Association of pruritus with comorbidities and survival in chronic kidney disease: a narrative review of the pre-difelikefalin era literature

Justine Saucereau; Emilie Brenaut; Anne-Sophie Ficheux; Guy Rostoker; Laurent Misery; Christelle Le Gall-Ianotto

doi:10.1080/0886022X.2026.2622801

. 2026 Feb 18;48(1):2622801. doi: 10.1080/0886022X.2026.2622801

Association of pruritus with comorbidities and survival in chronic kidney disease: a narrative review of the pre-difelikefalin era literature

Justine Saucereau ^a, Emilie Brenaut ^a,^b, Anne-Sophie Ficheux ^b, Guy Rostoker ^c, Laurent Misery ^a,^b, Christelle Le Gall-Ianotto ^a,^b,^✉

PMCID: PMC12918360 PMID: 41708519

Abstract

Pruritus is a frequent and distressing symptom in chronic kidney disease (CKD). This study aimed to evaluate the association between pruritus and comorbidities or survival in CKD before the approval of difelikefalin (DFK), a novel treatment for CKD-associated pruritus (CKD-aP). A systematic literature review was conducted using PubMed and Embase, including studies published between January 2000 and August 2022 that examined the link between CKD-aP and morbidity or survival in CKD. We analyzed 5,867 title/abstracts (3,541 from Pubmed, 2,313 from Embase, and nine additional articles) and excluded 5,721 references. Thirty-seven of the 146 articles that were eligible for full reading were included in the analysis. Thus, 18 identified a statistically significant association between CKD-aP and mortality. However, this association lost significance in 3 studies after adjusting for sleep. Two additional studies found no association between CKD-aP and mortality. In terms of sleep disturbance, 14 out of 15 studies reported a significant link with CKD-aP. Moreover, six studies demonstrated relationship between CKD-aP and cardiovascular events, which remained robust even after adjusting for diabetes. The connection between CKD-aP and mental health and depressive symptoms was investigated in 20 studies, with 18 confirming a significant association between the outcomes. Finally, six studies indicated that healthcare costs were higher in CKD-aP compared to those without. Pruritus appears to be associated with increased mortality, cardiovascular events, depressive symptoms, and healthcare costs in CKD patients. Early detection and treatment, particularly with new drugs like DFK, may improve patients’ quality of life and reduce CKD-aP related.

Keywords: Chronic kidney disease, pruritus, comorbidities, mortality, health costs

Introduction

Chronic pruritus is an unpleasant sensation that leads to the urge to scratch for more than 6 weeks [1,2].

It is a very distressing symptom: the impact on quality of life is similar to that of chronic pain [3,4]. The negative impact of pruritus on sleep quality, work productivity, depression, anxiety, and suicidal ideation have been demonstrated in dermatological or systemic conditions [5,6].

Chronic kidney disease-associated pruritus (CKD-aP), also known as uremic pruritus, has been studied extensively. A meta-analysis of 42 studies showed that pruritus was present in 55% of CKD patients [7]. Another study showed that the presence of pruritus was a risk factor for death after at 3 years in a small cohort of CKD patients [8].

Although pruritus is widely recognized as distressing, its association with comorbidities, disease progression, and survival has been little studied. This narrative review examines these aspects. Before 2021, its therapeutic management remained challenging with various topical and systemic therapies. In 2021, the FDA’s approval and marketing of difelikefalin (DFK), a new parenteral peripheral kappa opioid receptor agonist has changed the game by offering an effective treatment to reduce pruritus and improve patients’ quality of life [9,10]. However, its impact on the many physical and psychological parameters affected in these patients remains to be explored further. So, the aim of this study was to evaluate the association of pruritus with chronic kidney disease (CKD) comorbidities or survival in the literature prior to the DFK. We felt that an exhaustive description of the burden of CKD-aP prior to the DFK era was of paramount importance in order to accurately analyze the effects of this new drug in real life.

Methods

We conducted a narrative systematic review following PRISMA 2020 guidelines (Supplementary Figure 1) and approved by the International Prospective Register of Systematic Reviews, PROSPERO (CRD42022316850).

Source and research equation

Articles published between January 2000 and August 2022 were retrieved from PubMed and Embase using search terms related to pruritus, mortality, and comorbidities following the equation: (‘pruritus’ or ‘pruritis’ or ‘itch’ or ‘itching’) AND (‘mortality’ or ‘death’ or ‘prognosis’ or ‘prognostic’ or ‘development’ or ‘survival’ or ‘paraneoplasia’ or ‘risk’ or ‘morbidity’ or ‘comorbidity’), NOT (‘psoriasis’ or ‘eczema’ or ‘atopic dermatitis’ or ‘CTCL’ (cutaneous T-cell lymphoma) or ‘Sezary’ or ‘mycosis fungoid’ or ‘prurigo’ or ‘urticaria’ or ‘rash’ or ‘lichen’ or ‘pemphigoid’ or ‘pemphigus’ or ‘scabies’ or ‘lice’ or ‘chickenpox’ or ‘exanthema’).

Selection of studies and data extraction

Concerning inclusion criteria, only studies with adults (>18 years) were considered. Studies solely published as an abstract were included as long as quantitative information about presence of CKD-aP and its association with the patient outcomes was detailed.

Studies were excluded if they were in languages other than French or English and if they focused on dermatological conditions, animal models, climate-related topics, or pruritus as an adverse effect.

The initial screening was carried out by a single reviewer based on an examination of titles and abstracts, which resulted in an initial selection of eligible articles. In cases of doubt, the full article was analyzed. This list of eligible articles was validated by a second reviewer. In cases of disagreement, a discussion between the two reviewers based on the full-text article, took place in order to reach a consensus.

Data extraction was realized by one reviewer and included study details (authors, year, country), study design, sample size, pruritus intensity and etiology, comorbidities, mortality, sleep, anxiety, depression, and quantitative scales used when mentioned. The second reviewer confirmed and completed the extracted data if necessary.

Ethics statement

Ethical approval was not required for this systematic review, as the study was based solely on analysis of data from previously published research articles. No new data involving human participants or animals were collected or processed.

Results

Out of 5,867 articles, 37 were included: 27 on hemodialysis (HD), two on peritoneal dialysis (PD), two on non-dialysis CKD, and six on chronic renal failure (Figure 1, Table 1). Studies examined physical comorbidities (n = 16) among them cardiovascular comorbidities (n = 6), mortality (n = 18), biological parameters (n = 10), sleep (n = 14), psychological comorbidities (n = 20), and hospitalization/health cost (n = 6). Sample sizes of the studies ranged from 75 (a prospective observational study) to 70,500 patients (a retrospective observational study) [20,30].

Figure 1. — Flowchart of the study following the PRISMA guidelines.

Table 1.

Characteristics of the articles included concerning ‘Comorbidities’ item.

References Location	Study design	Strength of evidence	Population	Pruritus characteristics	Comorbidities data
Sukul et al. [11] USA	Prospective observational	High	23,264 patients Gender: 62% men	15,599 (67%) with pruritus During the past 4 weeks, to what extent were you bothered by itchy skin: Not at all: 7,665 (33%) patients Mean age: 63.6 ± 14.7 y Somewhat: 7,009 (30%) Mean age: 63.2 ± 14.4 y Moderately: 4,258 (18%) Mean age: 64.5 ± 14.4 y Very much: 2,711 (12%) Mean age: 64.7 ± 14.4 y Extremely: 1,621 (7%) Mean age: 64.7 ± 14.4 y	HR for skin-related infections was 1.41 (95%CI: 0.87–2.27) for extremely vs not at all bothered, p > 0.05. HR for cardiovascular events was 1.29 (95%CI: 1.06–1.57) for extremely vs not at all bothered, p < 0.05. In patients extremely affected by pruritus, PCS score was lower (−6.7 points (95%CI: 6.1–7.2)) in comparison with patients with no pruritus, p < 0.05.
Sukul et al. [12] USA	Prospective observational	High	3,560 patients Mean age: nm Gender: nm	2,973 CKD stage 3–5 and 587 patients with HD Pruritus score: CKDopps	Moderate to extreme pruritus was more common: In patients with diabetes (aOR = 1.41, 95%CI:1.11–1.80; p < 0.05), lung disease (aOR = 1.42, 95%CI: 1.13–1.79; p < 0.05).
Sukul et al. [13] USA	Prospective observational	High	25,916 patients Values, age, gender: nm	9,589 (37%) at least moderate bothered by pruritus Pruritus scale: During the past 4 weeks, how were you bothered by itchy skin? Not at all/somewhat/moderately/very much/extremely	Groups with more severe pruritus had higher cardiovascular comorbidities, and more diabetes.
Wikström [14] Sweden	Cross-sectional	Moderate	6,137 patients Age, gender: nm	2,823 (46%) had moderate to extreme pruritus Itchy skin the past 4 weeks: Not at all: 1,619 (26.4%) Somewhat: 1,699 (27.7%) Moderately: 1,140 (18.6%) Very much: 962 (15.6%) Extremely: 717 (11.7%)	Lower PCS (−3.3 points lower) in patients with extreme pruritus, when compared with those with no pruritus (p < 0.0001).
Pisoni et al. [15] USA	Cross-sectional	Moderate	13,300 patients (from DOPPS I and II) Group somewhat or no pruritus: Mean age: 60.3 ± 14.64 y Gender: 56.4% men	9,610 (72.3%) with pruritus. Group moderate to extreme pruritus: Mean age: 60.7 ± 14.49 y Gender: 60.3% men Pruritus in last 4 weeks: Not at all bothered: 3,690 (27.7%) Somewhat: 3,873 (29.2%) Moderately: 2,405 (18.1%) Very much: 1,919 (14.4%) Extremely bothered: 1,413 (10.6%)	Patients extremely bothered by itchiness had lower PCS scores (−6.4 points (95%CI: 29.8–25.4)) than patients not bothered by itchiness (p < 0.0001).
Sukul et al. [16] USA	Cross-sectional	Moderate	3,780 patients Mean age: 67 ± 13 y Gender: 61% men	907 (24%) at least moderate pruritus Bothered by pruritus during the last 4 weeks: No pruritus: 1,890 (50%) patients Mild pruritus: 990 (26.2%) Moderate to extreme pruritus: 900 (23.8%)	Patients with extreme pruritus had lower PCS scores (−7.6 points (95%CI: 29.8–25.4) than patients with no pruritus (p < 0.05).
Weisshaar et al. [17] Germany	Cross-sectional	Moderate	860 patients Mean age: 67 ± 13.4 y Gender: 57.2% men	217 (25.2%) with pruritus Pruritus score: VAS values: nm	Diabetes mellitus associated with CP (30.9% of CP in diabetes with complication vs. 42% without CP; 22.8% in diabetes without complication vs. 31.8% without CP; p < 0.05). No association with CP: Any other laboratory values, dialyzer type membrane used, arterial hypertension, anemia, hyperparathyroidism, congestive heart failure, peripheral vascular disease.
Asghar et al. [18] Pakistan	Cross-sectional	Moderate	135 patients, 50 (37%) with pruritus Mean age: 56.29 ± 10.51 y Gender: 56.3% men	Number of patients with pruritus: nm Pruritus scale: Validated for CKD patient (nm)	No significant association with hypocalcemia, hyperparathyroidism, serum urea or creatinine, body mass index, diabetes, hypertension, connective tissue disorder, or frequency of dialysis.
Li et al. [19] China	Cross-sectional	Moderate	362 patients Mean age: 49.9 ± 16.7 y Gender: 53.6% men	236 (62.5%) with pruritus Pruritus score: VAS No pruritus: VAS = 0: 126 (34.8%) patients Mild to moderate: VAS = 1–5: 190 (52.5%) patients Severe: VAS > 6: 46 (12.7%) patients	Pruritus was linked with: Time of PD (OR = 1.039, p = 0.004), Patients with severe pruritus had the longest duration of PD (23 months (12.5, 48; p < 0.001), highest diabetes mellitus (34.8%; p = 0.013)
Ramakrishnan et al. [20] USA	Retrospective observational	Low	70,500 PD patients	42,300 (60%) with CP Pruritus score: KDQOL Not at all bothered by CP: 28,073 (39.8%) patients Mean age: 60.34 y Gender: 44.82% men Somewhat bothered: 21,320 (30.2%), Mean age: 60.11 y Gender: 44.07% men Moderately: 10,869 (15.4%) Mean age: 60 y Gender: 43.44% men Very much: 6,521 (9.3%) Mean age: 59.58 y Gender: 47.22% men Extremely: 3,717 (5.3%) Mean age: 58.51 y Gender: 49.96% men	From the lowest to the highest itchiness severity category, increasing trend in: Skipping HD session (56.16–63.23%, p value not shown) PCS scores (−7.15 points, p < 0.001) Patients with higher degrees of pruritus have higher prevalence of: Diabetes mellitus (p < 0.0001) Cardiovascular diseases (28.5–32.7%, p < 0.0001) Liver diseases (1.8–2.7%, p = 0.0007) Infections-related conditions (septicemia 27.4–33.9%; p < 0.0001 and bacteremia 5.9–7.9%, p < 0.001)
Wikström et al. [21] Sweden	Retrospective observational	Low	7,151 patients Age, gender: nm	2,932 (41%) with moderate to extreme pruritus Pruritus score: nm	Patients with moderate to extreme pruritus had lower PCS scores in (−3.27 points) (p < 0.001)
Kimata et al. [22] Japan	Retrospective observational	Low	6,480 patients from 3 phases studies (JDOPPS 1, 2, and 2) Gender, age: nm	4,120 (63.5%) patients with pruritus, Moderately to extremely bothered by pruritus in the past 4 weeks: 2,851 (44%) patients	MHD patients with pruritus had lower scores on PCS (−6.4 points; p < 0.0001)
Narita et al. [23] Japan	Retrospective observational	Low	1,773 patients Mean age: 60.2 ± 12.8 y Gender: 58.9% men	1,292 (72.9%) with pruritus Pruritus score: VAS: Mild pruritus: VAS < 4: 826 (46.6%) patients Moderate: 4 < VAS < 7: 494 (27.8%) patients Severe: VAS > 7: 453 (25.6%) patients	Worse prognostic in patients with severe pruritus than the others (log rank test, χ² = 14.426; p = 0.0001).
Shafi et al. [24] USA	Retrospective observational	Low	3,639 patients Mean age: 58 y Gender: nm	2,543 (42%) with pruritus Pruritus score: KDQOL36 Values: nm	Pruritus: Independent factor for CKD progression (OR = 1.15, 95%CI: 1.02–1.29; p = 0.02), such as anorexia and fatigue.
Ozen et al. [25] Turkey	Retrospective observational	Low	249 patients Patients with no pruritus: Mean age: 62.46 ± 14.31 y Gender: 65 (56%) men	134 (53.4%) with pruritus Mean age: 62.54 ± 12.77 y Gender: 72 (54.1%) men Pruritus score: VAS: Mild: VAS < 4; 4 (3%) patients Moderate: 4 < VAS < 7; 67 (50.4%) Severe: 7 < VAS < 9; 50 (36.8%) Very severe: VAS > 9; 13 (9.8%)	Patients with pruritus have higher risks of cardiovascular diseases than those without pruritus (χ² = 4.649, p = 0.031). No correlation of pruritus with presence of diabetes.
Ting et al. [26] Taiwan	Retrospective observational	Low	44,280 patients, repartition HD/PD: nm Gender: 50% men 29,520 (65%) without CP Mean age: 60.4 ± 14.2 y	14,760 (35%) with pruritus Mean age: 62.7 ± 13.2 y Pruritus yes/no: Based on anti-H1 prescription with no other indication	CP was linked with: Infection-related hospitalization (HR = 1.18, 95%CI: 1.16–1.21), p < 0.001 Major adverse cardiac and cerebrovascular events (HR = 1.05, 95%CI: 1.01–1.09), p = 0.018 Heart failure (HR = 1.08, 95%CI: 1.01–1.16), p = 0.035 Catheter-related infection (HR = 1.16, 95%CI: 1.12–1.21), p < 0.001 Parathyroidectomy (HR = 1.10, 95%CI: 1.01–1.20), p = 0.026 No significative difference between CP and no CP group for: Acute myocardial infarction, OR = 0.95, 95%CI: 0.88–1.03, p = 0.208 Acute ischemic stroke OR = 1.04, 95%CI (0.98–1.11, p = 0.189 Intracerebral hemorrhage, OR = 0.97, 95%CI: 0.86–1.08, p = 0.556
Sun et al. [27] China	Retrospective observational	Low	129 patients, (121 (94%) HD/8 (6%) PD) Median age: 48 (40–55) y Gender: 46% men	85 (65.9%) with CP Pruritus score: No/mild pruritus: 44 (34%) Severe pruritus: 85 (66%)	Severe hypocalcemia following parathyroidectomy is linked to preoperative serum calcium, iPTH, and severe pruritus (AUC for pruritus: 0.591, 95%CI: 0.493–0.690), p = 0.047.
Plewig et al. [28] Germany	Retrospective observational	Low	104 patients Mean age: 60.8 ± 13.3 y Gender: 54.8% men	Pruritus score (VAS) between 2013 and 2017: 52 (50%) with persistent pruritus 52 (50%) with no more pruritus Mean VAS: 4.1 ± 2.2 points	Patients with persistent pruritus had: Significant more often osteoporosis (87.5%; n = 7) than patients with no current CP (12.5%; n = 1), p = 0.03.
Gomez et al. [29] USA	Retrospective observational	Low	692 patients Mean age: 38.5 ± 11.8 y Gender: 54.5% men	428 (64%) with pruritus Pruritus score: Likert scale	Pruritus linked with skipping or shortening HD sessions (knew as a risk factor for mortality in other studies)

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95%CI: 95% confidence interval; AB: antibiotic; AD: antidepressant; anti-H1: anti-histamin; aOR: adjusted odds ratio; AUC: area under the curve; BDI: Beck Depression Index; BZD: benzodiazepine; CES D: Center for Epidemiologic Studies-Depression; CP: chronic pruritus; DLQI: Dermatology Life Quality Index; DOPPS: Dialysis Outcomes and Practice Patterns Study; EPO: erythropoietin; HADS: Hospital Anxiety and Depression Scale; HbA1c: glycated hemoglobin; HD: hemodialysis; HR: hazard ratio; hs-CRP: hypersensible C-reactive protein; iPTH: intact parathyroid hormone; KDQOL: Kidney Disease Quality of Life; MCS: Mental Component Scale; MHD: maintenance hemodialysis; NA: not applicable; ne: not evaluated; nm: not mentioned; PCS: Physical Component Scale; PD: peritoneal dialysis; PHQ: Patient Health Questionnaire; OR: odds ratio; PSQI: Pittsburgh Sleep Quality Index; RR: relative risk; SAS: Self-Rating Anxiety Scale; SD: standard deviation; SDS: Sheehan Disability Scale; SF-12 Qol: Study Short Form 12 Quality of Life; SF36: Study Short Form 36 Scale; VAS: visual analogue scale; vs.: versus; UV: ultraviolet; WBC: white blood cells; y: years.

Strength of evidence is classified as high, moderate, and low according to the design of the studies.

CKD-aP and physical comorbidities – 21 articles (Table 1)

CKD-aP and physical component score (PCS) – seven articles

PCS (physical component summary) is summary score derived from the SF-36 (Short Form Health Survey) or SF-12 which measures overall physical health.

PCS scores are typically standardized with a mean of 50 and a standard deviation of 10, based on the general population. Higher scores indicate better physical health, whereas lower scores reflect greater physical limitations.

Thus, lower PCS scores were found in patients with pruritus in all articles.

PCS decreased while pruritus increased when the lowest and highest pruritus severity scores were compared (7.15 points difference; p < 0.0001) [20]. Hemodialysis patients with moderate to extreme pruritus had a summary PCS score 3.27 points lower than those with no/mild pruritus (p < 0.001) [21].

Among maintenance hemodialysis (MHD) patients, those without pruritus had a mean score of 39.2 ± 11.0 points, whereas those who presented with pruritus had 6.7 points lower (95% confidence interval (95%CI): 6.1–7.2) [11].

Similar PCS scores were found in three other studies: 4.4 points lower (p < 0.0001), 3.3 points lower (p < 0.0001), and 6.4 points lower (p < 0.0001) in patients moderately to extremely bothered by pruritus, when compared with patients without pruritus [14,15,22]. A similar association was found in non-dialysis patients: the average PCS score was 7.6 points lower in patients with extreme pruritus compared to those without (95%CI: 29.8–25.4) [16].

CKD-aP and comorbidities – 15 articles

Severe pruritus in CKD patients was linked to worse prognosis compared to no, mild, or moderate pruritus (log-rank test, χ² = 14.426; p = 0.0001) [23]. In non-dialysis CKD patients, pruritus independently contributed to CKD progression (odds ratio (OR) 1.15, 95%CI: 1.02–1.29; p = 0.02), along with anorexia and fatigue [24].

Six studies found an association between pruritus and cardiovascular comorbidities, five with a higher risk [11–13,25,26] and one found no association [17]. CKD-aP MHD patients had more cardiovascular comorbidities (values not detailed), diabetes (adjusted OR (aOR) = 1.41, 95%CI: 1.11–1.80), and psychiatric conditions (aOR = 1.66, 95%CI: 1.32–2.10) [12]. A higher cardiovascular disease risk in MHD patients with pruritus (χ² = 4.649; p = 0.031) [25], and major adverse cardiac and cerebrovascular events (hazard ratio (HR): 1.05, 95%CI: 1.01–1.09) or heart failure (HR = 1.08, 95%CI: 1.01–1.16) were related in pruritic CKD patients [26]. Higher long-term morbidity risks, including infection-related hospitalization (HR = 1.13, 95%CI: 1.16–1.21), catheter-related infections (HR = 1.16, 95%CI: 1.12–1.21), and parathyroidectomy (HR = 1.10, 95%CI: 1.01–1.20) [26], as well as more cardiovascular events and skin infections, were reported in severe pruritus cases (HR = 1.29; 95%CI: 1.06–1.57 and HR = 1.41, 95%CI: 0.87–2.27, respectively) [11].

Pruritus was an independent risk factor for severe hypocalcemia post-parathyroidectomy (area under the curve (AUC) 0.591, 95%CI: 0.493–0.690), alongside preoperative hypocalcemia and high intact parathyroid hormone (iPTH) levels [27]. Osteoporosis was found in 87.5% of MHD CKD patients with pruritus, compared to 12.5% without (p = 0.03) [28].

Pruritus caused 50% of patients to skip or shorten HD sessions at least occasionally [29] whereas severe pruritus led to 2.6 more missed dialysis sessions per year [20]. However, Asghar et al. found no association between pruritus and frequency of dialysis [18].

Five studies found an association between pruritus and diabetes mellitus [12,13,17–19]. Studies conducted by Sukul et al. and Li et al. found that patients with more severe pruritus had a higher prevalence of diabetes mellitus (OR = 1.41, 95%CI: 1.11–1.80 for [12] and 34.8% for [19], p = 0.013). Conversely, Weisshaar et al. found that diabetes mellitus, with or without complications, was significantly less prevalent in patients with pruritus (p < 0.05) [17], while for Asghar et al. there was no significant association (OR = 1.688, 95%CI: 0.832–3.426, p = 0.148) [18].

CKD-aP and mortality – 18 articles (Table 2)

Table 2.

Characteristics of the articles included concerning ‘Mortality’ item.

References Location	Study design	Strength of evidence	Population	Pruritus characteristics	Mortality data
Afsar and Elsurer [30] Turkey	Prospective observational	High	75 patients Mean age: 51.9 ± 13.5 y Gender: 54.6% men	Number of patients with pruritus: nm Pruritus score: VAS Mean 3.7 ± 2.4 points	Higher mortality risk (+11%, p = 0.04) in CKD patients with moderate to extreme pruritus.
Sukul et al. [11] USA	Prospective observational	High	23,264 patients Gender: 62% men	15,599 (67%) with pruritus During the past 4 weeks, to what extent were you bothered by itchy skin: Not at all: 7,665 (33%) patients, Mean age: 63.6 ± 14.7 y Somewhat: 7,009 (30%) Mean age: 63.2 ± 14.4 y Moderately: 4,258 (18%) Mean age: 64.5 ± 14.4 y Very much: 2,711 (12%) Mean age: 64.7 ± 14.4 y Extremely: 1,621 (7%) Mean age: 64.7 ± 14.4 y	Rates of all-cause and CV-related mortality: All 20% greater for patients extremely bothered vs. not at all bothered by pruritus.
Sukul et al. [13] USA	Prospective observational	High	25,916 patients Values, age, gender: nm	9,589 (37%) at least moderate bothered by pruritus Pruritus scale: During the past 4 weeks, how were you bothered by itchy skin? Not at all/somewhat/moderately/very much/extremely	Adjusted mortality HR (95%CI), in comparison with those with no pruritus, was: 1.02 (0.93, 1.11) for somewhat bothered, p > 0.05 1.13 (1.03, 1.24) for moderately bothered, p < 0.05 1.08 (0.98, 1.21) for very much bothered, p > 0.05 1.30 (1.15, 1.48) for extremely bothered, p < 0.05
Gjyzari et al. [31] Albania	Prospective observational	High	85 patients	52 (61%) with pruritus Age: 57.5 y (48.5–66.5) for patients with pruritus Gender: 79.9% men for patients with pruritus Pruritus score: nm Mild: 30 (35.3%) Moderate: 17 (20%) Severe: 5 (5.9%)	In Cox regression analysis: Moderate pruritus is an independent factor for mortality (64.7% dead vs. 35.3% survived within moderate pruritus) OR = 3.2, 95%CI: 1.4–9.0, p = 0.027
Chen et al. [32] USA	Prospective observational	High	321 patients Mean age: 60 ± 12 y Gender: 49.25% men 203 (63.2%) with pruritus	Pruritus score: VAS Absence: VAS = 0: 118 (36.8%) patients Mild: VAS 1–3: 76 (23.7%) Moderate: VAS 4–7: 89 (27.7%) Severe: VAS 8–10: 38 (11.8%)	Patients with moderate/severe pruritus: Worse overall survival than those with no/mild pruritus (χ² = 9.80, p = 0.0017, log rank test). Predictors of all-cause mortality: Moderate/severe pruritus: HR = 1.899, 95%CI: 1.107–3.256, p = 0.02 hsCRP: HR 1.175, 95%CI: 1.083–1.275, p < 0.001 Interaction between the 2 predictors (χ² = 6.42, p = 0.011) hsCRP and pruritus are independent predictors of mortality: Pruritus: HR = 3.125, 95%CI: 1.596–6.12, p = 0.001 hsCRP: HR = 1.261, 95%CI: 1.165–1.376, p < 0.001
Tayebeh et al. [33] Iran	Prospective observational	High	416 patients Age, gender: nm	158 (38%) with moderate to extreme pruritus (details not shown)	Severe insomnia: Risk factor for death (aOR = 1.72 (95%CI: 1.00–3.03), p = 0.05)
Orasan et al. [34] Romania	Prospective observational	High	170 patients Mean age: 59.3 y ± 15.1 Gender: 50% men	55 (32.3%) with pruritus Pruritus: present/absence	Survival at 20 months: Lower for patients with both insomnia and pruritus compared to group 1 (patients with neither pruritus or insomnia; p = 0.041), group 2 (pruritus but no insomnia; p = 0.037), and group 3 (insomnia but no pruritus; p = 0.019)
Wu et al. [35] Taiwan	Prospective observational	High	85 patients Mean age: 55.5 ± 12 y Gender: 35% men	24 (28.2%) with CP Pruritus score: VAS Median score: 4.36 points	After adjustment, VAS score: Independent risk factor for technique failure or death (HR = 1.64, 95%CI: 1.18–2.28; p = 0.003) Trend of lower event-free survival in patient with pruritus but no significative (p = 0.38)
Wikström [14] Sweden	Cross-sectional	Moderate	6,137 patients Age, gender: nm	2,823 (46%) had moderate to extreme pruritus Itchy skin the past 4 weeks: Not at all: 1,619 (26.4%) Somewhat: 1,699 (27.7%) Moderately: 1,140 (18.6%) Very much: 962 (15.6%) Extremely: 717 (11.7%)	Patients with moderate-to-extreme pruritus had a 15% higher mortality risk (p = 0.008) compared with those with no pruritus; not even significative after adjustment for sleep quality.
Pisoni et al. [15] USA	Cross-sectional	Moderate	13,300 patients (from DOPPS I and II)	9,610 (72.3%) with pruritus. Group somewhat or no pruritus: Mean age: 60.3 ± 14.64 y Gender: 56.4% men Group moderate to extreme pruritus: Mean age: 60.7 ± 14.49 y Gender: 60.3% men Pruritus in last 4 weeks: Not at all bothered: 3,690 (27.7%) Somewhat: 3,873 (29.2%) Moderately: 2,405 (18.1%) Very much: 1,919 (14.4%) Extremely bothered: 1,413 (10.6%)	Patients with moderate to severe pruritus had a 13% higher mortality risk (p = 0.01) compared with patients not bothered in DOPPS1, 21% in DOPPS2, 17% in DOPPS1 and 2; no longer significant when adjusted for sleep quality.
Wikström et al. [21] Sweden	Retrospective observational	Low	7,151 patients	2,932 (41%) with moderate to extreme pruritus Pruritus score, age, gender: nm	A 11% higher mortality risk (p = 0.04) in patient with moderate to extreme pruritus in comparison with those with no/mild pruritus, but no longer significant after adjustment for sleep quality
Kimata et al. [22] Japan	Retrospective observational	Low	6,480 patients from 3 phases studies (JDOPPS 1, 2, and 2) Gender, age: nm	4,120 (63.5%) patients with pruritus. Moderately to extremely bothered by pruritus in the past 4 weeks: 2,851 (44%) patients	Patients with moderate to extreme pruritus had a 37% higher mortality rate (p = 0.03) compared with patients not bothered by pruritus in JDOPPS3, 5–18% in JDOPPS1 and 22% in JDOPPS in all phases combined; even after adjusting for sleep quality (for JDOPPS 1 and 3)
Narita et al. [23] Japan	Retrospective observational	Low	1,773 patients Mean age: 60.2 ± 12.8 y Gender: 58.9% men	1,292 (72.9%) with pruritus Pruritus score: VAS: Mild pruritus: VAS < 4: 826, 46.6% patients Moderate: 4 < VAS < 7: 494, 27.8% patients Severe: VAS > 7: 453, 25.6% patients	Death due to infection: More prevalent in patients with severe pruritus but difference not significant. Severe pruritus: Independent predictive risk for death even after adjusting for other clinical risk factors in Cox model. After forcing severe pruritus: independent predictive risk for death even after adjustment (HR for severe pruritus = 1.595; 95%CI: 1.160–2.381; p = 0.0084). Worse prognosis for patients with severe pruritus than the others (log rank test χ² = 14.426), p = 0.0001
Shafi et al. [24] USA	Retrospective observational	Low	3,639 patients Mean age: 58 y Gender: nm	2,543 (42%) with pruritus Pruritus score: KDQOL36 Values: nm	No significative association between pruritus and death
Sukul et al. [36] USA	Retrospective observational	Low	7,976 patients Mean age, gender: nm	4,036 (50.6%) with pruritus Comparison on pruritus status between a year interval in same patient: Not bothered by itchy skin during year 1 (Y1) and 2 (Y2) (no/no): 3,940 (49%) patients At least bothered during Y1 (yes/no): 1,137 (14%) patients At least bothered during Y2 (no/yes): 1,330 (16%) patients At least bothered by itchy skin during Y1 and Y2 (yes/yes): 1,769 (21%) patients	The all-cause mortality HR vs. the no/no reference group: 1.22 (%95 CI: 0.99–1.51) for patient with pruritus in Y1 but no in Y2, p > 0.05 1.32 (%95 CI: 1.07–1.63) for patient without pruritus in Y1 but with pruritus in Y2, p < 0.05 1.31 (%95 CI: 1.11–1.56) for patient with pruritus in both Y1 and Y2, p < 0.05
Ting et al. [37] Taiwan	Retrospective observational	Low	75,144 patients Gender, age: nm	25,048 (33%) with CP CP: yes/no based on taking of >42 days of anti-H1 or UVB phototherapy within 1 year after dialysis initiation (dermatological disease and allergy indication excluded)	After 5 y follow up, CP group compared to no CP group had: Higher risk of all-cause mortality (HR = 1.05, 95%CI: 1.03–1.07), p < 0.05
Weng et al. [38] Taiwan	Retrospective observational	Low	866 patients Mean age: 56.18 y ± 13.59 Gender: 50.8% men	189 (21.8%) with pruritus Pruritus score: VAS Values: nm	Presence of CP increased all-cause mortality in the 24-month period by Kaplan–Meier’s analysis (log rank test, r² = 4.698, p = 0.03) and cardiovascular mortality in this period (log rank test, r² = 4.698, p = 0.03; after multivariate Cox proportional hazard regression: OR: 3.164; 95%CI: 1.743–5.744, p < 0.001); but did not increase infection related mortality. VAS: Not a significant factor to predict 24-month cardiovascular mortality, cardiovascular related mortality or infection related.
Grochulska et al. [39] Germany	Retrospective observational	Low	724 patients Mean age: 68.9 ± 12.8 y Gender: 56.5% men	95 (54.6%) with pruritus Pruritus score: VAS Values: nm	Mortality rate: 45.7% in the group suffering from CP vs. 54.9% in the group without CP. Patients with moderate to severe pruritus: Higher mortality rates (RR = 1.2; p < 0.02) compared with those with no/mild pruritus; no longer true after adjusting for age and sex.

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Strength of evidence is classified as high, moderate, and low according to the design of the studies.

An association between pruritus and mortality was found in 15/18 studies [11,13,22,23,30–38] though the association was no longer significant after adjusting for sleep in 3/15 [14,15,21]. Two studies found no association [24,39].

Severe pruritus was identified as an independent mortality predictor (HR = 1.595; 95%CI: 1.160–2.381; p = 0.0084) [23]. Moderate pruritus increased mortality risk (OR = 3.2; 95%CI: 1.4–9.0; p = 0.027) [31]. A study of 25,916 CKD MHD patients found a higher adjusted HR for mortality in the pruritus group: HR = 1.13 (95%CI: 1.03–1.24) for moderate pruritus and HR = 1.30 (95%CI: 1.15–1.48) for severe pruritus [13].

In the Dialysis Outcomes and Practice Pattern Study (DOPPS) from 2009 to 2018, in which patients with two CKD-aP assessments 12 months apart with bothering itch were evaluated, they showed that those affected by pruritus at any point in the year (Y) had higher rates of all-cause mortality (HR = 1.22 (95%CI: 0.99–1.51) for patients with pruritus at Y1 but not Y2, HR = 1.32 (95%CI: 1.07–1.63) for that developing pruritus at Y2, and HR = 1.31 (95%CI: 1.11–1.56) for those with pruritus at Y1 and Y2) [36]. A higher mortality rate in patients with moderate to extreme pruritus across Japan DOPPS phases of data collection (1999–2001 phase 1, 2002–2004 phase 2, and 2005–2008 phase 3) was evidenced, with a significant increase in JDOPPS 3 (37%, p = 0.03; 22%, p = 0.04) after sleep quality adjustment [22]. Decreased survival in MHD patients with moderate/severe pruritus was confirmed (χ² = 9.80; p = 0.0017) [32].

All-cause mortality (HR = 1.05; 95%CI: 1.03–1.07), infection-related death (HR = 1.08; 95%CI: 1.05–1.11), and cardiovascular death (HR = 1.06; 95%CI: 1.02–1.09) were increased in pruritic dialysis patients over five years [37], while a 20% higher cardiovascular and infection-related mortality in severe pruritus cases was found (HR = 1.29; 95%CI: 1.06–1.57; HR = 1.44; 95%CI: 1.05–1.96) [11]. MHD patients with pruritus had significantly higher all-cause and cardiovascular mortality at 24 months (log-rank test, r² = 4.698, p = 0.03), with pruritus predicting 24-month cardiovascular mortality (OR = 3.164; 95%CI: 1.743–5.744, p < 0.001) [38].

The higher mortality risk (11%, p = 0.04 in [30] and 15%, p = 0.008 in [11]) in CKD patients with moderate to extreme pruritus, was not confirmed after sleep quality adjustment in two studies [14,21]. The 17% increased mortality risk in MHD patients with pruritus described in the different studies operated by the authors was no longer significant after sleep adjustment [15].

Some studies found an association between pruritus, mortality, and sleep. Severe to extreme pruritus was associated with extreme insomnia (aOR = 8.80; 95%CI: 3.24–23.91), and as extreme insomnia was associated with higher mortality, this suggested an association between pruritus and death (aOR = 1.72; 95%CI: 1.00–3.03; p = 0.05) [33]. Lower 20-month survival in patients with both pruritus and insomnia was noted (p = 0.037), without any significant difference for pruritus alone [34].

Additional associations include worse survival in patients with both moderate/severe pruritus and high hs-CRP (χ² = 6.42, p = 0.011) [32].

CKD-aP PD patients with high VAS scores had a higher risk of technical failure or death (HR = 1.64; 95%CI: 1.18–2.28; p = 0.003) [35].

Anorexia was linked to CKD progression and death, but not significantly to pruritus [24]. In an observational study, the mortality rate was lower in the group with CKD-aP (45.7%) compared with the group without CKD-aP (54.9%) in MHD patients, without significance [39]. However, MHD patients with chronic secondary scratch lesions and chronic prurigo had a higher adjusted mortality risk compared to those without skin lesions [39].

CKD-aP and psychological comorbidities – 20 articles (Table 3)

Table 3.

Characteristics of the articles included concerning ‘Psychological comorbidities’ item.

References Location	Study design	Strength of evidence	Population	Pruritus characteristics	Depression/anxiety/mental health	QOL	Depression/anxiety/mental health/QoL data
Afsar and Elsurer [30] Turkey	Prospective observational	High	75 patients Mean age: 51.9 ± 13.5 y Gender: 54.6% men	Number of patients with pruritus: nm Pruritus score: VAS Mean 3.7 ± 2.4 points	BDI score Mean: 15.3 ± 9.3 points	SF36 Values: nm	VAS pruritus score associated with: BDI (95%CI: 0.060–0.0721), p = 0.025
Sukul et al. [11] USA	Prospective observational	High	23,264 patients Gender: 62% men	15,599 (67%) with pruritus During the past 4 weeks, to what extent were you bothered by itchy skin: Not at all: 7,665 (33%) patients Mean age: 63.6 ± 14.7 y Somewhat: 7,009 (30%) Mean age: 63.2 ± 14.4 y Moderately: 4,258 (18%), Mean age: 64.5 ± 14.4 y Very much: 2,711 (12%) Mean age: 64.7 ± 14.4 y Extremely: 1,621 (7%) Mean age: 64.7 ± 14.4 y	Depression = CES D Data evaluated on 19,526 patients: 8,591 (44%) had depression MCS	KDQOL-36, HR QoL Bothered by faintness or dizziness: data evaluated on 22,631 patients: 6,658 (25%) Bothered by feeling washed out or drained: Data evaluated on 22,484 patients: 9,803 (43.6%) PCS	Patients extremely bothered by pruritus vs. not at all had: 2–3 times higher rate of depressive symptoms, being bothered by faintness/dizziness and being bothered by feeling washed out/drained A higher rate of hospitalization for confusion or mental status: HR = 1.84; 95%CI: 1.18–2.87, p < 0.05 In patients extremely affected by pruritus, MCS scores were significantly lower (−9.1 points (95%CI: 8.4–9.8)) in comparison with patient with no pruritus, p < 0.05
Sukul et al. [12] USA	Prospective observational	High	3,560 patients Mean age: nm Gender: nm	2,973 CKD stage 3–5 and 587 patients with HD Pruritus score: CKDopps	nm	nm	Moderate to extreme pruritus was more common: In patients with psychiatric disease (aOR = 1.66, 95%CI: 1.32–2.10), p < 0.05
Wikström [14] Sweden	Cross-sectional	Moderate	6,137 patients Age, gender: nm	2,823 (46%) had moderate to extreme pruritus Itchy skin the past 4 weeks: Not at all: 1,619 (26.4%) Somewhat: 1,699 (27.7%) Moderately: 1,140 (18.6%) Very much: 962 (15.6%) Extremely: 717 (11.7%)	MCS	PCS	Lower MCS (−4.3 points) in patients with extreme pruritus, when compared with those with no pruritus (p < 0.0001) 2.3–5.2-fold higher odds of feeling drained (p < 0.0001) and a 1.3–1.7 times higher odds depression (p = 0.01, p < 0.0001, respectively) in patients with moderate to extreme pruritus, compared with patients not bothered by pruritus
Pisoni et al. [15] USA	Cross-sectional	Moderate	13,300 patients (from DOPPS I and II)	9,610 (72.3%) with pruritus Group somewhat or no pruritus: Mean age: 60.3 ± 14.64 y Gender: 56.4% men Group moderate to extreme pruritus: Mean age: 60.7 ± 14.49 y Gender: 60.3% men Pruritus in last 4 weeks: Not at all bothered: 3,690 (27.7%) Somewhat: 3,873 (29.2%) Moderately: 2,405 (18.1%) Very much: 1,919 (14.4%) Extremely bothered: 1,413 (10.6%)	MCS	SF36 and SF12; values: nm PCS	Patients extremely bothered by pruritus have lower MCS scores (−8.6 points) than patients not bothered by pruritus (p < 0.0001) Patients with moderate to extreme pruritus, compared with patients without pruritus, had: 2.3–5.2-fold higher odds of feeling drained (p < 0.001). 1.3–1.7 times higher odds of depression (p < 0.001).
Sukul et al. [16] USA	Cross-sectional	Moderate	3,780 patients Mean age: 67 ± 13 y Gender: 61% men	907 (24%) at least moderate pruritus Bothered by pruritus during the last 4 weeks: No pruritus: 1,890 (50%) patients Mild pruritus: 990 (26.2%) Moderate to extreme pruritus: 900 (23.8%)	Depression score: CES-D: No pruritus: 6.5 ± 4.6 points Mild: 7.5 ± 5.0 points Moderate to extreme: 9.9 ± 5.7 points MCS	KDQOL-SF, value nm PCS (points): No pruritus: 7.6 Mild: 7.5 ± 5.0 points Moderate to extreme: 9.9 ± 5.7 points	Patients with extreme pruritus had lower MCS scores (−6.2 points (95%CI: 28.5–23.9)) than patients with no pruritus, p < 0.05 In comparison with patients without pruritus: Depression symptom was 1.83-fold higher in patients with moderate pruritus (prevalence ratio (PR), 1.83; 95%CI: 1.58–2.11) and 2.55-fold higher in patients with moderate to extreme pruritus (PR = 2.55, 95%CI: 2.07–3.13), p < 0.05 for all
Li et al. [19] China	Cross-sectional	Moderate	362 patients Mean age: 49.9 ± 16.7 y Gender: 53.6% men	236 (62.5%) with pruritus Pruritus score: VAS No pruritus: VAS = 0: 126 (34.8%) patients Mild to moderate: VAS = 1–5: 190 (52.5%) patients Severe: VAS > 6: 46 (12.7%) patients	Depression score: BDI; mean value: 10 (5, 18.8)	SF36 Value: nm	Pruritus was linked with: PSQI (OR = 1.305, 95%CI: 1.08–2.38, p = 0.001) BDI (OR = 1.429, 95%CI: 1.05–1.52, p = 0.002) Patients with severe pruritus had the highest PSQI score (12.3 ± 5.6 points, p < 0.001)
Meng et al. [40] China	Cross-sectional	Moderate	305 patients Mean age: 52 y (22–84 y) Gender: 55.1% men	245 (80.3%) with pruritus Self-reported pruritus: No pruritus: 60 (19.7%) patients Sustainable: 202 (66.2%) Unbearable: 43 (14.1%)	SDS score: values nm SAS: Mild: 25.9% Moderate: 4.6%% Severe: 1.3%	ne	Higher degree of pruritus: Predictor of depression (OR 15.971, 95%CI: 5.173–49.315, p < 0.001) and anxiety for patients with occasional pruritus (OR = 3.849, 95%CI: 1.403–10.556, p < 0.05) or severe pruritus (OR = 5.912, 95%CI: 1.733–20.168, p < 0.05)
Satti et al. [41] Pakistan	Cross-sectional	Moderate	173 patients Mean age: 39.4 ± 4.3 y Gender: 100% men	85 (49.1%) with pruritus Pruritus score: 5-D itch scale: No pruritus: 88 (50.9%) patients Mild: (47 (27.2%) Moderate: 29 (16.8%) Severe: 9 (5.2%)	PHQ 9 score for depression Mean score: 9.8 ± 1.7 points	DLQI score Mean score: 9.8 ± 1.7	An ANOVA test showed that increasing 5-D itch score was linked with significative higher values of PHQ-9 (depression scale; p = 0.001) and DLQI (quality of life scale; p = 0.005).
Araujo et al. [42] Brazil	Cross-sectional	Moderate	400 patients Mean age: 51.6 ± 5.5 y Gender: 59% men	29 (9.8%) with pruritus Pruritus score: nm	BDI: Depression if score ≥16 points: 19.3% (77) patients	ne	Pruritus associated with depressive symptoms: Pruritus in patients without depressive symptom: 25/323 (8.2%) Pruritus in patients with depressive symptom: 14/77 (14.6%); OR = 2.011, 95%CI: 0.043–3.810, p = 0.045
Sakiqi et al. [43] Greece	Cross-sectional	Moderate	100 patients Age: 73% had >60 y Gender: 75% men	Number with pruritus: nm Have you had itching in your body since you started dialysis? No: 41.6 (8.6) patients Rarely/sometimes: 46.4 (8.7) Often/yes: 51.6 (9.0)	SDS	ne	Association between depression levels and pruritus (p = 0.001)
Areste-Fosalba et al. [44] Spain	Cross-sectional	Moderate	1,605 (92% MHD, 5% PD, 3% non-dialysis) patients Age, gender: nm	810 (50.5%) with pruritus 428 (26.7%) with moderate-to-severe pruritus Pruritus score: Short survey questionnaire	Short survey questionnaire, value nm	Short survey questionnaire, value nm	Pruritus is very prevalent in advanced CDK patient and is linked with mood changes, depression, impairing sexuality and affecting sleep (value nm).
Awosan et al. [45] Nigeria	Cross-sectional	Moderate	124 patients Mean age: 46.7 ± 14.9 y Gender: 98 (79%) men	20 (16.1%) with pruritus Pruritus scale: nm	Experience of suicidal ideation on 17 (13.7%) patients with CP	ne	No association between pruritus and suicidal ideation (p = 0.595)
Ramakrishnan et al. [20] USA	Retrospective observational	Low	70,500 patients	42,300 (60%) with CP Pruritus score: KDQOL: Not at all bothered by CP: 28,073 (39.8%) patients, Mean age: 60.34 y Gender: 44.82% men Somewhat bothered: 21,320 (30.2%) Mean age: 60.11 y Gender: 44.07% men Moderately: 10,869 (15.4%) Mean age: 60 y Gender: 43.44% men Very much: 6,521 (9.3%), Mean age: 59.58 y Gender: 47.22% men Extremely: 3,717 (5.3%) Mean age: 58.51 y Gender: 49.96% men	MCS	KDQOL-36 and SF-36	From the lowest to the highest itchiness severity category, decreasing trend in: MCS score (52.07–43.46, p = 0.0001) Daily Life Subscale Score (76.40–51.85, p < 0.0001) Burden of Disease Subscale Score (57.23–32.71, p < 0.0001) Symptom and Problem Subscale scores (85.73–52.26, p value NA)
Wikström et al. [21] Sweden	Retrospective observational	Low	7,151 patients Age, gender: nm	2,932 (41%) with moderate to extreme pruritus Pruritus score: nm	MCS	PCS MCS	When compared with patients with no/mild pruritus, patient with moderate to extreme pruritus had: More risk of feeling drained (aOR = 2.87, p < 0.001) More depression (aOR = 1.4, p < 0.001) Lower scores in MCS (−3.77 points p < 0.001)
Kimata et al. [22] Japan	Retrospective observational	Low	6,480 patients from 3 phases studies (JDOPPS 1, 2, and 2) Gender, age: nm	4,120 (63.5%) patients with pruritus Moderately to extremely bothered by pruritus in the past 4 weeks: 2,851 (44%) patients	MCS	SF36 SF 12 QoL PCS Values: nm	MHD patients with pruritus had lower scores on MCS (−4.6 points; p < 0.0001), and felt 2.2–5.8 times more exhausted (p < 0.0001)
Ozen et al. [25] Turkey	Retrospective observational	Low	249 patients Patients with no pruritus: Mean age: 62.46 ± 14.31 y Gender: 65 (56%) men	134 (53.4%) with pruritus Mean age: 62.54 ± 12.77 y Gender: 72 (54.1%) men Pruritus score: VAS: Mild: VAS < 4; 4 (3%) patients Moderate: 4 < VAS < 7; 67 (50.4%) Severe: 7 < VAS < 9; 50 (36.8%) Very severe: VAS > 9; 13 (9.8%)	HADS: depression in 193 (77.4%) patients	ne	Patients without pruritus: lower anxiety than those with pruritus (χ² = 4.110, p = 0.043) Positive relationship between VAS score and the HADS in patients with pruritus (p = 0.034)
Plewig et al. [28] Germany	Retrospective observational	Low	104 patients Mean age: 60.8 ± 13.3 y Gender: 54.8% men	Pruritus score (VAS) between 2013 and 2017: 52 (50%) with persistent pruritus 52 (50%) with no more pruritus Mean VAS: 4.1 ± 2.2 points	HADS (mean value):	ItchyQoL: for persistent CP SF-12	Patients with persistent pruritus had: Significantly higher scores in ItchyQoL when compared with their own score in 2013 (2.1 ± 0.7 with persistent pruritus vs. 1.7 ± 0.6) no current but previous pruritus (p < 0.05) Significantly higher scores in the HADS, when compared with their own score in 2013: 1.7 ± 0.6 points in 2013 vs. 2.2 ± 0.7 points 2017 and when compared with patient with no more pruritus (4.7 ± 4.2 with persistent pruritus vs. 6.6 ± 4.1 no current but previous pruritus in Depression Subscale, 5.1 ± 3.9 with persistent pruritus vs. 6.6 ± 3.9 no current but previous pruritus, p < 0.05 in Anxiety Subscale) SF-12 score: no difference between group
Hu et al. [46] China	Retrospective observational	Low	382 patients (138 HD patients) 41 PD patients, 203 CKD with no dialysis Gender: nm Non pruritus group: 185 patients (48.4%) Mean age = 50.92 ± 16.19 y	Pruritus score: VAS mean value = 3.21 ± 1.73 Pruritus group: 197 (51.6%) patients Mean age = 52.26 ± 14.86 y	nm	ne	No statistical link between pruritus and emotional influence even in HD and PD patients (χ² = 6.932; p = 0.316) No impact of pruritus on emotional well-being in CKD patients in the other (p = 0.316)

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Strength of evidence is classified as high, moderate, and low according to the design of the studies.

A significant association was found in 18/20 [11,12,14–16,19–22,25,28,30,40–44,47] while two did not [45,46].

The seven trials investigating pruritus and the Mental Component Score (MCS) which is summary score derived from the SF-36 or SF-12 measuring mental health, showed a significant correlation between pruritus and lower MCS. In dialysis patients, pruritus negatively impacted quality of life. Thus, increased pruritus severity led to a decrease in MCS (52.07–43.46; p < 0.0001) and worsened daily life, disease burden, and symptom scores [20]. MHD patients with severe pruritus had MCS scores 9.1 points lower than those without (95%CI: 8.4–9.8). They were also more likely to experience depressive symptoms, exhaustion, dizziness, and hospitalizations for mental status changes (HR = 1.84; 95%CI: 1.18–2.87 for hospitalizations) [11]. DOPPS-based studies revealed that MCS scores were lower by 3.77, 4.3, and 8.6 points in MHD patients with moderate to extreme pruritus (p < 0.0001) [14,15,21]. These patients were also 2.3–5.2 times more likely to feel exhausted (p < 0.0001) and 1.3–1.7 times more likely to have depressive symptoms (p < 0.001) [14,15]. MHD patients with pruritus had higher risk of being diagnosed with depression (aOR = 1.4, p < 0.001) [21]. In non-dialysis CKD patients, MCS declined if pruritus severity increased (−6.2 points, 95%CI: −8.5 to −3.9). Patients with extreme pruritus had a 2.5 times higher likelihood of depression (prevalence ratio (PR) = 2.55; 95%CI: 2.07–3.13) [16].

In the Japanese study JDOPPS, Kimata et al. showed that MHD patients with pruritus had lower MCS scores (−4.6 points, p < 0.0001) and were 2.2–5.8 times more likely to feel exhausted (p < 0.0001) [22].

A strong association between severe pruritus and depression (OR = 15.971; 95%CI: 5.173–49.315; p < 0.001) and anxiety was observed, with an increase with pruritus severity [35]. In a prospective study in 2016, Sukul et al. showed that pruritus is more common in patients with psychiatric disorders, although no real correlation could be established (aOR = 1.66; 95%CI: 1.32–2.10) [12]. However, visual analogue scale (VAS) and the Hospital Anxiety and Depression Scale (HADS) in MHD patients with pruritus were correlated (r² = 0.184, p = 0.034) [25].

Depressive symptoms in MHD patients correlated with pruritus severity (5-D scores) and were linked to higher PHQ-9 (Patient Health Questionnaire-9) (p = 0.001) and DLQI (Dermatology Life Quality Index) scores (p = 0.005) [41]. MHD patients with severe pruritus treated with PD had higher BDI (Beck Depression Inventory) scores (OR = 1.429; 95%CI: 1.05–1.52; p = 0.002) [19]. Afsar and Elsurer also described the significant association between VAS pruritus score and BDI score (95%CI: 0.060–0.0721, p = 0.025) [30]. Two cross-sectional studies confirmed independent associations between pruritus and depression (OR = 2.011; 95%CI: 0.043–3.81; p = 0.045 for [42], p = 0.001 for [43]).

Dialysis patients with pruritus experienced mood changes, depression, and sexual dysfunction [47]. ItchyQoL and HADS anxiety scores were worsened in patients with persistent pruritus (p < 0.05) [28].

Two studies found no association between pruritus and suicidal ideation in one (p = 0.595) [45] no impact of pruritus on emotional well-being in CKD patients in the other (p = 0.316) [46].

CKD-aP and sleep – 15 articles (Table 4)

Table 4.

Characteristics of the articles included concerning ‘Sleep’ item.

References Location	Study design	Strength of evidence	Population	Pruritus characteristics	Sleep evaluation	Sleep data
Sukul et al. [11] USA	Prospective observational	High	23,264 patients Gender: 62% men	15,599 (67%) with pruritus During the past 4 weeks, to what extent were you bothered by itchy skin: Not at all: 7,665 (33%) patients Mean age: 63.6 ± 14.7 y Somewhat: 7,009 (30%) Mean age: 63.2 ± 14.4 y Moderately: 4,258 (18%) Mean age: 64.5 ± 14.4 y Very much: 2,711 (12%) Mean age: 64.7 ± 14.4 y Extremely: 1,621 (7%) Mean age: 64.7 ± 14.4 y	Feeling sleep was restless during last week ≥3/week = poor sleep quality Data evaluated on 22,464 patients	7,211 (32.1%) poor sleepers
Tayebeh et al. [33] Iran	Prospective observational	High	416 patients Age, gender: nm	158 (38%) with moderate to extreme pruritus (details not shown)	SF-36: ‘Insomnia’: 204 (49%) patients	Severe insomnia: Risk factor for death (aOR = 1.72 (95%CI: 1.00–3.03), p = 0.05 Severe to extreme pruritus associated with: Severe insomnia (aOR = 8.8, 95%CI: 3.24–23.91), p < 0.001
Wikström [14] Sweden	Cross-sectional	Moderate	6,137 patients Age, gender: nm	2,823 (46%) had moderate to extreme pruritus Itchy skin the past 4 weeks: Not at all: 1,619 (26.4%) Somewhat: 1,699 (27.7%) Moderately: 1,140 (18.6%) Very much: 962 (15.6%) Extremely: 717 (11.7%)	Questionnaire (self-reported) during the past 4 weeks about sleep disturbance	1.5–4.1 higher odds of having sleep disturbance in patients with moderate-to-extreme itch. Patients with moderate-to-extreme have: 1.7–4.1 higher odds of being awake at night 1.5–4.1 higher odds of feeling sleepy during the day 1.5–2.3 higher odds not having enough sleep 1.5–2.3 than did patients not bothered by pruritus, p < 0.001 for all.
Pisoni et al. [15] USA	Cross-sectional	Moderate	13,300 patients (from DOPPS I and II)	9,610 (72.3%) with pruritus. Group somewhat or no pruritus: Mean age: 60.3 ± 14.64 y Gender: 56.4% men Group moderate to extreme pruritus: Mean age: 60.7 ± 14.49 y Gender: 60.3% men Pruritus in last 4 weeks: Not at all bothered: 3,690 (27.7%) Somewhat: 3,873 (29.2%) Moderately: 2,405 (18.1%) Very much: 1,919 (14.4%) Extremely bothered: 1,413 (10.6%)	SF-12, SF-36 Sleep disturbance: 45% in the moderate to extreme pruritus group 29% in the somewhat or no pruritus group	Patients with moderate to severe pruritus had a 13% higher mortality risk (p = 0.01) compared with patients not bothered in DOPPS1, 21% in DOPPS2, 17% in DOPPS1 and 2; no longer significant when adjusted for sleep quality. Patients with moderate to extreme pruritus, compared with patients without pruritus, had: 1.4–4.0 higher odds (p < 0.0002) of having sleep disturbance
Sukul et al. [16] USA	Cross-sectional	Moderate	3,780 patients Mean age: 67 ± 13 y Gender: 61% men	907 (24%) at least moderate pruritus, Bothered by pruritus during the last 4 weeks: No pruritus: 1,890 (50%) patients Mild pruritus: 990 (26.2%) Moderate to extreme pruritus: 900 (23.8%)	Restless >3/week: No pruritus: 26% patients Moderate to extreme pruritus: 48% patients	In comparison with patient without pruritus: Restless sleep was higher in patients with moderate pruritus (PR = 1.69, 95%CI: 1.49–1.91; p < 0.05) and extreme pruritus (PR = 2.10, 95%CI: 1.76–2.51; p < 0.05)
Li et al. [19] China	Cross-sectional	Moderate	362 patients Mean age: 49.9 ± 16.7 y Gender: 53.6% men	236 (62.5%) with pruritus Pruritus score (VAS) No pruritus: VAS = 0: 126 (34.8%) patients Mild to moderate: VAS = 1–5: 190 (52.5%) patients Severe: VAS > 6: 46 (12.7%) patients	Sleep score (PSQI); mean value: 9.4 ± 4.1 points	Pruritus was linked with: PSQI (OR = 1.305, p = 0.001) Patients with severe pruritus had the highest PSQI score (12.3 ± 5.6 with pruritus vs. 7.7 ± 5.6 points without pruritus, p < 0.001) Pruritus is an independent predictor for sleep disorder after adjustment for age and sex (OR = 1.653, p < 0.01)
Areste-Fosalba et al. [44] Spain	Cross-sectional	Moderate	1,605 (92% MHD, 5% PD, 3% non-dialysis) patients Age, gender: nm	810 (50.5%) with pruritus; 428 (26.7%): moderate-to-severe pruritus Pruritus score: Short survey questionnaire	Short survey questionnaire, value nm	Pruritus is very prevalent in advanced CDK patients and was linked with affecting sleep (value nm).
Awosan et al. [45] Nigeria	Cross-sectional	Moderate	124 patients Mean age: 46.7 ± 14.9 y Gender: 98 (79%) men	20 (16.1%) with pruritus Pruritus scale: nm	Proforma Sleep deprivation on 55 (44.4%) of patient	Pruritus more prevalent in subjects with sleep disturbance compared to those without (30.9% vs. 4.3%; p < 0.001)
Wikström et al. [21] Sweden	Retrospective observational	Low	7,151 patients Pruritus score, age, gender: nm	2,932 (41%) with moderate to extreme pruritus	Self-reported survey = ‘poor sleep quality’	When compared with patients with no/mild pruritus, patient with moderate to extreme pruritus had: Poorer sleep quality (aORs = 1.24–2.17, p < 0.001) 1.9–3.7 times higher of poor sleep quality, (p < 0.0001)
Kimata et al. [22] Japan	Retrospective observational	Low	6,480 patients from 3 phases studies (JDOPPS 1, 2, and 2) Gender, age: nm	4,120 (63.5%) patients with pruritus Moderately to extremely bothered by pruritus in the past 4 weeks: 2,851 (44%) patients	10-point (very bad to very good) or a 4-point (very bad, fairly bad, fairly good, very good) scale Values: nm	Patients with moderate to extreme pruritus had a 37% higher mortality rate (p = 0.03) compared with patients not bothered by pruritus in JDOPPS3, 5–18% in JDOPPS1 and 22% in JDOPPS in all phases combined; even after adjusting for sleep quality (for JDOPPS 1 and 3)
Narita et al. [23] Japan	Retrospective observational	Low	1,773 patients Mean age: 60.2 ± 12.8 y Gender: 58.9% men	1,292 (72.9%) with pruritus Pruritus score: VAS: Mild pruritus: VAS < 4: 826 (46.6%) patients Moderate: 4 < VAS < 7: 494 (27.8%) patients Severe: VAS > 7: 453 (25.6%) patients	Questionnaire (1,148 patients)	>70% of patients with severe pruritus complained sleep disturbance (vs. no sleep disturbance in the other groups): No sleep disturbance: 592 (51.57%) patients, 79.49% with mild pruritus, 28.11% with extreme Waking up less than a few times a night: 322 (28.05%), 19.23% with mild, 30.88% with extreme Waking up more than a few times a night: 156 (13.59%), 1.28% with mild, 25.34% with extreme Sleeplessness: 78 (6.79%), 0% with mild, 15.67% with extreme p < 0.001, χ² = 254.974
Plewig et al. [28] Germany	Retrospective observational	Low	104 patients Mean age: 60.8 ± 13.3 y Gender: 54.8% men	Pruritus score (VAS) between 2013 and 2017: 52 (50%) with persistent pruritus 52 (50%) with no more pruritus Mean VAS: 4.1 ± 2.2 points	Self-reported survey	Hour or sleep (p = 0.04): Persistent CP: 5.5 ± 1.3 h No more CP: 6.4 ± 1.3h Trouble falling asleep: Persistent CP: 80.8% No more CP: 62% Wake up > 1x/night: Persistent CP: 86.5% No more CP: 70% Patients with non-persistent CP: less likely (p < 0.04) to suffer from sleep disturbances.
Sukul et al. [36] USA	Retrospective observational	Low	7,976 patients Mean age, gender: nm	4,036 (50.6%) with pruritus Comparison on pruritus status between a year interval in same patient: Not bothered by itchy skin during year 1 (Y1) and 2 (Y2) (no/no): 3,940 (49%) patients At least bothered during Y1 (yes/no): 1,137 (14%) patients At least bothered during Y2 (no/yes): 1,330 (16%) patients At least bothered by itchy skin during Y1 and Y2 (yes/yes): 1,769 (21%) patients	Feeling sleep was restless during last week ≥3/week = poor sleep quality	Sleep disturbance had: Increased from 38% to 48% in the no/yes group Decreased from 48% to 40% in the yes/no group No change between year 1 and 2 in the no/no and yes/yes groups
Alchi et al. [47] UK	Retrospective observational	Low	131 patients Age, gender: nm	82 (62.6%) with pruritus Pruritus category: VAS VAS < 4 points = mild: 44 patients (53.7%) 4 < VAS < 7 = moderate: 28 (34.1%) VAS > 7 = severe: 10 (12.2%)	Questionnaire nm, score nm	Intensity of itching correlated with sleep disturbance (p < 0.0001)
Hu et al. [46] China	Retrospective observational	Low	382 patients (138 HD patients 41 PD patients, 203 CKD with no dialysis) Gender: nm	Pruritus score: VAS Mean value = 3.21 ± 1.73 No pruritus group: 185 patients (48.4%) Mean age = 50.92 ± 16.19 y Pruritus group: 197 (51.6%) patients Mean age = 52.26 ± 14.86 y	Questionnaire nm	Sleep quality: no difference between CP and no CP group, (χ² = 4.472; p = 0.593)

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Strength of evidence is classified as high, moderate, and low according to the design of the studies.

A total of 14/15 studies found a relationship between pruritus and sleep [11,14–16,21–23,28,33,36,44,45,47], but one did not [46].

Pruritus affected sleep quality in dialysis patients [44]. Patients with non-persistent CKD-aP had significantly less sleep disturbance than those with persistent pruritus (p < 0.04) [28]. Sukul et al. described that 32.1% of the 22,464 patients included in their observational study were poor sleepers [11]. This rate rose more than 70% of MHD patients with severe pruritus experiencing sleep disturbances in a longitudinal study [23]. Similar findings showed an increased risk of poor sleep quality in MHD patients with moderate to severe pruritus, with risks 1.9–3.7 times higher (p < 0.0001), 1.5–4.1 times higher, and 1.4–4.0 times higher (p > 0.001) [14,15,22]. Similar results were given in a retrospective study (aOR = 1.24–2.17, p < 0.001) [21].

The association between pruritus and sleep deprivation in dialysis patients was confirmed (30.9% vs. 4.3%, p < 0.001) [45]. Poor sleep quality included waking at night, insufficient sleep, and daytime sleepiness. MHD patients with severe pruritus had more severe insomnia (aOR = 8.8; 95%CI: 3.24–23.91) [33]. A strong association between sleep disturbance and pruritus intensity in MHD patients was shown (p < 0.0001), while PD patients with severe pruritus had worse Pittsburgh Sleep Quality Index (PSQI) scores than those without pruritus (p < 0.001) [19,47].

In a two-year longitudinal study, MHD patients who developed pruritus in the second year had an increase in sleep disturbances (38–48%), while those who no longer had pruritus saw a decrease (48–40%). Sleep disturbance rates remained stable if pruritus status did not change [36].

Among non-dialysis CKD patients, those with pruritus had significantly more restless sleep: PR of 1.69 (95%CI: 1.49–1.91) for moderate pruritus and 2.10 (95%CI: 1.76–2.51) for extreme pruritus [16].

The absence of association between pruritus and sleep quality in CKD patients was found in an only study [46].

CKD-aP and biological markers – 11 articles (Table 5)

Table 5.

Characteristics of the articles included concerning ‘Biological markers’ item.

References Location	Study design	Strength of evidence	Population	Pruritus characteristics	Biological markers data
Afsar and Elsurer [30] Turkey	Prospective observational	High	75 patients Mean age: 51.9 ± 13.5 y Gender: 54.6% men	Number of patients with pruritus: nm Pruritus score: VAS Mean 3.7 ± 2.4 points	VAS pruritus score associated with: Calcium–phosphorus product; (95%CI: 0.062–0.116), p = 0.015 iPTH (95%CI: 0.001–0.011), p = 0.041 HbA1c (95%CI: 0.062–0.721), p = 0.022 Pruritus and HbA1c: Independently related with each other (r: +0.602, p = 0.001)
Sukul et al. [11] USA	Prospective observational	High	23,264 patients Gender: 62% men	15,599 (67%) with pruritus During the past 4 weeks, to what extent were you bothered by itchy skin: Not at all: 7,665 (33%) patients Mean age: 63.6 ± 14.7 y Somewhat: 7,009 (30%) Mean age: 63.2 ± 14.4 y Moderately: 4,258 (18%) Mean age: 64.5 ± 14.4 y Very much: 2,711 (12%) Mean age: 64.7 ± 14.4 y Extremely: 1,621 (7%) Mean age: 64.7 ± 14.4 y	Patients extremely bothered by pruritus vs. not at all had (p > 0.05): Higher serum phosphorus levels Lower hemoglobin and serum albumin levels
Sukul et al. [13] USA	Prospective observational	High	25,916 patients Values, age, gender: nm	9,589 (37%) at least moderate bothered by pruritus Pruritus scale: During the past 4 weeks, how were you bothered by itchy skin? Not at all/somewhat/moderately/very much/extremely	Groups with more severe pruritus had lower hemoglobin and albumin level, p < 0.05.
Chen et al. [32] USA	Prospective observational	High	321 patients Mean age: 60 ± 12 y Gender: 49.25% men	203 (63.2%) with pruritus Pruritus score: VAS Absence: VAS = 0: 118 (36.8%) patients Mild: VAS 1–3: 76 (23.7%) Moderate: VAS 4–7: 89 (27.7%) Severe: VAS 8–10: 38 (11.8%)	Patients with moderate/severe pruritus and higher hs-CRP levels had worse overall survival, p < 0.05. Patients with moderate/severe pruritus had lower albumin (p = 0.036) and iPTH (p = 0.038) and higher hs-CRP (p = 0.001) than those with no/mild pruritus.
Tayebeh et al. [33] Iran	Prospective observational	High	416 patients Age, gender: nm	158 (38%) with moderate to extreme pruritus (details not shown)	Severe to extreme pruritus associated with Hyperphosphatemia (aOR = 1.34; 95%CI: 1.06–1.70), p = 0.01 Anemia (aOR = 1.27; 95%CI: 1.04–1.56), p = 0.02
Weisshaar et al. [17] Germany	Cross-sectional	Moderate	860 patients Mean age: 67 ± 13.4 y Gender: 57.2% men	217 (25.2%) with pruritus Pruritus score: VAS Values: nm	Weak statistically significant differences in: PTH (376 ng/L ± 380.2 vs. 289.9 ng/L ± 392.4) Creatinine (8.9 mg/dL vs. 7.8 mg/dL) Phosphorus level (1.0 mmol/L ± 0.6 vs. 1.7 mmol/L ± 0.5) p < 0.004 for all of them, which were higher in HD patients suffering from CP. No association with CP: Any other laboratory values, hyperparathyroidism
Asghar et al. [18] Pakistan	Cross-sectional	Moderate	135 patients, 50 (37%) with pruritus Mean age: 56.29 ± 10.51 y Gender: 56.3% men	Number of patients with pruritus: nm Pruritus scale: Validated for CKD patient (nm)	Independent factor associated with pruritus: Phosphate >4.5 mg/dL (aOR = 3.889 95%CI: 1.118–15.532), p = 0.033 Albumin <3.5 g/dL (aOR = 2.987, 95%CI: 1.156–7.716), p = 0.024 Potassium >5.1 mEq/L (aOR = 2.934, 95%CI: 1.030–8.355), p = 0.044 No significant association with hypocalcemia, hyperparathyroidism, serum urea, or creatinine.
Li et al. [19] China	Cross-sectional	Moderate	362 patients Mean age: 49.9 ± 16.7 y Gender: 53.6% men	236 (62.5%) with pruritus Pruritus score: VAS No pruritus: VAS = 0: 126 (34.8%) patients Mild to moderate: VAS = 1–5: 190 (52.5%) patients Severe: VAS > 6: 46 (12.7%) patients	Pruritus was linked with: iPTH level (OR = 1.317, 95%CI: 1.10–1.83), p = 0.014 Patients with severe pruritus had and higher iPTH level (327.7 pg/L (126.4, 610)). Patients with mild to moderate had higher iPTH level compared to patients with no pruritus (255.1 pg/L (130.6, 535.3) vs. 215.8 pg/L (113.2, 353.4); 95%CI: 1.10–1.83, p = 0.004)
Ozen et al. [25] Turkey	Retrospective observational	Low	249 patients Patients with no pruritus: Mean age: 62.46 ± 14.31 y Gender: 65 (56%) men	134 (53.4%) with pruritus Mean age: 62.54 ± 12.77 y Gender: 72 (54.1%) men Pruritus score: VAS: Mild: VAS < 4; 4 (3%) patients Moderate: 4 < VAS < 7; 67 (50.4%) Severe: 7 < VAS < 9; 50 (36.8%) Very severe: VAS > 9; 13 (9.8%)	WBC counts ≥6.7 × 10³/μL: more common in the group with pruritus (χ² = 3.883, p = 0.049) than without pruritus.
Alchi et al. [47] UK	Retrospective observational	Low	131 patients Age, gender: nm	82 (62.6%) with pruritus Pruritus category: VAS: VAS < 4 points = mild: 44 patients (53.7%) 4 < VAS < 7 = moderate: 28 (34.1%) VAS > 7 = severe: 10 (12.2%)	Correlation between higher serum urea and lower vitamin B12 levels and with presence (p < 0.01 and p < 0.01, respectively) and intensity (p < 0.01 and p < 0.05, respectively) of pruritus.
Hu et al. [46] China	Retrospective observational	Low	382 patients (138 HD patients, 41 PD patients, 203 CKD with no dialysis) Gender: nm No pruritus group: 185 patients (48.4%), Mean age = 50.92 ± 16.19 y	Pruritus score: VAS Mean value = 3.21 ± 1.73 Pruritus group: 197 (51.6%) patients, Mean age = 52.26 ± 14.86 y	CP patient had worse blood test compared with those with no CP: Serum urea nitrogen: CP HD patient: 25.35 mmol/L ± 11.45 vs. 19.08 ± 10.67 in no CP HD group, p < 0.001 CP CKD group: 21.24 ± 10.68 vs. 17.67 ± 11.65 in no CP CKD group, p = 0.015 Creatinine: HD CP group: 793.63 μmol ± 403.36 vs. 570.97 ± 354.75 in no CP HD group CP CKD group: 548.92 ± 347.83 vs. 396.92 ± 215.54 no CP CKD group, p < 0.001 Blood calcium: HD CP group: 1.98 ± 0.32 mmol/L vs. 2.09 ± 0.21 in no CP HD group, p = 0.003 Serum phosphorus: HD CP group: 1.97 mmol/L ± 0.57 vs. 1.65 ± 0.67 mmol/L in no CP HD group, p < 0.001 Calcium × phosphorus product: HD CP group: 3.83 ± 1.68 vs. 3.36 ± 1.46 in no CP HD group, p = 0.037 PTH: HD CP group: 608.15 ± 514.44 pg/mL vs. 243.46 ± 206.55 in no CP HD group, p < 0.001 CKD CP group: 447.61 ± 4,115.76 pg/mL vs. 236.26 ± 203.11 in no CP CKD group Pruritus intensity: not correlated with serum calcium level (p > 0.05)

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Strength of evidence is classified as high, moderate, and low according to the design of the studies.

A retrospective study of CKD and HD patients found that those with pruritus had worse biological parameters, including higher serum urea, creatinine, serum phosphorus, and iPTH levels (p < 0.05), as well as lower blood calcium levels compared to CKD patients without pruritus (p < 0.05). Pruritus intensity correlated with all these parameters except serum calcium [46].

Albumin <3.5 g/dL (aOR = 2.987; 95%CI: 1.156–7.716; p = 0.024), phosphate >4.5 mg/dL (aOR = 3.889; 95%CI: 1.118–15.532; p = 0.033), and potassium >5.1 mEq/L (aOR = 2.934; 95%CI: 1.030–8.355; p = 0.044) were significantly associated with pruritus in MHD patients. However, no association was found with hyperparathyroidism, hypocalcemia, creatinine, urea, or dialysis frequency [18].

Afsar and Elsurer showed that CKD patients with pruritus had higher calcium–phosphorus ratios (+0.624, 95%CI: 0.041–0.092, p < 0.0001), iPTH levels (+0.389, 95%CI: 0.002–0.006, p < 0.0001), and glycated hemoglobin (HbA1c) levels (+0.285, 95%CI: 0.024–0.547, p = 0.033) [30]. They also demonstrated that VAS score was significantly correlated with blood glucose (r = +0.271, p = 0.019), serum calcium (r = +0.534, p < 0.0001), serum phosphorus (r = +0.521, p < 0.0001), calcium–phosphate product (r = +0.609, p < 0.0001), iPTH (r = +0.422, p < 0.0001) and HbA1c (r = +0.602, p < 0.0001) [30].

Higher iPTH level was statistically associated with pruritus in a cross-sectional study of CKD patients undergoing PD with severe pruritus (OR = 1.317; 95%CI: 1.10–1.83, p = 0.014) [19]. Weisshaar et al. found higher PTH levels in MHD patients with pruritus (376 ng/L ± 380.2 vs. 289.9 ng/L ± 392.4, p < 0.004), along with significantly higher creatinine (8.9 mg/dL vs. 7.8 mg/dL) and phosphorus (1.0 mmol/L ± 0.6 vs. 1.7 mmol/L ± 0.5; p < 0.004 for both) [17]. However, no association was found between pruritus and anemia, hyperparathyroidism, or dialysis membrane type.

An observational study linked higher serum urea to the presence and intensity of pruritus in 131 MHD patients (p < 0.01 for both) and also to lower vitamin B12 levels (p < 0.01 and p < 0.05, respectively) [47].

Higher levels of hs-CRP and lower levels of iPTH (p = 0.038) and albumin (p = 0.036) were observed in MHD patients with moderate/severe pruritus compared to those with no/mild pruritus [32]. Lower albumin levels were also noted in patients with severe pruritus in four studies, significant in three [13,18,32], not significant for the other [11].

Severe to extreme pruritus was independently and significantly associated with hyperphosphatemia (aOR = 1.34; 95%CI: 1.06–1.70) and anemia (aOR = 1.27; 95%CI: 1.04–1.56) in an observational study of CKD patients undergoing HD [33].

Higher white blood cell count was significantly associated with pruritus in MHD patients (p = 0.049) [25].

CKD-aP and hospitalization/health cost – six articles (Table 6)

Table 6.

Characteristics of the articles included concerning ‘Hospitalization/Health costs’ item.

References Location	Study design	Strength of evidence	Population	Pruritus characteristics	Hospitalization/health costs data
Sukul et al. [11] USA	Prospective observational	High	23,264 patients Gender: 62% men	15,599 (67%) with pruritus During the past 4 weeks, to what extent were you bothered by itchy skin: Not at all: 7,665 (33%) patients Mean age: 63.6 ± 14.7 y Somewhat: 7,009 (30%) Mean age: 63.2 ± 14.4 y Moderately: 4,258 (18%) Mean age: 64.5 ± 14.4 y Very much: 2,711 (12%) Mean age: 64.7 ± 14.4 y Extremely: 1,621 (7%) Mean age: 64.7 ± 14.4 y	Patients extremely bothered by pruritus vs. not at all had: A higher rate of hospitalization for confusion or mental status: HR = 1.84, 95%CI: 1.18–2.87, p < 0.05
Ramakrishnan et al. [48] USA	Retrospective observational	Low	1,387 patients Age, gender: nm	Number with CP: nm Pruritus score: KDQOL itchiness	Risk factor: patients extremely bothered had more hospitalization vs. those not bothered by pruritus (42.5% vs. 28.4%) Patients extremely bothered by pruritus, when compared with those without pruritus, had higher overall health care cost: $33,755 vs. $26,933 for itchiness; $29,801 vs. $26,321 for dryness; and $29,249 vs. $26,736 for combined itchiness and dryness.
Ramakrishnan et al. [20] USA	Retrospective observational	Low	70,500 patients	42,300 (60%) with CP Pruritus score: KDQOL: Not at all bothered by CP: 28,073 (39.8%) patients, Mean age: 60.34 y Gender: 44.82% men Somewhat bothered: 21,320 (30.2%), Mean age: 60.11 y Gender: 44.07% men Moderately: 10,869 (15.4%) Mean age: 60 y Gender: 43.44% men Very much: 6,521 (9.3%) Mean age: 59.58 y Gender: 47.22% men Extremely: 3,717 (5.3%) Mean age: 58.51 y Gender: 49.96% men	From the lowest to the highest itchiness severity category, increasing trend in: Skipping HD session (56.16–63.23%, p value not shown) AB (4.1–20.7%, p < 0.05) EPO dose (55,653.03 units to 66,212.51 units p = 0.0001) Intravenous iron sucrose use (257.84 units to 262.55 units, p < 0.0001).
Narita et al. [23] Japan	Retrospective observational	Low	1,773 patients Mean age: 60.2 ± 12.8 y Gender: 58.9% men	1,292 (72.9%) with pruritus Pruritus score: VAS: Mild pruritus: VAS < 4: 826 (46.6%) patients Moderate: 4 < VAS < 7: 494 (27.8%) patients Severe: VAS > 7: 453 (25.6%) patients	The use of anti-pruritic treatment: correlated with the stratified intensity of pruritus (p < 0.001) for using anti-H1, anti-pruritic lotion and sedative. EPO use: significantly higher in the group with mild pruritus (p = 0.0105).
Ting et al. [26] Taiwan	Retrospective observational	Low	44,280 patients, repartition HD/PD: nm 29,520 (65%) without CP Mean age: 60.4 ± 14.2 y Gender: 50% men	14,760 (35%) with pruritus Pruritus yes/no: Based on anti-H1 prescription with no other indication 14,760 (35%) with pruritus Mean age: 62.7 ± 13.2 y	CP was linked with: Infection-related hospitalization (HR = 1.18, 95%CI: 1.16–1.21), p < 0.05 Patients with moderate to extreme pruritus use (p < 0.001): 2.1 times more antihistamines 1.5 times more hypnotics 1.2 times more benzodiazepines 1.5 times more antidepressants
Alchi et al. [47] UK	Retrospective observational	Low	131 patients Age, gender: nm	82 (62.6%) with pruritus Pruritus category: VAS: VAS < 4 points = mild: 44 patients (53.7%) 4 < VAS < 7 = moderate: 28 (34.1%) VAS > 7 = severe: 10 (12.2%)	Intensity of itching correlated with use of antidepressants (p < 0.05) AD treatment: more common in patients with pruritus (p < 0.05) Patients with pruritus used more antidepressants (p < 0.05)

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Strength of evidence is classified as high, moderate, and low according to the design of the studies.

The six articles that examined the relationship between pruritus and healthcare costs found an increase in the latter in case of pruritus [11,20,23,26,47,48].

A higher rate of hospitalization was observed in HD patients with severe pruritus compared to those without pruritus (42.5% vs. 28.4%), resulting in higher total healthcare costs for patients with severe pruritus ($33,755 vs. $26,933 for itch; $29,801 vs. $26,321 for dryness; and $29,249 vs. $26,736 for combined itch and dryness) [48]. MHD patients with severe pruritus were more likely to be hospitalized for psychiatric conditions such as altered mental status or confusion (HR = 1.84; 95%CI: 1.18–2.87) [11].

Four studies have highlighted the increased use of medication in MHD patients with pruritus. Thus, the intensity of pruritus was strongly correlated with the use of any type of antipruritic treatment (p < 0.001 for the use of antihistamines, antipruritic lotions, and sedatives), between the three groups of pruritus (mild, moderate, and severe) and between severe pruritus and the others [23]. The subgroup of MHD patients with mild pruritus used erythropoietin (EPO) more frequently than the other groups (p = 0.0105) [23]. In an observational prospective study on 70,500 patients, Ramakrishnan et al. described higher use of EPO doses (55,653.03 vs. 66,212.51 EPO units, p < 0.0001) and intravenous iron injections (257.84 units vs. 262.55 units, p < 0.0001) in patients with severe pruritus [20]. The use of antibiotics increased with the severity of pruritus (4.1% in patients with no pruritus to 20.7% in patients with severe pruritus, p < 0.05) [20]. MHD patients with moderate to extreme pruritus were 2.1 times more likely to use antihistamines, 1.5 times more likely to use hypnotics, 1.2 times more likely to use benzodiazepines, and 1.5 times more likely to use antidepressants (p < 0.001) [26]. The higher use of antidepressants in MHD patients with pruritus (p < 0.05) compared to those without pruritus was also reported [47].

Discussion

The primary objective of this study was to perform a meta-analysis. However, a minimum of five studies using comparable statistical methods, reporting the same outcomes, and involving similar populations is required to achieve a sufficiently powered analysis. Due to substantial heterogeneity in study design (prospective, retrospective, cross-sectional), data availability, and outcome assessment tools – particularly those used for pruritus (VAS, KDQOL, CKDopps, etc.) a formal meta-analysis was not feasible. Consequently, we conducted a narrative systematic review.

Our review of 37 studies consistently demonstrated that pruritus in CKD patients is associated with higher mortality, cardiovascular events, and increased healthcare costs. Beyond its psychosocial impact and reduction in quality of life, pruritus contributes to comorbidity, disease progression, and mortality, as highlighted by Molina et al. [49]. Specifically, pruritus was found to be linked with altered biological markers, higher risk of depression, sleep disturbance, increased healthcare utilization, and poorer survival outcomes.

Several studies also reported a significant association between pruritus and cardiovascular events. This relationship has been hypothesized to arise from systemic inflammation, as suggested by elevated hs-CRP levels, lower serum albumin and higher WBC counts in affected patients. CRP is considered to be the most reliable inflammatory marker in HD patients, it is quite surprising that its assay was only reported in one study [32].

Biological correlates of pruritus in CKD included elevated iPTH, creatinine, phosphorus, and urea in most studies, although some conflicting findings emerged. For example, one study reported lower iPTH levels [32], while others observed increased levels. The authors explain that high CRP reflects chronic inflammation, which could lead to metabolic disorders and/or parathyroid dysfunction, causing this decrease in iPTH. Furthermore, reduced calcium or albumin associated with iPTH variation may explain the higher frequency of osteoporosis in pruritic CKD patients [28]. These associations were confirmed in both non-dialysis CKD and HD populations [48,49]. Additional comorbidities, including infections and diabetes, were also more prevalent among patients with pruritus in both CKD and liver disease. However, for diabetes mellitus, despite the overall consistency of results, two studies reported conflicting findings. For instance, Weisshaar et al. did not confirm significant differences between patients with and without pruritus in congestive heart failure and peripheral vascular disease, and even reported fewer cases of diabetes in the CKD-aP group, contrary to most other studies [17]. Since pruritus is frequently reported in diabetes mellitus independently of CKD [50], these discrepancies may reflect small cohort sizes and study-specific limitations. Similarly, Asghar et al. [18] failed to demonstrate an association between pruritus and diabetes, likely due to insufficient statistical power.

Survival outcomes were extensively investigated: 16 studies assessed mortality in renal failure, and all but one found a positive association with pruritus. However, this association was attenuated after adjusting for sleep disorders in five studies, suggesting that insomnia may partially mediate the observed mortality risk. More broadly, inflammation and comorbidities appear to be key mediators, explaining the increased all-cause and cardiovascular mortality in pruritic patients. Reinforcing this evidence, two additional studies published after the inclusion period also confirmed an association between pruritus, mortality, cardiovascular events, and hospitalizations [51,52]. Furthermore, two studies linked pruritus to missed HD sessions, a factor independently associated with increased mortality [17,29].

Pruritus also has a profound psychosocial impact. In CKD patients, it is consistently associated with depression, anxiety, sleep disturbance, and impaired sexual function [44]. These complications not only worsen patients’ daily functioning but also contribute indirectly to increased morbidity and mortality. Additionally, they drive healthcare utilization: several studies showed nearly doubled healthcare costs per patient, due to higher medication use, longer hospital stays, and more psychiatric admissions. This finding was confirmed by an observational study published in June 2023, which demonstrated an association between pruritus, increased drug prescriptions, and higher hospitalization rates [53].

Based on the data from the various articles, we can put forward a ‘Strength of evidence’ for the various items described, summarized in Table 7. Across CKD populations, pruritus consistently appears as a clinically meaningful indicator rather than an isolated symptom. Several domains show robust and convergent evidence relationships. Concerning mortality, moderate to severe pruritus is associated with higher all-cause and cardiovascular mortality, with HRs around 1.1–1.9. The association often weakens after adjustment for sleep, suggesting partial mediation by sleep disturbance. Still, severe pruritus repeatedly emerges as a risk marker. Concerning comorbidities, patients with more severe pruritus tend to have a greater comorbidity burden, including more diabetes, cardiovascular disease, liver disease, and infections, as well as lower PCS scores. Although some comorbidities show variability across cohorts, the overall pattern suggests a more complex clinical profile in pruritic patients. About biological markers, repeated associations link pruritus with mineral metabolism disorders (increased phosphate, calcium–phosphorus, and iPTH), inflammation (hs-CRP increased), and poorer nutritional status (decrease of albumin and hemoglobin). Several abnormalities remain independent predictors, supporting a biologically plausible aspect. Concerning mental health and QoL, evidence is particularly strong for psychological impact. Pruritus severity correlates with higher rates of depression, anxiety, emotional exhaustion, and significantly lower MCS. Dose–response patterns are observed across multiple validated scales, and pruritus frequently acts as an independent predictor. Sleep impairment shows the strongest and most consistent association. Moderate to severe pruritus increases insomnia and nocturnal awakenings by 1.4–4 times, with severe forms affecting >70% of patients. Pruritus remains an independent determinant of poor sleep, reinforcing its clinical significance. Finally, concerning health costs, pruritic patients experience more hospitalizations, especially for confusion or infections, and require more medications (antihistamines, hypnotics, benzodiazepines, and antidepressants). Higher treatment burden translates into increased healthcare costs. Overall, together, these findings show that pruritus reflects a broader burden of disease in CKD – biological, clinical, psychological, and economic. Its systematic assessment can help nephrologists identify patients at higher risk and guide more comprehensive management.

Table 7.

Strength of evidence on CKD-associated pruritus.

Domain	Strength of association	Key findings	Level of evidence
Comorbidities	Frequent and coherent associations (CV, diabetes, infections)	↑ Cardiovascular disease, diabetes, septicemia ↓ PCS CKD progression	Moderate
Mortality	Reproducible effects, stronger in moderate/severe pruritus	HR ∼1.1–1.9; attenuated when adjusting for sleep quality	Moderate
Mental health and QoL	Clear dose–response patterns across validated tools	↑ Depression, anxiety, fatigue ↓ MCS OR > 2 for depressive symptoms	Strong
Sleep disturbance	Highly consistent, independent, and strong relationships	1.4–4 higher insomnia risk High PSQI >70% severe sleep disruption	Very strong
Biological markers	Repeated and consistent associations	↑ Phosphorus, ↑ Ca × P, ↑ iPTH, ↑ hs-CRP, ↓ albumin, ↓ hemoglobin several independent predictors	Moderate–strong
Hospitalization and healthcare costs	Consistent increases in service use and complications	↑ Hospitalizations (confusion, infections), ↑ costs, ↑ medication use	Moderate–strong

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CaxP: calcium–phosphorus; CKD: chronic kidney disease; CV: cardiovascular diseases; HR: hazard ratio; hs-CRP: hypersensible C-reactive protein; iPTH: intact parathyroid hormone; MCS: Mental Component Scale; PCS: Physical Component Scale; OR: odds ratio; PSQI: Pittsburgh Sleep Quality Index.

Several biases, found in clinical trials, are also present in these studied publications. First, heterogeneity in study design, populations, and assessment methods complicates comparisons and induces a detection bias. Studies varied in timing of pruritus assessment, which was sometimes performed only at baseline and not longitudinally, preventing causal inference [11,20]. Moreover, variability in measurement methods of pruritus (VAS, KDQOL, ItchyQoL, CKDopps, etc.) further hampers comparability.

Selection bias was also present, with many studies being single-center and involving small sample sizes. Of the 37 studies, 27 concerned HD patients, while only two investigated PD populations, and six did not distinguish between dialysis modalities. Although CKD-aP occurs in both PD and HD patients, prevalence estimates remain contradictory [54,55] limiting generalizability.

Patient attrition due to mortality may have introduced survival bias, as those with more severe pruritus and comorbidities may have been underrepresented in follow-up analyses [14,22,34].

Another limitation relates to the assessment of pruritus itself, which was predominantly self-reported. This approach is prone to recall and misclassification biases, especially when nonspecific quality-of-life tools rather than pruritus-specific scales were used.

Publication bias may also have influenced the available evidence, as studies with negative results are less likely to be published. We also acknowledge that the inclusion of abstracts may be criticized; however, we selected only those in which the association between pruritus and the outcome was explicitly quantified, while acknowledging that some relevant studies may have been missed due to search term limitations.

Conclusions

Despite these limitations, the convergence of findings across multiple studies in diverse settings supports the robustness of the observed associations. Taken together, the evidence strongly suggests that pruritus in CKD is not a benign symptom but a clinically relevant factor contributing to poorer quality of life, increased comorbidities, higher morbidity, increased healthcare utilization, and excess mortality. Dialysis patients may benefit from targeted treatments, including DFK.

These findings highlight the need for nephrologists and dermatologists to assess new therapies for pruritus and its broader health effects.

Supplementary Material

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IRNF_A_2622801_SM9167.docx^{(65KB, docx)}

Supplementary Figure 1_PRISMA_2020_checklist.docx

IRNF_A_2622801_SM9166.docx^{(268.9KB, docx)}

Acknowledgments

JS conceived, collected the data, realized the analysis, and wrote the manuscript; EB and ASF helped with the interpretation and the writing of the manuscript; GR and LM reviewed and edited the manuscript; CLGI helped with the analysis, the project administration and the writing of the original manuscript and the reviewed versions.

Funding Statement

This study was not supported by any sponsor or funder.

Ethics statement

Not applicable.

Disclosure statement

JS, ASF, EB, and CLGI have no conflicts of interest to declare. LM and GR declare conflict with Vifor.

Data availability statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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Associated Data

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

Supplementary Materials

manuscriptfinalcleanversion.docx

IRNF_A_2622801_SM9167.docx^{(65KB, docx)}

Supplementary Figure 1_PRISMA_2020_checklist.docx

IRNF_A_2622801_SM9166.docx^{(268.9KB, docx)}

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

[CIT0001] 1.Misery L, Ständer S, editors. Pruritus. Cham: Springer International Publishing; 2016. [Google Scholar]

[CIT0002] 2.Ständer S. Classification of itch. Curr Probl Dermatol. 2016;50:1–4. doi: 10.1159/000446009. [DOI] [PubMed] [Google Scholar]

[CIT0003] 3.Kini SP, DeLong LK, Veledar E, et al. The impact of pruritus on quality of life: the skin equivalent of pain. Arch Dermatol. 2011;147(10):1153–1156. doi: 10.1001/archdermatol.2011.178. [DOI] [PubMed] [Google Scholar]

[CIT0004] 4.Boyard A, Misery L.. Comparison of the burden of pruritus and pain: analysis of survey data from 4018 subjects. J Eur Acad Dermatol Venereol. 2024;38(11):e1007–e1009. doi: 10.1111/jdv.20100. [DOI] [PubMed] [Google Scholar]

[CIT0005] 5.Spindler M, Przybyłowicz K, Hawro M, et al. Sleep disturbance in adult dermatologic patients: a cross-sectional study on prevalence, burden, and associated factors. J Am Acad Dermatol. 2021;85(4):910–922. doi: 10.1016/j.jaad.2021.04.015. [DOI] [PubMed] [Google Scholar]

[CIT0006] 6.Sinikumpu S-P, Jokelainen J, Tasanen K, et al. Association between pruritus and psychosocial well-being: a population-based study among 6,809 subjects. Acta Derm Venereol. 2023;103:adv00837. doi: 10.2340/actadv.v103.2922. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0007] 7.Agarwal P, Garg V, Karagaiah P, et al. Chronic kidney disease-associated pruritus. Toxins. 2021;13(8):527. doi: 10.3390/toxins13080527. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0008] 8.Carmichael AJ, McHugh MI, Martin AM.. Renal itch as an indicator of poor outcome. Lancet. 1991;337(8751):1225–1226. doi: 10.1016/0140-6736(91)92898-c. [DOI] [PubMed] [Google Scholar]

[CIT0009] 9.Topf J, Wooldridge T, McCafferty K, et al. Efficacy of difelikefalin for the treatment of moderate to severe pruritus in hemodialysis patients: pooled analysis of KALM-1 and KALM-2 phase 3 studies. Kidney Med. 2022;4(8):100512. doi: 10.1016/j.xkme.2022.100512. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0010] 10.Xue G, Yuan H, Fan D, et al. Efficacy and safety of difelikefalin in the treatment of hemodialysis patients with pruritus: a meta-analysis and systematic review. Clin Nephrol. 2024;101(4):155–163. PMID: 38294219. doi: 10.5414/CN111169. [DOI] [PubMed] [Google Scholar]

[CIT0011] 11.Sukul N, Karaboyas A, Csomor PA, et al. Self-reported pruritus and clinical, dialysis-related, and patient-reported outcomes in hemodialysis patients. Kidney Med. 2021;3(1):42–53.e1. doi: 10.1016/j.xkme.2020.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Association of pruritus with comorbidities and survival in chronic kidney disease: a narrative review of the pre-difelikefalin era literature

Justine Saucereau

Emilie Brenaut

Anne-Sophie Ficheux

Guy Rostoker

Laurent Misery

Christelle Le Gall-Ianotto

Roles

Abstract

Introduction

Methods

Source and research equation

Selection of studies and data extraction

Ethics statement

Results

Figure 1.

Table 1.

CKD-aP and physical comorbidities – 21 articles (Table 1)

CKD-aP and physical component score (PCS) – seven articles

CKD-aP and comorbidities – 15 articles

CKD-aP and mortality – 18 articles (Table 2)

Table 2.

CKD-aP and psychological comorbidities – 20 articles (Table 3)

Table 3.

CKD-aP and sleep – 15 articles (Table 4)

Table 4.

CKD-aP and biological markers – 11 articles (Table 5)

Table 5.

CKD-aP and hospitalization/health cost – six articles (Table 6)

Table 6.

Discussion

Table 7.

Conclusions

Supplementary Material

Acknowledgments

Funding Statement

Ethics statement

Disclosure statement

Data availability statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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