Finding the transplant sweet spot: can minimising steroids help avoid post-transplant diabetes?

Renal transplantation is considered to be the best modality of renal replacement therapy, and is associated with improved survival rates and quality of life.¹ However, it is also associated with the development of post-transplant diabetes mellitus (PTDM), which is associated with poorer outcomes for patients, including an increased risk of graft failure, cardiovascular disease, infections and death.² 

Previous descriptions of PTDM have included widely differing rates of incidence, varying between 2%–53%, in some part due to the heterogeneity of diagnostic criteria used by different authors.³ The most recent joint guidelines from the Association of British Clinical Diabetologists and the Renal Association (now the UK Kidney Association) advise that a formal diagnosis of PTDM should be avoided in the first 6 weeks post-operatively (due to transient hyperglycaemia) and that it should be made using an oral glucose tolerance test (OGTT). Otherwise, an HbA_1c ≥48 mmol/mol combined with a fasting plasma glucose (FPG) ≥7.0 mmol/L are suitable diagnostic tests after the first 3 months post-transplant.⁴ Studies using the then-current American Diabetes Association criteria to identify PTDM describe a 24% incidence of PTDM at 1 year post-transplant when using OGTTs.⁵

The pathophysiology of PTDM is multifactorial and likely combines elements of both pancreatic beta-cell insufficiency and peripheral insulin resistance.⁶ The increase in incidence of PTDM in the first-year post-transplant reflects the addition of new transplant-specific factors to the baseline risks that predispose the general population to diabetes, and which are more common in patients on the waiting list for transplantation.⁷ Transplant-specific factors thought to contribute to the development of PTDM include weight gain, the restoration of renal insulin metabolism and immunosuppression regimens.⁸

Maintenance immunosuppression for renal transplants usually comprises a multidrug combination. Potential agents include calcineurin inhibitors (e.g. tacrolimus), antiproliferative agents (e.g. mycophenolate mofetil [MMF]), mTOR inhibitors (e.g. sirolimus) and steroids. In particular, calcineurin inhibitors and steroids are known to have a strong diabetogenic potential.⁹ Strategies to minimise or withdraw immunosuppression to reduce the risk of PTDM must be balanced against the risk of rejection and allograft damage. It should be noted that episodes of acute rejection have also been suggested to increase the risk of developing PTDM; however, it is difficult to determine whether this is due to underlying inflammation driven by rejection or by the treatment for rejection, which includes high-dose steroids and increased immunosuppression.¹⁰

A 2016 Cochrane review examined RCTs that compared steroid avoidance/withdrawal with maintenance in renal transplant recipients: although there was an increase in acute rejection in those treated for less than 14 days post-transplantation and in those withdrawn from steroids at a later point, there was no difference in incidence of PTDM or mortality and graft loss at 1 year.¹¹ The authors recommended further prospective long-term studies to determine the long-term consequences of minimising steroid exposure.

In their retrospective cohort study, Gardiner and colleagues analysed data from 577 patients who received their first kidney transplant between January 2010 and December 2021 under the care of the Leeds Renal Transplant Service.¹² Data was collected at timepoints ranging from 3 months prior to the transplant until 60 months post-transplant. As OGTTs rarely form part of routine clinical care, they defined the following criteria as constituting a diagnosis of PTDM: a first recorded prescription of oral hyperglycaemic agents or insulin continuing at or beyond 3 months post-transplant or at a subsequent time point, or a random blood glucose ≥11.1 mmol/L from 3 months post-transplant that remained elevated without any medication. Individuals who did not have a prednisolone prescription recorded at months 0 and 3 were judged to be steroid avoidant. 81% of patients were maintained on a steroid-free regimen. Of their cohort, 55 patients (10%) developed PTDM during a median follow-up of 7.1 years (0.9–13.8 years). 240 patients (41%) had pre-existing diabetes and 282 (49%) did not develop PTDM. Patients with PTDM tended to be male, older, have uncontrolled hypertension, a higher baseline BMI and greater 12-month percentage weight gain, were less likely to be of white ethnicity, and were more likely to have received steroids as part of the immunosuppression regimen. Most patients with PTDM (67%) were diagnosed within the first-year post-transplant, consistent with the literature. 

When comparing transplant outcomes for the three groups, there was no statistically significant difference in 10-year patient or graft survival between those without diabetes, those with pre-existing diabetes and those with PTDM. The 10-year survival was 78%, 73% and 68%, respectively; the graft survival was 82%, 74% and 79%, respectively. However, the wide confidence intervals are consistent with relatively small subgroups. 

Of note, the Leeds immunosuppression protocol consists of alemtuzumab and methylprednisolone induction, with only tacrolimus monotherapy as maintenance. (MMF is added for high-risk recipients.) Steroids are avoided unless there are additional risks, such as pre-existing autoimmune disease or increased risk of rejection. Alemtuzumab is only used as the main induction agent in three of the 18 renal transplant centres in the UK, where it is paired with a steroid-sparing maintenance regimen.¹³ Other centres use basiliximab as first-line induction agent, with varying steroid-weaning regimens; it therefore remains to be seen whether their outcomes are comparable to other renal centre populations and whether their conclusion about the safety of a steroid-avoidant regimen can be extrapolated.

The authors are to be congratulated on collecting data for over 10 years post-transplant, and for adding to the evidence base in this contentious and under-researched area of clinical practice.

A digest of the study can be read here.

References

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4. Chowdhury TA, Wahba M, Mallik R et al (2020) Association of British Clinical Diabetologist and Renal Association guidelines on the detection and management of diabetes post solid organ transplantation. Diabet Med 38: e14523
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12. Gardiner C, Keane D, Ho E et al (2025) Posttransplant diabetes mellitus and long-term outcomes after kidney transplantation in a steroid avoidance regimen: a cohort study. BMC Nephrol 26: 520
13. Chukwu CA, Spiers HVM, Middleton R et al (2022) Alemtuzumab in renal transplantation. Reviews of literature and usage in the United Kingdom. Transplant Rev(Orlando) 36: 100686