1. IntroductionDiabetic kidney disease (DKD) is a common reno-microvascular complication of diabetes mellitus, and 30 to 40% of people with diabetes progress to DKD [1]. According to the report released by the International Diabetes Federation, the number of patients with diabetes worldwide were 436 million in 2019, and this is estimated to reach 700 million by 2045 [2]. Moreover, China has currently the largest number of diabetic patients, accounting for approximately 116 million among the general population [2]. With the continuous increase in the incidence of diabetes, the prevalence of DKD is expected to rise. Interestingly, it seems that the incidence of DKD in China has surpassed chronic glomerulonephritis, and thus it has become the major contributing factor for chronic kidney disease (CKD) since 2011 [3].Depression and anxiety are common psychological disorders in patients with chronic illnesses. Recent studies have shown that approximately one-third of patients with diabetes suffers from depression disorders [4]. Patients with diabetes are twice as likely to develop depression and anxiety, compared to the general population [5]. Of equal importance is that diabetic complications including DKD are closely associated with depression [4]. Cohort studies have also reported that depression in patients with DKD is at an increased risk of progressing at a faster rate to end-stage renal disease (ESRD) [6]. Similarly, patients with CKD are often seen to have more depressive and anxiety symptoms, which often accompany adverse clinical outcomes, including the accelerated loss of kidney function, frequent hospitalizations, and high mortality rates, as well as poor quality of life [7,8]. Previous studies which focused on patients with diabetes or CKD identified several socio–demographic and clinical factors that could predispose these patients to developing psychopathological distress [4,9]. However, information about the prevalence and risk factors for depression and anxiety among DKD patients, and the association of DKD with a patient’s quality of life (QOL) remain poorly understood, especially in China. Also, little is known about whether and how psychopathological stress influences the progression of DKD.

Considering these findings, it seems essential to comprehensively investigate the QOL and psychological status of patients with DKD, to implement ameliorating supportive strategies for the prevention of depression and anxiety in these patients.

The aim of this study was to assess the prevalence and the relevant influencing risk factors for depression and anxiety among Chinese patients with DKD, and to analyze the predictive value of risk factors. We also explored the relationship between psychopathological issues and clinical outcomes that were adversely affected. The clinical outcomes included renal function, albuminuria, and the QOL in DKD patients. With these results, evidence was provided to offer suggestions for suitable and more optimal strategies for the management of DKD patients.

4. DiscussionThis study discovered that the prevalence rates of symptoms are 41.3% for depression and 45% for anxiety, and this indicates a high prevalence of depression and anxiety states in Chinese DKD patients. These results are comparable to those reported in a Japanese study where 37.3% of DKD patients had depressive symptoms [4], while data pertaining to the prevalence of anxiety in DKD patients are very limited. On the other hand, a series of studies have shown that 11.5–26.3% of diabetes patients have depressive symptoms, and 27.6–30.5% of diabetes patients presented with symptoms of anxiety [22,23,24]. Based on these data, symptoms of depression and anxiety may be more prevalent in diabetic patients with DKD, as compared with those without DKD [24,25]. Similarly, diabetic complications were also found to be associated with a further reduced QOL in diabetes patients [26], all of which indicate an additional negative impact of diabetic kidney complications on the psychopathological state and the QOL among diabetes patients.

In our current model, low education levels, physical inactivity, stroke, lower serum albumin levels, CKD Stages 3–4, macroalbuminuria, and a poor QOL were identified as the risk factors that were significantly associated with depression in DKD patients, while factors notably associated with anxiety were high education level, physical inactivity, neuropathy, retinopathy, lower hemoglobin levels, CKD stages 3–4, and a poor QOL. To our knowledge, this is the first study identifying the independent risk factors associated with depression and anxiety symptoms in Chinese patients with DKD. To further confirm the prediction efficiency of the combination of risk factors, we drew the ROC curve, and both of the AUC were greater than 0.7, which indicated that the above-identified risk factors have a relatively good predictive value for the occurrence of psychopathological disorders in DKD patients. Moreover, our study demonstrated that depression and anxiety were both associated with deteriorating kidney function and a poor QOL, indicating that a poor psychopathological state may be an important factor that exacerbates somatic symptoms and the deterioration of kidney function in DKD patients as well as impairing the health-related quality of life.

Several studies have been performed to explore the risk factors for anxiety and depression in patients with diabetes or CKD. Consistent with previous findings [9,27], we observed that patients with a lower educational level were more likely to develop depressive symptoms; whereas a higher education level increases the risk of having anxiety symptoms. Less-educated individuals may lack the accessibility to reliable information about diabetes and its complications, and this may cause them to worry about their disease status, thereby increasing the risk of developing depression [9]. Pu et al. speculated that patients with a higher education may be more capable of perceiving and recognizing the risk of DKD and they might at times be misled by misinformation, which may cause them to be vulnerable to anxiety [28]. Therefore, for patients with chronic diseases, including DKD, it is important that physicians provide more comprehensive and educational information in order to improve the awareness of the relevant disease and also the potential psychological repercussions. Generally, it is well recognized that lifestyle modification is strongly related to less psychological distress [25]. Our findings complement other studies showing that the lack of physical activity is closely associated with an increased risk of both depression and anxiety among patients with DKD. Cumulative evidence suggests that immune system malfunctions and chronic inflammation are linked to the development of depression [25,29]. In this regard, the protective effect of regular physical exercise on mental disorders in patients with chronic diseases may be attributed to the potential anti-inflammatory and immune function-boosting effects [29].Among the clinical factors we studied, diabetic retinopathy was associated with a higher risk of anxiety, this might be because vision impairment has a detrimental impact on daily activities, social life, and quality of life [30]. Rajput et al. also observed that nephropathy, retinopathy, and ischemic heart disease were significantly associated with depression and anxiety [24]. In addition, we observed that a comorbid stroke influenced mental well-being and increased depression levels in DKD patients. Similarly, a recent study from China has demonstrated that cerebrovascular disease in CKD populations was associated with the increased incidence of depressive symptoms [28]. This correlation may be related to inflammation, autonomic nervous system dysfunction, and platelet aggregation enhancement, all of which have been proposed to explain the link between depression and strokes [31,32]. In this study, a low serum albumin level was noted to be a predictive factor for depression among participants. A low level of serum albumin may reflect malnutrition, which has previously also been shown to be associated with depression and poor clinical outcomes in dialysis patients [33]. Similarly, the present study revealed that low hemoglobin levels were independently correlated with a high anxiety rate, which concurs with several previous studies [34,35]. A low serum hemoglobin, often classified as anemia, which is an important complication of CKD that increases fatigue and dyspnea and negatively affects social activity, may thus be linked to psychological disorders [28,35].DKD is typically characterized by an increased urinary albumin excretion and the progressive deterioration in kidney function, which ultimately may result in ESRD [1]. In the present study, comparing the DKD patients with CKD Stages 1–2 to those with CKD Stages 3–4, we found that the latter group had a significantly higher risk of depression or anxiety. Similarly, a cross-sectional study of 2212 diabetes patients in Japan demonstrated that the later stages of DKD were incrementally associated with more a severe and higher risk of depression [4]. In another study by Campbell et al., participants with a lower eGFR category (eGFR ≤ 29 mL/min/1.73 m2) had twice the risk of depression as compared to those with a high eGFR (≥90 mL/min/1.73 m2) among patients with diabetes and CKD [36]. On the other hand, we also noted that macroalbuminuria was a risk factor that was associated with depression in DKD patients; these results are consistent with other studies showing that there is a significant correlation between albuminuria and the severity of depressive symptoms in patients with CKD and DKD [4,27]. On the other hand, in the regression model, we observed that patients with DKD who had either depression or anxiety were more likely to have advanced stages of CKD and a poor QOL. Moreover, among the DKD patients with psychological symptoms in this study, a high proportion of the patients suffered from both depression and anxiety. It is conceivable that the DKD patients with a combination of depression and anxiety have a higher risk of kidney function deterioration and a poorer QOL, as compared with those who have only one or no psychological disorders; this speculation needs to be confirmed by further studies. Also, although this cross-sectional study was unable to clarify the causal relationship of the eGFR and albuminuria with depression and anxiety, several cohort studies have indicated that depressive symptoms may accelerate the decline of kidney function and contribute to adverse renal disease outcomes [6,37,38]. A 3-year cohort study suggested that CKD patients with depressive symptoms had higher risk for progression to dialysis and an all-cause mortality [37]. Horiba Y et al. reported that the presence of depression has a potential impact on the progression to ESRD in patients with advanced DKD [6]. Zhang Z et al. also reported that depressive symptoms in Chinese adults were significantly associated with a higher risk of the rapid decline of kidney function [38]. The potential mechanisms by which psychological disorders contribute to the deterioration of kidney function were also addressed. Interestingly, several studies have indicated that depression and anxiety may enhance the activity of the hypothalamic–pituitary–adrenal (HPA) axis, which would further increase the glucocorticoid corticosterone levels and leading to the impairment of immune system [39,40]. On the other hand, depressive symptoms are also associated with higher inflammatory cytokines levels, such as C-reactive protein and interleukin-6, which may contribute to systemic inflammation and deteriorating kidney function [37,38]. However, the underlying mechanisms controlling the contribution of depression and anxiety to the loss of kidney function remain largely unknown, and this is certainly worthy of further investigation.Health-related quality of life has increasingly become an important outcome in chronic diseases, including DKD. In this regard, the validated EQ-5D–3L instrument has been shown as a reliable tool to evaluate the QOL of patients with diabetes and its associated complications [41]. Our findings indicated that a poor QOL can increase the risk of depression and anxiety symptoms in patients with DKD. A poor QOL may have a negative impact on an individual’s independence in daily life, the ability to work and various aspects of health, and this may further be associated with developing psychiatric disorders [8]. A recent study using EQ-5D–3L to evaluate the QOL in diabetic patients showed that the QOL was worse in patients with additional diabetic complications [26], and improving the QOL may promote mental health in patients with DKD [25]. Conversely, our study also suggested that depression and anxiety were independently related to a poor QOL. The potential causes of depression and anxiety that adversely affect the QOL in DKD patients are likely to be linked to medication non-compliance, poor nutrition, and negative clinical outcomes [27,42]. These findings highlight the significant association between psychological disorders and the QOL in DKD patients. Comprehensive strategies, including early assessment and proactive treatment of depression and anxiety along with the use of emerging medications, may substantially improve the QOL and clinical outcomes in DKD patients (Table 7).