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  • In hepatitis C virus infected liver recipients the prevalence of NODAT has been reported to range between 40-60%.
  • *Sixty-six percent of patients without diabetes before transplantation developed inpatient hyperglycemia and required insulin at hospital discharge. Inpatient hyperglycemia was associated with a fourfold increase in the development of NODAT (14,15). **Statistics from refs. 1 and 2. †Statistic from ref. 3.
  • In addition to the known pitfalls of the HbA1c test (44), any blood transfusion at the time of transplantation would make HbA1c levels uninterpretable.
  • risk factors for diabetes (Table 1) should be probed once individuals are placed on the transplant registry. Patients with risk factors for diabetes
    (Table 1) should receive counseling on weight control, diet, and exercise during the pretransplant period (12). In addition, other cardiometabolic risk factors
    (hypertension, dyslipidemia, smoking) should be addressed.
  • Similarly, the glycemic targets recommended for non-critically ill patients treated with insulin [premeal blood glucose values< 140 mg/dl (<7.8 mmol/liter) and random glucose values <180 mg/dl (<10.0 mmol/liter)], may be used as a guide, given the lack of specific data for posttransplant patients.
  • For example, although metformin has been used in the post-kidney transplant population, patients with unstable glomerular filtration rate during the posttransplant period may be at increased risk of developing lactic acidosis. Sulfonylureas are associated with weight gain and hypoglycemia. The latter can be severe, prolonged, and potentially fatal in elderly and frail patients and those with limited hepatic function. The glucagon-like peptide-1 (GLP-1) agonists
    and the dipeptidylpeptidase (DPP)-4 inhibitors are less likely to induce hypoglycemia compared with sulfonylureas. The GLP-1 agonists are associated with decreased gut motility, nausea, and occasional emesis, which may interfere with the oral posttransplant immunosuppressive regimens.
  • Nodat

    1. 1. Dr.Robin Maskey,MD,Internal Medicine Fellow, Endocrinology Sir Gangaram Hospital
    2. 2.  Introduction  Epidemiology  Defination and Diagnosis of NODAT  Pathogenesis of NODAT  Risk Factors for NODAT  Sequelae of NODAT  Management  Controversies and Areas of Uncertainty
    3. 3.  Posttransplant diabetes, or new-onset diabetes after transplantation(NODAT), is observed after transplantation of kidney, liver, lung, heart, and other solid organs, as well as bone marrow and hematopoietic stem cells.  Also as Secondary type of diabetes mellitus  Among renal transplant patients, the risk of NODAT peaks within the first year, with incidence rates as high as 15%;thereafter, the annual incidence rate falls to6%. (J Clin Endocrinol Metab 96: 3289–3297, 2011 )
    4. 4. • The incidence of NODAT ranges from approximately 4% to 25% of renal allograft,2.5 to 25% of liver transplant,4 to 40% of heart transplant and 30 to 35% of lung transplant recipients. • The variation is due to lack of standard defination, duration of follow up, presence of of risk factors and type of organ transplant. Diabetes,Metabolic Syndrome and Obesity:Targets and Therapy,2011:4 175-186
    5. 5. • The true incremental incidence of diabetes occurs mainly during the first 6 months posttransplantation, when patients are treated with high doses of immunosuppression.  Approximately 50% of people diagnosed with NODAT experience improvement in glucose tolerance after the immunosuppressive agents have been decreased or tapered to maintenance doses. • The most accurate incidence of NODAT under calcineurin inhibitor (CNI) therapy is provided by the prospective study of Vincenti et al. reporting an incidence of NODAT reaching 20.5% within the first 6 months postrenal transplantation (J Clin Endocrinol Metab 96: 3289–3297, 2011 )
    6. 6. DIABETES CARE,VOLUME 36,MAY 2013
    7. 7. WHO AND 2003 updated ADA criteria :  Symptoms of diabetes mellitus + casual PG ≥200mg/dl(11.1 mM) or  FPG ≥ 126 mg/dl (7.0 mM) or  2-hr PPG ≥200mg/dl(11.1 mM) during OGTT  The use of glycosylated hemoglobin (HbA1c) for diagnosis of diabetes or prediabetes during the peritransplant period is not recommended. Diabetes,Metabolic Syndrome and Obesity:Targets and Therapy,2011:4 175-186
    8. 8. DIABETES CARE,VOLUME 36,MAY 2013
    9. 9. Immunosuppressive agents Pathogenic mechanisms Comments Corticosteriods • Decrease Peripheral insulin sensitivity •Inhibit pancreatic production & secretion •Increase Hepatic gluconeogenesis •lipolysis Cyclosporine •Decreased insulin secretion(CsA>Tac) •Decreased insulin synthesis •Decreased β cell density •Dose dependant •Impact of complete withdrawl of ch low dose steriods unclear •Potenital NODAT risk decreased in steroid free regimens •Dose dependant •Diabetogenic effect increased with increase steroid dose Tacrolimus •Decreased insulin secretion Same as cyclosporine Sirolimus •Impair pancreatic β cell response •increased Diabetogenic effect with CNIs
    10. 10.   In addition to the risk of developing the well-known long term complications of diabetes, NODAT also identifies patients at high risk for adverse clinical outcomes: loss of the renal allograft, infections, cardiovascular events, and increased mortality among renal transplant patients  Among liver transplant recipients, NODAT is associated with increased cardiovascular morbidity and mortality, more fatal infections more neuropsychiatric complications, higher rejection rates, and poorer graft survival  Among lung transplant recipients, cytomegalovirus (CMV) infection and acute rejection episodes (J Clin Endocrinol Metab 96: 3289–3297, 2011 )
    11. 11. Pretransplant period  Document baseline blood glucose status  Assess diabetes risk factors  Identify high-risk subjects  Initiate lifestyle intervention  Dietary counseling  Exercise counseling J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
    12. 12. Insulin infusion can be used, as appropriate, to manage perioperative stress hyperglycemia.  Once patients begin to eat after surgery, the regimen can be changed to sc insulin (basal or basalbolus, as appropriate).  With a decline in postoperative stress and reduction of steroid doses, many patients can be weaned off insulin before discharge.  J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
    13. 13. Posttransplant period  Immunosuppressive regimen Minimize steroid dose Minimize calcineurin inhibitor exposure  Treat hyperglycemia beginning in the peritransplant period  Close follow-up of all patients, especially those with prediabetes J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
    14. 14.  Patients discharged without hyperglycemia should have FPG testing at least weekly during the first month, then every 3 months for 1 yr, and annually thereafter.  Once a blood glucose-based diagnosis of NODAT has been established in a patient who is more than 3 months posttransplant, the HbA1c can be used to monitor glycemic control .
    15. 15. Posttransplant period      For those who develop NODAT Diabetes education Appropriate medical therapy based on severity of hyperglycemia Surveillance for microvascular complications Optimize insulin therapy during episodes of high-dose steroid exposure Evaluate and control comorbid conditions Hypertension Dyslipidemia Hyperuricemia Other      J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
    16. 16.  Depending on the organ transplanted and the state of kidney, liver, and cardiac function, some oral antidiabetes drugs may be absolutely or relatively contraindicated. In such instances, insulin often becomes an early option.  Careful attention must be paid to the toxicity profiles of antidiabetes agents in the transplant population
    17. 17.  The pancreatic b-cell is exposed to several stressors immediately after kidney transplant surgery, including the surgical procedure itself, high-dose corticosteroids, and initiation of CNIs.  Thus, resting the b-cell with basal insulin and optimizing bcell protection with tighter control to near-normoglycemic treatment goals could further reduce the number of patients with future impaired glucose tolerance and NODAT.  The standard regimens (basal insulin, split-mix, basal-bolus) are all applicable in the management of NODAT.
    18. 18.  Steroid-sparing or steroid- free regimens appear to be associated with decreased risk of NODAT  Tacrolimus, a potent inhibitor of insulin secretion, has been associated with a greater risk of NODAT compared with cyclosporine  Belatacept, a selective inhibitor of T-cell activation, is a parenteral immunosuppressant that replaces CNIs. Studies suggest that transplant recipients who receive belatacept have a better metabolic profile and a lower incidence of NODAT compared with those who receive CNIs .
    19. 19. The calcineurin inhibitors cyclosporine and tacrolimus are known to increase cholesterol levels, so patients may require adjustment of statin dose after transplant.  Pravastatin and fluvastatin, which are not metabolized by CYP3A4, tend to be used preferentially in transplant patients with dyslipidemia.  Sirolimus and glucocorticoids are associated with hypertriglyceridemia that may require treatment with fibrates. 
    20. 20. The National Kidney Foundation recommends that blood pressure control be maintained at below 130/80 mm Hg in renal transplant recipients  The beta- blockers and calcium channel blockers appear to be well tolerated and effective .  Microalbuminuria is a predictor of renal allograft loss and increased mortality  Besides the risk of gout, hyperuricemia is associated with cardiovascular disease, inflammation, insulin resistance, and decreased renal graft survival 
    21. 21.  Primary prevention of NODAT  Optimal immunosuppressive regimen  Optimal glycemic management J Clin Endocrinol Metab, November 2011, 96(11):3289–3297
    22. 22.  The current recommendation is to identify high- risk patients during the pretransplant period.  Once identified, such highrisk subjects can empirically be offered lifestyle intervention to decrease obesity and increase physical ctivity, as appropriate.  The use of medications to prevent type 2 diabetes has been well documented in the general population,but not yet in transplant recipients
    23. 23.      Type 2 diabetes mellitus and NODAT share similar risk factors, especially obesity. Obesity prevention may also benefit patients who already have received a transplant because there is an observed weight gain of 10% during the first year after transplant . Earlier studies documented a survival benefit associated with higher BMI in dialysis patients . Recent studies suggest that it is higher muscle mass, rather than higher fat mass, that predicts longer survival in dialysis patients. Thus, a lifestyle intervention aimed at lowering fat mass may be appropriate for the prevention of NODAT.
    24. 24.  Toxicities from antirejection immunosuppressive medications constitute the strongest trigger for NODAT  Aiming for the lowest effective dose of corticosteroids in the posttransplant patient minimizes the risk of dysglycemia.  Also, there are limited data showing benefit of substituting cyclosporine for tacrolimus in immunosuppressive regimens
    25. 25.  NODAThas been identified as a risk factor for graft rejection, long-term graft failure, and decreased patient survival, the mechanisms linking hyperglycemia to these adverse outcomes remain to be determined.  Improved glycemic control decreases infections in liver transplant recipients
    26. 26.  NODAT is a common complication after solid organ transplant and has variably adverse impact on patient and allograft outcomes.  The most important risk factor predisposing to the development of NODAT is the immunosuppressive drugs.  Risk stratification and intervention to minimize risk should be integral part of the management of NODAT patients.
    27. 27.  Thank you