Abstract
Rationale & Objective
Chronic kidney disease–associated pruritus is commonly related to reduced health-related quality of life, decreased adherence to dialysis, and increased mortality, yet it remains underrecognized and underdiagnosed. We conducted an analysis to characterize the relationship between pruritus and a recognized symptom cluster among hemodialysis patients.
Study Design
This retrospective study of adults receiving hemodialysis in a large US dialysis organization analyzed pruritus and the individual symptoms of sleep disturbance, depression, pain, anxiety, and low energy/fatigue. Data from the Kidney Disease Quality of Life 36-Item Short Form Survey (KDQOL-36) and the Patient Health Questionnaire-2 were extracted from electronic medical records.
Results
Of the 243,168 adults receiving hemodialysis during the study period who completed a KDQOL-36, 47,477 reported at least moderate bother from pruritus. An additional randomly sampled 33,833 adults not reporting at least moderate pruritus were also included. The KDQOL-36 ratings for each symptom (sleep disturbance, depression, pain, anxiety, and low energy/fatigue) exhibited a significantly (P < 0.001) greater burden with increased pruritus severity. Similar results were observed for KDQOL-36 summary scores. Extreme pruritus was associated with greater than 5-fold and 3-fold increased risk of depressive symptoms and sleep disturbance, respectively. Pruritus was also independently associated with Patient Health Questionnaire-2–defined depressive symptoms. The association of pruritus with co-occurring symptoms was demonstrated across all serum phosphorus concentration subgroups. Patients reporting higher degrees of bother from pruritus were significantly more likely to miss multiple hemodialysis sessions or have shortened treatment sessions.
Limitations
The cross-sectional nature of the study limits exploration of temporal relationships between the symptoms.
Conclusions
Among hemodialysis patients, pruritus is commonly reported and associated with reduced health-related quality of life. It should be considered alongside the following symptoms commonly observed: sleep disturbance, depression, pain, anxiety, and low energy/fatigue. The presence of one symptom should prompt further investigation, allowing for appropriate diagnosis and management.
Index Words: Chronic kidney disease, pruritus, hemodialysis, sleep, depression, pain, anxiety, fatigue
Plain-language Summary
This study of adults receiving hemodialysis examined the relationship between pruritus and the individual symptoms of sleep disturbance, depression, pain, anxiety, and low energy/fatigue. Data from the Kidney Disease Quality of Life 36-Item Short Form Survey and the Patient Health Questionnaire-2 were extracted from electronic medical records. The analysis found that the presence of at least moderate patient-reported pruritus was independently associated with depressive symptoms. The risk of sleep disturbance, depressive symptoms, pain, anxiety, and low energy is significantly increased among patients with pruritus. Routine quality-of-life screening is warranted; identification of one symptom should prompt inquiry about other symptoms.
Patients with kidney failure receiving dialysis can experience a broad range of symptoms associated with reduced health-related quality of life (HRQoL), including fatigue, depression, pain, anxiety, restless leg syndrome, cramping, nausea, sleep disturbance, and pruritus.1,2 Reductions in HRQoL have been associated with clinically meaningful increases in morbidity and mortality.3, 4, 5, 6 As such, improving HRQoL is a key goal in the management of patients with kidney failure, a concept exemplified by the 2008 guidance from the Centers for Medicare and Medicaid Services requiring routine assessment of HRQoL in hemodialysis patients.7, 8, 9, 10 More recently, Centers for Medicare and Medicaid Services has required routine screening for depression in this population as part of a quality incentive program.11
Across numerous clinical/therapeutic areas, a pentad of symptoms comprising sleep disturbance, depression, pain, anxiety, and low energy/fatigue often coexist as a symptom cluster.2,12 It has been suggested that chronic kidney disease–associated pruritus (CKD-aP), previously referred to as uremic pruritus, should be incorporated into this symptom cluster, given its frequent co-occurrence with the component symptoms.1,13 CKD-aP can vary in clinical presentation from mild to severe and, similar to components of the existing symptom cluster, has been associated with reduced HRQoL in addition to an increased risk of infection-related hospitalization, reduced adherence to hemodialysis treatments, and decreased survival.13, 14, 15, 16, 17, 18 In a US subset of hemodialysis patients (n = 2,070) in the Dialysis Outcomes and Practice Patterns Study, the prevalence of moderate to severe CKD-aP was 33%.16 In a large European study of more than 6,000 patients across a large dialysis organization, the prevalence of CKD-aP was 47.9%, and moderate to severe disease was identified in 22.6% of patients.19
An ideal HRQoL measure is quick and easy to administer and complete, while maintaining reliability and validity. The Kidney Disease Quality of Life 36-Item Short Form Survey (KDQOL-36; RAND and the University of Arizona) is commonly employed in dialysis centers. Although not diagnostic or ideal for capturing temporal trends in symptomatology, it serves as an important screening tool and provides valuable insights into HRQoL by allowing self-assessment of numerous disease-specific symptoms, including pruritus.10,20,21 The Patient Health Questionnaire-2 (PHQ-2) is an additional tool often used to screen for depression.22 We conducted a cross-sectional, retrospective analysis using scores on both KDQOL-36 and PHQ-2 to characterize the relationship between pruritus and each component of a recognized symptom cluster among hemodialysis patients. The study will inform potential additional investigations into the expansion of the pentad symptom cluster of sleep disturbance, depression, pain, anxiety, and low energy/fatigue.
Methods
Study Design and Population
We extracted deidentified data for adult, in-center hemodialysis patients across the United States with a KDQOL-36 recorded in a 2-year time frame between January 1, 2021, and February 28, 2023. Deidentified data from Fresenius Kidney Care electronic health records were retrieved from the Fresenius Medical Care data warehouse. Based on study definitions and requirements, raw data were extracted to form a study population data set. From this initial study population data set, the remaining raw data elements were extracted for the subset of patients for this study, which were then used to assemble the final analytic data set.
Patients were required to have been receiving hemodialysis for at least 30 days. Those patients receiving difelikefalin (Korsuva; Cara Therapeutics) to treat CKD-aP were excluded from the analysis, and patients receiving other therapies for itch were not excluded because the medications were not approved for the treatment of CKD-aP. Patients answering that they were “moderately,” “very much,” or “extremely” bothered by pruritus over the past 4 weeks (defined as “itchy skin” in KDQOL-36) were included in the analysis. In addition, a random sample of patients reporting that they were “not at all” or “somewhat” bothered by pruritus were included in the analysis to ensure that patients from each itch severity group would be adequately represented in the analysis population. We conducted stratified random sampling for efficiency of the analysis because the majority of patients would answer that the itch bothered them “not at all” or “somewhat,” which would lead to imbalances in the groups. We randomly selected people in each group to represent the experience in those populations. This study was reviewed by an independent review board (WIRB-Copernicus Group Institutional Review Board, #1-1675997-1) and was granted an exempt status determination under the Common Rule and applicable guidance because of its purely observational nature and use of only deidentified data.
Measures, Outcomes, and Statistical Analysis
The primary outcomes of the analysis were prevalence of the components of the sleep disturbance, pain, anxiety, depression, and low energy/fatigue symptom cluster across patient populations with varying levels of self-reported pruritus in KDQOL-36. On KDQOL-36, the symptoms are scored on a scale ranging from 1 (all of the time) to 6 (none of the time) for sleep disturbance, anxiety, and depression evaluations, and also ranging from 1 (not at all) to 5 (extremely) for pain and low energy assessments (Figs S1-S5). Symptom cluster components were analyzed by severity scores and dichotomized (present/absent) categories (Table 1). The KDQOL-36 subscales of Physical Functioning, Mental Functioning, Burden of Kidney Disease, Kidney Disease Symptoms, and Effects of Kidney Disease were calculated and represented secondary outcomes. Additional secondary measures included the number of missed and shortened dialysis treatments in the 30 days before completion of KDQOL-36.
Table 1.
Symptom Outcome Measures Used in the Study
| Symptom | Measure | Question(s) | Scoring | Categorical Criteria |
|---|---|---|---|---|
| Sleep | KDQOL-36 | How much of the time in the past 4 wk have you had a lot of energy? | 1 (all of the time) 2 (most of the time) 3 (a good bit of the time) 4 (some of the time) 5 (none of the time) 6 (none of the time) |
≥3 |
| Pain | KDQOL-36 | During the past 4 wk, how much did pain interfere with your normal work? | 1 (not at all) 2 (a little bit) 3 (moderately) 4 (quite a bit) 5 (extremely) |
≥3 |
| Anxiety | KDQOL-36 | During the past 4 wk, how much of the time have you felt calm and peaceful? | 1 (all of the time) 2 (most of the time) 3 (a good bit of the time) 4 (some of the time) 5 (none of the time) 6 (none of the time) |
≥3 |
| Depression | KDQOL-36 | How much of the time in the past 4 wk have you felt downhearted and blue? | 1 (all of the time) 2 (most of the time) 3 (a good bit of the time) 4 (some of the time) 5 (none of the time) 6 (none of the time) |
≥3 |
| Depression | PHQ-2 | Over the last 2 wk, how often have you been bothered by
|
0 (not at all) 1 (several days) 2 (more than half the days) 3 (nearly every day) |
Total ≥ 3 |
| Exhaustion | KDQOL-36 | During the past 4 wk, how much have you been bothered by being washed out or drained? | 1 (not at all) 2 (somewhat) 3 (moderately) 4 (very much) 5 (extremely) |
≥3 |
Abbreviations: KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey; PHQ-2, Patient Health Questionnaire-2.
For each eligible patient, demographic information (age, sex, race, and ethnicity), vascular access, and dialysis vintage were extracted from electronic medical records. Serum phosphorus levels within 4 weeks of KDQOL-36 assessment were also recorded. Scores on individual KDQOL-36 and PHQ-2 questions were recoded from 5- and 6-point Likert scales to a standard “burden score” to permit analysis (0 = highest burden to 100 = lowest burden). In the dichotomized analysis, symptoms were considered “present” when the burden score was less than 50. Analysis of variance, univariate logistic regression, and multivariable logistic regression were used to estimate the mean scores or odds ratios (ORs) across pruritus severity categories. Because some studies and anecdotal practice patterns suggest a link between hyperphosphatemia and increased pruritus,15,17,23 prespecified subgroup analyses were performed based on serum phosphorus level category (ie, using cutoffs of 4.5, 5.5, 6.5, and 7.5 mg/dL). Statistical analyses were performed using SAS Enterprise Guide 7.1 (SAS Institute Inc).
Results
Patient Characteristics
A total of 243,168 eligible patients received hemodialysis at Fresenius Kidney Care centers and completed KDQOL-36 during the study period. Of those, 47,477 reported that they were at least “moderately bothered by itch” and were included in the analysis. An additional 33,833 patients reporting lesser degrees of pruritus were randomly included in the study, resulting in an analysis population of 81,310 patients. KDQOL-36 data were available for every analyzed patient, and PHQ-2 data were available for 96% (n = 77,978) of the cohort.
Characteristics of the study population are summarized in Table 2. Patients with more extreme pruritus were significantly younger than those patients reporting milder or no pruritus. Extreme pruritus was significantly more common among patients with shorter dialysis vintages, but categorical differences were small. Patients with extreme pruritus were significantly more likely to have vascular access via a central venous catheter than those with milder symptoms.
Table 2.
Patient Characteristics Based on Symptoms of Pruritus
| Characteristic | Extent Bothered by Itching in Last 4 Wk |
Overall P Value | ||||
|---|---|---|---|---|---|---|
| Not at All (n = 16,974) | Somewhat (n = 16,859) | Moderately (n = 23,856) | Very Much (n = 14,972) | Extremely (n = 8,649) | ||
| Mean (SD) age, y | 63 (14) | 62 (14) | 62 (14) | 62 (14) | 60 (14) | <0.001 |
| Mean (SD) vintage, y | 3.4 (4.1) | 3.6 (4.1) | 3.4 (3.9) | 3.3 (3.9) | 3.2 (3.7) | <0.001 |
| Vintage category | <0.001 | |||||
| <90 d | 1,278 (8) | 1,237 (7) | 1,786 (8) | 1,151 (8) | 659 (8) | |
| 90 d to 1 y | 4,648 (27) | 4,300 (26) | 6,503 (27) | 4,212 (28) | 2,445 (28) | |
| >1 y | 11,048 (65) | 11,322 (67) | 15,567 (65) | 9,609 (64) | 5,545 (64) | |
| Sex | <0.001 | |||||
| Male | 10,056 (59) | 9,721 (58) | 13,588 (57) | 7,868 (53) | 4,345 (50) | |
| Female | 6,918 (41) | 7,138 (42) | 10,268 (43) | 7,104 (48) | 4,304 (50) | |
| Race | <0.001 | |||||
| Black | 6,023 (36) | 5,834 (35) | 7,248 (30) | 4,774 (32) | 3,066 (36) | |
| White | 9,597 (57) | 9,525 (57) | 14,345 (60) | 8,830 (59) | 4,789 (55) | |
| Asian | 496 (3) | 639 (4) | 1056 (4) | 613 (4) | 348 (4) | |
| American Indian or Alaska Native | 164 (1) | 179 (1) | 232 (1) | 130 (1) | 70 (0.8) | |
| Native Hawaiian/Pacific Islander | 251 (2) | 270 (2) | 403 (2) | 296 (2) | 157 (2) | |
| Unknown/missing | 443 (3) | 412 (2) | 572 (2) | 329 (2) | 219 (3) | |
| Ethnicity | <0.001 | |||||
| Hispanic/Latino | 3,099 (18) | 2,849 (16.9) | 3,926 (16.5) | 2,510 (16.8) | 1,230 (14) | |
| Non-Hispanic/Latino | 13,405 (79) | 13,574 (80.5) | 19,327 (81) | 12,107 (80.9) | 7,182 (83) | |
| Unknown/missing | 470 (3) | 436 (3) | 603 (2.5) | 355 (2.4) | 237 (3) | |
| Vascular access | <0.001 | |||||
| AVF | 8,517 (50) | 8,481 (50) | 11,559 (49) | 6,991 (47) | 3,854 (45) | |
| AVG | 2,341 (14) | 2,358 (14) | 3,127 (13) | 1,974 (13) | 1,169 (14) | |
| CVC | 5,692 (34) | 5,615 (33) | 8,530 (36) | 5,650 (38) | 3,390 (39) | |
| Missing | 424 (3) | 405 (2) | 640 (3) | 357 (2) | 236 (3) | |
Note: ANOVA and χ2 testing were used to determine statistical significance. Data are presented as n (%) unless otherwise specified.
Abbreviations: ANOVA, analysis of variance; AVF, arteriovenous fistula; AVG, arteriovenous graft; CVC, central venous catheter.
Symptom Cluster Components and Summary Scores Based on Pruritus Intensity
The KDQOL-36 ratings of each of the symptom cluster components exhibited significantly greater levels of burden with increasing pruritus severity (Fig 1A). Across all levels of patient-reported pruritus, sleep scores displayed the greatest burden among the symptoms assessed. In addition to the relation observed with KDQOL-36–assessed depression, patients also demonstrated an increasing burden of depressive symptoms, as assessed using PHQ-2 scores, with increasing pruritic symptoms (Fig 1B).
Figure 1.
Mean KDQOL-36 rating of (A) symptom cluster components and (B) PHQ-2 scores based on itch burden category. KDQOL-36 scores were standardized such that 0 = highest burden and 100 = lowest burden. Overall P < 0.001 for all. ANOVA was used to determine statistical significance. Abbreviations: ANOVA, analysis of variance; KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey; PHQ-2, Patient Health Questionnaire-2.
Using dichotomized definitions of symptom cluster components, the risk of each symptom increased in a stepwise manner with increasing severity of pruritus. The likelihood of depressive symptoms (PHQ-2 score > 3) among patients extremely bothered by pruritus was more than 6 times that reported by patients not at all bothered by pruritus (Fig 2A). Similarly, the risk of sleep disturbance (Fig 2B) and anxiety (Fig 2C) among patients extremely bothered by pruritus was increased approximately 3-fold relative to patients not bothered by pruritus. Compared with patients not bothered by pruritus, the risk of pain and exhaustion among patients extremely bothered by pruritus was increased approximately 4-fold (Fig 2D) and 6-fold (Fig 2E), respectively. Notably, even patients reporting milder levels of pruritus (“somewhat bothered”) exhibited a significantly increased risk of each of the 5 symptom cluster components.
Figure 2.
Association between pruritus category and the presence of (A) depression (PHQ-2 > 3); (B) sleep disturbance (KDQOL-36 ≥ 3; (C) anxiety (KDQOL-36 ≥ 3; (D) pain (KDQOL-36 ≥ 3; and (E) exhaustion (KDQOL-36 ≥ 3). Abbreviations: CI, confidence interval; KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey; OR, odds ratio; PHQ-2, Patient Health Questionnaire-2.
Greater severity of pruritus-associated bother was associated with significantly lower HRQoL across all KDQOL-36 summary scores (Fig 3). Physical functioning scores demonstrated the lowest levels of HRQoL relative to other summary scores (across all pruritus categories) yet exhibited the smallest absolute magnitude of change with increasing pruritus. In contrast, mean Kidney Disease Symptoms summary scores were consistently higher (ie, higher levels of HRQoL) yet exhibited the largest absolute mean changes with increasing pruritus severity.
Figure 3.
Mean KDQOL-36 summary scores based on pruritus category. ANOVA was used to determine statistical significance. Overall P < 0.001 for all. Abbreviations: ANOVA, analysis of variance; HRQoL, health-related quality of life; KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey.
The burden of each component of the predefined symptom cluster increased with increased pruritus severity across all serum phosphorus subgroups analyzed, whether analyzed using mean KDQOL-36 scores (Table S1), PHQ-2 scores (Table S2), or KDQOL-36 summary scores (Table S3).
Associations With Depressive Symptoms
In univariate logistic regression analysis, the presence of pruritus, anxiety, sleep disturbance, pain, and exhaustion was all significantly associated with depressive symptoms, based on KDQOL-36 scores. This association was observed when the analysis considered scaled KDQOL-36 scores (Table S4A) and categorical definitions of symptom presence/absence (Table S4B) were used. The presence of pruritus, anxiety, sleep disturbance, pain, and exhaustion was also associated with symptoms of depression in multivariable analyses. Multivariable models were adjusted with the other symptom scores as covariates; no additional confounders were included in the models. These associations remained evident whether scaled KDQOL-36 scores (Table 3) or categorical definitions (Table 4) were analyzed. Anxiety had the strongest association with depression (OR, 3.99; 95% confidence interval [CI], 3.79-4.21) followed by exhaustion (OR, 2.29; 95% CI, 2.17-2.42), pain (OR, 1.93; 95% CI, 1.83-2.04), pruritus (OR, 1.55; 95% CI, 1.46-1.64), and sleep disturbance (OR, 1.52; 95% CI, 1.41-1.63).
Table 3.
Multivariable Logistic Regression Analysis of Depression and Itch, Anxiety, Sleep Disturbance, Pain, and Exhaustion Using KDQOL-36 Scoring
| Outcome | Symptom | OR (95% CI) | P Value |
|---|---|---|---|
| Depression | Itch | 1.16 (1.14-1.19) | <0.001 |
| Anxiety | 1.64 (1.60-1.67) | <0.001 | |
| Sleep disturbance | 1.19 (1.16-1.22) | <0.001 | |
| Pain | 1.28 (1.25-1.30) | <0.001 | |
| Exhaustion | 1.41 (1.38-1.44) | <0.001 |
Note: Categorical criteria for symptom presence was defined as KDQOL-36 score ≥ 3. Multivariable models were adjusted with the other symptom scores as covariates.
Abbreviations: CI, confidence interval; KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey; OR, odds ratio.
Table 4.
Multivariable Logistic Regression Analysis of Depression and Itch, Anxiety, Sleep Disturbance, Pain, and Exhaustion Using Categorical Definitions
| Outcome | Symptom | OR (95% CI) | P Value |
|---|---|---|---|
| Depression | Itch | 1.55 (1.46-1.64) | <0.001 |
| Anxiety | 3.99 (3.79-4.21) | <0.001 | |
| Sleep disturbance | 1.52 (1.41-1.63) | <0.001 | |
| Pain | 1.93 (1.83-2.04) | <0.001 | |
| Exhaustion | 2.29 (2.17-2.42) | <0.001 |
Note: Categorical criteria for symptom presence was defined as KDQOL-36 score ≥ 3. Multivariable models were adjusted with the other symptom scores as covariates.
Abbreviations: CI, confidence interval; KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey; OR, odds ratio.
Adherence to Dialysis Treatments
In the overall analysis cohort, less than 18% of patients missed 2 or more dialysis sessions in the 30 days preceding completion of KDQOL-36. Among the patients who missed 2 more hemodialysis sessions in the 30-day period before KDQOL-36 completion, significantly more individuals reported extreme pruritus-associated bother compared with no pruritus-associated bother (24.1% vs 15.4%, P < 0.001; Table 5). Increased rates of missed hemodialysis sessions were observed across all pruritus categories. Increased severity of pruritus was also associated with significantly greater rates of shortened treatment sessions.
Table 5.
Adherence to Dialysis Treatments During the 30-D Period Before KDQOL-36 Completion
| Extent Bothered by Itching in Last 4 Wk |
Overall P Value |
|||||
|---|---|---|---|---|---|---|
| Not at All (N = 16,974) | Somewhat (N = 16,859) | Moderately (N = 23,856) | Very Much (N = 14,972) | Extremely (N = 8,649) | ||
| Patients with ≥2 missed treatments, n (%) | 2,607 (15.4) | 2,780 (16.5) | 4,247 (17.8) | 3,063 (20.5) | 2,082 (24.1) | <0.001 |
| Mean no. of missed treatments, among those with ≥2 missed treatments | 3.2 | 3.2 | 3.3 | 3.3 | 3.4 | <0.001 |
| Patients with ≥1 shortened treatment, n (%)a | 13,308 (78.4) | 13,305 (78.9) | 18,852 (79.0) | 12,189 (81.4) | 7,157 (82.8) | <0.001 |
| Mean no. of shortened treatments, among those with shortened treatments | 3.4 | 3.5 | 3.5 | 3.7 | 3.8 | <0.001 |
| Mean % of treatment time achieved | 98.0 | 97.8 | 97.8 | 97.3 | 96.7 | <0.001 |
Note: ANOVA and χ2 testing were used to determine statistical significance.
Abbreviations: ANOVA, analysis of variance; KDQOL-36, Kidney Disease Quality of Life 36-Item Short Form Survey.
Shortened treatment time is a change of at least 1 min.
Discussion
The results of this large retrospective study support the inclusion of CKD-aP within the existing symptom cluster of sleep disturbance, depression, pain, anxiety, and low energy/fatigue for patients receiving hemodialysis. Specifically, there was a strong association between the severity of pruritus reported by in-center hemodialysis patients and the risk of each component of the symptom cluster. Pruritus presenting with extreme bother was associated with a more than 3-fold increase in the risk of depressive symptoms, anxiety, pain, and exhaustion. The presence of pruritus was also independently associated with comorbid depressive symptoms. This study demonstrates the association between CKD-aP and each of the symptoms of the pentad cluster, providing initial data to inform potential further investigations into the expansion of the symptom cluster.
Despite growing evidence demonstrating the association of CKD-aP with adverse outcomes, multiple studies have shown that CKD-aP is underdiagnosed and underreported.24, 25, 26 For instance, in the multicenter study by Lanot et al,27 37.6% of clinicians did not diagnose and/or recognize pruritus among hemodialysis patients with pruritus. Potential reasons for the under-recognition of CKD-aP include low clinical awareness of the disorder and reduced recognition of pruritus as modifiable causes of impaired HRQoL.25 Importantly, the lack of prompts for assessment of pruritus during routine care has also been cited as a contributing factor.25
In the context of prior research, our findings emphasize the importance of asking patients about symptoms they may be experiencing. Assessing the presence of pruritus may help identify individuals at an increased risk of sleep disturbance, depressive symptoms, anxiety, pain, and fatigue. Conversely, hemodialysis patients identifying these other symptoms should be questioned about the presence of pruritus.
Our findings supporting the addition of CKD-aP to the existing symptom cluster that includes sleep disturbance and depression are consistent with prior data. Qualitative interviews have shown that physical function, including sleep, daily activities, social functioning and relationships, and emotional and psychological well-being, can all be negatively affected by CKD-aP.28 In the Dutch RENINE/PROMs registry of nearly 3,000 people receiving dialysis, sleep disturbance and psychological symptoms were significantly more common among patients with CKD-aP versus those without pruritus.29 The co-occurrence of symptoms resulted in lower HRQoL than either symptom alone.29
Although a temporal relationship between symptoms was not assessed in the current analysis, other research has suggested that CKD-aP can precede the onset of sleep disorders, anxiety, and depression.30 Considerable evidence supports the negative impact of CKD-aP leading to interference in sleep quality.23,31,32 A registry study of dialysis patients in Sweden found that those with pruritus were at a greater risk of sleep disorders, anxiety, depression, and hospitalization for severe infections.33 In a cohort of hemodialysis patients, moderate to severe pruritus resulted in a significantly higher adjusted risk of being awake at night and daytime sleepiness than was reported among patients not bothered by pruritus.17 It has also been suggested that the impact of CKD-aP on mortality may be modulated through impacts on sleep quality.17
Assessing HRQoL through the use of patient-reported outcomes is a foundational step in the implementation of patient-centric dialysis care.34 KDQOL-36 includes both generic and disease-specific domains, including a question on pruritus, but numerous CKD-aP–specific measures are available to assess the presence of and change in CKD-aP symptoms.35, 36, 37 The Worst Itching Intensity Numerical Rating Scale is a single-item, self-reported measure that asks patients to “describe the worst itch intensity they experienced over the last 24 hours” on a scale of 0 (no itch) to 10 (worst itch imaginable) and has been validated in CKD-aP.38 Although validated single-item measures such as the Worst Itching Intensity Numerical Rating Scale are easy to use and correlate with generic measures of HRQoL,35,38 unidimensional measures may underestimate the impact of pruritus compared with longer measures that ask about the impact of pruritus on daily activities (eg, the 5-D itch disability domain).39
The totality of evidence highlights the importance of assessing all hemodialysis patients for symptoms and comorbid conditions that can affect HRQoL. Independent of the specific measure used, recognition of bothersome symptoms allows the clinician to take further action—diagnostic and/or therapeutic. Positive findings on screening tools should prompt formal diagnostic assessment and management, as appropriate. Patients should also be encouraged to proactively discuss new or worsening symptomatology with the clinical team. For some causes of reductions in HRQoL, adjustment of the dialysis prescription, access intervention, and/or nutritional changes may be warranted. Given the potential for shared underlying etiologies, it is possible that management of one symptom will result in perceived improvement in others.13 For most of the symptoms examined in the present study, pharmacotherapies that might be prescribed for the general population are frequently not approved by the US Food and Drug Administration for specific use in hemodialysis populations.
The large, real-world population included in this study contributes to the relevance of the findings, but our results should be viewed in the context of several limitations. The Worst Itching Intensity Numerical Rating Scale is the preferred screening tool to assess for CKD-aP across Fresenius Kidney Care sites, and is administered annually to all hemodialysis patients. Given that reductions in HRQoL are dynamic, and that the Worst Itching Intensity Numerical Rating Scale is not administered simultaneously with KDQOL-36 across Fresenius Kidney Care centers, it was deemed necessary to rely on KDQOL-36 for quantification of pruritic symptoms. Because the study was conducted in a large dialysis organization in the United States, it may not be appropriate to generalize the results to other populations. Given the observational nature of the study, causality—including any relationship between HRQoL and missed dialysis sessions—cannot be established. Also, the cross-sectional nature of the data extracted from the medical records makes it impossible to explore the potential temporal relationship between the symptoms examined. Importantly, the measures used in this study are generally intended as screening, not diagnostic, tools. We did not examine diagnostic codes or the electronic medical record to establish formal diagnoses. As such, the presence of depressive symptoms cannot definitively be attributed to depression and the presence of pruritus cannot automatically be attributed to CKD-aP.
In summary, our findings support the addition of pruritus to the existing symptom cluster of sleep disturbance, depression, pain, anxiety, and low energy/fatigue and highlight the importance of using screening tools to assess pruritic symptoms in hemodialysis populations. The presence of pruritus should prompt physicians to inquire about other HRQoL concerns. Similarly, patients with other causes of reduced HRQoL should be screened for pruritus and CKD-aP. Increased understanding of HRQoL status will better equip clinicians to make informed treatment decisions for their patients receiving hemodialysis.
Article Information
Authors’ Full Names and Academic Degrees
Kunal Malhotra, MD, Tejas Desai, MD, Linda H. Ficociello, DSc, Hans-Juergen Arens, PhD, Rachel A. Lasky, MPH, and Michael S. Anger, MD.
Authors’ Contributions
Research conceptualization and study design: MSA, H-JA, TD, LHF, RAL; data analysis: LHF, RAL; data interpretation: MSA, H-JA, TD, LHF, RAL, KM; manuscript preparation and critical review: MSA, H-JA, TD, LHF, RAL, KM; provision of clinical insights: MSA, TD, KM. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.
Support
Vifor Pharma Inc provided funding for the analysis of the data as well as writing and editing services to assist with the preparation of this manuscript.
Financial Disclosure
Michael S. Anger reports ownership interest in Pfizer; research funding from Fresenius; and an advisory or leadership role in Fresenius. Michael S. Anger, Hans-Juergen Arens, Linda H. Ficociello, and Rachel A. Lasky are Fresenius Medical Care employees. Michael S. Anger, Linda H. Ficociello, and Hans-Juergen Arens have ownership interest in Fresenius Medical Care. Hans-Juergen Arens reports ownership interest in Abbott and AbbVie. Tejas Desai reports employment with CSL Vifor. Kunal Malhotra reports roles as an advisor to Calliditas and Fresenius Medical Care and a speaker for CSL Vifor.
Acknowledgments
Medical writing support was provided by Sharon Hwang, MD, MPH, of NorthStar Strategic Consulting LLC.
Data Sharing
The data set used in the presented analyses is not publicly available. The data set was captured from a private electronic medical record system that is restricted for use to authorized employees of Fresenius Medical Care. The data set can be made available upon reasonable request to access the data set, which would require an agreement to be established between Fresenius Medical Care and an external institution of any applicable requester. Requests to access the data set should be directed to Michael S. Anger, MD.
Peer Review
Received February 18, 2025, as a submission to the expedited consideration track with 1 external peer review. Direct editorial input from the Statistical Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form September 23, 2025.
Footnotes
Complete author and article information provided before references.
Figure S1: Association Between Pruritus and Sleep Disturbance.
Figure S2: Association Between Pruritus and Depression.
Figure S3: Association Between Pruritis and Pain.
Figure S4: Association Between Pruritis and Anxiety.
Figure S5: Association Between Pruritis and Exhaustion.
Table S1: Sleep, Pain, Anxiety, Depression, and Exhaustion KDQOL-36 Scores (Mean [SD]) by Extent Patients Were Bothered by Itching in the Last 4 Weeks by Serum Phosphorus Category.
Table S2: PHQ-2 Scores (Mean [SD]) by Extent Patients Were Bothered by Itching in the Last 4 Weeks by Serum Phosphorus Category.
Table S3: KDQOL-36 Subscale Scores (Mean [SD]) by Extent Patients Were Bothered by Itching in the Last 4 Weeks by Serum Phosphorus Category.
Table S4: Univariate Logistic Regression Analysis of Depression and Itch, Anxiety, Sleep Disturbance, Pain, and Exhaustion Using (A) KDQOL-36 Scoring, or (B) Categorical Definitions.
Supplementary Materials
Figures S1-S5; Tables S1-S4.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figures S1-S5; Tables S1-S4.