Dr Riaan Flooks, a nephrologist, helps us understand what post-transplant diabetes mellitus (PTDM) is and how it develops.
Chronic kidney disease
Chronic kidney disease (CKD) is quite common. This is when kidneys are damaged and can’t filter blood the way they should. Renal (kidney) transplantation is one of the treatment modalities thereof. The leading cause of CKD, worldwide, is said to be diabetes mellitus.
Kidney transplants
In 1964, it was recognised that hyperglycaemia (high-blood glucose) developed in some of the renal transplanted patients.
In South Africa, the first kidney transplants took place on 25 August 1966. But because of the lack of well-designed immunosuppressants, these transplants succumbed due to organ rejection.
Post-transplant diabetes mellitus (PTDM) is associated with increase in hospitalisations and deaths and is also known to cause cardiovascular disease and infections. The latter two conditions are also the leading causes of death in the transplant population.
History
After a meeting in 2003, guidelines were published that changed Transplant-Related Hyperglyceamia to New-Onset Diabetes After Transplantation (NODAT).
In 2014, new and updated guidelines were published, which renamed the disease: post-transplant diabetes mellitus.
Post-transplant diabetes mellitusÂ
This disease entity describes the presence of diabetes after transplantation, irrespective of the timing of diagnosis, or having had undetected elevated blood glucose levels prior to transplantation.
Some patients may develop elevated blood glucose levels immediately after the transplant, or soon thereafter. This group of patients would be referred to as having Transient Hyperglycaemia and is excluded from PTDM.
PTDM occurs in 4-25% of kidney recipients, and the variation is due to definition, duration of follow-up and the presence of risk factors for developing hyperglycaemia.
Risk factors for developing PTDM
The risk factors that predisposes to the development of PTDM has been grouped into two groups.
Traditional risk factors
Not forgetting that patients who are subjected to renal transplants may have the traditional risk factors that predisposes the general population to develop DM. These risk factors would include advanced age (>40yrs), obesity (BMI>30), Black race, a history of diabetes during pregnancy and a positive family history of DM.
Transplant-related risk factors
The second group of risk factors are referred to as transplant-related risk factors. They include immunosuppressive therapy, infections, impaired glucose tolerance and peri-operative hyperglycaemia and human leukocyte mismatching.
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Immunosuppressive drugs
Not all immunosuppressive drugs are known to contribute to the development of PTDM. Only the diabetogenic drugs are discussed below:
- Glucocorticoids/Steroids
These drugs have an effect on the production of glucose in the liver and it also reduces glucose uptake in fat cells. Higher doses of glucocorticoids in these patients has been associated with the development of PTDM.
- Calcineurin Inhibitors (tacrolimus and cyclopsorine)
Patients on tacrolimus have a higher chance of developing PTDM. Patients with higher tacrolimus drug levels (>15ng/mL) have a higher chance to develop PTDM.
Both these drugs are toxic to the pancreatic cells (reduces insulin secretion and makes cells resistant to the effects of insulin), and thus causes PTDM to develop.
- Sirolimus
This drug is also known to cause diabetes.
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Infections
There are certain infections that predisposes the recipients to develop PTDM. These infections would be hepatitis C and Cytomegalovirus (CMV).
- Hepatitis C is primarily a liver disease, which causes liver dysfunction and also causes pancreatic cell dysfunction. For these two latter reasons, this infection results in hyperglycaemia.
- CMV infection is also known to cause PTDM.
Patients who have impaired glucose tolerance (glucose level is elevated, but not high enough to make a diagnosis of DM) before transplantation are also more prone to develop PTDM. Patients who develop hyperglycaemia around the time of the transplantation are also at risk of developing PTDM.
Clinical relevance
PTDM is associated with the development of cardiovascular disease, and thus an increase in mortality. Studies have also shown that patients who had diabetes before the transplant compared to those who develop PTDM have an even higher cardiovascular mortality rate.
Although newer immunosuppressive therapies have improved allograft survival, the development of PTDM decreases the long-term allograft survival.
It is postulated that the recipients who develop PTDM, may be due to diabetic nephropathy (diabetic kidney disease) or the early efforts to reduce the diabetogenic immunosuppressants, which then lead to rejection.
PTDM is also associated with more frequent infections; the infections that seem to occur more commonly is CMV, urinary tract infections and lower respiratory tract infections.
Diagnosing PTDM
Elevated blood glucose levels are commonly seen in the peri-operative time period, and is related to surgical stress and the use of high-doses of steroid therapy that forms part of the induction therapy.
This is referred to as transient post-transplant hyperglycaemia, and can last up to six weeks. Thus, a diagnosis of PTDM should not be made within the first six weeks, post-transplantation. This group of patient is also at an increased risk of developing PTDM at a later stage.
The blood glucose level should be monitored weekly for the first four-six weeks post-transplantation and then at three months and six months.
To diagnose a patient with PTDM, you would prefer to have a non-acutely ill patient, who is stable on immunosuppressants and whose transplanted kidney is having stable renal function.
Diagnosis requires the same symptoms that is seen in non-transplanted diabetic, in combination with a biochemically proven hyperglycaemia.
The symptoms usually include: excessive thirst, excessive hunger, unintentional weight loss and excessive urination. These symptoms usually occur in combination with a random blood glucose level of ≥11,1mmol/L. The diagnosis can also be made by having a fasting blood glucose of ≥7mmol/L.
The HbA1c can also be used as a marker of glucose control after the first three months post-transplantation.
Management
The current treatments available include oral hypoglycaemic agents and insulin therapy. Adjustment of the immunosuppressive therapy should also be considered, but it should be weighed against the possibility of the recipient suffering an acute rejection episode.
Conclusion
Post-transplant recipients have similar complications as the non-transplanted diabetics. Immunosuppressive therapy has become more sophisticated and has improved long-term graft survival, but some of them still has diabetogenic effect. Also, with the change in the field of diabetes management, the treatment of PTDM has become slightly easier.
Read Jordan Barber’s story of developing post-transplant diabetes mellitus after a kidney transplant.Â
MEET THE EXPERT
Dr Riaan Flooks is a practising nephrologist at Bloemfontein Mediclinic. His interests include ICU Nephrology, Diabetic Kidney Disease, Hypertension and Transplant Medicine. He forms part of the Transplant Team in the Free State Province, and is an active member of the Bloemfontein Mediclinic Medical Board.
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