National Unified Renal Translation Research Enterprise - Chronic Kidney Disease
Conditions: Chronic Kidney Diseases
Sponsor: University of Nottingham

NURTuRE – CKD Protocol No: 16091                 Page 1 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
  
  
  
  
  
  
  
NATIONAL UNIFIED RENAL TRANSLATIONAL RESEARCH  
ENTERPRISE – CHRONIC KIDNEY DISEASE   
  
  
  
  
  
Version 4.4 11/4/2024 
Short title:   
  
  
  
NURTuRE - CKD  
Acronym:   
  
  
  
NURTuRE - CKD  
Trial Registration:  
  
  
www.clinicaltrials.gov  
ISRCTN:    
  
  
  
  
IRAS Project ID:  
  
  
 211479  
Trial Sponsor:   
  
  
University of Nottingham  
Sponsor reference:  16091  
  
  
Funding Source:  
Kidney Research UK  
 
 
 

NURTuRE – CKD Protocol No: 16091                 Page 2 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
TRIAL / STUDY PERSONNEL AND CONTACT 
DETAILS  
  
Sponsor:  
University of Nottingham  
Contact name  
Mr Ali Alshukry  
  
Research and Innovation 
  
University of Nottingham  
  
E-Floor, Yang Fujia Building 
  
Jubilee Campus  
  
Nottingham  
  
NG8 1BB  
Email: sponsor@nottingham.ac.uk  
  
Chief investigator:  
Maarten Taal  
Professor of Medicine  
  
Phone: 01332 724618  
  
  
Email: m.taal@nottingham.ac.uk  
  
  
  
Co-investigators:  
Paul Cockwell  
Consultant Nephrologist  
Email: paul.cockwell@uhb.nhs.uk  
  
Philip Kalra  
Consultant Nephrologist  
Email: philip.kalra@srft.nhs.uk  
  
Simon Fraser  
Associate Professor of Public Health  
Email: S.Fraser@soton.ac.uk 
  
David Wheeler  
Professor of Kidney Medicine  
Email: d.wheeler@ucl.ac.uk  
  
Trial / Study Statistician:  
Dr Retha Steenkamp Head of Operations  
  
UK Renal Registry  
  
Email: Retha.steenkamp@renalregistry.nhs.uk  
  
Trial / Study Coordinating Centre:  
  
 
Maarten Taal 
Centre for Kidney Research and Innovation   
Division of Medical Sciences and Graduate Entry  
Medicine, University of Nottingham  
Email: m.taal@nottingham.ac.uk  

NURTuRE – CKD Protocol No: 16091                 Page 3 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
SYNOPSIS  
  
Title  
NATIONAL UNIFIED RENAL TRANSLATIONAL RESEARCH 
ENTERPRISE – CHRONIC KIDNEY DISEASE  
Acronym  
NURTuRE - CKD  
Short title  
NURTuRE - CKD  
Chief Investigator  
Maarten Taal  
Objectives  
To investigate determinants of and risk factors for clinically 
important adverse outcomes in people with chronic kidney 
disease.  
Trial Configuration  
Multicentre prospective cohort study  
Setting  
Secondary care  
Sample size estimate  
For 3000 participants, an event rate for death of 5/100 participant years, 
an ESKD rate of 7-10/100 participant years and up to 5.5 years follow-up, 
the study will have 80% power at two-sided 5% significance level to 
detect a minimum HR of 1.52-1.70 for death and 1.39-1.47 for ESKD 
associated with a biomarker with baseline frequency of 50%.   
Number of participants  
3000 participants with CKD  
100 participants without CKD (normal controls for biomarker assays)  
Eligibility criteria  
Inclusion criteria  
1. 
Over 18 years of age   
2. 
Estimated GFR 59-15ml/min/1.73m² or eGFR >60ml/min/1.73m² 
and urine albumin to creatinine ratio >30mg/mmol 3.  
Seen at least 
once in a Nephrology Clinic  
4. 
Willing to participate in two study visits   
5. 
Able to give informed consent and participate in study procedures  
  
Exclusion criteria  
1. 
Recipient of a solid organ transplant  
2. 
Expected survival less than 1 year   
3. 
Acute kidney injury within 3 months of recruitment  
4. 
Major Acute Cardiovascular Event (MACE) within 3 months of 
recruitment  
5. 
Primary Focal and Segmental Glomerulosclerosis and Idiopathic  
Minimal Change Disease  
6. 
Current or planned chemotherapy for cancer  
Description of 
interventions  
Participants with CKD who meet the eligibility criteria and give informed 
consent will be asked to attend a study visit where they will be asked to 
complete a number of quality of life and function status assessments, 
anthropomorphic assessments and blood and urine tests. The same  

NURTuRE – CKD Protocol No: 16091                 Page 4 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
 
 
assessments will be repeated at a second study visit, 12-66 months after 
the first visit. Should participants consent they will be asked to complete 
an annual questionnaire by post.  Participants without CKD will attend 
one study visit only where anthropomorphic assessment and blood and 
urine test will occur.   
Duration of study  
Up to 15 years  
Randomisation and 
blinding  
Not applicable  
Outcome measures  
1. Progression of CKD to kidney failure as defined a  reduction in 
estimated GFR to <15ml/min/1.73m2 or initiation of kidney 
replacement therapy 
2. Major acute cardiovascular events  
Statistical methods  
The main analyses will be multivariable looking at the predictive 
performance of biomarkers alone and in combination with other socio- 
demographic and clinical variables. Time-to-event analyses 
(KaplanMeier, Cox regression) will be used to assess the relationship 
between baseline/follow-up variables and end points such as all-cause 
mortality, cardiovascular and ESKD assuming that the proportionality 
assumption is met.  
 
 

NURTuRE – CKD Protocol No: 16091                 Page 5 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
ABBREVIATIONS  
  
  
AE  
  
Adverse Event  
AKI  
  
Acute Kidney Injury  
CKD  Chronic Kidney Disease  
  
  
CI  
Chief Investigator overall  
  
  
CRF  
  
Case Report Form  
CVE  Cardiovascular Events  
  
  
DMC Data Monitoring Committee  
  
eGFR estimated Glomerular Filtration Rate  
  
ESKD End-stage Kidney Disease  
  
FSGS  Focal segmental glomerulosclerosis  
  
  
GCP Good Clinical Practice  
  
GFR  Glomerular Filtration Rate  
  
  
ICF  
Informed Consent Form  
  
MACE Major Acute Cardiovascular Events  
  
  
NHS  National Health Service  
  
  
PI  
  
Principal Investigator at a local centre  
PIS  
Participant Information Sheet  
  
  
REC  
  
Research Ethics Committee  
R&D  Research and Development department  
  
  
SAE  Serious Adverse Event  
 
 
 

NURTuRE – CKD Protocol No: 16091                 Page 6 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
TABLE OF CONTENTS  
SYNOPSIS ............................................................................................................................... 3  
ABBREVIATIONS ................................................................................................................. 5  
TRIAL / STUDYBACKGROUND INFORMATION AND RATIONALE ....................... 8  
TRIAL / STUDY OBJECTIVES AND PURPOSE .............................................................. 9  
 PURPOSE  
9  
 PRIMARY OBJECTIVE  
9  
 SECONDARY OBJECTIVES  
9  
DETAILS OF PRODUCT(S) ................................................................................................. 9 
TRIAL / STUDY DESIGN ..................................................................................................... 9  
 TRIAL / STUDY CONFIGURATION  
9  
 
Prospective, multicentre cohort study  
9  
 
Primary endpoints  
9  
 
Secondary endpoints  
9  
 
Stopping rules and discontinuation  
10  
 RANDOMIZATION AND BLINDING  
10  
 TRIAL/STUDY MANAGEMENT  
10  
 DURATION OF THE TRIAL / STUDY AND PARTICIPANT INVOLVEMENT  
11  
 
End of the Trial  
11  
 SELECTION AND WITHDRAWAL OF PARTICIPANTS  
11  
 
Recruitment  
11  
 
Eligibility criteria: Participants with CKD  
12  
 
Inclusion criteria  
12  
 
Exclusion criteria  
12  
 
Eligibility criteria: Participants without CKD (controls)  
12  
 
Inclusion criteria  
12  
 
Exclusion criteria  
12  
 
Expected duration of participant participation  
13  
Removal of participants from therapy or assessments/Participant Withdrawal 13  
 
Informed consent  
13  
STUDY REGIMEN ............................................................................................... ............... 13  
 
Participants with CKD: Study visit 1:  
13  
 
Participants acting as controls: Study Visit 1:  
16  
 
Participants with CKD: Study Visit 2  
16  
 
Compliance  
16  
 
Criteria for terminating trial  
17  
 RADIATION EXPOSURE  
17  
 TRANSPORT AND STORAGE OF THE TISSUES  
17  
 LABORATORY ANALYSES  
17  
STATISTICS ......................................................................................................................... 18  
 
Methods  
18  
 
Sample size and justification  
18  

NURTuRE – CKD Protocol No: 16091                 Page 7 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
ADVERSE EVENTS ............................................................................................................. 20  
ETHICAL AND REGULATORY ASPECTS .................................................................... 20  
 ETHICS COMMITTEE AND REGULATORY APPROVALS  
20  
 INFORMED CONSENT AND PARTICIPANT INFORMATION  
20  
 RECORDS  
21  
 
Case Report Forms  
21  
 
Sample Labelling  
21  
 
Source documents  
21  
 
Direct access to source data / documents  
21  
 DATA PROTECTION  
22  
QUALITY ASSURANCE & AUDIT ................................................................................... 22  
 INSURANCE AND INDEMNITY  
22  
 TRIAL CONDUCT  
22  
 TRIAL DATA  
22  
 RECORD RETENTION AND ARCHIVING  
23  
 DISCONTINUATION OF THE TRIAL BY THE SPONSOR  
23  
 STATEMENT OF CONFIDENTIALITY  
23  
PUBLICATION AND DISSEMINATION POLICY ......................................................... 23  
USER AND PUBLIC INVOLVEMENT ............................................................................. 24  
STUDY FINANCES ............................................................................................................. 24 
 
Funding source  
24  
 
Participant stipends and payments  
24  
SIGNATURE PAGES ........................................................................................................... 25  
REFERENCES ...................................................................................................................... 27  
  
 
 

NURTuRE – CKD Protocol No: 16091                 Page 8 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
TRIAL / STUDYBACKGROUND INFORMATION AND RATIONALE  
  
Chronic kidney disease (CKD) affects approximately 10% of the adult population worldwide 
[1] and is associated with increased risk of multiple adverse outcomes including end-stage 
kidney disease (ESKD), all-cause mortality, cardiovascular events (CVE) and acute kidney 
injury (AKI) [2-4]. The risk profile associated with CKD is however heterogeneous with the 
majority being at relatively low risk. There is therefore a need for methods to better predict 
adverse clinical outcomes in individuals with CKD, so that interventions to reduce risk can be 
targeted to those most likely to benefit, whereas those at low risk can be spared unnecessary 
intervention and anxiety. A risk prediction equation has been developed to estimate the risk 
of progression to ESKD using simple demographic and biochemical variables (age, gender, 
estimated glomerular filtration rate, urine albumin to creatinine ratio, serum albumin, 
bicarbonate, calcium and phosphate) [5, 6], but there is currently no validated method to 
assess the likelihood of future cardiovascular events or other adverse outcomes associated 
with CKD.  
  
Most forms of CKD progress slowly over years or decades before reaching ESKD. At present 
the only primary outcomes accepted by drug regulatory authorities for trials of renoprotective 
drugs in CKD are ESKD and ESKD or doubling of serum creatinine. This has proved to be a 
major barrier to the development of novel renoprotective drugs because clinical trials based 
on these primary outcomes require large numbers of participants and prolonged follow-up to 
accrue sufficient events. As a result, trials of new renoprotective drugs are extremely costly 
and this is likely to have contributed to a lack of new therapies for CKD. Identifying novel 
biomarkers that reflect the activity of biological pathways known to contribute to CKD 
progression and the associated adverse outcomes is likely to facilitate the development of 
surrogate outcome measures that would give drug developers greater confidence of a 
therapeutic effect prior to embarking on large clinical trials. This strategy may also lead to the 
acceptance of new primary outcome measures for trials [7]. Together these developments 
will be expected to substantially lower the cost of testing new renoprotective drugs and 
thereby facilitate the development of novel therapies.  
  
The NURTuRE-CKD study aims to develop and validate robust risk prediction methods for 
adverse outcomes associated with CKD using a combination of previously identified risk 
factors and novel biomarkers. A key novel dimension, not included in other cohort studies of 
CKD, will be analysis of kidney biopsy specimens. This will allow evaluation of biomarkers at 
the site of pathological damage in the kidneys as well as in blood and urine. Furthermore, 
storage of serum, plasma, urine, RNA and DNA will allow the investigators to study novel 
biomarkers that may not yet have been identified in order to ensure maximum benefit from 
the data collected.  
  
The NURTuRE project is a collaboration between several independent investigators working 
in partnership with pharmaceutical companies engaged in the development of new 
treatments for CKD. This collaborative approach is expected to maximise the scientific value 
of the study and to assist in drug development and testing. Stored biosamples will also be 
made available to investigators outside the steering committee and to pharmaceutical 
companies (via an independent access committee) to further increase the value of the 
dataset for research. As such the NURTuRE project represents an important development in 
the progress of renal research in the UK that will act as a springboard for similar 
developments in research on other aspects of kidney disease and specifically fulfils several 
of the objectives outlined in the recent UK Kidney Research Consortium’s Research Strategy 
Document.  
  

NURTuRE – CKD Protocol No: 16091                 Page 9 of 28        version 4.4    11/04/2024  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
TRIAL / STUDY OBJECTIVES AND PURPOSE  
  
PURPOSE  
To investigate determinants of and risk factors for clinically important adverse outcomes in 
people with chronic kidney disease.  
  
PRIMARY OBJECTIVE  
To investigate determinants of and risk factors for clinically important adverse outcomes in 
people with chronic kidney disease, including:  
• 
Death  
• 
Major Acute Cardiovascular Events (MACE)  
• 
Progression of CKD (KDIGO definition)  
• 
End-stage kidney disease (ESKD)  
• 
Acute Kidney Injury (AKI)  
• 
Hospital admissions  
• 
Infections requiring hospital admission  
• 
New Cancer diagnosis  
• 
Hip fractures  
 SECONDARY OBJECTIVES  
1. To identify and validate novel biomarkers to predict clinically important outcomes 
in people with CKD.  
2. To investigate novel mechanisms underlying the association between CKD and 
multiple adverse outcomes.  
3. To assess the performance of previously published risk scores for people with CKD 
(external validation).  
4. To develop and internally validate new risk scores to predict adverse outcomes in 
people with CKD and evaluate the potential benefit of adding novel biomarkers to 
existing risk scores.  
5. To assess the relationship between severity of CKD, comorbid conditions and 
Quality of Life.   
6. To investigate the resource use and costs of patients with CKD at different levels 
of severity with varying morbidity.  
  
DETAILS OF PRODUCT(S)  
Not applicable  
  
TRIAL / STUDY DESIGN  
  
TRIAL / STUDY CONFIGURATION  
Prospective, multicentre cohort study  
  
Primary endpoints  
1. Progression of chronic kidney disease to kidney failure (defined sustained decrease to 
<15mL/min/1.73m2 or initiation of kidney replacement therapy).  
2. Major Acute Cardiovascular Event (MACE) – cardiac death, non-fatal myocardial 
infarction, cerebral infarction or intracerebral haemorrhage, arterial revascularisation  
Secondary endpoints  
  
a. Death from any cause  

NURTuRE – CKD Protocol No: 16091                 Page 10 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
b. Progression of CKD (KDIGO definition) 
c. Rate of GFR decline 
d. Percentage GFR decline (30% or 40% or 50%) 
e. End-stage kidney disease (ESKD)  
f. Acute Kidney Injury (AKI)  
g. New diagnosis of cardiac failure  
h. Unplanned hospital admissions  
i. 
Infections requiring hospital admission  
j. 
Cancer diagnosis  
k. Hip fractures  
Stopping rules and discontinuation  
This is an observational study. Participants will be withdrawn from the study only if they 
withdraw their consent. The study will be discontinued only if for unforeseen circumstances it 
becomes clear that it is no longer feasible.    
  
  
RANDOMIZATION AND BLINDING  
Not applicable  
  
TRIAL/STUDY MANAGEMENT  
The Chief Investigator has overall responsibility for the study and shall oversee all study 
management. The study will be managed from the coordinating centre at the University of 
Nottingham by a project manager supported by the Chief Investigator. A Study Management 
Committee (SMC) will further support and coordinate delivery of the study and will be 
comprised of:  
• 
Chief Investigator  
• 
Principle Investigators  
• 
Project Manager  
• 
Data Manager (based at the UK Renal Registry)  
• 
Statistician  
• 
Kidney Research UK representative  
• 
Research Nurses  
The SMC will meet regularly (monthly) by teleconference with face to face meetings as 
required.   
  
A Joint Steering Committee (JSC) will provide oversight of the study and will review progress 
against the objectives and milestones. The JSC will be comprised of:  
  
• 
Kidney Research UK Director of Research Operations (JSC Chair)  
• 
Chief Investigator (for the NURTuRE-CKD)  
• 
Representative from each of the three pharmaceutical company partners (initial 
members)  
• 
Patient Representative  
• 
UK Renal Registry Representative  
• 
UK Biobank Representative  
• 
University of Birmingham (HBRC) Representative  
• 
Geneva University (HUG) Representative   
• 
Chief Investigator (for the NURTuRE-Nephrotic Syndrome study)  
  
Top level oversight of the biobanked samples will be provided by the NURTuRE Strategy 
Committee comprised of:  

NURTuRE – CKD Protocol No: 16091                 Page 11 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
• 
An independent Chair, appointed by Kidney Research UK  
• 
Patient representatives  
• 
One to three Independent Academic representatives  
 
 
The Strategy Committee will provide governance and oversight of the biorepository resources 
at Milton Keynes and the University of Birmingham and will appoint and oversee an 
Independent Biosample Access Committee that will consider and approve applications for 
access to all specimens in the biorepositories from independent investigators who wish to 
make use of the samples.   
  
The data custodian will be the Chief Investigator.  
  
  
DURATION OF THE TRIAL / STUDY AND PARTICIPANT INVOLVEMENT  
Study Duration: Enrolment will commence in the 2nd quarter of 2017 and will continue for 
12 months or until at least 3000 participants with CKD and 100 participants without CKD (50 
with diabetes and 50 without diabetes) have been recruited. Follow-up will continue for up to 
15 years. Analysis of data will continue for at least 3 years after the follow-up period. The total 
duration of the study will therefore be up to 20 years.  
  
Participant Duration: Participants with CKD will be actively involved for up to 66 months only. 
After the follow-up study visit outcome data will be collected via the UK Renal Registry for a 
further 14 years. Participants will be sent a questionnaire annually by post to assess quality of 
life (EQ-5D-5L) and health care resource utilisation during the previous year but will not attend 
for any further study visits. Participants without CKD (controls) will attend for a single study 
visit.  
  
End of the Trial  
The end of the study will be 15 years after the first study visit of the last recruited participant.  
  
  
SELECTION AND WITHDRAWAL OF PARTICIPANTS  
  
Recruitment  
Participants with CKD will be recruited from nephrology clinics at multiple (planned to start with 
11) participating centres.   
The initial approach will be from a member of the patient’s usual care team (which may include 
an investigator) either in person or by letter, and information about the trial will be on display 
in the relevant clinical areas. People who express an interest will be given a copy of the 
Participant Information Sheet and invited to contact the research team by telephone if they 
wish to participate or will have the opportunity to discuss the study at their next clinic visit. 
Potential participants who do not respond will be contacted once by phone, by a member of 
the usual care team, to check if they wish to participate.  
  
Control participants (without CKD) will be recruited from among hospital staff members, people 
attending diabetes clinics and the general public via advertisements placed in the hospitals 
and in the press. People interested in participating will be invited to call a telephone number 
and will be sent a Participant Information Sheet by post. If they remain willing to participate, 
they will be invited to call back to arrange a study visit.   
  

NURTuRE – CKD Protocol No: 16091                 Page 12 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
The investigator or their nominee, e.g. from the research team or a member of the participant’s 
usual care team, will inform the participant of all aspects pertaining to participation in the study. 
If needed, the usual hospital interpreter and translator services will be available to assist with 
discussion of the trial, the participant information sheets, and consent forms, but the consent 
forms and information sheets will not be available in other languages, other than Welsh.  
  
The voluntary nature of the study will be explained to the potential participant who will also be 
reassured that clinical care will not be affected by their decision. The right of the participant to 
withdraw at any time will be explained. The participant’s right not to attend follow-up visits will 
be explained as will the withdrawal of consent process. In the event of their withdrawal we will 
seek consent to use the data collected prior to withdrawal for analysis where appropriate. In 
the unlikely event that a participant withdraws consent for previously collected data to be used 
for analysis it will not be used. Similarly if a participant wishes previously stored samples not 
to be used, these will be destroyed.  
  
Eligibility criteria: Participants with CKD  
  
Inclusion criteria  
1. Age Over 18 years of age   
2. Estimated GFR 59-15ml/min/1.73m² or eGFR >60ml/min/1.73m² and urine albumin to 
creatinine ratio >30mg/mmol  
3. Seen at least once in a Nephrology Clinic  
4. Willing to participate in two study visits   
5. Able to give informed consent and participate in study procedures  
  
Exclusion criteria  
1. Recipient of a solid organ transplant  
2. Expected survival less than 1 year (in the opinion of local investigators)  
3. Acute kidney injury within 3 months of recruitment  
4. Major Acute Cardiovascular Event (MACE) within 3 months of recruitment  
5. Primary Focal and Segmental Glomerulosclerosis and Idiopathic Minimal Change 
Disease  
6. Current or planned chemotherapy for cancer  
  
Eligibility criteria: Participants without CKD (controls)  
  
Inclusion criteria  
1. Age over 18 years of age   
2. Willing to participate in one study visit   
3. Able to give informed consent and participate in study procedures  
4. No evidence of CKD  
5. No other major illnesses except for hypertension and diabetes mellitus (50 participants 
will have diabetes but no CKD). Those with diabetes may have retinopathy or 
neuropathy.  
  
Exclusion criteria  
  
1. Estimated GFR<60ml/min/1.73m2 in previous 12 months or last available result  
2. Urine albumin to creatinine ratio >3mg/mmol in previous 12 months or last available 
result  
3. Previous unilateral nephrectomy or partial nephrectomy  

NURTuRE – CKD Protocol No: 16091                 Page 13 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
4. Recipient of a solid organ transplant  
5. Expected survival less than 1 year (in the opinion of local investigators)  
6. Current or planned chemotherapy for cancer  
Expected duration of participant participation  
Study participants with CKD will participate in the study for 12-66 months of active follow-
up. After that participants will be sent a questionnaire annually by post to assess quality of 
life (EQ-5D-5L) and health care resource utilisation during the previous year and we will 
collect outcome data without the need for further study visits; this annual follow up by 
questionnaire will continue for up to 14 years following their second study visit.  Study 
participants acting as normal controls will attend only a single study visit.   
  
Removal of participants from therapy or assessments/Participant Withdrawal  
This is an observational study. Participants will be withdrawn from the study only if they 
withdraw their consent.  
  
Informed consent  
All participants will provide written informed consent. The Informed Consent Form will be 
signed and dated by the participant before they enter the trial. The Investigator will explain the 
details of the trial and provide a Participant Information Sheet, 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.   
  
Informed consent will be collected from each participant before they undergo any interventions 
(including physical examination and history taking) related to the study. 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 patient’s hospital records (paper or electronic).  
  
Should there be any subsequent amendment to the final protocol, which might affect a 
participant’s participation in the trial, continuing consent will be obtained using an amended 
Consent Form which will be signed by the participant. Should a participant be unable to attend 
the follow-up visit, they asked to sign the revised consent form having read the revised PIS. 
An opportunity to ask questions will be offered prior to signing. The signed consent form will 
be returned in a pre-paid envelope and then signed by the delegated member of the research 
team.  
  
STUDY REGIMEN  
Participants with CKD: Study visit 1:  
  
After providing written informed consent participants will undergo the following assessments 
and study procedures:  
  
Medical History: The following data will be collected by interview, questionnaire and 
examination of the participants’ medical records.  
• 
Socio-demographic: age, gender, ethnicity, first language, education status, marital 
status, employment, indices of multiple deprivation (IMD) score (derived from postcode 
of residence), smoking history, alcohol intake, dietary status (vegetarian/vegan)  
• 
Medical: All previous illnesses with particular focus on CKD diagnosis, previous AKI, 
hypertension, diabetes, cardiovascular disease (CVD), atrial fibrillation, rheumatoid 
arthritis, thyroid disease, retinopathy (if diabetic), peripheral neuropathy (if diabetic).  
These will be used to calculate the Charleston Comorbidity Index.  
• 
Family medical history: CVD before age 60 years, diabetes, CKD, ESKD.  

NURTuRE – CKD Protocol No: 16091                 Page 14 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
• 
All current medication including over the counter preparations and supplements/herbal 
preparations. 
• 
Vaccination status for influenza and pneumococcus  
• 
Prior laboratory results, especially prior serum creatinine results to enable analysis of 
trend in eGFR.  
• 
The above data will be recorded on a questionnaire that participants will be asked to 
complete at or prior to the baseline study visit. Questionnaires will be checked by 
research staff at the study visit and participants will be assisted in completing the 
questionnaires if required. Details of the medical history and blood results will be 
verified by inspection of participants’ hospital medical records.  
  
Quality of Life and Functional Status  
• 
Quality of life will be measured by EQ-5D-5L quality of life questionnaire  
• 
Functional status will assessed using the Karnofsky score  
• 
Current symptoms will be assessed using an Palliative Outcome Scale (POS) 
questionnaire (POS-Renal P7)  
• 
Health literacy will be assessed by questionnaire (single question SILS)  
• 
Cognitive function will be assessed with the “six item Cognitive Impairment Test” (6CIT) 
questionnaire  
• 
Anxiety and depression symptoms will be assessed with the “Hospital Anxiety and  
Depression Scale“ (HADS)   
  
Anthropomorphic assessment:  
• 
Height  
• 
Weight  
• 
Body Mass Index  
• 
Hip to waist ratio  
• 
Waist circumference   
• 
Mid-upper arm muscle circumference  
• 
Hand grip strength  
• 
Blood pressure (seated; average of 3 readings recorded with an oscillometric device in 
accordance with British Hypertension Society guidelines)  
• 
Urine dipstick test  
• 
“Timed up and go” (TUG) test  
  
Laboratory Assays:  
The following tests to be performed as part of routine clinical care:  
• 
Urea and electrolytes  
• 
Estimated GFR   
• 
Magnesium, calcium and phosphate  
• 
Serum albumin  
• 
Lipid profile (including triglycerides)  
• 
Random blood glucose   
• 
Haemoglobin A1C (if diabetic)  
• 
Bicarbonate  
• 
Uric acid  
• 
Full blood count  
• 
High sensitivity C-reactive protein (CRP)  
• 
Ferritin (if anaemic)  
• 
Folic acid (if anaemic)  
• 
Vitamin B12 (if anaemic)  

NURTuRE – CKD Protocol No: 16091                 Page 15 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
• 
Serum Parathyroid hormone  
• 
Urine albumin to creatinine ratio  
• 
Urine protein to creatinine ratio    
Specimens for Biorepository: In addition to the routine biochemistry detailed above, 
additional biosamples will be obtained from each participant at each study visit as follows:  
• 
10ml plasma (30mL of blood)  
• 
10ml serum (30mL of blood)  
• 
2 x 3ml whole blood for DNA extraction: genomics and epigenetics  
• 
1 x 2,5ml whole blood for RNA extraction  
• 
100ml urine  
  
Core Biomarkers: A core set of 30 plasma and urine biomarkers that have previously been 
shown to have prognostic value in CKD will be measured in a central laboratory at University 
Hospital Geneva and the University of Geneva. A provisional list of these biomarkers is as 
follows: serum/plasma: fibroblast growth factor 23 (FGF23), NT Pro Brain Natriuretic Protein 
(NT Pro-BNP), high sensitivity troponin T, asymmetrical dimethyl arginine (ADMA) and 
symmetrical dimethyl arginine (SDMA); Adiponectin, Adrenomedullin, Vitamin D, Pentraxin 
2, Galectin 3, neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, interleukin(IL)6, 
IL-17, high sensitivity C reactive protein (hsCRP); transforming growth factor beta (TGF- 
β), tumour necrosis factor alpha (TNF-α), tumour necrosis factor-like weak inducer of 
apoptosis (TWEAK)   urinary: transglutaminase 2 (uTG2), epidermal growth factor (uEGF), 
tissue inhibitor of matrix metalloproteinase 1 (uTIMP1), collagen 1 (uCol1), neutrophil 
gelatinase-associated lipocalin (uNGAL), kidney injury molecule-1(uKIM-1), Clusterin 
(uClusterin), Cadherin K (uCadherin K), matrix metalloproteinase 9 (uMMP-9), 
fibroblastspecific protein-1 (uFSP-1), N-acetyl-β-D-glucosaminidase (uNAG). However, it is 
anticipated that the list will change as new data become available during the recruitment 
phase of the study. Plasma, serum, whole blood and urine specimens will be stored until 
analysis in a central biorepository at the NIHR National Biosample Centre in Milton Keynes. 
Consent will be sought from participants for long term storage of biosamples and use of 
these biosamples in future studies.  
  
Kidney biopsy tissue: Participants who have undergone a kidney biopsy for clinical 
diagnosis will be invited to participate in a sub-study that will comprise at least 15% of the 
whole cohort. In addition to enrolling in the study, these participants will be asked to consent 
for any surplus biopsy material, over and above that required for routine diagnostic purposes 
at the enrolling centre, to be utilised for the study. This will permit direct assessment of the 
disease processes that are causing kidney disease, to identify those factors that are present 
that are predictive of future decline in kidney function (including ESKD), and provide 
information that can subsequently be used to direct the development and evaluation of 
treatments.   
  
Biopsy tissue that has been used in clinical laboratories for routine diagnosis will be 
transported to the Human Tissue Authority (HTA) licensed biorepository facility at University 
of Birmingham (Human Biomaterials Resource Centre - HBRC) for digital scanning and 
further analysis. This will include kidney biopsy sections analysed by clinical laboratories by 
staining including H&E, PAS and Masson’s Trichrome. Clinical laboratories will also be 
asked to supply digital images of immunostaining and electron microscopy performed for 
clinical diagnosis if these are available.  
  
Residual surplus kidney biopsy tissue will also be transported to the biorepository facility. 
From this surplus kidney biopsy tissue sections will be cut for additional assessment of the 
pathological changes associated with CKD by specialised stains and immunostaining.  

NURTuRE – CKD Protocol No: 16091                 Page 16 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
  
Digital images will be analysed to provide:  
• 
Confirmation and further classification of clinical diagnosis  
• 
Automated assessment of glomerulosclerosis, extent of interstitial fibrosis, inflammation, 
peritubular capillary density, collagen accumulation, resident and infiltrating cell 
phenotype  
  
Tissue sections will also be used for RNA extraction and analysis of gene expression. Surplus 
tissue will be stored in the University of Birmingham Biorepository facility and sections will be 
supplied to investigators as required. Consent will be sought from participants for long-term 
storage of residual kidney biopsy tissue and use of this tissue in future studies.  
  
Participants acting as controls: Study Visit 1:  
  
After providing written informed consent participants will undergo the following assessments 
and study procedures:  
  
Socio-Demographic data:  
Participants will be asked to give their sex and date of birth as well as post code of residence 
(to derive indices of multiple deprivation score)  
  
Anthropomorphic Assessment:  
• 
Height  
• 
Weight  
• 
Body Mass Index  
• 
Hip to waist ratio  
• 
Waist circumference   
  
Laboratory Assays:  
• 
Urea and electrolytes  
• 
Estimated GFR   
• 
Urine albumin to creatinine ratio  
• 
Random blood glucose  
• 
High sensitivity C-reactive protein  
• 
Haemoglobin A1C (if diabetic)  
  
 Specimens for Biorepository: In addition to the biochemistry detailed above, additional 
biosamples will be obtained as follows:  
• 
10ml plasma (30mL of blood)  
• 
10ml serum (30mL of blood)  
• 
100ml urine  
• 
2 x 3ml whole blood for DNA extraction: genomics and epigenetics  
• 
1 x 2,5ml whole blood for RNA extraction  
  
  
Participants with CKD: Study Visit 2  
  
Participants will be asked to attend a second study visit 12-66 months from the date of the first 
study visit. The assessments and procedures for the second study visit will be the same as for 
the first study visit. In addition, participants will be asked to complete a health utilisation 

NURTuRE – CKD Protocol No: 16091                 Page 17 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
questionnaire to obtain details regarding hospital admissions, GP visits and medication 
changes during the year since recruitment  
  
 
Compliance  
Compliance will be defined by attendance at the second study visit.  
  
Criteria for terminating trial  
The study will be discontinued only if for unforeseen circumstances it becomes clear that it is 
no longer feasible. If a participating centre is unable to recruit successfully, it will be withdrawn 
from the study and replaced by another centre. Participants already recruited from a centre 
that withdraws from the study will remain in the study.    
  
RADIATION EXPOSURE  
Not applicable  
TRANSPORT AND STORAGE OF THE TISSUES  
Samples will be stored in a linked anonymised format and labelled using a barcode linked to 
the study number to permit accurate linkage to study data and the consent form.   
  
Samples for NHS pathology analysis will be labelled in accordance with local NHS procedures.   
  
Serum, plasma and urine samples will be stored at each participating site initially at -20 degrees 
centigrade and transferred to -80 degrees centigrade within 72 hours of collection.  
Frozen samples will be transferred on dry ice by courier from each participating site to the 
NIHR National Biosample Centre in Milton Keynes approximately every 4 months.  All 
shipments will contain a complete inventory of all samples, along with the name of the 
person responsible for sending the samples. After completion of recruitment and follow-up, 
samples will similarly shipped from the National Biosample Centre to participating 
laboratories for analysis. Any sample left after analysis will either be returned to the National 
Biosample Centre or destroyed. A master database of all frozen samples will be held at the 
National Biosample Centre in a password protected file.  
  
Surplus kidney biopsy tissue embedded in paraffin blocks as well as stained microscope 
slides will be shipped at room temperature from each participating centre to the University of 
Birmingham Biorepository Centre. A small number of frozen surplus kidney biopsy 
specimens will be shipped on dry ice.  At the University of Birmingham Biorepository Centre 
slides will be photographed and digital images will be stored and identified using the 
participant identification number (PIN). The slides will then be returned by courier to the 
participating centre. Residual renal tissue in paraffin blocks will be further sectioned and 
placed on microscope slides for further analyses as planned by the investigators. These 
slides will be labelled with the PIN. Slides will be shipped to participating laboratories for 
analysis. A master database of all biopsy samples will be held at the University of  
Birmingham Biorepository Centre in a password protected file. Tissues not used by the end 
of the study will be returned to the Pathology Department of origin. If the surplus tissue is 
required by the clinical centre for further routine testing at any time, then it will be returned 
from the biorepository.  
  
LABORATORY ANALYSES  
Routine biochemistry tests will be performed in local NHS clinical biochemistry laboratories. 
Novel biomarkers in serum, plasma and urine will be assayed in research laboratories. DNA 

NURTuRE – CKD Protocol No: 16091                 Page 18 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
will be extracted from whole blood samples at the NIHR National Biosample Centre and stored 
for subsequent analysis.   
  
OUTCOMES  
Data regarding the primary and secondary outcomes will be obtained from multiple sources as 
summarised below:  
Outcome  
  
Source  
ESKD   
  
UK Renal Registry; and local laboratory results via Patient View  
CKD Progression  
Local laboratory results via Patient View  
Death  
Office of National Statistics (ONS) through Digital Health and 
Care Wales (DHCW)  
Hospital admission  
Hospital Episode Statistics (HES) through DHCW  
AKI  
HES through DCHW  
Infections  
HES through DHCW  
MACE  
ONS and HES through DHCW  
Fractures  
HES through DHCW  
New Cancers  
ONS Cancer Registry through DHCW  
  
An adjudication committee will be established at each site to verify and adjudicate outcome 
events including cause of death, cardiovascular events and others as required by evaluation 
of individual medical records.  
  
STATISTICS  
  
Methods  
  
Standard descriptive statistics will be used to describe patients at baseline 
(sociodemographic and clinical characteristics, laboratory parameters and biomarkers, 
quality of life).  Summary statistics (mean, SD, 95% confidence intervals, median IQR), 
frequency (percent) distribution tests and parametric (t-test) and non-parametric statistical 
methods will be used to assess group differences, as appropriate. Normality of the 
distributions will be assessed by Kolmogorov-Smirnov or Shapiro-Wilk tests, as appropriate, 
with logtransformation, as appropriate. Adjustment for multiple comparisons will be made by 
posthoc tests (e.g., Tukey), as necessary.   
  
Analyses of changes over time of selected clinical characteristics and biomarkers will be 
performed. Changes in serum creatinine levels and eGFR will be analysed using 
mixedeffects models and generalized estimation equations. The latter approaches facilitate 
handling of repeated measurements and the heterogeneity of individual creatinine levels.  
  
Time-to-event analyses (Kaplan-Meier, Cox regression) will be the principal approach to 
analysing end points such as all-cause mortality, cardiovascular and ESKD providing the 
proportionality assumption is met. A competing risk framework will be used. Also, logistic 
regression methods will be used for dichotomous outcomes in a fixed time period (e.g., 
progression of CKD) with time-independent covariates and Poisson regression will be used 
for count data (e.g., number of hospitalisations). Multivariable regression models will be used 
to study the associations between patient characteristics, biomarkers and the various study 
outcomes.   
  

NURTuRE – CKD Protocol No: 16091                 Page 19 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
Sample size and justification  
The study aims to recruit 3000 patients from 11 centres. This is a pragmatic approach based 
on feasibility and cost, and is similar to other large well phenotyped CKD cohorts (e,g. CRIC 
4000 [8], CKD Rein 3600 [9], German CKD 5000 [10].  It is not driven by a sample size 
based on a hypothesis for a specific primary outcome, however, a post-hoc estimation of 
power for each of the main comparisons and relationships will be performed. 100 participants 
without CKD (50 with type 2 diabetes mellitus and 50 without diabetes) will be recruited to act 
as controls for the biomarker assays.  
The main analyses will be multivariable looking at the predictive performance of biomarkers 
alone and in combination with other socio- demographic and clinical variables. A rule of 
thumb is that 10 events of interest are required per predictor (variable) in a final multivariable 
prognostic model. It is assumed also that the event rates will be dependent on a variety of 
factors in the recruited cohort such as on age, eGFR, co-morbidity and ethnic status, so they 
cannot be accurately specified a priori. However, initial estimates from the UK CRISIS study, 
which included participants similar to those required for NURTuRE-CKD indicated event 
rates of 5/100 person years for death (mortality) and 7-10/100 person years for ESKD [11].   
  
Therefore, the planned initial 5.5-year follow up of a 3000 person cohort should generate 
>100 events for all the key outcomes (deaths, ESKD, CV events, AKI, CKD progression). 
Such an a priori approximate estimation of study sample size and power, for logistic reasons 
only, may be based on the consideration for a minimum hazard ratio (HR) that could be 
detected for a baseline biomarker in time-to-event survival analysis (e.g. Kaplan-Meier) for an 
outcome such as mortality. In this sense, two approaches are available: balanced and 
unbalanced (unequal-size) groups.   
  
For example, if the baseline frequency of a biomarker level is 50% (i.e., a total of 3000 
patients or 2 equal groups of 1500 patients each) then a minimum HR of 1.52-1.70 for death 
(i.e. mortality of minimum 5% in the second, control group) can be detected with 80% power 
at two-sided 5% significance level (required minimum number of 114-182 events). For a less 
common biomarker, with a prevalence of 10% (n=300 patients), the minimum HR would rise 
to 2.34.  
  
Similarly for ESKD as an outcome, if the baseline frequency of a biomarker level is 50% (i.e., 
a total of 3000 patients or 2 equal groups of 1500 patients each) then a minimum HR of 
1.391.47 for ESKD (i.e., event rate of minimum 8.5% in the second, control group) can be 
detected with 80% power at two-sided 5% significance level (required minimum number of 
210-296 events). For a less common biomarker, with a prevalence of 10% (n=300 patients), 
the minimum HR would rise to 1.98.  
  
Multiple imputation will be used to deal with missing data.  
  
Definition of populations analysed  
All participants who complete the baseline study visit will be included in the primary analysis. 
All participants who complete the baseline and follow-up study visits will be included in 
analyses of change in baseline variables over time as well as the relationship of these 
changes to subsequent outcome events.  
Subgroup analysis will be conducted as indicated by the research question being investigated. 
Pre-specified subgroups will include:  
• 
Participants 65 years and older versus younger than 65 years  
• 
Male versus female participants  
• 
White versus Black versus South Asian participants  
• 
Participants with diabetes mellitus versus without diabetes  

NURTuRE – CKD Protocol No: 16091                 Page 20 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
• 
Participants with pre-existing cardiovascular disease versus without CVD  
• 
CKD categories (as specified by the KDIGO and NICE Classification)  
Health Economics Analyses  
Health economics analysis will form part of the study. Costs will be taken from the NHS and 
PSS perspective. A questionnaire will collect health resource use information from 
participants including medications, primary care visits, outpatient visits, A&E attendances and 
hospital admissions. These data will be combined with HES data and data from Renal 
Department databases to assess total health resource utilisation. Health related quality of life 
will be measured annually by EQ-5D-5L.   
The UK tariff will be used to translate the EQ-5D-5L questionnaire into utility scores. Area 
under the curve methods will be used to calculate the quality adjusted life year (QALY).  
Generalised linear mixed models will be employed to estimate the costs and QALYs 
associated with baseline characteristics including socio-economic groups, and clinical 
factors.  
  
  
ADVERSE EVENTS  
  
The primary and secondary endpoints of this study are all adverse events and data regarding 
these AEs will be collected and recorded as described in the protocol. As this is an 
observational study, the only AEs with a causal relationship to study procedures will be those 
directly related to study visits, which are expected to be extremely uncommon. Only SAEs 
and SUSARs related to study visits will be reported. Participants will be asked to report only 
AEs that could be related to study visits.  
  
  
  
ETHICAL AND REGULATORY ASPECTS  
  
ETHICS COMMITTEE AND REGULATORY APPROVALS  
The trial will not be initiated before the protocol, informed consent forms and participant and 
GP information sheets have received approval / favourable opinion from the Research Ethics 
Committee (REC), and the respective National Health Service (NHS) Research & 
Development (R&D) department. Should a protocol amendment be made that requires REC 
approval, the changes in the protocol will not be instituted until the amendment and revised 
informed consent forms and participant information sheets (if appropriate) have been reviewed 
and received approval / favourable opinion from the REC and R&D departments. A protocol 
amendment intended to eliminate an apparent immediate hazard to participants may be 
implemented immediately providing that the REC are notified as soon as possible and an 
approval is requested. Minor protocol amendments only for logistical or administrative changes 
may be implemented immediately; and the REC will be informed.  
  
The trial will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, 1996; the principles of Good Clinical Practice, and the Department of 
Health Research Governance Framework for Health and Social care, 2005.  
  
INFORMED CONSENT AND PARTICIPANT INFORMATION  
The process for obtaining participant informed consent will be in accordance with the REC 
guidance, and Good Clinical Practice (GCP) and any other regulatory requirements that might 
be introduced. The investigator or their nominee and the participant shall both sign and date 
the Informed Consent Form before the person can participate in the study.  

NURTuRE – CKD Protocol No: 16091                 Page 21 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
  
The participant will receive a copy of the signed and dated forms and the original will be 
retained in the Trial Master File. A second copy will be filed in the participant’s medical notes 
and a signed and dated note made in the notes (paper or electronic) that informed consent 
was obtained for the trial.   
  
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, or 
loss of benefits to which the participant is otherwise entitled. No trial-specific interventions will 
be done before informed consent has been obtained.  
  
The investigator will inform the participant of any relevant information that becomes available 
during the course of the study, and will discuss with them, whether they wish to continue with 
the study. If applicable they will be asked to sign revised consent forms.  
  
If the Informed Consent Form is amended during the study, the investigator shall follow all 
applicable regulatory requirements pertaining to approval of the amended Informed Consent 
Form by the REC and use of the amended form (including for ongoing participants).  
   
RECORDS  
Case Report Forms  
Each participant will be assigned a participant identification number, allocated at recruitment, 
for use on CRFs, other trial documents and any electronic database or spreadsheet used for 
analysis. The documents and database will also use their initials (of first and last names 
separated by a hyphen) and year of birth.  
  
This study will use electronic CRFs stored on a secure server at the UK Renal Registry 
(UKRR). The UKRR database will include participant identifiable data including names, date 
of birth, address, NHS and hospital numbers to facilitate collection of outcome data and 
routine biochemical data. The UKRR routinely deals with confidential patient data and has 
robust systems in place to ensure security and confidentiality of these data. CRFs will be 
treated as confidential documents and held securely in accordance with regulations. Access 
to CRFs shall be restricted to those personnel approved by the Chief or local Principal  
Investigator and recorded on the ‘Trial Delegation Log.’ Data that are exported from the UKRR 
database will have all participant identifiable data removed.  
  
The investigator will make a separate confidential record of the participant’s name, date of 
birth, local hospital number or NHS number, and Participant Trial Number (the Trial  
Recruitment Log), to permit identification of all participants enrolled in the trial, in accordance 
with regulatory requirements and for follow-up as required. This record will be held on a 
secure server in a password protected file.  
  
Sample Labelling  
Each participant will be assigned a participant trial identity code number (PIN) for use on the 
consent forms and other study documents and the electronic database. Samples will be 
labelled with a barcode linked to the PIN. The documents and database will also use their 
initials (of first and last names separated by a hyphen) and year of birth   
  
Samples for NHS pathology analysis will be labelled in accordance with local NHS 
procedures. Samples for storage and later analysis in research laboratories will be labelled a 
barcode linked to the PIN.  

NURTuRE – CKD Protocol No: 16091                 Page 22 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
  
Source documents  
  
Source documents will be filed at the investigator’s site and may include but are not limited to, 
consent forms, current medical records, laboratory results and records. A CRF may also 
completely serve as its own source data. Only trial staff as listed on the Delegation Log shall 
have access to trial documentation other than the regulatory requirements listed below.  
Direct access to source data / documents  
The CRF and all source documents, including progress notes and copies of laboratory and 
medical test results shall made be available at all times for review by the Chief Investigator, 
Sponsor’s designee and inspection by relevant regulatory authorities (e.g. DH, Human Tissue 
Authority).  
  
DATA PROTECTION  
  
All trial staff and investigators will endeavour to protect the rights of the trial’s participants to 
privacy and informed consent, and will adhere to the Data Protection Act, 2018. The CRF will 
only collect the minimum required information for the purposes of the trial. CRFs will be held 
on a secure server with password-protected access by the UK Renal Registry. Access to the 
information will be limited to the trial staff and investigators and relevant regulatory authorities 
(see above). Computer held data including the trial database will be held securely and 
password protected. All data will be stored on a secure dedicated web server. Access will be 
restricted by user identifiers and passwords (encrypted using a one way encryption method).  
Information about the trial in the participant’s medical records / hospital notes will be treated 
confidentially in the same way as all other confidential medical information.  
  
Electronic data will be backed up every 24 hours to both local and remote media in encrypted 
format.  
  
QUALITY ASSURANCE & AUDIT  
INSURANCE AND INDEMNITY  
Insurance and indemnity for trial participants and trial staff is covered within the NHS Indemnity 
Arrangements for clinical negligence claims in the NHS, issued under cover of HSG (96)48. 
There are no special compensation arrangements, but trial participants may have recourse 
through the NHS complaints procedures.  
  
The University of Nottingham as research Sponsor indemnifies its staff, research 
participants and research protocols with both public liability insurance and clinical trials 
insurance. These policies include provision for indemnity in the event of a successful litigious 
claim for proven non-negligent harm.   
  
TRIAL CONDUCT  
  
Trial conduct may be subject to systems audit of the Trial Master File for inclusion of essential 
documents; permissions to conduct the trial; Trial Delegation Log; CVs of trial staff and training 
received; local document control procedures; consent procedures and recruitment logs; 
adherence to procedures defined in the protocol (e.g. inclusion / exclusion criteria, correct 
randomisation, timeliness of visits); adverse event recording and reporting; accountability of 
trial materials and equipment calibration logs.  

NURTuRE – CKD Protocol No: 16091                 Page 23 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
  
The study Project Manager or, where required, a nominated designee of the Sponsor, shall 
carry out a site systems audit at least yearly and an audit report shall be made to the Study 
Advisory Group.  
  
TRIAL DATA  
Monitoring of trial data shall include confirmation of informed consent; source data verification; 
data storage and data transfer procedures; local quality control checks and procedures, 
backup and disaster recovery of any local databases and validation of data manipulation. The 
study Project manager, or where required, a nominated designee of the Sponsor, shall carry 
out monitoring of trial data as an ongoing activity.   
  
Entries on CRFs will be verified by inspection against the source data. A sample of CRFs (10% 
or as per the study risk assessment) will be checked during recruitment and follow-up phases 
for verification of all entries made. In addition, the subsequent capture of the data on the trial 
database will be checked. Where corrections are required, these will carry a full audit trail and 
justification.  
  
Trial data and evidence of monitoring and systems audits will be made available for inspection 
by REC as required. 
 
To facilitate data security during collaborative projects, a copy of all pseudonymised study data 
will be transferred from the UK Renal Registry to a "Trusted Research Environment" (TRE) 
hosted by the SAIL Databank, which is owned by Swansea University. Further, the UK Renal 
Registry will provide Digital Health and Care Wales (DHCW) with participant identifiers to 
enable DHCW to establish linkage of participant data to the HES and ONS databases, as 
facilitated by the partnership between NURTuRE and the British Heart Foundation Data 
Science Centre Cohorts Platform (based within the SAIL Databank). DHCW act as a linkage 
broker by sharing identifiers to any non-Welsh NHS bodies for linkage in those jurisdictions 
(England, Scotland, NI where relevant). Once the linkage has been established, participant 
identifiable data will be deleted by DHCW and the corresponding national health record 
providers in other UK constituent countries. Following this change, partners approved by the 
NURTuRE Strategy Committee will access the data via the TRE and will not receive physical 
copies of the data. Users will not be able to export the original data from the TRE. This 
arrangement will therefore facilitate improved data security. 
 
The UK Renal Registry will continue to hold a copy of the pseudonymised data and participant 
identifiers but will act only as a Data Processor. The UK Renal Registry will send annual 
updates of pseudonymised data to the SAIL databank. 
  
RECORD RETENTION AND ARCHIVING  
In compliance with the ICH/GCP guidelines, regulations and in accordance with the University 
of Nottingham Research Code of Conduct and Research Ethics, the Chief or local Principal 
Investigator will maintain all records and documents regarding the conduct of the study. These 
will be retained for at least 7 years or for longer if required. If the responsible investigator is no 
longer able to maintain the study records, a second person will be nominated to take over this 
responsibility.   
  
The Trial Master File and trial documents held by the Chief Investigator on behalf of the 
Sponsor shall be finally archived at secure archive facilities at the University of Nottingham.  
This archive shall include all trial databases and associated meta-data encryption codes.  

NURTuRE – CKD Protocol No: 16091                 Page 24 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
  
DISCONTINUATION OF THE TRIAL BY THE SPONSOR  
The Sponsor reserves the right to discontinue this trial at any time for failure to meet expected 
enrolment goals, for safety or any other administrative reasons.  The Sponsor shall take advice 
from the Trial Steering Committee and Data Monitoring Committee as appropriate in making 
this decision.  
  
STATEMENT OF CONFIDENTIALITY  
Individual participant medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted above. 
Participant confidentiality will be further ensured by utilising PIN code numbers to correspond 
to treatment data in the computer files.  
  
Medical information may be given to the participant’s medical team and all appropriate medical 
personnel responsible for the participant’s welfare. This will be made clear in the patient 
information sheet and during the consent process.  
  
If information is disclosed during the study that could pose a risk of harm to the participant or 
others, the researcher will discuss this with the CI and where appropriate report accordingly.  
  
Data generated as a result of this trial will be available for inspection on request by the 
participating physicians, the University of Nottingham representatives, the REC, local R&D 
Departments and the regulatory authorities.  
  
  
PUBLICATION AND DISSEMINATION POLICY  
Study results will be presented at national and international scientific conferences and will be 
published in peer-reviewed journals. It is anticipated that the study will generate a large number 
of presentations and publications over several years, starting with publication of baseline data. 
Participants will not be identified in any presentations or publications.  
  
USER AND PUBLIC INVOLVEMENT  
This protocol has been developed with input from patient advisers and has incorporated 
feedback received from participants in four previous cohort studies of CKD conducted by the 
investigators in the UK. The Study Advisory Group will include a patient representative who 
will contribute to the oversight of the study and provide advice from a patient perspective as 
required.  
  
STUDY FINANCES  
  
Funding source  
This study is funded by a grant from Kidney Research UK supported by funding from several 
pharmaceutical and biodiagnostic companies. The companies have been active collaborators 
in the development of the protocol and at time of submission comprise:  
UCB Pharma Ltd  
AbbVie  
Evotec International GmbH  
AstraZeneca 
Retrophin Inc. 
  

NURTuRE – CKD Protocol No: 16091                 Page 25 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
Participant stipends and payments  
Participants will not be paid to participate in the trial. Travel expenses will be offered for any 
hospital visits in excess of usual care.  
  
  
  
 

NURTuRE – CKD Protocol No: 16091                 Page 26 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
SIGNATURE PAGES  
  
Signatories to Protocol:  
  
Chief Investigator: Prof M.W.Taal  
  
  
Signature:   
  
  
Date:  
  
  
  
  
Co- investigator: Prof D. Wheeler  
  
  
Signature:______ ____________________________  
  
  
Date: ___________  
  
Co- investigator: Dr S. Fraser  
  
  
Signature:_____ _____________________________  
  
  
Date:  
 
  
Co- investigator: Prof P. Cockwell  
  
  
Signature:__________________________________  
  
  
Date: ___________  
  
Co- investigator: Prof P. Kalra  
  
  
Signature:__________________________________  
  
  
Date: ___________  
  
  
Trial Statistician: Dr R. Steenkamp  

NURTuRE – CKD Protocol No: 16091                 Page 27 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
 
 
 
Signature:____ ______________________________  
  
  
Date: ___________  
  
  
  
   
  
 

NURTuRE – CKD Protocol No: 16091                 Page 28 of 28        version 4.3    16/07/2021  
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorisation from 
the University of Nottingham  
REFERENCES  
  
1. 
Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and 
perspectives. Lancet. 2013 Jul 20;382(9888):260-72.  
2. 
Astor BC, Matsushita K, Gansevoort RT, et al. Lower estimated glomerular filtration 
rate and higher albuminuria are associated with mortality and end-stage renal disease. A 
collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011 Feb 
2;79:1331-40.  
3. 
Gansevoort RT, Matsushita K, van der Velde M, et al. Lower estimated GFR and 
higher albuminuria are associated with adverse kidney outcomes in both general and 
highrisk populations. A collaborative meta-analysis of general and high-risk population 
cohorts.  
Kidney Int. 2011 Feb 2;80:93-104.  
4. 
Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular 
filtration rate and albuminuria with all-cause and cardiovascular mortality in general 
population cohorts: a collaborative meta-analysis. Lancet. 2010 Jun 12;375(9731):2073-81.  
5. 
Tangri N, Grams ME, Levey AS, et al. Multinational Assessment of Accuracy of 
Equations for Predicting Risk of Kidney Failure: A Meta-analysis. JAMA. 2016 Jan 
12;315(2):164-74.  
6. 
Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic 
kidney disease to kidney failure. JAMA. 2011 Apr 20;305(15):1553-9.  
7. 
Schievink B, Lambers Heerspink H, Leufkens H, et al. The use of surrogate endpoints 
in regulating medicines for cardio-renal disease: opinions of stakeholders. PLoS One.  
2014;9(9):e108722.  
8. 
Denker M, Boyle S, Anderson AH, et al. Chronic Renal Insufficiency Cohort Study 
(CRIC): Overview and Summary of Selected Findings. Clin J Am Soc Nephrol. 2015 Nov 
6;10(11):2073-83.  
9. 
Stengel B, Combe C, Jacquelinet C, et al. The French Chronic Kidney Disease-Renal 
Epidemiology and Information Network (CKD-REIN) cohort study. Nephrol Dial Transplant.  
2014 Aug;29(8):1500-7.  
10. 
Titze S, Schmid M, Kottgen A, et al. Disease burden and risk profile in referred 
patients with moderate chronic kidney disease: composition of the German Chronic Kidney 
Disease (GCKD) cohort. Nephrol Dial Transplant. 2015 Mar;30(3):441-51.  
11. 
Hoefield RA, Kalra PA, Baker P, et al. Factors associated with kidney disease 
progression and mortality in a referred CKD population. Am J Kidney Dis. 2010 
Dec;56(6):1072-81.