Uremic pruritus and long-term morbidities in the dialysis population.

BACKGROUND: Uremic pruritus (UP) is a multifactorial problem that contributes to low quality of life in dialysis patients. The long-term influences of UP on dialysis patients are still poorly understood. This study aims to elucidate the contribution of UP to long-term outcomes. MATERIALS AND
METHOD: We used the Taiwan National Health Insurance Research Database to conduct this study. Patients on chronic dialysis were included and divided into UP and non-UP groups according to the long-term prescription of antihistamine in the absence of other indications. The outcomes include infection-related hospitalization, catheter-related infection, major adverse cardiac and cerebrovascular events (MACCE) and parathyroidectomy.
RESULTS: After propensity score matching, 14,760 patients with UP and 29,520 patients without UP were eligible for analysis. After a mean follow-up of 5 years, we found that infection-related hospitalization, MACCE, catheter-related infection, heart failure and parathyroidectomy were all slightly higher in the UP than non-UP group (hazard ratio: 1.18 [1.16-1.21], 1.05 [1.01-1.09], 1.16 [1.12-1.21], 1.08 [1.01-1.16] and 1.10 [1.01-1.20], respectively). Subgroup analysis revealed that the increased risk of adverse events by UP was generally more apparent in younger patients and patients who underwent peritoneal dialysis.
CONCLUSION: UP may be significantly associated with an increased risk of long-term morbidities.

Introduction

Uremic pruritus (UP) is a common problem among patients with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) receiving chronic dialysis [1-3]. The mechanism of UP is not fully understood, and current evidence suggests that its pathogenesis is multifactorial. The uremic toxin and metabolite hypothesis are supported by the observation that secondary hyperparathyroidism, hyperphosphatemia, hypercalcemia, elevated β-2 microglobulin, and inadequate dialysis clearance are associated with pruritus [3-6]. Local inflammatory mediators such as histamine and interleukin-31 may also play roles in pruritogenesis [7-9]. The opioid receptor has garnered attention because the k-opioid receptors agonist has an excellent effect on modulating pruritus in clinical trials [10, 11]. Substance P may also participate in pruritogenesis [12]. In addition, systemic therapy with gamma-aminobutyric acidergic agonist gabapentin and pregabalin also effective [1]. These all indicate that the pathogenesis of UP involves the interplay of uremic toxins, local inflammation, and neural circuit alterations.

UP not only negatively affects quality of life, sleep, and mood but may also contribute to worse long-term outcomes [2-4]. Our group reported that UP is associated with increased all-cause mortality, cardiovascular (CV) death and infection-related death [13]. In the current study, we further investigate the influence of UP on various types of long-term morbidities after starting dialysis therapy and also performed subgroup analysis on prespecified subgroups in the dialysis population by using Taiwan’s nationwide population-based database.

Materials and method

Data source and ethic statement

For this study, data were analyzed from the National Health Insurance Research Database (NHIRD) in Taiwan, which is a nationwide research database containing no identifiable personal information. The NHIRD contains 99.8% coverage for the 23 million residents in Taiwan and provides all data of inpatient and outpatient services, diagnosis, prescriptions, examinations, operations, and expenditures. Further information regarding NHI and NHIRD have been described in previous publications [14-16]. Because the NHIRD contains no identifiable personal information, the need for informed consent was waived because of its confidentiality and privacy are well-maintained. The study was approved by the Institutional Review Board of Chang Gung Memorial Hospital.

Study population and definition of uremic pruritus

The study population comprised patients who had been diagnosed with ESRD and were receiving permanent dialysis between January 1, 2001 and December 31, 2013. Permanent dialysis was verified by possession of a catastrophic illness certificate with the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnostic code 585. The date of application for the catastrophic illness certificate was defined as the index date.

We excluded patients with missing demographics, who were younger than 20 years old, who received parathyroidectomy, or who survived for less than 180 days after dialysis initiation to identify the population with stable dialysis. Previous studies defined a meaningful pruritus occur more than three times within a 2-week period or with a lower frequency but last longer than 6 months. Studies using NHIRD defined patients with a 42 or higher daily doses of anti-histamine to have uremic pruritus. By combining these tow criteria, we defined UP as the prescription of 84 daily doses of antihistamines or more, or received ultraviolet B phototherapy within 1 year after dialysis initiation. On the other hand, patients who received less than 42 daily doses of antihistamines were classified as non-UP. Patients who have diagnoses that requiring long-term use of antihistamine, including allergic rhinitis (ICD-9-CM 477.xx), urticaria (ICD-9-CM 708), psoriasis (ICD-9-CM 696), mycosis fungoides (ICD-9-CM 202.1), or Sezary disease (ICD-9-CM 202.2), are classified into non-UP group [17-21]. Patients who received 43 to 83 daily doses of anti-histamine within 1 year of dialysis were excluded because the antihistamine doses were inadequate to classify a “frequent and troublesome pruritus” [19-21] (Fig 1). The pruritus usually occurs at the stage of advanced CKD, and some continued after staring dialysis. Because our main interest was the pruritus that persists after starting dialysis, those patients who received antihistamine before index date were not excluded.

Fig 1

Flowchart of study patient inclusion.

Definitions of covariates

Disease was identified using ICD-9-CM diagnostic codes (S1 Table). Covariates included age, sex, initial dialysis modality, dialysis access type for hemodialysis, 10 comorbidities and history of events, and 14 types of medication. Comorbidity was defined as receipt of 2 outpatient diagnoses or one inpatient diagnosis in the previous year. Event history (including stroke, heart failure, and myocardial infarction) was determined using any inpatient diagnosis before the index date, with diagnoses available from the year 1997 onwards. Many of the diagnoses of these diseases in the NHIRD have been validated in other studies [22, 23]. Medication information was obtained using the claims data of outpatient visits or from pharmacy refills within 3 months prior to or after the index date.

Definitions of outcomes

The outcomes of this study were infection-related hospitalization, major adverse cardiac and cerebrovascular events (MACCE), catheter-related infection, and parathyroidectomy. The MACCE in our study includes acute myocardial infarction, acute ischemic stroke, intracerebral hemorrhage, and heart failure. We also performed subgroup analysis on these outcomes, including infection-related hospitalization, MACCE, catheter-related hospitalization, heart failure, and parathyroidectomy.

Death was defined as withdrawal from the National Health Insurance program. The diagnostic codes of components of MACCE have been validated in other studies [24-28]. The incidences of MACCE were defined according to the principal inpatient diagnosis. Parathyroidectomy was extracted using the Taiwan National Health Insurance reimbursement codes of inpatient claims. Infection-related hospitalization was defined using principal or secondary discharge diagnoses, including bacteremia (candidemia, viremia and sepsis), cardiovascular, central nervous system, gastrointestinal, hepatobiliary and peritoneal infections, genitourinary, pulmonary, skin and soft tissue, bone and joint, dialysis access and central venous catheters, other device/procedure and surgery-related infection. All patients were followed from the index date to the date of event occurrence, date of death, or December 31, 2013, whichever came first.

Statistical analysis

To reduce influence from potential confounding factors in this observational study, propensity score matching (PSM) was performed. The propensity score was the predicted probability of being in the UP group given the values of covariates according to the logistic regression. The variables selected for calculating propensity scores are listed in Table 1, and the follow-up year was replaced with the index date (Table 1). Each patient in the UP group was matched with 2 corresponding patients in the non-UP group. The matching was processed using a greedy nearest neighbor algorithm with a caliper of 0.2 times the standard deviation of the logit of propensity score, with random matching order, and without replacement. The quality of matching was evaluated using the absolute value of standardized difference (STD) between the groups, in which a value less than 0.1 was considered a negligible difference.

Table 1

Baseline characteristics of dialytic patients with and without uremic pruritus.

	Before matching			After matching
Variable	UP	Non-UP	STD	UP	Non-UP	STD
	(n = 14,777)	(n = 93,902)		(n = 14,760)	(n = 25,920)
Demographic
Age (years)	62.7 ± 13.2	60.4 ± 14.2	0.17	62.6 ± 13.2	62.9 ± 13.5	-0.02
Age ≥65 years	6,897 (46.7)	38,301 (40.8)	0.12	6,885 (46.6)	13,850 (46.9)	-0.01
Female	7,321 (49.5)	47,171 (50.2)	-0.01	7,311 (49.5)	14,552 (49.3)	<0.01
Initial modality
Hemodialysis (HD)	12,791 (86.6)	84,059 (89.5)	-0.09	12,776 (86.6)	25,476 (86.3)	0.01
Peritoneal dialysis	1,986 (13.4)	9,843 (10.5)	0.09	1,984 (13.4)	4,044 (13.7)	-0.01
Dialysis access type for hemodialysis
Fistula	10,239 (69.3)	71,362 (76.0)	-0.15	10,233 (69.3)	20,373 (69.0)	0.01
Graft	878 (5.9)	4,375 (4.7)	0.06	873 (5.9)	1,759 (6.0)	<0.01
Tunnel-catheter	1,674 (11.3)	8,322 (8.9)	0.08	1,670 (11.3)	3,344 (11.3)	<0.01
Comorbidity
Polycystic kidney disease	276 (1.9)	1,814 (1.9)	<0.01	276 (1.9)	565 (1.9)	<0.01
Old dementia	350 (2.4)	1,997 (2.1)	0.02	350 (2.4)	700 (2.4)	<0.01
Hypertension	12,191 (82.5)	69,932 (74.5)	0.20	12,174 (82.5)	24,772 (83.9)	-0.04
Diabetes mellitus	8,110 (54.9)	43,372 (46.2)	0.17	8,096 (54.9)	16,470 (55.8)	-0.02
Chronic obstructive pulmonary disease	1,108 (7.5)	6,118 (6.5)	0.04	1,105 (7.5)	2,236 (7.6)	<0.01
Peripheral arterial disease	466 (3.2)	2,599 (2.8)	0.02	466 (3.2)	909 (3.1)	<0.01
Ischemic heart disease	3,967 (26.8)	21,289 (22.7)	0.10	3,964 (26.9)	7,967 (27.0)	<0.01
History of event
Old stroke	2,506 (17.0)	13,605 (14.5)	0.07	2,499 (16.9)	5,081 (17.2)	-0.01
History of heart failure	3,489 (23.6)	18,923 (20.2)	0.08	3,485 (23.6)	6,897 (23.4)	0.01
Old myocardial infarction	864 (5.8)	4,447 (4.7)	0.05	861 (5.8)	1,698 (5.8)	<0.01
Medications
Steroid	1,625 (11.0)	6,118 (6.5)	0.16	1,610 (10.9)	3,046 (10.3)	0.02
Other immunosuppressive agent	250 (1.7)	1,668 (1.8)	-0.01	250 (1.7)	485 (1.6)	<0.01
Antiplatelet	4,269 (28.9)	20,711 (22.1)	0.16	4,261 (28.9)	8,606 (29.2)	-0.01
ACEI / ARB	6,836 (46.3)	35,237 (37.5)	0.18	6,822 (46.2)	13,870 (47.0)	-0.02
Beta-blocker	7,064 (47.8)	36,842 (39.2)	0.17	7,053 (47.8)	14,427 (48.9)	-0.02
Loop diuretics	7,959 (53.9)	40,032 (42.6)	0.23	7,947 (53.8)	16,170 (54.8)	-0.02
K-sparing diuretics	317 (2.1)	1,394 (1.5)	0.05	315 (2.1)	625 (2.1)	<0.01
Oral hypoglycemic agent	4,699 (31.8)	23,190 (24.7)	0.16	4,690 (31.8)	9,561 (32.4)	-0.01
Insulin	3,158 (21.4)	15,990 (17.0)	0.11	3,151 (21.3)	6,349 (21.5)	<0.01
Proton pump inhibitor	2,587 (17.5)	11,268 (12.0)	0.16	2,578 (17.5)	5,067 (17.2)	0.01
NSAID (including COX2)	2,845 (19.3)	9,882 (10.5)	0.25	2,828 (19.2)	5,320 (18.0)	0.03
Statin	3,285 (22.2)	16,661 (17.7)	0.11	3,283 (22.2)	6,661 (22.6)	-0.01
Fibrate or Gemfibrozil	848 (5.7)	3,672 (3.9)	0.09	845 (5.7)	1,660 (5.6)	<0.01
Vitamin D therapy	1,992 (13.5)	8,414 (9.0)	0.14	1,981 (13.4)	3,838 (13.0)	0.01
Follow-up duration (years)	4.7 ± 3.1	5.6 ± 3.5	-0.26	4.7 ± 3.1	4.9 ± 3.2	-0.03

UP, uremic pruritus; STD, standardized difference; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; NSAID, non-steroidal anti-inflammatory drug; COX-2, cyclo-oxygenase-2 inhibitor

Data were presented as frequency (percentage) or mean ± standard deviation.

The incidences of outcomes between groups were compared using the Fine and Gray subdistribution hazard model, which considered death to be a competing risk. The study group (UP vs. non-UP) was the only explanatory variable in the survival analyses. The within-pair clustering of outcomes after PSM was accounted for using a robust standard error, which is known as a marginal model [29] Finally, subgroup analysis was performed to determine whether the effect of UP on several outcomes (which were significantly different between the UP and non-UP groups) was similar among different levels of the 5 prespecified subgroup variables, including age, sex, initial dialysis modality, diabetes, and ischemic heart disease.

A 2-sided P value < 0.05 was considered to be statistically significant, and no adjustment for multiple testing (multiplicity) was made in this study. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results

During the study period, we identified 158,910 patients who were diagnosed with ESRD and received long-term dialysis therapy. After exclusion of those patients with incomplete data (n = 877), patients younger than 20 years of age (n = 725), patients who had received parathyroidectomy (n = 994), and patients for whom the follow-up duration was less than 365 days (n = 38,267), and patients who did not meet the criteria for anti-histamine dose (n = 9,368), we identified 14,777 dialysis patients in the UP group and 93,902 patients in the non-UP group (Fig 1). Before matching, the UP group were older, tend to use PD as the initial dialysis modality, less fistulas on hemodialysis initiation, had a higher prevalence of hypertension and diabetes, and received more medications (ASTD ≥ 0.1). After matching, all demographics, comorbidities, and medications were well-balanced between the groups (ASTD < 0.1; Table 1).

With a mean follow-up of 5 years (standard deviation: 3.3 years), the long-term outcomes are summarized in Table 2. The UP group exhibited a higher risk of long-term morbidities, including infection-related hospitalization (Subdistribution hazard ratio [SHR]: 1.13, 95% confidence interval [CI]: 1.16–1.21), catheter-related infection (SHR: 1.16, 95% CI: 1.12–1.21), MACCE (SHR: 1.05, 95% CI: 1.01–1.09), heart failure (SHR: 1.08, 95% CI: 1.01–1.16), and parathyroidectomy (SHR: 1.10, 95% CI: 1.01–1.20). Acute myocardial infarction, acute ischemic stroke, and intracerebral hemorrhage did not achieve statistical difference between the groups. The cumulative incidence functions of infection-related hospitalization and MACCE are depicted in Fig 2A and 2B.

Table 2

Follow up outcome of in dialytic patients with and without uremic pruritus.

	Number of event (%)		UP vs. non-UP
Outcome	UP	Non-UP	HR or SHR (95% CI)	P-value
	(n = 14,760)	(n = 29,520)
IRH	10,110 (68.5)	18,516 (62.7)	1.18 (1.16–1.21)	<0.001
Catheter related infection	3,752 (25.4)	6,580 (22.3)	1.16 (1.12–1.21)	<0.001
MACCE*	3,599 (24.4)	6,896 (23.4)	1.05 (1.01–1.09)	0.018
Acute myocardial infarction	947 (6.4)	1,977 (6.7)	0.95 (0.88–1.03)	0.208
Acute ischemic stroke	1,543 (10.5)	2,962 (10.0)	1.04 (0.98–1.11)	0.189
Intracerebral hemorrhage	451 (3.1)	927 (3.1)	0.97 (0.86–1.08)	0.556
Heart failure	1,207 (8.2)	2,236 (7.6)	1.08 (1.01–1.16)	0.035
Parathyroidectomy	789 (5.3)	1,429 (4.8)	1.10 (1.01–1.20)	0.026

UP, uremic pruritus; HR, hazard ratio; SHR, subdistribution hazard ratio; CI, confidence interval; IRH, infection-related hospitalization; MACCE, major cardiovascular and cerebral composite adverse event

* Anyone of acute myocardial infarction, acute ischemic stroke, intracerebral hemorrhage, heart failure

Data were presented as frequency (percentage).

Fig 2

Unadjusted cumulative incidence function of infection-related hospitalization (A) and major cardiovascular and cerebral composite adverse event (B) in the propensity score matched cohort.

As to the subgroup analysis of outcomes (which were significantly different between the UP and non-UP groups), the increased risk of infection-related hospitalization, MACCE, catheter-related infection, heart failure and parathyroidectomy by UP were mostly not different between age groups, sex, dialysis modality, presence of DM or ischemic heart disease, or use of vitamin D analogue (Fig 3A–3C, S1 and S2 Figs) The only significant interaction was found that the use of vitamin D analogue mitigated the detrimental effect of UP on catheter-related infection.

Fig 3

Prespecified subgroup analysis of outcomes, including infection-related hospitalization (A), major adverse cardiac and cerebrovascular event (B) and catheter-related infection (C).

Discussion

UP is not an uncommon problem among dialysis patients and impairs quality of life [2-4]. In our previous study, UP is associated with increased all-cause mortality, infection-related death, and CV death [13]. Pisoni et al. reported an increased mortality risk with severe pruritus, but this risk diminished after adjusting for sleep quality [3]. Narita et al. identified severe pruritus as a predictor of mortality, but they did not note differences among causes of death [2]. In 2014, Kimata et al. observed increased mortality among patients experiencing severe pruritus [4].

The association between UP and adverse long-term outcomes could be explained by several potential causes. Clinical studies have indicated that high PTH levels, hyperphosphatemia, and high urea nitrogen levels increase the intensity of pruritus [2, 3]. These factors usually indicate inadequate dialysis clearance or noncompliant dietary control. The elevation of PTH levels is also associated with left ventricular hypertrophy and CV events [30-33]. Several studies have reported amelioration of pruritus after parathyroidectomy in patients with uncontrolled secondary hyperparathyroidism undergoing dialysis [31, 34]. These reports correspond with our findings that UP is associated with higher mortality and increased rate of parathyroidectomy. The effect of UP on patients’ outcomes were relatively small but significant. This might be explained that other traditional cardiovascular risk factors, including diabetes, hypertension, dyslipidemia and dialysis-specific risk factors, including hyperparathyroidism, deranged calcium-phosphate balance, all contributes to worse outcome in dialysis population. The presence of UP could be view as one comorbidity among them.

Noncompliant dietary control could result in hyperphosphatemia, hyperparathyroidism and excessive interdialytic weight gain (IDWG). Excessive IDWG usually causes fluid overload, left ventricular hypertrophy, hypertension, and CV events [35-37]. Brain-type natriuretic peptide (BNP) is a surrogate marker of volume overload; in addition, BNP and its receptor have also been found in transient receptor potential (TRP) vanilloid 1 (TRPV1)–expressing neurons [38, 39]. The TRPV1-expressing neuron transmit itch sensation from the peripheral C-fiber to the central nervous system [40]. Therefore, the increase of BNP with volume overload may have a role in itching transmission. Clinically, Shimizu et al. reported an association between elevated BNP and the severity of pruritus [41]. This provides a possible link between pruritus and volume overload in dialysis patients.

We found that the infection-related hospitalization was more frequent in the UP group. This corresponds with the study by Narita et al., in which more severe pruritus is associated with higher infection-related mortality [2]. A direct relationship between UP and infection has not yet been confirmed. We hypothesize that frequent scratching results in microtrauma of cutaneous barriers, which is supported by a systematic review demonstrating that exfoliating skin disease is a risk factor for cellulitis [42]. Systemically, the uremic milieu is associated with impaired immunity [43]. The presence of UP is frequently associated with increased uremic toxins and, consequently, worse immunity. Secondary hyperparathyroidism may mediate immune dysfunction in UP patients. Tzanno-Martins et al. reported that high PTH levels can impair antigen-stimulated T cell proliferation from dialysis patients and the inhibition disappeared after parathyroidectomy [44].

The subgroup analysis found a protective effect from vitamin D analogue in patients with UP, and this diminished the excessive catheter-related infection risk carried by UP. The immune modulatory effect of vitamin D has been extensively studied, and in vitro findings suggest that vitamin D deficiency could be a risk factor for infection [45]. Observational studies indicated that a low plasma vitamin D concentration before admission is associated with higher risks of respiratory tract infection, bloodstream infection or sepsis during hospitalization [46-50]. Despite the association discovered in observational studies, the evidence of vitamin D supplementation on preventing various infection is inadequate. The strongest evidence supports the use of vitamin D in prevention of acute respiratory tract infection, especially in individuals who are vitamin D-deficient [51]. Whether vitamin D supplementation prevent the risk of other infections remains unclear and warrant further investigations.

Our study has certain limitations. First, the claim database does not contain information regarding pruritus severity. Some studies that have adopted the visual analogue scale (VAS) have demonstrated that severer pruritus was associated with poorer outcomes, whereas another study in Taiwan observed no such correlation [2–4, 6]. This inconsistency implies that a simple VAS may not be sufficient for predicting the overall effects of pruritus severity on outcomes. The Thai Renal Outcome Research group published a multidimensional assessment tool for UP, which included symptoms, signs, effects on sleep, and daily activities in 2017 [52]. This questionnaire may be adapted for future studies on UP. The lack of subjective responses from patients may also constitute a strength of our study because questionnaire-based study can be affected by interference as a result of recall bias or acquiescence bias [53, 54]. The second limitation of this study is the lack of lab data in the claims database. Our work may require further adjustment for identifying laboratory abnormalities or inadequate dialysis clearance. Third, we select UP patients by using the treatment criteria and did not classify disorders that may require long-term antihistamine or UVB therapy. Some diseases such as vitiligo (ICD 709.01) was extremely rare in our cohort (about 0.05%) and was consistent with previous study using Taiwan NHIRD [55]. The extremely low prevalence implies this disorder will not significantly affect our cohort selection by pruritus therapy. However, caution should be made when applying this criterion in population with higher prevalence of vitiligo.

Conclusion

This nationwide population-based cohort study demonstrated a positive association between the presence of UP and increased risk of long-term morbidities, including infection-related hospitalization, MACCE, catheter-related infection and parathyroidectomy.

ICD-9 CM diagnostic codes.

(DOCX)

Click here for additional data file.

Prespecified subgroup analysis of heart failure hospitalization.

(DOCX)

Click here for additional data file.

Prespecified subgroup analysis of receiving parathyroidectomy.

(DOCX)

Click here for additional data file.

8 Jul 2020

PONE-D-20-17073

Uremic Pruritus and Non-Fatal Long-Term outcomes in the Dialysis Population

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Reviewer #1: In the study, the association between uremic pruritus and non-fatal long term outcomes in dialysis patients were analyzed. The results showed that the risk of infection and cardiovascular events were increased. Here are the concerns from the reviewer:

1. The HR was only marginally increased (HR from 1 to around 1.1) which lessened the impact of this work.

2. What was the reason to exclude patients with parathyroidectomy?

3. For the outcomes, did the authors only count those with new events and exclude those with prior history, like what they did for parathyroidectomy?

4. What was the definition of infection-related hospitalization? There is a large spectrum of infection that requires hospitalization. Please try to classify the spectrum of infections, eg. viral/fungal/bacterial, common/opportunistic etc.

5. The definition of UP, "more than 42 daily doses of antihistamine", was a bit loose. How did the authors exclude pruritus caused by xerosis or xerotic dermatitis which is also a very common problem in dialysis patients.

6. What is the meaning of "non-fatal outcomes"? Infection and MACCE very often resulted in death, especially in immunocompromised patients. How did the authors tell "fatal" and "non-fatal" in this study?

Reviewer #2: Major commands

1. Your previous study in reference 13 discussed the association between uremic pruritus and long-term outcomes in patients undergoing dialysis. From the big database, it would be acceptable if the data presented were in sequence of a different sample size. I would strongly suggest to review the data presented.

2. You used standard deviation (STD) in Table 1 to represent the difference between 2 groups. It would be more clear to use p-value to show the results.

3. The information before matching does not need to be provided in table 1. It looked more complicated and I would suggest moving these to supplement data.

4. Your topic is about the association of uremic pruritis and non-fatal outcomes. It seems not suitable to put fatal outcomes in Table 2 as results.

5. In Figure 3, you did the subgroup analysis according to fatal outcomes. It would seem more suitable to do the analysis related to the non-fatal outcomes which is more related to your topic.

In general, the authors demonstrated expertise in big data analysis and in managing the data. Thus, I suggest taking into account to do several adjustments.

**********

6. 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

Reviewer #2: No

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21 Aug 2020

Response to reviewer 1

Reviewer #1: In the study, the association between uremic pruritus and non-fatal long-term outcomes in dialysis patients were analyzed. The results showed that the risk of infection and cardiovascular events were increased. Here are the concerns from the reviewer:

1. The HR was only marginally increased (HR from 1 to around 1.1) which lessened the impact of this work.

Thanks for your comment. We agreed that a marginally increased hazard ratio may imply that uremic pruritus contribute only a small portion to the adverse outcome in dialysis patients. However, we considered this result somehow reasonable, because other factors, such as traditional cardiovascular risk factors (diabetes, hypertension, dyslipidemia) and dialysis-specific risk factors, including hyperparathyroidism, deranged calcium-phosphate balance all have their effects on the morbidities of dialysis population. Uremic pruritus can be viewed as one comorbidity which is not negligible for predicting patient outcomes.

2. What was the reason to exclude patients with parathyroidectomy?

Thanks for your comment. In some dialysis patients, an elevated parathyroid hormone with refractory pruritus could be the indication of parathyroidectomy, and some case series showed that parathyroidectomy may help relieve the extent of pruritus. We would like to observe this surgery during follow up, therefore, patients who underwent parathyroidectomy were excluded because they could not have this surgery again (if total parathyroidectomy) or the chance will decrease (if subtotal parathyroidectomy).

3. For the outcomes, did the authors only count those with new events and exclude those with prior history, like what they did for parathyroidectomy?

For cardiovascular events, the disease burden may increase over time and episodes. We counted the events after index date, but used the past history for propensity score matching. For most of the infection, we counted the events after index date without considering the past history of infection.

4. What was the definition of infection-related hospitalization? There is a large spectrum of infection that requires hospitalization. Please try to classify the spectrum of infections, eg. viral/fungal/bacterial, common/opportunistic etc.

We are sorry for we did not report the definition of infection-related hospitalization in the original manuscript. We used the discharged diagnoses of selected infection-related ICD-9 diagnostic codes in each emergency department visit or hospitalization. By using these ICD-9 codes, we could differentiate the sites of infection. However, the pathogen causing infection is unable to identify by using ICD-9 code. This part is addressed in the method (Definitions of Outcomes subsection) and limitation sections of revised manuscript.

5. The definition of UP, "more than 42 daily doses of antihistamine", was a bit loose. How did the authors exclude pruritus caused by xerosis or xerotic dermatitis which is also a very common problem in dialysis patients.

Thanks for your comment.

Xerosis is a common phenomenon in dialysis patients, and is sometimes viewed as one of the contributing/aggravating factors in uremic pruritus. If the itching improves a lot after application of emollient

We considered uremic pruritus as a “syndrome” rather a specific disease entity, therefore, we used a treatment-based criterion to select dialysis patients who has a considerable severity of itching. In previous studies, the diagnosis of uremic pruritus usually based on questionnaires or visual analogue scale, with the exclusion of primary cutaneous diseases that may require long-term use of systemic therapies, such as chronic urticaria and atopic dermatitis. The utilization of questionnaire was not diagnostic for uremic pruritus, but for classification of itching severity.

During the study period, no mu-opioid receptor antagonist of kappa-opioid receptor agonist is available for treating uremic pruritus in Taiwan. Meanwhile, the prescription of gabapentinoids are not covered by national health insurance (NHI), therefore, the first line treatment for pruritus in dialysis patients are antihistamines.

In the revised manuscript, we tried to sort out patients with more severe pruritus by increasing the threshold of antihistamine prescription to be equal or more than 84 days. Patients with any concomitant diagnoses that may require frequent antihistamine therapy are also excluded. The flowchart, all tables and figures and the text have been revised accordingly.

6. What is the meaning of "non-fatal outcomes"? Infection and MACCE very often resulted in death, especially in immunocompromised patients. How did the authors tell "fatal" and "non-fatal" in this study?

Thanks for your comment. First, to avoid making confusion to the readers, we would like to adjust the term “non-fatal outcomes” into “outcomes” in the revised manuscript and “long-term morbidities” in the revised title. Second, as for the outcomes in our study, we only count those did not lead to death. That is to say, we count all emergency visit or hospitalization that patients were alive at discharge. The statistical analysis also utilized subdistribution hazard model, in which death is considered a competing risk.

--------------------------------------------------------------------------------

Response to reviewer 2

1. Your previous study in reference 13 discussed the association between uremic pruritus and long-term outcomes in patients undergoing dialysis. From the big database, it would be acceptable if the data presented were in sequence of a different sample size. I would strongly suggest to review the data presented.

Thanks for your comment. In correspondence with the other reviewer’s requirement, we changed to a stricter criterion of anti-histamine prescription to define uremic pruritus. The flowchart (and the number of eligible case), all tables and figures and the text have been revised accordingly.

2. You used standard deviation (STD) in Table 1 to represent the difference between 2 groups. It would be more clear to use p-value to show the results.

We thank for your comment. We used “standardized difference” (STD) because of the huge sample size. The p-value tends to be extremely low when the sample size is huge. In this situation, using the standardized difference is more suitable because it is not affected by the size of sample.

3. The information before matching does not need to be provided in table 1. It looked more complicated and I would suggest moving these to supplement data.

Thanks for your opinion. We prefer to demonstrate the data before and after matching in the main text, because we think it is necessary to show the real-world characteristics (data before matching) of patients with and without uremic pruritus. Showing the data after matching is also necessary because the readers can easily assess the quality of matching.

4. Your topic is about the association of uremic pruritis and non-fatal outcomes. It seems not suitable to put fatal outcomes in Table 2 as results.

Thanks for your reminding. We removed all the term of “fatal outcome” in this revised manuscript.

5. In Figure 3, you did the subgroup analysis according to fatal outcomes. It would seem more suitable to do the analysis related to the non-fatal outcomes which is more related to your topic.

We appreciate with your constructive suggestion. Based on the revised design, we performed subgroup analysis for selected morbidities/events which were significant between groups, including infection-related hospitalization, catheter related infection, major cardiovascular and cerebral composite adverse event, heart failure and parathyroidectomy. The Figure 3A-3B (forest plot for subgroup analysis) is revised and Supplemental Figure 1-3 have been added in this revised manuscript.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

7 Sep 2020

PONE-D-20-17073R1

Uremic Pruritus and Long-Term Morbidities in the Dialysis Population

PLOS ONE

Dear Dr. Chang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Both reviewers continued to have some concerns that require to be addressed.

Please submit your revised manuscript by Oct 22 2020 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'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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.

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

We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, PhD

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: (No Response)

Reviewer #2: (No Response)

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The current version showed substantial improvement. Some concerns remained from the reviewer:

1. The study populations is still a concern although the authors made efforts to re-define the populations. Did the authors exclude those who already started using antihistamine prior to the index date in the UP group? UVB treatment is frequently applied on psoriasis and vitiligo patients. Psoriasis was excluded as UP group. How about vitiligo?

2. Please recheck the panels in figure 3 and supplementary figure 1. The panels were mistaken here. Catheter-related infection should be placed in the main manuscript rather than in the supplementary data since it was a focus of discussion in the main text.

3. Supplementary Table 1: "Urticarial" should be "urticaria".

Reviewer #2: Dear Authors,

All my commands have been addressed adequately.

I made the following suggestions:

1. Please include the complete information of the reference 13. Accepted, unpublished article would be cited same as published articles, but substitute “Forthcoming” for page numbers or DOI.

2. I understand the author tried to match all factors that may affect the outcomes; however, some of the factors such as the dialysis duration was not included in the factor of matching. I suggested not include the information before matching because it looked more complicated.

In general, the authors tried to revise as the commands.

Thank you very much for your attention to my opinion.

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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.

Submitted filename: PONE-D-20-17073_R1 review.pdf

Click here for additional data file.

23 Sep 2020

Reviewer #1: The current version showed substantial improvement. Some concerns remained from the reviewer:

1. The study populations is still a concern although the authors made efforts to re-define the populations. Did the authors exclude those who already started using antihistamine prior to the index date in the UP group? UVB treatment is frequently applied on psoriasis and vitiligo patients. Psoriasis was excluded as UP group. How about vitiligo?

Thanks for your comment. We agreed that the current flowchart may count patients with vitiligo who also receive UVB therapy. The patients diagnosed with vitiligo were identified with the ICD-9 code 709.01. Within 52,357 patients who have any doses of antihistamine prescription or UVB therapy, only 24 patients were found to have vitiligo (24 / 52357 = 0.05%). This low prevalence of vitiligo is compatible with Chen et al., who also used Taiwan NHIRD and found a prevalence around 0.064% in general population of Taiwan (Comorbidity profiles in association with vitiligo: a nationwide population-based study in Taiwan. Chen YT, Chen YJ, Hwang CY, et al. J Eur Acad Dermatol Venereol. 2015 Jul;29(7):1362-9. doi: 10.1111/jdv.12870.). Because of the extremely low prevalence of vitiligo in our advanced CKD & ESRD cohort, we think it may barely affect the events of our study. We have written this limitation into the limitation section.

We did not exclude patients who use antihistamine before index date, because uremic pruritus is also very frequent at the stage of advanced chronic kidney disease, thus, they may use antihistamines before they initiate dialysis. Some patients’ pruritus improves after starting dialysis therapy; however, others may continue to have itching despite the dialysis. Hence, the main interest in this study focus on the long-term impact of uremic pruritus which still exist after starting dialysis. We addressed this focus in the revised manuscript.

2. Please recheck the panels in figure 3 and supplementary figure 1. The panels were mistaken here. Catheter-related infection should be placed in the main manuscript rather than in the supplementary data since it was a focus of discussion in the main text.

Thanks for your suggestion. We have put supplementary fig 1 and figure 3A-B together (revised to be figure 3A-C)

3. Supplementary Table 1: "Urticarial" should be "urticaria".

Thank you very much. We made the correction in the revised supplemental document.

------------------------------------------------------------------------------------------------------------------

Reviewer #2:

Dear Authors,

All my commands have been addressed adequately.

I made the following suggestions:

1. Please include the complete information of the reference 13. Accepted, unpublished article would be cited same as published articles, but substitute “Forthcoming” for page numbers or DOI.

Thank you very much. This research letter has been published in July 2020. We complete the information (including journal volume, issue and page) of this reference in the revised manuscript.

2. I understand the author tried to match all factors that may affect the outcomes; however, some of the factors such as the dialysis duration was not included in the factor of matching. I suggested not include the information before matching because it looked more complicated.

Thanks for your comment. The variables listed in Table 1 were all included in the calculation of propensity score, where the “follow up duration” indicated the duration from index date to the end of follow up. We did not include dialysis vintage in table 1, because we start the follow up at the first day that patients start dialysis; therefore, at baseline, all patients’ dialysis vintage is zero. Based on the above reason, we tend to retain data of both the before and after matching.

Submitted filename: Response to the reviewers.docx

Click here for additional data file.

6 Oct 2020

PONE-D-20-17073R2

Uremic Pruritus and Long-Term Morbidities in the Dialysis Population

PLOS ONE

Dear Dr. Chang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The reviewer #1 pointed out a minor issue regarding the legend of figure 3. Please fix the problem

Please submit your revised manuscript by Nov 20 2020 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'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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.

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

We look forward to receiving your revised manuscript.

Kind regards,

Yu Ru Kou, PhD

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: (No Response)

Reviewer #2: All comments have been addressed

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The questions were addressed properly. There is one minor point. The legend of figure 3 was not revised according to the change of the panels.

Reviewer #2: Dear Authors,

All my commands have been addressed adequately.

In general, the authors tried to revise as the commands.

Thanks for your attention to my opinion.

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Lai, Yu-Hsien

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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.

6 Oct 2020

Response to the reviewers

Reviewer #1: The questions were addressed properly. There is one minor point. The legend of figure 3 was not revised according to the change of the panels.:

Thank you very much. We revised the figure legend of figure 3.

Submitted filename: Response to the reviewers_1006.docx

Click here for additional data file.

8 Oct 2020

Uremic Pruritus and Long-Term Morbidities in the Dialysis Population

PONE-D-20-17073R3

Dear Dr. Chang,

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,

Yu Ru Kou, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

16 Oct 2020

PONE-D-20-17073R3

Uremic Pruritus and Long-Term Morbidities in the Dialysis Population

Dear Dr. Chang:

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. Yu Ru Kou

Academic Editor

PLOS ONE