Over the course of the past two decades, the science of renal transplantation has evolved exponentially. In the 20th century, when renal transplants were being performed, the concern was for immediate graft function and prevention of rejection. As immunosuppression became robust and standardized in keeping with improved knowledge of transplant immunology, improvement in long-term patient and graft outcomes became the priority. Today, the leading cause of death with a well-functioning allograft is cardiovascular disease. Posttransplant diabetes mellitus (PTDM) is associated with several significant adverse outcomes such as an increased risk of major cardiovascular events (hazard ratio [HR] 1.51) and a high risk of graft failure (HR 1.65).
The incidence of PTDM in renal transplant ranges between 10% and 40%, whereas in cardiac and lung transplants, the incidence is 20%–28% and 40% at 5 years, respectively. The last few years have seen a decline in the incidence of posttransplant diabetes. The incidence of PTDM declined from 18% in 1995 to 11% in 2012. While optimization of immunosuppression to desirable levels has contributed, change in the definition of PTDM has also played a part.
EVOLUTION OF THE DEFINITION OF POSTTRANSPLANT DIABETES MELLITUS
Before 2003, there was no formal definition for PTDM other than the one adopted from the World Health Organization (WHO) and the American Diabetes Association (ADA). In 2003, an international conference was held where a consensus was arrived to identify newly occurring diabetes after transplantation as a separate entity and called it “new-onset diabetes after transplant (NODAT).” This was a specific term that was introduced to differentiate posttransplant occurrence of diabetes from type 1 or type 2 diabetes that may occur in the general population. Subsequently, with the use of this definition, it was found that many individuals were not screened for diabetes pretransplant, and hence this term was not universally applicable. In a subsequent conference in Vienna in 2013, the term NODAT was changed to PTDM to allow it to become more inclusive. The term PTDM allows the inclusion of people not previously screened for diabetes. However, one distinction was made in that posttransplant hyperglycemia was excluded from the diagnosis of PTDM, since in many of these patients, the hyperglycemia resolves after the immediate posttransplant phase once the high doses of immunosuppression have been tapered. These changes in terminology have been presented in Figure 1.
DEFINITION OF POSTTRANSPLANT DIABETES MELLITUS
Diabetes is as defined as per the WHO and ADA criteria in the posttransplant setting in a patient who has previously not been diagnosed with diabetes mellitus with any one of the following:
- A fasting glucose >126 mg/dl
- A 2-h postprandial glucose of more than 200 mg/dl on a 75 g oral glucose tolerance test (OGTT)
- Random glucose of more than 200 mg/dl with symptoms of diabetes.
CAVEATS IN THE DEFINITION OF POSTTRANSPLANT DIABETES MELLITUS
- Glycated hemoglobin (HbA1c) is not used in the immediate posttransplant setting, since hemoglobin shows variability in the immediate posttransplant setting due to blood loss or anemia
- PTDM should not be diagnosed during an acute infective illness
- Renal function should be stable
- Posttransplant hyperglycemia should be excluded by waiting 6 weeks after transplantation for sugars to normalize.
WHAT’S THE EXPIRATION DATE?
When does it stop being PTDM and just occurrence of type 2 diabetes posttransplantation? If patients in the general population are followed for years, many of them may develop diabetes over time. There is currently no recommended “end-date” to the diagnosis of PTDM. The significance of the impact of PTDM in the 1st-year after transplantation versus occurrence at a later time is simply not known.
How is posttransplant diabetes different from type 1 or type 2 diabetes mellitus?
- The timing of the onset of PTDM and the definition separate PTDM from type 1 and type 2 diabetes
- Unlike type 1 diabetes mellitus and type 2 diabetes, where the pathophysiology of PTDM is insulin deficiency and insulin resistance, respectively, in PTDM, the main pathophysiology is pancreatic beta-cell dysfunction. The use of immunosuppression is an added risk factor which adds to the existing pathophysiologic changes in PTDM
- The treatment of PTDM is different and the drugs approved conventionally such as sodium-glucose cotransporter-2 (SGLT2) inhibitors need to be re-evaluated before they can be routinely recommended in patients with PTDM
- The glycemic targets in type 2 DM are set based on the development of microvascular complications, with PTDM the concern is more for precipitation of cardiovascular events and these targets may need to be re-visited
- Complications of diabetes develop at a faster rate in PTDM rather than type 2 DM. Unfortunately, the data thus far do not show an improvement or decrease in these events with the treatment of diabetes.
THE PATHOPHYSIOLOGY OF POSTTRANSPLANT DIABETES MELLITUS
The traditional view of diabetes mellitus pathophysiology usually involves a combination of factors such as a deficiency of insulin coupled with insulin resistance. Insulin resistance is defined as “any situation where the ability of insulin to exert its biological actions on the target tissues is diminished.” This may involve the liver, adipose tissue, or skeletal muscle.
A new concept with regard to the pathophysiology of PTDM is a beta-cell-centric view of PTDM. In patients who have an impaired glucose tolerance, this theory states that about 80% of pancreatic beta cells are already dysfunctional. The added insult of the transplants worsens this stress and precipitates PTDM. Not all patients with normal or impaired GTT have a normal pancreas. Some of the pancreatic beta cells may not be apoptotic but just de-differentiated. Maintaining a weight target and decreasing glucotoxicity may help cells to regain function. The converse is also true. It is interesting to note that in the setting of PTDM, both impaired GTT and PTDM carry almost the same mortality risk!!
RISK FACTORS FOR POSTTRANSPLANT DIABETES MELLITUS
Risk factors for the onset of PTDM are classified as modifiable and nonmodifiable [Figure 2]. It may also be classified based on the timing postrenal transplant [Figure 3]. PTDM occurs at two peaks posttransplant. One is the immediate posttransplant period over the initial 3 to 6 months, the other is after the first 2 to 3 years. While the first peak is usually due to the intense immunosuppression used at this time, the second one is most likely due to metabolic risk factors.
Immunosuppression is a potent risk factor in the development of PTDM. Each of the diabetogenic drugs has a different mechanism by which it induces PTDM [Figure 4].
MANAGEMENT OF POSTTRANSPLANT DIABETES MELLITUS
Evaluation of posttransplant diabetes mellitus
HbA1c is not used in the diagnosis of PTDM in the initial 3 months since both hemoglobin and graft function fluctuate widely during this time [Figure 5]. Some centers routinely do OGTT at 3 months. This is the ideal method of screening. However, it is cumbersome and not widely adopted.
Prevention of posttransplant diabetes mellitus
The first step in prevention is identifying the risk factors for disease. Some genetic predispositions can be identified by evaluating for interleukin-6 mutations and several other single nucleotide polymorphisms. However, no single gene has been implicated in PTDM diagnosis. Genetic evaluation is cumbersome and expensive and may not yield good results. A detailed and thorough family history may be helpful in this regard.
Chakkera et al. had suggested a risk score to identify at-risk patients for PTDM. This risk score included a total of seven variables, such as immunosuppressive use, age at transplantation, pretransplant factors such as body mass index, serum fasting glucose, serum fasting triglyceride, use of anti-gout medicines pretransplant, and family history of diabetes. This score has been subsequently validated in other cohorts. The score is no longer comprehensive as our knowledge of PTDM has expanded to add on several other risk factors. The need of the hour is to identify those at high risk of PTDM and use preventive strategies meticulously.
Types of preventive strategies
- One study suggested that the number of vegetables consumed in the diet was inversely proportional to the incidence of PTDM. However, such diets are also difficult to impose among dialysis patients considering the high potassium content in the vegetables
- Weight reduction is also a controversial topic among dialysis patients since the concept of “reverse epidemiology” is often applied to this population with regard to mortality risk
- Active lifestyle interventions, rather than more passive ones, have been proven to be effective to decrease fat mass and cause weight reduction after renal transplantation. This was shown in the “comparing glycemic benefits of active versus passive lifestyle intervention in kidney allograft recipients” study
- Gut dysbiosis has also been implicated in the development of PTDM. A diminished number of bacteria which produce butyrate have been associated with an increase in PTDM
- Bariatric surgery in obese patients has also been seen to decrease the incidence of PTDM.
Pharmacological approach to prevention
This involves intensively treating patients who develop early postoperative hyperglycemia.
In a study done by Hecking et al., patients with posttransplant hyperglycemia were classified into two groups. One group of 24 patients was treated aggressively with insulin if evening glucose was more than 140 mg/dl; the other group, however, were allowed a less stringent target and sugars were allowed up to 180 mg/dl before intervention was addressed. For the next year, it was noted that patients in whom glycemic targets had been stringent had a lesser incidence of PTDM. More recently, the insulin therapy for the prevention-NODAT study was done which also addressed the same issue of the use of insulin in the immediate posttransplant period. This study had some serious protocol violations. However, the per-protocol analysis of this study also yielded the same result whereby in patients in whom tighter glycemic goals were achieved in the immediate posttransplant period, the incidence of PTDM was lower. These two studies introduce the concept of “beta-cell rest” whereby, beta cells allowed rest in the initial posttransplant days function better later, thereby decreasing the incidence of PTDM.
NOVEL ANTIDIABETIC AGENTS IN THE MANAGEMENT OF POSTTRANSPLANT DIABETES MELLITUS
Sodium-glucose cotransporter-2 inhibitors in the management of posttransplant diabetes mellitus
Figure 6 addresses the issues associated with the use of SGLT2 inhibitors in renal transplant.
The worry in using SGLT2 inhibitors in the management of PTDM is that there may be an:
- Increased incidence of (urinary tract infection [UTI]) considering the intense immunosuppression prescribed to the patient
- Glomerular filtration rate (GFR) may decrease initially after initiation due to tubule-glomerular feedback
- Osmotic diuresis may occur causing dehydration particularly if oral fluid intake is not adequate.
Two trials have been published to date on the use of SGLT2 inhibitors in renal transplantation. One is the empagliflozin in posttransplantation-DM study done in Vienna where empagliflozin was used to replace insulin therapy among those with PTDM on insulin with a GFR of >30 ml/min and HbA1c of <8.5 mg%, particularly if the insulin use was <40 units per day. In this study, the glycemic control was found to be inadequate with the use of empagliflozin alone. Six of the 14 patients withdrew from the trial owing to inadequate glycemic control and two patients also developed UTI episodes. A few months after this trial was published, a randomized controlled trial (RCT) on the use of empagliflozin was published by the empagliflozin-renal transplant study group. The study was done in Oslo in 24 patients with stable PTDM were recruited, 1 year after the diagnosis was made. In this study, there were no patient withdrawals. Empagliflozin was used as monotherapy and other drugs were added on and titrated according to glycemia targets. There were no significant UTI episodes.
In conclusion, there is insufficient evidence as to whether SGLT2 inhibitors can be safely used in the setting of renal transplantation. On the one hand, the high incidence of cardiovascular events in PTDM makes SGLT2 inhibitors an ideal drug for cardiovascular disease prevention in this setting. On the other hand, the worry of UTI, osmotic diuresis, and initial drop in GFR need to be addressed.
GLUCAGON-LIKE PEPTIDE-1 AGONISTS IN RENAL TRANSPLANTATION
Most of the evidence of glucagon-like peptide-1 (GLP-1) agonists in renal transplant is from case series. As a whole, GLP-1 agonists appear to be able to safely reduce HbA1c and cause weight loss. They have no significant interactions with immunosuppressives like calcineurin inhibitors (CNI) either. However, GLP-1 agonists have the potential to decrease oral intake due to significant gastrointestinal side effects. They suppress central appetite and also delay gastric emptying. In the transplant setting, the combined use of these agents along with mycophenolic acid (MPA) compounds may cause increasing deleterious effects on oral intake. Keeping these adverse effects in mind, in the transplant setting these drugs are not prescribed solely for weight loss. Their cardioprotective and immunomodulatory properties in the transplant setting are not known and are areas of future research.
DIPEPTIDYL PEPTIDASE 4 INHIBITORS
Dipeptidyl peptidase-4 inhibitors (or gliptins) have been well-studied in renal transplant recipients and have been found to be safe and effective. RCTs have also been done in this setting. Gliptins significantly reduce HbA1C and contribute to better weight loss. They have also been shown to improve insulin resistance and reduce insulin requirement. However, its effect on reducing albuminuria in the posttransplant setting is unknown.
OTHER ANTIDIABETIC AGENTS IN POSTTRANSPLANT DIABETES MELLITUS
Metformin is the first-line agent for use in PTDM. This agent is both inexpensive and effective in the management of PTDM. At GFR <30 ml/min/1.73 m2 the use of metformin is contraindicated. At GFR <45 ml/min1.73 m2, metformin dose is generally reduced with an increased risk of lactic acidosis as the GFR declines. Sulphonylureas also have been safely used in PTDM.
MODULATION OF IMMUNOSUPPRESSION IN POSTTRANSPLANT DIABETES MELLITUS
Among the immunosuppressive medications used in renal transplant, the most diabetogenic are tacrolimus and steroids. Cyclosporine and mechanistic/mammalian target of rapamycin (mTOR) inhibitors follow close behind.
Tacrolimus is more diabetogenic than cyclosporine. This was shown in the DIRECT study where over a short-term follow-up of 6 months, insulin secretion was markedly lower in the cyclosporine group compared with the tacrolimus cohort. The issue however with switching from tacrolimus to cyclosporine for the purpose of treatment of PTDM is that there appears to be a higher probability of rejection among those treated with cyclosporine rather than tacrolimus, although the incidence of PTDM is lower. In general, there appears an increased risk of poorer graft function among people taking cyclosporine rather than tacrolimus, the latter being a more powerful immunosuppressive agent. Hence, switching from tacrolimus to cyclosporine solely for mitigating the risk of PTDM is not supported by the literature.
When mTOR inhibitors were introduced, it was thought that they would be less diabetogenic than CNI. However, this was quickly disproved. In the symphony trial, patients treated with sirolimus developed PTDM at a rate in-between those of patients receiving cyclosporine and tacrolimus. The mTOR inhibitors were unfortunately also associated with noncancer mortality and an increased risk of rejections when they were substituted for CNI. Hence, this practice is no longer recommended.
Belatacept brought with it a draft of fresh air with regard to glucose metabolism. Switching from tacrolimus to belatacept appears to be associated with better glucose tolerance and the removal of anti-diabetic agents.
Steroid withdrawal is a controversial topic with regard to PTDM. On the one hand, a Cochrane metanalysis published in 2016 that included most of the major trials that had been carried out till then, found no significant difference in the incidence of PTDM among those maintained at a low dose of steroid compared with those in whom steroids were completely withdrawn. On the other hand, the Harmony trial published subsequently showed that rapid steroid withdrawal was associated with a reduced PTDM incidence. There is insufficient evidence on the matter of steroid withdrawal and PTDM, although early and rapid withdrawal may be useful. There exists some debate as to whether spilled dosing of steroids may reduce the glycemic variability caused by steroids. More research is needed in this area.
The bottom line: Immunosuppression is to be decided solely based on the immune risk of the patient regardless of the risk of PTDM.
TARGETS OF TREATMENT
The Kidney Disease: Improving Global Outcomes (KDIGO) suggests maintaining HbA1c between 7% and 7.5%, whereas the ADA recommends HbA1c <7% for most patients with 3 monthly monitoring. HbA1c should be checked every 3 months. KDIGO 2014 guidelines also recommend statins to all transplant patients based on the Assessment of Lescol in Renal Transplantation trial. KDIGO also recommends keeping the blood pressure well controlled with a target of 130/80 mmHg.
PROGNOSIS AND SURVIVAL OF KIDNEY TRANSPLANTATION RECIPIENTS WITH POSTTRANSPLANT DIABETES MELLITUS
PTDM is associated with decreased overall patient survival in most studies. There also appears to be increased cardiovascular mortality among patients with PTDM. Allograft survival is also decreased. Acute rejection is the most important cause of allograft loss and appropriate immunosuppressive levels must be maintained. Diabetic kidney disease in the allograft may also contribute to graft loss.
PTDM is a distinct entity from type 2 diabetes mellitus. Its pathophysiology is multi-factorial. However, recent data suggest a beta-cell-centric model. Treatment depends on the timing of diagnosis. Newer drugs like SGLT2 inhibitors will need more studies before being used in PTDM. Immunosuppression should be tailored according to the immune risk of the patient rather than the risk of PTDM.
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Conflicts of interest
There are no conflicts of interest.
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