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Quick Steroid Withdrawal Works in Post-Transplant Diabetes

— Incidence dropped from 39% to about 24%

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CHICAGO -- The incidence of diabetes following a kidney transplant can be cut nearly in half -- at least in immunologically low-risk patients -- by initiating a rapid withdrawal from steroids, a researcher said here.

"In low-risk transplant patients, rapid steroid withdrawal was safe, with unchanged excellent survival," said , of University Hospital Carl Gustav Carus Dresden, in Germany, at the American Society of Nephrology's Kidney Week. "Most dramatically, rapid steroid withdrawal led to a marked reduction in post-transplant diabetes mellitus development within the first year." His group's study was .

Action Points

  • Note that this randomized trial evaluating the rapid cessation of corticosteroid after kidney transplant found that the rapid taper regimen was as effective as a regimen with sustained corticosteroid dosing.
  • Importantly, the rapid-taper regimen had a significantly lower incidence of diabetes.

In a study of 587 kidney transplant patients, two groups of patients who underwent rapid steroid withdrawal experienced post-transplant diabetes rates of 24% and 23% compared with 39% in a control group, Hugo noted.

A previous study, known as the ELITE [Efficacy Limiting Toxicity Elimination]-Symphony study, arrived at a "gold standard" immunosuppressive regimen for kidney transplants, determining that low-dose tacrolimus plus mycophenolate mofetil (MMF) and steroids yielded the best results in terms of kidney function at 1 year and 3 years, allograft survival, and acute rejection, "but -- and there was a major but -- it also was the worst regimen in regard to post-transplant diabetes mellitus," he said.

"So this stimulated us to ask the question of whether we could do a study in which rapid steroid withdrawal could eliminate this disadvantage of high post-transplant diabetes mellitus rates ... It was also not clear what would be the best induction therapy for achieving rapid steroid withdrawal."

The researchers designed a multi-center, open-label, randomized controlled trial with three arms:

  • Basiliximab induction with low-dose tacrolimus, 2 g mycophenolate mofetil, and steroid maintenance therapy (Arm A)
  • Basiliximab induction with low-dose tacrolimus, 2 g mycophenolate mofetil, and rapid steroid withdrawal on day 8 (Arm B)
  • Rabbit antithymocyte globulin (ATG) induction with low-dose tacrolimus, 2 g mycophenolate mofetil, and rapid steroid withdrawal on day 8 (Arm C)

The average age of patients in the study was 54; a total of 66% were male, and 99% were white. Causes of kidney disease included hypertension/large vessel disease (37%), glomerulonephritis (27.4%), polycystic kidney disease (19.3%), diabetes (10.6%), and interstitial nephritis/pyelonephritis (7.5%). A total of 87.1% of the kidney donors were deceased.

Participants were of low immunological risk; overall there were on average less than three antigen mismatches for A, B, and DR, almost 90% of recipients had no panel-reactive antibody, and they generally had a very short cold ischemia time -- below 12 hours, Hugo said.

The primary endpoint was the incidence of acute rejections at 1 year. The secondary endpoint was improved safety, including less post-transplant diabetes and improved kidney function and cardiovascular risk factors.

As to the primary endpoint, the incidence of kidney rejection did not differ significantly among the three groups, the researchers found. The secondary endpoints of patient survival at 1 year, death-censored allograft survival at 1 year, and graft loss or death at 1 year also didn't differ significantly among the groups.

However, the incidence of post-transplant diabetes was almost bisected after rapid steroid withdrawal in arms B and C compared with arm A, they found. And, Hugo added, although all the study evaluations were done "after 2 months and up to 12 months, excluding transient hyperglycemia in the early time, this effect of a difference after rapid steroid withdrawal also occurred when you started evaluation on day 0, 4 weeks, 8 weeks, 12 weeks -- whatever."

Interestingly, although the investigators hypothesized that rabbit ATG induction would work better than basiliximab induction for preventing acute rejection, that was not what they found; instead, both rapid-steroid-withdrawal groups had similar reductions in that outcome.

What should be made of these results? "The superiority we thought [was there] for rabbit ATG is not there," Hugo told ֱ. "On one hand, you can say for those who promote rabbit ATG, it's disappointing. But it also tells you that either way it's a success, because [with rapid steroid withdrawal] you get rid of something that makes side effects, you don't lose any effectiveness whatsoever -- acute rejection rates, allograft survival, and so on, is still the same -- but you have less diabetes after the kidney transplant. So you have a benefit but no disadvantage."

To sum it up, said Hugo, "For these patients, Harmony may be better than Symphony."

, of Kaiser Permanente in Washington, said she was excited about the trial results. "If you can have a trial outcome like this, where you can minimize a risk of having a complication downstream like that, that is just really huge for our patient population," she told ֱ. "The number 1 reason patients go on to dialysis for end-stage kidney disease is diabetes, and then hypertension, and steroids cause diabetes and hypertension."

"It was just really cool that those patients aren't going to have that life impediment going forward," added Brandt, who was not involved in the study. "They've already got a transplant, they've already got to take a lot of immunosuppressive medications the rest of their life, they've already got to go to doctor appointments; you don't want to add more to their algorithm downstream."

, of Oklahoma University in Oklahoma City, agreed. "The main cause of death for any patient with kidney disease, even after a kidney transplant, is cardiovascular events, and diabetes is also a covariable that increases the risk of heart disease," said Lane, who was not involved in the study. "So if we can prevent that, it not only improves renal survival, it also improves cardiovascular survival, and not having diabetes is certainly going to be a big quality-of-life improvement for the patients as well."

Primary Source

The Lancet

Hugo C, et al "Rabbit ATG or basiliximab induction for rapid steroid withdrawal after renal transplantation (Harmony): An open-label, multicentre, randomised controlled trial" Lancet 2016; DOI: 10.1016/S0140-6736(16)32187-0.