Effect of Immuno-nutrition on Systemic Inflammation in People Receiving Haemodialysis: a Pilot Study
Phase: NA
Conditions: Chronic Kidney Disease Requiring Chronic Dialysis
Sponsor: University of Nottingham

 
 
 
 
Page 1 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
 
 
 
 
 
 
Effect of immuno-nutrition on systemic inflammation in 
people receiving haemodialysis: a pilot study 
 
Version 2.0 
 
25 February 2022 
 
 
 
Short title:  
 
 
Immuno-nutrition in haemodialysis  
 
 
Acronym:   
 
 
 
 
 
IRAS Project ID: 
 
309937 
 
 
Study Sponsor:  
 
University of Nottingham 
 
 
Sponsor reference: 
 
21085 
 
 
Funding Source: 
Internal funds 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
Page 2 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
STUDY PERSONNEL AND CONTACT DETAILS 
 
Sponsor: 
            University of Nottingham 
 
 
            Ms Angela Shone 
Research and Innovation  
University of Nottingham, East Atrium, Jubilee Conference Centre  
Triumph Road  
Nottingham  
NG8 1DH 
Email: sponsor@nottingham.ac.uk 
 
Chief investigator: 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 3DT 
Phone: 01332 224618 
Fax: 01332 789352 
Email: m.taal@nottingham.ac.uk 
 
Co-investigators:      Dr Bethan E Phillips 
Associate Professor of Translational Physiology 
Academic Unit of Injury, Inflammation and Recovery Sciences, School 
of Medicine, University of Nottingham, Royal Derby Hospital 
Uttoxeter Rd, Derby, DE22 3DT 
Phone: 01332 724687 
Email: beth.phillips@nottingham.ac.uk 
 
Dr Daniela Viramontes Hörner 
Renal Research Fellow 
Academic Unit for Translational Medical Sciences, School of Medicine, 
University of Nottingham, Royal Derby Hospital 
Uttoxeter Rd, Derby, DE22 3DT 
Phone: 01332 788262 
Email: mszdv@nottingham.ac.uk 
 
Professor Philip Atherton 
Professor of Clinical, Metabolic and Molecular Physiology 
Academic Unit of Injury, Inflammation and Recovery Sciences, School 
of Medicine, University of Nottingham, Royal Derby Hospital 
Uttoxeter Rd, Derby, DE22 3DT 
Phone: 01332 724 725 
Email: philip.atherton@nottingham.ac.uk 
 
Professor Kenneth Smith 
Professor of Metabolic Mass Spectrometry 
Academic Unit of Injury, Inflammation and Recovery Sciences, School 
of Medicine, University of Nottingham, Royal Derby Hospital 
Uttoxeter Rd, Derby, DE22 3DT 
Phone: 01332 724700 
Email: ken.smith@nottingham.ac.uk 
 
 

 
 
 
 
Page 3 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
Professor Nicholas Selby  
Professor of Nephrology and Honorary Consultant Nephrologist 
Academic Unit for Translational Medical Sciences, School of Medicine, 
University of Nottingham, Royal Derby Hospital 
Uttoxeter Rd, Derby, DE22 3DT 
Phone: 01332 788262 
Email: nicholas.selby@nottingham.ac.uk  
 
Dr Daniel Wilkinson 
Assistant Professor of Metabolic Mass Spectrometry 
Academic Unit of Injury, Inflammation and Recovery Sciences, School 
of Medicine, University of Nottingham, Royal Derby Hospital 
Uttoxeter Rd, Derby, DE22 3DT 
Phone: 01332 724850 
Email: daniel.wilkinson@nottingham.ac.uk 
 
 
Study Statistician: 
Dr Daniel Wilkinson 
 
 
Study Coordinating Centre: Academic Unit for Translational Medical Sciences,  
School of Medicine, University of Nottingham 
 
 

 
 
 
 
Page 4 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
Effect of immuno-nutrition on systemic inflammation in people receiving 
haemodialysis: a pilot study. 
Acronym 
 
Short title 
Immuno-nutrition in haemodialysis 
Chief Investigator 
Professor Maarten Taal 
Objectives 
1. To investigate whether provision of an immuno-nutrition supplement 
decreases systemic inflammatory status in people on haemodialysis. 
 
2. To investigate the effect of an immuno-nutrition supplement on 
biochemical blood variables, body composition, dietary intake and muscle 
strength in people on haemodialysis. 
Study Configuration 
Single-centre, non-randomised, interventional pilot study. 
Setting 
Secondary care 
Sample size estimate 
As a pilot study power calculations are not appropriate 
Number of participants 
15 
Eligibility criteria 
Inclusion criteria:  
• 
CRP level >5 mg/L. 
• 
Age: >18 years (no upper age limit). 
• 
At least three haemodialysis sessions per week for ≥3 hours using 
a biocompatible dialyser. 
• 
Able to give informed consent. 
   
Exclusion criteria:  
• 
Treatment with drugs that cause immunosuppression. 
• 
Non-English speakers or those with special communication needs. 
• 
Pregnancy, breast feeding or intending pregnancy. 
• 
Expected survival <6 months. 
• 
Hospitalisation at the time of screening. 
• 
Known intolerance or allergy to oral nutritional supplement (or 
isolated ingredients). 
• 
Pre-dialysis serum potassium >5.0 mmol/L. 
• 
Unable to provide informed consent. 

 
 
 
 
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Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
Description of 
interventions 
Dietitian supervised nutritional support with an immuno-nutrition 
supplement (Oral Impact®, Nestle) 
Duration of study 
Duration of individual study participation: 6 weeks. 
Overall study duration: 3 months. 
Methods of analysis  
To compare baseline versus final evaluations, a Wilcoxon test or paired t-
test will be used in the case of dimensional variables, and McNemar test 
in the case of categorical variables. Inter-group comparisons will be 
performed using a Mann-Whitney test or Student t-test for continuous 
variables and χ2 test or Fisher’s exact test for categorical variables. A p 
value <0.05 will be considered to have statistical significance. 

 
 
 
 
Page 6 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
BMI 
Body Mass Index 
CI 
Chief Investigator  
CRF 
Case Report Form 
CRP 
C Reactive Protein 
GCP 
Good Clinical Practice 
HGS 
Handgrip strength 
NHS 
National Health Service 
ONS 
Oral Nutritional Supplement 
PIS 
Participant Information Sheet 
REC 
Research Ethics Committee 
R&D 
Research and Development department 
SAE 
Serious Adverse Event 
SAF 
Skin Autofluorescence 
TMF 
Trial Master File 
 
 
 
 

 
 
 
 
Page 7 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
STUDY PERSONNEL AND CONTACT DETAILS ................................................................... 2 
SYNOPSIS .................................................................................................................................. 4 
ABBREVIATIONS ..................................................................................................................... 6 
STUDY BACKGROUND INFORMATION AND RATIONALE ................................................ 9 
STUDY OBJECTIVES AND PURPOSE ................................................................................... 10 
PURPOSE 
10 
PRIMARY OBJECTIVE 
10 
SECONDARY OBJECTIVES 
10 
DETAILS OF PRODUCT(S)..................................................................................................... 10 
DESCRIPTION 
10 
MANUFACTURE 
10 
PACKAGING AND LABELLING 
10 
STORAGE, DISPENSING AND RETURN 
10 
KNOWN SIDE EFFECTS 
10 
STUDY DESIGN ....................................................................................................................... 10 
STUDY CONFIGURATION 
11 
Primary outcome 
11 
Secondary endpoints 
11 
Safety endpoints 
11 
STUDY MANAGEMENT 
11 
DURATION OF THE STUDY AND PARTICIPANT INVOLVEMENT 
11 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
11 
Recruitment 
11 
Eligibility criteria 
12 
Inclusion criteria: 
12 
Exclusion criteria: 
12 
Participant Withdrawal 
12 
Informed consent 
13 
STUDY REGIMEN ................................................................................................................... 13 
Criteria for terminating trial 
14 
TRANSPORT AND STORAGE OF THE TISSUES ................................................................. 14 
LABORATORY ANALYSES ................................................................................................... 14 
STATISTICS............................................................................................................................. 15 
Sample size and justification 
15 
Procedures for missing, unused and spurious data 
15 
Definition of populations analysed 
15 
ADVERSE EVENTS ................................................................................................................. 15 
Definitions 
15 
Causality 
16 
Reporting of adverse events 
17 
Study Intervention Related SAEs 
17 
Participant removal from the study due to adverse events 
18 
ETHICS COMMITTEE AND REGULATORY APPROVALS ................................................ 18 

 
 
 
 
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Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
RECORDS ................................................................................................................................ 18 
Case Report Forms 
18 
Sample Labelling 
19 
Source documents 
19 
Direct access to source data / documents 
19 
DATA PROTECTION .............................................................................................................. 19 
QUALITY ASSURANCE & AUDIT ......................................................................................... 19 
INSURANCE AND INDEMNITY 
19 
STUDY CONDUCT 
20 
STUDY DATA 
20 
RECORD RETENTION AND ARCHIVING 
20 
DISCONTINUATION OF THE STUDY BY THE SPONSOR 
20 
STATEMENT OF CONFIDENTIALITY 
21 
PUBLICATION AND DISSEMINATION POLICY ................................................................. 21 
USER AND PUBLIC INVOLVEMENT .................................................................................... 21 
STUDY FINANCES .................................................................................................................. 21 
Funding source 
21 
Participant spends and payments 
21 
SIGNATURE PAGES ............................................................................................................... 22 
REFERENCES.......................................................................................................................... 23 
APPENDICES ........................................................................................................................... 25 
APPENDIX 1 
25 
 

 
 
 
 
Page 9 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
STUDY BACKGROUND INFORMATION AND RATIONALE 
Low skeletal muscle mass is a highly prevalent problem of kidney disease occurring in 25-55% 
of people receiving haemodialysis treatment [1]. Moreover, loss of skeletal muscle mass is one 
of the strongest predictors of frailty, disability and increased mortality, severely affects health-
related quality of life, and increases hospital admissions and length of hospitalisations in this 
patient population, which results in higher hospital costs [2].  
 
Multiple factors contribute to skeletal muscle loss in those receiving haemodialysis, including: 
 
• reduced appetite and therefore dietary intake [3-6], resulting in lack of dietary amino acids - 
a key anabolic stimulus [7], 
• muscle tissue catabolism during haemodialysis [8, 9], reflected by increased urea production 
[10] and amino acid efflux from muscle [11], 
• physical inactivity, anxiety and depression [12, 13], and the 
• presence of other co-morbidities associated with muscle wasting, such as diabetes and heart 
disease [12].  
 
In addition, increased systemic inflammation, a frequent complication in the haemodialysis 
population, has been postulated to be a primary driver of skeletal muscle loss [12, 14]. To 
exemplify the magnitude of this problem, it has been reported that people on haemodialysis 
lose an average of 6.4 kg of lean tissue mass over 20 weeks, with associated significant 
reductions in muscle strength. In addition, and key to the research proposed herein, systemic 
inflammation was shown to markedly accelerate these muscle mass losses [15].  
 
Provision of dietetic advice and high-energy/high-protein conventional oral nutritional 
supplements (ONS) to people on haemodialysis has previously shown to improve 
postabsorptive plasma amino acid profiles, body mass index (BMI), and serum albumin and 
prealbumin levels [16, 17]. Despite this, conventional ONS have not been proven successful 
in stimulating muscle protein synthesis, and consequently in increasing skeletal muscle mass 
[18]. Therefore, achieving improvements in skeletal muscle mass in the haemodialysis 
population is challenging. In part, this appears to relate to non-adherence [18, 19]. Our 
previous experience, based on both research studies and clinical practice, is that the taste of 
some conventional ONS (often described as too sweet) is commonly cited by people on 
haemodialysis as a reason for non-adherence to prescribed supplementation regimes [19]. In 
addition to the challenge of long-term adherence to conventional ONS, the persistent systemic 
inflammation seen in people receiving haemodialysis plays a major role in causing “anabolic 
resistance”, a condition that inhibits improvements in skeletal muscle mass despite an increase 
in dietary energy and protein intake/availability [20].  
 
Immuno-nutrition supplements are high in energy and protein (similar to conventional ONS), 
but also contain a unique combination of nutrients (i.e., omega-3 fatty acids, L-arginine and 
nucleotides), each acting in a complementary way to suppress inflammation, while 
concomitantly enhancing immune function [21]. Immuno-nutrition supplements (specifically 
Oral Impact®, Nestle) have been mostly used in pre-surgical settings, and previous studies 
conducted in cancer populations have reported a decrease in post-operative infections and 
length of hospitalisation, underpinned by evidence of a decrease in systemic inflammation [22]. 
 
This will be the first study to explore the potential effect of an immuno-nutrition supplement 
(Oral Impact®, Nestle) to address systemic inflammation in people receiving haemodialysis. 
The findings of this pilot study will help to design a randomised controlled clinical trial 
investigating whether a treatment bundle of resistance exercise training and immuno-nutrition 
supplementation can improve skeletal muscle mass, other markers of nutritional status and 
quality of life in people on haemodialysis. 

 
 
 
 
Page 10 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
 
STUDY OBJECTIVES AND PURPOSE 
 
PURPOSE 
The purpose of the present study is to investigate the impact of an immuno-nutrition 
supplement on systemic inflammation in people receiving haemodialysis. 
 
PRIMARY OBJECTIVE 
 
To investigate whether provision of an immuno-nutrition supplement decreases systemic 
inflammatory status in people on haemodialysis. 
 
SECONDARY OBJECTIVES 
To investigate the effect of an immuno-nutrition supplement on biochemical blood variables, 
body composition, dietary intake, skin autofluorescence (SAF) and muscle strength in people 
on haemodialysis. 
 
DETAILS OF PRODUCT(S) 
 
Description  
Oral Impact® is a powdered oral nutritional supplement that contains a unique combination of 
ingredients with immuno-modulating properties, namely omega-3 fatty acids, arginine and 
nucleotides, as well as soluble fibre. 
 
Manufacture 
Oral impact® is manufactured by Nestlé Health Science, Reg. Trademark of Société des 
Produits Nestlé S.A. OIDC 001 
 
Packaging and labelling 
Oral impact® comes in a box that contains 5 sachets x 74g. Please see Appendix 1 for images 
of packaging and labelling. 
 
Storage, dispensing and return 
Oral impact® will be stored unopened in a locked room which should be cool, dry and away 
from light and humidity. Access to the room will be restricted to members of the research team. 
 
Known Side Effects 
No known side effects. However, Oral impact® is unsuitable for people with cow’s milk protein 
allergy and those who are severely septic. Oral impact® should not be mixed with medication 
and food. 
 
STUDY DESIGN 
This will be a single-centre, non-randomised, interventional pilot study where people on 
haemodialysis will receive an immuno-nutrition supplement (Oral Impact®, Nestle) for 6 weeks. 
 

 
 
 
 
Page 11 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
STUDY CONFIGURATION 
Primary outcome  
Change in C reactive protein (CRP), and pro- and anti-inflammatory cytokine levels (via 
multiplex plasma analysis) after 6 weeks of treatment with an immuno-nutrition supplement. 
 
Secondary endpoints  
Change after 6 weeks of treatment with an immuno-nutrition supplement in: 
• 
Biochemical blood variables including haemoglobin, urea, creatinine, potassium, 
phosphate, calcium, sodium, albumin, total proteins, total cholesterol and triglycerides. 
• 
Body composition assessed with bioelectrical impedance analysis and BMI. 
• 
Dietary intake assessed with 3-day food diaries. 
• 
Muscle strength assessed with handgrip strength (HGS). 
• 
SAF levels. 
 
Safety endpoints 
• 
AEs that occur will be reported during the study. 
• 
Participant reported tolerability of the immuno-nutrition supplement. 
• 
Monitoring of pre-dialysis serum potassium levels. 
 
STUDY MANAGEMENT 
The Chief Investigator (CI) has overall responsibility for the study and shall oversee all study 
management. The study will be co-ordinated from the University of Nottingham campus at the 
Royal Derby Hospital. Data will be collected at the Renal Dialysis Unit of the Department of 
Renal Medicine at the Royal Derby Hospital (University Hospitals of Derby and Burton NHS 
Foundation Trust) and stored at the University of Nottingham.   
 
The CI and Co-investigators are responsible for study planning, recruitment, consenting, data 
collection, handling and interpretation. The data custodian will be the CI, Professor Taal. 
 
DURATION OF THE STUDY AND PARTICIPANT INVOLVEMENT 
Participant recruitment will begin in January 2022 once all necessary approvals are in place, 
with an anticipated total recruitment and intervention delivery period of 3 months (i.e., end of 
March 2022). The study will end when the last participant completes their final study visit. 
 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Recruitment 
15 participants will be recruited from the Renal Dialysis Unit at the Royal Derby Hospital. 
Potential participants will be approached by the clinical care team (which may include 
members of the research team) with reference to the inclusion and exclusion criteria. Each 
eligible participant will be given a Participant Information Sheet (PIS) and a minimum of 24 
hours to consider whether they wish to participate in the study. At this time, the PIS will be 
discussed with them, any questions answered, and informed consent will be obtained by 
one of the investigators if they are willing to enter the study. 
 

 
 
 
 
Page 12 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
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 we will seek consent to use 
the data in the final analyses where appropriate. 
 
If needed, the hospital interpreter and translator services will be available to assist with 
discussion of the study, the PIS, consent form, and be available for the duration of the study 
if required. The consent form and PIS will not be available printed in other languages.  
 
Eligibility criteria 
Inclusion criteria: 
• 
CRP level >5.0 mg/L. 
• 
Age: >18 years (no upper age limit). 
• 
At least three haemodialysis sessions per week for ≥3 hours using a biocompatible 
dialyser. 
• 
Able to give informed consent. 
Exclusion criteria: 
• 
Treatment with drugs that cause immunosuppression. 
• 
Non-English speakers or those with special communication needs. 
• 
Pregnancy, breast feeding or intending pregnancy. 
• 
Expected survival <6 months. 
• 
Hospitalisation at the time of screening. 
• 
Known intolerance or allergy to ONS (or isolated ingredients). 
• 
Pre-dialysis serum potassium >5.0 mmol/L. 
• 
Unable to provide informed consent. 
 
Participant Withdrawal  
Participants will be withdrawn from the study if they:  
• 
Withdraw their consent at any time.  
• 
Become pregnant. 
• 
Receive a kidney transplant. 
• 
Do not adhere to the intervention; defined as <50% of the provided immuno-nutrition 
supplement being consumed. 
 
Participants do not have to provide a reason for withdrawal of consent. Participants will also 
be withdrawn if it is deemed unsafe or is found to be impossible to proceed in the opinion of 
the investigators.  
 
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 PIS and consent form) that should they withdraw the 
data collected to date cannot be erased and may still be used in the final analysis. 
 
Participants will not be replaced if they withdraw from the study. 
 
 

 
 
 
 
Page 13 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
Informed consent 
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 or their nominee and the participant 
shall both sign and date the consent form before the person can participate in the study. 
 
The participant will receive a copy of the signed and dated consent form and the original will 
be retained in the Study records. A second copy will be filed in the participant’s medical notes 
and a signed and dated note made in the notes that informed consent was obtained for the 
study. 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 study-specific 
procedures 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 consent form is amended during the study, the investigator shall follow all applicable 
regulatory requirements pertaining to approval of the amended consent form by the REC and 
use of the amended form (including for ongoing participants). 
 
STUDY REGIMEN 
 
Once participants have given their informed consent, they will be advised to take daily one 
sachet (74 g) of the immuno-nutrition supplement (Oral Impact®, Nestle) dissolved in 125 ml 
of water and will be followed-up for 6 weeks.  
  
Participants will receive individualised (to patient needs and food preferences) dietetic advice 
formulated and delivered by an experienced renal dietitian under an honorary NHS research 
contract (D.V.H), who is a member of the research team and will be supervised by an NHS 
renal dietitian, aiming to achieve estimated nutritional requirements for people on 
haemodialysis (i.e., energy: 30-35 kcal/kg/day, and protein intake: 1.0-1.2 g/kg/day) [23]. Each 
dietetic advice provided to participants will also be reviewed by the NHS clinical renal dietitians 
who are members of the participants’ usual clinical care team.   
 
Consumption of the immuno-nutrition supplement will be supervised during haemodialysis 
sessions (thrice weekly) and self-reported (written and counting empty sachets) on non-
dialysis days. Participants will receive precise oral instructions on how and when to take the 
supplement with close monitoring by the renal dietitian on the research team to encourage 
adherence to the intervention.  
 
Three-day food diaries (i.e., one dialysis day, one non-dialysis day and one weekend day) will 
be completed by the participants at baseline, 3 and 6 weeks of follow-up, and will be analysed 
(Microdiet, Downlee Systems Ltd, UK) to assess compliance with the advice provided and to 
assess energy, protein and fat intake across the study period. 
  
Data collection procedures 
Hospital electronic medical records will be used to collect relevant baseline participant 
characteristics, including age, sex, ethnicity, time since dialysis initiation, dialysis adequacy, 

 
 
 
 
Page 14 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
current medication, presence of diabetes and history of cardiovascular disease. Information 
regarding educational level, occupation status, and history of smoking will be obtained by direct 
interview with the participants at the time of the baseline assessment. A blood sample will be 
taken weekly pre-dialysis after commencing the immuno-nutrition supplement to monitor 
serum potassium. Results from routine clinical blood tests will be recorded at baseline and 6 
weeks of follow-up and will include haemoglobin, urea, creatinine, potassium, phosphate, 
calcium, sodium, albumin, total proteins, total cholesterol, triglycerides and CRP.  
 
Pre- and post-dialysis blood samples (10 mL) will be taken at baseline and 6 weeks of follow-
up and centrifuged at 2000g for 20-min to obtain at least 2 mL of plasma which will be frozen 
and stored at -80°C for subsequent analysis of circulating systemic pro- and anti-inflammatory 
cytokines via the Luminex multiplex platform.  
 
Handgrip strength (HGS) will be measured at baseline and 6 weeks of follow-up using the 
Takei 5401 handgrip digital dynamometer (Takei Scientific Instruments Co., Ltd., Tokyo, 
Japan) within the first hour of haemodialysis treatment. The highest value of 3 attempts in the 
non-fistula arm will be recorded as HGS.  
 
Body composition will be assessed via bioelectrical impedance analysis (InBody 770, InBody, 
Leicester, UK) and BMI at baseline and 6 weeks of follow-up.  
 
Skin autofluorescence (SAF) will be measured using a validated Autofluorescence Reader 
(AGE Reader, DiagnOptics, Groningen, The Netherlands) at baseline and 6 weeks of follow-
up. For each participant, three measurements will be performed on the volar surface of the 
lower arm at ~10 cm below the elbow, ensuring that the area has normal skin without visible 
vessels, scars or other abnormalities. Only the non-fistula arm will be used, and readings will 
be undertaken within the first hour of haemodialysis treatment. 
 
Criteria for terminating trial 
In the event of major safety concerns, new information, or issues with study conduct (e.g., poor 
recruitment, loss of resources), termination of the study will be considered by the sponsor. In 
the event of study termination, unused study resources will be reallocated as appropriate. 
 
TRANSPORT AND STORAGE OF THE TISSUES 
Pre- and post-dialysis blood samples (10 mL) will be collected at intervals as described above 
and centrifuged. At least 2 mL of plasma will be stored at -80°C for future analysis at the 
University of Nottingham Centre of Metabolism, Ageing & Physiology (COMAP).  
 
Samples and data will be stored in a linked anonymised format. Samples will be labelled using 
a combination of study reference, unique study identifier and cross referenced with location 
code numbers to permit accurate linkage to study data and the consent form.  
 
The master database will be held by the CI in a password encrypted file.  
 
Where participants do not agree to the future use of the samples, they will be destroyed in 
accordance with the Human Tissue Act, 2004. 
 
LABORATORY ANALYSES 
Blood samples will be taken at the Renal Dialysis Unit and transferred to the local NHS 
laboratory (which is serviced and managed according to national UKAS standards and 
governance frameworks) at the Royal Derby Hospital for routine biochemistry and 

 
 
 
 
Page 15 of 25 
 
Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
haematology testing. These samples will be labelled according to NHS requirements. No DNA 
or RNA extraction will occur as part of this study. 
 
STATISTICS 
Statistical analyses will be performed using SPSS version 28.0. Data will be presented as 
mean ± standard deviation, median (interquartile range), or percentages, as appropriate. To 
compare baseline versus final evaluations, a 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. An alpha error 
of less than 0.05 will be judged to be significant. All data will be analysed on University of 
Nottingham computers and backed up regularly. 
 
Sample size and justification 
A formal power calculation is not appropriate for this pilot study design, and consequently, the 
sample size has been selected on a pragmatic basis. We will aim to recruit 15 participants in 
total. 
 
Procedures for missing, unused and spurious data 
All missing data will be explained. If a space on the Case Report Form (CRF) is left blank 
because the procedure was not done or a question was not asked, “N/D” will be recorded. If 
the item is not applicable to the individual case, “N/A” will be recorded. All entries will be printed 
legibly in black ink. If any error is made in data entry, to correct the error, a single straight line 
will be drawn through the incorrect entry and the correct data entered above it. All such 
changes will be initialled and dated. Errors will not be erased or altered by any other method. 
For clarification of illegible or uncertain entries, the clarification will be printed above the item, 
initialled and dated. Correction fluid will not be used. 
 
Definition of populations analysed 
The study will analyse the following populations: 
• 
Safety set: All participants who underwent at least one study session. 
• 
Full Analysis set: All participants, who participated in at least one study session and for 
whom at least one post-baseline assessment of the primary endpoint is available.  
• 
Per protocol set: All participants in the Full Analysis set who are deemed to have no major 
protocol violations that could interfere with the objectives of the study. 
 
ADVERSE EVENTS  
 
Definitions 
An adverse event (AE) is any unfavourable and unintended sign, symptom, syndrome or illness 
that develops or worsens during the period of observation in the study.  
 
An AE does include a/an: 
 
1. Exacerbation of a pre-existing illness. 
2. Increase in frequency or intensity of a pre-existing episodic event or condition. 
3. Continuous persistent disease or symptoms present at baseline that worsen following the 
start of the study. 
 

 
 
 
 
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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 following are recognised complications related to chronic haemodialysis and will be 
recorded on the CRF, but do not need to be reported separately on an AE/Serious Adverse 
Event (SAE) form: 
 
• 
Related to dialysis: fistula bruising, dizziness, cramps, hypotension, minor bleeding. 
• 
Hospital admission for vascular access, acute coronary syndromes, arrhythmias, 
stroke, pneumonia and infections. 
• 
Death. 
 
An AE does not include a/an: 
 
1. Medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); 
however, the condition that led to the procedure is an AE. 
 
2. Pre-existing disease or conditions present or detected at the start of the study that did not 
worsen. 
 
3. Situations where an untoward medical occurrence has not occurred (e.g., hospitalisations 
for cosmetic elective surgery, social and/or convenience admissions). 
 
4. Disease or disorder being studied, or sign or symptom associated with the disease, or 
disorder unless more severe than expected for the participant’s condition. 
 
5. Overdose of concurrent medication without any signs or symptoms. 
 
A SAE is any AE occurring following study mandated procedures, directly related to the 
treatment or intervention that results in any of the following outcomes: 
 
1. Death. 
2. A life-threatening AE. 
3. Inpatient hospitalisation or prolongation of existing hospitalisation. 
4. A disability/incapacity. 
5. A congenital anomaly in the offspring of a participant. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalisation may be considered a SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient or participant and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. 
 
All AEs will be assessed for seriousness, expectedness and causality: 
 
A distinction is drawn between serious and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined using the criteria above. Hence, a severe AE need not 
necessarily be serious.  
 
Causality 
Not related or improbable: a clinical event including laboratory test abnormality with temporal 
relationship to study intervention administration which makes a causal relationship 
incompatible or for which other treatments, chemicals or disease provide a plausible 
explanation. This will be counted as “unrelated” for notification purposes. 

 
 
 
 
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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 
 
 
Possible: a clinical event, including laboratory test abnormality, with temporal relationship to 
study treatment/intervention administration which makes a causal relationship a reasonable 
possibility, but which could also be explained by other interventions, chemicals or concurrent 
disease. This will be counted as “related” for notification purposes. 
 
Probable: a clinical event, including laboratory test abnormality, with temporal relationship to 
study treatment/intervention administration which makes a causal relationship a reasonable 
possibility, and is unlikely to be due to other interventions, chemicals or concurrent disease. 
This will be counted as “related” for notification purposes. 
 
Definite: a clinical event, including laboratory test abnormality, with temporal relationship to 
study treatment/intervention administration which makes a causal relationship a reasonable 
possibility, and which can definitely not be attributed to other causes. This will be counted as 
“related” for notification purposes. 
 
With regard to the criteria above, medical and scientific judgment shall be used in deciding 
whether prompt reporting is appropriate in that situation. 
 
Reporting of adverse events 
Participants will be asked to contact the study site immediately in the event of any SAE. All 
AEs will be recorded and closely monitored until resolution, stabilisation, or until it has been 
shown that the study intervention is not the cause. The CI shall be informed immediately of 
any SAEs and shall determine seriousness and causality in conjunction with any treating 
medical practitioners. 
 
In the event of a pregnancy occurring in a study participant or the partner of a study participant, 
monitoring shall occur during the pregnancy and after delivery to ascertain any study related 
AEs in the mother or the offspring. Where it is the partner of a study participant, consent will 
be obtained for this observation from both the partner and her medical practitioner. 
 
All intervention related SAEs will be recorded and reported to the REC as part of the annual 
reports. Unexpected SAEs will be reported within the timeframes to the REC as stated below. 
The CI shall be responsible for all AEs reporting. 
 
Study Intervention Related SAEs 
A SAE that is unexpected in its severity and seriousness and deemed directly related to or 
suspected to be related to the study intervention shall be reported to the REC that gave a 
favourable opinion as stated below. 
 
The event shall be reported immediately of knowledge of its occurrence to the CI. 
 
The CI will: 
 
• 
Assess the event for seriousness, expectedness and relatedness to the study 
intervention. 
• 
Take appropriate medical action, which may include halting the study and inform the 
Sponsor of such action. 

 
 
 
 
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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 
 
• 
If the event is deemed related to the study treatment or intervention, shall inform the 
REC using the reporting form found on the HRA web page within 7 days of knowledge 
of the event. 
• 
Shall, within a further eight days, send any follow-up information and reports to the 
REC. 
• 
Make any amendments as required to the study protocol and inform the REC as 
required. 
 
Participant removal from the study due to adverse events 
Any participant who experiences an AE may be withdrawn from the study at the discretion of 
the Investigator. The overall risk of an AE directly connected to the study is low.  
 
ETHICS COMMITTEE AND REGULATORY APPROVALS 
 
The study will not be initiated before the protocol, consent form and PIS have received 
approval/favourable opinion from the REC, and the respective 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 form and PIS have been reviewed and received approval/favourable 
opinion from the REC and R&D department. A protocol amendment intended to eliminate 
an apparent immediate hazard to participants may be implemented immediately providing 
that the REC is 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 study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, 1996, the principles of GCP, and the UK Policy Framework 
for Health and Social Care Research 2017. 
 
RECORDS  
Case Report Forms  
Case Report Forms (CRFs) will be the primary data collection instrument. All data requested 
on the CRF will be recorded.  
 
Each participant will be assigned a study identity code number, for use on CRFs, other study 
documents and the electronic database.  
 
CRFs will be treated as confidential documents and held securely in accordance with 
regulations. The investigator will make a separate confidential record of the participant’s 
name, date of birth, local hospital number or NHS number, and Participant Study Number, 
to permit identification of all participants enrolled in the study, in case additional follow-up is 
required. This shall be kept securely in the Trial Master File (TMF). 
 
CRFs shall be restricted to those personnel approved by the Chief or local Investigator and 
recorded as such in the study records.  
 
All paper forms shall be filled in using black ballpoint pen. Errors shall be lined out but not 
obliterated by using correction fluid and the correction inserted, initialled and dated. 
 

 
 
 
 
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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 Chief or local Investigator shall sign a declaration ensuring accuracy of data recorded 
in the CRF. Electronic data will identify participants by study ID only. Records will be kept 
password protected and subject to regular back up procedures. 
 
Sample Labelling 
Each participant will be assigned a study identity code for use on the CRF, other study 
documents and the electronic database. Samples for NHS pathology analysis will be 
labelled in accordance with local NHS procedures.  
 
Source documents  
The source documents for each participant will consist of the demographic, co-morbidities and 
concomitant medication data collected from the participant’s health care records. This will be 
transferred into a CRF for that particular participant. Paper copies of haematological and 
biochemical laboratory test results from the electronic results system will be retained in the 
TMF as source documents. 
 
Source documents shall be filed at the investigator’s site and may include but are not limited 
to consent forms, study records. A CRF may also completely serve as its own source data. 
Only study staff shall have access to study 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 CI, Sponsor’s 
designee and inspection by relevant regulatory authorities (e.g., Health Research Authority, 
Human Tissue Authority). 
 
DATA PROTECTION  
 
All study staff and investigators will endeavour to protect the rights of the study’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 study. CRFs will 
be held securely, in a locked room, or locked cupboard or cabinet. Access to the information 
will be limited to the study staff and investigators and any relevant regulatory authorities (see 
above). Computer held data, including the study database, will be held securely and 
password protected. All data will be stored on secure UoN systems. Access will be restricted 
by user identifiers and passwords (encrypted using a one-way encryption method). 
 
Information about the study 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 clinical study participants and study staff is covered within the 
NHS Indemnity Arrangements for clinical negligence claims in the NHS, issued under cover 

 
 
 
 
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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 
 
of HSG (96)48. There are no special compensation arrangements, but study participants 
may have recourse through the NHS complaints procedures. 
 
The University of Nottingham as research Sponsor indemnifies its staff with both public 
liability insurance and clinical trials insurance in respect of claims made by research 
subjects. 
 
STUDY CONDUCT 
Study conduct may be subject to systems audit for inclusion of essential documents; 
permissions to conduct the study; CVs of study 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, timeliness of visits); accountability 
of study materials and equipment calibration logs. 
 
STUDY DATA  
Monitoring of study data shall include confirmation of informed consent; source data 
verification; data storage and data transfer procedures; local quality control checks and 
procedures, back-up and disaster recovery of any local databases and validation of data 
manipulation. The Study Coordinator or where required, a nominated designee of the 
Sponsor, shall carry out monitoring of study 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 on a regular basis for verification 
of all entries made. In addition, the subsequent capture of the data on the study database 
will be checked. Where corrections are required, these will carry a full audit trail and 
justification. 
 
Study data and evidence of monitoring and systems audits will be made available for 
inspection by the REC as required. 
 
RECORD RETENTION AND ARCHIVING 
In compliance with GCP guidelines and in accordance with the University of Nottingham 
Code of Research 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 TMF and study documents held by the CI on behalf of the Sponsor shall be finally 
archived at secure archive facilities at the University of Nottingham. This archive shall 
include all study databases and associated meta-data encryption codes. 
 
DISCONTINUATION OF THE STUDY BY THE SPONSOR  
The Sponsor reserves the right to discontinue this study at any time for failure to meet 
expected enrolment goals, for safety or any other administrative reasons. The Sponsor shall 
take advice as appropriate in making this decision. 
 

 
 
 
 
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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 
 
STATEMENT OF CONFIDENTIALITY  
Individual participant medical and/or personal information obtained as a result of this study 
are considered confidential and disclosure to third parties is prohibited. Such medical 
information may be given to the participant’s medical team and all appropriate medical 
personnel responsible for the participant’s welfare. 
 
Participant confidentiality will be further ensured by utilising identification code numbers to 
correspond to treatment data in the computer files.  
 
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 study will be available for inspection on request by the 
participating physicians, the University of Nottingham representatives, the REC, local R&D 
Department and the regulatory authorities. 
 
PUBLICATION AND DISSEMINATION POLICY 
 
The results of this study will be submitted to peer-reviewed journals for publication as soon 
as data analysis is completed. The results will also be presented at conferences. 
Participants will not be identified in any publications. However, participants will be informed 
of the results of the study via a lay summary written by members of the research team. 
 
This study will be registered with a publicly accessible database before recruitment of the 
first subject. 
 
USER AND PUBLIC INVOLVEMENT 
 
The Centre for Kidney Research and Innovation work closely with a Royal Derby Hospital 
patient focus group. All research studies are discussed with the group. The group provides 
advice with regards to studies acceptability and feasibility from a patient’s perspective. We also 
ensure that results from studies are fed back to participants.  
 
STUDY FINANCES 
 
Funding source  
This study is funded by internal funds from the University of Nottingham and Department of 
Renal Medicine, Royal Derby Hospital. 
 
Participant spends and payments 
Participants will not be paid to participate in the study. Travel expenses will be offered for 
any hospital visits in excess of usual care. All study assessments will take place at the time 
of routine haemodialysis treatment. 

 
 
 
 
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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: (name)__________________________________ 
 
 
Signature:__________________________________ 
 
 
Date: ___________ 
 
 
 

 
 
 
 
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Immuno-nutrition in haemodialysis - Protocol Version 2.0 
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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. Slee A, McKeaveney C, Adamson G, Davenport A, Farrington K, Fouque D, et al. Estimating 
the prevalence of muscle wasting, weakness, and sarcopenia in hemodialysis patients. J Ren 
Nutr. 2020;30(4):313-21. Erratum in: J Ren Nutr. 2021;31(2):e5. 
2. Carrero JJ, Johansen KL, Lindholm B, Stenvinkel P, Cuppari L, Avesani CM. Screening for 
muscle wasting and dysfunction in patients with chronic kidney disease. Kidney Int. 
2016;90(1):53-66. 
3. Ikizler TA, Cano NJ, Franch H, Fouque D, Himmelfarb J, Kalantar-Zadeh K, et al. Prevention 
and treatment of protein energy wasting in chronic kidney disease patients: a consensus 
statement by the International Society of Renal Nutrition and Metabolism. Kidney Int. 
2013;84(6):1096-107. 
4. Bergstrom J. Mechanisms of uremic suppression of appetite. J Ren Nutr. 1999;9(3):129-32. 
5. Bossola M, Muscaritoli M, Tazza L, Panocchia N, Liberatori M, Giungi S, et al. Variables 
associated with reduced dietary intake in hemodialysis patients. J Ren Nutr. 2005;15(2):244-
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6. Oliveira EA, Zheng R, Carter CE, Mak RH. Cachexia/Protein energy wasting syndrome in 
CKD: Causation and treatment. Semin Dial. 2019;32(6):493-9. 
7. Mitchell WK, Wilkinson DJ, Phillips BE, Lund JN, Smith K, Atherton PJ. Human skeletal 
muscle protein metabolism responses to amino acid nutrition. Adv Nutr. 2016;7(4):828S-38S. 
8. Stenvinkel P, Carrero JJ, von Walden F, Ikizler TA, Nader GA. Muscle wasting in end-stage 
renal disease promulgates premature death: established, emerging and potential novel 
treatment strategies. Nephrol Dial Transplant. 2016;31(7):1070-7. 
9. Lim VS, Ikizler TA, Raj DS, Flanigan MJ. Does hemodialysis increase protein breakdown? 
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10. Lim VS, Kopple JD. Protein metabolism in patients with chronic renal failure: role of uremia 
and dialysis. Kidney Int. 2000;58(1):1-10. 
11. Bohe J, Rennie MJ. Muscle protein metabolism during hemodialysis. J Ren Nutr. 
2006;16(1):3-16. 
12. Carrero JJ, Stenvinkel P, Cuppari L, Ikizler TA, Kalantar-Zadeh K, Kaysen G, et al. Etiology 
of the protein-energy wasting syndrome in chronic kidney disease: a consensus statement 
from the International Society of Renal Nutrition and Metabolism (ISRNM). J Ren Nutr. 
2013;23(2):77-90. 
13. Cukor D, Cohen SD, Peterson RA, Kimmel PL. Psychosocial aspects of chronic disease: 
ESRD as a paradigmatic illness. J Am Soc Nephrol. 2007;18(12):3042-55. 
14. Kalantar-Zadeh K. Recent advances in understanding the malnutrition-inflammation-
cachexia syndrome in chronic kidney disease patients: What is next? Semin Dial. 
2005;18(5):365-9. 
15. Visser WJ, Egmond A, Timman R, Severs D, Hoorn EJ. Risk factors for muscle loss in 
hemodialysis patients with high comorbidity. Nutrients. 2020;12(9). 
16. Malgorzewicz S, Galezowska G, Cieszynska-Semenowicz M, Ratajczyk J, Wolska L, 
Rutkowski P, et al. Amino acid profile after oral nutritional supplementation in hemodialysis 
patients with protein-energy wasting. Nutrition. 2019;57:231-6. 
17. Liu PJ, Ma F, Wang QY, He SL. The effects of oral nutritional supplements in patients with 
maintenance dialysis therapy: A systematic review and meta-analysis of randomized clinical 
trials. PLoS One. 2018;13(9):e0203706. 
18. Hendriks FK, Kooman JP, van Loon LJC. Dietary protein interventions to improve 
nutritional status in end-stage renal disease patients undergoing hemodialysis. Curr Opin Clin 
Nutr Metab Care. 2021;24(1):79-87. 
19. Viramontes Hörner D, Willingham FC, Selby NM, Taal MW. Impact of dietetic intervention 
on skin autofluorescence and nutritional status in persons receiving dialysis: a proof of principle 
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Immuno-nutrition in haemodialysis - Protocol Version 2.0 
Date 25 February 2022 
 
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 
 
20. van Vliet S, Skinner SK, Beals JW, Pagni BA, Fang HY, Ulanov AV, et al. Dysregulated 
handling of dietary protein and muscle protein synthesis after mixed-meal ingestion in 
maintenance hemodialysis patients. Kidney Int Rep. 2018;3(6):1403-15. 
21. Grimble RF. Basics in clinical nutrition: Immunonutrition – Nutrients which influence 
immunity: Effect and mechanism of action. e-SPEN. 2009;4:e10-e3. 
22. Adiamah A, Skorepa P, Weimann A, Lobo DN. The impact of preoperative immune 
modulating nutrition on outcomes in patients undergoing surgery for gastrointestinal cancer: A 
systematic review and meta-analysis. Ann Surg. 2019;270(2):247-56. 
23. Ikizler TA, Burrowes JD, Byham-Gray LD, Campbell KL, Carrero JJ, Chan W, et al. KDOQI 
Clinical Practice Guideline for Nutrition in CKD: 2020 Update. Am J Kidney Dis. 2020;76(3 
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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 
 
APPENDICES 
 
Appendix 1