FormalPara Key Summary Points

Why carry out the study?

The systematic review and meta-analysis comprised 60 studies with various designs

Patients with diabetic nephropathy have a 1.78 times higher risk of depression compared to those without nephropathy

What was learned from the study?

Subgroup analyses consistently demonstrated an increased risk of depression among diabetic nephropathy patients across diabetes types and study regions

The assessment and management of mental health are crucial for patients with diabetic nephropathy

Future research should focus on effective interventions and underlying mechanisms

Introduction

Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycaemia, has become a global public health concern due to its rapidly increasing prevalence and substantial socioeconomic burden [1]. According to the International Diabetes Federation (IDF), an estimated 537 million adults were living with diabetes in 2021, with the number projected to rise to 643 million by 2030 [2]. Diabetes, particularly type 2 diabetes, is associated with various complications that affect multiple organ systems, including the cardiovascular, renal, neurological, and ocular systems [3]. One of the most severe complications of diabetes is diabetic nephropathy, a progressive kidney disease that develops in approximately 40% of individuals with diabetes and is the leading cause of end-stage renal disease (ESRD) worldwide [4].

Diabetic nephropathy not only significantly impacts the quality of life of affected individuals but also contributes to a higher risk of morbidity and mortality [5]. The complex interplay between diabetes and its complications extends beyond physical health, as it is increasingly recognized that the psychological well-being of individuals with diabetes is also adversely affected [6]. Depression, a common mental health disorder, has been identified as a significant comorbidity among individuals with diabetes. Studies have reported that the prevalence of depression in people with diabetes is approximately twice that of the general population [7]. The presence of depression in individuals with diabetes has been linked to poorer glycaemic control, increased risk of diabetes-related complications, reduced adherence to treatment regimens, and diminished quality of life [8].

The association between diabetes and depression is well-established; however, the relationship between depression and diabetic nephropathy remains relatively underexplored. Patients with diabetic nephropathy often face a multitude of challenges, including complex treatment regimens, dietary restrictions, and the need for dialysis or kidney transplantation. These factors, coupled with the knowledge that the condition is progressive and potentially life-threatening, may contribute to the development of depression in this population [9]. Identifying the risk of depression among patients with diabetic nephropathy is of paramount importance, as depression can further exacerbate the severity of the illness, compromise treatment adherence, and increase the risk of adverse outcomes.

Despite the growing awareness of the potential interrelationship between depression and diabetic nephropathy, the literature on this topic is scarce and heterogeneous. Existing studies examining the prevalence and risk factors for depression in patients with diabetic nephropathy have reported varying results, with some studies suggesting a higher prevalence of depression in this population than in individuals with diabetes without nephropathy, while others have found no significant differences [10,11,12,13,14,15]. This discrepancy in findings may be attributed to differences in study designs, sample sizes, assessment tools, and patient populations. Consequently, there is a pressing need to synthesize and critically appraise the available evidence on the risk of depression in individuals with diabetic nephropathy to inform clinical practice, guide future research, and facilitate the development of targeted interventions for this vulnerable population.

In response to this knowledge gap, the present systematic review and meta-analysis aims to provide a comprehensive and robust summary of the existing literature on the risk of depression among patients with diabetic nephropathy. By pooling data from multiple studies, this review seeks to generate more precise estimates of the prevalence of depression in this population, identify potential risk factors associated with the development of depression, and explore the impact of depression on clinical outcomes in individuals with diabetic nephropathy. Ultimately, this review will contribute to a better understanding of the complex interplay between diabetes, diabetic nephropathy, and depression, thereby informing strategies for the prevention, early identification, and treatment of depression in this high-risk population.

Methods

This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16]. We developed our review protocol and research question based on the PECOS (population, exposure, comparisons, outcomes, study design) framework.

Inclusion Criteria

Study Design

There was no restriction in terms of study designs [randomized controlled trials (RCTs), non-randomized controlled trials, interventional studies, observational studies like case-control, cohort, and cross-sectional analytical studies were all eligible for review].

Study Participants

The review included studies on adult individuals aged ≥ 18 years with type 1 or type 2 diabetes. We performed a separate subgroup analysis for type 1 and type 2 diabetes to account for the different characteristics and treatment strategies associated with each.

Exposure and Comparison

Studies examining the risk of depression in patients with diabetic nephropathy compared to a control group of diabetes patients were included.

Outcomes

Primary outcomes included the prevalence or incidence of depression in patients with diabetic nephropathy.

Exclusion Criteria

We excluded review articles, editorials, commentaries, and case reports, as these do not present original research. We focused our review on adult individuals (≥ 18 years old) with either type 1 or type 2 diabetes, thus excluding studies on individuals with gestational diabetes or < 18 years. Additionally, studies that did not use validated assessment tools for evaluating depression were excluded.

Search Strategy

A systematic literature review was conducted by searching multiple databases, including PubMed Central, SCOPUS, EMBASE, MEDLINE, Google Scholar, and ScienceDirect. Our search strategy was developed using a combination of MeSH terms and free-text keywords related to 'diabetes mellitus', 'diabetic nephropathy', and 'depression'. Our choice of search terms was guided by the PECOS framework and by referring to similar reviews published in the literature. Appropriate Boolean operators ("AND" and "OR" and "NOT") were used between the predefined search terms. In addition to the systematic search of the databases, we also manually screened the reference lists of the identified articles and relevant systematic reviews to locate any additional studies that could potentially be included in our meta-analysis. This 'snowballing' technique is widely employed in systematic reviews to ensure a comprehensive literature search and can help to identify studies that might have been missed during the database search. We conducted our search from the inception of each database to March 2023. For MEDLINE, this meant beginning our search from 1964 till March 2023 without any language restrictions (Supplementary text 1).

Study Selection

During the initial stage of study selection, the title, keywords, and abstracts of the studies were screened by two independent investigators. The full texts of the studies meeting the eligibility criteria were retrieved and shortlisted for the second stage of screening. At the second stage, both investigators reviewed the full texts and selected those that met the eligibility criteria. Subsequently, these studies were included in the analysis.

Extracting Data

Once the eligible full-text articles for the review were finalized, the two investigators conducted a manual data extraction process using a predefined semi-structured data collection form that had been established during the protocol stage. For each study included in our review, we extracted the following variables using a standardized data collection form: author information and year of publication, country, study design, type of diabetes, sample size, study setting, criteria or data source used for diagnosing diabetic nephropathy, tool used for assessing depression, criteria for depression, mean age of participants, duration of diabetes, prevalence of diabetic nephropathy, prevalence of depression, co-morbidities, specific interventions and/or treatments, and any other factors that could potentially influence the association between diabetic nephropathy and depression. Risk of bias assessment was also conducted for each study. The first author recorded the data, and the second author reviewed the data entry for accuracy.

Risk of Bias

While our initial search strategy was designed to include both RCTs and observational studies, the final selection for our review comprised exclusively of observational studies. As such, we used the Newcastle-Ottawa (NO) Scale to evaluate the risk of bias within these studies [17]. The NO scale assesses the risk of bias based on selection, comparability, and outcome domains. The studies were identified to have low, high, or some concerns regarding bias risk based on the assessment criteria.

Statistical Analysis

The statistical analysis for this review was conducted using STATA version 14.2. As the outcome is binary (i.e., presence of depression), the frequency of events and participants in the diabetic nephropathy and control groups were entered, and the odds ratio (OR) with 95% confidence interval (CI) was calculated. The random-effects model with inverse variance technique was used [18]. Heterogeneity was assessed using the chi-square of heterogeneity and I2 statistic [18]. P value < 0.05 was indicative of substantial heterogeneity. Sensitivity analysis was conducted to identify the effects of individual studies on the pooled estimates. The funnel plot and Egger’s test were used to assess publication bias. P value < 0.05 indicates the possibility of presence of publication bias. Subgroup and meta-regression analyses were conducted to investigate the origin of heterogeneity.

Compliance with Ethical Guidelines

Ethics Committee Approval

Ethics committee approval was not required for this systematic review as it involved the synthesis and analysis of existing data from previously published studies. A systematic review does not involve direct contact with human subjects or the collection of new data. Instead, it entails the comprehensive and systematic analysis of data that have already been collected and reported in the literature. Therefore, obtaining ethics committee approval was deemed unnecessary for this study.

This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.

Results

Search Results

During the initial screening, we identified 2241 citations from different databases. After eliminating duplicates, 146 full-text studies were obtained, which were then narrowed down to 142. Moreover, we discovered four articles by examining the bibliographies of the screened studies. Following the secondary screening process, we incorporated data from 60 studies that satisfied the inclusion criteria (Fig. 1) [10,11,12,13,14,15, 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72].

Fig. 1
figure 1

Search strategy

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Characteristics of Studies Included

Most studies were conducted in India (9 studies), followed by Saudi Arabia (8 studies), the USA (6 studies), and China (5 studies). The majority of the studies included in our review (48 in total) employed a cross-sectional design, while the remainder were prospective cohort studies. However, in a few of these cohort studies, we only utilized the cross-sectional data, as the longitudinal data were collected with a different objective in mind. Forty-five out of 60 studies were conducted amongst type 2 diabetes mellitus patients, while rest were conducted amongst type 1 diabetes mellitus patients or both type 1 and 2. Patient Health Questionnaire (PHQ) was the most common scale used for assessing the depression. Medical records or self-reported data were the most common form of diagnosis for diabetic nephropathy. As all the studies included in our review turned out to be observational studies, we used the Newcastle-Ottawa Scale (NOS) for assessing their quality and risk of bias. There was almost equal distribution of high and low risk of bias studies (Table 1).

Table 1 Characteristics of the included studies (N = 60)
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Risk of Depression Amongst Patients with Diabetic Nephropathy

A total of 60 studies were included in our systematic review, with some reporting data as the number of events and participants and others reporting it as odds ratios. In total, 56 studies reported the aggregate data on number of events and participants. The pooled OR was 1.78 )95% CI 1.56–2.04; I2 = 83%). This indicates that the patients with diabetic nephropathy had significantly higher odds of developing depression compared to those diabetes patients without nephropathy (p < 0.001) (Fig. 2). Thirty-two studies reported the risk of depression in terms of odds ratio/risk ratio. Pooling the effect size across these studies showed that the pooled OR was 1.15 (95% CI 1.14–1.16; I2 = 88%; p < 0.001) (Supplementary Fig. 1).

Fig. 2
figure 2

Forest plot showing the risk of depression between diabetic nephropathy and non-nephropathy diabetic patients

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Subgroup Analysis

Subgroup analysis was performed for studies focusing on type 1 diabetes and type 2 diabetes separately to account for the distinct characteristics and disease profiles of each population. Analysis based on type of diabetes did not reveal a significant difference in terms of pooled estimate. The pooled OR for risk of depression amongst type 1 diabetes mellitus was 1.86 (95% CI 1.47–2.35; I2 = 59%; n = 6) and amongst type 2 diabetes mellitus was 1.78 (95% CI 1.48–2.16; I2 = 82%; n = 41), respectively (Fig. 3). Analysis including only longitudinal study data still revealed a significant association between depression and diabetic nephropathy (pooled OR = 1.50; 95% CI 1.16–1.95; I2 = 84%; n = 5; p = 0.002) (Fig. 4). Subgroup analysis based on study region also revealed that the effect size was almost similar across all the regions (Fig. 5). Analysis based on depression tool was not possible given the wide variation in the tool utilized by the individual studies.

Fig. 3
figure 3

Subgroup analysis based on the type of diabetes mellitus

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Fig. 4
figure 4

Forest plot showing the longitudinal risk of depression between diabetic nephropathy and non-nephropathy diabetic patients

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Fig. 5
figure 5

Subgroup analysis based on study region

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Additional Analysis

Publication bias assessment showed that the funnel plot was asymmetrical with statistically significant Egger’s test (p < 0.001) (Supplementary Fig. 2). Meta-regression was performed using the covariates such as study design, region, setting, diagnostic tool for depression, sample size, mean age, type of diabetes mellitus patients, and quality of the studies to explore the high heterogeneity. However, none of these factors were found to be a source of heterogeneity. Sensitivity analysis did not show any difference in terms of effect size or direction for any of the above outcomes. This suggests that there were no single-study effects with respect to any outcomes (Supplementary Fig. 3).

Discussion

This systematic review and meta-analysis aimed to evaluate the risk of depression in patients with diabetic nephropathy. By incorporating data from 60 studies, the results revealed a significantly increased risk of depression in patients with diabetic nephropathy compared to diabetes patients without nephropathy. This finding highlights the importance of addressing mental health concerns in patients with diabetic nephropathy, given the potential impact on overall well-being and treatment adherence.

Our study found that the odds of developing depression in patients with diabetic nephropathy were 1.78 times higher than in those without nephropathy. The increased risk persisted across different types of diabetes (type 1 and type 2), study designs, and regions. The association remained significant even when considering only longitudinal studies, suggesting a temporal relationship between diabetic nephropathy and depression risk. These findings are consistent with previous literature reporting a higher prevalence of depression among individuals with complications from diabetes, including nephropathy, retinopathy, and neuropathy [73,74,75]. However, the wide variation in depression assessment tools utilized by the individual studies precluded a meaningful subgroup analysis based on the diagnostic methods.

Our findings call for additional research to explore the underlying biological mechanisms that may contribute to the increased risk of depression in patients with diabetic nephropathy. Potential mechanisms could include the role of inflammatory processes, oxidative stress, and neuroendocrine dysregulation in the development of both diabetes complications and depression [76]. A better understanding of these mechanisms may pave the way for novel therapeutic targets and strategies to address depression in the context of diabetic nephropathy.

Nonetheless, the observed association between diabetic nephropathy and depression may be explained by various factors. Patients with diabetic nephropathy often experience physical discomfort, fatigue, and sleep disturbances, which are known to contribute to depressive symptoms [77]. Additionally, the burden of managing a complex chronic illness such as diabetic nephropathy, including the need for strict dietary and medication regimens, frequent medical appointments, and possible dialysis, may lead to feelings of helplessness and hopelessness, which are hallmarks of depression [78]. Moreover, the bidirectional relationship between diabetes and depression has been previously reported [73], suggesting that the presence of depression may exacerbate diabetic nephropathy, thus creating a vicious cycle.

The high heterogeneity observed in our meta-analysis can be attributed to the diverse methodologies and tools employed in the included studies. Differences in diagnostic criteria for depression, study settings, and patient populations might have contributed to the variation in the reported effect sizes. However, the high heterogeneity observed in our meta-analysis warrants further investigation, as we were unable to identify any specific factors contributing to the observed variability through meta-regression. Nonetheless, the overall effect estimate remained significant and robust in sensitivity analyses, indicating that our findings are unlikely to be affected by single-study effects.

Our study has several implications for clinical practice and future research. First, healthcare providers should be aware of the increased risk of depression among patients with diabetic nephropathy and should consider incorporating routine mental health screening into the management of these patients. Timely identification and treatment of depression can improve patients' quality of life and may enhance adherence to diabetic care, potentially reducing the risk of further complications. Second, multidisciplinary care teams, including mental health professionals, should be involved in the management of patients with diabetic nephropathy to ensure a comprehensive approach to care. Third, future research should investigate the effectiveness of targeted interventions aimed at reducing depression risk in patients with diabetic nephropathy, such as psychoeducation, cognitive-behavioral therapy, and psychopharmacological treatments.

Furthermore, our study underscores the need for increased awareness and education among patients with diabetic nephropathy regarding the potential risks associated with depression. Patient empowerment through self-management support programmes and psychoeducation can help individuals better understand their condition, cope with emotional challenges, and actively engage in their treatment plan. Involving family members and caregivers in the education process may also help create a supportive environment that fosters emotional well-being.

There are several notable strengths of our review that contribute to the robustness and reliability of our findings. We employed a rigorous and comprehensive search strategy across multiple databases to ensure a broad representation of the available literature, which minimized the risk of missing relevant studies. The inclusion of studies from various countries and settings provides a global perspective on the association between diabetic nephropathy and depression risk. The inclusion of data from 60 studies with a large total number of participants increases the statistical power of our analysis and improves the precision of our effect estimates, lending more confidence to our conclusions. We conducted several subgroup analyses based on factors such as type of diabetes, study design, and geographic region, which allowed us to explore potential sources of heterogeneity and examine the robustness of our findings across various contexts. Sensitivity analyses further confirmed the stability of our results, indicating that no single study had an undue influence on the pooled effect estimates. We systematically evaluated the risk of bias in the included studies using established tools for different study designs, providing a transparent appraisal of the quality of the evidence contributing to our review. These strengths bolster the credibility of our review findings and their implications for clinical practice and future research.

There are some limitations to our study. First, the majority of included studies were cross-sectional in design, limiting our ability to infer causality. Second, the high heterogeneity across studies may have affected the precision of our effect estimates. Third, potential publication bias was detected, which might have led to an overestimation of the association between diabetic nephropathy and depression risk. Fourth, inability to adjust for potential confounding variables in our meta-analysis, such as disease duration, socioeconomic status, and the presence of other diabetes-related complications, and stage of diabetic nephropathy, all of which could independently influence the risk of depression. Future research should aim to investigate the association between depression and different stages of chronic kidney disease (CKD) more comprehensively, considering the potential impact of treatment regimens, lifestyle modifications, and other factors specific to each CKD stage. Additionally, exploring the underlying reasons for depression in individuals with early-stage CKD, beyond the direct influence of diabetic nephropathy, would provide valuable insights into the multifaceted nature of depression in this population. Finally, inclusion of a diverse range of study designs might introduce methodological heterogeneity. However, this approach was adopted to capture the broadest possible range of available evidence linking diabetic nephropathy and depression.

Conclusion

Our systematic review and meta-analysis demonstrate a significant increase in the risk of depression among patients with diabetic nephropathy. Given the potential impact of depression on patients' quality of life and treatment adherence, healthcare providers should be vigilant in identifying and addressing mental health concerns in this population. Comprehensive, multidisciplinary care, including mental health support, is essential for managing both the physical and psychological aspects of diabetic nephropathy. Future research should focus on developing and evaluating targeted interventions to reduce depression risk and improve overall well-being in patients with diabetic nephropathy.