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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:681305 |
| Date | January 2015 |
| Creators | Nagaraja, Pramod |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/88165/ |
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