Glucose Metabolism Abnormalities After Renal Transplantation

227 Pages·2016·2.88 MB·English

Glucose Metabolism Abnormalities After Renal
Transplantation: Studies On Epidemiology,
Mechanisms And Outcomes

Submission for M.D.
CARDIFF UNIVERSITY
2015

Dr. Pramod Nagaraja
DECLARATION
Except where indicated by specific reference, the work submitted in this thesis is the result of
my own investigation and the views expressed are mine.
Signed .......................................(candidate) Date.............................

No portion of the work presented has been submitted in substance for any other degree or
award at this or any other university or place of learning, nor is being submitted concurrently
in candidature for any degree or other award.
Signed .......................................(candidate) Date.............................

This thesis is being submitted in partial fulfilment of the requirements for the degree of MD.
Signed .......................................(candidate) Date.............................

I hereby give consent for my thesis, if accepted, to be available for photocopying and for
inter-library loan, and for the title and summary to be made available to outside organisations.
Signed .......................................(candidate) Date.............................

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ACKNOWLEDGEMENTS
I am grateful to the kidney transplant patients attending clinics at the University Hospital of
Wales who consented to participate in the clinical studies to enable me to carry out research. I
am also grateful to all the staff in the transplant outpatient clinic for their help in carrying out
oral glucose tolerance tests on patients in the OGTT study.
I thank my supervisor Dr. Kesh Baboolal for providing me with the opportunity to undertake
a period of research and helping me throughout the course of the clinical studies. I am
particularly grateful to Dr. Vinod Ravindran, who co-supervised the work, for providing me
with the data of patients in the older era in the epidemiological study. His help in navigating
through the processes of R and D and ethics committees was invaluable. I am grateful to Prof.
Colin Dayan for agreeing to be my supervisor and helping me appreciate the results of the
studies in a new light. I thank Dr. Adnan Sharif (Consultant Nephrologist, Queen Elizabeth
Hospital, Birmingham), who was my predecessor in UHW and conducted the baseline
OGTTs, for providing me with the data of those patients. Mr. Gary Hunter helped me in
gathering data for the epidemiological study by using his expertise of the renal IT systems.
Finally, this work would not have been possible without the unflinching support and
encouragement from my wife Toyah, and I thank her very much for this.

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Dedicated
To my parents

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SUMMARY
Abnormal glucose metabolism, including new-onset diabetes after transplantation (NODAT),
is a common complication following kidney transplantation. Better understanding of the
causes, associations, prediction and outcomes of NODAT in the modern era of kidney
transplantation is essential.
Our central hypothesis was that early NODAT is distinct from type 2 diabetes mellitus
(T2DM), and is due to factors unique to the transplant setting, of which the predominant
factor is the use of specific immunosuppressive agents (calcineurin inhibitors-CNIs), and that
traditional risk factors for T2DM are the more significant factors late after transplantation.
In a series of observational studies, we found that recipient age, body mass index and
baseline plasma glucose levels were associated with the development of NODAT, both early
and late after transplantation. Exposure to tacrolimus and being transplanted in an older era
were associated with early NODAT development, but had no effect on late NODAT. There
was increasing insulin resistance but no compensatory increase in insulin secretion in patients
developing NODAT, suggesting an effect of CNIs. In an observational study using paired
oral glucose tolerance tests, there was worsening of glucose tolerance late after
transplantation. Metabolic syndrome was a risk factor for this deterioration. Finally, in an
epidemiological study, we show that immunosuppression regimens in Cardiff have evolved,
with the introduction of induction therapy and tacrolimus as the CNI of choice. Blood
tacrolimus levels, corticosteroid exposure and acute rejection rates were lower in a recent era
of transplantation, as was the incidence of NODAT. NODAT developing within the first year,
higher systolic blood pressure and higher serum creatinine level were all associated with
increased mortality.
In conclusion, traditional T2DM risk factors are important in causing both early and late
NODAT, with a strong influence from immunosuppressive agents early after transplantation.
NODAT and other cardiovascular risk factors were associated with mortality. Therefore, less
diabetogenic immunosuppressive regimes and interventions to reduce hyperglycaemia may
not improve mortality unless other cardiovascular factors are also managed simultaneously.

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Contents
DECLARATION ........................................................................................................................ i
ACKNOWLEDGEMENTS ....................................................................................................... ii
SUMMARY .............................................................................................................................. iv
PUBLICATIONS RESULTING FROM THIS WORK ........................................................... xi
LIST OF PRESENTATIONS TO LEARNED SOCIETIES .................................................... xi
LIST OF TABLES ................................................................................................................... xii
LIST OF FIGURES ................................................................................................................ xvi
LIST OF ABBREVIATIONS ................................................................................................. xix
CHAPTER 1: INTRODUCTION .............................................................................................. 1
1.1 Scope of kidney transplantation in the UK ......................................................................... 1
1.2 Scope of kidney transplantation in Cardiff ......................................................................... 4
1.3 Challenges in the long-term management of kidney transplant recipients ......................... 4
1.4 Normal glucose metabolism and insulin secretion .............................................................. 5
1.4.1 Role of calcineurin/NFAT pathway in the regulation of β-cell function .......................... 8
1.5 Pathophysiology of type 2 diabetes mellitus ..................................................................... 10
1.5.1 Decreasing insulin sensitivity or increasing insulin resistance ....................................... 12
1.5.2 β-cell dysfunction ........................................................................................................... 14
1.6 Pathophysiology of post-transplant hyperglycaemia and NODAT ................................... 17
1.7 Measures of insulin sensitivity and secretion .................................................................... 20
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1.7.1 Euglycaemic clamp ......................................................................................................... 20
1.7.2 Hyperglycaemic clamp ................................................................................................... 20
1.7.3 Indices derived from the oral glucose tolerance test ....................................................... 21
1.7.4 Indices derived from fasting samples ............................................................................. 22
1.7.5 Homeostasis model assessment of insulin resistance and secretion ............................... 23
1.7.6 McAuley’s Index ............................................................................................................ 27
1.7.7 Advantages and disadvantages of using surrogate markers of insulin sensitivity and
secretion ................................................................................................................................... 28
1.8 New-onset diabetes after kidney transplantation ............................................................... 29
1.8.1 Definition ........................................................................................................................ 29
1.8.2 Outcomes ........................................................................................................................ 30
1.8.3 Incidence of NODAT ...................................................................................................... 34
1.8.4 Risk factors for NODAT ................................................................................................. 36
1.8.4.1 Non-modifiable factors ................................................................................................ 37
i. Age ........................................................................................................................................ 37
ii. Ethnicity ............................................................................................................................... 37
iii. Cause of ESRF.................................................................................................................... 38
iv. Genetic polymorphisms ...................................................................................................... 38
v. Family history of T2DM ...................................................................................................... 39
1.8.4.2 Modifiable factors ........................................................................................................ 39
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i. Obesity .................................................................................................................................. 39
ii. Metabolic syndrome ............................................................................................................ 40
iii. Cytomegalovirus infection ................................................................................................. 41
1.8.4.3 Factors unique to the transplant setting ....................................................................... 41
i. Calcineurin inhibitors ........................................................................................................... 41
ii. Switching between CNIs ..................................................................................................... 43
iii. Sirolimus ............................................................................................................................. 45
iv. Corticosteroids .................................................................................................................... 46
1.9 Prediction of NODAT ........................................................................................................ 47
1.10 Pharmacological prevention and treatment options for post-transplant hyperglycaemia
and NODAT ............................................................................................................................. 48
1.11 Summary .......................................................................................................................... 54
1.12 Hypotheses and aims of studies presented in the thesis ................................................... 56
1.12.1 Central hypotheses ........................................................................................................ 56
1.12.2 Aims .............................................................................................................................. 57
CHAPTER 2: METHODS AND DESCRIPTION OF COHORTS ........................................ 58
2.1 Cic vs. Tac study cohort..................................................................................................... 58
2.1.1 Study design and population ......................................................................................... 58
2.1.2 Insulin resistance indices .............................................................................................. 58
2.1.3 Definitions....................................................................................................................... 59
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2.1.4 Immunosuppression regimen .......................................................................................... 59
2.2 OGTT study cohort ............................................................................................................ 61
2.2.1 Study design and population ........................................................................................... 61
2.2.2 Procedure for oral glucose tolerance test ........................................................................ 63
2.2.3 Definitions....................................................................................................................... 63
2.2.4 Groups at follow-up ........................................................................................................ 65
2.3 Historic vs. Recent cohorts study (Incidence study) ......................................................... 66
2.3.1 Study design .................................................................................................................... 66
2.3.2 Definitions....................................................................................................................... 66
2.3.3 Immunosuppression regimen in the old era .................................................................... 66
2.3.4 Immunosuppression regimen in the new era .................................................................. 67
2.4 Data collection ................................................................................................................... 70
2.5 Exclusion of pre-transplant diabetes mellitus .................................................................... 72
2.6 Statistical analysis ............................................................................................................ 72
2.6.1 Additional statistical analysis ......................................................................................... 73
CHAPTER 3: RESULTS FROM THE CIC VS. TAC STUDY .............................................. 74
3.0 Introduction ........................................................................................................................ 74
3.1 Incidence of NODAT, baseline and demographic characteristics ..................................... 75
3.2 Type of CNI and acute rejection episodes: Relationship with NODAT ............................ 76
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3.3 Differences in insulin resistance and secretion indices between NODAT and non-NODAT
patients ..................................................................................................................................... 78
3.4 Within-group differences in insulin resistance and secretion indices ................................ 83
3.4.1 Change in insulin resistance from pre-transplantation and correlation with NODAT ... 83
3.5 Changes in insulin parameters according to baseline CNI ................................................ 85
3.6 Risk factors for developing NODAT ................................................................................. 87
3.7 Survival analysis ................................................................................................................ 91
3.8 Discussion .......................................................................................................................... 97
CHAPTER 4: RESULTS FROM THE OGTT FOLLOW-UP STUDY ................................ 105
4.0 Introduction ...................................................................................................................... 105
4.1 General results ................................................................................................................. 106
4.2 Changes in glucose tolerance and cardio-metabolic profile from baseline to follow-up 107
4.3 Differences in characteristics between progressors and non-progressors ........................ 109
4.4 Association between metabolic syndrome and glucose tolerance abnormalities ............ 111
4.5 Factors associated with the progression of glucose intolerance ...................................... 114
4.6 Characteristics of patients who progressed to NODAT during follow-up ...................... 116
4.7 Factors independently associated with the development of NODAT in logistic regression
modelling ............................................................................................................................... 119
4.8 Discussion ........................................................................................................................ 122
CHAPTER 5: RESULTS FROM THE STUDY OF HISTORIC VS. RECENT
TRANSPLANTATION COHORTS (INCIDENCE STUDY) .............................................. 127
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