Understanding NODAT: Diabetes Post-Kidney Transplant

Transplant recipients can develop diabetes as a complication of transplantation

Kidneys
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While diabetes mellitus is a fairly common and well understood disease, few people know that diabetes can develop as a new bona fide complication in patients who receive a kidney transplant. Anybody with kidney failure considering kidney transplantation as treatment for kidney disease should be aware of this risk, better known as new-onset diabetes after transplant (NODAT).

While the risk is there, it's important to realize that not everybody is at risk, and those who are have treatment options should diabetes post-kidney transplantation develop.

How Common Is NODAT?

NODAT is a recognized problem in a significant number of patients who receive a kidney transplant. However, clear statistics on this number are not available. This is because there was no standardized definition of  NODAT for a long time, until 2003. Hence, depending on how you define NODAT, the incidence could vary.

Some studies seem to suggest that almost 30 percent of those who did not have diabetes prior to receiving a kidney transplant could develop persistent elevation in blood sugar levels suggestive of NODAT by six months after their kidney transplantation. This is clearly a significant number, suggesting that counseling about NODAT should be an integral part of care of kidney failure patients interested in getting a kidney transplant.

What Is the Impact of NODAT?

Newly developed diabetes after receiving a kidney transplant has wide-ranging effects, some of which are also seen in the typical person with diabetes.

Therefore, these people are susceptible to develop certain complications. A few examples include:

  • Ketoacidosis: increased ketone and acid levels in the blood seen in patients with deficiency of insulin, which can lead to profound dehydration and electrolyte disturbances, and elevated blood sugars. The affected patient is usually critically ill.
  • Neuropathy: that "pins and needles" sensation in hands and feet that afflicts poorly controlled diabetes.
  • Higher risk of infection since elevated blood sugar is a known cause of suppression of the immune system. This in turn can manifest as increased frequency of urinary tract infections, skin infections, lung infections, etc.
  • More specifically, NODAT will have an adverse effect on not just the patient's lifespan and risk of death, but also survival of the transplanted kidney. To put it in other words, a kidney transplant recipient who develops NODAT may have a shorter lifespan and see the transplanted kidney fail sooner as well.

    How big is this impact? Well, as per a study from the State University of New York, while survival for patients without diabetes at the end of five years after kidney transplantation was 92 percent, it was much less at 87 percent in recipients who did develop NODAT. Similarly, there has been evidence from studies that shows that survival of the transplanted kidney is shortened, should the recipient develop diabetes after receiving a kidney transplantation.

    Why Does NODAT Develop? What Are the Risk Factors?

    Although the impact is significant, note that not every kidney failure patient who received a transplanted kidney develops diabetes as a post-transplant complication. Certain medications and other risk factors do increase the likelihood of a particular patient developing NODAT. Some of these include:

    • Medications: these include glucocorticoids (e.g., prednisone) and other drugs that we use to suppress the immune system of a transplant recipient in order to prevent rejection of the transplanted kidney (since the recipient's immune system sees that kidney as a "foreign entity"). Examples of these medications include a class of drugs called "calcineurin inhibitors" (for instance tacrolimus and cyclosporine, the former being more likely to cause diabetes), and sirolimus. Please note that not all transplant rejection prophylaxis medications necessarily increase risk of NODAT (these include other common post transplant immunosuppression medications like mycophenolate mofetil, also known as CellCept).
    • Infections are a known cause. These include Hepatitis C virus (HCV), cytomegalovirus (CMV) infection.
    • In addition to the above specific drug/infection related risk factors, African-American race, obesity, and a family history of diabetes do increase risk of NODAT.

    Balancing the Risk of Rejection With the Risk of NODAT: A Catch 22 Situation

    As might be obvious from the above discussion, the same medications that we utilize to maintain adequate level of suppression of the recipient's immune system (so that they do not reject the new transplanted kidney), also increase the risk of diabetes. In other words, would you rather risk rejecting the organ, or would you rather risk developing diabetes? Either way, you might feel like you're putting the health of your transplant kidney, your new lease of life, in jeopardy. Balancing these two competing priorities is clearly important, so how do you deal with it?

    Here is the take home message: Rejection of the transplanted kidney is still the biggest factor that determines its ability to survive and work in a patient, even more than risk of newly developed diabetes

    Hence, most guidelines suggest prioritizing adequate immunosuppression to prevent rejection, even if it means an increase in risk of the transplant recipient developing NODAT.

    How Is NODAT Diagnosed?

    Since we do have a fair understanding of risk factors that increase the risk of NODAT, monitoring high risk patients is highly recommended. A good transplant center will counsel you about the risk of NODAT even before they receive the kidney so that you can make an informed decision.

    However, once you are being monitored after receiving the transplanted kidney, the following definitions will apply in order to diagnose new-onset diabetes after transplantation. These definitions have been set forth by an international expert panel:

    • Symptoms of diabetes in addition to random plasma glucose level greater than 200 mg/dL
    • Fasting plasma glucose greater than or equal to 126 mg/dL
    • 2-hour plasma glucose greater than or equal to 200 mg/dL during an oral glucose tolerance test
    • You might also be familiar with a common test called glycosylated hemoglobin A1c, which we use for diagnosis of diabetes in the general population. Its use as a diagnostic tool is not recommended during the first three months after a kidney transplant. However, after that, the same definition for diagnosis of diabetes as used in the general population applies. This would be a hemoglobin A1c levels greater than or equal to 6.5 precent in order to diagnose NODAT.

    Approach to Managing NODAT: The Initial Conservative Management

    Should you develop NODAT (especially in the setting of the above mentioned risk factors), a conservative approach is first instituted in order to treat elevated blood sugars. Here are some things to know:

    • Active surveillance for NODAT is obviously a part of standard care of the kidney transplant recipient. Blood sugar is measured as often as once a week at least for the first month, although the frequency of testing can be reduced later.
    • One of the ways to reduce the risk of NODAT, as well as reduce its severity once it has already developed, is to aim for a reduction in the dose of steroids (one of the linchpins of rejection prophylaxis medications). However, since the risk of rejecting a transplanted organ goes up significantly if steroids are stopped altogether, complete cessation is usually not recommended.
    • Similarly, the dose of tacrolimus (another common immunosuppression drug), as allowed by rejection risk, may be considered for reduction. If all else fails and the patient is having other signs/symptoms of NODAT, a switch to a similar medication called cyclosporine may become necessary.

    Approach to Managing NODAT: Definitive Medical Therapy

    If the above described conservative management does not help and diabetes continues to develop and worsen after kidney transplantation, the transplant recipient with newly developed diabetes might require specific management with diabetes medications. Just like any other person with diabetes, we typically start with oral medications.

    Common examples include a drug called glipizide (sometimes preferred because its excretion from the body does not depend too much on the kidneys' function; if that weren't the case, diabetes medications could accumulate to high levels in kidney disease patients and cause dangerously low blood sugar levels). If one medication is not sufficient, other medications are added until finally, subcutaneous insulin injections might become necessary to control the blood sugar levels adequately.

    Can You Prevent NODAT From Developing?

    Knowing the risk, you're likely also wondering whether there's anything you can do to reduce it. As a side note, some institutions do transplant the pancreas (the organ where insulin is produced and whose abnormalities can cause diabetes) simultaneously with the kidney in patients who have end-stage diabetic kidney disease. They are some studies which show that such a procedure results in a better and a longer lifespan.

    This is related in a big way to improved control of type 1 diabetes (which borders almost on a complete "cure" of the disease as a result of the transplanted pancreas), but there are yet no cases of such an approach having been tried in the case of NODAT, for the obvious reason that by definition, a NODAT patient would not have diabetes pre-transplant.

    A Word From Verywell

    Overall, the risk of developing NODAT may be difficult to accept and may cast doubt over whether you should go through the procedure. Make sure to bring up and discuss your concerns with your doctor. He or she will help you make the best decision for you. Oftentimes, given the management options if diabetes is developed, the quality of life post-transplant may outweigh the risk of NODAT.

    Sources:

    New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials.First MR, et al. Transplantation. 2013.

    New onset diabetes after transplantation (NODAT): an overview. Phuong-Thu T Pham. Diabetes Metab Syndr Obes. 2011.

    New-Onset Diabetes after Kidney Transplantation: Risk Factors. Emilio Rodrigo. Journal of American Society of Nephrology. 2006.

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