Critical Analysis of Risk Factors Associated with Depression Among Patients with Chronic Kidney Disease: A Systematic Review

Background: Chronic kidney disease (CKD) is progressive and advance medical condition in which the kidneys fail to perform their primary functions. The occurrence of CKD is on the increase globally which made it a public health issue. Depression among CKD patients is a complex and common phenomenon. The complexity of depression in CKD is associated with the similarities between depressive and uremic symptoms.


Introduction
Kidneys are very important organs in human body because of the roles they play in carrying out excretory and endocrine functions in our body [1]. According to Levey et al. [2] chronic kidney disease (CKD) refers to insidious renal damage or impairment in renal function characterised by decreased glomerular function below 60 ml/minute per 1.73 square metre for more than 3 months in respective of causative agent or risk factor. Pagels et al. [3] argue that CKD has upon mortality rates, they sampled 462,293 people, ages 20 and above in Taiwan. Further, from the sample, 12.3% are cases, while 87.7% are control groups. The study aimed to measure the prevalence and mortality rates associated with CKD among Taiwanese population. The researchers also found that of the total study population only 3.54% had prior knowledge of their CKD status, and that the study showed that CKD is responsible for up to 10% mortality which is the same with obesity and tobacco smoking (Wen et al. 2008).The researchers also found that CKD was under reported and that it had a negative impact on the socioeconomic status of victims. The authors concluded that CKD and its impact are of significant concern to public health. Mcmh, Thabet & Vostanis [5][6][7][8][9][10] reported that depression in CKD is pronounce and that it has a negative impact on the wellbeing of patients diagnosed with CKD. Cukor et al. [11] adds that while patients diagnosed with irreversible kidney disease are often depressed, making a formal diagnosis of depression can be challenging and complex due to significant symptomatic overlap between uremic and depressive symptoms in CKD.

Methods
This study is a secondary research; hence the method used is systematic review of primary articles which are relevant to the research question. Ethical approval was granted to carry out this study as a secondary research by the Ethic Committee of the University of Bedfordshire. During the course of study identification, the following inclusion and exclusion criteria were

Data Extraction
This technique allows for retrieving of relevant piece of information from primary journal articles. And the following headings were used for this purpose: Authors, year of publication, journal reference, title of journal/article, purpose of study, design of study, sampling, sample size, data collection method, identified examined risk factors of depression among CKD patients, statistical strengths of risk factors explaining depression among CKD patients, author's proposed limitations, recommendations and comments.

Quality Appraisal
This protocol is detailed towards evaluating the identified studies with a view to ascertaining the validity and reliability of each article selected for the study, using CASP's framework check list for cross-sectional and cohort studies. The protocol involves a rigorous and systematic process which is used to assess the weaknesses and strengths of the included studies based on their designs (Hek, Judd & Moule [12]; Young & Solomon [13]). During screening 13 primary articles were selected for the purpose of this study and two articles included from the references check list; and it was made explicit. Of the total 15 articles selected 12 are cross-sectional studies while three were cohort studies. In this review the quality appraisal was conducted in two phases according to the study design in order to achieve valid and reliable appraisal of the included studies in the review. Firstly, cross-sectional studies were appraised then the cohort studies using appropriate check list for quality appraisal. The adopted check lists used for quality appraisal are [14][15][16][17][18][19][20]

Outcomes of Quality Appraisal
The quality appraisal conducted focused clearly on evaluating the selected articles with a view to answering the research question.
A total of 15 articles were appraised out which 11 articles passed the quality appraisal protocol whereas, four articles were excluded because they did not meet the criteria. The strategy used for the quality appraisal was strictly based on CAPS check list parameters; in order to evaluate each study based on its methodological quality and it relevance to the research question. Similarly, the articles were also appraised in line with the inclusion criteria of the study. Of those articles which passed the quality appraisal nine were crosssectional studies and two cohort studies. Six of the cross-sectional studies have 100% response of the participants, the studies are as follows. All these studies have appropriate study design and have met majority of the criteria for appraisal and they were all scored strong apart from one study by [21][22][23][24][25][26] which has unclear sampling technique and it was scored moderate. The remaining three articles are 84% response,96.4% response and 51.6% response.
The first and second articles were scored strong because they have appropriately met majority of the criteria whereas, the third article in this group was scored moderate because of low response and unclear limitations however, the findings from this study are significant to the research question and were strongly associated with depression in CKD; besides, the study has appropriate design.
The two cohort studies included are scored high because the study has 77% response and has met majority of the criteria. While the second article by Young et al. [27] was scored as acceptable because the authors have not clearly analyses the study confounders, but the study has 70% response which is good. It states that response rate in research is flexible, however the author suggested that 75% or more is a good response rate. The studies excluded from quality appraisal are [28][29][30][31][32][33][34][35] these articles were rejected because they have not met the criteria for quality appraisal and the findings from these studies were found to be irrelevant to the research question.

Data analysis
All the included studies screened and evaluated were collated and synthesized in order to answer the research question. The included studies referred to those studies which passed the inclusion criteria for this review. It has been suggested by Polit & Beck [36] that data analysis is the process of synthesizing and appraising of data from selected studies that are extracted and evaluated based on quality appraisal framework aims at answering a research question. Therefore, the analysis focused on the study population, allo-cation of participants to groups according to the study design, and the study findings with a view to achieving a contextual analysis which is referred to as discourse appraisal of data [37][38][39][40]. Moreover, for the purpose of this study a narrative analysis was chosen because the included studies for this review involved studies with different study designs which make narrative analysis more appropriate than meta-analysis Lucas et al. [41]. Similarly, narrative analysis allows for a reflexive and detailed critical appraisal of data compared to meta-analysis. These qualities make narrative analysis more appropriate and suitable for this study. The process of data analysis was undertaken in a structured manner, using Popay et al. [42] framework guidelines for narrative analysis.

Descriptive Results
As can be seen in Figure 1

Types of Identified Risk Factors
The majority of the findings from the included studies were relevant to the research question and have significant association with depression in CKD. To start with, the studies conducted [51][52][53][54][55][56] in Table 3 below both looked at clinical variables as the key data in their results. It identifies low testosterone level among male patients with CKD as the key significant risk factor to depression, while reveals that low urea clearance due to inadequate dialysis and low serum albumin as the risk factors to depression among CKD patients irrespective gender [57][58][59][60]   Cross-sectional quantitative survey study. Investigating the impact of serum testosterone (male sex hormone) level as a potential risk factor of depression in patients diagnosed with CKD.
Participants were randomly selected from a single centre nephrology unit. A total of 109 patients were recruited to take part in the study. Patients were selected if they are diagnosed with CKD stage 3,4& 5, not on renal replacement therapy and have given their informed consent to take part in the study. The diagnosis and the stages of CKD were measured through laboratory analysis of creatinine clearance (CrCl), in addition to patients' previous health history and physical examination.
A 21 items Beck depression inventory (BDI) questionnaire was used to measure the level of depression among study participants. The score for BDI ranges from 0-63.
Low serum testosterone in male adults patients diagnosed with CKD is a significant risk factor for depression among these groups of patients in respective of their age.
2 Agganiset [22] Study conducted in the USA at 5 dialysis units in Boston. 51% of the study participants were males whereas, 49% were females. Race=21.6% African Americans. Age in years 63.8 +/-16.6. Participants were randomly selected from five haemodialysis centres (n=241) in Boston.
The study aims to investigate the influence of demographics and the characteristics of patients diagnosed with CKD and the impact it has on the occurrence of depression among the study group.
The criteria for selection are patients diagnosed with irreversible kidney disease, on maintenance renal replacement therapy, having adequate dialysis with urea clearance greater than one (Kt/V: >1.0), not in a state of -dementia or confusion during recruitment. Also, participants are included if they are fluent in English language and gave their informed consent to participate in the study. Participants' demographic data was used to source for information regarding their medical details and characteristics.
Depression was measured using a centre for epidemiological studies-depression scale (CES-D). The measurement was based on the characteristics of the participants, subjects who have CES-D score above 16 scale may likely suffer from depression.
The results suggested that the identified clinical variables are risk factors associated with depression among the study groups. The identified variables are low serum albumin and low urea clearance due to inadequate RRT. The measurement outcome yielded insignificant result. 3 Amira [23] The study was carried out at a teaching hospital in Lagos, Nigeria. Comprised of male (n=73) and female (n=45). Total n=118 patients diagnosed with CKD, aged between 42 +/-14 in years. Fifty healthy individuals were selected from among students and members of staff of the teaching hospital to form the control group; 52% men and 48% female.
Cross-sectional study. To examine the determinants of depression in CKD.
The participants for this study were classified into case and control groups. Demographic routine data and clinical data were used to access the health related issues about the case group. The participants gave their informed consent to partake in the study.
The potential participants were served with 20 item questionnaires as a tool for assessing their level of depression and its determinants respectively. The questionnaires were translated into the local dilate of the area, which is Yoruba language for the convenience of participants who cannot communicate in English. The study compared the status of CKD patients before commencing renal replacement therapy (RRT) with those who have transited onto RRT.
The results indicated that CKD patients on RRT are34.5% likely to develop depression, while those not on RRT are only 13.3% at risk of developing depression. This suggested that RRT is a significant risk factor which influences depression in CKD. The researcher observed that, the burden attached to RRT is the major risk factor linked with depression in CKD. 4 Chen [24] This study was conducted at Chang Gung hospital in Taiwan 11690 5 Chiang [25] The study was conducted in Taiwan at a hospital located in the southern part of the country. Total of 270 subjects diagnosed with CKD were enrolled out of which 61% were male and 39% were female. The participants selected have not commenced RRT, but were attending a health facility.
The study was a cross-sectional design which aims to identify the multiple variables associated with depression in CKD.
Study participants were purposively selected from a single centre in Taiwan. The selection process took seven months between January and August in the year 2011. The participants were allocated into groups as depressed and non-depressed.
Taiwanese depression questionnaire which is 18 items questionnaire was used as a measurement tool to evaluate depression among the groups.
Depression in CKD is significantly associated with the severity of the disease, also patients with insomnia, those who live sedentary life and patients who have no any religious belief are likely to be depressed. Similarly, this study reveals that gender is a significant risk factor associated with depression in CKD as female patients were found to be more at risk of developing depression compared to their male counterparts in the study. 6 Kang [26] The study was carried out in the United States of America at a health facility in Pittsburgh. The researchers recruited 169 subjects diagnosed with CKD. Of the total population 34.9% were female and 65.1% were male, within the ranges of 18 to 90 years; 56.8% of the participants are married.
A cross-sectional study set to investigate the association between sleep disorder and depression in CKD.
Participants were routinely selected at nephrology unit, RRT centre and renal transplant unit within three years; from 2004 to 2007. The subjects were divided into two groups, those with sleep disorder (49.1%) and those without sleep disorder (50.9%). Information was sourced through administrative questionnaire and shot health related interview, also routine data was collected through participants' medical records.
Depression was measured among the two groups using 9 item patient health questionnaires, or self reported use of antidepressants as intervention for depression.
The key finding from this study show that there is correlation between sleep disorder and the onset of depression among CKD patients in stages 4 and 5. 7 Kop [27] The study was conducted in the United States of America from four different local communities. The study population is 5785, 42.6% were male whereas, 57.4% were female. The participants are from 65years and above.
This study is a longitudinal cohort study. The aim of the study is to observe the association of depression with gender, marital status, level of education and race among patients with irreversible kidney disease.
The participants were randomly selected from four communities in the USA. The cohorts were assigned into two groups depending on the level of their depressive symptoms and they were followed-up for 14 years. Participants were excluded if they are not likely to be residence in the area of study for three years. Clinical data was collected via interviews and questionnaire. Data on hospital admissions during the followup period were collected.
During the course of the study depression was measured among the study population using centre for epidemiologic studies depression scales which is10-item measurement tool for depression.
The study reveals that demographic variables which include: gender, race, educational and marital status are significant risk factors for depression in patients with irreversible kidney disease. 8 Lopes [28] The study was conducted in Brazil at four dialysis centres in Salvador.  9 Nowak, Adamczak& Wiecek [29] This study was conducted in a Polish region of Silesia. A total of 694 CKD patients were recruited out of which 44.3% are women and 55.7% are men both participants are on maintenance RRT.
The study is a cross-sectional study which aims to investigate the associating risk factors for depression among haemodialysis patients with CKD.
Participants were recruited from multicentre dialysis units across Silesia region in Poland. Randomise sampling method was used to select sample and the selected subjects were assigned into two groups, which are: depressed and non-depressed.
Beck depression inventory scale for depression was used to measure depression among the study groups.
Patients with femoral catheter, central line or internal jugular (temporary access) high number of hospital admissions have greater risk of developing depression. Furthermore, the study reveals that patients who are married are less likely to develop depression which means the unmarried are at risk to develop depression. 10 Sezer [30] The study was conducted in Ankara the Anatolian region of the Turkish republic.
The study population comprises of 141 subjects, 38.2% of them were female and 61.8% were men; who were diagnosed with CKD and have transited on RRT.
The study is a cross-sectional study. The study aim is to investigate socioenomic risk factors associated with depression among CKD patients who are on RRT.
In this cross-sectional study participants were surveyed and selected. The criteria for selection are: Patients diagnosed with irreversible kidney disease, have commenced RRT for more than three months, not on psychiatry intervention and are above 18 years and were able to make an informed decision to participate.
The measurement tool used was Beck depression inventory scale.
The study found that CKD patients who are on RRT are faced with series of physical, social and economic challenges which significantly put them at greater risk of developing depression.

11
Young [31] The study was conducted in the USA in Washington at nine health facilities under the Group Health. The facilities are geographically located within the radius of about 40-miles of seattle. The study population is 4128 subjects out of whom 54.5% were male, 36.4% are single; the average years of the participants were 65.5.
The study was a prospective cohort study. The study's aim is to identify the association of lack of exercise and depression considering the characteristic of cohort group in the study.
The researchers surveyed and recruited subjects from multicentre non-profit health facilities in the state of Washington. Participants were selected through demographic data based on gender, race and their ethnic background. Clinical data was used to establish the causation of the disease (CKD) since the study focuses on patients with diabetic kidney. The timeline for follow-up was 6 years, from 2001-2007.
A 9 item patient health questionnaire was used to determine major depression and the level of depression was measured using Diagnostic s and Statistical Manual-4.

Physiological Risk Factors
Three studies revealed physiological factors as significant risk factors which are mainly based on pathological transformations which occurred due to CKD or in some cases the risk factors may be secondary to the common invention (Dialysis) used in managing CKD. Specifically, these studies were found that depression among male patients diagnosed with CKD is strongly associated with decrease sexual function which is due to significant reduction in the level sex hormone among male patients with CKD [61][62][63][64][65][66].
The study of revealed that depression in CKD was associated with lower level of albumin and failure of the kidneys to excrete toxic waste or as a result of poor urea clearance from dialysis.

Physical Risk Factors
The study is the only study which measured physical risk

Socioeconomic Risk Factors
The outcomes of narrative analysis show that social and economic factors are significant risk factors of depression in CKD.
Specifically, studies conducted revealed that the social status of CKD

Ageing and Gender Associated Risk Factors
The occurrence of depression among patients with chronic renal failure was significantly related to ageing according to the study carried out. The finding on age as a risk factor of depression in CKD is not significant based on the measurement outcome on age.
Though, the analysis outcome as reported revealed that majority of the patients studied were above 60 years and most of them have high depression score. Also, studies revealed gender as significant risk factor associated with depression in CKD. The studies examined both male and female subjects diagnosed with chronic renal failure; and from their analysis they found that most of the female subjects in their studies presented high depressive symptoms compared to their male counterparts.

Ethnic Risk Factors
Only one study revealed that ethnic background of an individual has significant correlation with depression in CKD. The Kop et al.

investigated their subjects based on their ethnic background and
classification. The outcome analysis shows that participants who belong to black race presented high score of depression compared with those that belongs to another race than black.

Life Style Associated Risk Factors
During synthesis and analysis of data from the included studies;

Treatment Associated Risk Factors
Treatment is an important factor associated with depression among CKD patients. It can be a primary risk factor of depression in CKD as well as influence the emergence of other significant risk factors as it has been observed in this review. Two studies which were conducted explicitly stated in their studies that RRT and the procedure involved, were found to have significant relationships with the onset of depression among CKD patients. The study by Amira confirmed that patients who are transiting onto dialysis and those receiving dialysis as intervention were found to have high depressive episode irrespective of the dosage. Likewise, depression in CKD was found to be associated with mode of vascular access used for renal dialysis. It was revealed that having catheter pass in the groin area or on the chest is stressful and uncomfortable to bear; these methods increase the risk of depression among CKD patients.

Religious Belief and Psychological Associated Risk Factors
One study revealed that patients diagnosed with chronic renal failure that have no religious belief have high incidence  hormonal impairment which appears to be a major source of stress among female patients compared with their male counterparts.
Furthermore, marital status of CKD patients has been found to be an essential risk factor which influences the incidence of depression in CKD. The main stream theory suggested that CKD patients who have no life partner or those that live alone present high depressive symptoms compared to those that live with their partners or spouse. The high depressive affect identified among single patients and those that live alone could be due to the fact that CKD patients are physically in active which implies that they need both physical and psychological support to be able to withstand the life challenges associated with their ailment (CKD).This therefore, connote that CKD patients who live alone or those who are single lack emotional and social support from their suppose or love one's which make them vulnerable to depression.
Educational and economic factors are discussed as very strong risk factors which are associated with depression in CKD considering the disease characteristic and treatment implications in CKD. It can be understood that the literacy level of the people and/or the level of awareness they have is a significant way to determine their health status (health behavior). These assertions is consistent with the a cancer study reported by Sanderson in which it was found that people whose educational level is low tend to have poor health seeking behavior compared to those who are highly as reported by Nowak, in this study. Specifically, this result is consistent with the finding in which the authors agreed that CKD patients are often depressed due to persistent hospital admission as a result of their ailment, compared to non-CKD patients.
Evidently, reported that lack of religion has been found to be very strong risk factor associated with the onset of depression among CKD patient; as it has been shown that CKD patients who lack religious belief presented high score of depressive symptoms compared to those with strong religious belief. This agrees with the theory of Koeing, which suggested that religion has the potential of reducing anxiety and depression in advance medical conditions. The implications of the most powerful (very strong) risk factors in this review strongly suggested that depression in CKD is significantly associated with physical, psychosocial and The outcomes of this study will encourage enactment of policies by the policy makers that will aim at empowering patients with CKD and their relations; in order to address their social and economic challenges as a result of their ailment. Interestingly, the study findings show that religion plays a vital role to the onset of depression in CKD because; people who do not have any religious belief were found to have high depression score compared to those with good religious background. For this reason, the findings will suggest active involvement of religious bodies for the management of depression among CKD patients. It was understood from this study that CKD is a chronic medical illness and that patients with CKD are mostly on maintenance dialysis. This intervention is challenging which made life difficult for patients with CKD. The outcome of the difficulties encountered by CKD patients due to treatment burden make them more likely to be depressed compared to those from healthy population. The study findings in this respect will enable health professionals and even the policy makers' device means through which the burden attached to RRT will be 11697 chances of progression of kidney disease from acute to chronic. In fact reducing the disease progression from acute to chronic would help to address the incidence of depression.
The study limitations are linked with the methodology and the key findings of the included studies. To start with this study was aimed to identify the risk factors of depression among CKD patients; therefore, cross-sectional studies may not be suitable to achieve this task. Gordis states, that cross-sectional study is a prevalence study which is not suitable for establishing causal inference of a disease or an event. Likewise, Gordis suggested that cohort study is open to possibilities of systematic errors because some participants may drop out which may lead to inconsistency and chance of confounding due to multiple causation. Furthermore, having observed the study designs of the included studies the limitations are evident. Firstly, the study of Afsar has evidence of systematic error because the author selected only male patients with CKD; besides, the criteria for selection of participants was age specific which is between 39 and 65 years. These criteria are likely to cause potential risk of selection bias, because there is likely chance of excluding potential participants. This barrier may leads to miss-presentation of target population which may likely affect the reliability of the study outcome. In a related study by Aggnis the researchers noted that one of the measurement tool they used, which is Centre for epidemiological studies-Depression scale cannot measure causation of depression rather it only measure the features of depression. This make the outcomes from Agganis et al.'s study confounding because there is likely hood that the features presented by their study sample may be due to uraemia not depression per say. This is a very important limitation in this study as it was reported earlier in this systematic review that depressive symptoms are very much similar with uremic symptoms. Therefore, Centre for epidemiological studies-Depression scale is not a gold standard tool for diagnosing depression as such the results obtained using this tool may be questionable. Also, Kang et al. explained that they have employed the use of self-report information from patients which proves evidence of the use of antidepressants; by their participants as a measurement tool for identifying depression among study group. This strategy may lead to limitation because it may likely exclude some potential subjects if they are unable to report the use of antidepressant; or in situation where the subjects intentionally decline to give accurate information. Similarly, the use of antidepressant could be as a result of events other than those associated with depression in CKD. Therefore, a systematic error may likely occur due to information bias and wrongful collection of data considering the procedure involved in the study.
It is pertinent at this point to state that one out the eleven articles included in this systematic review has issue with response rate which may raise concern with power analysis and robustness of the study procedure (Burns & Grove 2001;Polit & Beck 2004). The study with low response is the one conducted by Sezer the study has less than 60% response rate from participants. The study was included because according Bowling response rate is not an explicit barrier for excluding a study; however, Bowling confirmed that a response rate above 70% is most appropriate for health research.
Moreover, another limitation to this review was linked with the recruitment procedure adopted by Young. The researchers in their study enrolled participants with CKD based on the inference of causality which is diabetic nephropathy. In this study the causality has positive association with the outcome which is depression. Therefore, the study has a confounding issue which appeared to be the causal path to the risk factor and may result in mixing of effects considering the generalizability of the study findings. This is a major difficulty experience when conducting observational research.
Additionally, not enough literatures were explored to support the rationale for this review; as there where limited secondary studies done in the area of depression on CKD which could be viewed as a limitation. However, the rationale for this review was made clear and focus towards achieving the review's aims and objectives.
Similarly, the timeline and language barrier set in the inclusion and exclusion criteria for this review is likely to result in the exclusion of some useful information. On the issue of time line, the tendency to miss out relevant articles is very much likely and also it is possible that relevant primary articles were excluded because they were not published in English language. Though, the reason for setting these criteria was to access the must up to date articles relevant to the research question. Besides, to achieve a wider understanding of the topic and the lessons learnt from it. Despite, the weaknesses of this review it has some useful implications to the readers considering the findings which materialized.
To start with, the findings will suggest to the readers that patients with CKD are faced with numerous difficulties; which are as a result of their ailment and intervention. Also, it will suggest to readers that the difficulties experienced by CKD patients' influences the onset of depression in CKD. Similarly, it will inform readers that the difficulties could either be dependent or independent risk factors to the incidence of depression in CKD. Additionally, the findings will suggest that the identified risk factors are likely to increase the occurrence of depression among CKD patients.
Moreover, the findings will benefit the readers on the usefulness of psychological reassurance and counselling of CKD patients before they commence RRT; in order to prevent or minimise the onset of depression associated with the treatment burden (RRT).
The findings will suggest to the readers the benefit of physical and economic support to CDK patients who are diagnosed with depression with a view to improving their quality of life.

Conclusion
The occurrence of chronic kidney disease is on the increase worldwide which made the disease a public health issue to deal with.
Patients diagnosed with CKD are often depressed due to disease and treatment burden. Chronic kidney disease patients are left with only two options for their optimum survival which are dialysis or renal transplantation. These interventions are stressful, challenging and economically demanding most especially dialysis which is the common intervention received by the majority of CKD patients.
Detecting depression among CKD patients is problematic because the depressive symptoms and uremic symptoms are very much similar. The limitations of this review are mostly associated with the designs and methodology of the individual studies included; as well as the procedure adopted during the course of screening and selection of the included studies. The key implications of this study include creating awareness on the incidence of depression among CKD patients and its impact on the patients' outcome. Also, the study will benefit public health practitioners to develop measures which will enhance prevention and improvement of health in order to address the incidence of kidney failure in the public. Similarly, the implication of this study will benefit the service providers so they can differentiate the disparities between depressive and uremic symptoms. Most importantly the implication of this study will enhance early detection of depression in CKD in order to improve on the quality of life of victims. Lastly, this study has spiritual implication on the life of CKD patients with depression.