Managing and preventing diabetes after an organ transplant

Complications of post-transplant diabetes mellitus can develop quickly, but proper management can prevent them.

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 post-transplant diabetes mellitus (PTDM), they are at high risk quickly develop cardiovascular disease or other complications. Maria Paula Martinez-Cantarin, MD, a nephrologist and researcher at Thomas Jefferson University, describes how doctors can manage PTDM and prevent complications.

Q: What is post-transplant diabetes mellitus and how common is it in the United States?

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

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

Q: What are the risk factors for developing PTDM?

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

Risk factors that are not related to the transplant are the same as those for type 2 diabetes, including age, family history, excess fat in the abdomen, metabolic syndrome, intolerance to glucose or being Black/African American, Hispanic/Latino, Indian American, Alaskan Native, Asian American, or Pacific Islander.

Transplant risk factors include

  • Immunosuppressants such as calcineurin inhibitors (cyclosporine and tacrolimus), mammalian target of rapamycin (mTOR) inhibitors and corticosteroids which help prevent organ rejection but may affect pancreatic beta cells and increase resistance to ‘insulin. Some studies have also linked low magnesium, a side effect of calcineurin inhibitors, to the onset of PTDM.
  • Weight gain. Once 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 subsides. This, in addition to the fact that many patients were already overweight or obese 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 cytomegalovirus or chronic hepatitis C virus infection.

Q: What are the main complications of PTDM?

A: Patients with PTDM develop the same complications seen in patients with other types of diabetes, but more quickly. Major complications include heart attacks, strokes, peripheral vascular disease, kidney disease, and premature death. Interestingly, and despite the risk of macrovascular disease and death, the development of PTDM does not appear to have a significant effect on kidney longevity, hence the number of years a transplanted kidney will survive, after discarding functional grafts lost to patients. ‘death, is similar whether or not the person has PTDM.

Q: Are there specific tests that healthcare 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 hyperglycemia after a transplant is very common, especially right after surgery, due to stress, inflammation, nutrition given through a vein or with a tube in the stomach, steroids, infections and organ rejection.

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

The hemoglobin A1C test is not very reliable soon after the transplant, especially if the results are low. The red blood cell count can change due to kidney dysfunction or because medications can decrease or increase red blood cell production, making hemoglobin A1C a less accurate test.

Q: What should healthcare professionals consider when treating PTDM?

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

  • Drugs interactions between immunosuppressants and hypoglycemic drugs should be noted. Calcineurin inhibitors (CNIs) are metabolized in the liver by the enzyme cytochrome P450 3A4 (CYP3A4), so any diabetes medication that interacts with CYP3A4 could alter immunosuppressant levels. For example, some of the dipeptidyl peptidase 4 (DPP-4) inhibitors affect CNI levels.
  • Side effects immunosuppressants can add to and make the side effects of other medications worse, such as the gastrointestinal side effects of metformin. High blood sugar can be a side effect of immunosuppressants. We do not recommend switching immunosuppressants just to manage blood sugar, as you may increase the risk of losing the new kidney.
  • Kidney function does not recover 100% after transplant, so when adding new medication, always consider whether it is eliminated in the kidney.

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

A: Weight management education can help prevent PTDM since more than 25% of kidney transplant candidates on the waiting list have a BMI between 30 and 35, and 17.8% have a BMI of 35 or more, according to 2019 Report of the Scientific Registry of Transplant Recipients. Counsel patients on weight loss and prevention of weight gain after transplant to avoid complications. We need more data to understand the role of bariatric surgery in the management of PTDM. The use of insulin in the early management of post-transplant blood glucose levels above 140 mg/dL reduces stress and pancreatic beta cell damage and reduces the risk of PTDM.

Q: What research is being done on PTDM?

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

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

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