Title Diet and renal outcomes Author(s) Smyth, Coleman Andrew Publication Date 2014-11 Item ...

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Title Diet and renal outcomes
Author(s) Smyth, Coleman Andrew
Publication
2014-11
Date
Item record http://hdl.handle.net/10379/4960
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Diet and Renal Outcomes

A thesis submitted to the School of Medicine, National University of Ireland, Galway
in fulfilment of the requirements for the degree of Doctor of Philosophy

By

Coleman Andrew Smyth M.B., B.Ch., B.A.O., M. Med. Sc., M.R.C.P.I.

HRB Clinical Research Facility Galway
National University of Ireland Galway

Supervisor: Professor Martin O’Donnell

Date: November 2014

i
Table of Contents
Abstract ........................................................................................................ i
Declaration .................................................................................................. ii
Acknowledgements .....................................................................................iii
Dedication ................................................................................................... iv
List of Figures ...............................................................................................v
List of Tables ............................................................................................... vii
List of Abbreviations .................................................................................... ix
Chapter 1: Introduction ..............................................................................13
1.1 Importance of Chronic Kidney Disease ......................................................... 14
1.2 Definition of Chronic Kidney Disease ........................................................... 14
1.3 Background ................................................................................................ 17
1.3.1 Sodium ......................................................................................................... 17
1.3.2 Potassium ..................................................................................................... 17
1.3.3 Diet Quality .................................................................................................. 18
1.4 Measurement Issues ................................................................................... 18
1.5 Choice of Outcome Measures ...................................................................... 19
1.6 Overall Objective ........................................................................................ 20
1.7 Specific Objectives ...................................................................................... 20
Chapter 2: Sodium Intake and Renal Outcomes: A Systematic Review .........22
2.1 Introduction ............................................................................................... 23
2.2 Methodology .............................................................................................. 26
2.2.1 Search Strategy ............................................................................................ 26
2.2.2 Eligibility Criteria .......................................................................................... 26
2.2.3 Data Collection ............................................................................................. 28
2.2.4 Risk of Bias Assessment ............................................................................... 28
2.2.5 Statistical Analysis ........................................................................................ 28
2.3 Results........................................................................................................ 29
2.3.1 Search Results .............................................................................................. 29
2.3.2 Risk of Bias ................................................................................................... 29
2.3.3 Studies of Populations with Chronic Kidney Disease ................................... 29
2.3.4 Studies of Populations without Chronic Kidney Disease ............................. 30
2.4 Discussion ................................................................................................... 40
2.4.1 Summary of Findings .................................................................................... 40
2.4.2 Evidence to Support Guidelines ................................................................... 40
2.4.3 Comparison to Previous Systematic Review ................................................ 41
2.4.4 Sodium and Cardiovascular Disease in Patients with CKD ........................... 42
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2.4.5 Strengths ...................................................................................................... 44
2.4.6 Limitations .................................................................................................... 44
2.4.7 Conclusion .................................................................................................... 48
Chapter 3: Sodium and potassium excretion and renal outcomes ................49
3.1 Introduction ............................................................................................... 50
3.2 Methods ..................................................................................................... 50
3.2.1 Population .................................................................................................... 50
3.2.2 Laboratory Analysis ...................................................................................... 52
3.2.3 Outcomes ..................................................................................................... 53
3.2.4 Statistical Analysis ........................................................................................ 54
3.3 Results........................................................................................................ 56
3.3.1 Sodium ......................................................................................................... 63
3.3.2 Potassium ..................................................................................................... 71
3.3.3 Sensitivity analyses ...................................................................................... 79
3.3.4 Subgroup analyses ....................................................................................... 81
3.4 Discussion ................................................................................................... 88
3.4.1 Summary of Findings .................................................................................... 88
3.4.2 Sodium ......................................................................................................... 88
3.4.3 Potassium ..................................................................................................... 89
3.4.4 Strengths ...................................................................................................... 91
3.4.5 Limitations .................................................................................................... 91
3.4.6 Conclusions .................................................................................................. 92
Chapter 4: Diet and Major Renal Outcomes: The NIH-AARP Diet and Health
Study ..........................................................................................................93
4.1 Introduction ............................................................................................... 94
4.2 Methodology .............................................................................................. 94
4.2.1 Study Population .......................................................................................... 94
4.2.2 Dietary assessment ...................................................................................... 97
4.2.3 Follow-Up and Outcome Measures ........................................................... 100
4.2.4 Statistical Analysis ...................................................................................... 102
4.3 Results...................................................................................................... 104
4.3.1 Cross-Sectional Analyses ............................................................................ 104
4.3.2 Diet Quality and Outcomes ........................................................................ 111
4.3.3 Sodium and Potassium Intakes and Outcomes .......................................... 117
4.3.4 Interactions ................................................................................................ 121
4.3.5 Sensitivity Analyses .................................................................................... 121
4.4 Discussion ................................................................................................. 126
4.4.1 Summary of Findings .................................................................................. 126
4.4.2 Healthy Eating and Outcomes.................................................................... 126
4.4.3 Strengths .................................................................................................... 128
4.4.4 Limitations .................................................................................................. 128
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4.4.5 Conclusion .................................................................................................. 129
Chapter 5: Chronic kidney disease and functional impairment ................... 130
5.1 Introduction ............................................................................................. 131
5.2 Methods ................................................................................................... 131
5.2.1 Population .................................................................................................. 131
5.2.2 Data Collection ........................................................................................... 132
5.2.3 Functional Assessment............................................................................... 132
5.2.4 Statistical Analysis ...................................................................................... 133
5.3 Results...................................................................................................... 134
5.3.1 Chronic Kidney Disease and Activities of Daily Living ................................ 138
5.4 Discussion ................................................................................................. 142
5.4.1 Summary of Findings .................................................................................. 142
5.4.2 Comparison with Previous Studies ............................................................ 142
5.4.3 Under-Recognition of CKD ......................................................................... 142
5.4.4 Underlying Mechanisms ............................................................................ 143
5.4.5 Strengths .................................................................................................... 144
5.4.6 Limitations .................................................................................................. 144
5.4.7 Conclusion .................................................................................................. 145
Chapter 6: Sodium InTake In Chronic Kidney Disease (STICK): A Randomised
Controlled Trial ......................................................................................... 146
6.1. Background and Rationale........................................................................ 148
6.1.1. Burden of Chronic Kidney Disease ............................................................ 148
6.1.2. Sodium Intake and Hypertension.............................................................. 148
6.1.3. Sodium Intake and RAAS ........................................................................... 148
6.1.4 Current Evidence to Support Low Sodium Intake in CKD .......................... 149
6.1.5 Modifiability of Sodium Intake ................................................................... 150
6.1.6 Clinical Equipoise ....................................................................................... 150
6.1.7 Impact of Trial ............................................................................................ 151
6.2 Research Question .................................................................................... 151
6.3 Study Objectives ....................................................................................... 151
6.3.1 Primary Research Question........................................................................ 151
6.3.2 Secondary Research Questions .................................................................. 151
6.4 Study Design ............................................................................................. 152
6.4.1 Sampling Frame & Clinical Setting ............................................................. 152
6.4.2 Population .................................................................................................. 153
6.4.3 Feasibility ................................................................................................... 153
6.5 Eligibility Criteria....................................................................................... 155
6.5.1 Inclusion Criteria ........................................................................................ 155
6.5.2 Exclusion Criteria ........................................................................................ 155
6.6 Randomisation ......................................................................................... 156
6.6.1 Allocation Sequence Generation ............................................................... 156
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6.6.2 Allocation Concealment ............................................................................. 157
6.6.3 Blinding ...................................................................................................... 157
6.7 Intervention and Usual Care ...................................................................... 157
6.7.1 Pre-Randomisation & Screening Visit ........................................................ 157
6.7.2 Usual Care .................................................................................................. 160
6.7.3 Nutritional Assessment .............................................................................. 160
6.7.4 Nutritional Recommendations ................................................................... 160
6.7.5 Follow-Up Review ...................................................................................... 162
6.7.6 Sodium Intake in Control Group ................................................................ 162
6.7.7 Sodium Reduction Education Intervention ................................................ 162
6.7.8 Feasibility and Efficacy of Intervention ...................................................... 163
6.8 Contamination .......................................................................................... 164
6.9 Follow-Up Schedule .................................................................................. 164
6.9.1 Standardisation of Intervention & Follow-Up ............................................ 167
6.9.2 Methods to Maximise Participant Adherence ........................................... 167
6.10 Measurements ........................................................................................ 168
6.10.1 Screening .................................................................................................. 168
6.10.2 Baseline Characteristics ........................................................................... 168
6.10.3 Measurements at Randomisation ............................................................ 169
6.10.4 Measurements at Follow-Up Visits .......................................................... 169
6.10.5 Measurements at Final Visit .................................................................... 169
6.10.6 Measurements after Final Visit ................................................................ 170
6.10.7 Confounding Variables ............................................................................. 170
6.11 Criteria for Permanent Withdrawal of Intervention .................................. 170
6.12 Study Outcomes ...................................................................................... 170
6.12.1 Primary Outcome ..................................................................................... 170
6.12.2 Secondary Outcomes ............................................................................... 171
6.12.3 Outcome Events of Interest ..................................................................... 171
6.13 Functional Status .................................................................................... 171
6.13.1 Basic Activities of Daily Living .................................................................. 172
6.13.2 Instrumental Activities of Daily Living ...................................................... 172
6.13.3 Cognitive Function ................................................................................... 172
6.14 Statistical Analysis .................................................................................. 178
6.14.1 Sample Size Considerations ..................................................................... 178
6.14.2 Descriptive Statistics & Baseline Characteristics ..................................... 181
6.14.3 Statistical Analysis of Primary Outcome .................................................. 181
6.14.4 Statistical Analysis of Secondary Outcomes ............................................ 181
6.14.5 Subgroup & Sensitivity Analyses .............................................................. 181
6.14.6 Enrollment and Disposition ...................................................................... 182
6.14.7 Missing Data ............................................................................................. 182
6.14.8 Data Safety & Monitoring Board .............................................................. 183
6.15 Ethical Considerations ............................................................................. 184
v
6.15.1 Patient Confidentiality ............................................................................. 184
6.15.2 Risk-Benefit Ratio ..................................................................................... 185
6.16 Limitations & Methods to Control Bias .................................................... 185
6.17 Trial Administration ................................................................................ 189
6.17.1 Site ........................................................................................................... 189
6.17.2 Steering, Local Operations and Publication Committees ........................ 189
6.17.3 Study Monitoring ..................................................................................... 189
6.17.4 Data Collection & Quality Control ............................................................ 190
6.17.5 Study Timeline ......................................................................................... 191
6.18 Dissemination Strategy ........................................................................... 191
6.19 Protocol Amendments ............................................................................ 191
6.20 Ownership of Data and Use of Study Results ............................................ 191
6.21 Declaration of Interests ........................................................................... 192
6.22 Ancillary & Post-Trial Care ....................................................................... 192
Chapter 7: Overall Conclusions .................................................................. 193
Chapter 2 ....................................................................................................... 194
Chapter 3 ....................................................................................................... 195
Chapter 4 ....................................................................................................... 196
Chapter 5 ....................................................................................................... 197
Chapter 6 ....................................................................................................... 197
Future Directions ............................................................................................ 198
Appendices ............................................................................................... 200
Appendix 1: Outputs arising from this work .................................................... 201
Presentations: ..................................................................................................... 201
Publications ......................................................................................................... 201
Successful Funding Applications ......................................................................... 201
Appendix 2. Copyright Permission for “Sodium Intake and Renal Outcomes: A
Systematic Review” ........................................................................................ 202
Appendix 3. Copyright Permission for “The relationship between estimated
sodium and potassium excretion and subsequent renal outcomes” ................. 204
Appendix 4. Copyright Permission for “Mild chronic kidney disease and functional
impairment in community-dwelling older adults” ............................................ 205
Appendix 5: CLARITY Questionnaire ................................................................ 207
References ............................................................................................... 212
vi
Abstract
Chronic Kidney Disease (CKD) is associated with significant morbidity,
increased cardiovascular risk and premature mortality and advanced CKD places a
significant burden on patients and health systems. There is a need to reduce the
global CKD burden; dietary modification may be one approach. In this work, I examine
the association between diet and renal outcomes, using multiple methodologies.
First, I completed a systematic review of dietary sodium intake and renal
outcomes and report an association between high intake (>4.6g/day) and adverse
outcomes, but no difference between low (<2.3g/day) and moderate (2.3-4.6g/day)
intakes. Second, I completed post-hoc analyses of two large clinical trials (ONTARGET
and TRANSCNED) exploring the association between sodium and potassium intakes
and surrogate outcomes (n=28,879). This study showed no overall association
between sodium intake and surrogate renal outcomes (although trends towards
adverse outcomes with high intake). High potassium intake was associated with
reduced odds of outcomes (there was loss of statistical significance with eGFR<45 or
macroalbuminuria) but an increased risk of hyperkalemia. Third, I completed the first
renal analyses of a large prospective cohort study (n=544,635) exploring the
association between diet quality, sodium and potassium intake and hard outcomes
(dialysis or death from a renal cause). This study showed higher sodium intake was
associated with an increased risk of the outcome but higher potassium intake and diet
quality were associated with reduced risks. Fourth, I completed a cross-sectional
analysis (n=3,499) that showed CKD was associated with an increased risk of
functional impairment (patient-important outcome). Finally, I developed a clinical trial
protocol testing the hypothesis that low sodium (as recommended by guidelines)
improves renal outcomes. This trial, funded by the Health Research Board, will be one
of the longest trials of sodium restriction in patients with CKD.
This thesis provides novel observational evidence on the association between
diet and renal outcomes (including two of the largest prospective cohort studies) and
identified considerable uncertainty about the benefits of low sodium intake in
patients with CKD, which will be explored in an upcoming clinical trial.
i
Declaration

This thesis is submitted to National University of Ireland, Galway in accordance with
the requirements for the degree of Doctor of Philosophy (PhD) in the School of
Medicine.

I declare that this thesis is a record of my own work and has not been submitted for
any other academic award in this University, or elsewhere. All information sources
have been fully acknowledged and referenced.

Parts of this work have appeared in peer-reviewed publications and presentations
(Appendix 1).

Coleman Andrew Smyth
November 2014
ii
Acknowledgements
Firstly, I would like to thank my supervisor, Professor Martin O’Donnell for his
advice, support, guidance and encouragement throughout my research training. I
have been very fortunate to have a supervisor of his calibre, to allow me to develop
clinical research skills and to train as a clinician scientist.
A very special thank you to Dr. Michelle Canavan, my fellow PhD student, for
her friendship, help and support on both sides of the Atlantic.
Thank you to Dr. Donal Reddan and Professor Matthew Griffin of the
Department of Nephrology at Galway University Hospitals and the staff of the HRB
Clinical Research Facility Galway.
I would like to acknowledge the financial support of Health Service Executive
and Health Research Board National SpR/SR Academic Fellowship Programme.
I would also like to thank the staff of the Population Health Research Institute
and McMaster University, Hamilton, Canada. I would particularly like to thank
Professor Salim Yusuf, Dr. Koon Teo and Dr. Michael Walsh. A very special word of
thanks to Dr Jackie Bosch for her friendship, support and guidance throughout my
time in Canada.
Finally, I would like to thank my parents, my sisters, family and friends for
their support and encouragement.

iii