ISHLT: In Cardiac Transplant, Switching Immunosuppessants Helps Graft and Kidneys

April 26, 2007

SAN FRANCISCO -- A gradual swap of one form of immunosuppression for another in heart transplant recipients can preserve renal function without compromising the graft, said Mayo Clinic investigators.

SAN FRANCISCO, April 26 -- A gradual swap of one form of immunosuppression for another in heart transplant recipients can preserve renal function without compromising the graft, said investigators here.

Weaning patients off calcineurin inhibitors such as tacrolimus (Prograf) and cyclosporine and on to sirolimus (Rapamune) improved renal function, preserved cardiac function, and maintained good immunosuppression, reported Sudhir Kushwaha, M.D, of the Mayo Clinic, and colleagues, at the International Society of Heart and Lung Transplantation meeting.

"Immunosuppression for heart transplant patients using calcineurin inhibitors has been essentially unchanged for 25 years, and the results have not been ideal," said Dr. Kushwaha, a cardiologist at the Rochester, Minn., institution. "Five to 10 years post-transplant, 10% of patients are on dialysis or need a kidney transplant. And 10 years post-transplant, 50% of patients are either waiting for another heart transplant because of coronary artery disease or have died as a result of it."

Switching from a calcineurin inhibitor to sirolimus also appeared to slow progression of cardiac allograft vasculopathy, a common complication of heart transplantation.

But Dr. Kushwaha cautioned that a calcineurin inhibitor should still be used as the primary immunosuppressant immediately after transplant, and that the switch to sirolimus must be gradual rather than abrupt.

"Today, standard practice at Mayo Clinic is to consider converting all heart transplant patients from calcineurin inhibitors to sirolimus at six months post-transplant if there are no contraindications."

He and his colleagues reported results of two studies comparing calcineurin inhibitors with sirolimus.

In the first study, they reported results of a stepwise protocol for withdrawing calcineurin inhibitors and substituting sirolimus in 78 heart graft recipients. Of these patients, 58 had calcineurin-inhibitor-induced renal impairment, defined as a glomerular filtration rate (GFR)

In contrast, filtration rate among the controls declined from 41.4 13.5 ml/minute to 36.4 12.5 ml/min over 19.6 6.4 months of follow up (P=0.05).

There was no significant difference in cardiac rejection rates between the sirolimus-treated patients and controls, and no difference in cardiac allograft function.

The authors saw a significant increase in proteinuria following conversion to sirolimus, from 298 623 to 473 764 mg/day (P=0.001), compared with no change in controls. But patients on sirolimus also had a significant reduction in uric acid, from 7.6 2.4 to 6.2 1.9 mg/dl (P=0.0007). Uric acid values for patients maintained on calcineurin inhibitors were not reported.

In the second study, Dr. Kuswaha and colleagues used three-dimensional intravascular ultrasound to gauge the progression of cardiac allograft vasculopathy in 29 patients on sirolimus-based immunosuppression for nearly four years. Controls were 40 patients maintained on calcineurin inhibitors over the same period. In both groups the secondary immunosuppressants and maintenance steroids remained the same.

They found that among controls, the mean plaque (defined as media and intima) volume and plaque index (plaque volume/vessel volume %) increased significantly from baseline to one year, compared with no changes in the sirolimus-treated group.

Among patients studied within the first two years after transplantation, there were significantly smaller increases in plaque volume and plaque index among patients treated with sirolimus. Among patients studied beyond the first two years after transplant the increase in plaque index, but not plaque volume, was significantly less among the sirolimus-treated patients.

The results suggested that "withdrawal of calcineurin inhibitors and replacement with sirolimus prevents progression of cardiac allograft vasculopathy, and is unrelated to secondary immunosuppressant," the authors wrote in the study abstract. "This effect is more prominent within the first two years and suggests the possibility of cardiac allograft vasculopathy prevention with early use of sirolimus as primary immunosuppression after cardiac transplantation."