Fatigue assessment and its predictors in pediatric patients with chronic kidney disease stages III to V

Chronic fatigue is an intense subjective feeling of mental or physical exhaustion. It influences patients’ daily functioning and quality of life, delays recovery, and increases mortality, especially in chronic kidney disease (CKD) patients. The aim of this study is to assess and determine predictors of chronic fatigue in children with ESRD, dialysis, and pre-dialysis stages that can affect the patients’ quality of life (QOL). We conducted a cross-sectional study on 114 patients diagnosed with CKD stages III to V, following at the nephrology outpatient clinic and hemodialysis (HD) unit of Cairo University Children’s Hospital during the period September 2020 till April 2021. Demographic and laboratory data of patients were gathered, and dialytic analysis in the form of frequency, duration of dialysis sessions, and adequacy of hemodialysis was calculated. The fatigue severity score (FSS) questionnaire was used to assess fatigue’s effects on daily functions, querying its relationship to motivation, physical activity, work, family, and social life. The mean age in the current study was (8.8 ± 1.8) years, with 62% being males. The median FSS score was 5.8, with a higher FSS score in stage V CKD patients. High e-GFR, serum sodium, folic acid, and L-carnitine supplementation all reduced the intensity of fatigue, while prolonged HD duration, acidosis, hypertension, and non-compliance to vitamin D replacement increased tiredness severity. Routine fatigue assessment and measures to reduce it is a fundamental issue in pediatric CKD patients for better QOL.


Background
Chronic kidney disease (CKD) is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. The Kidney Disease Outcomes Quality Initiative (KDOQI) and the international guideline group Kidney Disease Improving Global Outcomes (KDIGO) guidelines define CKD as either kidney damage or a decreased glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m 2 for at least 3 months [1,2].
The term CKD defines renal dysfunction as a continuum, rather than a discrete change in renal function, and whatever the underlying etiology, once the loss of nephrons and reduction of functional renal mass reaches a certain point, the remaining nephrons begin a process of irreversible sclerosis that leads to a progressive decline in the GFR, and end-stage renal disease (ESRD) develops representing the final stage of CKD, eventually resulting in the need for renal replacement therapy to sustain life [3]. There is increasing awareness in the renal community of the high symptom burden and impaired healthrelated quality of life (HRQOL) experienced by patients with advanced CKD. Of the myriad of symptoms experienced by CKD and ESRD patients, fatigue is one of the most frequently reported symptoms. It affects 60-97% of patients on long-term renal replacement therapy and up to 84% of CKD stage 5 patients. There are no large studies comparing the severity of fatigue among non-dialysisdependent CKD and ESRD population [4].
Fatigue is defined as a subjective overwhelming feeling of tiredness at rest, exhaustion with activity, lack of energy that impedes daily tasks, lack of endurance, or as loss of vigor that can be unpleasant, distressing, and can interfere with physical and social activity [5]. There are a number of factors that may exacerbate clinically significant fatigue among individuals with CKD, including sleep disorders, depression, anemia, and chronic inflammation. Some of these factors (i.e., anemia and inflammation) are in the forefront of clinical attention, while other contributing factors often remain unrecorded [6].
Severe anemia is related to fatigue in general and several factors. Some studies suggest that markers of systemic inflammation, C-reactive protein, and IL-6, and decreased levels of albumin are associated with fatigue in individuals with ESRD who are receiving dialysis [7], also potential causative factors include impaired oxygen delivery, altered cardiovascular response to exertion, and metabolic acidosis [8].
Researchers have recognized the difficulties associated with identifying the appropriate method of measuring fatigue and evaluated fatigue rating measurement scales to improve the recognition and treatment of fatigue in chronic illness. There have been several reviews of fatigue instruments, some examining scales measuring fatigue intensity alone and others which integrate dimensions of fatigue intensity and functional outcomes associated with fatigue [5].
The aim of this study is to assess chronic fatigue of children with ESRD, dialysis and pre-dialysis stages, predictors of fatigue severity, and its impact on those patients' quality of life. Also, to determine the variables that may help to ameliorate fatigue symptoms and reduce its severity in those patients.

Methods
This was a prospective cross-sectional study that included 114 pediatric patients with confirmed chronic kidney disease (CKD) recruited from the nephrology outpatient clinic and the hemodialysis (HD) unit, Cairo University Children's Hospital, during the study period between September 2020 and April 2021.
All patients aged 6-14 years of both sexes with stages III to V CKD and ESRD patients with established regular HD for at least 3 months according to KDIGO classification were enrolled.
Excluded patients included unwilling parents to participate, refusal of assignment of the informed consent, patients with known neuromuscular disorders, and patients with subnormal mental status.
Demographic data including age, sex, CKD etiology, age of onset and duration of disease or HD, general examination of the candidates looking for pallor, signs of vitamins and minerals deficiency, and measurements of systolic and diastolic blood pressure looking for hypertensive patients with ≥ 95 th percentile for age, gender, and height, were all recorded.
Biochemical variables (pre-dialysis in case of HD patients) as creatinine, blood urea nitrogen, venous blood gases, plasma electrolytes, albumin, calcium, phosphorous, hemoglobin, hematocrit, defining anemic patients as those with hemoglobin <11.5 gm/dl 1 , and asking for the patient's compliance to medications as calcium, phosphate binders, vitamin D, iron, folic acid, erythropoietin were gathered.
Dialytic analysis in the form of frequency of dialysis, duration of the dialysis session, and adequacy of HD by Kt/V was calculated per session, where K stands for the dialyzer clearance (mL/min), t stands for time, Kt represents the volume of fluid completely cleared of urea during a single treatment, divided by V which stands for the volume of distribution of urea, approximately equal to patient's total body water. Also, GFR estimation was done by the Schwartz formula, based on serum creatinine readings using the Jaffe technique.
Patient's fatigue was assessed using the fatigue severity score (FSS) questionnaire, which is a nine-item instrument designed to assess fatigue as a symptom of chronic conditions. The scale addresses the effect of fatigue on daily functioning, including motivation, physical activity, work, family, and social life. It is based on the subjective rating of the impact of fatigue and the degree to which the symptoms poses a problem (Table 1) [9]. Each of the nine items is scored 1-7 and the average is the final FSS score. Severe fatigue has been defined as a score ≥ 5 [10,11].
The questionnaire was translated into Arabic by the international translation center in Cairo. Questionnaires were administered to the patients' caregivers, then, linguistic validation was performed through independent back translation to English.
Patients were divided into two groups (around the median FSS score) for studying the relation between fatigue and possible contributing factors.

Statistical analysis
Data were coded and entered using Microsoft Excel 2013, and data analysis was performed using the Statistical Package for Social Science (SPSS) version 21 (SPSS, Armonk, New York: International Business Machines Corporation).
Simple descriptive statistics: arithmetic mean ± standard deviation/median (IQR) was used for the summary of quantitative data and frequencies (%) were used for qualitative data.
Bivariate relationship of qualitative data was displayed in cross-tabulations and comparison of frequencies was performed using the chi-square test or Fisher's exact whenever appropriate.
Independent t-test/one-way ANOVA with post hoc tests was used to compare normally distributed quantitative data. Mann-Whitney test is used to compare not normally distributed data.
Pearson correlation was used to test the linear association of the normally distributed quantitative data.
The baseline demographic, clinical, and laboratory factors affecting severe fatigue were included in the multivariable logistic regression models (odds ratio (OR), 95% confidence interval (95% CI), and p-value).
The level of significance was set at probability (P) value < 0.05.

Results
We conducted an analytical cohort study on 114 patients diagnosed with CKD stages III to V and followed at CUCH's nephrology outpatient clinic and department.
Twenty percent of our patients were diagnosed with kidney and urinary tract anomalies (CAKUT) as a primary cause for CKD, 12.3% diagnosed with FSGS, 11.4% of patients with bilateral atrophic kidneys, 5.3% with primary hyperoxaluria, 4.4% with nephronophthisis, 3.5% with polycystic kidney, and other causes as a hemolytic uremic syndrome, Joubert syndrome, cystinosis, Bardet-Biedl syndrome, and Barter syndrome.
The demographic and laboratory findings of the studied patients were taken at the time of the study, revealing that as for CKD III and IV patients in comparison to CKD V patients, metabolic acidosis was more prevalent in CKD III and IV patients while patients with CKD V reported significantly hyperkalemia, reduced platelet counts and hyponatremia (Table 3).
In the current study, 40.4% (n=46) of our patients were classified as hypertensive and required one or more   antihypertensive medications (75.2% were on two antihypertensive medications and 24.8% were on three drugs). Hypertension has been associated with deterioration of renal functions, with 59% of stage V CKD patients being hypertensive while only 7.3% of stage III/IV CKD patients are hypertensive (Table 3). Our patients showed a mean ±SD FSS of 4.94 ±1.3 and a median FSS of 5.8. Thirty-eight patients had FSS of less than 4, 2 patients with scores 4-5, and the majority of our patients (64.9%) had FSS of more than 5 (Fig. 1).
There were significantly (p < 0.001) higher FSS results in stage V CKD patients (5.89 ± 0.7) compared with those with stage III/IV CKD (3.25 ± 0.6). About twothirds of patients with less severe fatigue (n = 41) were in CKD stages III/IV. Seventy out of the 73 CKD V patients had occasional once or more PD sessions for contraindications to HD. Dialysis was found to be risk factor for severe fatigue. Hepatitis C virus (HCV) markers are done routinely in CKD V patients on maintenance hemodialysis and severe fatigue was described in 21.2% of HCVpositive patients (Table 4). In the final multivariable regression model, there were several predictors of severe fatigue among the studied cohort: age at onset, serum creatinine, e-GFR, HD duration, SBP, BE, and Na levels ( Table 5).
For age, with 1-year increase in age, there was a 19% reduction in the risk of having severe fatigue (AOR = 0.814, 95% CI: 0.68-0.97, p-value = 0.024). Table 3 Comparison between CKD stages III IV, and V on HD laboratory findings and blood pressure assessment CKD chronic kidney disease, HD hemodialysis, ALP alkaline phosphatase, SBP systolic blood pressure, DBP diastolic blood pressure *Significant p value < 0.05 a Count (percent). CKD V patients had significantly lowered platelet counts, serum sodium levels, and higher serum potassium and creatinine levels than CKD III-IV patients. Also, hypertension is significantly correlated to CKD V patients

CKD III-IV (n=41) CKD V (n= 73) P value
Hemoglobin (gm/dl) 10  Regarding e-GFR, with one-point increase in the e-GFR, there was a 10.5% decrease in the probability of having severe fatigue (AOR = 0.895, 95% CI: 0.84-0.95, p-value < 0.001). Likewise, with 1 meq/L increase in the serum sodium, there was an 8% decrease in the liability of severe fatigue among patients (AOR = 0.923, 95% CI: 0.86-0.99, p-value = 0.033). In addition, patient compliant to folic acid therapy showed a significant decrease in the risk of severe fatigue among patients, and this is attributed to the importance of folic acid to improve anemia in CKD.
Similarly, there was a 20% increase in the likelihood of having severe fatigue with every one-point increase in the BE (AOR = 1.198, 95% CI: 1.04-1.39, p-value = 0.011). Only 68 of our patients (59.6%) were adherent to their active vit. D supplementations, cases non-compliant to vitamin D replacement, and L-carnitine supplementations were more likely to have severe fatigue.

Discussion
Chronic kidney disease is a major health problem worldwide with increasing incidence and prevalence that is threatening to bring on the onset of a real "epidemic" [12]. It has been suggested to affect 15-74.7 children per million globally [13].
Fatigue is a clinical symptom of frailty. This phenotype has been widely found in the adult population and recently in the pediatric population [14,15]. It is a complex, multifactorial phenomenon which has been defined as 'extreme and persistent tiredness, weakness or exhaustion mental, physical or both' . Common symptoms also include reduced motivation and physical activity, in addition to general lethargy. Renal patients adjust the timing and intensity of their daily activities in order to accommodate their fatigue. For example, some dialysis patients who suffer from post-treatment fatigue require more than 3 h of rest after each session to recover, which is a considerable burden on top of the treatment regimen [16]. Accordingly, monitoring fatigue in pediatric CKD patients and its management is an important clinical priority for enhancing the QOL of those patients.
In this study, we conducted a cross-sectional study on 114 patients diagnosed with CKD stages III-V, to assess the chronic fatigue of those children that can affect their QOL. The predominance of males in our study is in accordance with data from other pediatric CKD registries [17][18][19] that can be explained by the impact of the most common causes of CKD in children, such as CAKUT and genetic renal diseases, which affect boys more than girls.
The average age of the patients studied was 8.8 ± 1.8 years. CAKUT and genetic renal diseases were identified earlier than glomerular diseases, whose prevalence increased with age and CKD stage [17].
Children with CKD are at increased risk for cardiovascular morbidity and mortality. HTN is a major comorbidity associated with CKD and one of the main factors contributing to the progression of CKD, increased risk of cardiovascular disease, and impaired neurocognitive function [20]. In the current study, 40.4% of our patients were classified as hypertensive and required one or more antihypertensive medications. Furthermore, HTN in children is uncommon, with a prevalence of 3-9%; however, in children with CKD, the rate rises to 50% [13,21].
Nevertheless, the scales sufficiently address the perceived impact of fatigue in general. Despite that preschool children were not included, Pediatric-specific assessments such as that of Karava et al. [ 22], published towards the end of our study, could add further value in future studies.
To the best of our knowledge, we are the first to discuss the relation between pediatric CKD (stages [3][4][5] and related fatigue by using FSS. The median FSS score was 5.8 well matches the previously reported ranges for severe fatigue (≥5) [10,11]. Our study showed that the percent scored ≥ 5 (n=74) (Fig. 1). With higher FSS score in stage V CKD patients on regular HD (5.89 ± 0.7) compared with those with stage III/IV CKD (3.25 ± 0.6) (p < 0.001). This was consistent with the findings of Roumelioti et al., who reported that participants with an e-GFR of 30 mL/min/1.73 m 2 had a 3.92 higher likelihood of having more severe weakness than those with an e-GFR of 50 mL/min/1.73 m 2 . They also had little energy, had difficulty sleeping, and were feeble [23]. Fatigue is not simply a biological side effect of the disease and its treatment but also the result of the physical and psychosocial challenges of growing up with a chronic disease. Hepatitis C markers in the current study were done routinely in CKD 5 patients on maintenance hemodialysis. Severe fatigue was described in 11 hepatitis C virus patients (21.2%), and fatigue was considered also as a nonspecific symptom of hepatitis C [24].
In agreement with Jacobson et al., the severity of exhaustion in our patients had a significant effect on the amount of sleep and insomnia [25] which will subsequently have a great effect on their growth and their QOL.
Fatigue and related pain in severe CKD patients may be explained by a number of factors including persistent inflammation (as indicated by lowered albumin), malnutrition, and the anemia of chronic disease [16,26]. In addition, we observed several predictors of fatigue in patients with CKD in this study as longer HD duration, which is in concordance with previous observations that patients who recently started dialysis treatment sometimes report more fatigue as compared with patients who were treated for longer periods [27]. However, frequent hemodialysis sessions may be associated with reduced fatigue and an improved patients' quality of life [28]. Also, patients with hemodialysis experience an aggravation of the fatigue during and after the dialysis therapy, a phenomenon labeled "post-dialysis fatigue" [27].
Another predictor of fatigue in our patients included high blood pressure, lack of vitamin D supplementation, and acidosis; all were linked to fatigue severity; however, higher e-GFR, serum sodium, folic acid, and L carnitine regular replacement, on the other hand, reduce fatigue severity.
The authors are aware of the need for the use of pediatric-specific tools for the assessment of fatigue, as well as post-dialysis fatigue. The establishment of cut-off scores for significant and severe fatigue in this population requires large multicenter studies.

Conclusion
Fatigue is commonly expressed by CKD children. Those with CKD stage V and on regular HD frequently experienced much more fatigue than patients with CKD III-IV who experienced mild to moderate fatigue. Age of the patients, serum creatinine level, HD duration, lack of vitamin D supplementation, metabolic acidosis, and hypertension have been the most common fatigue predictors with negative effects on their QOL. On the other side, tiredness in patients with CKD can be reduced by folic acid and L carnitine supplementation, which help to lessen the intensity of their fatigue.
Frequent laboratory assessment, monitoring of electrolyte imbalance, and correction of deficient minerals, all of these with close monitoring of blood pressure and correction of hypertension, are mostly important in those patients. Recommendations for regular replacements with activated vitamin D, folic acid, and L carnitine supplementation would help to reduce their tiredness and improve the activity level and quality of life for pediatric CKD patients.