Introduction

Chronic kidney disease (CKD) is characterized by progressive renal injury with inevitable functional deterioration. This functional loss is usually slow, progressive and irreversible [1]. The frequency of end-stage renal disease (ESRD) in the Brazilian pediatric population is still uncertain, but the authors of a study conducted in São Paulo reported 23.4 cases of ESRD per million children and adolescents [2]. However, pre-dialysis stages of CKD still remain underdiagnosed and underestimated in pediatric patients since most data sources rely on information gathered from dialysis and/or transplant centers [2, 3].

CKD can profoundly influence the daily routines of pediatric patients and their families, requiring significant social adaptation by both patient and family [4]. Ideally, the management of CKD in children and adolescents requires a multidisciplinary team [1]. Although marked therapeutic advances have been made in recent years, CKD can be especially devastating to the pediatric patient because of its high mortality rate (up to 30-fold higher than that of same-age children in the general population) [5] and frequent hospitalizations, with significant impairment of health-related quality of life (HRQoL) [4, 6]. Despite the limited information currently available in pediatric CKD, research has confirmed that HRQoL is generally compromised, with CKD patients scoring lower than their healthy peers [4, 6–8]. However, Varni and co-workers reported that children with ESRD exhibited better emotional scores of HRQoL than children with other chronic diseases, including diabetes, asthma, cerebral palsy and cardiac and rheumatologic diseases [9].

The behavioral response to chronic diseases in childhood and adolescence has been studied over the past years, with somewhat conflicting results [10–14]. Meta-analyses have confirmed an increased risk for overall adjustment disorders in these children and adolescents [10, 11], with impaired development of self-concept or self-esteem and an elevated prevalence of externalizing (e.g. hyperactivity or aggression) or internalizing symptoms, such as anxiety, social withdrawal and depression [10, 11]. Accordingly, screening for psychiatric symptoms and signs of psychological distress should be a concern of pediatric health practitioners and others working with children with chronic illnesses [10]. CKD studies in the pediatric patient population have found an elevated frequency of psychiatric disorders, with the most commonly observed disorders being adjustment disorders, depressive symptoms, anxiety and cognitive impairment[4, 12–14]. However, the association between clinical or laboratory features, disease duration and severity and psychological variables remains undetermined [4, 10–14].

The concept of resilience has emerged from studies on successful adaptation despite challenging or threatening circumstances [15]. The first subjects of such studies were children who had been exposed to stressful environments or traumatic events and who had, theoretically, a higher risk for developing psychopathological conditions but who had managed to overcome related difficulties. Therefore, resilience refers to an adaptive behavior associated with either internal states of well-being or adequate functioning in the environment and can be also defined as “a dynamic, multidimensional process, which results in positive adaptation in adverse contexts” [16]. Resilience in the context of CKD is much less investigated. Ma et al. [17] found that pre-dialysis adult patients had lower scores of resilience than newly diagnosed CDK patients and high-risk individuals (families of CKD patients) and that resilience positively correlated with health-promoting behaviors. Lee et al. [18] reported that hemodialysis patients with more depressive symptoms had lower resilience scores in the Hamilton Depression Rating scale. In their 2007 multi-center study, Varni et al. [9] used the Child Health and Illness Profile—Adolescent Edition (CHIP-AE) to assess resilience in children with CKD. The resilience domain of the CHIP-AE consists of the subdomains Family Involvement, Physical Activity, Social Problem-solving, and Home Health and Safety, and the higher the score, the better the functioning of the patient for that subdomain. CKD patients scored higher than the control group of healthy adolescents in the subdomain Home Health and Safety and did not differ in their total score from the controls. Dialysis patients scored lower than pre-dialysis and post-transplant patients [9]. To our knowledge, there are no studies that have evaluated resilience in children and adolescents with pre-dialysis CKD using specific resilience scales. The last report of the National Institutes of Health task force on research priorities in CKD in children pointed out the need for research into secondary prevention of depression in children and their parents and into the contribution of education and lifestyle, together with methods to facilitate rehabilitation, maximize educational experience and assess self-esteem and self-worth [19].

The aim of this study was to investigate resilience, QoL, anxiety and depressive symptoms in children and adolescents with pre-dialysis CKD and compare these values to those of healthy controls. Our hypothesis was that pre-dialysis CKD children and adolescents are at risk for a lower HRQoL and for psychiatric disorders, with higher morbidity possibly related to disease duration or severity, as well as to other clinical or laboratory variables. The capacity for resilience, on the other hand, would be a protective factor. The identification of co-morbidities in children with CKD could help decrease the burden of CKD.

Methods

Study design

This cross-sectional study included 28 pediatric pre-dialysis CKD patients (stages 1–4) followed-up at the Pediatric Nephrology Unit, UFMG University Hospital, from June to December 2013 and 28 healthy controls who were age- and sex-matched, from public schools located in the same geographic area. Diagnostic criteria for CKD were based on the National Kidney Foundation’s Kidney Disease Outcomes Quality Practice classification [20].

The local Ethics Committee evaluated and approved this study. Informed consent was obtained from all parents, CKD patients and healthy controls included in the study. The research protocol did not interfere with any medical recommendation(s) or prescriptions.

Inclusion and exclusion criteria

CKD patients

All CKD children and adolescents at CKD stages 1–4 who were followed-up at UFMG University Hospital from June to December 2013 and for whom an informed consent form was obtained were eligible for enrolment in the study. Patients with acute illness (e.g. infections, clinical instabilities or glomerular disease activity) were not scheduled for interviews during the period of the acute illness or disease activity. Literate individuals of both sexes, regardless of socioeconomic status, were included. The age of the patients ranged from 9 to 18 years. Exclusion criteria were hearing impairment, writing or reading disabilities and previous diagnosis of intellectual disability or autism spectrum disorders (eight patients were excluded and three refused to participate).

Controls

The control group consisted of healthy sex- and age-matched children from public schools who gave informed consent to take part in the study. All controls were normotensive and had no medical or family history of renal diseases. Healthy status was determined through a review of the medical history and either a parental report or self-report to rule out the presence of chronic or acute diseases. Subjects with hearing impairment, writing or reading disabilities and a previous diagnosis of intellectual disability or autism spectrum disorders were excluded.

Study protocol

After informed consent had been provided, CKD patients, controls and their parents were asked to complete several psychometric instruments that are designed for evaluation of anxiety, depressive symptoms, HRQoL and resilience, as detailed in the section Demographic and psychological assessment. Clinical and laboratory data were already available as part of the routine protocol for managing CKD patients at our unit, as described in detail elsewhere [1, 21]. Medical visits were scheduled at intervals of approximately 3 months, and a complete physical examination and battery of laboratory tests were repeated on each occasion. Glomerular filtration rate (GFR) was estimated (eGFR) adopting the original Schwartz formula [22]. Associated conditions were managed as per our unit protocol. Supplements of electrolytes, vitamin D and erythropoietin were given according to standard recommendations [23, 24]. Blood pressure was classified according to the Fourth Task Force guidelines [25], and antihypertensive drugs were used for patients with blood pressure persistently above the 95th percentile.

Clinical and laboratory measurements

Clinical characteristics, anthropometric measurements and laboratory test results were evaluated during the clinic visit and by reviewing medical records at the time of interview. Clinical data included gender, age, height, weight, body mass index, etiology and stage of CKD and the presence of hypertension.

Laboratory tests included serum levels of creatinine, hemoglobin, albumin, cholesterol, triglycerides, total calcium, phosphorus, bicarbonate, parathormone and uric acid; in addition, the ratio between protein and creatinine in spot urine was analyzed. GFR was calculated by Schwartz’s equation [22] to classify CKD stage [20].

Demographic and psychological assessment

Demographic data were collected by interview with the parents or caregivers of the patients and controls. Delayed educational attainment was defined as an inadequate correspondence between the subject’s age and school level.

All psychometric instruments used for psychological assessment were read to the participants to reduce differences due to educational levels and performance.

Resilience

The Wagnild and Young Resilience Scale [26] was used to evaluate resilience. This instrument has been validated by Pesce et al. [27] for Brazilian adolescents. It contains 25 affirmative items with a Likert-type scale response from 1 (strongly disagree) to 7 (strongly agree). The scores range from 25 to 175 points, with higher values indicating higher resilience.

Quality of life

We used the Pediatric Quality of Life Inventory 4.0 (PedsQLTM; referred to further in text as the PedsQL) to evaluate the QoL. This instrument was designed by Varni et al. [28] with the aim to measure HRQoL as outlined by the World Health Organization. It consists of 23 items, which are inversely scored and subsequently translated to a scale of 0–100, meaning that the higher the score the better the QoL. It was validated in Brazil by Klatchoian et al. [29]. The results assess physical and psychosocial dimensions in four multidimensional subscales, namely, physical functioning (8 items), emotional functioning (5 items), social functioning (5 items) and school functioning (5 items), and measures a total (global) scale (23 items) score and psychosocial (15 items) score.

Psychiatric symptoms

  • Child Depression Inventory (CDI): This instrument is an adaptation of the Beck Depression Inventory which is based on the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. CDI was developed by Kovacs [30] to screen young people (age 7–18 years) for depressive symptoms. It is composed of 27 items with three possible responses, scored from 0 to 2. The cut-off point of 18 has been used for the Brazilian population [31].

  • Self-report for Childhood Anxiety Related Disorders (SCARED): This instrument was designed by Birmaher et al. [32] to screen for symptoms of anxiety. It consists of 41 items, and five subscales or factors, which are in correspondence to DSM-IV anxiety disorders. Each item has three options of answers, with scores of 0 (never or almost never), 1 (sometimes) or 2 (often). Total scores can range from 0 to 82. It can also be scored per subscale: panic/somatic, generalized anxiety, separation anxiety, social phobia and school phobia. The total cut-off point for the Brazilian population was set at 22 [33].

Statistical analysis

The software Statistical Package for Social Sciences (SPSS) version 16.0 (Chicago, SPSS Inc, 2007) was used for statistical analysis. Values were expressed as the median and range (minimum and maximum values) or as the mean and standard deviation, where appropriate. Dichotomous variables were expressed as numbers and percentages and compared using the chi-square test. The normality of the distribution was evaluated by the Shapiro–Wilk test and histogram for each group. The unpaired Student’s t test was used to compare means when normally distributed variables were assessed, while the Mann–Whitney and Kruskal-Wallis tests were used to compare medians between two and three or more groups, respectively. The analysis of dichotomous variables was performed using the chi-square test. The Spearman test was used to evaluate correlations. The level of significance was set at p < 0.05.

Results

CKD patient characteristics

In CKD patients the average disease duration was 11.7 ± 3.3 years, which was very similar to the duration of treatment or follow-up (11.0 ± 3.3 years). The majority of CKD patients (67.9 %) were prescribed anti-hypertensive drugs. Only one patient was using a psychotropic drug (fluoxetine 10 mg) which had been prescribed due to overweight. Two patients (7 %) were hospitalized in the previous year. In terms of the causes of CKD in our patient population, the most predominant were congenital anomalies of the kidney and urinary tract (CAKUT) (50 %), followed by glomerular diseases (17.9 %), cystic diseases (10.7 %) and other causes (21.4 %). Regarding the stage of CKD, six patients were at stage 1 (21.4 %), seven at stage 2 (25 %), eight at stage 3 (28.6 %) and seven at stage 4 (25 %). Clinical and laboratory features are shown in Table 1.

Table 1 Clinical characteristics, etiology of chronic kidney disease (CKD), CKD stages and laboratory values of children and adolescents with pre-dialysis CKD
Full size table

When patients were grouped according to stage of CKD, there was no difference among subgroups in terms of age, disease or treatment duration, number of medications in use and SCARED, CDI, PedsQLTM and resilience scale scores. There was also no difference when patients with CKD stages 1 and 2 were combined and compared to those with stages 3 and 4 combined. There was no significant correlation between the psychological variables and either laboratory values or eGFR (data not shown).

Demographic factors

Children and adolescents with CKD did not differ from controls in terms of age, sex or school attendance (Table 2). However, there was a significant difference in the frequency of grade retention (p < 0.001), delayed educational attainment (p < 0.001) and interruption of studies (p = 0.004), with 32 % of CKD patients having interrupted their studies at some point (for an average of 4.8 months), among whom 44.4 % attributed this interruption to CKD or its treatment. Sixteen (57 %) children and adolescents with CKD were delayed in school. There was also a difference regarding a history of previous psychiatric or psychological treatment(s), which had occurred in ten patients with CKD (35.7 %) compared to only one of the controls (3.6 %) (p = 0.002).

Table 2 Social, demographic and educational characteristics of the pediatric patients with chronic kidney disease (CKD) and the controls
Full size table

Resilience and QoL

The resilience scores did not differ between patients and controls (Table 3). In the univariate analysis, resilience was not associated with grade retention, delayed educational attainment or interruption of studies. Resilience also did not correlate with either the years of schooling or the length of school absenteeism. The univariate analysis did reveal an association between lower scores of resilience and clinically significant depressive symptoms (Table 4). There was no significant correlation between resilience and other psychological scores in CKD patients, whereas, in the control group, resilience was negatively correlated with CDI score (r = −0.496, p = 0.007).

Table 3 Scores of resilience and quality of life (Peds-QLTM) in children and adolescents with chronic kidney disease (CKD) and the controls
Full size table
Table 4 Univariate analyses including gender, previous psychiatric treatment and depression in children and adolescents with chronic kidney disease
Full size table

The results for HRQoL were significantly lower in the group of CKD patients for the global, psychological, educational and psychosocial dimensions of the PedsQL. Surprisingly, QoL scores did not significantly differ in the physical dimensions (Table 3). In CKD patients, male sex was associated with impaired social HRQoL (p = 0.027; Table 4). Previous psychiatric treatment was associated with worse HRQoL scores. There was no difference in terms of adequate education or interruption of studies due to illness.

Anxiety and depression

Anxiety and depressive symptoms in CKD patients and controls are shown in Table 5. There was no difference between the scores of global anxiety and depressive symptoms among children and adolescents with CKD and controls. For the SCARED subscales, CKD patients showed higher scores only in the subscale separation anxiety (p = 0.018). When subjects were categorized based on each subscale’s cut-off score, children and adolescents with CKD exhibited higher frequencies of clinically significant depressive symptoms (p = 0.04) compared to controls. On the other hand, clinically significant anxiety was similar in both groups. In the control group, girls showed more symptoms in the panic subscale (p = 0.029).

Table 5 Psychiatric symptoms in chronic kidney disease patients and controls
Full size table

Depressive and anxiety symptoms negatively correlated with all domains of HRQoL (r values varying from −0.385 to −0.652, with p values ranging from 0.001 to 0.043, and r values varying from −0.399 to −0.748, with p values ranging from 0.001 to 0.035). Disease duration negatively correlated with psychosocial, psychological and school domains of PedsQL TM (r values varying from −0.444 to 0.586, with p values ranging from 0.001 to 0.026) and positively with the scores of CDI (r = 0.425, p = 0.027) and SCARED (r = 0.404, p = 0.037).

Discussion

The aim of this study was to investigate resilience, HRQoL, anxiety and depressive symptoms in pediatric CKD patients and to compare the scores of this patient group to those of age- and sex-matched healthy peers. Since studies focusing on pre-dialysis CKD in children and adolescents are scarce, the evaluation of this population is important for delineating more effective interventions to alleviate disease burden. In our study, children and adolescents with CKD had lower scores for HRQoL in comparison to the controls, regardless of their clinical severity. Depressive and anxiety symptoms negatively influenced HRQoL perception. Moreover, lower resilience scores were associated with clinically significant depressive symptoms.

In terms of the main causes of CKD, our sample was comparable to those of previous studies with the same age interval [4, 9]. The overlap of disease and treatment duration may also reflect the higher frequency of congenital and hereditary abnormalities in our sample.

We found a significant difference in the frequency of grade retention, delayed educational attainment and interruption of studies between CKD patients and matched controls. This high frequency of patients with delayed educational attainment may be indicative of possible cognitive impairment related to CKD [34]. It is worth mentioning that cognitive performance can be aggravated by school absenteeism. Delayed educational attainment was also described by Roscoe et al. [35] who reviewed medical records of 118 adolescents with CKD. These authors reported a delay in educational acquisition in all age groups and that 22 % of CKD adolescents did not finish high school. In a study which included adults with CKD since childhood, Morton et al. reported that 71 % of patients stated that they had interrupted their study due to illness [36]. In our study we also found marked differences in school attendance between controls and CKD patients, with 57 % of our patients reporting delayed educational acquisition—although this value is still within the average statistics for our country. The rate of age/grade inadequacy (percentage of children attending school who are not in their expected grades) in southeastern Brazil was between 37.4 and 68 % in 2000 according to a Brazilian census [37].

A previous history of psychiatric and/or psychological treatment may reflect a greater vulnerability to the development of psychiatric or behavioral disorders. In the study of Morton and colleagues, 47 % of CKD patients reported psychological problems during childhood, of whom 27 % had been referred for treatment [36]. In our sample, the frequency of previous referrals to a psychologist and/or a psychiatrist was 35.7 % among CKD patients, compared with only 3.5 % of controls. This finding was also associated with poorer overall HRQoL scores, and lower scores in the school, social and psychosocial subdomains.

Adjustment to chronic illness and the risk of behavioral morbidity is a complex and continuous process in which a variety of factors, other than disease-related parameters may influence psychosocial adjustment [11, 38]. Depression is one of the most studied psychiatric disorders and the most frequently in patients with ESRD [38, 39]. In our sample the average scores on the CDI did not differ between patients and controls. However, while the percentage of children and adolescents with CKD who exhibited clinically significant depressive symptoms was 14.3 %, none of the controls scored above this cut-off point in the CDI. Kogon et al. [14], also using the CDI, found a similar overall frequency (18 %) of clinically significant depressive symptoms in patients with CKD, with patients on dialysis being less likely than patients with pre-ESRD to be depressed. Using the Beck Depression Inventory to measure depression, Penkower and co-workers [40] identified a higher percentage (36.4 %) of significant depressive symptoms among adolescents 3 months after renal transplant.

The frequency of anxiety symptoms found in both CKD patients and controls is higher than that in the general population. However, the authors of the SCARED validation study in Brazil [33] found a prevalence of 37 % of at least one anxiety disorder, with mean scores of 23.51, which are similar to those scores of our controls (22.8). This elevated frequency might be explained by the screening nature of this highly sensitive tool. Similar to our results, Kilis-Pstrusińska and colleagues [12] found no significant correlation between anxiety symptoms and clinical or laboratory parameters of CKD.

Fukunishi and colleagues [13] reported that 65.4 % of their a sample of 53 children and adolescents with CKD had separation anxiety. The percentage of our sample demonstrating this anxiety symptom, using the cut-off validated for the Brazilian population [33], was 22.7 %. While the average age in Fukunishi et al.’s study was 9.4 and 9.7 years for patients on peritoneal dialysis and post-transplant, respectively, the average age of our sample was 13.7 years. Separation anxiety affects around 5 % of children in the general population [41], but its frequency decreases as the children get older. Separation anxiety is associated with an increased risk of developing other psychiatric disorders, such as panic disorder [42]. Anxiety in children and adolescents with medical illnesses may develop in response to several factors. Pao and Bosk [43] proposed that anxiety could predispose biological mechanisms related to the disease itself as a response to being ill or in the hospital or as a result of genetic and other psychosocial factors. Also, parental anxiety can lead to interactions that are maladaptive in the long-term, determining separation difficulties, school phobia, body overconcern/dissatisfaction and school underachievement—a situation also referred to as the ‘vulnerable child syndrome’ [43, 44]. The 22 % frequency of separation anxiety found in our sample, composed mostly of teenagers, could be indicative of problems of children and adolescents with CKD in developing and acquiring autonomy [45].

In an attempt to investigate factors associated with psychiatric symptoms and impaired HRQoL, we included an evaluation of resilience in our study. Resilience has been conceptualized as a moderating factor between the burden associated with chronic diseases and the possibility of positive response to this burden [16]. In our study, resilience scores were similar in patients and controls, but lower scores were associated with depressive symptoms. This finding may indicate that children and adolescents with CKD may develop adaptive mechanisms to deal with the disease. Indeed, resilience does not equate to the suppression or avoidance of stress, but to the management of stressors in a positive manner, increasing self-confidence and social competence [46]. Resilience was not associated with school attendance or with demographic and social parameters in our sample.

It is well established that multidisciplinary care improves the clinical outcomes (such as anemia management, bone mineral metabolism, nutrition) and renal disease progression in CKD pediatric patients [47]. The support of such a management team, which in our Pediatric Nephrology Unit consists of pediatric nephrologists, nurses, psychologists, nutritionists and social workers, may also have influenced the positive resilience scores among our patients, as previously described by Grunberg in a case study [6]. Resilience scores were lower among patients with clinically significant depressive symptoms, as has also been observed in previous studies [18, 48]. In addition, resilience scores were inversely correlated with depressive scores in the control group. Resilience, therefore, could be a protective factor against the development of psychiatric co-morbidity, especially depressive disorders. On the other hand, screening and identifying depression earlier could also favorably promote resilience [18]. An educational–behavioral intervention program (COPE), which included increasing parent information and participation in child care and activities (such as puppet play and stories about a young child who successfully copes with a stressful hospitalization), resulted in significantly fewer adjustment disorders in hospitalized children [49].

As with other chronic diseases and for adult patients with CKD, studies have identified impairment in HRQoL in children and adolescents with CKD [4, 6–9]. In our study, children and adolescents with pre-dialysis CKD achieved worse scores than controls in the global scores and in the psychological, educational and psychosocial subdomains. These findings are similar to those reported previously [4, 6–9].

More advanced stages of CKD were not associated with psychological variables, but we did study identify a correlation between patient age and disease duration and worse HRQoL scores. In addition, depressive symptoms negatively correlated with all (sub)domains of HRQoL, as observed in other studies [4, 50].

One of the major limitations of our study was the sample size, which was restricted by the age limits and by the inclusion of only pre-dialysis CKD patients. Another important limitation was the use of screening instruments of psychiatric symptoms and not structured clinical interviews for formal psychiatric diagnoses. Our evaluation included clinical and laboratory variables of CKD, but these patients may be under the influence of many other stressors that we were unaware of or unable to take into account. Future studies evaluating psychiatric morbidity and the HRQoL of caregivers could provide more information on these stressors. Longitudinal follow-up of these children and adolescents might clarify the role of resilience and psychiatric disorders on the progression of CKD. Although this was a cross-sectional study, it contributes to a broader understanding of pre-dialysis CKD pediatric patients since psychiatric morbidity, resilience and HRQoL were regarded as research priorities in the last report of the NIH Task Force [19].

In conclusion, the QoL of children and adolescents with pre-dialysis CKD was impaired compared to that of the controls, without any association with clinical or laboratory parameters. Patients and controls exhibited similar scores of resilience, but CKD negatively influenced HRQoL, contributing to a higher frequency of depression and separation anxiety in the pediatric CKD patients. More studies are needed in the pediatric population, especially those addressing factors associated with the promotion of resilience and the development of psychiatric symptoms or HRQoL impairment in CKD.