Exercise Training and Cognitive Function in Kidney Disease
Phase: NA
Conditions: Cognitive Function, Preclinical, Chronic Kidney Diseases, Older Adults
Sponsor: University of Illinois at Chicago

Exercise Training and Cognitive Function in Kidney Disease 
 
NCT03197038 
 
October 1, 2018 
 
 

 
 
 
Exercise Training and Cognitive Function in Kidney Disease 
Principal Investigator: 
Ulf G. Bronas, PhD, ATC, FSVM, FAHA 
Associate Professor University of Illinois at Chicago 
College of Nursing, Biobehavioral Health Science  
College of Nursing 
Department of Biobehavioral Health Science (M/C 802) 
845 S. Damen Avenue 
Chicago, IL  60612-7350 
Tel 312-355-5886 
Email: bronas@uic.edu 
Co-Investigators: 
Melissa Lamar, PhD 
Associate Professor  
Rush Alzheimer's Disease Center 
1750 W Harrison Street, Suite 1000 
Chicago, IL 60612 
Phone: (312) 942-3365 
melissa_lamar@rush.edu 
& 
Alana Steffen, PhD 
Research Assistant Professor University of Illinois at Chicago 
College of Nursing, Biobehavioral Health Science  
College of Nursing 
Department of Biobehavioral Health Science (M/C 802) 
845 S. Damen Avenue 
Chicago, IL  60612-7350 
Tel: 312 413 5632 
Email: steffena@uic.edu 
& 
James Lash, MD 
Professor  
Department 
College of Medicine, Division of Nephrology 
820 S. Wood Street (M/C 793) 
Chicago, IL 60612 
jplash@uic.edu 
312-996-7729 
& 
Xiaohong Joe Zhou, PhD 
Professor  
1801 W. Taylor St. Chicago IL 60612 (MC 707) 
xjzhou@uic.edu 
312-413-3979 

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Study Location(s):  
Lead site:  
University of Illinois at Chicago College of Nursing, 2nd floor Clinical Health Research 
Laboratory (845 S Damen Ave, room 229) Chicago, IL  60612-7350 
MRI collection site  
Magnetic Resonance Imaging Center 2242 W. Harrison St. Chicago IL 60612. 
 
Version: 9.0 
Date: 10-1-2018 

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TABLE OF CONTENTS 
Page 
Table of Contents ............................................................................................................ 3 
List of Abbreviations ........................................................................................................ 4 
1.0 Project Summary/Abstract ...................................................................................... 5 
2.0 Background/Scientific Rationale .............................................................................. 7 
3.0 Objectives/Aims ...................................................................................................... 7 
4.0 Eligibility .................................................................................................................. 8 
4.1 Inclusion Criteria ............................................................................................... 8 
4.2 Exclusion Criteria .............................................................................................. 8 
4.3 Excluded or Vulnerable Populations ................................................................. 9 
5.0 Subject Enrollment .................................................................................................. 9 
6.0 Study Design and Procedures ............................................................................... 11 
7.0 Expected Risks/Benefits........................................................................................ 19 
8.0 Data Collection and Management Procedures ...................................................... 20 
9.0 Data Analysis ........................................................................................................ 21 
10.0 Quality Control and Quality Assurance.................................................................. 21 
11.0 Data and Safety Monitoring ................................................................................... 21 
12.0 Statistical Considerations ...................................................................................... 23 
13.0 Regulatory Requirements ...................................................................................... 24 
13.1 Informed Consent ....................................................................................... 24 
13.2 Subject Confidentiality ................................................................................ 25 
13.3 Unanticipated Problems ............................................................................. 26 
14.0 References ............................................................................................................ 27 
Appendices ................................................................................................................... 30 
 

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LIST OF ABBREVIATIONS  
 
COI 
 
 
Conflict of Interest 
DHHS  
 
Department of Health and Human Services 
DMC  
 
Data Monitoring Committee 
DSMB  
 
Data and Safety Monitoring Board 
DSMP  
 
Data and Safety Monitoring Plan 
FERPA 
 
Family Educational Rights and Privacy Act 
FDA  
 
Food and Drug Administration 
GCP  
 
Good Clinical Practice 
HIPAA 
 
Health Insurance Portability and Accountability Act 
IBC 
 
 
Institutional Biosafety Committee 
ICD 
 
 
Informed Consent Document 
ICH 
 
 
International Conference of Harmonization 
IDE 
 
 
Investigational Device Exemption 
IDS 
 
 
Investigational Drug Service 
IND 
 
 
Investigational New Drug  
IRB 
 
 
Institutional Review Board 
LAR  
 
Legally Authorized Representative 
OHRP  
 
Office of Human Research Protections 
OPRS  
 
Office for the Protection of Research Subjects 
PHI 
 
 
Protected Health Information 
PI 
 
 
Principal Investigator 
PPRA  
 
Protection of Pupil Rights Amendment 
QA/QI  
 
Quality Assurance/Quality Improvement 
SAE  
 
Serious Adverse Event 
SOP  
 
Standard Operating Procedure 
 
 

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1.0 
Project Summary/Abstract 
 
Chronic kidney disease (CKD), affects over 45% of all individuals over 70 years of age. 
Patients with moderate CKD have more than a two-fold increased risk of cognitive 
impairment than those without CKD; furthermore, as many as 20-70% of patients with 
CKD have established cognitive impairment and overt dementia. The burden of 
cognitive impairment and dementia leads to functional decline and accelerated loss of 
independence, contributing to the tremendous individual, societal, and economic burden 
of CKD (i.e., 20% of Medicare expenditures in adults >65 years of age). There is no 
recommended treatment to prevent cognitive decline in CKD patients, and the few 
medications available for cognitive impairment have only short term modest effects. 
There is a critical need to evaluate therapies to forestall cognitive impairment, and 
maintain or improve cognitive functioning in older patients with CKD. To address this 
need, we will test the hypothesis that older patients with moderate/severe CKD and pre-
clinical cognitive impairment randomized to a 6-month home-based exercise program 
will improve cognitive function and MRI measured brain structure, compared to a usual 
care control group. We are focusing on patients with pre-clinical cognitive impairment in 
order to capture a therapeutic window in the disease process, which will allow us to 
possibly prevent dementia before brain atrophy becomes irreversible. This is a pilot 
study for feasibility. Our central hypothesis is that the accelerated cognitive decline in 
CKD results from a vascular dysfunction-induced reduction in the integrity of the brain 
white matter and that exercise training provides a cerebro-protective effect by improving 
cerebral vascular health. We will combine an assessment of cognition with MR imaging 
techniques to fully evaluate brain structure, blood flow, and behavior relationships at a 
level previously not conducted in this population. This study is designed to improve or 
forestall cognitive decline in CKD patients by establishing an intervention that is 
implemented individually in the community, and will provide the first step in providing an 
effective treatment designed to delay physical and cognitive function-related loss of 
independence, and curb the escalating costs in the growing CKD population. This is a 
population with accelerated brain aging and a high prevalence of cognitive impairment, 
making the potential clinical impact tremendous. 
 
Anticipated risks associate with the study: We will monitor heart rate and blood pressure 
during all testing. There is a very small risk associated with the 6 minute walk exercise 
test and training.  The risk of serious adverse events (such as death or heart attack) 
with maximal exercise testing has been estimated to be 0.5 per 10,000 tests (Stuart, 
1980 Chest), the risk of death associated with a 6-minute walk is currently not known, 
but is considered minimal risk.  The exercise test (6 minute walk) and training proposed 
in this study is considered no more than usual activity of daily living and is considered 

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moderate intensity exercise.  There is a slight risk of abnormally high blood pressure, 
shortness of breath, muscle injury, and muscle soreness associated with exercise 
training in a sedentary (not used to exercise) population. There is a slight risk for pain 
and bruising with the venipuncture.   There is a slight risk for loss of confidentiality 
(being identified) and there may be some discomfort felt by participants when answering 
questions about their medical history and during cognitive testing: The risks associated 
with the procedures of this study are minimal – no greater than those encountered 
during daily life. MRI scans: The MRI does not use x-ray radiation or radioactive 
material. The magnetism of the machine attracts certain metals, which could put 
participants at risk. Therefore, people with pacemakers, infusion pumps, metal 
prostheses, metallic-backed transdermal patches or metallic shrapnel will be excluded 
from the study.  A checklist will be completed that addresses issues of MRI safety. 
Some people may feel somewhat closed-in (claustrophobic) during the MRI procedure. 
The MRI scans can get quite noisy and this may cause some discomfort. We will 
provide padding, a blanket, and ear plugs to ensure comfort. During the vascular 
testing; the blood pressure cuff could feel too tight and it may cause discomfort and 
there might be pressure on the neck from the ultrasound Doppler transducer, which 
could feel uncomfortable. Participants’ can withdraw at any time and we will closely 
monitor them to ensure safety and comfort.  
Anticipated Benefits: This is a pilot study for feasibility and no benefits should be 
expected. Walking exercise training has been associated with significant improvement 
in fitness (aerobic capacity), blood pressure, and ability to perform activities (physical 
function). The effect of exercise training on cognition is promising, but currently 
unknown. 
Subject population: We anticipate randomizing 72 men and women with and without 
CKD between 60 and 80 years of age with no contraindications to moderate-intensity 
exercise that answered “yes” to the question “Do you feel like your memory or thinking 
skills have gotten worse recently?”.  (please see detailed inclusion/exclusion criteria, 
section 4), In order to achieve this we anticipate sending 2000 letters to potential 
participants at UIC. 
 

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2.0 
Background/Scientific Rationale  
Patients with CKD have more than a two-fold increased risk of cognitive impairment 
than those without CKD.1-3 As many as 20-50% of patients with moderate CKD have 
established cognitive impairment or overt dementia.1-7 Cognitive impairment leads to 
decreased medical care compliance, functional decline and loss of independence.8 
There are no recommended treatments to prevent cognitive decline in CKD patients. 
There is therefore a need for therapies aimed to improve cognitive outcomes in older 
patients with CKD. The accelerated cognitive decline in older CKD patients is due, in 
part, to the CKD disease process itself, which creates a toxic vascular milieu that 
consists of chronic inflammation, oxidative stress, uremia, and systemic vascular 
endothelial dysfunction. This toxic internal vascular milieu leads to vascular dysfunction 
related impairment of the white matter that is superimposed on neurodegenerative 
damage.9 The white matter is important for coordinating interactions between different 
regions of the brain and is essential for normal functioning of the brain.10-14 Impaired 
white matter integrity appears to be a primary contributor to cognitive decline in CKD 
and is strongly affected by the internal vascular milieu.10,11 We have previously 
demonstrated that exercise training improves the vascular milieu in patients with CKD 
by reducing systemic inflammation and oxidative stress, and improving vascular 
function.15,16 Regular exercise and higher fitness levels in non-CKD patients with and 
without cognitive impairment has been associated with improved cognitive function, 
white matter integrity, and hippocampal volume suggesting a possible cerebro-
protective effect of exercise.17-28 This is conjectured to be due to an improvement in 
vascular function related increases in cerebral blood flow.18 The effect of exercise 
training on cognitive function and white matter integrity in CKD patients is unknown. 
 
3.0 
Objectives/Aims 
This is a pilot study for feasibility. The objective of this study is to test the hypothesis 
that older participants with moderate/severe chronic kidney disease (CKD) and 
preclinical cognitive impairment randomized to a 6-month home-based exercise 
program (n=12), will improve cognitive functioning and white matter integrity (WMI), 
compared to participants in a usual care control group (n=12). Our central working 
hypothesis is that the accelerated cognitive decline that occurs in CKD results, in part, 
from a vascular-dysfunction induced impairment of white matter integrity that is 
superimposed on a neurodegenerative process, and that exercise training may provide 
a cerebro-protective effect by improving systemic and cerebral vascular health.  
 
Aim 1: Determine the feasibility and preliminary efficacy of a 6-month home-based 
exercise program to improve or maintain cognitive function in older participants with 
moderate/severe CKD and preclinical cognitive impairment, compared to usual care 
control group.  

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Hypotheses: Participants in the exercise group compared to the usual care control 
group at 6-months will:   
H1a. Demonstrate a higher score on composite global cognitive functioning.    
H1b. Demonstrate higher scores on executive functioning, learning/memory, and 
attention/information processing. 
Aim 2. Determine the cerebro-protective effect of a 6-month exercise program 
compared to usual care on white matter integrity as quantified by Diffusion Tensor 
Imaging (DTI)-derived MRI measures of mean diffusivity (MD) and fractional 
anisotrophy (FA). Intact white matter is important because it allows the brain to function 
properly and these are indices of white matter integrity.  
H2a. Participants in the exercise group will demonstrate an improvement in 
overall white matter integrity as measured by DTI, i.e., lower MD and higher FA, 
compared to control.   
H2b. Change in cognitive function will be positively correlated with change in 
WMI.  
Aim 3 (secondary MRI outcomes): Determine the cerebro-protective effect of a 6-month 
exercise program compared to control on hippocampal volume and cerebral blood flow.  
Hypothesis:  Participants in the exercise group will have a larger hippocampal volume 
and improved cerebral blood flow post 6-month intervention, compared to the control 
group.  
 
Study Duration: 12 months.  Study duration for enrolled participants is anticipated to be 
27 weeks. 
 
4.0 
Eligibility 
 
The eligibility check lists are attached. The PI (Ulf G. Bronas) will ensure that subjects 
meet eligibility requirements. An eligibility checklist will be completed prior to any study 
participation during the initial phone screen and during the initial visit following informed 
consent. Eligibility criteria will be continuously monitored by the PIs and document via 
an eligibility checklist at baseline and at the 24 week follow up. 
 
4.1 Inclusion Criteria (self-reported and ICD code) 
• English speaking men and women 
• 60-80 years of age,  
• self-experienced persistent decline in cognitive capacity determined as self-
reported cognitive complaint (i.e., answering “yes” to the question: “Do you feel 
like your memory or thinking skills have gotten worse recently?” (before any 
clinical impairment of cognition has occurred);26,29,30  
• no history of major head trauma. 
 
4.2 Exclusion Criteria (self reported or ICD code) 

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• Diagnosed Dementia or a score of <2 on the mini-cog assessment 
• Ischemic ulcerations or gangrene on the feet or legs;  
• Participating in a supervised exercise program with intent to increase 
fitness levels 3 days/week, 
• Requires assistive ambulation;  
• Limited exercise capacity due to conditions other than claudication 
o unstable angina,  
o Claudication 
o severe arthritis,  
o extreme dyspnea on exertion,  
o unstable coronary artery disease;  
o Class III-IV heart failure;  
o Current uncontrolled sustained arrhythmias,  
o severe/symptomatic aortic or mitral stenosis, 
o  hypertrophic obstructive cardiomyopathy,  
o severe pulmonary hypertension,  
o active myocarditis/pericarditis,  
o thrombophlebitis,  
o recent systemic/pulmonary embolus (within 3 months);  
• Resting systolic BP >200 mmHg or resting diastolic BP >110 mmHg;  
• Revascularization procedures within the previous 6 months;  
• Any unforeseen illness or disability that would preclude exercise testing or 
training based on patient provider opinion; 
• Pregnancy 
 
4.3 Excluded or Vulnerable Populations 
Vulnerable populations are not included in this study.  In addition, the following 
populations are excluded from this study: 
1. Pregnant women: Pregnant women are excluded to limit any potential 
influence on measures.  Non-English speaking population:  Non-English 
speaking population will be excluded to allow patients to fully understand the 
English speaking study forms, instructions, and procedures used in this pilot 
study.   
 
5.0 
Subject Enrollment 
Subjects will be recruited through fliers and a recruitment brochure in Chicago, surrounding 
communities, and at the outpatient clinics, and a via letters of invitation at UIC. The UI 
medical center electronic medical records database and the University of Illinois Hospital & 
Health Sciences System Clinical Research Data Warehouse (CRDW) will be employed to 
identify potential patients for the study, following HIPPA standards of authorization.  The EMR 
and The University of Illinois Hospital & Health Sciences System Clinical Research Data 
Warehouse (CRDW) will be searched for diagnosis of CKD using creatinine and estimated 
glomerular filtration rate.  Name, address, email, phone numbers, and medical record number 
will be extracted into a file for research use.    

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1. Patients that have a diagnosis code or meet criteria for CKD based on ICD codes or 
creatinine levels (or estimated glomerular filtration rate) will be sent a letter or an email of 
invitation mentioning that they might be eligible for a research study and why, and a self-
addressed return envelope. Patients will also receive a letter of invitation that that states that 
they should return the envelop (or email) stating that they do not wish to be contacted by the 
research staff via telephone and a self-addressed return envelope.  We will call all patients 
that meet criteria for CKD that did not send back the letter stating that they did not wish to be 
contacted.  Phone calls will start 2 weeks after the mailing has been completed. 
2. We will post media advertisements on sites such as Craig’s list, UIC list-serve, Redeye 
newspaper, and other relevant media using the advertisement called “media ad”. 
3. We will send letters advertising the study to persons over 60 years of age in Chicago and 
surrounding areas using the form titled study interest letter and study brochure.  
4. We will send a notice via the CCTS research match service using the form titled “research 
match”   
5. We will approach patients that have expressed an interest in the study to their provider at 
UIH clinics, this will include a brief medical records review for eligibility. 
 
Individuals who do not qualify for the study will be informed immediately after the 
telephone screening. Following initial screening by phone interview and if no exclusion 
criteria are met and with the participant's consent, they will be scheduled for an initial 
visit during which formal consent procedures will be executed.  After completion of the 
study, we will provide subjects with copies of their records upon request.  Any abnormal 
results will be reported to study participants for appropriate medical follow-up as well as 
their provider upon consent. 
 
Subjects that contact the study team will be given as much time as they feel necessary 
to decide if they would like to participate.  Subjects will be encouraged to ask any 
questions at any time throughout the course of the study.  Research personnel will be 
available to answer these questions.  Subjects will be informed that participating in this 
research is voluntary. Subjects will be informed that they may withdraw from the 
research at any time without penalty.  The patient provider is not part of the study team.   
 
Precautions to protect subject privacy will be taken throughout the course of the study.  
All telephone conversations with potential subjects will be conducted in a private setting. 
Face to face conversations will be conducted within a private setting within the College 
of Nursing clinical health laboratory with private rooms.  Strict procedures will be put in 
place to minimize the risk of breach of confidentiality.  All subjects will be assigned a 
study code.  The master list of the subject’s name and the linked code will be kept by 
the study manager in a locked file cabinet in a locked office.  All information provided by 
subjects will kept strictly confidential and will not be reported on an individual basis.  
None of the information provided by subjects will become part of the medical record.  
Hard copy data will be stored in a locked office, and electronic data will be stored on a 
password-protected computer.  Hard copy and electronic data will be coded, with the 
master list kept separately in a secure file in the principal investigator’s office.  A HIPAA 

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authorization form has been developed for this study to use/disclose protected health 
information.  Subjects will be asked to sign the HIPAA consent form.  Subjects who 
refuse to agree to the HIPAA authorization will not be able to participate in this study. 
 
6.0 
Study Design and Procedures 
This is a pilot study for feasibility. The study is designed as a randomized, controlled 
study.   
Screening procedures: 
1. Subjects will be recruited through fliers and a recruitment brochure in Chicago, 
surrounding communities, and at the outpatient clinics, and a via letters of 
invitation at UIC. The UI medical center electronic medical records database and 
the University of Illinois Hospital & Health Sciences System Clinical Research 
Data Warehouse (CRDW) will be employed to identify potential patients for the 
study, following HIPPA standards of authorization.  The EMR and The University 
of Illinois Hospital & Health Sciences System Clinical Research Data Warehouse 
(CRDW) will be searched for diagnosis of CKD using creatinine and estimated 
glomerular filtration rate.  Name, address, email, phone numbers, and medical 
record number will be extracted into a file for research use.    
1. Patients that have a diagnosis code or meet criteria for CKD based on ICD codes or 
creatinine levels (or estimated glomerular filtration rate) will be sent a letter or an email of 
invitation mentioning that they might be eligible for a research study and why, and a self-
addressed return envelope. Patients will also receive a letter of invitation that that states that 
they should return the envelop (or email) stating that they do not wish to be contacted by the 
research staff via telephone and a self-addressed return envelope.  We will call all patients 
that meet criteria for CKD that did not send back the letter stating that they did not wish to be 
contacted.  Phone calls will start 2 weeks after the mailing has been completed. 
2. We will post media advertisements on sites such as Craig’s list, UIC list-serve, Redeye 
newspaper, and other relevant media using the advertisement called “media ad”. 
3. We will send letters advertising the study to persons over 60 years of age in Chicago and 
surrounding areas using the form titled study interest letter and study brochure.  
4. We will send a notice via the CCTS research match service using the form titled “research 
match”   
5. We will approach patients that have expressed an interest in the study to their provider at 
UIH clinics, this will include a brief medical records review for eligibility. 
 
 
2. Patients who are interested in participating in the study will have a phone 
interview to assess exclusion criteria.  The phone calls will be conducted in by 
the study manager in a private room located at the UIC College of Nursing, room 
229.  It is estimated that the telephone screen will take approximately 10 
minutes. This is the document titled “Telephone Screening-Eligibility checklist” 
and we will follow the telephone screening script titled “Phone Script” 
 
3. a Following initial screening by phone interview the interested participants will 
be scheduled to come in to the College of Nursing 2nd floor Clinical Research 
Laboratory (845 S Damen Ave) room 229. During this visit, the study will be 

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thoroughly explained and all questions will be answered.  Comprehension of all 
study procedures will be ascertained by non-leading open-ended questions.  If 
participants express an understanding of the study and study procedures and 
would like to participate in the study, written informed consent will be obtained.  
No study procedures will take place prior to written informed consent.   
 
3. b Following the informed consent process, medical history, the Charlson co-
morbidity index questionnaire, blood pressure, heart rate, height, and weight, will 
be obtained by the PI and/or research assistant.  If there are no known 
contraindications to exercise the participant will continue study participation. 
These are the documents titled “medical history and “Charlson score tally”  We 
will complete the document titled “In-Person Screening Eligibility Checklist” and 
ask the participant to fill out the form titled “demographics” and the form titled 
“Face sheet”.   
 
3. c. Following these procedures participants will be asked to complete several 
questionnaires to assess their cognitive function. These questionnaires will be 
performed pre- and post-intervention with alternative forms where available to 
avoid practice effects. In addition to an overall global composite of cognitive 
functioning, we will evaluate the following domains of functioning with the below 
noted tests. (time~1 hour): The forms are titled: Learning & Memory=California 
Verbal Learning Test-II (CVLT-II); Attention/Information Processing=Trail Making 
Test Part A (TMT-A) and Digit Symbol Substitution Test (DSST); Executive 
Functioning, Phonemic and Semantic Fluency=Trail Making Test Part B and part 
M (TMT-B) and Digit Span subtest (DSp); Global Cognition=MOCA and WTAR 
(please see enclosed questionnaires). Quality of life will be assessed via the 
kidney disease quality of life questionnaire. These questionnaires will be 
administered at baseline and at 24 week follow up. The study satisfaction 
questionnaire will be administered at 24 weeks only. 
 
Cognitive Outcomes (Table 1) will be performed pre- and post-intervention with 
alternative forms where available to avoid practice effects. In addition to an 
overall global composite of cognitive functioning, we will evaluate the following 
domains of functioning with the below noted tests. (time~1 hour)  
 
Table 1. Cognitive Protocol 
Domain 
Tests 
Outcome variables 
Learning & Memory 
California Verbal Learning 
Test-II (CVLT-II) 
CVLT-II: Trials1-5 and learning 
slope; Long Delay Free Recall and 
Recognition Memory Discriminability  
Attention/Information 
Processing 
Trail Making Test Part A 
(TMT-A); Digit Symbol 
Substitution Test (DSST) 
TMT-A time to completion and 
errors; DSST time to completion and 
errors 
Executive 
Functioning 
Phonemic and Semantic 
Fluency; Trail Making Test 
Total correct words produced for 
Phonemic and Semantic fluency 

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Part B (TMT-B); Digit 
Span subtest (DSp) 
separately; TMT-B time to 
completion and errors; DSp total 
score 
Global Cognition 
MOCA and WTAR*  
Total MOCA score; WTAR 
Estimated verbal IQ 
*WTAR will only be given once as premorbid IQ is not anticipated to change with 
intervention 
 
3. d. Following these procedures a CCTS travel nurse will perform a standard 
venipuncture.  Ten milliliters will be collected for determination of complete 
blood cell count and basic metabolic panel in order to characterize the sample. 
Coded blood samples will be analyzed by Quest diagnostics. An additional 10 
ml will be collected for analysis of vascular health biomarker in Dr. Bronas lab.   
 
3. e. Following blood draw we will ask the participants to perform the short 
physical performance battery; participants attempt to stand for 10 seconds with 
their feet side by side, standing with the side of the heel of one foot touching the 
big toe of the other foot for about 10 seconds; and with the heel of one foot in 
front of and touching the toes of the other foot for about 10 seconds, they will 
then walk at a normal speed for a total of 4 meters (this test is repeated twice); 
the last part is called a chair rise where participants stand up from a chair 5 
times (see manual in the appendix).  Thereafter a 6-minute walk will be 
performed to determine total walking distance.  Participants will follow standard 
testing procedures for older patients. Participants will be asked to walk up and 
down a 100 foot long corridor as fast as they can without running. They will turn 
around a cone placed at each end of the walk. No encouragement will be given 
and participants will be allowed to stop and rest whenever they need. Heart rate 
(measured by a polar heart rate monitor) will be monitored at rest, during and 
following the walking test to ensure safety. Blood pressure will be assessed prior 
to and immediately following the 6-minute walk. The 6-minute walk is considered 
to be within usual activities of daily living and should not pose any risk to 
participants. The 6-minute walk test is an accepted method for determination of 
total walking distance in older adults with chronic illness (see appendix for 
manual). The document used are titled “6 minute walk test” and Short Physical 
Performance Battery”. These will be administered at baseline and at the 24 
week follow up.   
 
The total time estimated for visit 1 is 2-3 hours. 
 
Following completion of the initial visit we will ask the participants to wear a 
physical activity monitor, similar to a fancy pedometer, (actigraph GXT3 the size 

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of a small matchbox) on their hip for one week in order to collect their usual 
activities of daily living. 
 
Visit 2 (about 1 week following visit 1): If able to undergo MRI scan: The patient 
will return to UIC and the center for Magnetic Resonance Imaging Center UIC 
2242 W. Harrison St. Chicago IL 60612.  During visit 2 we will ask participants 
to have their brain imaged by an MRI machine for assessment of their brain 
structure. The imaging will be performed on GE 3T MRI research dedicated 
scanner (MR 750) pre- and post-intervention. Padding will ensure comfort and 
limit excessive motion during scanning. After a brief scout image for localization, 
we will acquire the following whole brain images using diffusion tensor imaging, 
DTI; T1- and T2-weighted imaging; and arterial spin labeling (ASL). 
(time~1hour) 
 
Image acquisition will be performed on GE 3T MRI research dedicated scanner (MR 
750) pre- and post-intervention. After a brief scout image for localization, we will acquire 
whole brain images using diffusion tensor imaging (DTI); and high-resolution 3D T1-
weighted imaging. We will determine and quantify white matter integrity (DTI-FA/MD); 
and hippocampal volume (T1). These are indices of alterations of brain inter-
connections, structure, and function, which are associated with cognitive functioning 
(details, table 2).    
Table 2. Imaging Parameters 
Technique 
Purpose 
Parameters (TE=echo time; TR=repetition time; 
BW=bandwidth; FOV=field of view; TI=inversion time) 
DTI 
White matter 
integrity 
(FA/MD) 
quantification 
single-shot EPI & parallel imaging using the same 32-
channel phased-array head coil; TE/TR~70/5525ms, b-
values 0,1000s/mm2, 33 directions, FOV=20cm2, matrix 
160x160, NEX 2, parallel imaging acceleration factor 2; 
6 B0 images, Slice thickness 3 mm 
T1/BRAVO Hippocampal 
Volume 
Quantification 
Coronal; TI=4.5, Flip=13º, 1.5mm slice thickness, no 
gap, BW=±25kHz, FOV=22cm2 
T2-FLAIR 
White matter 
hyperintensity 
quantification  
Coronal; TE/TR=104.5/9500ms, TI=2.5sec, FOV 22cm2 
ASL 
Cerebrovascular 
perfusion 
Cerebral blood 
flow 
axial; Spiral-FSE acquisition; post-label delay time = 1.8 
sec, TE/TR=minimum, flip angle=90°, slice thickness = 
3-5 mm, matrix size = 128x128, FOV 22cm2 
Resting-
state fMRI 
Resting state 
networks 
Subjects will be instructed to keep their eyes open, 
focus on a fixation point, and “not think of anything in 
particular”. Resting-state data will be acquired: total 
scan time = 8 minutes.  
 

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Image Analyses DTI: FSL with TBSS, we will quantify FA and MD from whole brain 
and tract specific white matter. T1/FSPGR: Using FreeSurfer, we will extract 
hippocampal volumes (right and left) as well as sub-fields of the hippocampas adjusted 
for intracranial volume.T2-FLAIR: Using standard software, we will quantify white matter 
hyperintensity volumes across the entire brain white matter.  We will use a seed-based 
approach to measure resting state networks of interest. Functional connectivity 
networks: Functional brain networks will be generated using the resting-state fMRI 
toolbox, CONN (http://www.nitrc.org/projects/conn; (Whitfield-Gabrieli and Nieto-
Castanon, 2012)). In brief, raw EPI images are realigned, co-registered, normalized, 
and smoothed before analysis.  Any confound effects from motion artifact, white matter, 
and CSF are regressed out of the signal. Using the same label maps as the structural 
brain networks, functional brain networks will derived using pairwise BOLD signal 
correlations. 
 
The total estimated time during visit 2 is 1-2 hours. 
 
Visit 3. (about 1 week following visit 2): During this visit we will assess vascular 
health (arterial stiffness, endothelial function, and carotid artery compliance).  
 
Participants will be asked to come back the college of nursing in the morning 
between 7-11:00 am following an overnight fast with no caffeinated or sugary 
beverages in the morning of the test.  This is done to avoid any diurnal variability.  
Following a 15-minute supine rest will assess several vascular health indices 
listed below:  
 
Arterial Stiffness will be measured using carotid-femoral pulse wave velocity 
following standard procedures:   
1. A blood pressure cuff is placed around the upper arm and is automatically 
inflated and deflated for determination of blood pressure and for pulse wave form 
analysis.  This is similar to a usual blood pressure assessment during a clinical 
visit.  
2. A blood pressure cuff will be placed around the upper thigh of the subject and 
a hand-held tonometer (similar to the eraser end of a pencil) will be placed overt 
the carotid (neck) artery.  Once the tonometer detects a carotid pulse the blood 
pressure cuff is inflated (similar to a blood pressure obtained in a clinical visit, but 
on the upper thigh) and the pulse wave form is automatically collected.  This 
measure will be repeated 3 times and the average pulse wave velocity will be 
used. Total time=10 minutes 
 
Endothelial function will be assess using brachial artery flow mediated 
vasodilation following standard guidelines:   
1. The participant’s brachial artery in the upper arm will be imaged using 
ultrasound. The ultrasound transducer will be placed on the participant’s upper 
arm and a baseline picture of the brachial artery will be obtained.  
2. A blood pressure cuff will be placed on the forearm of the participant.  The 
blood pressure cuff will be inflated to 20 mm Hg above the systolic pressure for 5 

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minutes followed by a rapid deflation of the cuff.  The brachial artery will be 
imaged for 3-5 minutes follow deflation of the cuff.  Total time=10 minutes 
 
Carotid artery compliance will be assessed using ultrasound of the carotid artery.  
The carotid artery will be imaged using ultrasound.  The ultrasound transducer 
will be placed over the carotid artery and the carotid artery will be imaged for 
approximately 30 seconds.   
 
Following the vascular assessment, the NIH Toolbox measures for Cognitive 
function will completed using the standard NIH Ipad (see administration manual): 
C.2.1 NIH Toolbox Picture Vocabulary Test page 46  
C.2.2 NIH Toolbox Flanker Inhibitory Control and Attention Test page 49  
C.2.3 NIH Toolbox List Sorting Working Memory Test page 61  
C.2.4 NIH Toolbox Dimensional Change Card Sort Test (DCCS) page 82  
C.2.5 NIH Toolbox Pattern Comparison Processing Speed Test page 109  
C.2.6 NIH Toolbox Picture Sequence Memory Test page 118  
C.2.7 NIH Toolbox Oral Reading Recognition Test page 137  
C.2.8 Oral Symbol Digit Test page 140  
C.2.9 Auditory Verbal Learning Test (Rey) page 142  
 
 
Following the NIH Toolbox measures for Cognitive function, the NIH toolbox 
motor measures will completed using the standard NIH Ipad (see administration 
manual): 
Pegboard dexterity test 
Balance measures with the addition of iPod app for assessment of sway. 
Two-minute walk (already assessed at visit 1, already IRB approved) 
Timed-up and go (TUG) 
Grip strength (using handheld dynamometer) 
4 meter walk (already IRB approved and assessed during visit 1) 
 
Upon completion of Visit 3, the patient will be randomized to the 24-week walking 
program or usual care.  The randomization will be assignment by chance using a 
1:1 chance of being assigned to the exercise group over the usual care group. 
Participants cannot choose which exercise group they will be in.  The assignment 
is done by a randomized numbers table in computer program that acts like 
flipping a coin to decide which group they will be placed in.   
 
The total estimated time during visit 3 is 1-2 hours. 
 
The exercise training group will participate in an educational session on 
walking exercise for CKD during visit 2. Participants will receive a packet of 
information previously developed by the PI with exercise prescription and 
information, and a heart rate monitor that monitors the exercise. The documents 
handed out to the exercise group are titled “Exercise Recommendations” and 
“work effort scale”.We will work with the participant to 1) set up a schedule that 

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fits with the participant’s schedule for home-based exercise; 2) identify time-slots 
for exercise; 3) work with the participants to assess their readiness to do 
exercise; 4) address perceived barriers to exercise, and 5) build a relationship 
with the participants to provide support and address concerns. This will be done 
to empower participants to take individual control of the exercise program. 
Participants will be asked to exercise (a brisk walk) at home, 3 times per week, 
for 30-60 minutes for 24 weeks.  
 
Participants randomized to the exercise group will be contacted via phone 
biweekly or more frequently if they are slightly behind the exercise routine, and 
we will meet with them once per month to provide encouragement and 
progression of exercise, and to download the heart rate monitor. Participants will 
have to option to upload their physical activity remotely if they prefer, but they will 
still be asked to meet in person as scheduled. This system will allow us to 
monitor and address any issues to achieve optimal compliance to the 
intervention. We have successfully conducted this type of partially supervised 
exercise program in CKD patients with excellent adherence and compliance rate 
(80-87%). 
 
The monthly meetings (once per month) will occur at months, 1, 2, 3, 4, and 5 
following randomization.  The PI and study staff will continue to work with the 
participants to assess their readiness to do exercise; 2) address perceived 
barriers to exercise, and 3) provide support and address concerns related to the 
exercise program. The meetings will last 30 minutes.  We will assess for any 
adverse events during the bi-weekly phone calls using the document title 
“Adverse Event Monitoring”. The total number of visits in the exercise group is 
11.  
 
Usual medical care control group 
The usual care group will receive standard instructions on exercise for patients 
with kidney disease. These documents are titled “Exercise Recommendations” 
and “work effort scale”.This is similar to what is commonly done in clinical 
practice. The control group will not receive an exercise prescription or heart rate 
monitor. Participants will be contacted via phone biweekly to answer any 
questions and ensure continued study participation.  In order to minimize any 
feeling of disenfranchisement in the control group we will offer them the exercise 
training prescription following all post-test data collection procedures. The usual 
care group will NOT meet monthly.  We will assess for any adverse events during 
the bi-weekly phone calls using the document title “Adverse Event Monitoring”. 
The total number of visits for the usual care group is 5. 

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Ten participants with an eGFR of >60 ml/min will only undergo baseline testing and 
not partake in the intervention or follow up.  We will ask if the participants with an 
eGFR >60 ml/min prefer to only to the baseline versus intervention. 
 
Follow-up testing will occur at 24 weeks over 2 visits about 1 week apart.  During 
the follow up testing we will ask participants to perform one 6-minute walk test 
and the short physical performance battery, and the NIH toolbox measures as 
described above, as well as completing the questionnaires and imaging 
procedures described above.   
 
During the 24-week visit we will query patients using structured interviews and 
open-ended questions as to whether participants liked the independent home-
based walking program. Study satisfaction will be assessed using a likert scale 
and open-ended question at the end of the 24 week follow up test..   
 
Physical activity and exercise monitoring and Assessment of Adherence to 
Exercise Rehabilitation Program (fidelity of treatment): 
1. Adherence to the exercise program in the intervention group will be tracked 
using a heart rate monitor.  The heart rate monitor will track when exercise 
training has been performed (date), duration of the exercise, and the intensity of 
the exercise.  These data will be downloaded at each monthly visit to assess 
adherence to the program (this is coded data).  Adherence and volume of 
exercise will be calculated as number of exercise sessions performed divided by 
number of prescribed exercise session x 100.   
 
2.  We will also ask all participants regardless of group assignment to wear the 
lightweight accelerometer worn on the hip (Actigraph GTX3, Actigraph) for 7 days 
at weeks 6, 12, 18, and 24 following randomization. Participants will be mailed 
the actigraph and reminded to wear it during the biweekly phone calls. They will 
be asked to return the actigraph after 1 week using a stamped self-addressed 
return envelope. This is done to assess daily physical activity and is not an 
intervention.56 
 
 
The study manager will be trained and checked off by the PI in the measurement 
of the 6-minute walk and short physical performance battery.  Fidelity and 
competence will be continuously monitored by the PI and protocol fidelity will be 
ascertained during bi-weekly phone calls and the once per month visits.  
 
 
 
 

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7.0 
Expected Risks/Benefits 
Risk associated with the medical history assessment 
Discomfort could be felt by participants when answering questions about their 
medical history. 
Risk associated with the physical function battery 
There is a slight risk of falling during the balance testing.  
Risk associated with the 6 minute walk 
There is a slight risk of abnormally high blood pressure, shortness of breath, 
muscle injury, and muscle soreness.  The risk of serious adverse events with 
maximal exercise testing has been estimated to be 0.5 per 10,000 tests (Stuart, 
1980 Chest), the risk of death associated with a 6-minute walk is currently not 
known, but is considered minimal risk.  The exercise test (6 minute walk) 
proposed in this study is considered no more than usual activity of daily living 
and is considered moderate intensity exercise.  There is a risk that underlying 
disease may be uncovered during study participation. This would most likely be 
undiagnosed cerebrovascular disease, previous stroke or mini-stroke.  These 
findings would be immediately related to the patient and the providers (upon 
patient approval).  These findings may require additional testing and procedures 
as deemed necessary by the patient's provider.   
Risks associated with the walking exercise training 
There is a slight risk of injury associated with exercise training in a sedentary. 
population.  There is a slight risk of abnormally high blood pressure, shortness 
of breath, muscle injury, and muscle soreness associated with exercise training 
in a sedentary (not used to exercise) population.  The risk of serious adverse 
events with maximal exercise testing has been estimated to be 0.5 per 10,000 
tests (Stuart, 1980 Chest), the risk of death associated with walking exercise 
training is currently not known, but is considered minimal risk.  The exercise 
training proposed in this study is considered no more than usual activity of daily 
living and is considered moderate intensity exercise.  There is a risk that 
underlying disease may be uncovered during study participation. This would 
most likely be undiagnosed cerebrovascular disease, previous stroke or mini-
stroke.  These findings would be immediately related to the patient and the 
providers (upon patient approval).  These findings may require additional testing 
and procedures as deemed necessary by the patient's provider.   

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Risks associated with the venipuncture (blood draw) 
The blood draw may cause pain and bruising. There is a slight risk for infection, 
lightheadedness and fainting. 
Risk associated with the cognitive function questionnaires.  
There is a slight risk that participants will feel uncomfortable with filling out the 
questionnaires. Participants could find answering the questions boring and/or 
tiring. We will monitor the progress and allow participants to take breaks as 
needed. If they become upset or uncomfortable, they may skip a given question. 
Risks associated with the MRI: 
The MRI does not use x-ray radiation or radioactive material. The magnetism of 
the machine attracts certain metals, which could put participants at risk. 
Therefore, people with pacemakers, infusion pumps, metal prostheses, metallic-
backed transdermal patches or metallic shrapnel will be excluded from the 
study.  A checklist will be completed that addresses issues of MRI safety. Some 
people may feel somewhat closed-in (claustrophobic) during the MRI procedure. 
The MRI scans can get quite noisy and this may cause some discomfort. We will 
provide padding, a blanket, and ear plugs to ensure comfort. This risk is 
minimized by careful screening by qualified research personnel prior to entry 
into the MRI room. Subjects with metal implantations will not be recruited. 
Participants’ can withdraw at any time and we will closely monitor them to 
ensure safety and comfort. 
Risks associated with ultrasound procedure: 
 
There could be pressure felt on the neck from the hand-held tonometer, which 
might make participants feel uncomfortable.  The inflation of the blood pressure 
cuffs might feel too tight and cause discomfort (similar to that of having a blood 
pressure measured in clinic).   
The blood pressure cuff could feel too tight and it may cause discomfort and 
pain.  
There might be pressure on the neck from the ultrasound Doppler transducer, 
which could feel uncomfortable 
If any of these occur the measurement will stop immediately.  
 
8.0 
Data Collection and Management Procedures 
 
Results from all measurements, and questionnaires will be recorded on coded 
source documents before being entered into the electronic database that is 
password protected and housed on a secure CON server that only the PIs and 
statistician have access to.  Source documents will be stored in a locked file 
cabinet in a locked office that only the PIs have access to.  coded exercise data 
from the heart rate monitor and actigraph will be downloaded at each follow-up 

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visit to a password protected secure CON server and analyzed before being 
entered into the main database as described above.   
 
 
9.0 
Data Analysis 
Dr. Alana Steffen of the College of Nursing statistician will conduct all analyses.  
The apriori stated analysis is listed below. 
This is a pilot study for feasibility. For these pilot data we will emphasize 
descriptive statistics such as means, standard deviations, effect sizes, medians, 
interquartile ranges, frequencies, and percentages to demonstrate the feasibility 
of recruitment, adherence, and retention, treatment effects over time, and proof 
of concept.  Our statistical approach for a full trial of these hypotheses will be 
Generalized Linear Mixed Models (GLMM) with an identity link function for a 
continuous outcome or a logit link function for a binary outcome.  Conceptually, 
GLMM is a more advanced version of repeated measures ANOVA that can 
account for potential correlation among multiple measurements over time while 
having flexibility in fitting outcomes with different distributions (such as normal, 
binomial or Poisson, etc.). One advantage of this approach over repeated 
measures ANOVA is that there is no assumption that participants are measured 
at every, or even the same, time points. Therefore, these models are very 
flexible at handling missing data. Participants who have a missing observation 
are not excluded, thus, this produces the intention to treat (ITT) full information 
maximum likelihood (FIML) model.  Conducting these models on pilot data help 
with sample size calculations for a future R01 submission. 
   
10.0 Quality Control and Quality Assurance 
Data will be evaluated for protocol adherence during weekly meetings with the 
PIs and the study manager. Dr. Bronas will evaluate all data for quality during 
weekly study meetings. Biweekly visits will be conducted by the PI to ensure 
that data collection is carried out according to the protocol. 
   
11.0 Data and Safety Monitoring 
Serious adverse events will be monitored and tracked at each follow-up period 
and biweekly phone calls.  Patients will be queried at the biweekly phone calls 
and at 24 weeks if they have had any visits to the emergency department or 
hospitalizations (see attached checklist).  We will also ask if they have had any 
symptoms of cardiac-related problems such as chest, arm or jaw pain while 
exercising or not exercising. Data will be recorded on an excel spreadsheet and 
reviewed by the PI at weekly study meetings.  Any unanticipated adverse events 
or problems will be reported to the IRB within 7 days on notification.  Ulf G. 
Bronas, PhD, ATC, FSVM, FAHA will monitor safety data.  Subjects are free to 
withdraw from the study at any time.  If a subject withdraws from the study we 
will ask the subject (only once) if they are willing to come back for the follow-up 
tests.  If the subject does not want to complete the study, not further contact 
attempts will be conducted and the subject will be discontinued from the study 
(this will be reported at the annual continuing review).  

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This study is funded by the Midwest Roybal Center for Health Promotion and 
Translation and is required to follow their NIH approved DSMB plan outlined 
below:  The PI will be responsible for ensuring participants' safety on a daily 
basis.  The Safety Officer (SO; Dr. Susan Hughes, Roybal PI) in conjunction 
with a Data Safety Monitoring Roybal Center Committee will act in an advisory 
capacity to the NIA Director to monitor participant safety, evaluate the progress 
of the study, to review procedures for monitoring the confidentiality of the data, 
the quality of data collection, management, and analyses. 
 
Safety Officer Membership and Affiliation. 
Dr. Susan Hughes, Midwest Roybal grant PI, has accepted the position as the 
Safety Officer and will work with the study PI to review pilot study data and 
safety monitoring.  
Title: Co-Director, Center for Research on Health and Aging and 
         Professor, Community Health Sciences  
 
Organization/Affiliation: Institute for Health Research and Policy and School of 
Public Health, UIC 
 
Data Safety Monitor Committee 
Dr. Susan Hughes will serve as chair of the committee, and as SO for any 
adverse event reports. Other members will include David Marquez, PhD 
(Kinesiology), Margaret Baumann, MD (Medicine), and Laurie Ruggiero, PhD 
(School of Public Health) 
 
Conflict of Interest for SO. 
 
The SO and DSM committee will adhere to the Conflict of Interest Policy and 
procedures of the University of Illinois.  
 
The PI will meet semiannually with the DSM Committee, either in-person or by 
teleconference call to review study progress, data quality, and participants’ 
safety. Written summary reports will be submitted twice a year and will include 
a detailed analysis of study progress, data and safety issues. The PI will be 
informed of serious adverse events as soon as they occur and will notify the SO 
within 24 hours of notification. In addition, serious adverse events will be 
reported to the UIC IRB and NIA consistent with their established protocols. 
 
Content of Data and Safety Monitoring Report/SO Reports. 
 
The content of the SO report will include study status/quality, participant 
descriptive information, adverse events, and dropout rates/reasons. 
 
Protection of Confidentiality. 
 

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Data will be presented to the SO and DSM committee in a blinded manner 
during meetings and in written reports. The content of the SO reports and 
discussions will be treated as confidential. Participant identities will not be 
known to the SO. 
 
SO and DSM committee Responsibilities.  
 
The responsibilities of the SO DSM committee include: 
• 
Review the research protocol, informed consent documents and plans for 
data safety and monitoring; 
• 
Recommend subject recruitment be initiated after receipt of a satisfactory 
protocol; 
• 
Evaluate the progress of the trial, including periodic assessments of data 
quality and timeliness, recruitment, accrual and retention, participant risk versus 
benefit, performance of the trial sites, and other factors that can affect study 
outcome; 
• 
Consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an 
impact on the safety of the participants or the ethics of the trial; 
• 
Review study performance, make recommendations and assist in the 
resolution of problems reported by the Principal Investigator; 
• 
Protect the safety of the study participants;  
• 
Report to NIA on the safety and progress of the trial; 
• 
Make recommendations to the NIA and the Principal Investigator 
concerning continuation, termination or other modifications of the trial based on 
the observed beneficial or adverse effects of the treatment under study; 
• 
Ensure the confidentiality of the study data and the results of monitoring; 
and  
• 
Assist the NIA by commenting on any problems with study conduct, 
enrollment, sample size, and/or data collection. 
 
Serious adverse events will be monitored and tracked during each phone call 
(every two weeks).  Patients will be queried they have had any visits to the 
emergency department or hospitalizations.  We will also ask if they have had 
any symptoms of cardiac-related problems such as chest, arm or jaw pain while 
exercising or not exercising. Lastly, we will ask patients if they have had any 
falls. Data will be recorded on an excel spreadsheet and reviewed by the PI 
and study team at weekly study meetings. 
 
12.0 Statistical Considerations 
Dr. Alana Steffen of the College of Nursing statistician will conduct all analyses.  
The apriori stated analysis is listed below. 
This is a pilot study for feasibility. For these pilot data we will emphasize 
descriptive statistics such as means, standard deviations, effect sizes, medians, 
interquartile ranges, frequencies, and percentages to demonstrate the feasibility 
of recruitment, adherence, and retention, treatment effects over time, and proof 

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of concept.  Our statistical approach for a full trial of these hypotheses will be 
Generalized Linear Mixed Models (GLMM) with an identity link function for a 
continuous outcome or a logit link function for a binary outcome.  Conceptually, 
GLMM is a more advanced version of repeated measures ANOVA that can 
account for potential correlation among multiple measurements over time while 
having flexibility in fitting outcomes with different distributions (such as normal, 
binomial or Poisson, etc.). One advantage of this approach over repeated 
measures ANOVA is that there is no assumption that participants are measured 
at every, or even the same, time points. Therefore, these models are very flexible 
at handling missing data. Participants who have a missing observation are not 
excluded, thus, this produces the intention to treat (ITT) full information maximum 
likelihood (FIML) model.  Conducting these models on pilot data help with sample 
size calculations for a future R01 submission. 
   
This is a pilot study investigating the feasibility and proof-of-concept.  There is no 
power-calculation for this study:  This study may not be powered to find 
statistically significant differences between groups due to the smaller sample 
size.  Based on previous studies, we do expect to find at a minimum a trend for 
improvement cognitive function and brain structure.  We expect to be able to use 
these data for determination of the necessary sample size for detection of 
significant differences between groups 
 
13.0 Regulatory Requirements 
13.1 Informed Consent 
Each interested subject will be mailed a copy of the consent form 1 week prior to 
scheduling the initial consent visit.  This will be done to allow potential subjects 
sufficient time to consider participation. Informed consent will be obtain in the 
CON Health Research Laboratory 229 at the baseline visit. Informed consent will 
be obtained using procedures and documents understandable to the subject.  
Individuals who are unable to give informed consent will be excluded from 
participation in this research.  All study personnel will have received the required 
UIC CITI and HIPAA training prior to initiation of the study.  The PI (Ulf Bronas), 
and the study manager will obtain consent.  Subjects that contact the study team 
will be given as much time as they feel necessary to decide if they would like to 
participate.  Subjects will be encouraged to ask any questions at any time 
throughout the course of the study.  Research personnel will be available to 
answer these questions.  Subjects will be informed that participating in this 
research is voluntary. Subjects will be informed that they may withdraw from the 
research at any time without penalty.  Patient providers are not part of the study 
team.  Informed consent documents will be kept in a locked file cabinet in a 
locked office separate from other study documents.  Only the PI (Ulf Bronas) will 
have access to these files.   

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We have requested approval for a waiver of consent for recruitment purposes 
only to identify potential subjects from the medical records.  We will only obtain 
patients name, address, medical record number, and whether they have the ICD 
code for diagnosis of CKD.  This is minimal risk. We are requesting an alteration 
of consent to conduct the telephone screening for all potential subjects that have 
expressed an interest in the study and would like to be contacted by the stud 
team.  The telephone screen will be used to determine initial eligibility and to 
schedule the consent visit.  The telephone screen is minimal risk.  The only 
potential risk to participating in the telephone screen is loss of confidentiality.  
The initial telephone screening and interview is a component of the study and 
involves an assessment to determine if individuals potentially interested in 
participating meet the preliminary qualification criteria and attests to their interest 
in participating in the entire study.  Candidates who meet the screening criteria 
and agree to participate will be invited to schedule an initial visit during which 
formal written consent processes will be executed.  The telephone screening 
obviates the need for unnecessary visits to UIC.  This represents an alteration in 
the consent process 
13.2 Subject Confidentiality  
Precautions to protect subject privacy will be taken throughout the course of the 
study.  All telephone conversations with potential subjects will be conducted in a 
private setting.  Face to face conversations will be conducted within a private 
setting within the College of Nursing clinical health laboratory with private rooms.  
Strict procedures will be put in place to minimize the risk of breach of 
confidentiality.  All subjects will be assigned a study code.  The master list of the 
subject’s name and the linked code will be kept by the study manager in a locked 
file cabinet in a locked office.  All information provided by subjects will kept 
strictly confidential and will not be reported on an individual basis.  None of the 
information provided by subjects will become part of the medical record.  Hard 
copy data will be stored in a locked office, and electronic data will be stored on a 
password-protected computer.  Hard copy and electronic data will be coded, with 
the master list kept separately in a secure file in the principal investigator’s office.  
A HIPAA authorization form will be developed for this study to use/disclose 
protected health information.  Subjects will be asked to sign the HIPAA consent 
form.  Subjects who refuse to agree to the HIPAA authorization will not be able to 
participate in this study. Study data will be coded in numerical order (e.g. 
CKD001, CKD002 etc.). The link to the code will be maintained by the project 
manager and will be kept in a locked file cabinet in a locked office separate from 
study data.  An electronic copy of the masterfile will be kept in a folder, separate 
from the data and study forms, on a UIC secured drive. The project manager and 
PIs will have access to the code.   The link to identifiers will be destroyed after 6 

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years.  The study statistician will have access to the de-identified database for 
analysis purposes.   
13.3 Unanticipated Problems 
• All study-related, serious, unanticipated adverse events will be reported to the 
IRB within 48 hours of discovery.  Other unanticipated events will be reported to 
the IRB at the time of continuing review.  We will comply with university policies 
and procedures regarding any unforeseen identifiable data loss. 

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14.0 References 
1. Kurella M, Chertow GM, Fried LF, et al. Chronic kidney disease and cognitive impairment 
in the elderly: The health, aging, and body composition study. J Am Soc Nephrol. 
2005;16(7):2127-2133. 
2. Yaffe K, Ackerson L, Kurella Tamura M, et al. Chronic kidney disease and cognitive 
function in older adults: Findings from the chronic renal insufficiency cohort cognitive study. 
J Am Geriatr Soc. 2010;58(2):338-345. 
3. Etgen T, Sander D, Chonchol M, et al. Chronic kidney disease is associated with incident 
cognitive impairment in the elderly: The INVADE study. Nephrol Dial Transplant. 
2009;24(10):3144-3150. 
4. Rodriguez-Angarita CE, Sanabria-Arenas RM, Vargas-Jaramillo JD, Ronderos-Botero I. 
Cognitive impairment and depression in a population of patients with chronic kidney disease 
in colombia: A prevalence study. Can J Kidney Health Dis. 2016;3:26-016-0116-7. 
eCollection 2016. 
5. Kurella Tamura M, Yaffe K, Hsu CY, et al. Cognitive impairment and progression of CKD. 
Am J Kidney Dis. 2016;68(1):77-83. 
6. Kurella Tamura M, Wadley V, Yaffe K, et al. Kidney function and cognitive impairment in 
US adults: The reasons for geographic and racial differences in stroke (REGARDS) study. 
Am J Kidney Dis. 2008;52(2):227-234. 
7. Kurella M, Chertow GM, Luan J, Yaffe K. Cognitive impairment in chronic kidney disease. J 
Am Geriatr Soc. 2004;52(11):1863-1869. 
8. Murray AM, Knopman DS. Cognitive impairment in CKD: No longer an occult burden. Am 
J Kidney Dis. 2010;56(4):615-618. 
9. Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA. Cognitive disorders and 
dementia in CKD: The neglected kidney-brain axis. J Am Soc Nephrol. 2013;24(3):353-363. 
10. Sedaghat S, Cremers LG, de Groot M, et al. Kidney function and microstructural 
integrity of brain white matter. Neurology. 2015;85(2):154-161. 
11. Tuladhar AM, van Norden AG, de Laat KF, et al. White matter integrity in small vessel 
disease is related to cognition. Neuroimage Clin. 2015;7:518-524. 
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APPENDICES 
 
 
Recruitment documents 
Eligibility Checklist 
Data Collection Tables/Forms 
Questionnaires