Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study

Jian-Hui Zhao; Qiu-Shuang Zhu; Yi-Wen Li; Li-Li Wang

doi:10.1371/journal.pone.0245370

. 2021 Jan 20;16(1):e0245370. doi: 10.1371/journal.pone.0245370

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study

Jian-Hui Zhao ^1,^2,^*, Qiu-Shuang Zhu ^1,², Yi-Wen Li ³, Li-Li Wang ²

Editor: Girish Chandra Bhatt⁴

PMCID: PMC7817000 PMID: 33471852

Abstract

Background

Uremic pruritus (UP) is a common and frustrating symptom in patients receiving hemodialysis (HD). The majority of patients have mild to moderate itching of the skin, and a small percentage have severe itching, which seriously affects their quality of life and survival rate. However, little is known about factors that influence the intensity of itching in patients.

Methods

A cross-sectional study on uremic pruritus in male and female patients receiving HD was conducted in September 2019. This study included 148 eligible patients who received HD at the Blood Purification Center of Xinchang County People’s Hospital, Zhejiang Province, China from March 2019 to June 2019. We collected general data consisted of age, sex, body mass index (BMI), place of residence, educational level, diabetes mellitus status and duration of HD; as well as clinical, biochemical indicators, including serum calcium (Ca), serum phosphorus (P), serum albumin (ALB), haemoglobin (Hb), serum intact parathyroid hormone (iPTH), pre-dialysis serum urea nitrogen (BUN), normalized protein catabolic rate (nPCR), urea nitrogen clearance index (KT/V), ferritin (FER) and pre-dialysis serum creatinine (sCR). We also assayed the inflammatory cytokine serum high sensitivity C-reactive protein (hs-CRP). The Five-Dimensional Itching Scale (5DIS) was used to evaluate the degree of skin itching (none, mild, moderate, or severe). We used multiple logistic regression to analyze influencing factors on the degree of skin itching in patients with UP.

Results

Of the 148 patients, 60 had uremic pruritus (incidence rate, 40.54%). These included 22 cases of mild skin itching (14.86%), 30 of moderate skin itching (20.27%), and 8 of severe skin itching (5.41%). Compared with uremia patients without skin pruritus, patients with UP had higher levels of iPTH, Hb, BUN, nPCR, and hs-CRP. The composition ratio showed significant differences between urban and rural patients with different degrees of skin itching (P = 0.017); moreover, the difference of iPTH and hs-CRP levels were statistically significant (P = 0.009 and < 0.001, respectively). Using no itching as a reference, multiple logistic regression analysis showed that as hs-CRP level increased, the patient’s risks of mild skin itching (odds ratio [OR] = 1.740; 95% confidence interval [CI], 1.061–2.854; P = 0.028), moderate skin itching (OR = 2.8838 95% CI, 1.744–4.718; P < 0.001), and severe skin itching (OR = 9.440; 95% CI, 3.547–25.124; P < 0.001) all increased as well. Compared with urban residents, rural residents have a higher risk of moderate itching (OR = 3.869; 95% CI, 1.099–13.622; P = 0.035).

Conclusion

Levels of hs-CRP were associated with the intensity of skin itching in patients with UP. Higher hs-CRP levels were closely related to severe skin itching. The relationship between the intensity of skin itching and the environment in maintenance hemodialysis patients needs further clarification.

Introduction

Background

Itchy skin is a common and distressing symptom in patients with chronic kidney disease. Uremic pruritus mainly manifests as skin itching of varying degrees, either systemically or locally, of which the back, extremities, chest, and head are common. Itching appears as paroxysmal episodes of varying duration. Those with milder symptoms can have intermittent attacks, lasting several minutes each time, while those with more severe symptoms last longer, and the symptoms are usually most apparent at night [1]. Epidemiological data indicated that approximately 40% of patients with end-stage renal disease (ESRD) experience moderate to severe itching [2]. The Dialysis Outcomes Practice Patterns Study (DOPPS), conducted from 2012 to 2015, showed that 26%–48% of patients had at least moderate skin itching, whereas 13%–26% of patients had severe or extreme itching [3]. The higher the degree of skin itching, the higher the mortality rate [4]. Several causes of or factors contributing to uremic pruritus (UP) have been proposed, including increasing systemic inflammation; abnormal levels of serum parathyroid hormone (PTH), serum calcium (Ca), and serum phosphorus (P); opioid receptor imbalance; and neuropathological processes [2]. However, the factors affecting the intensity of skin itching in patients with uremia are still unclear. We used a five-dimensional itching scale [5] to evaluate skin itching across multiple dimensions in uremic patients undergoing maintenance HD. We also included general patient data consisted of age, sex, body mass index (BMI), place of residence, educational level, diabetes mellitus status, and duration of HD; as well as clinical indicators comprised of Ca, P, serum albumin(ALB), Hemoglobin(Hb), PTH, serum creatinine(sCR), serum urea nitrogen (BUN), urea nitrogen clearance index (KT/V), ferritin (FER) before dialysis, and hs-CRP to analyze the determinants of Itching in these patients.

Objectives

Explore the prevalence of UP in maintenance HD patients and the demographic and clinical characteristics of pruritus patients.
Analyze the relationship between high-sensitivity C-reactive protein and other factors and the intensity of skin itching.

Methods

Study design

This study is a cross-sectional study on UP in patients receiving HD. The Ethics Committee approved this study of Xinchang County People’s Hospital, Zhejiang Province, China (Approval No. XCXRMYY2018-001), and all patients signed written informed consent.

Study setting

We included a total of 148 subjects who received HD at the Blood Purification Center of Xinchang County People’s Hospital, Zhejiang Province, China from March 2019 to June 2019. each of them signed an informed consent form. Collection of data was by the authors or research personnel, and all personnel received training and guidance from the corresponding author. Data statistics and analysis were from September to December 2019.

Participants

Inclusion criteria were as follows: (1) ≥1 month of HD in dialysis units and (2) age 20–90 years. Exclusion criteria were as follows: (1) primary skin diseases (e.g., eczema, psoriasis, neurodermatitis, allergic dermatitis, and drug rash), (2) use of right-cyclic saccharin, analgesics, antibiotics, or lipid-lowering drugs, (3) peripheral neuropathy, thyroid disease, leukaemia, lymphoma, bile siltation, liver lesions, or pregnancy, (4) patients with hearing/communication impairments who could not complete the study, and (5) patients with infections, malignant tumours, cardiovascular disease, or tissue damage. These criteria were applied to each patient.

Variables

The diagnostic criteria for uremic pruritus adopted internationally are as follows: (1) uremia patients exclude skin pruritus caused by other diseases; (2) itching occurs at least three days within two weeks, and itches several times a day, each time itching It lasts a few minutes and affects the patient’s life; (3) Itching in a specific pattern lasts for more than six months [6]. We used the Five-Dimensional Itching Scale (5DIS) to assess itching based on the five dimensions of degree, duration, direction, disability, and distribution. The total score ranged from 5 (no itching) to 25 (most severe Itching). Patients with scores <5 points were defined as having no itching; those with scores 6–25 points were considered itch patients. The score of 6–10 points indicated mild itching, 11–20 points marked moderate itching, and 21–25 points indicated severe Itching. Diagnosis of uremia pruritus meets the following conditions: 1. The total score of pruritus, according to 5DIS is between 6–25 points. 2. Meet the international diagnostic criteria for uremic pruritus (2) and (3). 3. Meet the exclusion criteria. ultimately, we included a total of 60 patients with UP and 88 patients without UP. Body Mass Index (BMI) was calculated using the following formula: weight (kg) / height (m)². Lean patients were defined as those with BMI ≦18.4 kg/m², patients with normal BMI 18.5–23.9 kg/m², heavy patients with BMI 24.0–27.9 kg/m², and obese patients with BMI ≧28.0 kg/m². According to the World Health Organization (WHO) standards, elderly patients were defined as those age ≧65 years, and non-elderly patients as those age <65 years.

Data source/Measurement

Patients data included of Sex, Age, BMI, place of residence (rural or urban), educational level (illiterate or semi-literate, primary, junior high school, high school, or university or above), diabetes mellitus status (present or absent) and duration of maintenance HD (Months) were obtained by the investigator interviewing the patients. We assayed biochemical indicators comprised of Ca, P, iPTH, Hb, ALB, sCR, Bun, nPCR, FER, KT/V and hs-CRP. The hospital’s central laboratory performed all of the laboratory tests, and auto-analyzers were used to determine biochemical data, iPTH was measured with Roche second-generation assay. The clinical biochemical indicators were based on the data within three months from the survey day. If there is no data within three months, the patient is required to re-test. If the patient is unwilling to cooperate with the test, it was considered a missing value. spKT/V (single pool KT/V) = -ln(R − 0.008t) + (4 − 3.5R) * (ΔBW/BW). Note: K refers to Blood urea clearance rate of dialyzer (L/h), T is the dialysis time (h), and V is the distribution volume of urea (V). R is the ratio of blood urea nitrogen after dialysis to blood urea nitrogen before dialysis; t is single dialysis time in h; ΔBW is the weight change value before and after dialysis, ultrafiltration, unit L; BW is weight in kg. Blood collection requirements: blood samples before dialysis from the artery end of the vascular path, after dialysis before blood sample collection to stop ultrafiltration, reduce blood flow of 50 ml/min, wait 15 seconds after blood collection from the artery as a blood sample after dialysis. nPCR(g/kg/d) = C₀/[a + b × KT/V + c ÷ (KT/V)] + 0.168 [7], where C₀ indicates pre-dialysis blood urea nitrogen in mg/dl (1mmol/L urea nitrogen is equal to 2.802mg/dl). a, b, c has different coefficients depending on the time of the dialysis schedule. In our blood purification center, patients are dialyzed three times a week, either on Mondays, Wednesdays, Fridays or either Tuesdays, Thursdays, Saturdays, so that the time between the first dialysis sessions at the beginning of the week is longer. The following formula is used: beginning-of-week: nPCR(g/kg/d) = C₀/[36.3 + 5.48 × KT/V + 53.5 ÷ (KT/V)] + 0.168. https://dx.doi.org/10.17504/protocols.io.bp94mr8w [PROTOCOL DOI].

Sample size

Epidemiological data indicated that approximately 40% of patients with end-stage renal disease (ESRD) experience UP [2]. The overall prevalence of uremia and pruritus is 0.4, and the tolerance is set to 0.1, taking a = 0.05, the total amount of hemodialysis in our blood purification center is 180 patients. According to PASS 15 Power Analysis and S ample Size Software (NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass), the calculated sample size is 121 people, assuming that the dropout rate is 20%, and the total sample size is 152 people.

Statistical methods

We performed statistical processing using line data from SPSS software version 24.0 (IBM Corp., Armonk, New York, US). Quantitative data from a normal distribution are expressed as mean ± standard deviation and comparison between groups were made using one-way analysis of variance or t-test. Quantitative data from a non-normal distribution are expressed as medians and interquartile ranges and comparison between groups of continuous variables were made using a non-parametric test. comparison between groups of classification variables was based on the rank-sum or chi-square test. A multiple logistic regression model analyzed the factors associated with the degree of skin itching in patients with uremia. All variables were diagnosed by collinearity. After elimination of the collinearity problem, the variables with statistical significance in the univariate analysis and the variables with statistical differences between the groups of different degrees of skin pruritus were included in the multivariate analysis (P<0.05 considered statistically different). Finally, we had four factors, including Hb, PTH, hs-CRP, place of residence in the multiple logistic regression model. P < 0.05 was statistically significant. In this study, the variables iPTH, hs-CRP, BUN, KT/V have two missing values, respectively, and therefore a total of 8 missing values. The analysis of missing values indicates that these variables were not MCAR (missing completely at random), so this study uses the EM (expectation-maximization) algorithm to fill in.

Results

Participants

Our blood Purification Center has a total of 180 patients. 20 patients were excluded, and 10 of them were unwilling to participate in the survey. 5 were peritoneal dialysis combined with hemodialysis, but hemodialysis was only treated once a week, and the remaining 5 were scheduled for 2 dialysis a week. Therefore, a total of 160 patients who regularly underwent hemodialysis three times a week were included in this study, 3 of them did not respond. Besides, we excluded 1 case of cirrhosis, 1 of dialysis allergy, 1 of drug rash, 3 of nodule itch, and 3 of hearing impairment that rendered the patient unable to communicate; ultimately, we included a total of 148 eligible subjects, in which 89 males (60.1%) and 59 females (39.9%). The median duration of HD was 42 months. There were 60 cases of UP (prevalence rate, 40.54%), including 22 mild cases (14.86%), 30 moderate cases (20.27%), and 8 severe cases (5.41%), As shown in Fig 1.

Descriptive data

The primary clinical characteristics of the included patients are shown in Table 1.

Table 1. Demographic and clinical characteristics of patients enrolled at baseline.

Variable	Results
Sex, n (%)
Male	89 (60.1%)
Age, n (%)
Non-elderly	99 (66.9%)
Educational level, n (%)
Illiterate or semi-literate	23 (15.5%)
Primary school	36 (24.3%)
Junior high school	54 (36.3%)
High school	19 (12.8%)
University and above	16 (10.8%)
Place of residence, n (%)
Rural	100 (67.6%)
BMI, n (%)
≦18.4	25 (16.9%)
18.5–23.9	101 (68.3%)
24–27.9	15 (10.1%)
≧28	7 (4.7%)
Diabetes mellitus, n (%)
Present	35(23.6)
Ca, mmol/L	2.23 (2.10–2.34)
P, mmol/L	1.74 (1.48–2.22)
iPTH, pg/ml	308.50 (153.50–581.50)
Hb, g/L	102.00 (95.25–110.00)
ALB, g/L	38.25 (35.20–40.00)
sCR, μmol/L	840.00 (666.00–910.00)
BUN, mmol/L	19.50(18.10–21.08)
nPCR, g/kg/d	0.81(0.75–0.86)
KT/V	1.27(1.23–1.31)
FER, ng/ml	193.80(129.63–220.00)
hs-CRP, mg/L	1.11 (0.60–2.00)
Duration of HD, months	42.00 (18.50–77.25)

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Notes: BMI, body mass index; Ca, serum calcium; P, serum phosphorus; iPTH, serum intact parathyroid hormone; Hb, Hemoglobin; ALB, serum albumin; sCR, serum creatinine; BUN, urea nitrogen; KT/V, urea nitrogen clearance index; nPCR, normalized protein catabolic rate; FER, ferritin; hs-CRP, serum hypersensitive C-reactive protein. Continuous variables with skewed data are summarized as the median (interquartile range); Dichotomous or categorical data are summarized as counts (percentages).

Outcome data

Compared with uremia patients without skin pruritus, patients with UP had higher levels of IPTH, Hb, BUN, nPCR and hs-CRP. No statistically significant differences were found in demographic characteristics such as Sex, Age, Educational level, BMI, Diabetes mellitus status or Place of residence; in levels of Ca, P, ALB, FER, KT/V, or sCR; or in HD duration (Table 2).

Table 2. Demographic and clinical characteristics of patients with and without uremic pruritus.

Variable	Pruritic group (n = 60)	Non-pruritic group (n = 88)	P
Sex, n (%)			0.318
Male	39 (65%)	50 (56.8%)
Age, n (%)			0.083
Non-elderly	45 (75%)	54 (61.4%)
Educational level, n (%)			0.623
Illiterate or semi-literate	7 (11.7%)	16 (18.2%)
Primary school	13 (21.7%)	23 (26.2%)
Junior high school	28 (46.7%)	26 (29.5%)
High school	8 (13.3%)	11 (12.5%)
University and above	4 (6.7%)	12 (13.6%)
Place of residence, n (%)			0.602
Rural	42 (70%)	58 (65.9%)
BMI, n (%)			0.079
≦18.4	13 (21.7%)	12 (13.6%)
18.5–23.9	41 (68.3%)	60 (68.2%)
24–27.9	5 (8.3%)	10(11.4%)
≥28	1 (1.7%)	6 (6.8%)
Diabetes mellitus, n (%)			0.099
Present	10 (16.7%)	25 (28.4%)
Ca, mmol/L	2.24 (2.13–2.36)	2.19 (2.09–2.34)	0.211
P, mmol/L	1.85 (1.50–2.34)	1.72 (1.44–2.15)	0.117
iPTH, pg/ml	368.00 (229.75–754.25)	220.50 (111.75–503.25)	0.001^*
Hb, g/L	104.00 (98.25–111.75)	100.00 (91.00–109.00)	0.025^*
ALB, g/L	38.10 (35.13–40.00)	38.45 (35.80–40.08)	0.972
sCR, μmol/L	853.00 (686.00–950.00)	824.00 (629.25–899.75)	0.420
BUN, mmol/L	19.95 (18.28–21.65)	19.10 (17.60–20.38)	0.028^*
nPCR, g/kg/d	0.83(0.78–0.89)	0.80(0.74–0.84)	0.033^*
KT/V	1.27 (1.24–1.31)	1.27 (1.22–1.32)	0.567
FER, ng/ml	200.20 (127.58–218.25)	190.50 (129.63–221.50)	0.696
hs-CRP, mg/L	2.00 (1.00–3.00)	0.90 (0.50–1.50)	<0.001^*
Duration of HD, months	45.50 (18.00–77.00)	42.00 (20.25–78.75)	0.936

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Notes: The above numerical variables are all non-normal distribution data, articulated by the median (interquartile range). Intergroup comparisons of variables were made using the Mann–Whitney U test. Categorical variables are expressed as counts (percentages). Unordered categorical variables were tested by chi-square; ordered categorical variables including BMI and educational level were tested by Kruskal–Wallis H. BMI, body mass index; Ca, serum calcium; P, serum phosphorus; iPTH, serum intact parathyroid hormone; Hb, Hemoglobin; ALB, serum albumin; sCR, serum creatinine; BUN, urea nitrogen; nPCR, normalized protein catabolic rate; KT/V, urea nitrogen clearance index; FER, ferritin; hs-CRP, serum hypersensitive C-reactive protein.

*P < 0.05.

The composition ratio showed a difference between rural and urban patients with varying degrees of skin itching (P = 0.017). Differences in IPTH and hs-CRP levels of patients with different degrees of skin itching were statistically significant (P = 0.009 and <0.001, respectively), as shown in Table 3.

Table 3. Baseline characteristics of patients with varying degrees of skin itching.

Variable	No itching (n = 88)	Mild itching (n = 22)	Moderate itching (n = 30)	Severe itching (n = 8)	P
Sex, n (%)					0.495
Male	50 (56.8%)	16 (72.7%)	19 (63.3)	4 (50%)
Age, n (%)					0.262
Non-elderly	54 (61. 4%)	15 (68.2%)	24 (80.0%)	6 (75.0%)
Educational level, n (%)					0.478
Illiterate or semi-literate	16 (18.2%)	2 (9.1%)	4 (13.3%)	1 (12.5%)
Primary school	23 (26.1)	3 (13.6%)	8 (26.7%)	2 (25%)
Junior high school	26 (29.5%)	11 (50.0%)	12 (40.0%)	5 (62.5%)
High school	11 (12.5%)	2 (9.1%)	6 (20.0%)	0 (0.0%)
University and above	12 (13.6%)	4 (18.2%)	0 (0.0%)	0 (0.0%)
Place of residence, n (%)					0.017^*
Rural	58 (65.9%)	10 (45.5%)	25 (83.3%)	7 (87.5%)
BMI, kg/m²					0.300
≦18.4	12 (13.6%)	4 (18.2%)	6 (20.0%)	3 (37.5%)
18.5–23.9	60 (68.2%)	16 (72.8%)	21 (70.0%)	4 (50.0%)
24–27.9	10 (11.4%)	1 (4.5%)	3 (10.0%)	1 (12.5%)
≥28	6 (6.8%)	1 (4.5%)	0 (0.0%)	0 (0.0%)
Diabetes mellitus, n (%)					0.326
Present	25 (28.4%)	4 (18.2%)	4 (13.3%)	2 (25%)
Ca, mmol/L	2.19 (2.09–2.34)	2.25 (2.15–2.33)	2.24 (2.12–2.45)	2.17 (2.05–2.31)	0.485
P, mmol/L	1.72 (1.44–2.15)	1.90 (1.50, 2.47)	1.90 (1.62, 2.25)	1.49 (1.30–2.26)	0.227
iPTH, pg/ml	220.50 (111.75–503.25)	377.50 (280.00–719.00)	360.00 (207.00–793.34)	497.50 (229.50–801.25.)	0.009^*
Hb, g/L	100.00 (91.00–109.00)	103.50 (98.75–109.25)	105.00 (98.75–109.25)	107.00 (93.25–118.75)	0.138
ALB, g/L	38.45 (35.80–40.08)	38.05 (36.68–40.85)	38.25 (34.73–39.63)	36.60 (31.73–39.83)	0.472
sCR, μmol/L	824.00 (629.25–899.75)	853.00 (710.00–974.75)	850.50 (709.50–955.00)	788.50 (422.75–905.00)	0.565
BUN, mmol/L	19.10 (17.60–20.38)	19.90 (18.18–22.43)	19.80 (18.18–21.20)	20.35 (19.43–21.73)	0.118
nPCR, g/kg/d	0.80(0.74–0.84)	0.82(0.76–0.91)	0.82(0.77–0.86)	0.85(0.81–0.88)	0.136
KT/V	1.27 (1.22–1.32)	1.28 (1.26–1.33)	1.27 (1.23–1.31)	1.27 (1.22–1.33)	0.708
FER, ng/ml	190.50 (129.63–221.50)	203.00 (116.50–231.00)	200.50 (142.26–206.00)	153.75 (109.25–203.85)	0.628
hs-CRP, mg/L	0.90 (0.50–1.50)	1.08 (0.50–2.63)	2.15 (1.18–2.93)	3.93 (2.83–5.18)	<0.001^*
HD duration, months	42.00 (20.25–78.75)	38.50 (17.25–83.25)	37.00 (14.00–68.25)	67.00 (56.00–89.25)	0.119

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Notes: P, Hb, ALB, Ca, PTH, sCR, hs-CRP, and HD duration are all non-normal data, articulated by the median (interquartile range); dichotomous or categorical data are summarized as counts (percentages). Kruskal–Wallis probability between the four groups, with subsequent multiple Mann–Whitney U test if significant. Categorical variables are expressed as counts (percentages), unordered categorical variables were tested by chi-square, and ordered categorical variables were tested by Kruskal–Wallis H. BMI, body mass index; Ca, serum calcium; P, serum phosphorus; iPTH, serum intact parathyroid hormone; Hb, Hemoglobin; ALB, serum albumin; sCR, serum creatinine; BUN, urea nitrogen; nPCR, normalized protein catabolic rate; KT/V, urea nitrogen clearance index; FER, ferritin; Hb, Hemoglobin; ALB, serum albumin; hs-CRP, serum hypersensitive C-reactive protein; HD, hemodialysis.

*P < 0.05.

Main results

Degree of skin itching in patients with uremic pruritus as analyzed by the single-factor logistic-regression model

Compared with patients without uremic pruritus, mild itching (OR = 1.917; P = 0.010), moderate itching (OR = 2.696, P < 0.001), and severe itching (OR = 6.915; P < 0.001) were all related to hs-CRP level. The higher hs-CRP level was closely related to severe itching. iPTH was weakly associated with severe itching (OR = 1.001, P = 0.031). Hb was slightly associated with moderate itching (OR = 1.036, P = 0.026) and severe itching (OR = 1.036, P = 0.170), as shown in (Fig 2, S1 Table).

Fig 2 — The error bars represent the lower and upper limits of the 95% confidence interval. The symbol is a circle for mild itching, a triangle for moderate itching, and a square for severe itching. The dashed line in the figure indicates that the odds ratio is equal to 1.

Degree of skin itching in patients with uremic pruritus as analyzed by multivariate logistic regression

We included four variables (hs-CRP, Hb, PTH, Place of residence) in multiple logistic regression analysis. Using no itching as a reference, the results showed that risk of skin itching increased with level of hs-CRP (mild skin itching, OR = 1.740; 95% CI, 1.061–2.845; P = 0.028; moderate skin itching, OR = 2.838; 95% CI, 1.744–4.618; P < 0.001; severe skin itching, OR = 9.440; 95% CI, 3.547–25.124; P < 0.001). Compared with urban residents, rural residents have a higher risk of moderate itching (OR = 3.869; 95% CI, 1.099–13.622; P = 0.035). as shown in (Fig 3, S2 Table).

Fig 3 — The error bars represent the lower and upper limits of the 95% confidence interval. The symbol is a circle for mild itching, a triangle for moderate itching, and a square for severe itching. The dashed line in the figure indicates that the odds ratio is equal to 1.

Other analyses

The level of iPTH in patients with mild itching was higher than in those with no skin itching, to a statistically significant degree (P <0.05). Levels of hs-CRP in patients with moderate and severe skin itching were statistically significantly higher than in patients without itching (all P <0.001). There was no statistically significant difference in place of residence in patients with mild, moderate, and severe itching compared with no skin itching (all P > 0.05), As shown in Fig 4.

Fig 4 — (A) Intergroup comparison of iPTH levels; (B) intergroup comparison of hs-CRP levels; (C) intergroup comparison of the composition ratio of rural to urban residents. ****P < 0.0001, *P < 0.05. Error line represents the minimum and maximum values.

Discussion

Key results

In this study, we found that among 148 eligible patients receiving maintenance HD, 60 had UP (prevalence rate, 40.54%); they included 22 mild cases of skin itching (14.86%), 30 moderate cases (20.27%), and 8 severe cases (5.41%). The composition ratio of rural to urban patients, levels of IPTH and hs-CRP were statistically significantly different in patients with varying degrees of skin pruritus. Single-factor logistic-regression analysis discovered a link between hs-CRP, Hb and iPTH and varying degrees of itching. Multifactor logistic regression analysis indicated that patients with higher hs-CRP levels had higher risks of mild, moderate, and severe skin itching. Interestingly, the multivariate analysis showed that rural residents have a higher risk of moderate skin itching than urban residents.

Limitations

Our study had some limitations. Firstly, it was a single-center, cross-sectional study that did not show a causal relationship between severity of skin itching in UP and hs-CRP, so further validation is needed from multicenter, large-sample, prospective cohort studies. Secondly, this study did not include some of the influences known in the literature such as diet, insulin resistance, interleukins 6 and 2, and κ opioid receptor distribution. Thirdly, the number of patients with severe pruritus is small (n = 8), so readers may not understand a meaningful association with severe pruritus. Fourthly, the sample size of this study was limited and uneven between groups. Fifthly, this study recruited 160 patients, 3 of whom were non-responders, and these non-responders may have differed from responders in some critical clinical features or exposures; however, the proportion (1.87%) was small. Finally, during participation in the questionnaire of this study, some patients may be limited by their cultural level or subjective perceptions, which may lead to discrimination in the individual skin itch scale scores, thus affecting the accuracy of the assessment of the itchiness of the patient’s skin. For the study participants who took part in the questionnaire, we trained two research staff, and the final results were taken as the mean of the two-pruritus skin itch scale scores.

Interpretation

This study showed that median hs-CRP level gradually increased along with the degree of skin itching in patients with uremic pruritus (no itching, 0.90; mild skin itching, 1.08; moderate skin itching, 2.15; severe skin itching, 3.93). Furthermore, hs-CRP levels in patients with moderate and severe skin itching were significantly higher than in those without itching. These findings suggested that hs-CRP levels might be associated with the severity of skin itching. Jiang et al. [8] reported that levels of C-reactive protein (CRP) and leukocyte interleukin-6 (IL-6) in patients receiving high-flux hemodialysis improved, compared with those in patients who received hemodialysis filtration. Another study also showed that HD patients with UP had significantly higher serum CRP and IL-6 levels compared to HD patients without UP, UP seems to be associated with an up-regulation of micro-inflammation in uremia [9]. Mahmudpour’s team [10] indicated that the average reduction in VAS scores in the montelukast group was greater than that in the placebo group, and average levels of hs-CRP in this group showed a downward trend. However, average hs-CRP levels in the placebo group gradually increased, showing that the effect of montelukast treatment in UP might be related to a reduction in an inflammatory response. A factor analysis also shows a close correlation between UP and levels of the inflammatory factors CRP and leukocyte IL-6 [11]. Based on this study and previous studies, inflammatory responses appear to play an important role in UP.

We analyzed the factors affecting the intensity of skin itching in UP patients and corrected for patients’ levels of Hb and iPTH, Place of residence. Multifactor logistic-regression analysis found that hs-CRP levels were associated with the intensity of skin itching and were a risk factor. Compared with patients without itching, the OR value for mild skin itching was 1.740, that for moderate skin itching was 2.838, and that for severe skin itching was 9.440, indicating that degree of skin itching increased along with hs-CRP levels. A previous multivariable logistic-regression analysis confirmed that older age and higher CRP levels are associated with severe itching [3]. Still, in our study, neither single-factor nor multifactor logistic-regression analysis showed any differences in skin itching between elderly and non-elderly patients. In our study, the OR value for hs-CRP of patients with severe skin itching was significantly higher than that of patients without itching, suggesting that higher hs-CRP levels were closely associated with severe skin itching, which was consistent with the results of an earlier study. Pakfetrat et al. [12] assessed the effect of sertraline on UP. Patients were randomly divided into two groups, the trial group receiving sertraline and the control group taking a placebo. Their severity of itching was measured by two scoring systems (visual-simulation score and DUO scoring system [13]). The researchers found that differences in skin itching intensity between the two scoring systems and between the two groups were directly related to CRP level, and they believed that sertraline reduced skin itching, perhaps due to its effect of reducing the number of inflammatory cytokines. Tseng et al. [14] studied a possible association between vegetarians and UP. They found that levels of inflammatory factors such as leukocyte IL-2 and hs-CRP, visual-simulation score (Analog Score and VAS), and itching score were all lower in vegetarian patients than in non-vegetarian ones. This study demonstrated that a vegetarian diet might be associated with improvement of uremic-pruritus severity in hemodialysis patients.

In our study, the composition ratio showed a significant difference between rural and urban patients with different degrees of skin itching. Although the single factor analysis did not indicate that the place of residence was related to the intensity of the patient’s skin itching, the multifactor analysis demonstrated that rural residents had a higher risk of moderate skin itching than urban residents. UP in patients receiving maintenance HD is associated with air pollutants such as NO2 and CO [15]. A cross-sectional study also suggested that UP in patients receiving maintenance HD might be associated with the number of days in which environmental particulate matter ≤2.5 μ in diameter (PM2.5) exceeds standard levels [16]. The above mentioned two studies suggest that itching of the skin might be associated with the patient’s living environment. In this study, there were a total of 148 patients with uremia and eight patients with severe skin pruritus, accounting for 5.4% of the total patients. 2012–2015 DPPSO study [3] surveyed 7,629 people, divided into five groups (not at all, somewhat, moderately, Very Much, Extremely) according to the degree of itchy skin. Extreme itching accounted for 7%, which is slightly higher than 5.4% of patients with severe itching in this study. The reason for the differences may lie in the different criteria used to assess the degree of pruritus in the patient’s skin.

iPTH levels differed between patients with varying degrees of skin itching. Median iPTH level in patients with severe skin itching was higher than that in patients without itching. Still, there was no statistically significant difference between iPTH levels across groups, and single-factor regression analysis suggested a weak association between higher iPTH levels and severe skin itching. However, after we corrected for hs-CRP and Hb levels, place of residence, that association disappeared. After parathyroid excision, iPTH level and serum phosphate concentration are significantly reduced, and skin itching disappears [17, 18]. A study by Moldovan et al. [19] suggested that the average value of PTH decreased significantly after parathyroidectomy. However, itching of the skin did not improve. Levy et al. [20] studied the associated symptoms of secondary hyperparathyroidism in patients receiving maintenance HD. Results showed that an increase in PTH levels was associated with skin itching worsening over time, and the effect was more obvious with larger changes in PTH level. However, the combination of the disease, detection of medication, the inclusion of up to 19 symptoms, the larger P-value threshold (0.1), and other promiscuous factors might have affected the reliability of that study. It is therefore controversial whether there is a link between iPTH and the degree of itchiness of the skin.

Some studies suggested that UP is related to Ca, P, ALB, and uremic toxins [12, 21]. Nevertheless, contradictory data on the impact of Ca and P have been reported [22]. In this study, no statistically significant differences were found in Ca, P, ALB, and creatinine when comparing groups of patients with different degrees of skin pruritus. Besides, single-factor logistic regression analysis also did not find an association between these factors and the degree of skin pruritus. Therefore, these factors were ultimately not included in the multifactor logistic regression analysis. In fact, despite various substances have been discussed as potential pruritogens in chronic renal diseases, a causal relationship could never be established [23].

At present, only a few studies have explored the factors affecting skin itching intensity in these patients. Wieczorek et al. [24] documented Intensity of skin itching have a significant negative correlation with expression of κ opioid receptors in patients with HD. Also, hs-CRP levels, male sex, HD duration, insulin resistance, insufficient dialysis adequacy, and hyperphosphatemia are positively correlated with UP intensity [25] and increasing the blood flow of the HD machine can reduce the intensity and frequency of skin itching [26]. However, the above preliminary research used visual-analogue scoring (VAS) to evaluate the degree of skin itching. In this study, we used a five-dimensional itching scale to evaluate skin itching across multiple dimensions in uremic patients undergoing maintenance HD. Although VAS is sufficient to assess the severity of symptoms, it does not take into account other aspects of pruritus, such as the relative impact of pruritus on quality of life, changes in pruritus over time, and the location of pruritus. The 5-D score was strongly correlated with the numerical rating scale (NRS) and VAS [5, 27], which is a questionnaire with acceptable validity, reliability and sensitivity to change to evaluate pruritus in Thai and Arabic patients [27, 28]. The 5-dimensional Pruritus Scale is recommended to assess the severity of pruritus because it is more accurate than VAS and more sensitive to the multidimensional nature of pruritus [29].

Generalizability

In conclusion, our study suggested that the intensity of skin itching in patients with UP was associated with hs-CRP and that higher hs-CRP levels were associated with severe skin itching. Besides, the environment may be related to the degree of itchy skin in uremia patients.

Supporting information

S1 Table. Single-factor logistic-regression analysis of the degree of skin itching in patients with uremic pruritus.

(DOCX)

Click here for additional data file.^{(18.4KB, docx)}

S2 Table. Multiple logistic regression analysis of factors influencing skin itching in patients with uremic pruritus.

(DOCX)

Click here for additional data file.^{(19.3KB, docx)}

Acknowledgments

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Data Availability

All relevant data are within the paper and its Supporting information files.

Funding Statement

The authors received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0245370.r001

Decision Letter 0

Girish Chandra Bhatt

24 Sep 2020

PONE-D-20-18098

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: a corss-sectional study

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Reviewer #1: The authors performed a cross-sectional analysis of 148 hemodialysis patients to identify factors associated with uremic pruritus. They found that higher levels of PTH, hemoglobin, and hs-CRP as well as rural residence of patients were associated with worse pruritus. There are major concerns with the lack of dialysis and other pertinent laboratory data. Overall, the results do not add new data to the existing literature.

Comments:

1) There is no data provided for dialysis adequacy, which has been shown to be associated with pruritus in prior studies. Likewise, BUN levels, nPCR, ferritin levels, and diabetic status should be included in the analysis.

2) The authors used the Five-Dimensional Itching Scale (5DIS) to assess the degree of pruritus in patients, noting that this scale would “produce more objective and comprehensive results” compared to the visual-analogue scoring scale. The authors should provide data to justify this statement.

3) A large proportion of the discussion was dedicated to the finding that higher hs-CRP levels were associated with pruritus. A prior study has previously reported this finding, along with levels of cytokines and T cells (PMID 16249205); this reference should be cited.

4) The number of patients with severe pruritus is small (n=8) and therefore meaningful associations with severe pruritus may not be appreciated.

Reviewer #2: In this study, the authors studied uremic pruritus using the five dimensional itch scale in 148 adult patients of end-stage renal disease receiving haemodialysis and report prevalence of 40.5% and association with parathormone (PTH), hemoglobin and high-sensitive C reactive protein (hs-CRP) on bivariate analysis and hs-CRP alone on multiple logistic regression. The study seems to be designed logically, conducted scientifically and analyzed with due statistical rigour. However, the manuscript is lengthy, does not have a smooth flow of information and requires rewriting as per the STROBE checklist. Major observations are described below. Minor observations are inserted in the uploaded version of the manuscript as “sticky notes” at appropriate places.

Major observations

1. The introduction should succinctly summarize the present state of knowledge on uremic pruritus, highlight the gap in knowledge the study sought to address and state the study’s objective. Comparison with previous studies (measurement of severity of itching) should be reserved for discussion.

2. The stated aims of the study are to “1. explore the prevalence of UP in maintenance HD patients and the demographic and clinical characteristics of pruritus patients.

2.explore determinants of higher pruritus intensity based on participants’ clinical and biochemical parameters and their pruritus assessments by 5DIS at baseline”. The second aim is somewhat unclear. Were characteristics of patients with higher pruritus intensity to be compared with those of patients with of lower pruritus intensity or with those of patients without pruritus? Clear statement in the PICO format is suggested. What is the novelty of the research question? This needs to be justified.

3. The setting of the study may be described in “Methods”.

4. How were biochemical parameters such as serum calcium, phosphorus, creatinine, etc assayed? The detailed methods need not be described but should be referenced.

5. The study reports no significant association of uremic pruritus with factors such as calcium, phosphorus, creatinine and albumin. However, the sample size calculation was made to estimate the prevalence of uremic pruritus. Could the study have been underpowered for the study of these factors?

6. The following factors influencing uremic pruritus have not been studied: diet, insulin resistance, dialysis adequacy, interleukins 6 & 2, and κ opioid receptor distribution. These need to be acknowledged as limitations.

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PLoS One. 2021 Jan 20;16(1):e0245370. doi: 10.1371/journal.pone.0245370.r002

Author response to Decision Letter 0

21 Oct 2020

Response to the PLOS ONE’s editor

Thank you for the hard work of the academic editors of “PLOS ONE”. Thank you for accompanying me and helping me grow up. As for the issues that need my attention, I summarize as follows.

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We have revised the paper following your journal's formatting requirements for title, authorship, and text.

2.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

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A total of four images are in the paper, and the image files have been uploaded to the PACE software, all with a resolution of 600ppi, 2000-4500 pixels wide and 1358-3925 pixels high, and are currently sealed in the PACE software.

Response to Reviewer

Thank the reviewers for these lovely comments concerning our manuscript entitled “Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study”. These comments are all valuable and very helpful for revising and improving our paper, as well as the essential guiding significance to our researches. We have studied comments carefully and have made corrections which we hope to meet with approval. The response to the reviewer’s comments are as follows:

Reviewer #1

The authors performed a cross-sectional analysis of 148 hemodialysis patients to identify factors associated with uremic pruritus. They found that higher levels of PTH, hemoglobin, and hs-CRP, as well as the rural residence of patients were associated with worse pruritus. There are major concerns with the lack of dialysis and other pertinent laboratory data. Overall, the results do not add new data to the existing literature.

1. There is no data provided for dialysis adequacy, which has been shown to be associated with pruritus in prior studies. Likewise, BUN levels, nPCR, ferritin levels, and diabetic status should be included in the analysis.

Response:

The revision adds these factors, such as urea nitrogen, ferritin level, diabetes, and single pool KT/V(spKT/V), to the list of factors related to hemodialysis. Normalized protein catabolic rate (nPCR) is a nutritional index for hemodialysis patients. Its measurement requires multiple blood collections, which can be challenging to obtain, especially with the inclusion of serum albumin, which is a nutritional index. The spKT/V index reflects the adequacy of single hemodialysis.

This section is mainly shown on pages 6-11, tables 1-3.

2. The authors used the Five-Dimensional Itching Scale (5DIS) to assess the degree of pruritus in patients, noting that this scale would “produce more objective and comprehensive results” compared to the visual-analogue scoring scale. The authors should provide data to justify this statement.

Response:

In this study, we used a five-dimensional itching scale to evaluate skin itching across multiple dimensions in uremic patients undergoing maintenance HD. Although VAS is sufficient to assess the severity of symptoms, it does not take into account other aspects of pruritus, such as the relative impact of pruritus on quality of life, changes in pruritus over time, and the location of pruritus. The 5-D score was strongly correlated with the numerical rating scale（NRS）and VAS[5, 26], which is a questionnaire with acceptable validity, reliability and sensitivity to change to evaluate pruritus in Thai and Arabic patients[26, 27]. The 5-dimensional Pruritus Scale is recommended to assess the severity of pruritus because it is more accurate than VAS and more sensitive to the multidimensional nature of pruritus[28].

This section is detailed on page15, line 29-38.

3. A large proportion of the discussion was dedicated to the finding that higher hs-CRP levels were associated with pruritus. A prior study has previously reported this finding, along with levels of cytokines and T cells (PMID 16249205); this reference should be cited.

Response：

This section is detailed on Reference #8（page 13, line35）

4. The number of patients with severe pruritus is small (n=8) and therefore, meaningful associations with severe pruritus may not be appreciated.

Response：

In this study, there were a total of 148 patients with uremia and eight patients with severe skin pruritus, accounting for 5.4% of the total patients. 2012-2015 DPPSO study[3] surveyed 7,629 people, divided into five groups (not at all, somewhat, moderately, Very Much, Extremely) according to the degree of itchy skin. Extreme Itching accounted for 7%, which is slightly higher than 5.4% of patients with severe Itching in this study. The reason for the differences may lie in the different criteria used to assess the degree of pruritus in the patient's skin.

This section is detailed on page 14, lines 37-43

Reviewer #2

In this study, the authors studied uremic pruritus using the five-dimensional itch scale in 148 adult patients of end-stage renal disease receiving hemodialysis and report the prevalence of 40.5% and association with parathormone (PTH), hemoglobin and high-sensitive C reactive protein (hs-CRP) on bivariate analysis and hs-CRP alone on multiple logistic regression. The study seems to be designed logically, conducted scientifically and analyzed with due statistical rigour. However, the manuscript is lengthy, does not have a smooth flow of information and requires rewriting as per the STROBE checklist. Major observations are described below. Minor observations are inserted in the uploaded version of the manuscript as “sticky notes” at appropriate places.

Response:

1）We have rewritten the paper according to the STROBE checklist, details of which can be found in the attached STROBE checklist.

2）Concerning some minor observation, we have followed your comments with deep appreciation.

Major observation:

1. The introduction should briefly summarize the present state of knowledge on uremic pruritus, highlight the gap in understanding the study sought to address and state the study’s objective. Comparison with previous studies (measurement of severity of Itching) should be reserved for discussion.

Response:

The reviewer's suggestions were excellent, and we have corrected them.

This section has been moved to page 15, lines 23-29.

2. The stated aims of the study are to “1. explore the prevalence of UP in maintenance HD patients and the demographic and clinical characteristics of pruritus patients. Explore determinants of higher pruritus intensity based on participants’ clinical and biochemical parameters and their pruritus assessments by 5DIS at baseline”. The second aim is somewhat unclear. Were characteristics of patients with higher pruritus intensity to be compared with those of patients with of lower pruritus intensity or with those of patients without pruritus? Clear statement in the PICO format is suggested. What is the novelty of the research question? This needs to be justified.

Response:

objectives

(1). explore the prevalence of UP in maintenance HD patients and the demographic and clinical characteristics of pruritus patients.

(2). analyze the relationship between high-sensitivity C-reactive protein and different degrees of skin itching.

This section has been moved to page 2, lines 28-32.

3. The setting of the study may be described in “Methods”.

Response:

This section is detailed on Methods (study setting), page2, lines 38 & page3, lines 1-5.

4.How were biochemical parameters such as serum calcium, phosphorus, creatinine, etc assayed? The detailed methods need not be described but should be referenced.

Response:

We assayed biochemical indicators such as Ca, P, iPTH, Hb, ALB, sCr, Bun, FER, sp/KTV and hs-CRP. The hospital's central laboratory performed all of the laboratory tests, and auto-analyzers were used to determine biochemical data, iPTH was measured with Roche second-generation assay. The clinical biochemical indicators are based on the data within three months from the survey day. If there is no data within three months, the patient is required to re-test. If the patient is unwilling to cooperate with the test, it is a missing value. spKT/V（single pool KT/V）=-ln⁡(R-0.008t)+(4-3.5R)*(∆BW/BW). Note: K refers to Blood urea clearance rate of dialyzer（L/h）, t is the dialysis time (h), and V is the distribution volume of urea (V). R is the ratio of blood urea nitrogen after dialysis to blood urea nitrogen before dialysis; t is single dialysis time in h; ∆BW is the weight change value before and after dialysis, i.e. ultrafiltration, unit L; BW is weight in kg. Blood collection requirements: blood samples before dialysis from the artery end of the vascular path, after dialysis before blood sample collection to stop ultrafiltration, reduce blood flow of 50 ml/min, wait 15 seconds after blood collection from the artery as a blood sample after dialysis.

This section is detailed on page 3, lines 36-41 & page 4, lines 1-7.

5.The study reports no significant association of uremic pruritus with factors such as calcium, phosphorus, creatinine and albumin. However, the sample size calculation was made to estimate the prevalence of uremic pruritus. Could the study have been under powered for the study of these factors?

Response:

Some studies suggested that UP is related to Ca, P, ALB, and uremic toxins[11, 20]. Nevertheless, contradictory data on the impact of Ca and P have been reported[21]. In this study, no statistically significant differences were found in Ca, P, ALB, and creatinine when comparing groups of patients with different degrees of skin pruritus. There may indeed be a lack of test power（Since the data for these factors are non-normally distributed, the exact distribution is unknown. Based on statistical theory, it is not possible to calculate the true test power with certainty.）, which is considered to be related to the small sample size of this study and the unbalanced sample size among the groups. However, single-factor logistic regression analysis also did not find an association between these factors and the degree of skin pruritus. Therefore, these factors were ultimately not included in the multifactor logistic regression analysis. In fact, despite various substances have been discussed as potential pruritogens in chronic renal diseases, a causal relationship could never be established[22].

This section is detailed on page 15, lines 14-22.

6.The following factors influencing uremic pruritus have not been studied: diet, insulin resistance, dialysis adequacy, interleukins 6 & 2, and κ opioid receptor distribution. These need to be acknowledged as limitations.

Response:

Firstly, this study was a single-center study with a limited number of people on hemodialysis, and therefore the number of people included in the study was limited. Many factors influence skin itching in uremic patients, and it is not practical to include all relevant aspects of the study. Secondly, there is the issue of patient compliance. For example, to study diet factor, we need to distinguish between vegetarian and non-vegan patients, which requires strict control of the patient's diet. For insulin resistance, if the HOMA model is used to assess the resistance of the body to insulin (HOMA-IR), fasting blood glucose and fasting insulin levels need to be measured based on the formula HOMA-IR=FPG×FINS/22.5, therefor, fasting blood needs to be collected before hemodialysis. Some patients are difficult to cooperate, the missing value of the study will be further increased. Thirdly, for dialysis adequacy, we included a urea clearance index (kt/v) to assess this. In conclusion, it is essential to acknowledge the limitations of this study.

This section is detailed on page 13, lines 17-19.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(32.9KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0245370.r003

Decision Letter 1

Girish Chandra Bhatt

20 Nov 2020

PONE-D-20-18098R1

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study

PLOS ONE

Dear Dr. Zhao,

Please submit your revised manuscript by Jan 04 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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We look forward to receiving your revised manuscript.

Kind regards,

Girish Chandra Bhatt, MD, FASN

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have revised the manuscript in response to the initial comments. Improvements include addition of other variables that have been associated with pruritus into their analysis along with data to support their proposed use of the 5D score to assess pruritus. Overall, the manuscript adds to existing reports of hsCRP’s association with uremic pruritus. One minor comment to consider is that the nPCR can be obtained from the kinetic modeling used to obtain spKt/V. But since the BUN levels were not different across pruritus severity, it is unlikely that the nPCR will be different.

Reviewer #2: The authors have rewritten the manuscript and it reads much more clearly. Small changes are suggested. These have been indicated as "sticky notes" at the appropriate places in the uploaded version of the manuscript.

**********

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Reviewer #1: No

Reviewer #2: No

Attachment

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PLoS One. 2021 Jan 20;16(1):e0245370. doi: 10.1371/journal.pone.0245370.r004

Author response to Decision Letter 1

3 Dec 2020

Dear Dr Girish Chandra Bhatt, MD, FASN and Reviewers

Thank you for giving us the opportunity to submit a revised draft of the manuscript “Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study” for publication in the Journal of PLOS ONE.

We have incorporated all of the suggestions made by the reviewers. Those changes are highlighted in the revised manuscript with tracked changes. Please see a point-by-point response to the reviewers’ comments and concerns. Page numbers and line numbers in the original manuscript are shown in black and bold; page numbers and line numbers in revised manuscript with tracked changes are shown in normal type.

We hope that the revised manuscript is acceptable manuscript for publication in your Journal.

Sincerely yours,

Jian-Hui Zhao

Response to academic editor

1.If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

Response: we would not like to make changes to our financial disclosure.

2.If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Response: Our study is a clinical cross-sectional survey study and does not involve complex laboratory procedures and clinical research methods. However, we have found a simple formula for calculating normalized protein catabolic rate (nPCR). In this formula, as long as there is urea nitrogen before hemodialysis and the KT/V result of single hemodialysis, nPCR can be calculated accurately. We deposit this method on the protocols.io website to get the doi number (https://dx.doi.org/10.17504/protocols.io.bp94mr8w) [PROTOCOL DOI].

3.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Response: We have updated Fig 1, but Fig 2-4 do not require any changes. PACE can ensure that these figures are PLOS compliant.

Response to Reviewer

Reviewer #1

The authors have revised the manuscript in response to the initial comments. Improvements include addition of other variables that have been associated with pruritus into their analysis along with data to support their proposed use of the 5D score to assess pruritus. Overall, the manuscript adds to existing reports of hsCRP’s association with uremic pruritus. One minor comment to consider is that the nPCR can be obtained from the kinetic modeling used to obtain spKt/V. But since the BUN levels were not different across pruritus severity, it is unlikely that the nPCR will be different.

Response:

Thank you for your suggestions on the data integrity and statistical analysis aspects of your paper, we see that you have given us a kind reminder in your comments. Here are the answers to your concerns.

Following your suggestion, we have added a variable (nPCR) in the revised manuscript, based on pre-dialysis blood urea nitrogen levels in combination with spKT/V, to introduce the formula: nPCR((g/kg)/d)=C_0/[a+b×KT/V+c÷(KT/V)] +0.168,where C0 indicates pre-dialysis blood urea nitrogen in mg/dl (1mmol/L urea nitrogen is equal to 2.802mg/dl). a, b, c has different coefficients depending on the time of the dialysis schedule. In our blood purification center, patients are dialyzed three times a week, either on Mondays, Wednesdays, Fridays or either Tuesdays, Thursdays, Saturdays, so that the time between the first dialysis sessions at the beginning of the week is longer. The following formula is used: beginning-of-week: nPCR(g/kg/d)=C_0/[36.3+5.48×KT/V+53.5÷(KT/V)] +0.168.

Our statistical analysis showed that patients with pruritus have a higher nPCR level compared to patients without pruritus (p=0.028), however, there is no statistically significant difference between patients with different levels of pruritus (p=0.136). Furthermore, the single factor analysis also did not show a statistically significant correlation, thus the results of the multifactorial analysis did not change and the conclusions of the paper were unchanged.

This section was shown in lines 7-13, page 4 in revised manuscript with tracked changes and the detailed data are shown in Tables 1-3.

Reviewer #2

The authors have rewritten the manuscript and it reads much more clearly. Small changes are suggested. These have been indicated as "sticky notes" at the appropriate places in the uploaded version of the manuscript.

Response:

We appreciate your suggestions regarding the language structure of our paper, which is very conducive to improving the quality of the paper, and the following is an itemized response to your small comments.

1. Line 25, page 2: diabetes mellitus (avoid unnecessary capitalization)

This phrase was modified according to the comment. (Line 24, page 2).

2. Line 29, page 2: Objectives (headings should be capitalized)

Thank you for pointing this out. As you suggested, we have corrected the “objectives” to “Objectives”. (Line 28, page 2).

3. Line 30 page 3: we feel sorry for our carelessness in our resubmitted manuscript, the error is revised.

We have corrected “BMI” to “Body Mass Index (BMI)”. (Line 27, page 3).

4. Line 31 page 3:

We have corrected “normal patients with BMI” to “patients with normal BMI”. (Line 28, page 3).

5. line 36 page 3:

Thank you for pointing this out. As you suggested, we have corrected the “Place of residence “to “place of residence”. (Line 33, page 3).

6. line 39 page 3: Avoid using the term "such as".

“such as “is replaced with “comprised of”. (line 36 page 3)

7. line 4 page 4:

Thank your suggestions, we have corrected it. (line 41 page 3)

8. line 12 page 4: The section on bias may be included into the discussion as part of limitations of the study.

The section on bias was included into the discussion as part of limitations of the study. (lines 19-27, page13).

9. line 27 page 4

This phrase was modified according to the comment. (Line 14, page 4).

10. line 30 page 4

This phrase was modified according to the comment. (Line 17, page 4).

11. line 34 page 4: The section on "quantitative variables" may be included in "statistical methods". This may be rewritten with a more logical flow.

The section on "quantitative variables" have been included in "statistical methods" according to your suggestions and we also rewritten this section. (lines 22-37 page 4)

12. line 9 page 5: Is it 4 missing values in two patients and therefore a total of 8 missing values?

Respond: yes.

13. line 14 page 5: There were a total of 180 patients. Why were 20 patients excluded. This should be clarified.

14. Duplication should be avoided. For instance, if the number of males is shown, the number of females need not be shown.

We have modified these phrase, See Table 1 for details.

15. The values are shown as n (%) or median (IQR). This should be specified in the table.

Continuous variables with skewed data are summarized as the median (interquartile range); Dichotomous or categorical data are summarized as counts (percentages).

As shown in the section on notes in Table 1 for details.

16. Line 2 page 13: This section of key result in discussion may be rewritten with brevity.

The section has been rewritten and streamlined. (lines3-11 page 13).

17. Line 22 page 13: This section may be rewritten with brevity.

The section has been rewritten and streamlined. (lines 29-40 page 13 & lines1-44 page 14 & lines 1-35 page 15).

Attachment

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PLoS One. doi: 10.1371/journal.pone.0245370.r005

Decision Letter 2

Girish Chandra Bhatt

30 Dec 2020

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study

PONE-D-20-18098R2

Dear Dr. Zhao,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Girish Chandra Bhatt, MD, FASN

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

In the abstract section, please remove numbering as 1), 2) and 3).

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

PLoS One. doi: 10.1371/journal.pone.0245370.r006

Acceptance letter

Girish Chandra Bhatt

11 Jan 2021

PONE-D-20-18098R2

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study

Dear Dr. Zhao:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Girish Chandra Bhatt

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Single-factor logistic-regression analysis of the degree of skin itching in patients with uremic pruritus.

(DOCX)

Click here for additional data file.^{(18.4KB, docx)}

S2 Table. Multiple logistic regression analysis of factors influencing skin itching in patients with uremic pruritus.

(DOCX)

Click here for additional data file.^{(19.3KB, docx)}

Attachment

Submitted filename: PONE-D-20-18098_with minor observations.pdf

Click here for additional data file.^{(1.7MB, pdf)}

Attachment

Submitted filename: Response to Reviewers.docx

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Attachment

Submitted filename: PONE-D-20-18098_R1 minor observations.pdf

Click here for additional data file.^{(3.8MB, pdf)}

Attachment

Submitted filename: Response to Reviewers.docx

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Data Availability Statement

All relevant data are within the paper and its Supporting information files.

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PERMALINK

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study

Jian-Hui Zhao

Qiu-Shuang Zhu

Yi-Wen Li

Li-Li Wang

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Background

Objectives

Methods

Study design

Study setting

Participants

Variables

Data source/Measurement

Sample size

Statistical methods

Results

Participants

Fig 1. Patient screening and grouping.

Descriptive data

Table 1. Demographic and clinical characteristics of patients enrolled at baseline.

Outcome data

Table 2. Demographic and clinical characteristics of patients with and without uremic pruritus.

Table 3. Baseline characteristics of patients with varying degrees of skin itching.

Main results

Degree of skin itching in patients with uremic pruritus as analyzed by the single-factor logistic-regression model

Fig 2. Single-factor logistic-regression analysis of the degree of skin itching in patients with uremic pruritus.

Degree of skin itching in patients with uremic pruritus as analyzed by multivariate logistic regression

Fig 3. Multiple logistic regression analysis of factors influencing skin itching in patients with uremic pruritus.

Other analyses

Fig 4. Comparison of patients with varying degrees of skin itching and varying hs-CRP and IPTH levels.

Discussion

Key results

Limitations

Interpretation

Generalizability

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Girish Chandra Bhatt

Roles

Author response to Decision Letter 0

Decision Letter 1

Girish Chandra Bhatt

Roles

Author response to Decision Letter 1

Decision Letter 2

Girish Chandra Bhatt

Roles

Acceptance letter

Girish Chandra Bhatt

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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