New-onset diabetes mellitus after solid-organ trans­plant makes for complicated tacrolimus immuno­suppression. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year-old women, hos­pitalized with diabetic ketoacidosis, 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. Clinicians should be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant as with other solid-organ transplants.

Key words : Tacrolimus, Acute leukemia, Diabetic ketoacidosis

Introduction

New-onset diabetes mellitus after solid-organ trans­plant makes for complicated tacrolimus immuno­supression.¹ The type of diabetes mellitus commonly occurs as type 2 diabetes mellitus. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year-old women hospitalized with diabetic ketoacidosis 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. She was admitted to our emergency clinic in a state of unconsciousness. Her laboratory tests revealed a severe hyperglycemia glucose level of 890 mg/dL, a metabolic acidosis level (pH 6.9), and ketonuria, although diabetes mellitus had never been diagnosed before. After treating the diabetic ketoacidosis and arranging her immunosuppressive treatment, she was discharged from the hospital. Tacrolimus may produce β-cell toxicity, reduce insulin synthesis or release, and decrease peripheral insulin sensitivity.² Clinicians must be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant, as with other solid-organ transplants.

Case report

A 24-year­old woman, who had received a full match bone marrow transplant for acute myeloid leukemia 70 days earlier was admitted, unconscious, to our emergency department. Her induction regimen consisted of busulfan and fludarabine, and her immunosuppressive regimen consisted of mycophenolate mofetil and tacrolimus. She had been taking tacrolimus (Prograf®, 1 mg capsules, Astellas Ireland, Cokerry, Ireland) dosages of 2 × 1 mg daily with no evidence of recurrent graft-versus-host disease. During follow-up, the corticosteroids were successfully tapered, and only tacrolimus was maintained at a dosage of 2 × 1 mg; the trough blood level was within target range of 5 to 15 mg/dL. There had been no evidence of hyperglycemia on routine blood chemistry testing. She was not obese (159 cm, 52 kg, BMI = 20.8 kg/m²), and she had no family history of diabetes mellitus. At the time of her admission to the emergency department, her blood pressure was 95/45 mm Hg, her pulse was 140 beats/minute, her respiratory rate was 32 inspirations/minute, and her body temperature was 37.2°C.

On physical examination, she showed a de­hydrated tongue and skin, and diffuse abdominal tenderness. Her initial laboratory tests revealed hyperglycemia and acidosis. Initial arterial blood gap analysis showed pH 6.9; P_CO2, 7.1 mm Hg; PO₂, 154 mm Hg; HCO₃, 4.0 mmol/L, and the initial anion gas was calculated at 33.8 mmol/L. A diagnosis of diabetic ketoacidosis was made, and she was treated with intravenous saline, sodium bicarbonate, and continuous insulin infusion. Her hemoglobin A1c level was 9.18% (range, 3.9%-6.10%) and plasma C-peptide was 0.20 mmol/L (range, 0.30-2.35). Urinalysis showed glycosuria and strong positivity for ketonuria. Blood levels of tacrolimus were within the normal range. After treating her diabetic ketoacidosis, her immuno­suppressive treatment was switched to cyclosporine (Sandimmun Neoral, 100 mg capsules, Novartis Pharma AG, Basel, Switzerland) 200 mg twice daily and she was discharged home.

Discussion

Diabetes mellitus after an organ transplant has been associated with the use of immunosuppressive drugs, especially with tacrolimus.¹ However, to the best of our knowledge, diabetic ketoacidosis has not been reported previously in an allogeneic bone marrow transplant. Tacrolimus is a calcineurin inhibitor, an important pathway that regulates pancreatic development. Tacrolimus may produce β-cell toxicity, reduce insulin synthesis or release, and decrease peripheral insulin sensitivity.² One potential mechanism for tacrolimus inhibition of insulin secretion is inhibition of protein kinase C-mediated (Ca-dependent and independent) and Ca-independent guanosine 5'-triphosphate signaling pathways.³ Several studies have shown β-cell impairment with tacrolimus. Maybe the cumulative dosage of steroids was another cause for diabetic ketoacidosis.

To the best of our knowledge, there is no reported case in the literature. Clinicians must pay more attention after bone marrow transplant to hyper­glycemic states within the use of tacrolimus for immunosuppression.

References:

1. Im MS, Ahn HS, Cho HJ, Kim KB, Lee HY. Diabetic ketoacidosis associated with acute pancreatitis in a heart transplant recipient treated with tacrolimus. Exp Clin Transplant. 2013;11(1):72-74.
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2. Rangel EB. Tacrolimus in pancreas transplant: a focus on toxicity, diabetogenic effect and drug-drug interactions. Expert Opin Drug Metab Toxicol. 2014;10(11):1585-1605.
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3. Uchizono Y, Iwase M, Nakamura U, Sasaki N, Goto D, Iida M. Tacrolimus impairment of insulin secretion in isolated rat islets occurs at multiple distal sites in stimulus-secretion coupling. Endocrinology. 2004;145(5):2264-2272.
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