prurito Uremico

1. Original Article
Development and Validation of a Uremic Pruritus
Treatment Algorithm and Patient Information Toolkit in
Patients With Chronic Kidney Disease and End Stage
Kidney Disease
Jessica Ragazzo, PharmD, Annemarie Cesta, BScPhm, S. Vanita Jassal, MD, Nicholas Chiang, PharmD, and
Marisa Battistella, BScPhm, PharmD
University Health Network (J.R., A.C., S.V.J., M.B.), Toronto; and University of Toronto (J.R., S.V.J., N.C., M.B.), Toronto, Canada
Abstract
Context. Uremic pruritus (UP) affects up to half of all patients with kidney disease and has been independently associated
with poor patient outcomes. UP is a challenging symptom for clinicians to manage as there are no validated guidelines for its
treatment.
Objectives. The study aimed to develop and validate an algorithm and patient information toolkit for the treatment of UP
in patients with kidney disease.
Methods. The study involved a literature search and development of an initial draft algorithm, followed by content and
face validation of this algorithm. Validation entailed three rounds of interviews with six nephrology clinicians per round.
Participants assessed the relevance of each component of the algorithm and then rated a series of statements on a scale of 1-5
to assess face validity of the algorithm. After each round, the content validity index (CVI) of each algorithm component was
calculated, and the algorithm was revised by the study team in response to findings. This process was followed by a second
study that developed and validated a patient information pamphlet and video.
Results. Algorithm validation participants were affiliated with three institutions and included seven physicians, four
registered nurses, three nurse practitioners, three pharmacists, and a dietician. The average CVI of the algorithm components
across all three rounds was 0.89, with 0.80 commonly cited as the lower acceptable limit for content validation. More than 78%
of participants rated each face validity statement as ‘‘Agree’’ or ‘‘Strongly Agree’’. For the patient information tools, five
clinicians and 15 patients were included in validation. The average CVI was 1.00 for both tools, and the average face validity
was 92%.
Conclusion. A treatment algorithm and patient information toolkit for managing UP in patients with kidney disease were
developed and validated through expert review. Further research will be conducted on implementation of the treatment
algorithm and evaluating patient-reported outcomes. J Pain Symptom Manage 2020;59:279e292. Ó 2019 American Academy of
Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
Key Words
Uremic pruritus, chronic kidney disease, end stage kidney disease, treatment algorithm, hemodialysis, peritoneal dialysis
Key message
This article describes a study in which a treatment
algorithm and patient information toolkit for uremic
pruritus were developed and validated via expert re-
view. The results indicate that the algorithm and tool-
kit possess a high degree of content and face validity.
Address correspondence to: Marisa Battistella, BScPhm,
PharmD, 200 Elizabeth St. Toronto, ON, Canada M5G
2C4. E-mail: marisa.battistella@uhn.ca
Accepted for publication: October 1, 2019.
Ó 2019 American Academy of Hospice and Palliative Medicine.
Published by Elsevier Inc. All rights reserved.
0885-3924/$ - see front matter
https://doi.org/10.1016/j.jpainsymman.2019.10.003
Vol. 59 No. 2 February 2020 Journal of Pain and Symptom Management 279

2. Introduction
Symptom management in patients with advanced
diseases has gained attention in recent years,
including the kidney disease population.1
Research
has shown that patients with kidney disease experi-
ence a high degree of physical and psychologic symp-
tom burden.2
It has also been recognized that in the
end stage kidney disease (ESKD) population, espe-
cially those with a life expectancy of less than one
year, the standard approach to dialysis care may not
be sufficient to address goals of care.3
In response to
these findings, the area of palliative nephrology has
emerged, with a major component being manage-
ment of the symptoms associated with kidney disease
and dialysis.1,3
Uremic pruritus (UP), or uremic itch, is a well-
documented distressing symptom experienced by up
to half of all patients with chronic kidney disease
(CKD) and ESKD receiving dialysis.4
It is commonly
described as a daily or near-daily occurrence of itch
that spans large bilaterally symmetrical surface areas.4
UP may vary from a localized itch, commonly in the
back, face, and arms, to a generalized itch involving
the entire body.5
Primary skin lesions may present
with similar symptoms,4
and any suspicion of an un-
derlying primary lesion should be first evaluated by
dermatology.
The underlying pathophysiology of UP is likely
multifactorial,4
limiting the ability to determine tar-
geted therapies. Some proposed mechanisms include
uremic neuropathy, skin or nerve inflammation due
to kidney failure, an increase in activity of m-opioid
receptors due to kidney failure, or accumulation of
pruritogenic substances.4,5
UP has been indepen-
dently associated with increased mortality6
as well as
depression, poor sleep, and reduced quality of
life.7,8
The treatment of UP has also been identified
as a high-priority research area by patients with
CKD and ESKD.9,10
For these reasons, greater atten-
tion to UP as a symptom of kidney disease is needed,
as it is often underappreciated and overlooked in
clinical practice despite being a priority to
patients.4,11
There is currently weak and conflicting evidence
for various therapies for UP, and as such, there is
currently no validated, gold standard clinical deci-
sion tool or guideline for its treatment. Despite a
large body of literature examining many different in-
terventions, the majority contains flawed methodol-
ogy, high risk of bias, small sample size, and study
heterogeneity, with a significant lack of large-simple
randomized trials.4
This has largely prevented any
strong and robust treatment recommendations
from emerging.
As the optimal treatment for UP remains unclear,
the current practice is for patients and clinicians to
try a multitude of therapies, often in a random and
haphazard manner. As a result, many patients are pre-
scribed treatment based on clinicians’ preference.
The majority receive antihistamines or steroid creams
with little to no follow-up, which, as noted in the
following paragraph, often results in poor relief of
itch with the potential for new complications or symp-
toms.8,11
There is insufficient evidence to recommend
antihistamines for UP,5
and their adverse effects
including drowsiness and anticholinergic effects pose
risks to these patients, especially the elderly. It is likely
that their sleep-inducing properties are responsible
for decreasing the perception of itch, rather than
treating the cause of itch.12
Steroid creams are also
prescribed for extended periods of time and on large
body surface areas, which can pose risks to patients
while likely providing inadequate symptom relief. Cli-
nicians therefore would benefit from a validated step-
wise approach to prescribing therapies for their
patients experiencing UP.
Clinical decision tools and algorithms are increas-
ingly being adopted in various health-care settings to
increase efficiency and improve quality of care.13
Algo-
rithms formalize a series of instructions in a logical
manner to guide decision-making in complex disease
states such as kidney disease and may aid in either
diagnosis or treatment.14
Controversy or conflicting
findings in the literature often result in these tools
containing a combination of evidence- and
consensus-based recommendations.13
The shift in focus toward quality assurance within
health care has led to the concept of validation of clinical
decision tools and treatment algorithms.14
There is no
gold standard process to validate treatment algorithms.
However, content and face validity of the algorithm can
be assessed via expertreview to ensure usability, accuracy,
comprehensiveness, and utility. Content validity indi-
cates that the algorithm encompasses all relevant items
pertaining to the subject area.15
Face validity indicates
that the algorithm appears to be effective in fulfilling
its stated purpose.16
Validation of the UP algorithm via
review by experts in clinical nephrology assesses both
types of validity and helps determine whether the tool
will be accepted by its target end-users.
The objectives of the study were to develop a UP
treatment algorithm for use in patients with CKD
and ESKD and to validate the algorithm with clinicians
for content and face in a structured manner. A second
study using similar methodology was also conducted
to develop and validate a patient information toolkit
(consisting of a pamphlet and a video) as companions
to the treatment algorithm.
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Ragazzo et al.

3. Methods
Creation of the treatment algorithm and patient in-
formation toolkit were each completed in two phases,
development and validation, based on Lynn’s method
of content validation.15
This study was approved by the
study site’s institutional research ethics board (17-
6045).
Development of the Algorithm
A literature search using MEDLINE (1946 to
October 8, 2017) and CINAHL (1981 to October 8,
2017) was conducted to identify any existing clinical
decision tools or algorithms used for UP manage-
ment. No existing validated algorithms or clinical de-
cision tools were found. To identify existing literature
on UP treatment, a separate literature search within
the same databases was conducted using a combina-
tion of keywords and MeSH terms to cover the con-
cepts ‘‘kidney disease’’ and ‘‘pruritus’’ as
appropriate. See Appendix I for literature search
strategy.
The treatment algorithm was developed based on
resulting literature findings. A focus group consisting
of the study team (a pharmacy resident, two pharma-
cists with over 10 years of experience in nephrology
and treating UP, and a nephrologist practicing in
both CKD and dialysis with publications in palliative
nephrology) met to create and refine the algorithm.
This was performed based on the first stage of the
two-stage process of content validity of a clinical tool
described by Lynn, the ‘‘developmental stage.’’ 15
The developmental stage involves three steps: domain
identification, item generation, and instrument for-
mation. The focus group began this process by first
identifying the domains that the algorithm should
encompass, which were determined to be assessment
of UP, treatment of UP, and follow-up. Then, a list of
items to be included in each domain of the algorithm
was generated based on both the results of the litera-
ture search and the clinical experience of the group.
The assessment domain was divided into three sec-
tions, within which items were sorted: history and ex-
amination, rule out other causes, and determine
treatment goals. Items to be included in the treatment
domain were also sorted into three groups: nonphar-
macological strategies, medicated topical agents, and
systemic therapies. The follow-up domain listed items
such as timeframes for patient reassessment, assess-
ment of adverse effects, and setting and meeting treat-
ment goals. Once a list of items was generated, the
focus group then determined which items should be
included in the initial draft of the algorithm and
which should be discarded. For example, in the treat-
ment domain, the focus group opted to include treat-
ments that have shown positive outcomes in the UP
literature or which have a very low risk for adverse ef-
fects and discard treatments that have shown inconsis-
tent or negative outcomes. The focus group then
completed the third step of algorithm development,
which was to arrange the domains and their items
into a useable form. The group opted for a stepwise
approach to the algorithm, beginning with assess-
ment, followed by the three treatment steps arranged
from the lowest risk of adverse effects to the highest
(i.e., nonpharmacological strategies, medicated
topical agents, systemic therapies) with follow-up and
reassessment points in between each treatment step.
Once the focus group unanimously agreed on all as-
pects of this process, the initial draft of the algorithm
was complete.
Validation of the Algorithm
Study participants were recruited from three
different academic hospital institutions and included
individuals from different disciplines with experience
in clinical nephrology. Inclusion criteria were as fol-
lows: licensed health-care professional (including phy-
sicians, nurse practitioners, registered nurses,
registered dieticians, or pharmacists); experience in
nephrology, palliative care, or dermatology of at least
1 year; and experience in treating UP. Lynn’s method
states that a minimum of five and a maximum of 10 cli-
nicians per round be used to control for chance agree-
ment and to sample from an adequate range of
disciplines;15
therefore, our study chose to include
six participants per round. Three rounds of face and
content validation were completed with a total of 18
clinicians.
Each round of validation involved individual inter-
views with study participants. Within each interview,
participants completed a questionnaire divided into
parts A and B to assess content and face validity,
respectively.
Part A of the algorithm was developed based on the
second stage of the two-stage process of content valid-
ity of a clinical tool described by Lynn, the ‘‘judgment-
quantification stage,’’ 15
and DeVon et al.’s review of
the validation process.16
The algorithm was divided
into 12 individual components, and participants rated
each component on a scale of one to four assessing its
relevance. A score of three or four indicated that the
component was very relevant and required either a mi-
nor change or no change. A score of two or one indi-
cated that the component was less relevant and either
required a major change or should be removed from
the algorithm entirely.
In part B of the questionnaire, participants rated a
series of statements assessing face validity on a scale
of one to five according to their level of agreement
with the statement, with one being ‘‘strongly disagree’’
and five being ‘‘strongly agree.’’ Any comments from
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Uremic Pruritus Algorithm Validation

4. participants to justify a rating in either part A or B of
the questionnaire were noted, and overall feedback
and suggestions for improvement were collected at
the end of the questionnaire. See Appendix II for
the questionnaire, including the preliminary draft of
the algorithm.
After each round of six questionnaires, data were
compiled and revisions were made to the algorithm
collaboratively by the study team. The revised algo-
rithm was then presented to the next round of partic-
ipants. Any algorithm components that were rated as
one or two (i.e., less relevant) in part A of the ques-
tionnaire by at least two out of six participants and
any statements that were rated as one, two, or three
(i.e., strongly disagree, disagree, or neutral) in part
B of the questionnaire were deemed to require revi-
sion. The entire process was then repeated for two
more rounds of questionnaires and revisions, after
which validation of the algorithm was complete and
a final version of the algorithm was accepted by the
study team.
Statistical Analysis
The two steps of Lynn’s judgment-quantification
stage are to calculate the content validity of each
item of the tool, followed by that of the entire
tool.15
An item content validity index (I-CVI) was
calculated for each individual component of the tool
using the ratings given by study participants in part
A of the questionnaire. A score of three or four for
relevance indicated that the practitioner rated the
component as valid, while a score of one or two indi-
cated that the practitioner rated the component as
invalid. The I-CVI for each validation round was the
proportion of the six participants who rated that
item as valid. Lynn’s method describes how many par-
ticipants must agree with validity of an item for it to be
considered content valid as being based on the num-
ber of participants in that round, with this cutoff in-
tended to identify real agreement as opposed to
chance. According to this method, when six partici-
pants are used, an item is considered invalid when
two or more participants rate it as such. This corre-
sponded to an I-CVI score of 0.67 or less (i.e., 4 out
of 6). To calculate the overall scale content validity in-
dex (S-CVI), each I-CVI across all three validation
rounds were added together and averaged. The S-
CVI threshold above which the algorithm would be
considered content valid was 0.8, which is commonly
cited in the literature surrounding content validity of
clinical decision tools.17
Face validity of the algorithm was reported as the
percentage of study participants who rated the state-
ments in part B of the questionnaire as either four
or five (i.e., agree or strongly agree).
Patient Information Toolkit
After development and validation of the UP treat-
ment algorithm were completed, two patient informa-
tion tools (pamphlet and video) were also developed
and validated using similar methodology. First, a liter-
ature search was conducted using MEDLINE (1990 to
2019) to identify relevant information that patients
desire in informational materials. Based on these find-
ings, information from the final version of the UP
treatment algorithm was then used to create a
pamphlet and a video. The initial drafts of these tools
were created by a pharmacy student and reviewed by
three pharmacists and one clinical research analyst.
Once development of the initial drafts of these tools
was complete, validation of the tools was then con-
ducted using the same process and a questionnaire
as that of the UP treatment algorithm except with
four rounds of validation (the first round with five
nephrology clinicians and an additional three with
five hemodialysis patients each), with revisions by the
study team between each.
Results
Literature Search
Our literature search retrieved 580 MEDLINE arti-
cles and 80 CINAHL articles (Appendix I). After
screening the retrieved records for duplicates and
excluding irrelevant records based on title or abstract,
161 articles were deemed to be relevant to our study.
We then reviewed the full text of those 161 articles
and opted to include only primary literature, system-
atic reviews, and meta-analyses relating to the treat-
ment of UP for the creation of the initial draft of
the algorithm, which left 53 articles.4,5,11,12,18e66
The
remaining 107 articles were not used for reasons
such as being pathophysiology based rather than treat-
ment based, pediatric studies, studies of treatments
not available in Canada, or letters to the editor. The
literature search relating to the patient information
tools yielded 54 articles, of which 21 were deemed
relevant after title, abstract, and/or full-text
review.67e87
Study Participants
Eighteen study participants were recruited for the
validation phase from three participating study sites.
Participants included nephrologists, pharmacists,
registered nurses, nurse practitioners, and a dieti-
tian. Participants practiced in either hemodialysis,
peritoneal dialysis, and/or the Multi-Care Kidney
Clinic. Characteristics of study participants are
shown in Table 1. See Appendix III for characteris-
tics of individual study participants in each validation
round.
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Ragazzo et al.

5. Five clinicians (one registered dietician, two pharma-
cists, one registered nurse, and one nephrologist) and
15 patients receiving hemodialysis participated in valida-
tion of the patient information tools. See Appendix IV
for characteristics of these participants.
Content Validation
The I-CVI of each component of the algorithm per
round of validation is shown in Table 2. The S-CVI
calculated for rounds 1, 2, and 3 of validation was
0.85, 0.89, and 0.94, respectively. The overall S-CVI
of the algorithm calculated after completion of three
rounds of validation was 0.89.
For the patient information tools, the S-CVI for all
four rounds of validation was 1.00, with an overall S-
CVI of 1.00 for both tools.
Face Validation
Level of agreement with face validity statements in
part B of the questionnaire is shown in Table 3. Of
the 18 participants, 78% agreed that the algorithm is
clear and understandable, 89% agreed that the
algorithm uses appropriate language and wording
and flows in a logical manner, and 94% agreed that
the algorithm is an accurate representation of the
standards of practice. Eighty-three percent of partici-
pants would use the algorithm in their own practice,
and 89% would be confident recommending the use
of the algorithm.
For the patient information tools, the face validity
for the both the pamphlet and the video was rated
86% by clinicians, 100% by patients in the first two
rounds of validation, and 83% in the final round of pa-
tient validation.
Validation Themes
Three themes commonly arose throughout the
three rounds of algorithm validation.
The most common feedback received with respect
to the algorithm’s content was to add hyperphosphate-
mia as a differential diagnosis for potential causes of
pruritus other than UP.
There was also feedback throughout all three valida-
tion rounds with respect to setting goals of therapy,
the nature of which varied based on the participant’s
profession. Registered nurses and nurse practitioners
felt that setting goals of therapy should be done after
determining treatment rather than before, although
most stated this was not something that was typically
part of their practice at all. More experienced ne-
phrologists did not feel that setting goals of therapy
was a necessary component of the algorithm, but
less-experienced nephrologists as well as all pharma-
cist participants felt that it was an important part of
the algorithm.
Finally, the major feedback that arose in all three
rounds of validation with respect to face validity of
the algorithm was to reduce the amount of text con-
tained within the algorithm itself and improve its
user-friendliness.
The most common feedback received during valida-
tion of the patient information tools was that the video
Table 1
Algorithm Validation Participant Characteristics (N ¼ 18)
Characteristic n (%)
Location of Practice
Hospital 1 (study site) 12 (67)
Hospital 2 5 (28)
Hospital 3 1 (5)
Profession
Physician 7 (39)
Registered nurse 4 (22)
Nurse practitioner 3 (17)
Pharmacist 3 (17)
Dietitian 1 (5)
Practice unit
Hemodialysis 12 (67)
Peritoneal dialysis 8 (44)
CKD clinic 8 (44)
Number of years of practice,
median (IQR)
12.5 (14.5)
CKD ¼ chronic kidney disease; IQR ¼ interquartile range.
Table 2
Content Validity Indices of Treatment Algorithm
Algorithm Component
Round 1
I-CVI
Round 1
S-CVI
Round 2
I-CVI
Round 2
S-CVI
Round 3
I-CVI
Round 3
S-CVI
Average
I-CVI
Overall
S-CVI
A. History/examination 1.00 0.85 0.67 0.89 1.00 0.94 0.89 0.89
B. Rule out other causes 0.83 1.00 1.00 0.94
C. Treatment goals 0.67 0.67 0.83 0.72
D. Nonpharmacological 0.83 1.00 1.00 0.94
E. Dialysis-provoked pruritus 0.67 1.00 0.83 0.83
F. Nonmedicated moisturizer 0.83 1.00 0.83 0.89
G. Reassessment (step 1) 1.00 0.83 1.00 0.94
H. Noninflamed skin 1.00 1.00 1.00 1.00
I. Inflamed skin 1.00 1.00 1.00 1.00
J. Reassessment (step 2) 0.83 1.00 0.83 0.89
K. First-line oral therapy 0.67 0.67 1.00 0.78
L. Second-line oral therapy 0.83 0.83 1.00 0.89
I-CVI ¼ item content validity index; S-CVI ¼ scale content validity index.
Vol. 59 No. 2 February 2020 283
Uremic Pruritus Algorithm Validation

6. was preferred over the pamphlet as it was easier to un-
derstand given that it includes both an audio and vi-
sual component. The pamphlet was viewed as a
source of information to be given to patients initially
and to have as a reference, while the video was seen
to be more useful for providing a better understand-
ing to patients of UP.
Final Algorithm and Patient Information Toolkit
The final algorithm following three rounds of vali-
dation and revisions is shown in Figure 1. When devel-
oping our treatment algorithm, we chose to include
steps on appropriate assessment of the patient at the
beginning. A thorough history of symptoms and exam-
ination of the patient is included to inform which
treatment strategies will be selected, individualized
to the patient’s specific concerns. There are several
other common causes of pruritus which patients with
kidney disease can experience, and identification
and treatment of these disease states ensure that
appropriate therapy is not delayed. Establishing real-
istic treatment goals and expectations with patients is
also key as many patients will not be able to achieve
complete resolution of all their symptoms.
We opted for a stepwise treatment approach to
ensure that patients have adequate trials of lower
risk therapies, such as medicated topical agents,
before escalating to agents with greater potential for
adverse effects, such as systemic therapies. Our aim
was to incorporate therapies that have been described
in the UP literature and have shown positive out-
comes. However, given the paucity of high-quality evi-
dence for UP treatment, we included agents that have
not been studied thoroughly but have a very low risk
for adverse effects, such as nonmedicated moistur-
izers, or agents that clinicians in our practice have pre-
viously used in this patient population with success.
The final version of the pamphlet is shown in
Figure 2, and the final version of the video can be
found at https://youtu.be/xVhYhh8DQQg. Both the
pamphlet and the video focus on describing UP, po-
tential causes of UP, and nonpharmacological
strategies, as well as nonmedicated moisturizers, all
in patient-friendly language.
Discussion
To our knowledge, this is the first treatment algo-
rithm that has been validated to guide the manage-
ment of UP in patients with CKD and ESKD. This
algorithm was developed to improve outcomes of UP
treatment, to discourage the use of treatments or stra-
tegies that are ineffective or unsafe, and to standardize
treatment at our institution as well as others who may
adopt its use.
Algorithms have been used in other areas of the
treatment of kidney disease with success. One such
example is the management of anemia of kidney dis-
ease, where several algorithms have been
published.88e91
Efficacy was demonstrated in helping
patients achieve target hemoglobin levels, with addi-
tional benefits seen including increasing cost savings
and standardizing care. These studies show that the
use of algorithms in the kidney disease population
may not only improve patient outcomes but may also
decrease costs and create a standard of care especially
in areas where there are no published guidelines or a
paucity of data.
The overall S-CVI of the algorithm was 0.89, with
0.80 commonly cited in the literature as the lower
acceptable limit of content validation.14
This shows
that the nephrology clinicians sampled considered
the content of the algorithm to be appropriate and
relevant for the treatment of UP. For each individual
round of validation interviews, the S-CVI was 0.85,
0.89, and 0.94 for rounds one, two, and three, respec-
tively. The S-CVI increased with each round of valida-
tion, which we predicted as the algorithm was assessed
and revised by the study team after each round of vali-
dation. This pattern held true despite the final round
of validation including solely clinicians from outside
of the study site, showing that our treatment algo-
rithm is reflective of practice at varying locations of
practice and translates well across different
professions.
All face validity statements had a high level of agree-
ment from participants. The statement with the lowest
level of agreement related to clarity and understand-
ability of the tool, but the percentage of participants
who agreed was 78%, which is the majority. In addi-
tion, 89% agreed that the algorithm uses appropriate
language and wording and flows in a logical manner
despite the lower level of agreement with the previous
statement. Almost all participants agreed that the algo-
rithm is an accurate representation of the standards of
practice at 94%. This suggests that the algorithm
incorporated a highly accurate selection of treatments
Table 3
Agreement With Face Validity of Algorithm
Statement
Strongly
Agree or Agree (%)
The tool is clear and understandable 78
The tool uses appropriate language
and wording
89
The tool flows in a logical manner 89
This tool is an accurate representation
of the standards of practice
94
I would use this tool in my own practice 83
I would be confident recommending
the use of this tool
89
284 Vol. 59 No. 2 February 2020
Ragazzo et al.

7. for UP both from the literature as well as from expert
opinion and clinical experience. Finally, 83% and 89%
agreed that they would use the algorithm in their own
practice and would be confident recommending the
use of the algorithm, respectively. This indicates that
the treatment algorithm fills a strong need by aiding
clinicians in the management of UP.
A common suggestion from clinicians in all three
rounds of validation was to add hyperphosphatemia
as a differential diagnosis for potential causes of
pruritus other than UP. Many nephrology clinicians
commonly attribute pruritus in their patients to
elevated serum phosphate levels and, as such, opt to
manage pruritus by treating this hyperphosphatemia.
However, to date, there is no consistent relationship
between treatment of hyperphosphatemia and subse-
quent reduction in UP shown in the literature.15
Consequently, focusing therapy solely on the manage-
ment of serum phosphate levels to reduce pruritus can
lead to delaying appropriate UP treatment for
UREMIC PRURITUS
Is skin inflamed?
Treatment Step 1
Assessment
A. History/Examinaon
B. Rule out other causes
C. Determine treatment goals
Reassess paent in
1-2 weeks
Connue treatment and
reassess paent as needed
Is skin inflamed? Add Treatment Step 2B
Add Treatment Step 2A
Reassess paent in
1-2 weeks
Trial other Treatment Step 2
agents as appropriate
OR
Proceed to Treatment Step 3
Stop steroid (if used),
Connue other intervenons,
Reassess paent as needed
Yes
Yes
No
Are goals being met?
Yes
No
Are goals being met?
Yes No
No
TREATMENT STEP 1:
Non-pharmacological strategies
AND
Moisturize skin
Apply moisturizer liberally to itchy areas 4-6
mes per day as needed and aer bathing
(i.e. while skin is sll wet)
Mild-moderately dry skin cream/loon
Very dry skin ointment
TREATMENT STEP 2:
Connue Treatment Step 1
Intervenons
and ADD
2A: Medicated Topical Agents
Apply to affected area(s) 3-4 mes daily
OR
2B: Topical Steroids
Apply to affected area(s) BID x 5-10 days,
then disconnue
TREATMENT STEP 3:
Connue Treatment Step 1
Intervenons
and ADD systemic therapy:
Oral medicaons
AND/OR
Narrowband UVB Phototherapy
2-3 mes per week
(requires dermatology referral)
Fig. 1. Uremic pruritus treatment algorithm. UVB ¼ ultraviolet type B.
Vol. 59 No. 2 February 2020 285
Uremic Pruritus Algorithm Validation

8. ASSESSMENT
A. History/Examinaon
- Duraon, ming, severity
- Distribuon (affected body parts)
- Exacerbang or relieving factors
- Treatments/measures tried and response
- Medicaon history (including when
started/stopped in relaon to onset of
pruritus)
- Assess skin for excoriaons/infestaon
B. Rule out other causes
Drug/Dialysis-related:
- Opioid-related pruritus
- Drug hypersensivity or
adverse effect
- Contact dermas
- Allergy
- Icodextrin
Differenal diagnoses:
- Xerosis (dryness)
- Infestaons (i.e. scabies)
- Iron deficiency
- Liver disease
- PCV/Leukemia/Lymphoma
- Hypothyroidism
- Uncontrolled diabetes
C. Determine treatment goals
- Establish realisc expectaon of
reducon in itch
- Example goal: Aer 2 weeks,
experience no disturbed sleep
due to itch on at least 50% of
nights.
When reassessing paent (aer 1-2 weeks):
- Reassess symptoms as per inial assessment
- Assess for adverse effects specific to prescribed treatment
- Assess for barriers to treatment adherence
- Assess paent’s sasfacon with treatment
TREATMENT STEP 1: Nonpharmacological Strategies + Skin Hydraon
Non-pharmacological strategies: Addional strategies for dialysis-provoked pruritus:
Keep cool
- Use fan at night
- Wear light clothing
- Use coon sheets
Keep skin hydrated
- Use humidifier
- Avoid hot water, use
lukewarm
- Avoid excessive bathing
Avoid skin irritants
- Eliminate wool/irritang clothing
- Use gentle/fragrance-free soap and
laundry detergent, extra laundry rinse
- Keep fingernails trimmed
- If under-dialyzed, opmize dialysis efficiency as appropriate
- Potenal heparin allergy – change heparin brand OR switch to
NS flush/citrasate dialysate/sodium citrate lock soluon
- Consider change in dialyzer, tubing, PD soluon
Examples of creams/loons: Examples of ointments:
Aveeno®
CeraVe®
Cetaphil® Cream
Curel®
Complex 15®
Dermal Therapy®
Dormer 211®
Eucerin®
Glaxal Base®
Lipikar® Baume AP cream
Udderly Smooth®
Vaseline® Intensive Care
Petroleum jelly (e.g. Vaseline®) Aquaphor® ointment
TREATMENT STEP 2: Add Medicated Topical Agents
2A: Medicated Topical Agents
Note: the following treatments are not covered under
Ontario Drug Benefit (ODB)
Choose one of the following four opons:
- 0.25% camphor + 0.25% menthol in vehicle*
- Pramoxine 1% cream/loon (Gold Bond® An-Itch)
- Capsaicin 0.025% cream
- Doxepin 5% cream
2B: Topical Steroids
Mildly inflamed:
Hydrocorsone 1% powder#
in vehicle*
Moderately-severely inflamed:
Betamethasone valerate 0.1%#
in vehicle*
#: +/- camphor 0.25% + menthol 0.25% *Vehicle:
Dry skin = petroleum jelly
Non-dry skin = Glaxal base®
TREATMENT STEP 3: Oral Agents
Discuss risks/benefits of prescribed treatment with paent prior to iniaon
Treatment Dose/Details Comments
FIRST LINE
THERAPIES
Gabapenn 100mg po qHS (or post-dialysis)
May trate up by 100mg every 2 weeks to max of
300mg/day (dialysis) or 600mg/day (non-dialysis,
CrCl30mL/min)
1. Use lowest effecve dose
2. Reassess (and trate dose if required) at
two-week intervals
3. STOP if treatment is not meeng
paent’s goals aer at least 6 weeks and trial
other first-line therapy or proceed to second-
line therapy
Pregabalin 25mg po qHS (or post-dialysis)
May trate up by 25mg every 2 weeks to max of
75mg/day (dialysis) or 150mg/day (non-dialysis,
CrCl30mL/min)
SECOND LINE
THERAPIES
Choose based on
paent’s other
concurrent
symptoms and
lack of
contraindicaons
Paroxene 10mg po daily;
Reassess in 4 weeks, increase to 20 mg daily if needed
Paroxene and sertraline preferred in
paents with anxiety, depression.
Naltrexone contraindicated in paents
taking opioids.
All four agents can increase fall risk.
STOP therapy aer 3 months if not meeng
paent’s goals and consider trial of other
agents/intervenons
Sertraline 25mg po daily;
Reassess in 4 weeks, trate to 75mg daily if needed
Doxepin 10mg po daily at bedme;
Reassess in 4 weeks, trate to max 30 mg daily if needed
Naltrexone
(not covered by
ODB)
12.5mg po once daily;
Reassess and increase by 12.5 mg weekly to max 50 mg
daily if needed
Anhistamines
(not covered by
ODB)
Diphenhydramine 25mg po TID prn
Hydroxyzine 10mg po TID prn
Cerizine 5-10mg po daily (dialysis: 5mg daily)
Loratadine 10mg po daily (dialysis: 10mg q48h)
Desloratadine 5mg po daily (dialysis: 5mg q48h)
MOST SEDATING
USE WITH CAUTION
LEAST SEDATING
Fig. 1. (continued).
286 Vol. 59 No. 2 February 2020
Ragazzo et al.

9. patients. As such, we did not include hyperphosphate-
mia as a differential diagnosis in our algorithm as we
believe UP should be treated independently of serum
phosphate levels.
The second major theme that emerged with respect
to the algorithm’s content was relating to setting goals
of therapy. Registered nurses and more experienced
nephrologists felt it was an unnecessary component
of the algorithm that did not fit with their usual prac-
tice, while less-experienced nephrologists and phar-
macists felt it was an important part of UP
treatment. We opted to keep this component in the
final version of the algorithm as we believe that
treatment goals should be established as part of
patient-centered care. Given the nature of pruritus
as a symptom, it is often unlikely that patients will
have their symptoms reduced to zero, thus more real-
istic expectations should be set with patients before
treatment begins.
A frequent suggestion from study participants across
all three rounds of validation interviews was to reduce
the amount of text contained within the algorithm.
Therefore, we modified the layout of the algorithm
to contain only high-level headings within the flow di-
agram and the treatment steps on the first page and
more detailed information with respect to each step
Fig. 2. Patient information pamphlet.
Vol. 59 No. 2 February 2020 287
Uremic Pruritus Algorithm Validation

10. on the second page of the algorithm. This modifica-
tion took place after the three rounds of validation
were complete. With this layout, more experienced cli-
nicians who wish to use the treatment algorithm as a
quick reference guide may simply follow the steps on
the first page without having to read through large
quantities of text. More detailed information about
each treatment step can be found on the second
page as a reference for clinicians less experienced in
the management of UP.
Our study was strengthened by the participation of
clinicians from multiple institutions. Nephrology
clinicians from different professions were sampled
to incorporate varying perspectives into each domain
of the algorithm and improve its utility for multiple
members of the interdisciplinary team. The robust-
ness of our validation process was improved by
having different clinicians participate in each of
three rounds of validation. In this way, we were
able to revise the algorithm after each round and
have a different group of participants review the
changes each time, rather than having only one
round with no opportunity to obtain feedback on
those changes.
Fig. 2. (continued).
288 Vol. 59 No. 2 February 2020
Ragazzo et al.

11. The main limitation with our study is that there is
no gold standard for validation of treatment algo-
rithms. Therefore, the process we developed was
based on expert experience and a review of the litera-
ture on validation of clinical decision tools. We used
the Lynn method of content validation as it is well
documented in the literature and was the most appli-
cable and feasible method for this study. There is also
a lack of complete consensus in the literature on the
threshold for content validity or the preferred method
for calculating the S-CVI of the tool. A third limitation
is that the validation process only included three insti-
tutions, with two-thirds being from the study site. How-
ever, the S-CVI for round three of validation was the
highest at 0.94 despite this round including no partic-
ipants from the study site, indicating that the algo-
rithm translates well to practice at other sites. A final
limitation is that because there is a lack of strong,
robust evidence for most treatments for UP, deciding
which treatments to be included in the algorithm
was a challenge. Therefore, we took both literature
and expert opinion into account to create a stepwise
treatment approach to UP. Despite this limitation,
94% of participants agreed that the algorithm is an ac-
curate representation of the standards of practice.
To further evaluate this treatment algorithm, our
study group is conducting a quality-improvement proj-
ect at this study site’s hemodialysis unit. This involves
implementation of the use of the algorithm and pa-
tient information tools on the hemodialysis unit and
analyzing patient pruritus scores after implementa-
tion. Current practice at our site’s hemodialysis unit
is to measure pruritus scores on a scale of 0-10, with
zero being no itch at all and 10 being worst itch imag-
inable, and this is done on a monthly basis. We will
also administer a survey to the clinician group on
our hemodialysis unit 6-12 months after implementa-
tion to assess prescriber satisfaction and suggestions
for the algorithm.
A treatment algorithm and related patient informa-
tion tools for the management of UP were developed
and validated for content and face via expert review.
Despite the limitations of our validation process, we
conclude that given the S-CVI of the algorithm and
the high level of agreement with face validity state-
ments from different professions, the algorithm pos-
sesses a high level of content and face validity.
Similarly, the S-CVI of the patient information tools
and the high level of agreement with face validity state-
ments indicate that both clinicians and patients found
the tools to be relevant and valid. This is the first study
that we are aware of that has developed and validated
a treatment algorithm for managing UP in patients
with CKD and ESKD. Future research will focus on im-
plementation of the algorithm and patient informa-
tion tools and evaluating patient-reported outcomes.
Disclosures and Acknowledgments
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-
for-profit sectors. The authors have no conflicts to
disclose.
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tients. Int J Nephrol Renovasc Dis 2015;8:65e75.
89. Rogers J, Leung M, Beaulieu M, et al. Evaluation of ane-
mia management by algorithms in patients with chronic kid-
ney disease who are not receiving dialysis. Can J Hosp Pharm
2011;64:141e146.
90. Charlesworth EC, Richardson RM, Battistella M. Cost
savings using a protocol approach to manage anemia in a he-
modialysis unit. Am J Nephrol 2014;39:509e514.
91. Nhan J, Jensen L, McMahon A. Evaluation of an anemia
algorithm in chronic hemodialysis patients. CANNT J 2007;
17:48e58. 62-73; quiz 59-61, 74-76.
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15. Appendix I. Key Words Used in Literature Search
MEDLINE:
Database: Ovid MEDLINE: Epub Ahead of Print, In-Process Other Non-Indexed Citations, Ovid MEDLINEÒ
Daily and Ovid MEDLINEÒ 1946-Present
Search Strategy:
--------------------------------------------------------------------------------
1 exp Kidney Diseases/(499867)
2 exp Pruritus/(12,929)
3 1 and 2 (580)
****************************
CINAHL:
No. Query Limiters/Expanders Last Run Via Results
S3a
S1 AND S2 Search modes, Boolean/Phrase Interface, EBSCOhost Research databases
Search Screen, Advanced Search
Database, CINAHL
80
S2a
(MH Pruritus) Search modes, Boolean/Phrase Interface, EBSCOhost Research databases
Search Screen, Advanced Search
Database, CINAHL
1479
S1a
(MH Kidney Diseasesþ) Search modes, Boolean/Phrase Interface, EBSCOhost Research databases
Search Screen, Advanced Search
Database, CINAHL
35,386
a
All results limited to English language.
Appendix II. Validation Questionnaire
Validation of Treatment Algorithm
Study: Development and validation of a uremic pruritus algorithm in patients with chronic kidney disease
(CKD) and end stage kidney disease (ESKD)
The purpose of this questionnaire is to undergo face and content validation of an algorithm used for managing
uremic pruritus in patients with chronic kidney disease (CKD) or end stage kidney disease (ESKD). Please follow
the instructions provided and complete Part A and Part B of the questionnaire below based on your own exper-
tise. Participation in this session is completely voluntary. If you have questions at any time, please feel free to ask
the member of the study team leading the session. If you have questions following completion of the question-
naire, please contact Marisa Battistella, (416) 340-4800 ext.3207.
Part A: Content Validation
You have been provided with a copy of the algorithm. The algorithm has been divided into individual compo-
nents (A, B, C, etc.). Please rate each component on a scale of one (irrelevant) to four (extremely relevant). For
any component you do not find relevant, please provide a comment regarding why. A score of one or two indi-
cates that the component should be removed or revised.
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16. Component Irrelevant Less Relevant Relevant
Extremely
Relevant
A 1 2 3 4
B 1 2 3 4
C 1 2 3 4
D 1 2 3 4
E 1 2 3 4
F 1 2 3 4
G 1 2 3 4
H 1 2 3 4
I 1 2 3 4
J 1 2 3 4
K 1 2 3 4
L 1 2 3 4
Strongly Disagree Disagree Neutral Agree Strongly Agree Comments
The tool is clear and understandable 1 2 3 4 5
The tool uses appropriate language and
wording
1 2 3 4 5
The tool flows in a logical manner 1 2 3 4 5
This tool is an accurate representation of
the standards of practice
1 2 3 4 5
I would use this tool in my own practice 1 2 3 4 5
I would be confident recommending the
use of this tool
1 2 3 4 5
Part B: Face validation
Please circle your level of agreement with each statement in the questionnaire. For any statement which you do
not rate ‘‘5’’ or ‘‘Strongly Agree’’, please provide a comment regarding why and/or how the algorithm may be
improved in that aspect. A score of 1, 2, or 3 for any statement suggests that the aspect of the algorithm requires
revision.
Additional Comments:
______________________________________________________________________________________________
______________________________________________________________________________________________
______________________________________________________________________________________________
Study Identifier #: __________________________________
Profession: ______________________________
Location of practice (Hospital and unit): ______________________________
Number of years of practice: ______________________________
Date: ________________________
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19. Appendix III. Participant Characteristics Per Validation Round
Round Profession Practice Site Location of Practice
1 Nurse practitioner Study site Hemodialysis
Physician Study site Hemodialysis, peritoneal dialysis
Registered nurse Study site CKD clinic
Registered nurse Study site CKD clinic
Registered nurse Study site Peritoneal dialysis
Registered nurse Study site Peritoneal dialysis
2 Physician Study site Hemodialysis
Dietitian Study site Hemodialysis, peritoneal dialysis
Physician Study site Hemodialysis, CKD clinic
Physician Study site Peritoneal dialysis, CKD clinic
Physician Study site Hemodialysis, CKD clinic
Pharmacist Study site Peritoneal dialysis
3 Physician Hospital 1 Hemodialysis, peritoneal dialysis, CKD clinic
Nurse practitioner Hospital 1 Hemodialysis
Nurse practitioner Hospital 1 Hemodialysis
Pharmacist Hospital 1 Hemodialysis
Physician Hospital 1 Hemodialysis, CKD clinic
Pharmacist Hospital 2 Hemodialysis, peritoneal dialysis, CKD clinic
Appendix IV. Patient Information Toolkit Validation Participants
Total Clinicians N ¼ 5
Profession (number)
Dietitian 1
Pharmacist 2
Nurse 1
Nephrologist 1
Number of years of practice (mean SD) 8.67 5.08
Median number of years of practice 10
Clinician characteristics:
Total Patients N ¼ 15
Number of years on hemodialysis (mean SD) 3.3 3.56
Median number of years on hemodialysis 2.5
History with Uremic Pruritus (% of patients) 100%
SD ¼ sample standard deviation.
Patient characteristics:
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