(9.04) Tacrolimus induced diabetes ketoacidosis (DKA) among solid organ transplant patients

Calcineurin inhibitors (CNIs) frequently correlate with disruption in glucose metabolism. Tacrolimus (TAC), currently a cornerstone in triple-drug immunosuppression following solid organ transplantation, stands out as the most potent CNI. It has been associated with islet cell damage and a reduction in insulin secretion, potentially contributing to post-transplant diabetes mellitus and, rarely, DKA. We describe five cases of DKA occurring in post-transplant patients undergoing TAC treatment.

Case(s) Description :

1:

A 58-year-old man, 14 months post-liver transplant, with pre-existing T2DM, presented with labs consistent with DKA: AG 17 mEq/L, CO2 18 mEq/L, BG 456 mg/dL, BHB 1.75 mmol/L, A1C 8.8%. Immunosuppressants included MMF 1000 mg BID, TAC 4 mg BID (TAC trough 14.5 ng/mL) at presentation. GAD, ICA, ZnT8 Ab were negative, C-peptide 0.2 ng/mL, BG 162 mg/dL. DKA resolved after 8 hours with IV insulin; and TAC dose reduced.

2:

A 72 y/o woman, 108 months post-kidney transplant, with pre-existing T2DM,, presented with labs consistent with DKA: AG 27 mEq/L, CO2 9 mEq/L, BG 674 mg/dL, BHB 7.74 mmol/L, and A1C 10.9%. Immunosuppressants included MMF 250 mg BID, prednisone 5 mg daily, and TAC 2 mg BID (TAC trough 17.7 ng/mL) at presentation. GAD, ICA, ZnT8Ab not performed, C-peptide 0.9 ng/mL, BG 249 mg/dL. DKA resolved after 62 hours with IV insulin; and TAC dose reduced.

3:

A 51 y/o man, 12 months post-kidney transplant, presented with new-onset PTDM. Labs indicated DKA: AG 28 mEq/L, CO2 6 mEq/L, BG 1393 mg/dL, BHB 5.91 mmol/L, and A1C 10.7%. Immunosuppressants included MMF 500 mg BID, prednisone 5 mg daily, and TAC 12 mg daily (TAC trough level 9.1 ng/mL) at presentation. GAD, ICA, ZnT8 Ab were negative, C-peptide 0.2 ng/mL, BG 236 mg/dL. DKA resolved after 28 hours with IV insulin;  and TAC dose reduced.

4:

A 68 y/o man, 8 months post-heart transplant, with pre-existing T2DM, presented with DKA: AG 22 mEq/L, CO2 19 mEq/L, BG 735 mg/dL, BHB 5.10 mmol/L, and A1C 12.2%. Immunosuppressants included MMF 1000 mg BID and TAC 2 mg in am /1.5 mg in pm  (trough level 11 ng/mL) at presentation. GAD and ZnT8 Ab were negative, C-peptide 0.4 ng/mL, BG 177 mg/dL. DKA resolved after 13 hours with IV insulin; and TAC dose reduced.

5:

A 57 woman, 14 months post-heart transplant, with pre-existing T2DM, presented with DKA: AG 19 mEq/L, CO2 15 mEq/L, BG 267 mg/dL, BHB 2.52 mmol/L, and A1C 5.2%. Immunosuppressants included MMF 180 mg BID, prednisone 5 mg daily, and TAC 7 mg in am /6 mg in pm  (trough level >30 ng/mL) at presentation. GAD, ICA, ZnT8 Ab, and C-peptide levels were not performed. DKA resolved after 25 hours with IV insulin;  andTAC dose was reduced.

 

Discussion : The primary diabetogenic effect of TAC results from its suppression of insulin secretion from pancreatic beta cells, rather than any deterioration in peripheral insulin sensitivity. We have documented instances of DKA occurring in post-transplant patients receiving TAC, with no discernible alternative cause. Notably, all five cases exhibited rapid improvement upon administering insulin infusion and adjusting TAC doses. This indicates a potential link between TAC use and the onset of DKA in this particular group of patients.