A Feasibility Study Exploring the Impact of a Low Advanced Glycation End-product (AGE) Diet on Skin Autofluorescence (SAF) Levels in Kidney Transplant Recipients
Phase: NA
Conditions: Renal Transplant
Sponsor: University Hospitals of Derby and Burton NHS Foundation Trust

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
 
 
 
 
A feasibility study exploring the impact of a low Advanced Glycation End-product (AGE) 
diet on skin autofluorescence (SAF) levels in kidney transplant recipients. 
  
SHORT TITLE/ ACRONYM 
Kidney Transplant Low-AGE Diet Study (Transplant LAD) 
Version and Date of 
Protocol: 
 
Version 1.0 – 09.09.2021 
Sponsor:  
University Hospitals of Derby & Burton NHS Foundation Trust 
 
Chief Investigator: 
Catherine Johnson  
Consultant Nurse 
Royal Derby Hospital 
Uttoxeter Road, Derby DE22 3NE. 
Phone: 01332 789354 
Email: Catherine.johnson16@nhs.net 
 
Local Reference: 
UHDB/2020/018 
IRAS Number: 
 
298681 
ClinicalTrials.gov number: 
 
NCT05104242 
Funder(s): 
British Renal Society 
c/o Executive Business Support 
Davidson Road, Lichfield, Staffordshire WS14 9DZ 
 
Kidney Care UK 
3 The Windmills,  
St Marys Close, Turk Street, Alton GU34 1EF 
 
 
This protocol has regard for the HRA guidance 
 
 
 
 
 
 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
IRAS ID: 298681 
Confidentiality Statement 
 
This document contains confidential information that must not be disclosed to anyone other than 
the Sponsor, the Investigator Team, host NHS Trust, regulatory authorities, and members of the 
Research Ethics Committee. 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the 
Chief Investigator agrees to conduct the study in compliance with the approved protocol and will 
adhere to the principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other 
regulatory requirement. 
 
I agree to ensure that the confidential information contained in this document will not be used for 
any other purpose other than the evaluation or conduct of the investigation without the prior 
written consent of the Sponsor. 
 
I also confirm that I will make the findings of the study publicly available through publication or 
other dissemination tools without any unnecessary delay and that an honest accurate and 
transparent account of the study will be given; and that any discrepancies from the study as planned 
in this protocol will be explained. 
 
Protocol Version 1 - 09.09.2021 authorisation signatures: 
 
Chief Investigator: 
Signature: 
 
……………………………………………………….. 
 
Date: 
          ………/………/……………… 
Name (please print): 
 
……………………………………………………….. 
 
 
 
For and on behalf of the Study Sponsor (if required): 
Signature: 
 
……………………………………………………….. 
 
Date: 
          ………/………/……………… 
Name (please print): 
 
……………………………………………………….. 
 
 
Position: 
 
……………………………………………………….. 
 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
KEY STUDY CONTACTS 
 
Chief/Principal Investigator: 
Catherine Johnson  
Consultant Nurse 
Royal Derby Hospital 
Uttoxeter Road, Derby DE22 3NE 
Phone: 01332 789354 
Email: catherine.johnson16@nhs.net 
Co-Investigator(s): 
Professor Maarten Taal 
Professor of Medicine and Honorary Consultant Nephrologist 
Academic Unit for Translational Medical Sciences, School of 
Medicine, University of Nottingham, Royal Derby Hospital, 
Uttoxeter Rd, Derby, DE22 3NE 
Phone: 01332 224618 
Email: m.taal@nottingham.ac.uk; maarten.taal1@nhs.net 
 
Dr Janson Leung 
Consultant Nephrologist 
Royal Derby Hospital, Uttoxeter Road, Derby DE22 3NE 
Phone: 01332 789344 
Email: janson.leung@nhs.net 
 
Dr Daniela Viramontes Hörner 
Post-Doctoral Research Fellow 
Academic Unit for Translational Medical Sciences, School of 
Medicine, University of Nottingham, Royal Derby Hospital, 
Uttoxeter Rd, Derby, DE22 3NE 
Phone: 01332 788262 
Email: mszdv@nottingham.ac.uk 
Sponsor: 
University Hospitals of Derby & Burton NHS Foundation Trust 
Royal Derby Hospital, Uttoxeter Road, Derby, DE22 3NE 
Phone: 01332 724639 
Email: uhdb.sponsor@nhs.net  
Funder(s): 
British Renal Society 
c/o Executive Business Support 
Davidson Road, Lichfield, Staffordshire WS14 9DZ 
01543 442153 
Email: info@britishrenal.org 
 
Kidney Care UK 
3 The Windmills,  
St Marys Close, Turk Street, Alton GU34 1EF 
01420 541424 
Email: info@kidneycareuk.org 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
IRAS ID: 298681 
Clinical Trials Unit: 
Derby Clinical Trials Support Unit 
Medical School, Office 5033, Royal Derby Hospital, 
Derby, DE22 3DT 
Email: uhdb.DerbyCTSU@nhs.net 
Statistician: 
Not required, all statistical analysis will be performed by the 
investigating team 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
STUDY SUMMARY 
 
Study Title: 
A feasibility study exploring the impact of a low Advanced 
Glycation End-product (AGE) diet on skin autofluorescence (SAF) 
levels in kidney transplant recipients. 
 
Local Study Reference: 
UHDB/2020/018 
Study Design: 
This is a feasibility study consisting of 2 components: 
1. A randomised controlled trial (RCT) to investigate the impact of a 
low AGE diet on SAF levels in kidney transplant recipients.  
2. A nested qualitative interview study to assess the facilitators and 
barriers to adherence. 
Study Participants: 
Kidney transplant recipients who receive their transplant follow-up care at 
the Royal Derby Hospital 
Planner Number of Sites: 
Single site: The Royal Derby Hospital 
Planned Sample Size: 
RCT 
40 kidney transplant recipients. Participants will be randomized in an 
unrestricted 1:1 ratio in random varying block sizes using a computer-
generated random number into two groups: a) standard diet (control 
group) or b) low-AGE diet (intervention group). 
 
Nested Qualitative Study 
A sample of (n=15) participants will be purposefully selected; n=10 from 
the intervention group and n=5 from the control group. 
Treatment Duration: 
6 months 
Follow-Up Duration: 
No follow-up 
Planned Start Date: 
1st October 2021 
Planned Recruitment End Date: 
30th December 2021 
Planned Study End Date: 
30th December 2022 
Research Question/ Aims: 
Does a low-AGE diet reduce SAF levels and improve cardiovascular health 
in kidney transplant recipients? 
 
Specifically, this study will address: 
• 
Whether it is possible to conduct an RCT of the dietary 
intervention compared to a standard diet for kidney transplant 
recipients. 
• 
Determine whether the intervention is acceptable and participant 
views and experiences of the intervention. 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
FUNDING AND SUPPORT IN KIND 
 
Funder(s) 
Financial and Non-Financial Support Given 
British Renal Society 
c/o Executive Business Support 
Davidson Road, Lichfield, Staffordshire WS14 9DZ 
 
Joint BRS/KCUK grant 
Total Funding = £18,787 
 
Kidney Care UK 
3 The Windmills, St Marys Close, Turk Street, 
Alton GU34 1EF 
 
Joint BRS/KCUK grant 
Total Funding = £18,787 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
ROLES & RESPONSIBILITIES 
Sponsor 
The Sponsor, University Hospitals of Derby & Burton NHS Foundation Trust, take on overall 
responsibility for appropriate arrangements being in place to set up, run and report the research 
project. A Division of Responsibilities between the Sponsor and the Chief Investigator (CI) will outline 
the delegation of certain responsibilities from the Sponsor to the CI. 
 
Funder 
The study is funded by a joint research grant from the British Renal Society and Kidney Care UK 
 
Study Management Committees 
Trial Management Group  
The trial management group members are Catherine Johnson Chief Investigator, Dr Daniela 
Viramontes Hörner, Dr Janson Leung and Professor Maarten Taal. The group will meet monthly to 
oversee the day-to-day management of the trial, including all aspects of the conduct of the trial. Any 
problems with study conduct and participating centres will be raised and addressed during TMG 
meetings.  
 
Protocol Contributors 
A number of protocol contributors have been involved in the development of this protocol, these 
include Catherine Johnson the Chief Investigator, Co-investigators Dr Daniela Viramontes Hörner 
Post-Doctoral Research Fellow, Professor Maarten Taal and Dr Janson Leung and the Trial manager 
Rachelle Sherman.  
 
Protocol contributors are responsible for inputting into the design of the study, ensuring that it is 
designed transparently and efficiently.  

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
IRAS ID: 298681 
Contents 
SIGNATURE PAGE .................................................................................................................................... 3 
KEY STUDY CONTACTS ............................................................................................................................ 4 
STUDY SUMMARY ................................................................................................................................... 6 
FUNDING AND SUPPORT IN KIND ........................................................................................................... 7 
ROLES & RESPONSIBILITIES ..................................................................................................................... 8 
LIST OF ABBREVIATIONS ....................................................................................................................... 11 
PROJECT GANTT CHART ........................................................................................................................ 12 
1. 
BACKGROUND ............................................................................................................................... 13 
2. 
RATIONALE .................................................................................................................................... 14 
3. 
OBJECTIVES AND OUTCOME MEASURES/ ENDPOINTS ................................................................. 14 
3.1. 
Objectives.............................................................................................................................. 14 
3.2. 
Outcome ............................................................................................................................... 15 
4. 
STUDY DESIGN............................................................................................................................... 15 
5. 
STUDY SETTING ............................................................................................................................. 15 
6. 
ELIGIBILITY CRITERIA ..................................................................................................................... 15 
6.1. 
Inclusion Criteria ................................................................................................................... 15 
6.2. 
Exclusion Criteria ................................................................................................................... 16 
7. 
STUDY PROCEDURES ..................................................................................................................... 16 
7.1. 
Recruitment .......................................................................................................................... 16 
7.1.1. 
Patient Identification .................................................................................................... 16 
7.1.2. 
Screening ....................................................................................................................... 17 
7.2. 
Consent ................................................................................................................................. 17 
7.3. 
The Randomisation Scheme.................................................................................................. 17 
7.3.1. 
Method of Implementing the Allocation Sequence ...................................................... 18 
7.4. 
Study Assessments ................................................................................................................ 19 
7.5. 
Schedule of Assessments ...................................................................................................... 21 
7.6. 
Withdrawal Criteria ............................................................................................................... 21 
7.7. 
Storage and Analysis of Samples .......................................................................................... 22 
7.8. 
End of Study .......................................................................................................................... 22 
8. 
SAFETY REPORTING ....................................................................................................................... 22 
8.1. 
Definitions ............................................................................................................................. 22 
8.2. 
Operational Definitions for (S)AEs ........................................................................................ 23 
8.3. 
Recording and Reporting SAEs .............................................................................................. 23 
8.3.1. 
Assessment of AEs and SAEs ......................................................................................... 24 
8.4. 
Pregnancy reporting.............................................................................................................. 24 
8.5. 
Reporting Urgent Safety Measures ....................................................................................... 25 
9. 
DATA HANDLING ........................................................................................................................... 25 
9.1. 
Data Collection Tools and Source Document Identification ................................................. 25 
9.2. 
Source Data ........................................................................................................................... 25 
9.3. 
Data Handling and Record Keeping ...................................................................................... 25 
9.4. 
Access to Data ....................................................................................................................... 25 
9.5. 
Archiving ............................................................................................................................... 25 
10. 
STATISTICS AND DATA ANALYSIS .............................................................................................. 26 
10.1. 
Sample Size Calculation..................................................................................................... 26 
10.2. 
Planned Recruitment Rate ................................................................................................ 26 
10.3. 
Statistical Analysis ............................................................................................................. 26 
10.3.1. 
Summary of Baseline Data and Flow of Patients .......................................................... 26 
10.3.2. 
Outcome Analysis.......................................................................................................... 27 
10.4. 
Subgroup Analyses ............................................................................................................ 27 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
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10.5. 
Adjusted analyses ............................................................................................................. 27 
10.6. 
Interim Analysis and Criteria for the Premature Termination of the Study ..................... 27 
10.7. 
Analysis Groups ................................................................................................................. 27 
10.8. 
Procedure(s) to Account for Missing or Spurious Data..................................................... 28 
11. 
MONITORING, AUDIT & INSPECTION ........................................................................................ 28 
12. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................................................ 28 
12.1. 
Assessment and Management of Risk .............................................................................. 28 
12.2. 
Peer review ....................................................................................................................... 28 
12.3. 
Public and Patient Involvement ........................................................................................ 28 
12.4. 
Research Ethics Committee (REC) & Regulatory Considerations...................................... 29 
12.5. 
Protocol Compliance ......................................................................................................... 30 
12.6. 
Notification of Serious Breaches to GCP and/or the Protocol .......................................... 30 
12.7. 
Data Protection and Patient Confidentiality ..................................................................... 30 
12.8. 
Financial and Other Competing Interests for the Chief Investigator, Principal 
Investigators at Each Site and Committee Members for the Overall Study Management .............. 30 
12.9. 
Indemnity .......................................................................................................................... 30 
12.10. 
Amendments ..................................................................................................................... 31 
12.11. 
Access to Final Study Dataset ........................................................................................... 31 
13. 
DISSEMINATION POLICY ............................................................................................................ 31 
13.1. 
Dissemination Policy ......................................................................................................... 31 
13.2. 
Authorship Eligibility Guidelines and any Intended Use of Professional Writers ............. 32 
14. 
REFERENCES .............................................................................................................................. 32 
15. 
APPENDICES .............................................................................................................................. 34 
15.1. 
Appendix 1 – Reference values of skin autofluorescence per age group. ........................ 34 
15.2. 
Appendix 2 – Amendment History .................................................................................... 34 
 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
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LIST OF ABBREVIATIONS 
 
Define all unusual or ‘technical’ terms related to the study. Add or delete as appropriate to your 
study. Maintain alphabetical order for ease of reference. 
 
AE 
Adverse Event 
AGE 
aPWV 
BMI 
CI 
Advanced glycation end-products 
Aortic Pulse Wave Velocity 
Body mass index 
Chief Investigator 
CKD 
CRF 
Chronic kidney disease 
Case Report Form 
ESKD 
GCP 
hsCRP 
End-stage kidney disease 
Good Clinical Practice 
High-sensitive C reactive protein 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials  
NHS  
National Health Service  
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
R&D 
SAE 
Research & Development 
Serious Adverse Event 
SAF 
Skin autofluorescence 
SGA 
SOP 
Subjective Global Assessment 
Standard Operating Procedure  
TMG 
UHDB 
Trial Management Group 
University Hospitals of Derby and Burton NHS Foundation Trust 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1.0 – 09.09.2021  
IRAS ID: 298681 
PROJECT GANTT CHART 
 
 
Task name 
2021 
2022 
Qtr 1 
Qtr 2 
Qtr 3 
Qtr 4 
Qtr 1 
Qtr 2 
Qtr 3 
Qtr 4 
Finalise study protocol 
 
 
 
 
 
 
 
 
Prepare study documentation 
 
 
 
 
 
 
 
 
Complete ethics application 
 
 
 
 
 
 
 
 
Await REC/HRA and R&D approvals 
 
 
 
 
 
 
 
 
Eligibility assessment/screening 
 
 
 
 
 
 
 
 
Recruitment  
 
 
 
 
 
 
 
 
Data collection/Study procedures and assessments 
 
 
 
 
 
 
 
 
Qualitative study interviews 
 
 
 
 
 
 
 
 
Data collation, analyses and dissemination 
 
 
 
 
 
 
 
 
Trial Management Group meetings 
 
 
 
 
 
 
 
 
PPI meetings 
 
 
 
 
 
 
 
 
 
 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
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STUDY PROTOCOL 
 
1. 
BACKGROUND 
 
Kidney transplantation is the optimal treatment option for end-stage kidney disease (ESKD). 35,823 
adult patients had a functioning kidney transplant for ESKD in the UK on 31/12/2017, which 
represented 55.2% of the renal replacement therapy population. Transplantation is not only 
beneficial for the individual but also represents value to the greater health economy. The first year 
of care after a kidney transplant costs around £17,000 and £5,000 for every subsequent year 
compared to the average yearly cost of dialysis of £26,835 (UK Renal Registry, 2019). 
 
Cardiovascular disease is the leading cause of death in persons with chronic kidney disease (CKD) 
including post-transplant. Whilst quality of life and clinical outcomes have improved in recent years, 
the survival of persons on dialysis remains poorer than that of many cancers. When compared to 
healthy subjects of the same age, persons receiving haemodialysis have a fivefold shorter life 
expectancy (Ardhanari et al., 2014). Reduced following kidney transplantation, this cardiovascular 
risk remains high with the greatest excess morbidity and mortality seen amongst youngest 
individuals (Jardine et al., 2011) 
 
Advanced glycation end-products (AGEs) are a group of compounds formed by the non-enzymatic 
glycation of proteins, lipids or nucleic acids which progressively disrupt protein structure ultimately 
affecting tissue structure and function (Mallipattu et al., 2012). AGE formation in the body is 
increased by exposure to high glucose levels (in diabetes) and by inflammation and oxidative stress. 
In addition, AGEs may accumulate from exogenous sources including food (especially when cooked 
at high temperatures by baking, grilling, frying or roasting) and tobacco smoke (Uribarri et al., 2010; 
Arsov et al., 2014). AGEs are also produced normally in the body and their accumulation is a 
recognised manifestation of the normal aging process. Importantly, accumulation of AGEs has been 
highlighted as a risk factor associated with increased risk of cardiovascular mortality and morbidity 
(Meerwaldt et al., 2005; Shardlow et al., 2020). 
 
The measurement of skin autofluorescence (SAF) is a validated non-invasive way to assess tissue 
accumulation of AGEs. SAF levels are a strong predictor of cardiovascular events in CKD (Shardlow et 
al., 2020) and of death and graft loss in transplant recipients (Hartog et al., 2006). Crowley et al. 
(2013) reported significantly lower SAF levels in kidney transplant recipients compared to persons on 
dialysis; however, these remained elevated when compared to the general population. In a small 
number of patients with pre-transplant measurements, a reduction in SAF was observed at a mean 
of 16 months post-transplant. However, there is still a lack of evidence in this area.  
 
Due to the adverse outcomes associated with higher levels of SAF, several options focused on 
reducing the accumulation of AGEs have been proposed. One of these promising interventions is the 
reduction of dietary AGE intake. It has been suggested that cooking techniques that avoid very high 
temperatures such as poaching, steaming, stewing and boiling can significantly reduce the AGE 
content of food when compared to frying, broiling, grilling and roasting (Uribarri et al., 2010). 
Several randomized controlled trials (RCT) conducted in healthy overweight and/or obese volunteers 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
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(Harcourt et al., 2011; Mark et al., 2014; Macías-Cervantes et al., 2015), persons with diabetes and 
the metabolic syndrome (Vlassara et al., 2002; Cai et al., 2004; Vlassara et al., 2016), and in those 
with CKD (Peppa et al., 2004; Vlassara et al., 2009) and performing peritoneal dialysis (Yacoub et al., 
2017) have reported that restriction of dietary AGE intake is associated with a reduction in 
circulating AGE levels, suggesting that a low AGE diet may also be associated with a decrease in SAF. 
 
2. 
RATIONALE 
 
A systematic review (Clarke et al., 2016) concluded there was evidence to suggest that dietary 
modification to reduce dietary AGE intake was promising as an intervention to reduce AGE 
accumulation, highlighting the potential benefits of a simple dietary intervention in the prevention 
and treatment of chronic conditions.  However, they noted that most of the evidence regarding 
dietary modifications to reduce exogenous AGEs is of low quality highlighting the need for further 
studies, which was of interest as this simple intervention is unstudied in kidney transplant recipients. 
 
3. 
OBJECTIVES AND OUTCOME MEASURES/ ENDPOINTS 
 
3.1. 
Objectives 
 
The aim of this study is to establish the feasibility of conducting a definitive RCT which will 
investigate whether a low AGE diet leads to reduced SAF levels and improves cardiovascular health 
in kidney transplant recipients. 
 
This innovative proposal is designed to test the feasibility of answering the question:  
 
Does a low AGE diet reduce SAF levels and improve cardiovascular health in kidney transplant 
recipients? 
 
Specifically, this study will address: 
• 
Whether it is possible to conduct an RCT of the dietary intervention compared to a 
standard diet for kidney transplant recipients. 
• 
Whether the intervention is acceptable, and participant views and experiences of 
the intervention. 
Specifically, this study will address the following: 
• 
Eligibility, recruitment and dropout rates, with reasons for loss to follow-up. 
• 
Proportion of eligible participants recruited. 
• 
The suitability and sensitivity of outcome measures for use in a larger trial. 
• 
The most appropriate primary outcome measure for use in a larger trial and 
completeness of data. 
• 
Estimates of the effects of the intervention to inform a sample size calculation for a 
larger trial. 
• 
The feasibility of health economic data collection and preliminary cost data 
collection and calculations. 

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Kidney Transplant Low AGE Diet Study (Transplant LAD) Version 1 – 09.09.2021  
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• 
The feasibility of delivering the intervention to the population group. 
• 
Fidelity and adherence with the intervention. 
• 
Determine whether the intervention is acceptable and participant views and 
experiences of the intervention. 
3.2. 
Outcome 
 
Primary outcome: SAF values at 6 months. 
 
Secondary outcomes:  
 
• 
Participant adherence to dietary intervention (achieving dietary AGE intake <8000 kilounits 
[kU]/day). 
• 
Slope of SAF values over 6 months. 
• 
Change in SAF values at 6 months. 
• 
Change in weight over 6 months. 
• 
Change in aortic pulse wave velocity (aPWV). 
• 
Change in high-sensitive C reactive protein (hsCRP). 
• 
Change in quality of life. 
 
4. 
STUDY DESIGN 
 
This is a feasibility study consisting of 2 components: 
 
1. An RCT to investigate the impact of a low AGE diet on SAF in kidney transplant recipients.  
2. A nested qualitative interview study to assess the facilitators and barriers to adherence. 
 
5. 
STUDY SETTING 
 
This study will take place within an NHS Renal outpatient setting at University Hospitals of Derby and 
Burton NHS Foundation Trust (UHDB).  
 
6. 
ELIGIBILITY CRITERIA 
 
Potential participants will be kidney transplant recipients who receive their follow-up care with the 
Transplant team at UHDB. 
 
6.1. 
Inclusion Criteria 
 
• 
Adults (>18 years) with a functioning (not on dialysis) kidney transplant. 
• 
More than 12 months post-transplant.  
• 
Able and willing to give informed consent. 
• 
SAF levels above the general population mean value for age (Appendix 1). 
 
 

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6.2. 
Exclusion Criteria 
 
• 
Persons with dark skin colour (i.e. Fitzpatrick skin colour type 5-6). 
• 
Persons with malnutrition (Subjective Global Assessment [SGA] score <5). 
• 
Pregnancy or breast feeding or intending pregnancy. 
• 
Active infection. 
• 
Active rejection. 
• 
Persons with learning difficulties. 
• 
Prisoners. 
 
7. 
STUDY PROCEDURES 
 
7.1. 
Recruitment 
 
7.1.1. 
Patient Identification  
 
Identification and enrolment of participants from the existing kidney transplant recipient population 
at The Royal Derby Hospital will be undertaken by the Chief Investigator Catherine Johnson, a 
member of the transplant team.  
 
Initial contact will be made during a routine follow-up appointment. The initial details of the study 
and Screening Participant Information Sheet (PIS) will be provided by the usual care team (which 
may include the researcher). Participants will then be given ample time during their appointment to 
ask questions and consider whether they wish to participate with screening. Having obtained 
consent to screen Chief Investigator Catherine Johnson, a member of the transplant team will 
measure a SAF level. SAF level results are obtained within 3-5 minutes. 
 
Participants with a SAF that is above the general population mean for age will then be invited to 
participate in the study. The Participant Information Sheet will be provided for the participants to 
take home. Participants will then be given ample time to ask questions and consider whether they 
wish to participate before being re-contacted by the Chief Investigator. If they do wish to participate, 
a further visit scheduled on the same day as their next routine appointment will be arranged to 
obtain consent and undertake baseline assessments. 
 
It will be explained to the potential participant that entry into the study is entirely voluntary and that 
their treatment and care will not be affected by their decision. It will also be explained that they can 
withdraw at any time. In the event of their withdrawal, it will be explained that their data collected 
so far cannot be erased and will be used in the final analyses where appropriate. 
 
The participant’s general practitioner will not be informed about the study because there are no 
implications for other aspects of treatment. 
 
Participants will not be paid to participate in the study. Travel expenses will be offered for any 
hospital visits in excess of usual care. The majority of study assessments will be timed to take place 
at the time of routine visits, treatment or assessment. 
 

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7.1.2. 
Screening 
 
Patient details will be assessed against the inclusion and exclusion criteria. Only those who meet the 
inclusion criteria and without exclusion criteria will be invited to participate. 
 
At the initial contact visit outlined above, Chief Investigator Catherine Johnson, a member of the 
transplant team, will seek consent to measure SAF levels (i.e. consent to screen). Only patients with 
an SAF value that is above the general population mean for age will be invited to participate. 
 
7.2. 
Consent 
 
Consenting of participants will be undertaken by the Chief Investigator Catherine Johnson, or an 
appropriately trained and delegated member of the research team. 
 
The process for obtaining participant informed consent will be in accordance with the Research 
Ethics Committee (REC) guidance, Good Clinical Practice (GCP) and any other regulatory 
requirements that might be introduced. The Investigator has training and experience in assessing 
participant capacity and gaining informed consent in the clinical context. 
 
Detailed information will be provided on the study to ensure that participants understand the 
purpose and potential risks involved. All participants will provide written informed consent. The 
Informed Consent Form will be signed and dated by the participant before they enter the study. The 
Investigator will explain the details of the study and provide a PIS, ensuring that the participant has 
sufficient time to consider participating or not. The Investigator will answer any questions that the 
participant has concerning study participation. 
  
The decision regarding participation in the study is entirely voluntary. The Investigator or their 
nominee shall emphasize to them that consent regarding study participation may be withdrawn at 
any time without penalty or affecting the quality or quantity of their future medical care. 
 
Informed consent will be obtained from each participant before they undergo any interventions 
related to the study. Informed consent must be obtained prior to the participant undergoing 
procedures that are specifically for the purposes of the study (including the collection of identifiable 
participant data). One copy of this will be kept by the participant, one will be kept by the 
Investigator, and a third will be retained in the participant’s hospital records.  
 
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants 
at their site and must ensure that any person delegated responsibility to participate in the informed 
consent process is duly authorised, trained and competent according to the REC approved protocol 
and applicable guidelines and regulations. 
 
7.3. 
The Randomisation Scheme 
 
Participants will be randomised in an unrestricted 1:1 ratio in random varying block sizes using a 
computer-generated random number into two groups: a) standard diet (control group) or b) low 

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AGE diet (intervention group). Advice regarding both diets will be provided by an experienced 
dietitian. Both groups will receive precise oral and written instructions on how to follow the diets. 
Dietary advice will be individualised to patients’ food preferences. 
 
Standard diet (control group) 
The standard diet will include energy intake of 30-35 kcal/kg of ideal body weight (IBW)/day 
(Mlinsek, 2016) and protein intake of 0.75 g/kg of IBW/day for females and 0.84 g/kg of IBW/day for 
males (Nolte Fong and Moore, 2018).  
 
 
Low AGE diet (intervention group) 
The low AGE diet will be the same as the standard diet in terms of calories (i.e. 30-35 kcal/kg/day) 
and protein (0.75-0.84 g/kg/day). However, it will reduce the dietary AGE content by changing 
cooking methods in food preparation to avoid exposure to dry heat such as frying, broiling, grilling 
and roasting, and to favour cooking with lower temperatures and high-water content as in stewing, 
steaming, boiling and poaching. In addition, the low-AGE group will be instructed to choose foods 
with low content of AGEs based on a food choice list that will contain examples of foods commonly 
available in the UK to be chosen as “allowed,” “moderate intake,” or “occasional.” The goal will be to 
reduce dietary AGE intake to less than 8000 kU/day.  
 
Dietary advice will be provided in person by an investigator with training and previous experience as 
a dietitian. Adherence to diets will be evaluated by means of a 3-day food diary (2 weekdays and 1 
weekend day) every month. Monthly forms and written instructions on how to complete the 3-day 
food diaries will be sent by post to the participants. We will ask participants to return the completed 
food diaries in a pre-paid envelope. If needed, supplementary relevant diet information will be 
obtained by telephone consultation once the food diaries have been recorded and returned to the 
research dietitian.   
 
There will be a follow-up meeting or discussion by telephone with participants randomised to the 
intervention group after 2 weeks of starting the study in order to reinforce the adherence and 
understanding of the intervention.  
 
7.3.1. 
Method of Implementing the Allocation Sequence 
 
The system to be used to coordinate randomisation is www.sealed envelope.com  
 
The Chief Investigator, Catherine Johnson and Dr Daniela Viramontes Hörner will be aware of 
allocation which will be documented in the CRF (paper). 
 
There is no expectation that randomisation codes will need to be accessed out-of-hours or in an 
emergency. 
 
 
 

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7.4. 
Study Assessments 
 
Once eligible participants have read the PIS and given their informed consent, relevant participant 
characteristics will be extracted either from electronic data captured in medical records and from a 
self-reported questionnaire at baseline and will include demographic characteristics, educational 
level, employment status, duration of renal replacement therapy, transplant type and vintage, 
number of rejection episodes, aetiology of CKD, medical history (e.g. history of cardiovascular 
disease, diabetes and hypertension), current co-morbidities, alcohol history, smoking status and 
current medication.  
 
The accumulation of AGEs will be assessed by measuring SAF using a validated Autofluorescence 
Reader Standard Unit version 2.4.3 (AGE Reader, DiagnOptics, Groningen, The Netherlands) at 
baseline, 3 and 6 months, as described in more detail elsewhere (Shardlow et al., 2020). In brief, the 
AGE Reader directs an ultraviolet excitation light (intensity 300-420 nm) through an illumination 
window of approximately 1 cm2 on a skin area (free of visible vessels, scars, tattoos or any other skin 
irregularities) of the volar surface of the forearm at approximately 10 cm below the elbow. The AGE 
Reader then measures the amount of emitted light that is reflected back from the skin (intensity 
300-600 nm) using a spectrometer (AVS-USB2000, Avantes Inc., Eerbeek, The Netherlands) and a 
200-µm glass fibre. SAF is calculated by dividing the average emitted light intensity in the range 
between 420-600 nm by the average excitation light intensity in the range between 300-420 nm and 
expressed as arbitrary units (AU). Three measurements will be obtained and the average of these 
will be used for analysis. Valid SAF readings cannot be obtained when the skin reflectivity is lower 
than 6% (Mulder et al., 2006); therefore, persons with dark skin colour (i.e. Fitzpatrick skin colour 
type V-VI), who have an ultraviolet reflectance of less than 6%, will be excluded from this study. 
 
Routine blood/laboratory tests will be performed at baseline, 3 and 6 months and will include 
haemoglobin, white cell count, hsCRP, glucose, HbA1C, urea, creatinine, potassium, phosphate, 
calcium, sodium, albumin, total proteins, cholesterol, triglycerides, intact parathyroid hormone and 
immunosuppression levels. 
 
Nutritional assessments will be performed at baseline and at 3 and 6 months of treatment and will 
include: 3-day food diary (2 weekdays and 1 weekend day) to assess energy, fat and protein intake; a 
validated food frequency questionnaire to evaluate dietary AGE intake (Luévano-Contreras et al., 
2013); the 7-point scale SGA for the classification of the nutritional status (well-nourished [SGA 
scores 6-7] or malnourished [SGA scores 1-5]); handgrip strength and anthropometric measurements 
and indexes, including weight, height, body mass index (BMI), mid-arm circumference, triceps 
skinfold thickness and mid-arm muscle circumference. 
 
Cardiovascular evaluation will be performed at baseline, 3 and 6 months of treatment and will 
include traditional cardiovascular risk factors such as blood pressure, HbA1c, BMI and cholesterol. In 
addition, aPWV (a measure of arterial stiffness) will be assessed using the validated Vicorder device 
(Skidmore Medical, Bristol, UK) which is a predictor of cardiovascular mortality and morbidity 
(Lioufas et al., 2019).  
 

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Health-related quality of life will be evaluated at baseline, 3 and 6 months of follow-up with the EQ-
5D-5L questionnaire. 
 
 
Nested Qualitative Study 
A sample of (n=15) participants will be purposefully selected; n=10 from the intervention group and 
n=5 from the control group, ensuring as far as possible that the sample includes a diverse 
representation of the study population for age, gender and ethnicity. 
 
Potential participants will be given or sent an invitation letter and PIS, have the study explained to 
them and consented separately. 
 
Semi-structured interviews will take place on completion of the intervention period broadly 
considering the acceptability and tolerability of the intervention in addition to the study process. 
These interviews will be facilitated by a trained researcher who is not a part of the clinical team to 
encourage free expression by the individuals involved. The interview will take place at a time and 
location convenient to the participants and will take about 60 minutes. 
 
Data will be collected via digital audio equipment and transcribed by a Trust vendor qualified 
transcription service. Analysis will follow the conventions of framework analysis as outlined by Gale 
et al., 2013. Framework analysis involves a seven-stage process of coding and organising qualitative 
data in order to provide a structured interpretation of the data, which is finally presented in themes. 
The stages are: 1. Transcription, 2. Familiarisation with data, 3. Coding, 4. Developing a working 
analytical framework, 5. Applying the analytical framework, 6. Charting the data into the framework 
matrix, 7. Interpreting the data. The initial coding and development of the analytical framework will 
be in order to consensually develop the framework. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.5. 
Schedule of Assessments 
 
 
7.6. 
Withdrawal Criteria 
 
Participants will be withdrawn from the study if they withdraw their consent at any point or decline 
to comply with the dietetic intervention or develop malnutrition. Female participants will be 
withdrawn from the study if they become pregnant.   
 
Participants may be withdrawn from the study either at their own request or at the discretion of the 
Investigator. The participants will be made aware that this will not affect their future care. 
Participants will be made aware (via the information sheet and consent form) that should they 
withdraw the data collected to date cannot be erased and will be used in the final analysis. 
 
If participants fail to attend for their study visits, a member of the research team will try to contact 
them by telephone within 24 hours of their appointment and by written correspondence within a 
week of the missed appointment. Multiple attempts at contact will be made by the research team 
over a period of a month before stating that a participant has been lost to follow-up.  
Study 
Procedures/Assessments Screening Recruitment Baseline 
Months  
Post-
intervention 
1 2 3 4 5 6 
Eligibility assessment 
x 
 
 
 
 
 
 
 
 
 
Study discussed and PIS 
given 
 
x 
 
 
 
 
 
 
 
 
Informed consent 
 
x 
 
 
 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
Participant 
characteristics 
 
 
x 
 
 
 
 
 
 
 
Skin autofluorescence 
x 
 
x 
 
 
x 
 
 
x 
 
Routine blood tests 
 
 
x 
 
 
x 
 
 
x 
 
3-day food diaries 
 
 
x 
x 
x 
x 
x 
x 
x 
 
Dietary AGE food 
frequency questionnaire 
 
 
x 
 
 
x 
 
 
x 
 
Subjective Global 
Assessment 
 
 
x 
 
 
x 
 
 
x 
 
Handgrip strength 
 
 
x 
 
 
x 
 
 
x 
 
Anthropometric 
measurements 
 
 
x 
 
 
x 
 
 
x 
 
Cardiovascular 
evaluation 
 
 
x 
 
 
x 
 
 
x 
 
Quality of life 
questionnaire (EQ-5D-5L) 
 
 
x 
 
 
x 
 
 
x 
 
Treatment adherence 
 
 
 
x 
x 
x 
x 
x 
x 
 
Qualitative study 
interviews 
 
 
 
 
 
 
 
 
 
x 
Adverse event 
assessments  
 
 
 
x 
x 
x 
x 
x 
x 
 
Physician’s Withdrawal 
Checklist 
 
 
 
x 
x 
x 
x 
x 
x 
 

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Data that is collected prior to withdrawal will be kept and analysed as part of the data set. The date, 
time and reason for participant withdrawal will be documented on the case report form (CRF). 
 
7.7. 
Storage and Analysis of Samples 
 
Routine blood/laboratory tests will be analysed in a local NHS laboratory at the Royal Derby 
Hospital, which is serviced and managed according to national standards and governance 
frameworks. Following analysis, samples will be destroyed according to local practice and no 
samples will be kept for longer than required for the study.  
 
7.8. 
End of Study 
 
The end of study will be defined as when the final patient attends for their last assessment. The CI 
will notify the Sponsor and REC within 90 days of the end of study. The clinical study report will be 
written within 12 months of the end of study.  
 
 
8. 
SAFETY REPORTING 
 
8.1. 
Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant, including occurrences 
which are not necessarily caused by or related to study procedures. 
Related AE  
An untoward and unintended response in a participant to a study 
procedure. This means that a causal relationship between the study 
procedure and an AE is at least a reasonable possibility, i.e. the 
relationship cannot be ruled out. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of 
the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to 
an event in which the participant was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
Related SAE 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of 
the study procedures. 

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Related & 
Unexpected SAE  
A serious adverse event that: 
• 
is believed with reasonable probability to be due to one of the study 
procedures. 
• 
the nature and severity of which is not consistent with the 
information provided in the protocol i.e. it is not listed as an 
expected occurrence.  
 
8.2. 
Operational Definitions for (S)AEs 
 
As a low-risk intervention, there is no requirement for non-serious AEs to be recorded or reported. 
Any AEs that meet the definition of serious (SAE) as per Section 8.1 and are not listed below must be 
reported.   
 
Exceptions to SAE reporting: 
- 
Rejection 
- 
Infection 
- 
Graft Failure 
- 
New Onset Diabetes after Transplantation 
 
The following circumstances are usually not considered SAEs:  
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
• 
Treatment, which was elective or pre-planned, for a pre-existing condition not associated 
with any deterioration in condition. 
• 
Any admission to hospital or other institution for general care where there was no 
deterioration in condition. 
• 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious as given above and not resulting in hospital admission. 
 
In all cases AEs and/or laboratory abnormalities that are critical to the safety evaluation of the 
participant must be reported. Where certain AEs are not required to be reported to the Sponsor 
(e.g. expected SAEs for the disease or intervention), these should be listed in the protocol and still be 
recorded in the participant’s medical records. 
 
8.3. 
Recording and Reporting SAEs 
 
All AEs and SAEs must be recorded from the time of written informed consent until after the last 
visit. All (S)AEs occurring during the duration of the study must be reported by the investigator 
within the CRF. The PI is responsible for checking for AEs when participants attend for treatment and 
follow-up. All related and unexpected SAEs must be recorded by the investigator using the ‘non-
CTIMP safety report to REC form’ from the HRA website. The completed form should be submitted 
to the Sponsor and REC within 15 days of the CI becoming aware of the event. Safety information 
will be reviewed during trial management group meetings.  
 
 

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UHDB contact information: 
Email: uhdb.randdsae@nhs.net 
8.3.1. 
Assessment of AEs and SAEs 
 
8.3.1.1 
Severity 
 
The investigator should determine the severity of the AE: 
• 
Mild: no interference with daily activities. 
• 
Moderate: moderate interference with daily activities. 
• 
Severe: considerable interference with daily activities (e.g. inability to work). 
 
NOTE: to avoid confusion or misunderstanding, the term “severe” is used to describe the intensity of 
the event, which may be of relatively minor medical significance, and is NOT the same as “serious” 
which is described in the safety definitions.  
 
8.3.1.2 
Causality 
 
Clinical judgement should be used to determine the relationship between the study procedures and 
the occurrence of each AE:  
• 
Not-related: There is no evidence of a causal relationship between the event and study 
procedures. 
• 
Related: There is evidence of a causal relationship between the event and study procedures 
i.e. a relationship to the study procedures cannot be completely ruled out. 
 
 
Assessment of causality must be made by a medically qualified doctor (usually the PI).  
 
8.3.1.3 
 
Expectedness 
 
The assessment of expectedness is only required if the event is deemed to be related to study 
procedures.  
• 
Expected: Event previously identified and described in the protocol. 
• 
Unexpected: Event not previously described in the protocol.  
 
The expectedness assessment is delegated to Catherine Johnson.  
 
8.4. 
Pregnancy reporting 
 
If a participant becomes pregnant or is suspected to be pregnant from the time of consent up to the 
final study visit, they will be withdrawn from the study. There is no follow-up reporting required.  
 
 
 
 

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8.5. 
Reporting Urgent Safety Measures 
 
If any urgent safety measure is taken, the research team should inform the Sponsor with 24 
hours using the Sponsors safety incident reporting form. The Sponsor will inform the REC and 
participating sites of the measures taken and the circumstances giving rise to those measures 
within 3 days on implementation of the urgent safety measure. 
 
9. 
DATA HANDLING 
 
9.1. 
Data Collection Tools and Source Document Identification 
 
Data will be collected on a CRF (paper) and transcribed onto an electronic database. CRFs will be 
stored as part of the ISF, which will be kept in a secure location with restricted access.  
 
9.2. 
Source Data 
 
For the purposes of this study, source data shall be defined as medical records of the participant 
(electronic or paper), any self-reported questionnaires and in some instances, the CRF may serve as 
its own source data for information collected directly from the participant. 
 
 
9.3. 
Data Handling and Record Keeping 
 
A validated spreadsheet (the database) will be developed and used for the transcription of data from 
the CRF, as described in the applicable SOP of the Sponsor. Validation will ensure data is entered in 
the correct format at the point of transcription in an effort to reduce transcription errors. The 
database will be stored on an NHS computer on a drive that is regularly backed up to a centrally 
hosted server (in the UK). Access to the database will be password protected and limited only to the 
appropriate members of the research team.    
 
All data collected on the CRF and subsequently on the database will be pseudonymised, containing 
no identifiable data and using only a unique study ID to identify the study participant.  
 
9.4. 
Access to Data 
 
Direct access will be granted to authorised representatives from the Sponsor, host institution and 
the regulatory authorities to permit study-related monitoring, audits and inspections. 
 
9.5. 
Archiving 
 
At the end of the study, following completion of the end of study report, UHDB will securely archive 
all centrally held study related documentation for a minimum of 5 years. At the end of the defined 
archive period, arrangements for confidential destruction will be made. It is the responsibility of the 
Investigator to ensure that data and all essential documents relating to the study are retained 
securely for a minimum of 5 years after the end of study, and in accordance with national legislation. 
UHDB will notify the Investigator when study documentation may be archived, and then destroyed. 

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All archived documents must continue to be available for inspection by appropriate authorities upon 
request.  
 
10. 
STATISTICS AND DATA ANALYSIS  
 
Statistical analysis will be undertaken by Dr Viramontes Hörner with support from Prof Taal and Dr 
Leung. Data management and statistical analyses will be performed using statistical software SPSS 
version 26.0.  
 
To compare baseline versus final evaluations, Wilcoxon test or paired t-test will be used in the case 
of dimensional variables, and McNemar test in the case of categorical variables. Intergroup 
comparisons will be performed using Mann Whitney test or Student t test for continuous variables 
and χ2 test or Fisher’s exact test for categorical variables.  
 
10.1. 
Sample Size Calculation 
 
As this is a feasibility RCT, no formal sample size calculation is required; however, the aim will be to 
recruit 40 kidney transplant recipients to test the study procedures and the feasibility of delivering 
the intervention. Power calculation using ClinCalc indicates that, assuming an SAF value of 2.81 ± 
0.64 AU in the control group (Crowley et al., 2013), having a sample size of 18 in each group would 
give 80% power (=0.05) to detect a difference in SAF of 0.6 AU between the groups at 6 months. 
The proposed recruitment would achieve this and allow for 10% drop-out. 
  
10.2. 
Planned Recruitment Rate 
 
This is a single centre pilot study aiming to recruit 40 adult (>18 years) kidney transplant recipients. 
This centre’s kidney transplant recipient population numbers more than 300. With around 50 kidney 
transplant recipients attending for outpatient follow-up weekly, it is expected that the recruitment 
duration will be minimal. 
 
10.3. 
Statistical Analysis 
 
10.3.1. 
Summary of Baseline Data and Flow of Patients 
 
Descriptive statistics will be presented to summarize the distribution of baseline variables across 
each of the randomisation groups. The continuous baseline variables (e.g. SAF, age, height, weight 
and blood pressure) will be reported with means and standard deviations, if shown to be normally 
distributed, using a combined skewness and kurtosis test, otherwise will be reported with medians 
and Interquartile Ranges (IQR). The categorical variables (e.g. sex, ethnicity and employment status) 
will be reported with frequencies and percentages. 
 
A Consolidated Standards of Reporting Trials (CONSORT) flow diagram will be produced, showing the 
frequency of patients/participants: 
• 
Assessed for eligibility or found eligible, 
• 
Excluded before randomisation (and the frequency of each reason for exclusion), 
• 
Randomised, 

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• 
Allocated to each randomisation group, 
• 
That received each allocated intervention, 
• 
That did not receive each allocated intervention, 
• 
Lost to follow-up (and the frequency of each reason for loss to follow-up) for each 
randomisation group, 
• 
Analysed for each randomisation group, 
• 
Not analysed (and the frequency of each reason for not being analysed) for each 
randomisation group. 
 
10.3.2. 
Outcome Analysis 
 
Summary measures of all baseline variables will be calculated and reported. Primary and secondary 
outcomes will be compared between the two groups (Low AGE Diet vs. Standard Diet) at 6 months 
using a t-test if data are normally distributed or a Mann Whitney U test if not. Analysis will be by 
intention to treat. 
 
10.4. 
Subgroup Analyses 
 
Due to the limited number of participants, we will conduct only a single subgroup analysis by 
evaluating the results in participants with and without diabetes. Since diabetes is relatively common 
in kidney transplant recipients and may be a dominant factor affecting SAF in these people, it would 
be important to investigate whether a low AGE diet is effective in people with diabetes. 
 
10.5. 
Adjusted analyses 
 
As this is a feasibility study, we do not plan to conduct adjusted analyses. 
 
10.6. 
Interim Analysis and Criteria for the Premature Termination of the Study 
 
As this is a feasibility study with minimal risk of harm, we do not plan to conduct an interim analysis. 
 
The Sponsor may suspend or prematurely terminate either the entire study, or the study at an 
individual site, for significant reasons that must be documented (e.g. an unacceptable risk to 
participants or serious repeated deviations from the protocol/regulations). If this occurs, the 
Sponsor shall justify its decision in writing and will promptly inform any relevant parties (i.e. 
participants, investigators, participating sites, REC, regulatory bodies).  
 
10.7. 
Analysis Groups 
 
The two groups for analysis will be the Low AGE diet and Standard diet groups. Analyses will be by 
intention to treat and will include all participants who were randomised and received at least one 
session of dietary counselling regarding their diet (all-treated population). 
 
 
 

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10.8. 
Procedure(s) to Account for Missing or Spurious Data 
 
Missing data will be omitted from the analyses. The group sizes are too small to consider multiple 
imputations. 
 
11. 
MONITORING, AUDIT & INSPECTION 
 
The Investigator(s) must ensure that source documents and other documentation for this study are 
made available to study monitors, the REC or regulatory authority inspectors. Authorised 
representatives of the Sponsor may visit the participating sites to conduct audits/inspections.  
 
Monitoring and source data verification will be conducted by the Sponsor according to their 
requirements, based on the risk assessment of the study. As a low-risk study, routine monitoring is 
not expected but may be conducted on an ad-hoc bases. The study may be audited by the Sponsor 
at any time, according to the Sponsor’s audit programme. 
 
12. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
12.1. 
Assessment and Management of Risk 
 
The Sponsor has conducted the necessary risk assessment for this study and determined it as a low-
risk study.  
 
12.2. 
Peer review 
 
This study has been peer reviewed as part of the British Renal Society and Kidney Care UK Research 
Grant application process. 
 
12.3. 
Public and Patient Involvement  
 
The Centre for Kidney Research and Innovation (CKRI) at UHDB NHS Foundation Trust has an 
established patient focus group that meets regularly to discuss all research projects and activities. 
This proposal was discussed at that meeting; the group felt that this was an interesting and 
important area to study; many gave their own anecdotes of their own and fellow patients 
experience of heart problems causing ill health and death. In addition, this project has been 
discussed with the more than 20 kidney transplant patients who participated in my MSc; these are 
the patients who have pushed for continued research in this area as they recognise the potential 
benefits for themselves and their fellow kidney transplant recipients. The focus group has agreed to 
review and feedback on this project, in addition to reviewing the study documentation and 
dissemination of its findings. 
 
A member of the CKRI focus group is an advocate of co-production with both clinical staff and 
patients having an equal voice working together to create something new that meets everyone’s 
needs and improves the lives of those who are affected by kidney disease and believes that utilizing 
this approach for this project will maximize its impact. Mr H. is especially supportive of this project 

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as he believes this is a novel research area that has potentially wide-ranging benefits for people 
affected by kidney disease and both the transplant and renal communities. 
 
Mr H. is an academic with experience of research design including both qualitative and quantitative 
methodology and skills in academic writing. He is also under the care of the renal team at UHDB and 
as such has a specific interest in this research design. Mr H. was involved in the development of this 
application and will provide ongoing support in: 
• 
Writing the plain English summary. 
• 
Reviewing the study documentation (e.g. the PIS) and study processes (e.g. Recruitment 
strategies). 
• 
Reviewing the appropriateness of the outcome measures. 
• 
Contribute to the development of the intervention. 
• 
Contribute to the development of the semi-structured interview. 
• 
Will be involved in the analysis of the qualitative interviews by acting as a third coder. 
• 
Contribute to the dissemination of the study. 
• 
Contribute to the development of the definitive study. 
 
It is recognised that Mr H will need to be appropriately reimbursed for his commitment and costs 
have been calculated in line with the INVOLVE Guidance (www.invo.org.uk)  
 
12.4. 
Research Ethics Committee (REC) & Regulatory Considerations 
 
The study will be conducted in compliance with the approved protocol and the Declaration of 
Helsinki. The protocol and all related documentation (e.g. informed consent form, PIS, 
questionnaires) will be reviewed by a Research Ethics Committee (REC). The investigator will not 
begin any participant activities until approval from the HRA and REC has been obtained and 
documented. All documentation and correspondence must be retained in the trial master 
file/investigator site file. Substantial amendments that require HRA and REC (where applicable) 
review will not be implemented until the HRA and REC grants a favourable opinion (with the 
exception of those necessary to reduce immediate risk to participants).  
 
It is the responsibility of the CI to ensure that an annual progress report (APR) is submitted to the 
REC within 30 days of the anniversary date on which the favourable opinion was given, annually until 
the study is declared ended. The CI is also responsible for notifying the REC of the end of study (see 
Section 6.9) within 90 days. Within one year of the end of study, the CI will submit a final report with 
the results, including any publications/abstracts to the REC. 
 
Before any site can enrol a patient into the study, confirmation of capacity must be sought from the 
site’s research and development (R&D) department. In addition, for any amendment that will 
potentially affect the site’s permission, the research team must confirm with the site’s R&D 
department that permission is on-going (Section 12.10). 
 
 
 

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12.5. 
Protocol Compliance 
 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures described in this protocol. Prospective, planned deviations and/or waivers to the 
protocol are not acceptable. Accidental protocol deviations may happen and as such these must be 
reported according to the Sponsors SOP. Deviations from the protocol which are found to frequently 
recur are not acceptable, will require immediate action, and could potentially be classified as a 
serious breach. 
 
12.6. 
Notification of Serious Breaches to GCP and/or the Protocol 
 
A “serious breach” is a departure from the protocol, Sponsor procedures (i.e. SOPs), or regulatory 
requirements which is likely to effect to a significant degree – 
(a) The safety or physical or mental integrity of the subjects of the study; or 
(b) The scientific value of the study. 
 
If a serious breach is identified, the investigator should notify the Sponsor immediately (i.e. within 1 
working day) using the ‘Non-CTIMP Notification of a Serious Breach’ form. The report will be 
reviewed by the Sponsor and CI, and where appropriate, the Sponsor will notify the REC within 7 
calendar days of being made aware of the breach.  
 
12.7. 
Data Protection and Patient Confidentiality 
 
The study will be conducted in accordance with the Data Protection Act 2018. The investigator must 
ensure that participant’s anonymity is maintained throughout the study and following completion of 
the study. Participants will be identified on all study specific documents (except for the informed 
consent form and enrolment log) only by the participants study specific identifier (and initials if 
deemed necessary). This identifier will be recorded on documents, biological samples and the 
database. The Investigator Site File will hold an enrolment log detailing the study specific identifier 
alongside the names of all participants enrolled in the study.  
 
All documents will be stored securely with access restricted to study staff and authorised personnel. 
Catherine Johnson will act as the custodian of the data generated in the study. 
 
12.8. 
Financial and Other Competing Interests for the Chief Investigator, Principal 
Investigators at Each Site and Committee Members for the Overall Study 
Management 
 
The CI, PI and all committee members have no conflicts of interest to declare. 
 
12.9. 
Indemnity 
 
As UHDB is acting as the research Sponsor for this study, NHS indemnity applies. NHS indemnity 
provides cover for legal liabilities where the NHS has a duty of care. Non-negligent harm is not 
covered by the NHS indemnity scheme. UHDB, therefore, cannot agree in advance to pay 

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compensation in these circumstances. In exceptional circumstances, an ex-gratia payment may be 
offered. 
 
12.10. 
Amendments 
 
Changes to the protocol will be documented in written protocol amendments. The Sponsor is 
responsible for deciding if an amendment should be deemed substantial or non-substantial. 
Substantial amendments will be submitted to the relevant regulatory bodies (i.e. REC, HRA) for 
review and approval. The amendments will only be implemented after approval and a favourable 
opinion has been obtained. Non-substantial amendments will be submitted to the HRA for their 
approval/ acknowledgment. Amendments will not be implemented until all relevant approvals are in 
place. 
 
12.11. 
Access to Final Study Dataset 
 
The Chief Investigator Catherine Johnson and Co – Investigators Professor Maarten Taal, Dr Janson 
Leung and Dr Daniela Viramontes Hörner will have access to the final dataset. 
 
13. 
DISSEMINATION POLICY 
 
13.1. 
Dissemination Policy 
 
The aim of this dissemination plan is to ensure the impact of the new knowledge generated is 
maximized. 
 
Findings will be disseminated in the following ways: 
• 
Abstracts will be submitted to professional conferences including nationally at UK Kidney 
Week and The British Transplantation Society in addition to local meetings. Internationally at 
The American Society of Nephrology, The European Renal Association and The European 
Society for Organ Transplantation. 
• 
We will work with our organisation’s communication team to share the findings of this study 
across the organisation and more widely. 
• 
We will utilise social media platforms to share our findings. We have an established Renal 
Team and CKRI twitter account accessed by both patients and staff to support this. 
• 
Articles will be submitted to peer review journals. 
• 
Via social media which I believe is an underutilized resource for engagement, recruitment 
and dissemination. 
• 
The success of this work will also be used to promote the non-medical clinical academic 
career organizationally, locally and nationally through the National Institute of Health 
Research 70 at 70 network which the CI is a member of. 
 
In addition, the findings of this study will be specifically shared with patients: 
• 
The findings of this study will be disseminated via patient groups nationally such as Kidney 
Care UK and locally through the Derby Kidney Patients Association and the CKRI PPI group, in 
addition to the annual renal showcase.  

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IRAS ID: 298681 
• 
We will work with our organisations communication team to share the findings of this study, 
specifically to patients linking it to our patient facing website. 
 
If this feasibility study is successful, we will submit a grant application (Research for Patient Benefit) 
to fund a large randomized controlled trial. 
 
13.2. 
Authorship Eligibility Guidelines and any Intended Use of Professional Writers 
 
The Chief Investigator Catherine Johnson and Co – Investigators Professor Maarten Taal, Dr Janson 
Leung and Dr Daniela Viramontes Hörner will be granted authorship on the final study report. 
 
14. 
REFERENCES 
 
Ardhanari, S., Alpert, M.A., Aggarwal, K. (2014) Cardiovascular disease in chronic kidney disease: risk 
factors, pathogenesis, and prevention. Advances in Peritoneal Dialysis. 30:40-53. 
 
Arsov, S., Graaff, R., van Oeveren, W., et al. (2014) Advanced glycation end-products and skin 
autofluorescence in end-stage renal disease: a review. Clinical Chemistry and Laboratory Medicine. 
52:11-20. 
 
Cai, W., He, J.C., Zhu, L., et al (2004). High levels of dietary advanced glycation end products 
transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase 
stimulant in diabetic patients. Circulation. 110:285-291. 
 
Clarke, R.E. Dordevic, A.L. Tan, S.M. Ryan, L. Coughlan, M.T. (2016) Dietary Advanced Glycation end-
products and Risk Factors for Chronic Disease: A Systematic Review of Randomised Controlled Trials. 
Nutrients. 8 (3):125.  
 
Crowley, L.E. Johnson, C. P. McInytre, N. J. Fluck, R. J. McInytre, C.W.  Taal, M.W.  Leung, J.C.H. 
(2013) Tissue-Advanced Glycation End Product Deposition after Kidney Transplantation. Nephron 
Clinical Practice. 124: 54-59. 
 
Gale, N.K., Heath, G., Cameron, E. et al. (2013) Using the framework method for the analysis of 
qualitative data in multi-disciplinary health research. BMC Medical Research Methodology. 13: 117. 
 
Harcourt, B.E., Sourris, K.C., Coughlan, M.T., et al. (2011) Targeted reduction of advanced glycation 
improves renal function in obesity. Kidney International. 80:190-198. 
 
Hartog, J.W.L. de Vries, A.P.J. Bakker, S.J.L. Graaff, R. van Son, W.J. et al (2006) Risk Factors for 
Chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced 
glycation end products in renal transplant recipients. Nephrology Dialysis and Transplantation. 
8:2263-2269. 
 
Jardine A.G. Gaston R.J. Fellstrom B.C. Holdass, H. (2011) Prevention of cardiovascular disease in 
adult recipients of kidney transplants. Lancet. 378:1419-1427. 
 
Luevano-Contreras, C., Durkin, T., Pauls, M. et al. (2013) Development, relative validity, and 
reliability of a food frequency questionnaire for a case-control study on dietary advanced glycation 
end products and diabetes complications. International Journal of Food Sciences and Nutrition. 64: 
1030–1035. 
 

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IRAS ID: 298681 
Lioufas, N., Hawley, C. M., Cameron, J. D., Toussaint, N. D. (2019). Chronic kidney disease and pulse 
wave velocity: a narrative review. International journal of hypertension. 2019: 9189362. 
 
Macias-Cervantes, M.H., Rodriguez-Soto, J.M., Uribarri, J., et al. (2015) Effect of an advanced 
glycation end product-restricted diet and exercise on metabolic parameters in adult overweight 
men. Nutrition. 31:446-451. 
 
Mallipattu, S.K., He, J.C., Uribarri, J. (2012) Role of advanced glycation end-products and potential 
therapeutic interventions in dialysis patients. Seminars in Dialysis. 25:529-538. 
 
Mark, A.B., Poulsen, M.W., Andersen, S., et al (2014). Consumption of a diet low in advanced 
glycation end products for 4 weeks improves insulin sensitivity in overweight women. Diabetes Care. 
37:88-95. 
 
Meerwaldt, R. Hartog, J.W. Graaf, R. Huisman, R.J. Oomen, Links, T.P. et al (2005) Skin 
autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, 
predicts mortality in haemodialysis patients. Journal of the American Society of Nephrology. 16: 
3687-3693. 
 
Mlinšek, G. (2016) Nutrition after kidney transplantation. Clinical Nutrition ESPEN. 14: 47-48. 
 
Mulder, D.J., Water, T.V., Lutgers, H.L., Graaff, R., Gans, R.O., Zijlstra, F.,  et al. (2006) Skin 
autofluorescence, a novel marker for glycemic and oxidative stress-derived advanced glycation 
endproducts: an overview of current clinical studies, evidence, and limitations. Diabetes Technology 
and Therapeutics. 8: 523-535. 
 
Nolte Fong, J.V., Moore, L.W. (2018) Nutrition trends in kidney transplant recipients: the importance 
of dietary monitoring and need for evidence-based recommendations. Frontiers in Medicine. 5(302). 
 
Peppa, M., Uribarri, J., Cai, W., Lu, M., Vlassara, H. (2004) Glycoxidation and inflammation in renal 
failure patients. American Journal of Kidney Diseases. 43:690-695. 
 
Shardlow A, McIntyre NJ, Kolhe NV, Nellums LB, Fluck RJ, McIntyre CW, Taal MW. (2020) The 
association of skin autofluorescence with cardiovascular events and all-cause mortality in persons 
with chronic kidney disease stage 3: a prospective cohort study. PLOS Med 17(7):e1003163. 
 
UK Renal Registry (2019) UK Renal Registry 21st Annual Report – data to 31/12/2017, Bristol, UK. 
Available from https://www.renalreg.org/publications-reports/ 
  
Uribarri, J. Woodruff, S. Goodman, S et al (2010) Advanced glycation end products in foods and a 
practical guide to their reduction in diet. Journal of the American Dietetic Association 110(6): pp. 
911-916.  
 
Vlassara, H., Cai, W., Crandall, J., et al. (2002) Inflammatory mediators are induced by dietary 
glycotoxins, a major risk factor for diabetic angiopathy. Proceedings of the National Academy of 
Sciences of the United States of America. 2002;99:15596-15601. 
 
Vlassara, H., Cai, W., Goodman, S., et al. (2009) Protection against loss of innate defenses in 
adulthood by low advanced glycation end products (AGE) intake: role of the antiinflammatory AGE 
receptor-1. Journal of Clinical Endocrinology and Metabolism. 94:4483-4491. 
 

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Vlassara, H., Cai, W., Tripp, E., et al. (2016) Oral AGE restriction ameliorates insulin resistance in 
obese individuals with the metabolic syndrome: a randomised controlled trial. Diabetologia. 
59:2181-2192. 
 
Yacoub, R., Nugent, M., Cai, W., et al. (2017) Advanced glycation end products dietary restriction 
effects on bacterial gut microbiota in peritoneal dialysis patients; a randomized open label 
controlled trial. PLoS One. 12:e0184789. 
 
15. 
APPENDICES 
 
15.1. 
Appendix 1 – Reference values of skin autofluorescence per age group. 
 
Age group (years) Skin autofluorescence value (mean ± SD) 
10-19 
1.11 ± 0.20 
20-29 
1.53 ± 0.30 
30-39 
1.73 ± 0.42 
40-49 
1.81 ± 0.36 
50-59 
2.09 ± 0.36 
60-69 
2.46 ± 0.57 
70-80 
2.73 ± 0.55 
>80 
2.71 ± 0.44 
Adapted from: Koetsier M, Lutgers HL, de Jonge C et al. (2010) Reference values of skin autofluorescence.  
Diabetes Technol Ther 12, 399–403. 
 
15.2. 
Appendix 2 – Amendment History 
 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made