You've Heard About the Benefits of Using mTOR Inhibitors, Here Are Some of the Risks

Howard J. Eisen


American Journal of Transplantation. 2021;21(2):449-450. 

Cardiac transplantation has been an enduring therapy for patients with advanced heart failure. One of the earliest sequelae noted in heart transplant recipients was cardiac allograft vasculopathy (CAV), which resulted in the death of the third patient to undergo heart transplantation.[1] Despite improvements in immunosuppression over the decades that heart transplantation was first developed and the evidence that statins can ameliorate CAV, leading to their widespread use in these patients, CAV remains one the leading causes of death after the first posttransplant, even as acute cellular rejection and infections in the first year posttransplant have been tamed.[2–4] Therefore, the results of multicenter clinical trials in de novo heart transplant patients using sirolimus and everolimus, which showed a reduction in the progression and incidence of CAV defined by intravascular ultrasound (IVUS) when compared first to azathioprine and then mycophenolate mofetil (MMF), generated much optimism that this problem could also be tamed.[5–7] Tempering the optimism were the adverse events in these clinical trials, which showed increased risk of renal dysfunction in patients receiving calcineurin inhibitor and mammalian target of rapamycin (mTOR) inhibitors. Use of sirolimus outside of clinical trials in de novo heart transplant patients resulted in an increased incidence of mediastinitis and impaired wound healing.[8]

Consequently, approaches were developed to initiate mTOR inhibitors at later dates beyond the early posttransplant period as in the first clinical trials of these agents. The Scandinavian SCHEDULE trials randomized patients to be switched from calcineurin inhibitors (CNI) to everolimus in addition to MMF and corticosteroids or to remain on CNI plus MMF and steroids at weeks 7–11 posttransplant.[9] The CNI-free everolimus regimen was associated with less progression and a lower incidence of CAV defined by IVUS and with better renal function than the CNI regimen. A small number of patients in the CNI-free everolimus group had frequent ≥2R rejection episodes necessitating the addition of low-dose CNI to their regimen. Nonetheless, this study demonstrated the feasibility of using CNI-free mTOR inhibitor–based regimens in the early posttransplant period with excellent outcomes including less progression of CAV and improved renal function.

The Mayo Clinic has pioneered a unique approach to the utilization of mTOR inhibitors by switching patients from CNI-based immunosuppression to CNI-free, mTOR inhibitor (sirolimus), demonstrating not just reduced CAV progression but also improved survival, and reduced the incidence of CAV-related events. In that pivotal study, 268 of 402 patients were converted from CNI to sirolimus and 235 had sequential IVUS to assess CAV progression. They were compared to 134 patients treated with CNI, of whom 99 had sequential IVUS studies.[10,11] From this same group, an observation published in the current issue of the American Journal of Transplantation, regarding the prognostic implications of proteinuria in 137 of the patients switched to sirolimus and who had sequential IVUS studies.[12] One hundred one of these patients had no significant proteinuria, with a median of 126 mg/24 h at baseline, increasing to 168 mg/24 h at 1 year posttransplant compared to 36 patients with significant increases in proteinuria with a median of 235 mg/24 h at baseline to 1265.5 mg/24 h 1 year later. Patients with increased proteinuria had increased all-cause mortality; at baseline, those with proteinuria had a higher incidence of hypertension, and had increased serum creatinines and decreased eGFRs. There was no difference in the incidence of diabetes at baseline. Thus, the development of proteinuria over the first year of transplant in patients switched to sirolimus is a warning sign (caveat) or harbinger of bad outcomes. It should be noted that the immunosuppressive protocol and posttransplant monitoring algorithms described in this article are largely unique to the Mayo Clinic.

As to why the development of proteinuria after 1 year of mTOR inhibitor therapy post–heart transplant is associated with increased all-cause mortality but not CAV-related events may be due to relatively small numbers of patients with CAV-related events in the proteinuria and nonproteinuria groups. This would explain why the increased CAV progression seen in patients with proteinuria did not translate into significantly more CAV-related events. This may also explain the lack of significant differences in other specific causes of death including malignancies, right heart failure, and renal failure. This study is limited by the fact that it is retrospective. However, potentially important information can be obtained from this study. Specifically, a significant proportion of heart transplant patients switched to sirolimus posttransplant develop proteinuria, which is first manifested at 3 months posttransplant. This allows for time to potentially make changes to try to prevent the increased all-cause mortality associated with the development of proteinuria. These approaches could include more aggressive control of blood pressure, perhaps using angiotensin-converting enzyme inhibitors such as ramipril, which have been shown to mitigate CAV, as well as limiting protein intake.[13] Whether these approaches can improve survival in heart transplant recipients on sirolimus while maintaining the amelioration of CAV will need to be learned from future prospective studies. If proteinuria cannot be mitigated with these approaches, then conversion from sirolimus back to CNI-based immunosuppression can lead to the resolution of proteinuria. Whether these patients then develop worsening CAV would also be learned from future prospective studies. Finally, this study provides a guide as to which patients are at risk of developing proteinuria and its attendant adverse consequences after being switched to mTOR inhibitors. Specifically, those patients with baseline advanced renal dysfunction defined as those with eGFR < 30 mL/min and/or baseline elevated proteinuria should only be switched to sirolimus with great caution. Prospective studies of how to manage proteinuria and avert adverse consequences in heart transplant recipients switched to sirolimus will be important in determining how to go forward and use this promising strategy optimally beyond the Mayo Clinic.