Epidemiological characteristics and factors associated with chronic kidney disease-associated pruritus in the Chinese adult dialysis population: a multicenter, cross-sectional study

Abstract

To our knowledge, no large‑sample epidemiological studies on chronic kidney disease‑associated pruritus (CKD‑aP) have been reported in China in recent years. We aimed to investigate the prevalence and related factors of CKD-aP in Chinese dialysis population. This study included data on 9,589 dialysis patients across 30 provincial-level administrative divisions in mainland China between May 2022 and December 2022. The EQ-5D was used to collect patient information. Pruritus severity was assessed using the Numerical Rating Scale (NRS). Generalized estimating equations (GEE) were used to explore the potential influencing factors of CKD-aP. The prevalence of CKD-aP in Chinese adult dialysis patients was 60.3%. The prevalence of mild, moderate, and severe pruritus was 44.4%, 12.5%, and 3.3%, respectively. The prevalence of pruritus, moderate-to-severe pruritus, and severe pruritus in hemodialysis (HD) patients was 59.9%, 16.0%, and 3.4%, respectively. The prevalence of pruritus, moderate-to-severe pruritus, and severe pruritus in peritoneal dialysis (PD) patients was 61.8%, 14.1%, and 2.8%, respectively. No significant difference in pruritus prevalence was observed between HD (59.9%) and PD (61.8%) patients. Only 2.9% of the patients received potentially effective treatment (gabapentinoids 2.8%, kappa opioid receptor agonists 0.1%). Smoking history, diabetic nephropathy, cardiovascular diseases, dialysis vintage, eosinophil count, serum total calcium, and serum phosphorus were factors associated with CKD-aP. CKD-aP is highly prevalent among Chinese dialysis patients, with comparable rates between HD and PD populations. Several modifiable and non-modifiable factors were significantly associated with pruritus. Few patients received potentially effective treatment. These results highlight the potential targets for improving patient management.

Introduction

Chronic kidney disease-associated pruritus (CKD-aP) is a common clinical symptom in patients with CKD [1]. Approximately half of dialysis patients and a quarter of non-dialysis CKD patients experience bothersome pruritus [2]. The prevalence of CKD-aP varies by country, dialysis modality, dialysis unit, and study population [3]. International studies have reported that CKD-aP affects 25% to 62% of patients undergoing peritoneal dialysis (PD) and 38% to 84% of those undergoing hemodialysis (HD) [4]. However, few studies have investigated the prevalence of CKD-aP in China. In a study by Li et al., a visual analogue scale was used to assess the prevalence of pruritus in 362 continuous ambulatory peritoneal dialysis (CAPD) patients between January 2012 and April 2013, revealing a CKD-aP prevalence of 65% [5]. A meta-analysis, which contained 42 studies involving 11,800 patients, found that the overall prevalence of CKD-aP in adult dialysis patients was 55% [6]. Another meta-analysis of 27 studies (10,346 Chinese maintenance hemodialysis patients) found a 52% prevalence of CKD-aP: 26% mild, 22% moderate, and 8% severe [7]. To date, there remains a lack of high-quality, large-scale, multicenter epidemiological studies on CKD-aP in China.

Pruritus associated with CKD is a complex set of disorders [8]. CKD-aP can affect multiple parts of the body, including back, face, arms, and even the entire body [9]. Aggravating factors of CKD-aP include extreme temperatures, dry skin, or showering [10]. CKD-aP is associated with decreased quality of life and increased inflammation and parathyroid hormone markers [11]. Most patients experience worsening nocturnal pruritus symptoms, leading to difficulty falling asleep and awakening at night, and severe itching is an independent risk factor for patient death [12]. Studies have identified several potential associated factors for CKD-aP, including calcium-phosphate, age, sex, race and country of residence, comorbidities, dialysis characteristics, anemia, and inflammatory markers [10,13]. Therefore, understanding the prevalence of pruritus in China and finding-related influencing factors are of great significance for improving the quality of life of patients and decrease mortality.

The pathogenesis of CKD-aP has not yet been definitively established, but proposed mechanisms include dysregulation of the endogenous opioid system, uremic neuropathy, metabolic disturbances, immune dysregulation, xerosis, and neuropeptide natriuretic polypeptide B (NPPB) [14,15]. Further studies are needed to elucidate these mechanisms and to develop corresponding therapeutic strategies.

Determining the prevalence and associated factors of pruritus can help improve the management of the disease. Currently, there is a lack of large-scale cross-sectional studies on CKD-aP in China, along with insufficient data on the prevalence of pruritus among uremic patients. Accordingly, we conducted this multicenter, comprehensive investigation to gain a thorough understanding of the prevalence and factors associated with CKD-aP in China.

Methods

Study design and subjects

This was a nationally representative, multicenter, randomized, cross-sectional survey conducted from May 2022 to December 2022, covering 102 centers in 30 provincial-level administrative regions in mainland China. Eligible adults in dialysis centers who met the inclusion criteria were invited to participate in the survey. The subjects were patients with end-stage renal disease (ESRD) who received hemodialysis or peritoneal dialysis, or hemodialysis plus peritoneal dialysis. The main inclusion criteria were as follows: (1) adult patients (≥18 years) with chronic kidney disease who received regular peritoneal dialysis or hemodialysis; (2) maintenance dialysis patients with dialysis duration ≥90 days and (3) the data entered were clinical data within 3 months prior to the registration date and closest to the registration date. The main exclusion criteria were as follows: (1) pruritus due to a primary skin disease or another clearly diagnosed condition and (2) patients who were considered inappropriate to participate in this questionnaire survey by the investigator. Sampling methods were as follows: (1) Patients with dialysis duration ≥90 days were included in each center, and those eligible for inclusion were numbered according to unique information such as case number or hospitalization number; (2) the number was entered into the random scale to generate the patient number randomly selected and (3) the selected patients filled out questionnaires until the center reached the number of questionnaires assigned for the project. If the center had both HD and PD patients, the number of questionnaires was assigned in an 8:2 ratio, and if the center had only one dialysis mode, it did not need to be assigned. Clinical information such as the time of onset, duration, and location of pruritus, which differed among patients with mild, moderate, and severe pruritus, was collected. This study was performed in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (IIT20220141B-R1). All patients signed the written informed consent.

European quality of life-5 dimensions questionnaire (EQ-5D)

EQ-5D is a multidimensional measure of health-related quality of life. The EQ-5D health description system includes five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression [16]. Each questionnaire was reviewed by two researchers and 30% of all questionnaires were reviewed in person or by telephone. An audit report was issued by a third party (BEIJING BIOKNOW INFORMATION TECHNOLOGY CO., LTD, Beijing, China).

The distribution area of patients with dialysis

The resident areas of dialysis patients are divided into seven regions, including South China, East China, Central China, North China, Northeast China, Southwest China, and Northwest China region. Each dialysis patient filled out a carefully designed questionnaire to collect information on their sociodemographic information, health status, dialysis modalities and blood test results. A total of 10,000 patients received the questionnaire, and 104 were excluded from the final analysis (10 of whom were younger than 18 years and 94 had incorrect dialysis vintage), resulting in 9,589 patients included in the final analysis.

Numerical rating scale (NRS) score

NRS was used to evaluate the severity of pruritus [17]. Explain the purpose and method of the assessment to the patient, ensuring that the patient understands the meaning of the 0 to 10 scale: 0 means ‘no pruritus’ and 10 means ‘the worst imaginable pruritus’. A paper scale, electronic form, or verbal inquiry may be used, chosen flexibly based on the patient’s condition. Ask the patient to select a number between 0 and 10 that represents the severity of their pruritus based on their own perception. For example, if the patient feels mild pruritus, they might choose 2 or 3; if the pruritus is very severe, they might choose 8 or 9. The scoring criteria are as follows: 1–3 on the NRS scale indicates mild condition, 4–6 indicates moderate condition, and 7–10 indicates severe condition. Pruritus severity was reported by patients, with a physician assisting them in completing the questionnaire. The degree of pruritus was evaluated based on symptoms over the past 2 weeks at the time of the survey: pruritus occurring on at least 3 days within the 2 weeks, with multiple episodes daily, each lasting several minutes, and affecting the patient’s life [18].

Statistical analysis

Dialysis patients were divided into two groups according to pruritus status. The figures were performed using the R software, version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). The remaining statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC), involving indicators including the incidence of CKD-ap with its 95% CI, and the OR of associated factors with their corresponding 95% CI. The continuous variables were described by median (inter-quartile range [IQR]), and the comparison between groups was performed by Wilcoxon rank sum test. Categorical data were described by the frequency, and the category proportion of each index in the pruritus group and the non-pruritus group was described. Chi-square test was used for comparison between groups, and CMH chi-square test was used for data of multiple categories and grades.

The generalized estimating equations (GEE) model was used to explore the potential influencing factors of CKD-aP. To explore the potential influencing factors of CKD-aP, we constructed three GEE models, aiming to assess the stability of associations after controlling for progressively more clinical variables. Model I adjusted for sociodemographic and lifestyle factors (population epidemiology, smoking and drinking, education level and reimbursement type); Model II additionally adjusted for clinical characteristics (primary disease, comorbidities, dialysis information and blood pressure value); Model III further added laboratory indicators (albumin, alkaline phosphatase, calcium, phosphorus, CRP, creatinine and eosinophil count). Considering the missing data of covariates, we used multiple imputation models with 10 imputations based on the Markov Chain Monte Carlo (MCMC) method. Additionally, the sensitivity analyses of GEE were conducted in the population without missing data (complete dataset). The value of serum calcium was corrected based on serum albumin: corrected calcium (mmol/L) = measured total calcium + 0.02 × (40 – albumin concentration g/L). The subgroup analyses were performed based on age and mode of dialysis.

OR >1 and p < 0.05 indicated that it was associated with pruritus or moderate-to-severe pruritus. p < 0.05 indicated that the difference was statistically significant.

Results

Prevalence of CKD-aP

A total of 9,589 patients treated with dialysis were enrolled, including 60% men and 40% women (Table 1). The mean age of enrolled patients was 56 years. The prevalence of pruritus in adult dialysis patients was 60.3% (5,781/9,589). Most of the dialysis patients with pruritus symptoms were over 50 years old (66.0%). HD was performed in 8,116 uremic patients, and pruritus developed in 4,861 patients (59.9%). There were 1,416 uremic patients underwent PD, and pruritus developed in 875 patients (61.8%). Among the patients with pruritus, the proportions of males, cardiovascular disease, and cholestasis were higher than those without pruritus (P < 0.05).

Table 1.

General characteristics of the study population.

		With or without pruritus
Characteristics	All patients (n = 9,589)	Without pruritus (n = 3,808)	With pruritus (n = 5,781)	P value
Age (years)	56 (45, 66)	56.00 (44, 66)	56 (45, 66)	0.303
Age group (n, %)				0.893
18–49	3,260 (34.0)	1,328 (34.9)	1,932 (33.4)
50–64	3,603 (37.6)	1,359 (35.7)	2,244 (38.8)
≥ 65	2,726 (28.4)	1,121 (29.4)	1,605 (27.8)
Male (n, %)	5,761 (60.1)	2208 (58.0)	3,553 (61.6)	0.001
Smoking history (n, %)	2,308 (24.1)	772 (20.3)	1,536 (26.6)	<0.001
Drinking history (n, %)	1,171 (12.2)	396 (10.4)	775 (13.4)	<0.001
Primary disease of end-stage renal disease (n, %)				0.021
Chronic glomerulonephritis	4,484 (46.8)	1,846 (48.5)	2,638 (45.6)
Diabetic nephropathy	2,170 (22.6)	826 (21.7)	1,344 (23.3)
Hypertensive nephropathy	1,537 (16.0)	574 (15.1)	963 (16.7)
Polycystic kidney	382 (4.0)	144 (3.8)	238 (4.1)
Others/Unknown	1,016 (10.6)	418 (11.0)	598 (10.3)
Comorbidities (n, %) Diabetes	2,751(28.7)	1,073 (28.2)	1,678 (29.0)	0.369
Cardiovascular and cerebrovascular diseases	4,356 (45.4)	1,597 (41.9)	2,759 (47.7)	<0.001
Hyperthyroidism/ hypothyroidism	1,300 (13.6)	538 (14.1)	762 (13.2)	0.185
Cholestasis	159 (1.7)	49 (1.3)	110 (1.9)	0.021
Malignancy	217 (2.3)	91 (2.4)	126 (2.2)	0.498
Dialysis vintage (years)	3.7 (1.8, 7.3)	3.3 (1.4, 6.8)	4.1 (2.0, 7.6)	<0.001
Dialysis modality (n, %)				0.006
Hemodialysis	8,116 (84.6)	3,255 (85.5)	4,861 (84.1)
Peritoneal dialysis	1,416 (14.8)	541 (14.2)	875 (15.1)
Hemodialysis combined with peritoneal dialysis	57 (0.6)	12 (0.3)	45 (0.8)
Hemoglobin (g/L)	109.0 (98.0,119.0)	109.0 (98.0,119.0)	109.0 (98.0,119.0)	0.513
Eosinophil count (109/L)	0.19 (0.10,0.34)	0.17 (0.09,0.31)	0.20 (0.11,0.36)	<0.001
Albumin (g/l)	39.00 (36.10,41.80)	39.00 (36.30,41.80)	39.05 (36.10,41.70)	0.600
Alkaline phosphatase (U/L)	83.00 (65.00,109.75)	81.00 (63.40,105.00)	84.00 (65.00,112.00)	<0.0001
Serum calcium (mmol/L)	2.3 (2.1, 2.4)	2.3 (2.1, 2.4)	2.3 (2.1, 2.4)	0.001
Serum phosphorus (mmol/L)	1.8 (1.4, 2.2)	1.7 (1.4, 2.1)	1.86 (1.5, 2.3)	<0.001
Parathyroid hormone (pg/mL)	258 (133, 457)	254 (132,4 36)	263 (135, 469)	0.050
CRP (mg/L)	3.0 (1.2,7.1)	2.88 (1.1, 6.7)	3.1 (1.2, 7.6)	0.000
Creatinine (μmol/L)	922.2 (729.5,1124.0)	894.6 (703.0,1086.0)	942.0 (750.0,1149.0)	<0.001
Dialysis adequacy (urea clearance index Kt/V value)	1.35 (1.20,1.60)	1.38 (1.20,1.65)	1.33 (1.20,1.57)	<0.001

Epidemiological characteristics of different degrees of pruritus

The prevalence of mild, moderate, and severe pruritus was 44.4%, 12.5%, and 3.3%, respectively (Figure 1). The prevalence of pruritus was 60.3% (95% CI: 59.3–61.3%) (Supplementary table 1). Among patients who already had pruritus, the proportion of moderate or severe pruritus increased with age. In the 50–64 age group, the prevalence of moderate-to-severe pruritus was 16.5% (95% CI: 15.3–17.7%), and the prevalence of severe pruritus was 3.6% (95% CI: 3.0–4.2%). In patients ≥65 years of age, the prevalence of moderate to severe pruritus was 19.0% (95% CI: 17.5–20.4%), and the prevalence of severe pruritus was 4.3% (95% CI: 3.5–5.1%). Male patients treated with dialysis were more likely than women to have moderate-to-severe pruritus (16.8% vs. 14.4%). Dialysis patients with a history of smoking and drinking were more likely to have moderate-to-severe pruritus. Patients with ESRD whose cause was diabetic nephropathy had the highest rate of moderate-to-severe pruritus (17.5%). Dialysis patients with cardiovascular and cerebrovascular diseases, and malignancy had a higher proportion of moderate or severe pruritus than those without (Supplementary table 1). The prevalence of pruritus, moderate-to-severe pruritus, and severe pruritus in HD patients was 59.9%, 16.0%, and 3.4%, respectively (Figure 1). The prevalence of pruritus, moderate-to-severe pruritus, and severe pruritus in PD patients was 61.8%, 14.1%, and 2.8%, respectively (Supplementary table 1). The highest rate of moderate to severe pruritus was observed in patients receiving both HD and PD (31.6%).

Figure 1.

Epidemiological characteristics of patients with mild, moderate, and severe pruritus.

We describe the baseline characteristics of patients with mild, moderate, and severe pruritus (Table 2). Due to the absence of NRS values for 43 patients, the number of patients with mild pruritus is 4,262. We found that age, some comorbidities (diabetes mellitus, cardiovascular disease, hyperthyroidism, malignancy), and clinical laboratory indicators (dialysis vintage, diastolic blood pressure before dialysis, albumin, alkaline phosphatase, total serum calcium, serum phosphorus, C-reactive protein (CRP), creatinine before dialysis, and dialysis adequacy) were correlated with the severity of pruritus (p < 0.05).

Table 2.

Description of baseline variables in patients with pruritus symptoms.

		Severity of pruritus
Characteristics	All patients with pruritus(n = 5,781)	Mild (n = 4,262)	Moderate (n = 1,201)	Severe (n = 318)	P value
Age group (n, %)					<0.001
18–49 years	1,932 (33.4)	1,525 (35.8)	336 (28.0)	71 (22.3)
50–64 years	2,244 (38.8)	1,649 (38.7)	465 (38.7)	130 (40.9)
≥65 years	1,605 (27.8)	1,088 (25.5)	400 (33.3)	117 (36.8)
Male (n, %)	3,553 (61.5)	2,585 (60.7)	765 (63.7)	203 (63.8)	0.047
BMI	22.35 (20.15,24.88)	22.40 (20.20,24.86)	22.11 (20.03,24.80)	22.50 (20.28, 25.40)	0.259
Smoking history (n, %)	1,536 (26.6)	1,092 (25.6)	337 (28.1)	107 (33.6)	0.001
Drinking history (n, %)	775 (13.4)	560 (13.1)	169 (14.1)	46 (14.5)	0.320
End stage renal disease (n, %)					0.123
Chronic glomerulonephritis	2,638 (45.6)	1,956 (45.9)	531 (44.2)	151 (47.5)
Diabetic nephropath	1,344 (23.3)	965 (22.6)	295 (24.6)	84 (26.4)
Hypertensive nephropathy	963 (16.7)	708 (16.6)	210 (17.5)	45 (14.2)
Polycystic kidney	238 (4.1)	177 (4.2)	43 (3.6)	18 (5.7)
Others/Unkown	598 (10.3)	456 (10.7)	122 (10.2)	20 (6.3)
Diabetes mellitus (n, %)	1,678 (29.0)	1,199 (28.1)	381 (31.7)	98 (30.8)	0.027
Cardiovascular disease (n, %)	2,759 (47.7)	1,961 (46.0)	641 (53.4)	157 (49.4)	0.000
Hyperthyroidism/hypothyroidism (n, %)	762 (13.2)	556 (13.1)	174 (14.5)	32 (10.1)	0.779
Cholestasis (n, %)	110 (1.9)	79 (1.9)	27 (2.3)	4 (1.3)	0.994
Malignancy (n, %)	126 (2.2)	83 (2.0)	31 (2.6)	12 (3.8)	0.018
Dialysis vintage (years)	4.1 (2.0,7.6)	3.9 (1.9,7.4)	4.50 (2.2, 8.1)	5.13 (2.7,9.2)	<0.001
Dialysis modality (n, %)					0.008
Hemodialysis	4,861 (84.09)	3,560 (83.53)	1,027 (85.5)	274 (86.2)
Peritoneal dialysis	875 (15.1)	675 (15.8)	160 (13.3)	40 (12.6)
Hemodialysis combined with peritoneal dialysis	45 (0.78)	27 (0.63)	14 (1.17)	4 (1.26)
Systolic blood pressure before dialysis	140.00 (128.00, 153.00)	140.00 (128.00, 153.00)	141.00 (128.00, 154.50)	140.00 (126.00, 153.00)	0.595
Diastolic blood pressure before dialysis	80.00 (70.00, 89.00)	80.00 (71.00, 89.00)	79.00 (70.00, 88.00)	76.00 (69.00, 86.00)	0.001
Hemoglobin (g/L)	109.0 (98.0, 119.0)	110.0 (98.0, 120.0)	109.0 (97.0, 118.0)	108.0 (98.0, 117.0)	0.057
Eosinophil count (109/L)	0.20 (0.11, 0.36)	0.20 (0.10, 0.36)	0.20 (0.11, 0.37)	0.22 (0.11, 0.37)	0.240
Albumin (g/L)	39.05 (36.10, 41.70)	39.20 (36.20,41.80)	38.60 (35.90, 41.40)	39.30 (35.30, 41.70)	0.003
Alkaline phosphatase (U/L)	84.00 (65.00, 112.00)	83.80 (65.00, 111.00)	85.45 (66.95, 113.05)	89.00 (70.00, 120.00	0.009
Serum calcium (mmol/L)	2.3 (2.1, 2.4)	2.3 (2.1, 2.4)	2.3 (2.1, 2.4)	2.3 (2.2, 2.5)	<0.001
Serum phosphorus (mmol/L)	1.9 (1.5, 2.3)	1.9 (1.5, 2.2)	1.9 (1.5, 2.4)	1.9 (1.6, 2.3)	0.006
Parathyroid hormone (pg/mL)	263.20 (134.60, 469.40)	267.00 (137.60,470.36)	253.30 (120.80, 464.00)	263.70 (152.30, 475.00)	0.481
CRP (mg/L)	3.10 (1.20, 7.64)	3.00 (1.20, 7.30)	3.28 (1.40, 8.00)	4.10 (1.30, 9.70)	0.014
Creatinine (μmol/L)	942.0 (750.0, 1149.0)	951.0 (761.0, 1153.0)	911.0 (72,600, 1137.0)	902.0 (705.6, 1,138.0)	0.031
Dialysis adequacy (urea clearance index Kt/V value)	1.33 (1.20, 1.57)	1.34 (1.20,1.58)	1.30 (1.19, 1.53)	1.34 (1.20, 1.56)	0.002

In addition, we analyzed the differences in treatment modalities among different degrees of pruritus and the impact on patients’ lifestyle (Table 3). Uremic patients mainly presented with pruritus within 3 months after dialysis treatment (68.0%). The duration of pruritus episodes was generally less than 3 months (56%). The initial diagnosis of pruritus in uremic patients was mainly in the department of nephrology (64.1%). The occurrence time, duration, and location of pruritus in patients with different degrees of pruritus were significantly different (P < 0.001). The time from the onset of pruritus to the first treatment was mainly within 3 months. During the past 2 weeks, the frequency of occasional pruritus in patients with mild pruritus was 41.9%, the frequency of frequent pruritus in patients with moderate pruritus was 33.6% and the frequency of daily pruritus in patients with severe pruritus was 47.2%. Common sites of pruritus in patients with CKD-aP included the back, limbs, chest and head. Different degrees of pruritus have different effects on patients’ sleep (P < 0.001). Patients with CKD-aP received primarily oral agents (54.9%). These oral medications include antihistamines (H1 antagonists such as loratadine, cetirizine, ketotifen) (10.0%, 577/5781), gabapentinoids (gabapentin, pregabalin) (2.8%, 163/5781), kappa opioid receptor agonist (morphine, nalfurafine, etc.) (0.1%, 3/5781), others, and unknown (glucocorticoids, antidepressants, hypnotics, traditional Chinese medicine, phosphate-lowering drugs, cinacalcet, parathyroid surgery, etc.) (49.3%, 2848/5781). They were 6.0% (348/5781) of patients received combination therapy (oral combined with topical; two or more oral medications). EQ-5D-5L was used to assess differences in health status among patients with different degrees of pruritus. The results showed that there were significant differences in self-care, pain/discomfort, and anxiety/depression among patients with different degrees of pruritus (p < 0.001).

Table 3.

Disease characteristics in patients presenting with pruritus.

		Severity of pruritus
Characteristics	All patients with pruritus (n = 5,781)	Mild (n = 4,262)	Moderate (n = 1,201)	Severe (n = 318)	P value
Time to onset of pruritus after dialysis treatment (n, %)					0.000
Within 3 months	1,848 (32.0)	1,403 (32.92)	343 (28.6)	102 (32.1)
3 to 6 months	822 (14.2)	623 (14.6)	173 (14.4)	26 (8.2)
6 to 12 months	721 (12.5)	535 (12.6)	152 (12.7)	34 (10.7)
1 to 3 years	1,126 (19.5)	823 (19.31)	239 (19.9)	64 (20.1)
More than 3 years	1264 (21.9)	878 (20.6)	294 (24.5)	92 (28.9)
Duration of pruritus episodes in patients (n, %)					<0.001
<3 months	3,236 (56.0)	2,690 (63.1)	450 (37.5)	96 (30.2)
3 to 6 months	935 (16.2)	658 (15.4)	240 (20.0)	37 (11.6)
6 to 12 months	425 (7.4)	247 (5.8)	146 (12.2)	32 (10.1)
>12 months	1,185 (20.5)	667 (15.7)	365 (30.4)	153 (48.1)
Departments in which the patients were diagnosed with UP (n, %)					<0.001
Nephrology department	3,704 (64.1)	2,695 (63.2)	818 (68.0)	191 (60.1)
Dermatology department	248 (4.3)	149 (3.5)	71 (5.91)	28 (8.8)
Diagnosis undetermined	1,758 (30.4)	1,360 (31.9)	302 (25.2)	96 (30.2)
Other departments	71 (1.2)	58 (1.4)	10 (0.8)	3 (0.9)
Time from the onset of pruritus to the first treatment (n, %)					<0.001
<3 months	3,845 (66.5)	2,948 (69.2)	708 (59.0)	189 (59.4)
3 to 6 months	738 (12.8)	492 (11.5)	215 (17.9)	31 (9.8)
6 to 12 months	309 (5.4)	225 (5.3)	66 (5.5)	18 (5.7)
>12 months	889 (15.4)	597 (14.0)	212 (17.7)	80 (25.2)
Patient’s frequency of pruritus during the past 2 weeks (n, %)					<0.001
Daily	759 (13.1)	314 (7.4)	295 (24.6)	150 (47.2)
Frequently	810 (14.0)	318 (7.5)	403 (33.6)	89 (28.0)
Occasionally	2,422 (41.9)	1,996 (46.8)	387 (32.2)	39 (12.3)
Rarely	1,044 (18.1)	965 (22.6)	62 (5.2)	17 (5.4)
No	746 (12.0)	669 (15.7)	54 (4.5)	23 (7.2)
Sites where the pruritus had occurred during the previous 2 weeks (n, %)
Head/scalp	950 (16.4)	571 (13.4)	278 (23.2)	101 (31.8)	<0.001
Face	572 (9.9)	336 (7.9)	165 (13.7)	71 (22.3)	<0.001
Chest	1,143 (19.8)	669 (15.7)	351 (29.2)	123 (38.7)	<0.001
Abdomen	1,246 (21.6)	791 (18.6)	347 (28.9)	108 (34.0)	<0.001
Backside	3,842 (66.5)	2,741 (64.3)	855 (71.2)	246 (77.4)	<0.001
Hip and upper leg area	589 (10.2)	318 (7.5)	192 (16.0)	79 (24.8)	<0.001
Thigh	1,744 (30.2)	1,106 (26.0)	469 (39.1)	169 (53.1)	<0.001
Crus	1,912 (33.1)	1,268 (29.8)	482 (40.1)	162 (50.9)	<0.001
The dorsum of the foot/toe	548 (9.5)	322 (7.6)	165 (13.7)	61 (19.2)	<0.001
Sole	300 (5.2)	177 (4.2)	88 (7.3)	35 (11.0)	<0.001
Palm	366 (6.3)	225 (5.3)	94 (7.8)	47 (14.8)	<0.001
Back of the hand/fingers	498 (8.6)	300 (7.0)	140 (11.7)	58 (18.2)	<0.001
Forearm	1,113 (19.3)	650 (15.3)	337 (28.1)	126 (39.6)	<0.001
Arm	878 (15.2)	479 (11.2)	293 (24.4)	106 (33.3)	<0.001
Parts that touch clothing	422 (7.3)	250 (5.9)	131 (10.9)	41 (12.9)	<0.001
Groin	238 (4.1)	113 (2.6)	90 (7.5)	35 (11.0)	<0.001
Effect of pruritus on patient’s sleep (n, %)					<0.001
Never affect	2,551 (44.1)	2,308 (54.2)	215 (17.9)	28 (8.8)
Occasionally affecting sleep	2,219 (38.4)	1,599 (37.52)	558 (46.5)	62 (19.5)
Frequent disturbance of sleep	521 (9.0)	176 (4.1)	250 (20.8)	95 (29.9)
Affecting sleep and occasionally awaking during the night	271 (4.7)	109 (2.6)	115 (9.6)	47 (14.8)
Affecting sleep and waking up frequently during the night	219 (3.8)	70 (1.6)	63 (5.3)	86 (27.04)
Self-care (n, %)					<0.001
No difficulty	5,074 (87.8)	3,856 (90.5)	971 (80.9)	247 (77.7)
A little bit difficult	418 (7.23)	255 (6.0)	138 (11.5)	25 (7.9)
Moderate difficulty	161 (2.8)	85 (2.0)	56 (4.7)	20 (6.3)
Have serious difficulties	63 (1.1)	31 (0.7)	17 (1.4)	15 (4.7)
Unable to move around	65 (1.1)	35 (0.8)	19 (1.6)	11 (3.5)
Pain/discomfort (n, %)					<0.001
No pain or discomfort	4,159 (71.9)	3,260 (76.5)	734 (61.1)	165 (51.9)
A little pain or discomfort	1,317 (22.8)	867 (20.3)	362 (30.1)	88 (27.7)
Moderate pain or discomfort	240 (4.2)	102 (2.4)	94 (7.8)	44 (13.8)
Severe pain or discomfort	48 (0.8)	25 (0.6)	8 (0.7)	15 (4.7)
Very severe pain or discomfort	17 (0.3)	8 (0.2)	3 (0.3)	6 (1.9)
Anxiety/depression (n, %)					<0.001
No anxiety or depression	3,886 (67.2)	3,140 (73.7)	618 (51.5)	128 (40.3)
A little anxiety or depression	1,558 (27.0)	988 (23.2)	475 (40.0)	95 (29.9)
Moderate anxiety or depression	279 (4.8)	116 (2.7)	97 (8.1)	66 (20.8)
Severe anxiety or depression	43 (0.7)	14 (0.3)	10 (0.8)	19 (6.0)
Very severe anxiety or depression	15 (0.3)	4 (0.1)	1 (0.1)	10 (3.1)
Treatment protocols given to patients with pruritus (n, %)
Increasing dialysis dose	1,242 (21.5)	908 (21.30)	263 (21.0)	71 (22.3)	0.563
Combined with hemoperfusion	1,808 (31.3)	1,244 (29.2)	425 (35.4)	139 (43.7)	<0.001
Topical medication	1,011 (17.5)	617 (14.5)	306 (25.5)	88 (27.7)	<0.001
Oral medication	2,987 (51.7)	2,129 (50.0)	657 (54.7)	201 (63.2)	<0.001
Intravenous medication	160 (2.8)	95 (2.2)	42 (3.5)	23 (7.2)	<0.001
Physical therapy (UVB therapy, etc.)	36 (0.6)	21 (0.5)	12 (1.0)	3 (0.9)	0.055
Traditional Chinese medicine	47 (0.8)	29 (0.7)	14 (1.2)	4 (1.3)	0.070
Others	151 (2.6)	107 (2.5)	34 (2.8)	10 (3.1)	0.385
EQ-5D Utility Value	1.00 (0.89,1.00)	1.00 (0.94,1.00)	0.95 (0.82, 1.00)	0.89 (0.71, 1.00)	<0.001

EQ-5D, European Quality of Life-5 Dimensions Questionnaire.

GEE analysis of factors associated with pruritus

Three models were built based on different variables to analyze the factors associated with pruritus (Table 4). Model I found that smoking history was significantly associated with the risk of developing CKD-aP (OR = 1.20, 95% CI: 1.08–1.34; p = 0.001). Model II found that smoking history (OR = 1.21, 95% CI:1.08–1.34; p < 0.001), cardiovascular disease (OR = 1.18, 95% CI: 1.06–1.32; p = 0.002), dialysis vintage (OR = 1.04, 95% CI: 1.03–1.05; p < 0.001), peritoneal dialysis (OR = 1.46, 95% CI: 1.06–2.01; p = 0.021), and hemodialysis combined with peritoneal dialysis (OR = 1.96, 95% CI: 1.18–3.25; p = 0.009) were the factors associated with CKD-aP. Model III found that smoking history (OR = 1.17, 95% CI: 1.02–1.36; p = 0.03), cardiovascular and cerebrovascular diseases (OR = 1.20, 95% CI: 1.04–1.37; p < 0.01), dialysis vintage (OR = 1.03, 95% CI:1.02–1.06; p < 0.001), peritoneal dialysis (OR = 1.36, 95% CI:1.17–1.58; p < 0.001), serum calcium (OR = 1.38, 95% CI: 1.10–1.73; p = 0.006), serum phosphorus (OR = 1.27, 95% CI: 1.07–1.51; p = 0.008), creatinine (OR = 1.00, 95% CI: 1.00–1.00; p = 0.004), and dialysis adequacy (OR = 0.88, 95% CI: 0.78–0.99; p = 0.035) were factors related to CKD-aP. In addition, we used complete data with no missing data for all variables to analyze the factors associated with CKD-aP. The results of Model III showed that smoking history, cardiovascular diseases, dialysis vintage, serum calcium, serum phosphorus, creatinine, and dialysis adequacy were associated with the prevalence of pruritus in uremic patients (Supplementary table 2).

Table 4.

GEE analysis of risk factors for CKD-aP (important variables).

Characteristics	Model I		Model II		Model III
	OR (95％ CI)	P value	OR (95％ CI)	P value	OR (95％ CI)	P value
Age group, years
18–49	Ref	–	Ref	–	Ref	–
50–64	1.20 (1.08–1.33)	<0.001	1.17 (1.05–1.29)	0.004	1.29 (1.12–1.48)	<0.001
≥65	1.09 (0.97–1.23)	0.137	1.10 (0.97–1.25)	0.119	1.26 (1.07–1.47)	0.005
Sex (female vs. male)	0.92 (0.83–1.01)	0.081	0.91 (0.83–1.00)	0.050	0.94 (0.84–1.06)	0.314
BMI (kg/m2)	1.00 (0.99–1.01)	0.858	1.00 (0.99–1.02)	0.679	1.00 (0.98– 1.01)	0.647
Smoking history (yes vs. no)	1.20 (1.08–1.34)	0.001	1.21 (1.08–1.34)	<0.001	1.17 (1.02–1.36)	0.030
Cardiovascular disease (yes vs. no)			1.18 (1.06–1.32)	0.002	1.20 (1.04–1.37)	0.010
Hyperthyroidism/hypothyroidism (yes vs. no)			1.23 (1.04–1.45)	0.015	1.13 (0.92–1.37)	0.237
Dialysis vintage (years)			1.04 (1.03–1.05)	<0.001	1.03 (1.02–1.05)	<0.001
Dialysis modality (n, %)
Hemodialysis			Ref	–	Ref	–
Peritoneal dialysis			1.46 (1.06–2.01)	0.021	1.46 (0.95–2.24)	0.082
Hemodialysis combined with peritoneal dialysis			1.96 (1.18–3.25)	0.009	1.74 (0.93–3.24)	0.081
Serum calcium (mmol/L)					1.38 (1.10–1.73)	0.006
Serum phosphorus (mmol/L)					1.27 (1.07–1.51)	0.008
Creatinine (μmol/L)					1.00 (1.00–1.00)	0.004
Dialysis adequacy (urea clearance index Kt/V value)					0.88 (0.78–0.99)	0.035

CKD-aP, chronic kidney disease (CKD)-associated pruritus. GEE, Generalized estimating equations.

We next analyzed factors associated with pruritus in patients with moderate to severe pruritus (Table 5). Based on Model III, we found that age (50–64, ≥65), smoking history (OR = 1.24, 95% CI: 1.00–1.53, p = 0.047), cardiovascular diseases (OR = 1.32, 95% CI: 1.07–1.62, p = 0.01), dialysis vintage (OR = 1.03, 95% CI:1.02–1.05, p < 0.001), hemodialysis combined with peritoneal dialysis (OR = 2.01, 95% CI: 1.06–3.82, p = 0.032), albumin (OR = 0.98, 95% CI: 0.96–0.99, p = 0.006), serum calcium (OR = 1.68, 95% CI: 1.28–2.20, p < 0.001), and serum phosphorus (OR = 1.41, 95% CI: 1.26–1.58, p < 0.001) were associated with the occurrence of moderate-to-severe pruritus. In addition, we used complete data with no missing data for all variables to analyze the factors associated with CKD-aP of more than moderate severity. When included in Model III, we found that age, smoking history, cardiovascular diseases, serum calcium, and serum phosphorus were associated with the occurrence of moderate-to-severe pruritus (Supplementary table 3).

Table 5.

GEE analysis of pruritus-related factors in patients with moderate-to-severe pruritus (important variables).

Characteristics	Model I		Model II		Model III
	OR (95％ CI)	P value	OR (95％ CI)	P value	OR (95％ CI)	P value
Age group, years
18–49	Ref	–	Ref	–	Ref	–
50–64	1.35 (1.18–1.55)	<0.001	1.26 (1.09–1.46)	0.002	1.42 (1.17–1.71)	<0.001
≥65	1.68 (1.44–1.95)	<0.001	1.56 (1.31–1.86)	<0.001	1.77 (1.39–2.24)	<0.001
Gender (female vs. male)	0.91 (0.81–1.02)	0.112	0.89 (0.79–1.00)	0.051	0.96 (0.82–1.12)	0.576
Smoking history (yes vs. no)	1.23(1.05–1.44)	0.010	1.23 (1.05–1.44)	0.009	1.24 (1.00–1.53)	0.047
Cardiovascular disease (yes vs. no)			1.32 (1.13–1.56)	<0.001	1.32 (1.07–1.62)	0.010
Hyperthyroidism/hypothyroidism (yes vs. no)			1.24 (0.99–1.55)	0.059	1.30 (0.97–1.74)	0.083
Dialysis vintage (years)			1.04 (1.02–1.05)	<0.001	1.03 (1.02–1.05)	<0.001
Dialysis modality (n, %)
Hemodialysis			Ref	–	Ref	–
Peritoneal dialysis			1.32 (0.99–1.75)	0.055	1.34 (0.94–1.92)	0.105
Hemodialysis combined with peritoneal dialysis			2.40 (1.56–3.68)	<0.001	2.01 (1.06–3.82)	0.032
Systolic blood pressure before dialysis			1.00 (1.00–1.01)	0.068	1.00 (1.00– 1.01)	0.100
Eosinophil count (109/L)					1.09 (0.99–1.21)	0.080
Albumin (g/L)					0.98 (0.96– 0.99)	0.006
Serum calcium (mmol/L)					1.68 (1.28–2.20)	<0.001
Serum phosphorus (mmol/L)					1.41 (1.26–1.58)	<0.001
CRP (mg/L)					1.00 (1.00–1.00)	0.057
Dialysis adequacy (urea clearance index Kt/V value)					0.77 (0.60–1.00)	0.050

CRP, creatinine and eosinophil count. GEE, Generalized estimating equations.

Since age and dialysis mode were associated with the severity of pruritus, we performed subgroup analyses based on age and dialysis mode to compare differences in clinical factors across age and dialysis mode groups. We then performed subgroup analyses based on Model III for age and dialysis mode. When grouping by age (18–49, 50–64, ≥65), we found that diabetic nephropathy, cardiovascular diseases, dialysis vintage, and serum phosphorus were related to the occurrence of pruritus (P < 0.05) (Supplementary table 4). When grouping by dialysis modality, we found that gender, southwest China region, dialysis vintage, diastolic blood pressure before dialysis, eosinophil count, alkaline phosphatase, CRP, and creatinine were associated with the occurrence of pruritus (P < 0.05) (Supplementary table 5).

Discussion

The prevalence of CKD-aP varies by country and study population [19]. In our study, the prevalence of CKD-aP in adult dialysis patients was 60.3%, and the prevalence of pruritus in patients undergoing HD and PD was 59.9% and 61.8%, respectively. The prevalence of CKD-aP in this study was similar to that reported in other studies; for instance, a meta-analysis found a prevalence of CKD-related pruritus of 55% in adult dialysis patients [6]. However, their study enrolled different populations, and the heterogeneity among samples was relatively large. In a retrospective cohort study involving 73,124 ESKD participants undergoing HD or PD, pruritus was reported in 60% of patients [20]. Min et al. found the prevalence of CKD-aP in PD patients was 62.6% [21]. Notably, the prevalence of moderate-to-severe pruritus in our study was lower than in other studies. We found the prevalence of moderate-to-severe pruritus in HD and PD patients was 16.0% and 14.1%, respectively. A study from the Japanese Dialysis Outcomes and Practice Patterns Study (DOPPS) Cohort (JDOPPS) showed that 44% HD patients experienced moderate-to-extreme pruritus, but prevalence varied widely among centers, ranging from 20% to 70% [22]. A study of 38,315 US HD patients found a prevalence of at least moderate pruritus of 30% [20]. The prevalence of moderate-to-severe pruritus in German HD patients is 27% [23]. Regional differences in CKD-aP prevalence may be due to differences in the scoring method of pruritus, dialysis method, living environment, diet, and level of medical care [24,25]. In addition, the description of pruritus is subjective and may be influenced by culture, education, and socioeconomic status [26].

We found no significant difference in the prevalence of pruritus between HD and PD patients. However, the effect of HD and PD on pruritus is controversial. The meta-analysis of Hu et al. (n = 11,800) found that the prevalence of CKD-related pruritus in HD and PD was 55% and 56%, respectively [6]. However, Wu et al. (n = 380) found that the severity of CKD-related pruritus was significantly higher in HD patients than in PD patients [27]. They suggested that the reason for the lower severity of CKD-aP in PD patients may be that PD treatment can better preserve residual renal function and PD patients have less inflammation [27]. Conversely, the study by Min et al. (n = 648) found that the prevalence and severity of CKD-aP were significantly higher in PD patients than in HD patients [21]. They suggested that the increased accumulation of uremic toxins in PD patients may contribute to the higher prevalence and intensity of CKD-aP compared with HD patients. Therefore, more studies are needed to explore the effects of HD and PD on CKD-aP.

Understanding the factors associated with CKD-aP is helpful for the management of CKD-aP. In this study, the factors associated with CKD-aP were analyzed by GEE. Our results showed that smoking history, diabetic nephropathy, cardiovascular diseases, dialysis vintage, eosinophil count, serum calcium, and serum phosphorus were significantly associated with the occurrence of CKD-aP. Diabetes can cause microvascular and nerve damage, leading to diabetic dermatoses, which in turn cause systemic or local pruritus [28]. High concentrations of calcium and phosphorus may form microprecipitates in the skin and cause pruritus in HD patients [25]. We observed that although serum calcium and phosphorus levels in patients with different degrees of itching showed statistically significant differences, the actual values were very similar, and thus, these differences may have limited clinical significance. Consistent with our findings, Wu et al. found that a longer duration of dialysis was one of the associated factors for pruritus [29]. Life experiences affect symptom presentation and self-care practice in dialysis patients [30]. Our data showed that Kt/V is an associated factor for moderate-to-severe pruritus. This was consistent with the findings of Li et al. [7]. Ko et al. found that targeting a Kt/V ≥ 1.5 for hemodialysis and using high-flux dialyzers can reduce the intensity of pruritus in patients on chronic hemodialysis [31]. However, further clinical trials are still needed to determine the optimal dialysis dose and regimen for CKD-aP.

Comorbidities may increase the degree of pruritus in uremic patients. We found that dialysis patients with cardiovascular and cerebrovascular diseases, malignancy, and rheumatic immune diseases had a higher proportion of moderate to severe pruritus. Pisoni et al. also found that the presence of cardiovascular disease was associated with an increased risk of severe pruritus [32]. Cardiovascular diseases are often accompanied by poor peripheral blood circulation, which could theoretically promote the accumulation of metabolites in the skin and increase nerve stimulation [33]. This undoubtedly increases the risk of CKD-aP in dialysis patients with cardiovascular diseases. Some cancers cause abnormal reactions in the skin or internal organs that stimulate nerve endings and trigger an unbearable itching sensation [34]. Therefore, the management of comorbidities may improve CKD-aP.

Current treatments for CKD-aP include topical agents, systemic medications, other therapies, and kidney transplantation [35]. Systemic medications mainly consist of antihistamines, antiepileptic drugs, and κ opioid receptor (KOR) agonists. Antihistamines such as diphenhydramine, loratadine, and cetirizine have limited efficacy in treating CKD-aP [36]. For patients with moderate-to-severe or refractory CKD-aP, antiepileptic drugs such as gabapentin and pregabalin may be considered, but clinical adverse effects should be weighed [37–40]. KOR agonists can be used as effective systemic agents for treating CKD-aP. Nalfurafine hydrochloride is the first KOR agonist approved in China for the treatment of hemodialysis-associated pruritus. Clinical studies have confirmed that nalfurafine can effectively relieve pruritus in dialysis patients, with a low incidence of adverse reactions [41–43]. In the future, other KOR agonists may also be available as treatment options [44,45].

Our research found that CKD-aP patients mainly received oral medication treatment (51.7%). In our study, only 12.9% of patients received oral treatments that could be considered for pruritus (antihistamines 10.0%, gabapentinoids 2.8%, kappa opioid receptor agonists 0.1%). Since there is no reliable evidence that antihistamines are effective in alleviating CKD-aP, only 2.9% of patients were considered to have received potentially effective treatment. Studies from abroad have also reported on the treatment of CKD-aP. Rigatto et al. reported 11% gabapentin use, varying by diagnosis type [39]. Rayner et al. found 18% never treated for pruritus and 17% never reported symptoms; 57% of medical directors used antihistamines as first-line therapy, while 45% used gabapentin [13]. The DOPPS 5 study revealed that 17% of CKD-aP patients did not report their itching symptoms to medical staff, and 69% of physicians underestimated the prevalence of CKD-aP in their dialysis centers [35]. Potential reasons for the above differences include patient-related underreporting, non-evidence-based practices, and variations in cognitive levels, drug accessibility, and multidisciplinary collaboration among centers [46,47]. Therefore, the proportion of patients with pruritus may be underestimated, and the level of disease awareness leads to a low rate of effective treatment.

Our study had some limitations. First, we only studied the prevalence of CKD-aP in adults because children were not sampled in the surveillance. Secondly, the results of regression analysis may be affected by unknown factors (e.g., recall bias due to self-reported questionnaires). Besides, like any cross section, we cannot make causal inferences about the relationship between CKD-aP and relevant factors. Finally, our study did not conduct a statistical analysis on the correlation between the usage rates of various oral medications and CKD-aP. Future studies should include children with dialysis in the investigation and analyze the differences in the prevalence and factors associated with CKD-aP between them and adult patients.

Innovation and clinical significance of this study

Large-sample analysis of PD patients: The inclusion of PD patients is a distinctive feature of this study, as few previous studies have conducted such detailed comparisons between HD and PD. New findings on eosinophils: This study is the first to confirm an independent association between eosinophils and CKD-aP in a Chinese population. First depiction of regional differences: It reveals variations in the distribution of pruritus across seven major geographical regions in China. Clinical insights from Kt/V stratified analysis: Provides a basis for optimizing dialysis prescriptions.

Conclusion

The prevalence of CKD-aP in Chinese adult dialysis patients was 60.3% (95% CI: 59.3–61.3%). The prevalence of mild, moderate, and severe pruritus was 44.4%, 12.5%, and 3.3%, respectively. Smoking history, diabetic nephropathy, cardiovascular diseases, dialysis vintage, eosinophil count, serum total calcium, and serum phosphorus were factors associated with CKD-aP. The prevalence of CKD-aP in HD patients and PD patients is similar. Only 2.9% of patients received potentially effective treatment. These results highlight potential targets for improving patient management.

Funding Statement

This research was supported by grants from National Natural Science Foundation of China (82000637).

Disclosure statement

The authors declare that they have no conflict of interest.

Human ethics and consent to participate declarations

This study was performed in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (IIT20220141B-R1). All patients signed the written informed consent.

Data availability statement

All the datasets generated and/or analyzed during this study are included in the article. The data can be provided by the corresponding author upon reasonable request.