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Page 4 of 14 Jagpal et al. Vessel Plus 2018;2:24 I http://dx.doi.org/10.20517/2574-1209.2018.27
[19]
induced nephrotoxicity .

Ciclosporin
The discovery of ciclosporin in the early 1970s revolutionised the field of transplantation. Initially developed
as an anti-fungal, the potent immunosuppressive properties of ciclosporin were first recognised in 1986 (Borel,
1986). Ciclosporin was approved for use in kidney transplantation in 1979. This dramatically improved
the mortality of transplant patients and provided sufficient evidence to permit approval for use in heart
transplantation in 1980. Five years after introducing the drug to cardiac transplant recipients, Shumway’s
[20]
group reported a 1-year survival rate of 83% . In 1994, the original oil-based drug was replaced by a new
micro-emulsion formulation (Neoral, Novartis). This provided greater bioavailability and more predictable
[21]
pharmacokinetics, enhancing the role of ciclosporin in immunosuppression . The use of ciclosporin in
transplantation has led to a steady increase in survival, with worldwide 1-year survival now approaching
[22]
90% .
The calcineurin inhibitor, ciclosporin inhibits T-cell proliferation by blocking its activation. When entering
lymphocytes, ciclosporin binds to cyclophilin, a type of immunophilin. This ciclosporin-cyclophilin complex
binds to and inhibits the action of calcineurin. As a result, the IL-2 transcription cascade is halted. This
ultimately blocks T-cell activation, preventing allograft rejection process.

Tacrolimus
Tacrolimus, a macrolide antibiotic, was found to possess potent immunosuppressive qualities in 1984. The
[23]
compound was first approved for use in transplantation in Japan, 1993 . Due to its decreased incidence
of rejection when combined with MMF, tacrolimus has surpassed ciclosporin to become the cornerstone
[24]
of immunosuppressant therapy today . Over 70% of patients worldwide are on a tacrolimus and MMF
[12]
combination therapy, further highlighting the superiority of tacrolimus .
Tacrolimus exhibits similar immunosuppressive activity to that of ciclosporin. However, tacrolimus inhibits
calcineurin through binding to a different immunophilin, FK506 binding protein (FKBP12). Tacrolimus is
[25]
also effective as a rescue rejection therapy .
Although CNIs play a critical role in the preservation of allograft function, these drugs cause a variety of
side effects, including hyperglycaemia. This in turn can result in significant morbidity and reduced quality
[26]
of life .

Post-transplant diabetes mellitus
Diabetes is a metabolic disorder characterised by chronic hyperglycaemia, resulting from defects in insulin
[27]
secretion, insulin action, or both . There are several diagnostic tests for diabetes shown in Table 1, each
[28]
test is used alongside any symptoms a patient is experiencing . Although it has been proposed that PTDM
[29]
could be a distinct entity, the natural history of diabetes after transplantation resembles type 2 diabetes .
Since the onset of both PTDM and type 2 diabetes can be insidious and patients may be asymptomatic for
years before symptoms present. Accordingly, PTDM management follows the conventional approach used
[30]
for patients with type 2 diabetes . PTDM is not always permanent and may stabilise within weeks or
[31]
months .
PTDM is a major problem among this population of patients as impaired glucose metabolism can contribute
to increased risk of cardiovascular disease, subsequently reducing mortality in these patients.

CNI induced diabetes
The exact mechanism by which CNIs induce diabetes is unknown. One mechanism that has gained
popularity involves calcineurin expression in pancreatic insulin-secreting b-cells. Here, calcineurin