The Tongue Features Associated With Chronic Kidney Disease
Conditions: CKD
Sponsor: China Medical University, Taiwan

Research Protocol 
 
 
 
The tongue features associated with chronic kidney disease (CKD) 
 
Version 2，25-4-2019 
 
 
 
 
 
Principal Investigator: 
Principal Investigator(s): Jia-Ming Chen 
Institution: CHANGHUA CHRISTIAN HOSPITAL,TAIWAN 
CCH IRB No. : 190404 
Date of Approval: May 9, 2019 
Address: 135 Nanxiao St., Changhua City, Changhua County 500, Taiwan (R.O.C.) 
Tel: 886-4-723-8595 
 
 

The tongue features associated with chronic kidney disease- study 
protocol for a randomized crossover trial 
 
I. Study Objectives 
 
The objectives of this protocol are to apply the noninvasive ATDS to evaluate tongue 
manifestations in patients with CKD, and to provide valuable information for clinical 
doctors, which can be used to facilitate the early detection and diagnosis of CKD, to 
analyze the current status of patients, and to dynamically schedule treatment plans. 
This protocol is a cross-sectional, case-controlled observational study investigating 
the usefulness of the ATDS in clinical practice by examining its efficacy as a 
diagnostic tool for CKD. 
 
II. Background and Rationale 
Chronic kidney disease (CKD) is an important global public health problem. 
According to related literatures, the prevalence of CKD is about 11% .(1) CKD is a 
progressive disease. If it progresses to end-stage renal disease (ESRD), renal 
replacement therapy: dialysis and renal transplantation, is required to maintain life(2). 
The growing prevalence and progression of chronic kidney disease (CKD) raises 
concerns about our capacity to manage its economic burden to patients, caregivers, 
and society. The societal direct and indirect costs of CKD and end-stage renal disease 
are substantial and increase throughout disease progression. There is significant 
variability in the evidence about direct and indirect costs attributable to CKD and end-
stage renal disease, with the most complete evidence concentrated on direct health 
care costs of patients with advanced to end-stage CKD.(2) 
CKD, also called chronic kidney failure, is described as a sustained reduction in 
glomerular filtration rate or evidence of structural or functional kidney 
abnormalities.(3) Chronic kidney disease (CKD) refers to all five stages of kidney 
damage, from very mild damage in stage 1 to complete kidney failure in stage 5. CKD 
symptoms include pain, itch(pruritus), peripheral numbness, sleep disturbances, 
depression, fatigue, nausea and vomiting. Factors that contribute to these symptoms 
include anaemia, uraemic toxins, reduced renal capacity, chronic disease-related 
inflammation, and psychological stress associated with long-term illness.(4) 
If it progresses to end-stage renal disease (ESRD), renal replacement therapy, 
including hemodialysis, peritoneal dialysis and kidney transplantation, is required to 
maintain life. Therefore, it is essential to find effective and conservative treatment 
methods to delay the progression of CKD. 
 

 
Diagnosis in traditional Chinese medicine (TCM) is based on four procedures, 
observation, smelling or listening, inquiry, and palpation. Tongue diagnosis, serving 
as a vital non-invasive tool to provide useful clinical information, plays a pivotal role 
in TCM.The tongue is considered to reflect the physiological and pathological 
condition of the body, as well as the degree and progression of disease, through the 
meridians that connect the tongue to theinternal organs.By observing tongue features, 
TCM practitioners can probe qi-blood, yin-yang disorders which are important in 
treatment selection and prognosis.[18,19] Clinically, practitioners observe tongue 
characteristics, such as tongue color and shape, fur color and thickness, and the 
amount of saliva, to help deduce the primary pattern of a patient. However, tongue 
diagnosis is often biased by subjective judgment, which originates from personal 
experience, knowledge, diagnostic skills, thinking patterns, and color 
perception/interpretation. The inconsistency of subjective diagnosis can be improved 
by using the development of validated instruments. The automatic tongue diagnosis 
system (ATDS) has shown high consistency and can provide objective and reliable 
information and analysis of tongue features, facilitating doctors in making effective 
observations and diagnoses of specific diseases. [10] [18] Previous studies have been 
conducted on exploring the association between tongue characteristics and specific 
diseases, including rheumatoid arthritis,[11] breastcancer,[12,13] type 2 diabetes,[14] 
metabolic syndrome,[15] eczema,[16] dysmenorrhea,[17] and functional 
dyspepsia,[22] gastroesophageal reflux disease(). However, to the best of our 
knowledge, no study has yet been performed on the comprehensive scrutiny of tongue 
features in patients with CKD using ATDS. 
 
III. Procedures  
A. Research and Design  
Subject Selection/Sample  
Inclusion criteria & Exclusion criteria:  
All individuals were recruited were informed of the study purpose, procedures, 
potential risks and benefits, and then the consent form were signed. Subjects will be 
eligible if they satisfy the following criteria: age over 20 years old; with CKD stage 3-
5 including dialysis patients , or who without symptoms and visit clinic for health 
examination; volunteered to join this research and signed the institutional review 
board agreement. Both men and women will be enrolled. Subjects with any of the 
following conditions will be excluded: cancer; acute infection; unable to protrude the 
tongue stably; risk of temporomandibular joint dislocation  
 

Study setting  
The trials will be conducted at the Changhua Christian Hospital. This study will adhere to 
the recommendations of the Consolidated Standards of Reporting Trials (CONSORT) 
[15] to allow for greater completeness, transparency and accuracy of reporting. This 
protocol is a cross-sectional, case-controlled observational study investigating the 
usefulness of the ATDS in clinical practice by examining its efficacy as a diagnostic tool 
for CKD stage 3-5 patients. After giving their consent, participants will undergo tongue 
image capturing using the ATDS. The ATDS examination will be performed under 
constant environmental conditions and by the same educated operator. The tongue images 
of both groups: experimental and control groups, were collected by the validated 
Automatic Tongue Diagnosis System (ATDS) with the corresponding tongue features 
automatically extracted. We analyzed the data of the subjects and the tongue features 
from the ATDS. 
  
Eligibility criteria  
Information including demography, body mass index (BMI, kg/m2), estimated glomerular 
filtration rate (eGFR) and CKD Staging were gathered for each subject. The duration of 
CKD history, comorbidity and complication in experimental group were also collected. 
Tongue images were collected for each subject to further derive the relevant tongue 
features of every participant. All personal details and photographs of subjects recruited 
were encrypted to ensure confidentiality. 
 
Ethics 
This research protocol adheres to the principles of the Declaration of Helsinki and has 
been approved by the institutional review boards of the Changhua Christian Hospital 
(No. : 190404). Informed consent will be obtained from each participant before any 
treatment is given. All subjects will have the right to withdraw from the study at any time. 
 
B. Measurement/Instrumentation  
Information including demography, body mass index (BMI, kg/m2), estimated 
glomerular filtration rate (eGFR) and CKD Staging were gathered for each subject. 
The duration of CKD history, comorbidity and complication in experimental group 
were also collected. Tongue images were collected for each subject to further derive 
the relevant tongue features of every participant. All personal details and photographs 
of subjects recruited were encrypted to ensure confidentiality. 
Primary outcome measures. Nine primary tongue features will be extracted from the 
ATDS as follows: tongue shape: small and thin, moderate, large, and fat; tongue 
color: 

slightly white, slightly red, red, dark red, and dark purple; tooth mark: includes 
number, average covering area, maximum covering area, minimum covering area, and 
organs corresponding to the covering area; tongue fissure: amount, average covering 
area, shortest length, and longest length; fur color: white, yellow, and dye; fur 
thickness: none, thin, thick; fur amount, average covering area, maximum covering 
area, minimum covering area, and organs corresponding to the covering area; saliva: 
includes total area and the amount of saliva (none, little, normal, excessive); 
ecchymosis: amount, average covering area, maximum covering area, minimum 
covering area, and organs corresponding to the covering area; red dots: number, 
average covering area, maximum covering area, minimum covering area, and organs 
corresponding to the covering area. Feature identification will be further subdivided 
into 5 segments (spleen–stomach, liver-gall-left, liver-gall-right, kidney, and heart–
lung area) according to the theory of traditional Chinese medicine. 
 
 
Statistical Considerations:  
A. Sample Size:  
We calculated the sample size will be about 500 with power=0.9,alpha=0.05, effect size 
convention r=0.3, and an anticipateddrop-out rate of 10%, using G∗Power 3.0.1.0 
software which isdownload from http://www.gpower.hhu.de.. Every effort will be made 
to reduce attrition; consent documents will emphasize the importance of complete data 
and encourage patients to return for the follow-up visit.  
B. Randomization:  
Patients will be randomized to one of the two treatment options with equal allocation. In 
an attempt to balance severity across treatment cohorts the randomization scheme will be 
stratified by baseline severity of RLS symptoms as measured by the International Restless 
Legs Severity Scale (severe vs. very severe). The randomization scheme will be generated 
by the study statistician with varying block sizes and uploaded to a web-based 
randomization program. After the patients eligibility has been confirmed and consent 
documents signed the research coordinator will randomize the patient to one of the two 
treatment options via the web-based randomization program. The PI will not randomize 
patients or have access to their treatment assignments.  
C. Analysis plan:  
All statistical analyses will be performed using the SPSS statistical package program, 
version 17.0 (SPSS Inc., Chicago, IL). Chisquare tests will be applied for categorical data 
and Analysis of variance tests will be applied for continuous data. Logistic regression will 
be used to estimate the odds ratio and the probability of a binary response, based on one 
or more independent variables. P-values <.05 will be considered statistically 

significance.For study-related patient data (case report forms) a unique identifier will be 
used. Study-related documents will be kept in a locked cabinet in a locked office. A 
separate list (paper-only) will be made containing the unique identifier and the name of 
each participant. This list will be kept separate from the study related documents. Study 
databases will be stored on a password protected computer network in a locked office and 
kept for 5 years. 
 
 

IV. Bibliography  
References  
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El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology 
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Fayek M, Gerdes H. Risks of esophagogastroduodenoscopy and esophageal 
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Behrouzian F, Sadrizadeh N, Nematpour S, et al. The effect ofpsychological 
preparation on the level of anxiety before uppergastrointestinal endoscopy. J 
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4. 
Kirschbaum B. Atlas of Chinese Tongue Diagnosis. Eastland Press, 
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Anastasi JK, Currie LM, Kim GH. Understanding diagnostic reasoning in TCM 
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Lo LC, Chen YF, Chiang JY, et al. Education of Chinese medicine tongue 
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Lo LC, Chen CY, Chiang JY, et al. Tongue diagnosis of traditional Chinese 
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9. 
Lo LC, Cheng TL, Chiang JY, et al. Breast cancer index: a perspective on 
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11. Hsu PC, Huang YC, Chiang JY, et al. The association between arterial stiffness 
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patients with eczema. Technol Health Care 2017;25:143–9. 
14. Kim J, Lee H, Kim H, et al. Differences in the tongue features of primary 
dysmenorrhea patients and controls over a normal menstrual cycle. Evid Based 
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automatic tongue diagnosis system and traditional Chinese medicine 

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