March 12, 2025
Immunosuppressive therapy is the cornerstone of all transplant therapies. It's essential to mitigate the risk of organ rejection. But it's not without side effects, including infection, kidney damage and skin cancer.
For orthotopic heart transplant (OHT) recipients, standard protocol calls for the calcineurin inhibitor (CNI) tacrolimus with an antimetabolite, commonly mycophenolate, and prednisone. However, long-term use of CNIs has been shown to cause chronic kidney disease and may not provide sufficient protection against cardiac allograft vasculopathy (CAV) after OHT.
The International Society for Heart and Lung Transplantation (ISHLT) recommends transitioning patients to mammalian targets of rapamycin (mTOR) inhibitors, such as sirolimus (SRL). Past studies conducted by Mayo Clinic have shown SRL's superiority over CNIs in mitigating CAV risk, nonmelanoma skin cancer risk and kidney dysfunction.
"At Mayo Clinic, we use sirolimus preemptively, as endorsed by the ISHLT, and we've had much success," says Drew N. Rosenbaum, M.D., a transplant cardiologist at Mayo Clinic in Minnesota.
Still, many institutions only transition from a CNI to SRL as a reactionary step when a patient develops CAV because of a perceived risk of rejection.
To inform other heart transplant clinicians about how to successfully use sirolimus for OHT recipients, Dr. Rosenbaum and colleagues conducted a retrospective study to evaluate the incidence and risk factors for biopsy-proven, clinically relevant rejection following conversion from CNI to SRL immunosuppression. The results from this study were published in The Journal of Heart and Lung Transplantation in 2024.
Methods
Dr. Rosenbaum and colleagues conducted a single-center retrospective study of 317 consecutive adult patients (72% male, mean age 51.5 ± 12.6 years) who underwent OHT and CNI-free SRL conversion between January 1999 and January 2023.
All post-OHT biopsy data were graded using standard ISHLT criteria: acute cellular rejection (ACR) and pathologic antibody-mediated rejection (pAMR).
The primary end point was early rejection, defined as grade 2R ACR or pAMR 1 or greater, within six months after conversion.
Results
Study results showed age and time from transplantation as the greatest factors influencing rejection.
Rejection rates were highest if converted before six months and lowest if converted after 12 months post-OHT. Older patients had lower rejection rates at the time of conversion, while younger patients had higher rates of rejection upon conversion from CNI to SRL immunosuppression.
"Looking at our findings, we suggest waiting to convert until at least one year, depending on early angiogram findings," explains Dr. Rosenbaum.
He adds, "It's also important to note that we did not see an increased risk of CAV in those who developed rejection after sirolimus conversion, which is likely due to the association between sirolimus and attenuated CAV progression and fewer CAV events."
SRL improves kidney function relative to tacrolimus. SRL has also been demonstrated to lower the risk of skin cancer in OHT recipients.
While a smaller proportion of patients do not tolerate SRL well due to a number of side effects — such as mouth sores, acne, swelling, protein in the urine and a small risk of lung disease — the benefits of early conversion to SRL immunosuppression outweigh the risks for most OHT recipients.
For more information
Asleh R, et al. Incidence of malignancies in patients treated with sirolimus following heart transplantation. Journal of the American College of Cardiology. 2019;73:2676.
Inglis SS, et al. Incidence and risk factors for rejection after conversion from calcineurin inhibitor to sirolimus-based immunosuppression in orthotopic heart transplant recipients. The Journal of Heart and Lung Transplantation. In press.
Refer a patient to Mayo Clinic.