Another Detrimental Effect of Immunosuppression: Metabolic Syndrome

Modern organ transplantation only exists because of the efficacy of the current immunosuppressive (IS) regimens in wide use. The incredible reduction in rejection rates with the introduction of calcineurin inhibitors and antimetabolites, such as mycophenolic acid, has allowed hundreds of thousands of patients to return to relatively normal lives after transplantation.1,2 However, these agents are also the root of many health challenges that we must address in our posttransplantation patients. Notably, the risk of increased infections has been obvious from the very beginning, and our decades-long experience has also shown us that these medications lead to increases in cancer and organ-specific damage, such as renal injury. Yet, we, as a field, are still finding new issues that develop over time because of these medications. Along these lines, the commendable work by Angelico et al3, in this issue of Transplantation, clearly shows the impact of IS exposure on the metabolic health of liver transplant patients and the benefit of limiting IS for these patients. Using data collected during their previous IS weaning trials, Angelico et al3 found a marked increase in the prevalence of metabolic syndrome among liver transplant patients on IS who had no issues with obesity, cardiac disease, or diabetes at the time of transplant. Importantly, they also showed that weaning off IS completely or decreasing the dosing to <25% of the initial maintenance dosing can prevent nearly all de novo cases of metabolic syndrome (8.3% in patients on minimal IS compared with 47.8% of patients on standard dosing). Amazingly, the benefit of weaning IS extends to patients who have already developed metabolic syndrome due to IS treatment. Among liver transplant patients with metabolic syndrome at the time of IS weaning commencement, more than half showed regression of metabolic syndrome. Thus, metabolic syndrome attributable to IS exposure can be both prevented and, in many cases, reversed by a careful reduction in the overall IS dosing. The research in this article highlights a few key topics in transplantation that warrant further scrutiny, namely, (1) the need to expand and standardize IS reduction regimen and better understand the impact of even mild reduction in IS on metabolic syndrome, (2) a better understanding of the metabolic health implications of IS for patients with nonalcoholic steatohepatitis (NASH)/metabolic-associated fatty liver disease (MAFLD), and (3) the importance of research into new IS regimens and tolerogenic strategies remains of paramount importance for our patients. The goal of reducing IS over time has long been an important aspect of posttransplant patient care. This work on the effect of IS on metabolic syndrome and the established fact that heart disease is among the leading causes of death among transplant patients should only further emphasize the need to reduce IS whenever possible.4,5 Additionally, clinicians should incorporate routine assessment of metabolic function when determining the need to reduce IS for a patient. As the article acknowledges, the study is a single-center, retrospective trial and additional work is needed to solidify the findings. It will be particularly important to determine whether weaning of specific IS agents has a stronger impact on the metabolic syndrome than others. Furthermore, it will be of interest to understand the impact of smaller reductions of IS on metabolic syndrome. A more nuanced understanding of IS dosing and its impact on metabolic syndrome will be of particular importance to patients who received other organ transplants, where withdrawal or significant reduction in IS is not possible. Given the rapid increase in NASH/MAFLD, which is now the second leading cause of liver failure among waitlist patients in the United States,6 the finding that metabolic effects of IS can be significantly mitigated by reducing the IS dosing could have profound effects. One significant limitation of the current study is the exclusion of NASH/MAFLD patients in the evaluation. As the goal of the work was to understand the specific impact of IS on metabolic syndrome development and the benefit of IS withdrawal, it makes sense to avoid the confounding effects of including patients who already have metabolic syndrome. However, future work must include patients with NASH/MAFLD, as these patients may be at heightened risk for the metabolic sequelae of IS, and the long-term health and survival benefits of IS minimization may be even more profound. The importance of understanding the impact of IS on patients already with metabolic syndrome will also impact non–liver transplants, where metabolic syndrome is very prevalent. Furthermore, the high rate of metabolic syndrome due to IS, as demonstrated by Angelico et al3, should motivate further research into optimal strategies for countering the metabolic effects of IS. With new weight loss and diabetes management strategies, such as glucagon-like peptide 1 agonists, proactive approaches to addressing metabolic syndrome for patients newly on IS should be thoughtfully considered. Finally, the impact of IS on metabolic syndrome further motivates research into new strategies to control the immune system without the harmful effects of our current IS. This includes the importance of developing more specific immune regulation strategies that have few off-target effects, as well as developing tolerogenic protocols, such as cell-based therapies or concomitant bone marrow transplants, that could help decrease or eliminate the need for traditional IS. All future work into new IS strategies will need to include careful evaluation of the impact on metabolic syndrome. IS regimens have always been known to be a “necessary evil” for our patients. The work of Angelico et al3 highlights yet another important health impact of these medications. This work can have an immediate impact on how we assess our patients on IS and how we counsel them on the need for IS minimization strategies. It also provides another motivation for continued research into how we reduce the amount of IS needed, the development of new IS medications and strategies, and tolerogenic protocols.