People with end-stage kidney disease achieve better quality of life and survival rates with a kidney transplant than with dialysis, but if they develop posttransplant diabetes mellitus (PTDM), they are at high risk for rapidly developing cardiovascular disease or other complications. Maria Paula Martinez-Cantarin, MD, a nephrologist and researcher at Thomas Jefferson University, describes how physicians can manage PTDM and prevent complications.

Q: What is posttransplant diabetes mellitus, and how common is it in the United States?

A: Posttransplant diabetes mellitus is diabetes that is diagnosed after a solid organ transplant. PTDM used to be known as new-onset diabetes after transplantation, but in 2013, an international consensus panel recommended changing the name to PTDM, as we understand that some of the patients that are diagnosed with PTDM had diabetes before the procedure and did not know it. In fact, approximately 10% of patients with PTDM had diabetes that was not diagnosed before the transplant.

Estimates of PTDM prevalence vary due to studies using different populations and diagnostic criteria. However, PTDM affects between 10% and 30% of patients who receive a kidney transplant and is most commonly diagnosed during the first year after transplant.

Q: What are the risk factors for developing PTDM?

A: There are unrelated and transplant-related risk factors for PTDM.

Risk factors that are unrelated to the transplant are the same as the ones for type 2 diabetes, including age, family history, excessive fat in the abdomen, metabolic syndrome, impaired glucose tolerance, or being Black/African American, Hispanic/Latino, American Indian, Alaska Native, Asian American, or Pacific Islander.

Transplant-related risk factors include

• Immunosuppressants such as calcineurin inhibitors (cyclosporine and tacrolimus), mammalian target of rapamycin (mTOR) inhibitors, and corticosteroids that help prevent organ rejection but may affect pancreatic beta cells and increase insulin resistance. Some studies have also linked low magnesium, a side effect of calcineurin inhibitors, to onset of PTDM.
• Weight gain. After kidney function is restored, it is very common for patients to gain weight as the lack of appetite that occurs in people with advanced kidney disease resolves. This, in addition to many patients already being overweight or having obesity before the transplant, becomes an important risk factor. 
• Inflammatory markers such as tumor necrosis factor alpha and low levels of adiponectin, a hormone that has anti-inflammatory and anti-diabetic functions.
• Infections by the cytomegalovirus or chronic infection by the hepatitis C virus.

Q: What are the main complications of PTDM?

A: Patients with PTDM develop the same complications that we see in patients with other types of diabetes but more rapidly. Main complications include heart attack, stroke, peripheral vascular disease, kidney disease, and premature death. Interestingly, and despite the risk of macrovascular disease and death, developing PTDM does not seem to have an important effect on kidney longevity, so the number of years that a transplanted kidney will survive, after discounting the functional transplants that are lost due to the patients’ death, is similar whether the person has PTDM or not.

Q: Are there specific tests that health care professionals should use to diagnose PTDM, and how long after transplantation should they wait to diagnose the disease?

A: To diagnose PTDM, we use many of the same tests that we use for other types of diabetes. It is important to know that high blood glucose after a transplant is very common, especially right after surgery, because of stress, inflammation, nutrition delivered through a vein or with a tube in the stomach, steroids, infection, and organ rejection.

Time for diagnosis may vary, but most physicians agree that it is appropriate to wait at least 3 months before making a diagnosis of PTDM. We often rely on the fasting plasma glucose test, but since we tend to see abnormal glucose levels more often after lunch, the best test for the diagnosis of PTDM is the oral glucose tolerance test. However, we know this test is not easy to do, so we only use it for patients that are at high risk.

The hemoglobin A1C test is not very reliable soon after transplant, especially if the results are low. Red blood cell numbers may change because of kidney dysfunction, or because medicines can decrease or increase red blood cell production, making hemoglobin A1C a less accurate test.

Q: What should health care professionals consider when treating PTDM?

A: There are few studies of the PTDM population that can tell us the ideal blood glucose targets to decrease risk of future complications. We assume that the medicines used for other types of diabetes work the same in PTDM, but we do not have robust evidence to support this. Three important things to remember about medicines for diabetes before starting treatment in a patient with PTDM are drug interactions, side effects, and kidney function.

• Drug interactions between immunosuppressants and hypoglycemic medicines need to be noted. Calcineurin inhibitors (CNIs) are metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme, so any medicines for diabetes treatment that interact with the CYP3A4 could alter immunosuppressants levels. For example, some of the dipeptidyl peptidase 4 (DPP-4) inhibitors affect CNI levels. 
• Side effects of the immunosuppressants can add to the side effects from other medicines and make them worse, such as gastrointestinal side effects from metformin. High blood glucose can be a side effect of immunosuppressants. We do not recommend changing the immunosuppressants just to manage blood glucose levels, because you can increase the risk of losing the new kidney.
• Kidney function does not recover 100% after transplant, so when adding a new medicine, always consider if it is eliminated in the kidney.

Q: What can health care professionals do to help prevent PTDM in patients receiving an organ transplant?

A: Weight management education may help prevent PTDM since more than 25% of waitlisted kidney transplant candidates have a BMI between 30 and 35, and 17.8% have a BMI of 35 or more, according to a 2019 report by the Scientific Registry of Transplant Recipients. Counsel patients on losing weight and preventing weight gain after the transplant to avoid complications. We need more data to understand the role of bariatric surgery in managing PTDM. Insulin use in early management of posttransplant blood glucose levels that are higher than 140 mg/dL reduces stress and deterioration of the pancreatic beta cells and reduces the risk of PTDM.

Q: What research is being conducted on PTDM?

A: Three main areas of research are treatment; prevention; and pathogenesis, or the changes in the body that lead to the disease. 

• Treatment. There are clinical trials testing sodium-glucose cotransporter-2 (SGLT2) inhibitors in kidney transplant recipients to evaluate if the positive cardiovascular effects we see in patients with other types of diabetes will also happen in patients with PTDM, and to study the use of SGLT2 inhibitors for the prevention of damage to kidney tissue.
• Prevention. Some clinical trials are testing DPP-4 inhibitors, such as vildagliptin and sitagliptin, as well as other medicines like metformin, to see if they effectively prevent PTDM.
• Pathogenesis. Some research groups are working on understanding the effect of calcineurin inhibitors on pancreatic beta cell function and the molecular changes. Our group is studying pretransplant inflammation, including adiponectin resistance, and progression to PTDM. Understanding these mechanisms may lead to development of new medicines that can work in these specific pathways.