Post-Transplant Diabetes Mellitus

Post-transplant diabetes mellitus is diabetes diagnosed after solid organ transplantation by usual glucose criteria, formally assessed once the patient is clinically stable on a steady immunosuppressive dose without acute infection.

It is common, with reported frequency varying widely by organ and diagnostic method; kidney, liver, heart and lung recipients are all affected. Early post-operative hyperglycaemia is more frequent and often transient.

Risk factors are age over 45, obesity, family history, impaired glucose tolerance before transplant, hepatitis C, cytomegalovirus infection, black or Hispanic ancestry, polycystic kidney disease and deceased donor grafts.

Drug causes are tacrolimus (more than ciclosporin), glucocorticoids and the mammalian target of rapamycin inhibitors sirolimus and everolimus. Mycophenolate and azathioprine have little effect.

Pathophysiology.

Calcineurin inhibitors reduce insulin gene transcription and beta cell survival. Glucocorticoids add insulin resistance, and weight gain after transplant compounds it.

Hepatitis C and cytomegalovirus infection impair beta cell function. Changes in kidney function alter insulin clearance.

• Often asymptomatic and found on screening. Polyuria and thirst when glucose is over 12 mmol/L.
• Rising insulin or glucose lowering drug requirement, weight gain, recurrent infections and delayed wound healing.

Red flags.

• Hyperosmolar presentation with glucose over 30 mmol/L.
• New hyperglycaemia with fever or graft pain: exclude infection and rejection.

• Fasting glucose 7.0 mmol/L or more, 2-hour glucose 11.1 mmol/L or more on a 75 g oral glucose tolerance test, or random glucose 11.1 mmol/L or more with symptoms. The oral glucose tolerance test is the most sensitive test.
• HbA1c 48 mmol/mol (6.5%) or more is valid only after 3 months, because anaemia, transfusion, kidney dysfunction and erythropoietin distort early values.
• Screening: fasting glucose weekly for the first 4 weeks, then at 3, 6 and 12 months and yearly, with a pre-transplant oral glucose tolerance test where possible.
• Assess cardiovascular risk: lipids, blood pressure, urine albumin to creatinine ratio.

Differential diagnosis.

• Pre-existing undiagnosed diabetes.
• Transient hyperglycaemia from high dose steroids, sepsis or surgical stress.
• Pancreatogenic diabetes after pancreas or liver disease, and hepatitis C related diabetes.
• Type 1 diabetes recurrence in a combined kidney and pancreas recipient.

• Early post-operative hyperglycaemia: insulin, with isophane insulin matched to steroid dose, targeting 7.8 to 10 mmol/L in hospital.
• Stable patients: lifestyle change plus metformin if eGFR is 30 or more (maximum 1000 mg daily at eGFR 30 to 44; stop under 30).
• Dipeptidyl peptidase-4 inhibitors have few interactions: linagliptin needs no kidney adjustment; sitagliptin is 100 mg daily at eGFR 45 or more, 50 mg at 30 to 44, 25 mg under 30.
• Sodium-glucose cotransporter 2 inhibitors are used in stable kidney recipients with eGFR 30 or more once the graft is settled, with attention to genital infection, volume depletion and euglycaemic ketoacidosis. Avoid in the early post-operative period.
• Glucagon like peptide-1 receptor agonists can help weight, but nausea and diarrhoea may alter tacrolimus absorption; check tacrolimus levels.
• Repaglinide levels rise with ciclosporin. Sulphonylureas carry hypoglycaemia risk when kidney function is reduced.
• Use the lowest effective steroid dose. Changing tacrolimus or ciclosporin is a transplant specialist decision.
• Treat cardiovascular risk: statin, blood pressure under 130/80 mmHg and albuminuria control.

Special groups. Kidney transplant recipients: adjust all glucose lowering drugs to graft eGFR. Lung transplant recipients with cystic fibrosis: expect insulin dependence.

Monitoring. HbA1c every 3 months (interpret with haemoglobin and kidney function), annual retinal screening, foot checks and urine albumin to creatinine ratio.

Referral and escalation. Transplant physician before any change to immunosuppression. Diabetes team for insulin initiation.