 2,804 participants were enrolled into the study. At baseline, information on a wide range of demographic, biological, clinical, psychosocial, and behavioral characteristics were collected via interviews and assessments conducted in English, Chinese, or Malay by trained research nurses. The study was approved by the National University of Singapore Institutional Review Board, and informed consent was obtained from all participants.
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Depressive Symptoms in Older Adults With Chronic Kidney Disease Individuals with CKD, based on their eGFR results and restricted to those with Stage 3 and 4 diseases, were identified from the 2,804 participants at baseline. Among the 494 participants who had Stage 3 and 4 CKD (eGFR between 15 and 60 mL/minute/ 1.73 m2), 362 participants who had at least one repeat assessment for depressive symptoms from the follow-ups constituted the analytical sample in this study. Compared with the 362 patients, those excluded from the analysis (n ¼ 132) were significantly (p <0.05) older, were more likely to report depressive symptoms and poor cognitive and physical health, were more likely to live in lower end housing, and had lower hemoglobin concentrations. Measurements Kidney Function. eGFR was calculated using the Modification of Diet in Renal Disease formula, which is based on baseline age, gender, race, and serum creatinine concentration.26 Serum creatinine was measured by an enzymatic creatinine method calibrated to the NIST LC-IDMS method recommended by the National Kidney Disease Education Programme and traceable to NIST SRM967. Depressive Symptoms. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15),27 which has been validated for use in local Chinese, Malay, and Indian subjects.28,29 The internal reliability coefficient (Cronbach’s a) was 0.84. Scores on the scale range from 0 to 15, with higher scores indicating greater severity. In this population, the presence of depressive symptoms was denoted by a GDS score of 5 and more, which has been shown to have high sensitivity (97%) and specificity (95%) in identifying cases of major depressive disorder from structured diagnostic interview with SCID.28 Depressive symptoms assessed at all three time points (baseline, 2-year, and 4-year) were used in the data analysis. Quality of Life. Quality of life was assessed by SF12,30 a shorter version of the SF-36, and its reliability and validity have been documented. Summary measures (PCS-12/MCS-12) were calculated using the standard SF-12 items and regression weights. Scores were transformed to have a mean (SD) of 50 (10) in the U.S. general population, which is the recommended scoring for intercountry comparability. Scale scores were estimated for PF (physical
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function), RE (role emotional), RP (role physical), and MH (mental health) using 2 items each; and BP (body pain), GH (general health),VT (vitality), and SF (social function), represented by a single item each. All the raw scale scores were transformed to a 0 to 100 scale, with a higher score reflecting better quality of life. Available quality of life data obtained at baseline and follow-up at 2 years were used in this study. Medical Illnesses. Medical illnesses were based on self-reported history of chronic diseases in a checklist over the previous 12 months, which was corroborated by the use of specific medications (visually verified from medication packages). The presence of hypertension was defined by self-report of hypertension with antihypertensive medication use, or blood pressure measurement (untreated hypertension); diabetes mellitus was defined by self-report of diabetes on antidiabetic medications, or by elevated fasting blood sugar (untreated diabetes); myocardial infarction, atrial fibrillation, and congestive heart failure from self-report, ECG evidence, and/or use of appropriate medications; stroke from self report of stroke or transient ischemic attack. Participants were classified to have cardiovascular diseases or stroke if they have any one of the following conditions comprising heart attack, atrial fibrillation, congestive heart failure, and stroke. Other than diabetes, hypertension, and cardiovascular disease or stroke, other comorbid illnesses were defined as the sum total of number of, and included history of cataracts, glaucoma, and eye diseases, asthma, chronic obstructive pulmonary disease, arthritis, hip fracture, cancer, and other problems (e.g., thyroid disorders, gastrointestinal and liver, gynecologic, neurologic, etc.). Cognitive Function. Global cognitive function was measured by Mini-Mental State Examination.31 The local translated versions of the instrument has been validated for local use in Singaporean older adults,32 with the conventional cutoff of 23/24 used to determine cognitive impairment. Functional Disability. Functional disability was assessed by self-reported measures of instrumental and basic activities of daily living (IADL and BADL).33,34 BADLs include bowels, bladder, grooming, toilet use, feeding, transferring, mobility, dressing, stairs, and bathing, and IADLs consist of performance in using telephone, traveling, shopping, preparing meals, house work, taking medicine, and
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Feng et al. managing money. We defined functional impairment as present if the respondent reported difficulty with one or more of these activities in ADL or IADL scale. In this study, a categorical variable with three classes was defined on the basis of BADL and IADL: noBADL or IADL disability, IADL disability alone, BADL disability. Other Variables. Other variables measured at baseline included demographic characteristics (age, gender, education, marital status, ethnicity, housing type [a proxy for income]), hemoglobin (measured by light scattering flow cytometry, cytochemistry, and microscopy), serum albumin (measured by bromcresol green dye binding method), smoking, and physical activities.
Generalized Estimating Equation was used to identify factors that were correlated with the presence of depressive symptoms, and was analyzed by SAS PROC Genmod. The mean response variable of depressive symptoms was modeled as logistic regression and we assumed an exchangeable working correlation. There was no significant interaction between time and any covariates for both mixed-effects modeling and Generalized Estimating Equation modeling. A p value of less than 0.05 was used to evaluate statistical significance. All analyses were performed using SAS 9.2 software. (SAS Institute, Inc., Cary, NC)
RESULTS Statistical Analysis GDS scores of depression were analyzed as a continuous variable, and GDS score of 5 and more (depressive symptoms) as a categorical variable in bivariate and multivariate analyses. Group differences were compared by t-tests for continuous variables and c2 tests for categorical variables. Variables with p <0.25 from bivariate analyses or those known to be clinically relevant were included in multivariate models. These variables included age, gender, marital status, housing type, functional status, diabetes, hypertension, cardiovascular disease, other illnesses, cognitive impairments, smoking, physical activity, eGFR, albumin, and hemoglobin. Antidepressant usage was not controlled for because only 2 patients with depressive symptoms were on drug treatment. Multiple logistic regression was performed to determine the association of baseline depressive symptoms with cumulative mortality. ANCOVA (analysis of covariance) was used to examine the relationship between baseline depressive symptoms and quality of life at 2-year follow-up. Adjusted mean scores of each subscale of SF-12 were compared by depressive symptoms, and Bonferroni correction was utilized to control the probability of false positive results from these small subsets of multiple comparisons. We used linear mixed-effects model by SAS PROC MIXED procedure to explore correlates of depression score and compound symmetry was chosen as covariance structure. Analysis using
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Of the original 494 individuals with Stage 3 and 4 CKD, 12.8% (N ¼ 63) had depressive symptoms at baseline. In the analytical sample of 362 participants who had repeated measures of depressive symptoms at follow-up, the proportion was 11.2% (N ¼ 42). At baseline, the average eGFR was 51.0 8.3 mL/ minute/1.73 m2. The mean age of the patients was 70.3 7.8 years; 42.4% was male. The prevalence of diabetes was 21.6%, cardiac or cerebrovascular (stroke) diseases, 19.3%; hypertension, 75.7%; and ADL disability, 6.2% (Table 1). Compared with nondepressed patients at baseline, depressed patients were more likely to report functional disability, cognitive impairment, lower Physical Component Score and Mental Component Score quality of life scores and had higher proportion of mortality. There were no significant differences between depressed and nondepressed participants in other baseline characteristics (Table 1). A total of 22 (6.1%) participants died during the 4-year follow-up period. The unadjusted and adjusted associations between baseline depressive symptoms and mortality over the follow-up are shown in Table 2. Depressed patients at baseline were at greater risk of death, based on bivariate association (odds ratio [OR]: 3.17; 95% confidence interval: 1.17e8.61; c2 ¼ 5.11; df ¼ 1; p ¼ 0.023), although the adjusted OR of association (OR: 2.62; 95% confidence interval: 0.77e8.89; c2 ¼ 2.37; df ¼ 1; p ¼ 0.13) was not significant in multivariate analyses. The relationships between depressive symptoms at baseline and quality of life at first follow-up were
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Depressive Symptoms in Older Adults With Chronic Kidney Disease
TABLE 1. Baseline Characteristics and Outcomes of CKD Patients by Depressive Symptoms (N [ 362)
Baseline variables Demographics Age, mean (SD) Male Education Primary and below Secondary and above Marital status Married others Ethnicity Chinese Others Housing type <3 rooms 3 rooms Clinical variables and life style Functional status Independent Only IADL dependent ADL dependent or both Diabetes Hypertension Cardiovascular disease or stroke Other illnesses 0 and 1 2 Cognitive impairment Smoking Never Current smoker Physical activities Never Sometimes or often Laboratory values Hemoglobin (mg/dL), mean (SD) Serum albumin (g/L),mean (SD) eGFR (mL/minute/1.73 m2), mean (SD) Outcomes PCS-12, mean (SD) MCS-12, mean (SD) Mortality
Depressed (N [ 42)
Nondepressed (N [ 320)
t-test (df)/c2(df)
pa
71.6 (7.9) 16 (38.1)
70.1 (7.8) 138 (43.1)
1.18 (360) 0.38 (1) 0.43 (1)
0.24 0.53 0.51
26 (61.9) 16 (38.1)
181 (56.6) 139 (43.4) 2.84 (1)
0.09
24 (57.1) 18 (42.9)
224 (70.0) 96 (30.0) 0.20 (1)
0.65
40 (95.2) 2 (4.8)
299 (93.4) 21 (6.6) 3.37 (1)
0.066
17 (40.5) 25 (59.5)
86 (26.9) 234 (73.1) 15.37 (2)
<0.001
21 13 8 11 31 11
220 81 14 67 243 59
(50.0) (31.0) (19.1) (26.2) (73.8) (26.2)
(69.8) (25.7) (4.4) (20.9) (75.9) (18.4)
20 (47.6) 22 (52.4) 10 (23.8)
195 (60.9) 125 (39.1) 34 (10.6)
37 (88.1) 5 (11.9)
301 (94.4) 18 (5.6)
26 (61.9) 16 (38.1)
164 (51.3) 156 (48.9)
0.61 0.09 1.43 2.73
(1) (1) (1) (1)
0.44 0.76 0.23 0.10
6.04 (1) 2.46 (1)
0.014 0.12
1.77 (2)
0.19
13.0 (1.6) 41.7 (3.8) 48.6 (9.9)
13.6 (1.6) 42.0 (3.3) 51.3 (8.1)
2.01 (360) 0.56 (360) 1.95 (360)
0.05 0.58 0.05
40.6 (9.6) 43.6 (10.1) 6 (14.2)
47.7 (7.3) 54.6 (7.5) 16 (5.0)
4.64 (47.6) 6.8 (47.3) 5.61 (1)
<0.001 <0.001 0.023
Notes: PCS: Physical Component Score; MCS: Mental Component Score. a Determined by c2 tests or t-tests.
TABLE 2. Unadjusted and Adjusteda Association Between Baseline Depressive Symptoms and Mortality Over 4 Years
Baseline Not depressed Depressed
Unadjusted
Adjusted
Mortality (n Case/N Total)
OR (95% CI)
c (df)
p
OR (95% CI)
c2(df)
p
16/320 6/42
1.00 3.17 (1.17-8.61)
5.11 (1)
0.023
1.00 2.62 (0.77-8.89)
2.37 (1)
0.13
2
Notes: 95% CI: confidence interval. a Adjusted for baseline age, gender, marital status, housing type, functional status, cognitive impairments, diabetes, hypertension, cardiovascular disease, other illnesses, smoke, physical activities, eGFR, albumin and hemoglobin.
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TABLE 3. Mean Quality of Life at First Time Follow-up by Depressive Status at Baseline (N [ 315) Depressed
Physical component score Mental component score Physical function domain Role emotional domain Role physical domain Body pain domain General Health Vitality Social function Mental Health
Nondepressed
Mean
SD
Mean
SD
44.9 46.9 81.7 68.1 58.3 74.3 42.4 54.9 72.2 65.3
8.44 10.77 34.83 44.96 51.40 27.04 13.12 33.38 29.14 26.46
49.8 55.1 87.4 90.7 87.4 84.9 49.6 70.6 91.3 84.2
6.06 6.10 23.49 27.31 31.26 19.38 15.37 21.73 19.54 15.37
F-testa (df) 6.91 12.60 2.52 4.46 10.44 5.53 1.35 5.41 8.77 17.59
(1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294)
h
pb
c 2
0.009 <0.001 0.11 0.036 0.001 0.019 0.25 0.021 0.003 <0.001
0.015 0.030 0.009 0.015 0.034 0.018 0.005 0.018 0.029 0.056
a
Adjusted for baseline quality of life, age, gender, marital status, housing type, functional status, cognitive impairment, diabetes, hypertension, cardiovascular disease, other illnesses, smoke, physical activities, eGFR, albumin, and hemoglobin. b The significant level is 0.005 after Bonferroni correction for multiple comparisons. c 2 h : effect size.
explored in ANCOVA models. The adjusted mean scores for SF-12 component scale scores and individual domain scores are shown in Table 3. The mean summary score of MCS-12 (F[1, 294] ¼ 12.60; p <0.001), and domain score of RP (F[1, 294] ¼ 10.44; p ¼ 0.001), SF (F[1, 294] ¼ 8.77; p ¼ 0.003), and MH (F[1, 294] ¼ 17.59; p <0.001), in patients with depressive symptoms were significant lower than in nondepressed patients. The mean score difference was not significant with regard to other domains, after Bonferroni correction. As shown in Table 4, baseline cognitive impairment (t ¼ 3.07; df ¼ 338; p ¼ 0.002), functional disability (t ¼ 0.52; df ¼ 327; p ¼ 0.602 for only IADL independent; t ¼ 4.20; df ¼ 334; p <0.001 for ADL dependent), and other chronic illnesses (t ¼ 2.45; df ¼ 323; p ¼ 0.015) were each independently associated with increasing GDS depression scores repeated over follow-up, whereas other variables including eGFR, albumin, hemoglobin, and diabetes did not show significant associations. In multivariate analyses of depressive symptoms (GDS 5) during follow-up as dependent variable, the significant baseline variables were ADL disability (c2 ¼ 0.34; df ¼ 1; p ¼ 0.56 for only IADL independent; c2 ¼ 16.49; df ¼ 1; p <0.001 for ADL dependent), increased number of chronic illnesses (c2 ¼ 4.41; df ¼ 1; p ¼ 0.03), and housing category (c2 ¼ 3.95; df ¼ 1; p ¼ 0.046). There was a nonsignificant association of cognitive impairment with depressive symptoms (c2 ¼ 3.21; df ¼ 1; p ¼ 0.07). Other
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variables including eGFR were not correlated with depressive symptoms.
DISCUSSION In this study of older Asian adults with Stage 3 and 4 CKD, we observed that about 13% had depressive symptoms and that their presence contributed to poorer quality of life on follow-up. Baseline cognitive impairment, functional disability, and chronic illnesses were significant risk factors associated with increasing number of depressive symptoms or the presence of significant depressive symptoms (5GDS depression symptoms). Although our observed prevalence of depressive symptoms appears high, it was still relatively lower compared with those reported in other studies of CKD patients prior to dialysis.8,9 Using the Beck Depression Inventory, Andrade et al.9 reported a prevalence of 37.7% in nondialysis patients with CKD, whereas Hedayati et al.,8 using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) reported that the prevalence of major depression was 21% in predominantly male patients with Stage 2e5 CKD. Heterogeneity in study populations, assessment tools for depression, and the presence of comorbid conditions are likely to contribute to these observed variations.35 In this study, we failed to demonstrate that the presence of depressive symptoms among our CKD
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Notes: Multivariate regression via random effects models and Generalized Estimating Equation approach, based on evaluable data; percentage of missing data on GDS scores was 10% at first follow-up and 39% at second follow-up. Variables in the models include: follow-up duration (in years), age, gender, marital status, housing type, functional status, cognitive impairment, diabetes, hypertension, cardiovascular diseases, other illnesses, smoke, physical activities, eGFR, albumin, and hemoglobin. B: unstandardized regression coefficeient. SE: standard error; 95% CI: confidence interval.
0.046 3.95 (1) Referent 0.57 (0.31e1.00) 0.009 6.76 (1) Referent 0.45 (0.25e0.82)
Referent Referent (327) 0.602 1.61 (0.85e3.07) 2.13 (1) 0.14 1.24 (0.61e2.51) 0.34 (1) 0.56 (334) <0.001 6.48 (2.76e15.25) 18.36 (1) <0.001 6.32 (2.60e15.38) 16.49 (1) <0.001 (345) 0.078 2.22 (0.88e5.58) 2.82 (1) 0.09 2.61 (0.77e8.81) 2.38 (1) 0.12 (323) 0.015 1.35 (1.04e1.74) 5.11 (1) 0.024 1.36 (1.02e1.82) 4.41 (1) 0.03 0.52 4.20 1.77 2.45
0.52 0.07 0.42 (1) 3.21 (1) 0.037 1.01 (0.98e1.05) 0.008 1.94 (0.94e4.01) 4.32 (1) 7.10 (1) 0.26 0.97 (0.94e0.99) 0.002 2.63 (1.29e5.37) 1.12 (333) 3.07 (338)
t-test (df) B (SE) p t-test (df) B (SE)
eGFR 0.0187 (0.01) 1.55 (347) 0.12 0.0143 (0.01) Cognitive impairment 1.1883 (0.30) 3.92 (357) <0.001 0.9880 (0.32) Functional status Independent Referent Referent Only IADL dependent 0.3534 (0.23) 1.57 (346) 0.12 0.1263 (0.24) ADL dependent or both 1.8642 (0.41) 4.50 (348) <0.001 1.7733 (0.42) Current smoker 0.7727 (0.41) 1.86 (362) 0.063 0.7434 (0.42) Number of other illnesses 0.2546 (0.10) 2.66 (337) 0.008 0.2354 (0.10) Housing type <3 rooms 3 rooms
c2 (df) OR (95% CI)
c (df)
p
Adjusted
Depression Score Unadjusted
TABLE 4. Correlates of Depression Scores and Depressive Symptoms
Adjusted
p
OR (95% CI)
2
Unadjusted
Depressive Symptoms (GDS ‡5)
p
Depressive Symptoms in Older Adults With Chronic Kidney Disease participants was significantly associated with mortality risk. The death rate in both depressed and nondepressed group may be too small to detect a significant association. The recent findings in a similar nondialysis CKD population36 also failed to demonstrate a significantly elevated mortality risk associated with depression, although this association has been consistently reported in studies of patients with ESRD or on dialysis.10,37 In line with previous studies of patients with CKD and ESRD,14,15 we observed that depressive symptoms were associated with poorer quality of life as measured by the mental and physical component scores of SF-12. The impact of depression on quality of life appeared substantial, judging from up to 30 percentage point differences in quality of life scores. A number of different mechanisms have been suggested to explain the relationship between depressive symptoms and adverse outcomes in individuals with CKD. There is some evidence to suggest that depression may be associated with factors that could predispose patients to develop cardiac disease, such as lower heart rate variability,16 increased cortisol and norepinephrine excretion,38 and alteration in immunologic and stress responses.17,39 Depression is also associated with poorer nutrition40 and leads to upregulation of inflammatory mediators.41 However, we found that the association between depressive symptoms and quality of life was independent of cardiac disease and nutritional factor (as indicated by albumin). Finally, the negative impact of depression could be due to reduced compliance with medical regimens.42 Decreased behavioral adherence is consequently associated with decreased survival.43 The effect of depressive symptoms on quality of life in individuals with CKD suggest the potential usefulness of screening for depressive symptoms to improve outcome among earlier stage CKD patients before dialysis therapy initiation. We observed that cognitive impairment, ADL disability, number of other illnesses, and socioeconomic status were significant independent correlates of depressive symptoms (GDS 5) or depression score among the CKD participants. These correlates of depressive symptoms are well established in the general population of older adults.44,45 The association between cognitive impairment and depressive symptoms has not been reported in previous studies of CKD patients, and although well studied in general
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Feng et al. populations of older adults,24 their relationship and responsible mechanisms are less well understood in CKD patients. Cognitive impairment may be both an epiphenomenon of depression as well as the result of CNS neuronal dysfunction, possibly due to neurotoxic metabolites such as homocysteine,46,47 which is commonly elevated in CKD. Also, hypercortisolemia in persons with depression has been shown to be associated with memory impairment.48 Depressive symptoms have been reported to be associated with diabetes and cardiac disease in previous studies.4,8 This association was not observed in this study, but this is perhaps not surprising, considering the smaller representation of diabetes (22%) and cardiac diseases (16.0%) in our study population. Previous studies4 have examined hemodialysis patients, and this may explain the larger negative impact of diabetes and depression on their patients. A noteworthy negative finding is the observed lack of relationship between kidney function assessed by eGFR and depressive symptoms. This finding corroborates other findings that the prevalence of major depression diagnosis or depressive symptoms (using Beck Depression Inventoryscores) did not differ across different CKD Stages 1e5 in patients with CKD who were not treated by dialysis.8,23 There is thus evidently no direct relationship between eGFR and depression. The possible explanations include a lack of clear symptoms and of patient awareness of kidney disease during CKD progression, even in patients with moderate to advanced CKD.8,23 The presence of diabetes, hypertension, and atherosclerotic vascular and cardiac diseases, which are common causes or comorbidities of CKD, are also likely to be comediating causes of depression in individuals with CKD.49 This study has limitations. First, depressive symptoms were assessed by GDS, which is not tantamount to a clinical diagnosis of depression. Second, although prospective design was used to
investigate correlates of depressive symptoms, causal relationships cannot be inferred, because depressive symptoms defined by GDS may vary over time. It remains uncertain whether depressive symptoms precede or follow the correlates. Finally, around 27% (n ¼ 132) patients were eliminated from the analysis because of missing data for all follow-up. Given the higher prevalence of depressive symptoms and poorer physical and cognitive functions of these excluded participants, this could have lead to some underestimation of the actual association. Our data thus suggest that depressive symptoms reduced quality of life in predialysis older CKD patients, but were not conclusive in demonstrating an association with increased mortality risk. Physical functional disability, higher number of medical illnesses, and cognitive impairment were significant risk factors or correlates of increasing numbers of depressive symptoms and depressive symptoms denoting clinical depression. As depressive symptoms and major depression are amenable to treatment, more studies are warranted. The study is supported by a research grant 03/1/21/ 17/214 from the Biomedical Research Council, Agency for Science, Technology and Research (A*STAR). There are no other agreements of authors or their institutions that could be seen as involving a financial interest in this work. Dr. Feng performed the literature review, formulated the hypothesis, analyzed the data, and drafted and revised the manuscript. Mr. Yap participated in the conceptualization of the study, the interpretation of the results, and review of the manuscript. Dr. Ng conceptualized the study, designed the epidemiologic survey, interpreted the results, and reviewed and revised the manuscript. No commercial company sponsored or played any role in the design, methods, subject recruitment, data collections, analysis, and preparation of article. The authors declare no conflicts of interest.
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3. Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296e1305 4. Lopes AA, Bragg J, Young E, et al: Dialysis Outcomes and Practice Patterns Study (DOPPS): Depression as a predictor of mortalityand hospitalization among hemodialysis patients in the United States and Europe. Kidney Int 2002; 62:199e207
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Depressive Symptoms in Older Adults With Chronic Kidney Disease 5. Walters BA, Hays RD, Spritzer KL, et al: Health-related quality of life, depressive symptoms, anemia, and malnutrition at hemodialysis initiation. Am J Kidney Dis 2002; 40:1185e1194 6. Hedayati SS, Grambow SC, Szczech LA, et al: Physician-diagnosed depression as a correlate of hospitalizations in patients receiving long-term hemodialysis. Am J Kidney Dis 2005; 46:642e649 7. Ibrahim S, El Salamony O: Depression, quality of life and malnutrition-inflammation scores in hemodialysis patients. Am J Nephrol 2008; 28:784e791 8. Hedayati SS, Minhajuddin AT, Toto RD, et al: Prevalence of major depressive episode in CKD. Am J Kidney Dis 2009; 54:424e432 9. Andrade CP, Cruz MC, Urrutia M, et al: Evaluation of depressive symptoms in patients with chronic renal failure. J Nephrol 2010; 23:168e174 10. Boulware LE, Liu Y, Fink NE, et al: Temporal relation among depression symptoms, cardiovascular disease events, and mortality in end-stage renal disease: contribution of reverse causality. Clin J Am Soc Nephrol 2006; 1:496e504 11. Hedayati SS, Bosworth HB, Briley LP, et al: Death or hospitalization of patients on chronic hemodialysis is associated with a physician-based diagnosis of depression. Kidney Int 2008; 74: 930e936 12. Kaveh K, Kimmel PL: Compliance in hemodialysis patients: multidimensional measurements in search of a gold standard. Am J Kidney Dis 2001; 37:244e266 13. Lopes AA, Albert JM, Young EW, et al: Screening for depression in hemodialysis patients: associations with diagnosis, treatment, and outcomes in the DOPPS. Kidney Int 2004; 66:2047e2053 14. Kalender B, Ozdemir AC, Dervisoglu E, et al: Quality of life in chronic kidney disease: effects of treatment modality, depression, malnutrition and inflammation. Int J Clin Pract 2007; 61:569e576 15. Cukor D, Coplan J, Brown C, et al: Course of depression and anxiety diagnosis in patients treated with hemodialysis: a 16month follow-up. Clin J Am Soc Nephrol 2008; 3:1752e1758 16. Carney RM, Blumenthal JA, Stein PK: Depression, heart rate variability, and acute myocardial infarction. Circulation 2001; 104:2024e2028 17. Otte C, Neylan TC, Pipkin SS, et al: Depressive symptoms and 24hour urinary norepinephrine excretion levels in patients with coronary disease: findings from the Heart and Soul Study. Am J Psychiatry 2005; 162:2139e2145 18. Daneker B, Kimmel PL, Ranich T, et al: Depression and marital dissatisfaction in patients with end-stage renal disease and in their spouses. Am J Kidney Dis 2001; 38:839e846 19. Dobbels F, Skeans MA, Snyder JJ, et al: Depressive disorder in renal transplantation: an analysis of Medicare claims. Am J Kidney Dis 2008; 51:819e828 20. Hedayati SS, Bosworth HB, Kuchibhatla M, et al: The predictive value of self-report scales compared with physician diagnosis of depression in hemodialysis patients. Kidney Int 2006; 69:1662e1668 21. Kalender B, Ozdemir AC, Koroglu G: Association of depression with markers of nutrition and inflammation in chronic kidney disease and end-stage renal disease. Nephron Clin Pract 2006; 102:c115ec121 22. Szeifert L, Molnar MZ, Ambrus C, et al: Symptoms of depression in kidney transplant recipients: a cross-sectional study. Am J Kidney Dis 2010; 55:132e140 23. Cohen SD, Patel SS, Khetpal P, et al: Symptoms of depression in kidney transplant recipients: a cross-sectional study. Clin J Am Soc Nephrol 2007; 2:919e925 24. Potter GG, Steffens DC: Contribution of depression to cognitive impairment and dementia in older adults. Neurologist 2007; 13: 105e117
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25. Ng TP, Niti M, Chiam PC, et al: Prevalence and correlates of functional disability in multiethnic elderly Singaporeans. J Am Geriatr Soc 2006; 54:21e29 26. Levey AS, Coresh J, Greene T, et al: Chronic Kidney Disease Epidemiology Collaboration: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006; 145:247e254 27. Yesavage J: Geriatric Depression Scale. Psychopharmacol Bull 1988; 24:709e711 28. Nyunt MS, Fones C, Niti M, et al: Criterion-based validity and reliability of the Geriatric Depression Screening Scale (GDS-15) in a large validation sample of community-living Asian older adults. Aging and Mental Health 2009; 13:376e382 29. Broekman BF, Nyunt SZ, Niti M, et al: Differential item functioning of the Geriatric Depression Scale in an Asian population. J Affect Disord 2008; 108:285e290 30. Ware JE, Kosinski M, Keller SD: SF-12Ò: How to Score the SF-12Ò Physical and Mental Health Summary Scales. 3rd ed. Lincoln, RI: QualityMetric Incorporated, 1998 31. Folstein MF, Folstein SE, McHugh PR: Mini-mental state. J Psychiatr Res 1975; 12:189e198 32. Ng TP, Niti M, Chiam PC, et al: Ethnic differences in cognitive performance on Mini-Mental State Examination in Asians. Am J Geriatr Psychiatry 2007; 15:130e139 33. Lawton MP, Brody EM: Assessment of older people: selfmaintaining and instrumental activities of daily living. Gerontologist 1969; 9:179e186 34. Mahoney FI, Barthel DW: Functional evaluation: the Barthel Index. Md State Med J 1965; 14:61e65 35. Hedayati SS, Finkelstein FO: Epidemiology, diagnosis, and management of depression in patients with CKD. Am J Kidney Dis 2009; 54:741e752 36. Hedayati SS, Minhajuddin AT, Afshar M, et al: Association between major depressive episodes in patients with chronic kidney disease and initiation of dialysis, hospitalization, or death. JAMA 2010; 303:1946e1953 37. Kimmel PL, Peterson RA, Weihs KL, et al: Multiple measurements of depression predict mortality in a longitudinal study of chronic hemodialysis outpatients. Kidney Int 2000; 57:2093e2098 38. Otte C, Marmar CR, Pipkin SS, et al: Depression and 24-hour urinary cortisol in medical outpatients with coronary heart disease: the Heart and Soul Study. Biol Psychiatry 2004; 56:241e247 39. Empana JP, Sykes DH, Luc G: Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2005; 111:2299e2305 40. Bonnet F, Irving K, Terra JL, et al: Anxiety and depression are associated with unhealthy lifestyle in patients at risk of cardiovascular disease. Atherosclerosis 2005; 178:339e344 41. Miller AH, Maletic V, Raison CL: Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65:732e741 42. Ziegelstein RC, Fauerbach JA, Stevens SS, et al: Patients with depression are less likely to follow recommendations to reduce cardiac risk during recovery from a myocardial infarction. Arch Intern Med 2000; 160:1818e1823 43. Kimmel PL, Peterson RA, Weihs KL, et al: Psychosocial factors, behavioral compliance and survival in urban hemodialysis patients. Kidney Int 1998; 54:245e254 44. Lam TH, Li ZB, Ho SY, et al: Smoking and depressive symptoms in Chinese elderly in Hong Kong. Acta Psychiatr Scand 2004; 110: 195e200
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Feng et al. 45. Djernes JK: Prevalence and predictors of depression in populations of elderly: a review. Acta Psychiatr Scand 2006; 113:372e387 46. Seshadri S, Wolf PA: Homocysteine and the brain: vascular risk factor or neurotoxin? Lancet Neurol 2003; 2:11 47. Feng L, Ng TP, Chuah L, et al: Homocysteine, folate, and vitamin B-12 and cognitive performance in older Chinese adults: findings from the Singapore Longitudinal Ageing Study. Am J Clin Nutr 2006; 84:1506e1512
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48. Egeland J, Lund A, Landrø NI, et al: Cortisol level predicts executive and memory function in depression, symptom level predicts psychomotor speed. Acta Psychiatr Scand 2005; 112: 434e441 49. Perlman RL, Finkelstein FO, Liu L, et al: Quality of life in chronic kidney disease: a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis 2005; 45: 658e666
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Objective: Among patients with chronic kidney disease (CKD), we investigated the prevalence of depressive symptoms, their impact on mortality and quality of life, and correlates of depressive symptoms. Design: Prospective cohort study, followed up to 4 years. Setting: General community. Participants: A total of 362 older adults with CKD (Stages 3 and 4 assessed from estimated glomerular filtration rate [eGFR]) drawn from the Singapore Longitudinal Aging Study cohort. Measurements: Scores on the Geriatric Depression Scale (GDS) and the prevalence of depressive symptoms (GDS 5) and other variables were assessed at baseline, and SF-12 quality of life (QOL) (at 2 years) and mortality determined from 4 years of follow-up. Results: Depressive symptoms were present in 13% of the participants at baseline, and were associated with poorer SF-12 QOL scores (up to 30 percentage point differences). There was a significant association between depressive symptoms and increased mortality risk (odds ratio: 3.17; 95% confidence interval: 1.17e8.61; c2 ¼ 5.11; df ¼ 1; p ¼ 0.023), which was statistically significant in unadjusted analysis, but not in multivariate analysis that accounted for covariates (odds ratio: 2.62; 95% confidence interval: 0.77-8.89; c2 ¼ 2.37; df ¼ 1; p ¼ 0.13). Baseline cognitive impairment, functional disability, and other chronic illness were significantly associated with both increasing GDS scores and depressive symptoms. No relationship between eGFR and depressive symptoms was observed. Conclusion: Depression among individuals with CKD was significantly associated with poorer quality of life, but not with increased mortality in predialysis CKD patients. More prospective studies are needed to establish the effects of depression on adverse CKD outcomes in predialysis CKD patients. (Am J Geriatr Psychiatry 2013; 21:570e579) Key Words: Chronic kidney disease, cognitive impairment, depression, mortality, quality of life, risk factors
C
hronic Kidney disease (CKD) is an important public health problem in older populations. The prevalence of CKD increases with older age and
approximately half of all new cases of end-stage renal disease (ESRD) are older adults age 60 years and older.1,2 CKD is known to be associated with
Received November 16, 2010; revised November 27, 2011; accepted December 27, 2011. From the Gerontological Research Programme (LF, TPN) and Department of PsychologicalMedicine (LF, TPN), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and Department of Geriatric Medicine, Alexandra Hospital, Singapore (KBY). Send correspondence and reprint requests to Tze-Pin Ng, M.D., Gerontological Research Programme, Department of Psychological Medicine, National University of Singapore, NUHS Tower Block, 9th Floor, 1E Kent Ridge Road, Singapore 119228. e-mail: [email protected] Ó 2013 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2012.12.020
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Feng et al. increased risks of mortality, cardiovascular event, and hospitalization.3 CKD is classified into 5 stages: Stage 1, kidney damage with normal or relatively high glomerular filtration rate (GFR) (90 mL/minute/1.73 m2); Stage 2, mild reduction in GFR (60e89 mL/minute/1.73 m2) with kidney damage; Stage 3, moderate reduction in GFR (30e59 mL/minute/1.73 m2); Stage 4, severe reduction in GFR (15-29 mL/minute/1.73 m2); and Stage 5, established kidney failure (GFR <15 mL/ minute/1.73 m2). Major depression or depressive symptoms is commonly associated with late-stage CKD. The reported point estimates varied from 15% to 45% for patients with ESRD or dialysis populations,4e7 and is highest in older patients. However, there are few published data on the prevalence of depressive symptoms in patients with earlier stage CKD before dialysis therapy initiation.8,9 Studies of patients with ESRD have shown that depression contributed to adverse outcomes including increased risks of mortality, hospitalization, cardiovascular events,10,11 peritonitis,4 and poor dialysis adherence.12,13 Physician-diagnosed depression or depressive symptoms was reportedly associated with poorer self-rated quality of life among both patients with ESRD and patients with CKD.14,15 The association between depression and poor outcomes in patients with CKD may be explained by biological factors such as altered autonomic tone16 and systemic inflammation.17 The risk factors and correlates of depression in CKD patients reportedly include younger age, female sex, low income, social support, marital satisfaction,4,13,18,19 and comorbid medical conditions including cardiac diseases, diabetes, and hypertension.4,6,20 In dialysis populations, depression has been reported to be correlated with low hemoglobin, low albumin, and C-reactive protein.7,21 The evidence for an association of the level of renal function measured by estimated glomerular filtration rate [eGFR] with depression is equivocal. A study of renal transplant patients22 reported that an increase in eGFR was associated with lower risk of depression, but other studies have failed to observe an association.8,23 No studies have investigated the association of cognitive impairment with depression in CKD patients, although this association is well studied in general populations of older adults.24
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The bulk of findings described earlier have been reported in studies of ESRD or dialysis patients. There is a dearth of population-based and longitudinal studies of older persons with earlier stage CKD not on dialysis therapy. A better understanding of the burden, correlates, and impact of depression in elderly populations with CKD has important implications for reducing morbidity and mortality, and improving quality of life. We conducted a population-based prospective study of 362 older adults with CKD (Stages 3 and 4) who were drawn from a cohort in the Singapore Longitudinal Aging Study. In this study population, we aimed to examine the baseline prevalence of depressive symptoms and its association with mortality and quality of life outcomes from 4 years of follow-up. We hypothesized that depressive symptoms among individuals with CKD would be associated with poorer quality of life and higher mortality risk. We also explored the significant correlates of depressive symptoms in older adults with CKD.
METHODS Study Population The participants in this study were drawn from cohort members in the Singapore Longitudinal Aging Study, a 4-year prospective study of aging and health among community-dwelling older adults resident in five districts in South East Region of Singapore. The baseline assessment began in 2004e2005, with subsequent interviews conducted at 2-yearly intervals. Details of the study design and subject recruitment have been published elsewhere.25 Briefly, the eligible population consisted of all persons age 55 years and older, who were Singaporean citizens or permanent residents. Individuals with serious physical or mental illnesses that rendered them incapable of participating were excluded. A total of 2,804 participants were enrolled into the study. At baseline, information on a wide range of demographic, biological, clinical, psychosocial, and behavioral characteristics were collected via interviews and assessments conducted in English, Chinese, or Malay by trained research nurses. The study was approved by the National University of Singapore Institutional Review Board, and informed consent was obtained from all participants.
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Depressive Symptoms in Older Adults With Chronic Kidney Disease Individuals with CKD, based on their eGFR results and restricted to those with Stage 3 and 4 diseases, were identified from the 2,804 participants at baseline. Among the 494 participants who had Stage 3 and 4 CKD (eGFR between 15 and 60 mL/minute/ 1.73 m2), 362 participants who had at least one repeat assessment for depressive symptoms from the follow-ups constituted the analytical sample in this study. Compared with the 362 patients, those excluded from the analysis (n ¼ 132) were significantly (p <0.05) older, were more likely to report depressive symptoms and poor cognitive and physical health, were more likely to live in lower end housing, and had lower hemoglobin concentrations. Measurements Kidney Function. eGFR was calculated using the Modification of Diet in Renal Disease formula, which is based on baseline age, gender, race, and serum creatinine concentration.26 Serum creatinine was measured by an enzymatic creatinine method calibrated to the NIST LC-IDMS method recommended by the National Kidney Disease Education Programme and traceable to NIST SRM967. Depressive Symptoms. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15),27 which has been validated for use in local Chinese, Malay, and Indian subjects.28,29 The internal reliability coefficient (Cronbach’s a) was 0.84. Scores on the scale range from 0 to 15, with higher scores indicating greater severity. In this population, the presence of depressive symptoms was denoted by a GDS score of 5 and more, which has been shown to have high sensitivity (97%) and specificity (95%) in identifying cases of major depressive disorder from structured diagnostic interview with SCID.28 Depressive symptoms assessed at all three time points (baseline, 2-year, and 4-year) were used in the data analysis. Quality of Life. Quality of life was assessed by SF12,30 a shorter version of the SF-36, and its reliability and validity have been documented. Summary measures (PCS-12/MCS-12) were calculated using the standard SF-12 items and regression weights. Scores were transformed to have a mean (SD) of 50 (10) in the U.S. general population, which is the recommended scoring for intercountry comparability. Scale scores were estimated for PF (physical
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function), RE (role emotional), RP (role physical), and MH (mental health) using 2 items each; and BP (body pain), GH (general health),VT (vitality), and SF (social function), represented by a single item each. All the raw scale scores were transformed to a 0 to 100 scale, with a higher score reflecting better quality of life. Available quality of life data obtained at baseline and follow-up at 2 years were used in this study. Medical Illnesses. Medical illnesses were based on self-reported history of chronic diseases in a checklist over the previous 12 months, which was corroborated by the use of specific medications (visually verified from medication packages). The presence of hypertension was defined by self-report of hypertension with antihypertensive medication use, or blood pressure measurement (untreated hypertension); diabetes mellitus was defined by self-report of diabetes on antidiabetic medications, or by elevated fasting blood sugar (untreated diabetes); myocardial infarction, atrial fibrillation, and congestive heart failure from self-report, ECG evidence, and/or use of appropriate medications; stroke from self report of stroke or transient ischemic attack. Participants were classified to have cardiovascular diseases or stroke if they have any one of the following conditions comprising heart attack, atrial fibrillation, congestive heart failure, and stroke. Other than diabetes, hypertension, and cardiovascular disease or stroke, other comorbid illnesses were defined as the sum total of number of, and included history of cataracts, glaucoma, and eye diseases, asthma, chronic obstructive pulmonary disease, arthritis, hip fracture, cancer, and other problems (e.g., thyroid disorders, gastrointestinal and liver, gynecologic, neurologic, etc.). Cognitive Function. Global cognitive function was measured by Mini-Mental State Examination.31 The local translated versions of the instrument has been validated for local use in Singaporean older adults,32 with the conventional cutoff of 23/24 used to determine cognitive impairment. Functional Disability. Functional disability was assessed by self-reported measures of instrumental and basic activities of daily living (IADL and BADL).33,34 BADLs include bowels, bladder, grooming, toilet use, feeding, transferring, mobility, dressing, stairs, and bathing, and IADLs consist of performance in using telephone, traveling, shopping, preparing meals, house work, taking medicine, and
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Feng et al. managing money. We defined functional impairment as present if the respondent reported difficulty with one or more of these activities in ADL or IADL scale. In this study, a categorical variable with three classes was defined on the basis of BADL and IADL: noBADL or IADL disability, IADL disability alone, BADL disability. Other Variables. Other variables measured at baseline included demographic characteristics (age, gender, education, marital status, ethnicity, housing type [a proxy for income]), hemoglobin (measured by light scattering flow cytometry, cytochemistry, and microscopy), serum albumin (measured by bromcresol green dye binding method), smoking, and physical activities.
Generalized Estimating Equation was used to identify factors that were correlated with the presence of depressive symptoms, and was analyzed by SAS PROC Genmod. The mean response variable of depressive symptoms was modeled as logistic regression and we assumed an exchangeable working correlation. There was no significant interaction between time and any covariates for both mixed-effects modeling and Generalized Estimating Equation modeling. A p value of less than 0.05 was used to evaluate statistical significance. All analyses were performed using SAS 9.2 software. (SAS Institute, Inc., Cary, NC)
RESULTS Statistical Analysis GDS scores of depression were analyzed as a continuous variable, and GDS score of 5 and more (depressive symptoms) as a categorical variable in bivariate and multivariate analyses. Group differences were compared by t-tests for continuous variables and c2 tests for categorical variables. Variables with p <0.25 from bivariate analyses or those known to be clinically relevant were included in multivariate models. These variables included age, gender, marital status, housing type, functional status, diabetes, hypertension, cardiovascular disease, other illnesses, cognitive impairments, smoking, physical activity, eGFR, albumin, and hemoglobin. Antidepressant usage was not controlled for because only 2 patients with depressive symptoms were on drug treatment. Multiple logistic regression was performed to determine the association of baseline depressive symptoms with cumulative mortality. ANCOVA (analysis of covariance) was used to examine the relationship between baseline depressive symptoms and quality of life at 2-year follow-up. Adjusted mean scores of each subscale of SF-12 were compared by depressive symptoms, and Bonferroni correction was utilized to control the probability of false positive results from these small subsets of multiple comparisons. We used linear mixed-effects model by SAS PROC MIXED procedure to explore correlates of depression score and compound symmetry was chosen as covariance structure. Analysis using
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Of the original 494 individuals with Stage 3 and 4 CKD, 12.8% (N ¼ 63) had depressive symptoms at baseline. In the analytical sample of 362 participants who had repeated measures of depressive symptoms at follow-up, the proportion was 11.2% (N ¼ 42). At baseline, the average eGFR was 51.0 8.3 mL/ minute/1.73 m2. The mean age of the patients was 70.3 7.8 years; 42.4% was male. The prevalence of diabetes was 21.6%, cardiac or cerebrovascular (stroke) diseases, 19.3%; hypertension, 75.7%; and ADL disability, 6.2% (Table 1). Compared with nondepressed patients at baseline, depressed patients were more likely to report functional disability, cognitive impairment, lower Physical Component Score and Mental Component Score quality of life scores and had higher proportion of mortality. There were no significant differences between depressed and nondepressed participants in other baseline characteristics (Table 1). A total of 22 (6.1%) participants died during the 4-year follow-up period. The unadjusted and adjusted associations between baseline depressive symptoms and mortality over the follow-up are shown in Table 2. Depressed patients at baseline were at greater risk of death, based on bivariate association (odds ratio [OR]: 3.17; 95% confidence interval: 1.17e8.61; c2 ¼ 5.11; df ¼ 1; p ¼ 0.023), although the adjusted OR of association (OR: 2.62; 95% confidence interval: 0.77e8.89; c2 ¼ 2.37; df ¼ 1; p ¼ 0.13) was not significant in multivariate analyses. The relationships between depressive symptoms at baseline and quality of life at first follow-up were
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Depressive Symptoms in Older Adults With Chronic Kidney Disease
TABLE 1. Baseline Characteristics and Outcomes of CKD Patients by Depressive Symptoms (N [ 362)
Baseline variables Demographics Age, mean (SD) Male Education Primary and below Secondary and above Marital status Married others Ethnicity Chinese Others Housing type <3 rooms 3 rooms Clinical variables and life style Functional status Independent Only IADL dependent ADL dependent or both Diabetes Hypertension Cardiovascular disease or stroke Other illnesses 0 and 1 2 Cognitive impairment Smoking Never Current smoker Physical activities Never Sometimes or often Laboratory values Hemoglobin (mg/dL), mean (SD) Serum albumin (g/L),mean (SD) eGFR (mL/minute/1.73 m2), mean (SD) Outcomes PCS-12, mean (SD) MCS-12, mean (SD) Mortality
Depressed (N [ 42)
Nondepressed (N [ 320)
t-test (df)/c2(df)
pa
71.6 (7.9) 16 (38.1)
70.1 (7.8) 138 (43.1)
1.18 (360) 0.38 (1) 0.43 (1)
0.24 0.53 0.51
26 (61.9) 16 (38.1)
181 (56.6) 139 (43.4) 2.84 (1)
0.09
24 (57.1) 18 (42.9)
224 (70.0) 96 (30.0) 0.20 (1)
0.65
40 (95.2) 2 (4.8)
299 (93.4) 21 (6.6) 3.37 (1)
0.066
17 (40.5) 25 (59.5)
86 (26.9) 234 (73.1) 15.37 (2)
<0.001
21 13 8 11 31 11
220 81 14 67 243 59
(50.0) (31.0) (19.1) (26.2) (73.8) (26.2)
(69.8) (25.7) (4.4) (20.9) (75.9) (18.4)
20 (47.6) 22 (52.4) 10 (23.8)
195 (60.9) 125 (39.1) 34 (10.6)
37 (88.1) 5 (11.9)
301 (94.4) 18 (5.6)
26 (61.9) 16 (38.1)
164 (51.3) 156 (48.9)
0.61 0.09 1.43 2.73
(1) (1) (1) (1)
0.44 0.76 0.23 0.10
6.04 (1) 2.46 (1)
0.014 0.12
1.77 (2)
0.19
13.0 (1.6) 41.7 (3.8) 48.6 (9.9)
13.6 (1.6) 42.0 (3.3) 51.3 (8.1)
2.01 (360) 0.56 (360) 1.95 (360)
0.05 0.58 0.05
40.6 (9.6) 43.6 (10.1) 6 (14.2)
47.7 (7.3) 54.6 (7.5) 16 (5.0)
4.64 (47.6) 6.8 (47.3) 5.61 (1)
<0.001 <0.001 0.023
Notes: PCS: Physical Component Score; MCS: Mental Component Score. a Determined by c2 tests or t-tests.
TABLE 2. Unadjusted and Adjusteda Association Between Baseline Depressive Symptoms and Mortality Over 4 Years
Baseline Not depressed Depressed
Unadjusted
Adjusted
Mortality (n Case/N Total)
OR (95% CI)
c (df)
p
OR (95% CI)
c2(df)
p
16/320 6/42
1.00 3.17 (1.17-8.61)
5.11 (1)
0.023
1.00 2.62 (0.77-8.89)
2.37 (1)
0.13
2
Notes: 95% CI: confidence interval. a Adjusted for baseline age, gender, marital status, housing type, functional status, cognitive impairments, diabetes, hypertension, cardiovascular disease, other illnesses, smoke, physical activities, eGFR, albumin and hemoglobin.
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TABLE 3. Mean Quality of Life at First Time Follow-up by Depressive Status at Baseline (N [ 315) Depressed
Physical component score Mental component score Physical function domain Role emotional domain Role physical domain Body pain domain General Health Vitality Social function Mental Health
Nondepressed
Mean
SD
Mean
SD
44.9 46.9 81.7 68.1 58.3 74.3 42.4 54.9 72.2 65.3
8.44 10.77 34.83 44.96 51.40 27.04 13.12 33.38 29.14 26.46
49.8 55.1 87.4 90.7 87.4 84.9 49.6 70.6 91.3 84.2
6.06 6.10 23.49 27.31 31.26 19.38 15.37 21.73 19.54 15.37
F-testa (df) 6.91 12.60 2.52 4.46 10.44 5.53 1.35 5.41 8.77 17.59
(1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294) (1,294)
h
pb
c 2
0.009 <0.001 0.11 0.036 0.001 0.019 0.25 0.021 0.003 <0.001
0.015 0.030 0.009 0.015 0.034 0.018 0.005 0.018 0.029 0.056
a
Adjusted for baseline quality of life, age, gender, marital status, housing type, functional status, cognitive impairment, diabetes, hypertension, cardiovascular disease, other illnesses, smoke, physical activities, eGFR, albumin, and hemoglobin. b The significant level is 0.005 after Bonferroni correction for multiple comparisons. c 2 h : effect size.
explored in ANCOVA models. The adjusted mean scores for SF-12 component scale scores and individual domain scores are shown in Table 3. The mean summary score of MCS-12 (F[1, 294] ¼ 12.60; p <0.001), and domain score of RP (F[1, 294] ¼ 10.44; p ¼ 0.001), SF (F[1, 294] ¼ 8.77; p ¼ 0.003), and MH (F[1, 294] ¼ 17.59; p <0.001), in patients with depressive symptoms were significant lower than in nondepressed patients. The mean score difference was not significant with regard to other domains, after Bonferroni correction. As shown in Table 4, baseline cognitive impairment (t ¼ 3.07; df ¼ 338; p ¼ 0.002), functional disability (t ¼ 0.52; df ¼ 327; p ¼ 0.602 for only IADL independent; t ¼ 4.20; df ¼ 334; p <0.001 for ADL dependent), and other chronic illnesses (t ¼ 2.45; df ¼ 323; p ¼ 0.015) were each independently associated with increasing GDS depression scores repeated over follow-up, whereas other variables including eGFR, albumin, hemoglobin, and diabetes did not show significant associations. In multivariate analyses of depressive symptoms (GDS 5) during follow-up as dependent variable, the significant baseline variables were ADL disability (c2 ¼ 0.34; df ¼ 1; p ¼ 0.56 for only IADL independent; c2 ¼ 16.49; df ¼ 1; p <0.001 for ADL dependent), increased number of chronic illnesses (c2 ¼ 4.41; df ¼ 1; p ¼ 0.03), and housing category (c2 ¼ 3.95; df ¼ 1; p ¼ 0.046). There was a nonsignificant association of cognitive impairment with depressive symptoms (c2 ¼ 3.21; df ¼ 1; p ¼ 0.07). Other
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variables including eGFR were not correlated with depressive symptoms.
DISCUSSION In this study of older Asian adults with Stage 3 and 4 CKD, we observed that about 13% had depressive symptoms and that their presence contributed to poorer quality of life on follow-up. Baseline cognitive impairment, functional disability, and chronic illnesses were significant risk factors associated with increasing number of depressive symptoms or the presence of significant depressive symptoms (5GDS depression symptoms). Although our observed prevalence of depressive symptoms appears high, it was still relatively lower compared with those reported in other studies of CKD patients prior to dialysis.8,9 Using the Beck Depression Inventory, Andrade et al.9 reported a prevalence of 37.7% in nondialysis patients with CKD, whereas Hedayati et al.,8 using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) reported that the prevalence of major depression was 21% in predominantly male patients with Stage 2e5 CKD. Heterogeneity in study populations, assessment tools for depression, and the presence of comorbid conditions are likely to contribute to these observed variations.35 In this study, we failed to demonstrate that the presence of depressive symptoms among our CKD
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Notes: Multivariate regression via random effects models and Generalized Estimating Equation approach, based on evaluable data; percentage of missing data on GDS scores was 10% at first follow-up and 39% at second follow-up. Variables in the models include: follow-up duration (in years), age, gender, marital status, housing type, functional status, cognitive impairment, diabetes, hypertension, cardiovascular diseases, other illnesses, smoke, physical activities, eGFR, albumin, and hemoglobin. B: unstandardized regression coefficeient. SE: standard error; 95% CI: confidence interval.
0.046 3.95 (1) Referent 0.57 (0.31e1.00) 0.009 6.76 (1) Referent 0.45 (0.25e0.82)
Referent Referent (327) 0.602 1.61 (0.85e3.07) 2.13 (1) 0.14 1.24 (0.61e2.51) 0.34 (1) 0.56 (334) <0.001 6.48 (2.76e15.25) 18.36 (1) <0.001 6.32 (2.60e15.38) 16.49 (1) <0.001 (345) 0.078 2.22 (0.88e5.58) 2.82 (1) 0.09 2.61 (0.77e8.81) 2.38 (1) 0.12 (323) 0.015 1.35 (1.04e1.74) 5.11 (1) 0.024 1.36 (1.02e1.82) 4.41 (1) 0.03 0.52 4.20 1.77 2.45
0.52 0.07 0.42 (1) 3.21 (1) 0.037 1.01 (0.98e1.05) 0.008 1.94 (0.94e4.01) 4.32 (1) 7.10 (1) 0.26 0.97 (0.94e0.99) 0.002 2.63 (1.29e5.37) 1.12 (333) 3.07 (338)
t-test (df) B (SE) p t-test (df) B (SE)
eGFR 0.0187 (0.01) 1.55 (347) 0.12 0.0143 (0.01) Cognitive impairment 1.1883 (0.30) 3.92 (357) <0.001 0.9880 (0.32) Functional status Independent Referent Referent Only IADL dependent 0.3534 (0.23) 1.57 (346) 0.12 0.1263 (0.24) ADL dependent or both 1.8642 (0.41) 4.50 (348) <0.001 1.7733 (0.42) Current smoker 0.7727 (0.41) 1.86 (362) 0.063 0.7434 (0.42) Number of other illnesses 0.2546 (0.10) 2.66 (337) 0.008 0.2354 (0.10) Housing type <3 rooms 3 rooms
c2 (df) OR (95% CI)
c (df)
p
Adjusted
Depression Score Unadjusted
TABLE 4. Correlates of Depression Scores and Depressive Symptoms
Adjusted
p
OR (95% CI)
2
Unadjusted
Depressive Symptoms (GDS ‡5)
p
Depressive Symptoms in Older Adults With Chronic Kidney Disease participants was significantly associated with mortality risk. The death rate in both depressed and nondepressed group may be too small to detect a significant association. The recent findings in a similar nondialysis CKD population36 also failed to demonstrate a significantly elevated mortality risk associated with depression, although this association has been consistently reported in studies of patients with ESRD or on dialysis.10,37 In line with previous studies of patients with CKD and ESRD,14,15 we observed that depressive symptoms were associated with poorer quality of life as measured by the mental and physical component scores of SF-12. The impact of depression on quality of life appeared substantial, judging from up to 30 percentage point differences in quality of life scores. A number of different mechanisms have been suggested to explain the relationship between depressive symptoms and adverse outcomes in individuals with CKD. There is some evidence to suggest that depression may be associated with factors that could predispose patients to develop cardiac disease, such as lower heart rate variability,16 increased cortisol and norepinephrine excretion,38 and alteration in immunologic and stress responses.17,39 Depression is also associated with poorer nutrition40 and leads to upregulation of inflammatory mediators.41 However, we found that the association between depressive symptoms and quality of life was independent of cardiac disease and nutritional factor (as indicated by albumin). Finally, the negative impact of depression could be due to reduced compliance with medical regimens.42 Decreased behavioral adherence is consequently associated with decreased survival.43 The effect of depressive symptoms on quality of life in individuals with CKD suggest the potential usefulness of screening for depressive symptoms to improve outcome among earlier stage CKD patients before dialysis therapy initiation. We observed that cognitive impairment, ADL disability, number of other illnesses, and socioeconomic status were significant independent correlates of depressive symptoms (GDS 5) or depression score among the CKD participants. These correlates of depressive symptoms are well established in the general population of older adults.44,45 The association between cognitive impairment and depressive symptoms has not been reported in previous studies of CKD patients, and although well studied in general
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Feng et al. populations of older adults,24 their relationship and responsible mechanisms are less well understood in CKD patients. Cognitive impairment may be both an epiphenomenon of depression as well as the result of CNS neuronal dysfunction, possibly due to neurotoxic metabolites such as homocysteine,46,47 which is commonly elevated in CKD. Also, hypercortisolemia in persons with depression has been shown to be associated with memory impairment.48 Depressive symptoms have been reported to be associated with diabetes and cardiac disease in previous studies.4,8 This association was not observed in this study, but this is perhaps not surprising, considering the smaller representation of diabetes (22%) and cardiac diseases (16.0%) in our study population. Previous studies4 have examined hemodialysis patients, and this may explain the larger negative impact of diabetes and depression on their patients. A noteworthy negative finding is the observed lack of relationship between kidney function assessed by eGFR and depressive symptoms. This finding corroborates other findings that the prevalence of major depression diagnosis or depressive symptoms (using Beck Depression Inventoryscores) did not differ across different CKD Stages 1e5 in patients with CKD who were not treated by dialysis.8,23 There is thus evidently no direct relationship between eGFR and depression. The possible explanations include a lack of clear symptoms and of patient awareness of kidney disease during CKD progression, even in patients with moderate to advanced CKD.8,23 The presence of diabetes, hypertension, and atherosclerotic vascular and cardiac diseases, which are common causes or comorbidities of CKD, are also likely to be comediating causes of depression in individuals with CKD.49 This study has limitations. First, depressive symptoms were assessed by GDS, which is not tantamount to a clinical diagnosis of depression. Second, although prospective design was used to
investigate correlates of depressive symptoms, causal relationships cannot be inferred, because depressive symptoms defined by GDS may vary over time. It remains uncertain whether depressive symptoms precede or follow the correlates. Finally, around 27% (n ¼ 132) patients were eliminated from the analysis because of missing data for all follow-up. Given the higher prevalence of depressive symptoms and poorer physical and cognitive functions of these excluded participants, this could have lead to some underestimation of the actual association. Our data thus suggest that depressive symptoms reduced quality of life in predialysis older CKD patients, but were not conclusive in demonstrating an association with increased mortality risk. Physical functional disability, higher number of medical illnesses, and cognitive impairment were significant risk factors or correlates of increasing numbers of depressive symptoms and depressive symptoms denoting clinical depression. As depressive symptoms and major depression are amenable to treatment, more studies are warranted. The study is supported by a research grant 03/1/21/ 17/214 from the Biomedical Research Council, Agency for Science, Technology and Research (A*STAR). There are no other agreements of authors or their institutions that could be seen as involving a financial interest in this work. Dr. Feng performed the literature review, formulated the hypothesis, analyzed the data, and drafted and revised the manuscript. Mr. Yap participated in the conceptualization of the study, the interpretation of the results, and review of the manuscript. Dr. Ng conceptualized the study, designed the epidemiologic survey, interpreted the results, and reviewed and revised the manuscript. No commercial company sponsored or played any role in the design, methods, subject recruitment, data collections, analysis, and preparation of article. The authors declare no conflicts of interest.
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