Correspondence: Nurten Ozen, Department of Midwifery, Faculty of Health Sciences, Istinye University, İstinye Üniversitesi Topkapı Kampüsü, Maltepe Mah. Edirne Çırpıcı Yolu, No:9, 34010, Zeytinburnu/Istanbul, Turkey, E-mail: Introduction
Uremic pruritus (UP) is a common and disturbing problem in patients undergoing hemodialysis (HD) treatment [1,2]. The incidence of UP is 15% to 49% in the pre-dialysis period, and 50% to 90% during dialysis treatment [3]. Although its pathophysiology is not well understood, UP is thought to be multifactorial. Many hypotheses have been proposed regarding the development of UP. Recent hypotheses suggest that changes in the immune and opioid systems are to blame for UP [4].
The immune system hypothesis suggests that an increase in the Th1, Th2 cell ratio causes pruritus. Th1 cells are believed to cause pruritus by activating cytokines and inflammatory cells, and Th2 cells by ensuring the secretion of anti-inflammatory cytokines [2,5]. In contrast, the opioid system hypothesis suggests that irregularities in the opioid receptors cause UP. For example, an increase in μ receptor agonists is reported to trigger itching, while an increase in the κ receptor agonist has the opposite effect [6].
Although the pathophysiology of UP is not completely understood, several factors are thought to be involved in its development [7]. These predisposing risk factors include increased blood urea nitrogen (BUN), calcium, phosphorus and β2-microglobulin [8]. Other contributing factors are as follows: serum magnesium and vitamin A excess; an increased aluminum level; anemia; erythropoietin deficiency; high ferritin levels; low transferrin and albumin levels; secondary hyperparathyroidism; increased calcium, phosphate and magnesium levels; and an increase in substances released from mast cells (histamine, interleukin [IL]-2, protease, etc.) [9]. Dry skin is caused by sweat gland atrophy and dehydration of the skin’s stratum corneum layer. These factors are also reported to play a role in UP development [7].
Patients with UP have difficulty coping with it, and develop associated stress [4]. UP is an increasingly important problem among dialysis patients. It has a negative effect on patients’ quality of life, sleep, emotional state, and social relations [1,10]. Pruritus also contributes to the development of skin and soft tissue lesions and/or infections [10]. UP affects close to 90% of dialysis patients, and corresponds to increased morbidity and mortality [7]. The mortality risk of UP was found to be > 17% based on 18,000 HD patients in the International Dialysis Outcomes and Practice Patterns Study (DOPPS) [2]. Overall, UP is typically resistant to treatment and difficult to manage.
Despite multiple attempts to identify the risk factors of UP, including calcium and phosphate levels, dialysis adequacy, depression, and anxiety, controversy remains [10–13]. Dry skin, which develops due to reduced sweat gland volume, is thought to play a role in UP development; however, these data are also contradictory [13,14]. UP causes depressive symptoms in dialysis patients, which have been reported to be related to an increase in hospitalization and mortality rates [15]. However, only a few studies have investigated the relationship between UP and depression [2,16] and anxiety [17,18].
In this study, we have two aims: 1) we evaluated the socio-demographic and medical factors and biochemical factors that play a role in pruritus development, the various factors involved in the effect of pruritus on sleep and the social support, and anxiety and depression states all together; and 2) we conducted the study in four dialysis centers in Turkey, a country with an increasing number of patients on HD treatment, so that the results would guide health care professionals in the presentation of health care services.
Methods
Patients and study design
This descriptive study was conducted between November 2015 and June 2016 at four dialysis centers in Ankara, Turkey. The study inclusion criteria were as follows: 1) patients who had been undergoing HD treatments for four hours a day, three days a week for a minimum of six months; 2) patients 18 years old or over; 3) no communication difficulty; 4) no psychiatric disorders that may lead to cognitive deficiencies such as Alzheimer’s disease or psychosis; and 5) no diagnosis of active infection, skin disease, acute hepatitis, cholestatic liver disease or cancer. The dialysis technique was HD. There were various dialysis machines and sets used at the four dialysis centers where the study was conducted. The HD water purifying systems were regularly inspected by the relevant authorities. A total of 249 patients met the inclusion criteria and were accepted to participate. Ethical consent was obtained from the hospital ethical committee (session number: 12, registration number: 384). All of the participating dialysis centers gave permission for their participation. The investigators explained the purpose of study to the patients by the investigators. The participants then provided written informed consent to participate.
Data collection and procedure
Data collection forms were completed face-to-face by the investigators during the second hour of an HD treatment session. The patients were verbally informed about the study, and their consent was obtained before data collection began. The patients were asked to answer the questions with regard to the last month. The forms took approximately 15 to 20 minutes to complete. Biochemical parameters from the prior month were obtained from hospital records. The data collection form consisted of the following five sections: 1) Patient characteristics form; 2) Data collection form for pruritus status; 3) Visual analog scale (VAS); 4) Laboratory parameters form; and 5) the Hospital Anxiety and Depression Scale (HADS).
Identification of uremic pruritus
UP was defined as pruritus lasting for longer than three months with a VAS score of 4 or more (where 0 indicates no pruritus, and 10 unbearable pruritus) [5]. The patients answered the VAS questionnaire by only considering the last month.
Patient characteristics form
The patient characteristics form was developed based on a review of the relevant literature [1,5–9]. It includes data regarding the socio-demographic and clinical characteristics of the patients. The socio-demographic data included age and gender. The medical data included duration of dialysis, interdialytic weight gain (IDWG), causes of chronic renal failure, diabetes, hypertension, cardiovascular or pulmonary disease, erythropoietin and high-flux dialysis use, and anxiety and depression scores. The IDWG was defined as the difference between the predialytic weight and the weight at the end of the previous dialysis session. The skin structure was determined by researchers as “normal” or “dry.”
Data collection form for pruritus status
The data collection form for pruritus status evaluated the following parameters: 1) the most involved area, including either head-neck, back, abdomen, arm, leg, or entire body; 2) the period of most intense pruritus, including during dialysis, the day of dialysis, the day after dialysis, or the evening before dialysis; 3) the pruritus severity with VAS; 4) pre-medications used for pruritus; and 5) sleep changes due to pruritus, such as: “I do not wake up, I wake up several times a night, I wake up quite often, or I am always sleepless.”
Visual analogue scale
The VAS is the most commonly used scoring system for UP severity [12,14]. VAS is used to convert values that cannot be measured numerically into numerical values. This a 10-point scale in which 0 indicates no pruritus, and 10 indicates very severe pruritus. The numerical values are separated by one cm intervals. We used the categorization by Reich et al [19] as a reference when classifying the VAS score. We classified the severity of pruritus as follows: < 4 points was considered mild; ≥ 4 points but < 7 points was moderate; ≥ 7 points but < 9 points severe; and ≥ 9 points very severe pruritus.
Data collection form for biochemical characteristics
The following biochemical parameters were recorded: entry and exit values for Kt/V, urea reduction ratio (URR), calcium, white blood cell (WBC), hemoglobin, hematocrit, albumin, phosphorus, calcium-phosphorus (CaxP), parathyroid hormone, C-reactive protein (CRP), ferritin and BUN. These measurements are routinely performed every month at the dialysis centers included in the study. Biochemical parameters of the last month were evaluated. The Daugirdas formula was used in the calculation of the Kt/V value [20].
The patients were divided into two groups according to their WBC level (either < 6.7 × 103/μL or ≥ 6.7 × 103/μL) similar to the methods of Pisoni et al [2]. In the study of Pisoni et al [2], the laboratory values with the likelihood of patients having moderate to extreme pruritus vs. mild/no pruritus in the combined DOPPS I and II study sample. The National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) guide [21] recommends that the CaxP level be < 55 mg2/dL2. Therefore, patients were divided into two groups according to a CaxP level < 55 mg2/dL2 or ≥ 55 mg2/dL2. The target values recommended by the Hemodialysis Adequacy 2006 Work Group [22] for Kt/V and URR are 1.4 and 70%, respectively. The patients in this study were divided into two groups according to Kt/V levels of < 1.4 or ≥ 1.4, and URR levels of < 70% or ≥ 70%.
Hospital Anxiety and Depression Scale
The HADS was developed by Zigmond and Snaith [23] in order to identify anxiety and depression risk in patients. The HADS also measures the level and severity of anxiety and depression. Aydemir et al [24] studied the validity and reliability of the HADS scale for Turkey. The HADS is used to quickly diagnose anxiety and depression, and to determine the risk group. However, it is not used to diagnose patients with other medical disease. Seven of the 14 questions measure anxiety, while the other seven address depression. The responses are scored based on a four-point Likert scale, with each response ranging 0 to 3. The lowest score that a patient can achieve from either subscale is 0, and the highest is 21. The cut-off points of the Turkish HADS are 10 for the anxiety subscale, and 7 for the depression subscale.
Statistical analysis
The SPSS software program for Windows (ver. 15.00; SPSS Inc., Chicago, IL, USA) was used for data evaluation and statistical analysis. The descriptive statistics are shown as numbers and percentages for counted numerical variables (such as gender, marital status), and means ± standard deviations for measured numerical variables (such as age, calcium and albumin value). The Kolmogorov–Smirnov test was used to evaluate the normality of the data. According to the data distribution, either the t test for independent groups or Mann–Whitney U test was used for comparisons between the two groups. The chi-square test was used for nominal data in pair wise comparisons. The multivariate logistic regression analysis was conducted to determine the factors associated with pruritus development. Variables were included in the regression analysis as candidate variables if they had a P value of ≤ 0.25, and demonstrated clinical importance in the single comparisons. P values < 0.05 were considered statistically significant.
Results
Patient characteristics
We found that 53.4% of the included patients were experiencing pruritus. Table 1 presents the subjects’ descriptive characteristics and presence of pruritus. The mean age of the patients with pruritus was 62.54 ± 12.77 years. A slight majority of the patients were male (54.1%). The mean HD treatment duration was 61.35 ± 43.30 months. There was a low risk of anxiety in 78.2% of patients. However, there was a high of depression in 77.4% of patients. The mean age of patients without pruritus was 62.46 ± 14.31 years, 56.0% of whom were male. The mean HD treatment duration was 66.28 ± 52.81 months in those without pruritus. There was a low risk of anxiety in 87.9% of these patients. Again, however, there was a high risk of depression in 84.5%.
Patients without pruritus had statistically significantly lower risks of cardiovascular disease and anxiety than did those with pruritus (χ2 = 4.649, P = 0.031 and χ2 = 4.110, P = 0.043, respectively). There were no statistically significant differences between the groups with regard to the other variables (P > 0.05).
Prevalence and characteristics of uremic pruritus
The descriptive characteristics of patients with pruritus are presented in Table 2. The pruritus affected the whole body in 35.3% of patients, and was most intense on the day after the dialysis in 39.1%. The mean pruritus severity was 6.47 ± 1.56, and 50.4% experienced moderate pruritus. Pruritus led to sleep disturbances in 33.8% of patients. In addition, 60.9% of patients used medications, such as oral antihistamines or topical therapies, for their pruritus. There was no significant relationship between the type of medication and the pruritus severity (data not presented, Z = −0.813; P = 0.416).
Table 3 demonstrates the relationship between the VAS level and HADS score in patients with pruritus. There was a weakly positive relationship between the VAS score and the Hospital Depression Score in patients with pruritus (P = 0.034).
Univariate regression analysis was used to identify factors potentially correlated to pruritus development. The odds ratio (OR) of WBC was 0.220 (95% confidence interval [CI]). Patients with dry skin were 0.2 times more likely to suffer from very severe pruritus than were those with normal skin (Table 4). None of the other variables had a statistically significant effect on pruritus development.
Multivariate regression analysis was used to identify the factors potentially related to pruritus development. The OR for WBC was 0.225 (95% CI). Patients with dry skin were 0.194 times more likely to suffer from very severe pruritus compared to those with normal skin (Table 5). However, the data in this model had a weak fit (R2 = 0.11). None of the other variables were significantly associated with pruritus development.
Table 6 presents the biochemical parameters according to the presence of pruritus. WBC counts ≥ 6.7 × 103/μL were significantly more common in the group with pruritus (χ2 = 3.883, P = 0.049) than in that without pruritus. However, there was no statistically significant difference between the groups with regard to other variables (P > 0.05).
Determinants of the prevalence and intensity of uremic pruritus
Logistic regression analysis was used to identify factors that are potentially related to pruritus development. The OR for WBC count was 1.730 (95% CI), as shown in Table 7. The other variables did not have a statistically significant effect on the possibility of pruritus development.
Discussion
This study sought to identify the risk factors of UP in HD patients. UP is a common symptom in HD patients that can cause severe discomfort. It is difficult to treat, as its underlying pathophysiological mechanism is not precisely known [10]. The prevalence of UP varies between 30% and 64% in the literature [2,5,25–28]. We found that 53.4% of our patients had UP, which is comparable to prior reports. The UP severity was 7/10 in more than half of studies that evaluated its severity. Similarly, the mean pruritus severity was 6.47 (0–10) in this study.
We found that WBC counts ≥ 6.7 × 103/μL were also relevant to UP development, and increased its risk by 1.73 times. Prior literature has emphasized the importance of inflammation and proinflammatory factors in the development of UP [29]. We found that the levels of serum pro-inflammatory cytokines (such as IL-6) and CRP were higher in UP patients than in those without UP. The WBC count is also thought to be an important marker, with a WBC count > 6.7 × 103/μL particularly significant for UP development [2,5]. Kimata et al [30] found that higher WBC counts increased the risk of UP development by 1.04-fold. Similarly, Pisoni et al [2] found that a WBC count > 8.4 × 103/μL increased the risk of UP development by 1.20-fold.
UP frequently causes significant mood impairment, including depression and anxiety [16]. Similarly, patients with depressive symptoms have significantly higher odds of developing severe pruritus [31]. Depression was reported to develop 1.3 to 1.7 times more commonly in UP patients [2,15] In addition, Araujo et al [16] reported a significant relationship between depressive symptoms and UP. Other groups have not identified a statistically significant correlation between pruritus and depression using the HADS [17,18]. We also did not find that depression was a risk factor for UP development, although the depression score increased with increasing VAS scores. This discrepancy with the findings in the literature may be a result of the use of a self-administered questionnaire to assess anxiety and depression. Prior studies have mandated psychiatric consultation in cases in which depression or anxiety is suspected based on the self-administered questionnaires [32]. In contrast, psychiatric involvement was not included in our protocol. Therefore, further studies are needed in which a definite diagnosis (of a psychiatric disorder) is made by a physician once it is suspected by self-administered questionnaires. Prior studies of HD patients have focused more on depression than on anxiety. Therefore, the relationship between anxiety and UP development must be studied further.
Dry skin, caused by sweat gland atrophy and dehydration of the stratum corneum layer, is thought to play a role in the development of UP. Dry skin has previously been suggested as a potential causative factor for UP [7]. Kiliç Akça and Taşci [25] reported that the incidence of UP in patients with dry skin is 3.9 times higher than in those without dry skin. We similarly found that dry skin is a risk factor for UP.
The study has several limitations. For instance, the study was inherently subject to recall bias and false declarations based upon its design. In addition, we were unable to measure eosinophil levels in our patients with pruritus. Eosinophils produce multiple substances that are relevant to pruritus. Therefore, future studies ought to investigate whether the eosinophil level is associated with the prevalence of UP.
In conclusion, we found that a WBC count ≥ 6.7 × 103/μL was a risk factor for UP development in HD patients. Overall, despite its high prevalence and negative impact on quality of life, UP is disregarded by many health care professionals. Therefore, we recommend that providers monitor the potential risk factors for UP, such as the WBC count, in their HD patients who are at risk.
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