By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
February, 2012
In recent years, complications other than rejection after organ transplantation have received increasing attention because of their effects on morbidity and mortality. This is especially true in kidney and heart transplantation, where the incidence of rejection has been minimized and metabolic complications such as diabetes and high blood pressure affect graft function over time. Similarly, although rejection remains the primary obstacle to better long-term outcomes after lung transplantation, diabetes has a significant impact on morbidity and quality of life. Complications of diabetes include stroke, heart attack, kidney failure, vision loss, peripheral vascular disease and infections. The prevalence of diabetes in the general population in the United States varies from 5 to 15%, and this has been increasing as the incidence of obesity has been increasing. Approximately 25% of lung transplant recipients develop diabetes within one year of transplantation, and the incidence increases to 35% to 40% within five years of transplantation.
Diabetes is a metabolic disorder characterized by abnormally high blood sugar. It develops as a result of either a lack of production of sufficient amounts of insulin or a resistance to the effects of insulin. Insulin, a hormone produced by the pancreas, plays a central role in carbohydrate and fat metabolism. It stimulates the uptake of glucose by various tissues including the liver, fat, and muscle. In type-1 diabetes, pancreatic beta cells do not secrete insulin as a result of autoimmune inflammation. This results in chronically elevated blood sugar, which is spilled in the urine causing frequent urination, increased thirst, and weight loss. Type-1 diabetics are insulin-dependent and cannot be treated with oral medicines. In type-2 diabetes, the pancreas secretes insulin, but the cells that normally take up glucose are resistant to the effects of insulin. The result is similar to type-1 diabetes with high blood sugar resulting in the same symptoms. However, type-2 diabetics can be managed with exercise, weight loss, dietary modifications, and oral medicines if necessary, although treatment with insulin is also sometimes necessary.
The medical regimen after transplantation increases the risk of diabetes. Prednisone can cause insulin resistance, and this is true for all steroids. The effect is most pronounced on blood sugar measurements after meals while the early morning fasting measurements often remain in the normal range. The effect of prednisone on blood sugar is dose-dependent, but doses as low as 10 mg a day or less increase the risk of diabetes almost two fold. In addition, weight gain is another side effect of prednisone and this exacerbates the insulin resistance. Furthermore, tacrolimus is also diabetogenic and this effect is directly associated with blood levels. In general, it is thought that the risk of diabetes is higher with tacrolimus than cyclosporine. However, tacrolimus is more effective in preventing and treating rejection, and it has supplanted cyclosporine as the calcineurin inhibitor of choice at most lung transplant centers. Lastly, sirolimus, which is structurally similar to tacrolimus, is also diabetogenic, and its effects on insulin resistance may be more pronounced than tacrolimus or cyclosporine. In contrast, azathioprine and mycophenolate mofetil are not known to cause or exacerbate diabetes independently.
All patients are screened for diabetes after transplantation with fasting blood sugar measurements. Additionally, patients routinely have their blood sugar measured before meals in the immediate period after transplantation because the steroid doses are typically highest in the first few weeks. At this stage, diabetes is usually managed with sliding scale insulin, and the dose requirement often predicts the need for ongoing treatment as the prednisone dose is reduced. In some cases, prednisone is tapered to lower doses more rapidly than usual to improve glycemic control, but this approach needs to be balanced with the risk of rejection. Furthermore, while some patients require insulin in the first few months after transplantation, this may be withdrawn as the prednisone dose is tapered and the targeted tacrolimus levels are reduced. In addition to insulin, a number of oral agents are available and can be tried. Lifestyle modifications are also critical to managing diabetes. Exercise and weight loss ameliorate the insulin resistance associated with obesity, and dietary modifications are important. Formal diabetic education is usually necessary to instruct patients how to check their blood sugar, inject insulin if necessary, and the symptoms of hypoglycemia. Finally, regular screening for the complications of diabetes including annual eye exams and urine tests is necessary.