Inhibiting the mTORC Pathway in Antiphospholipid Syndrome

Hillary Maitland, MD, MS

The mTORC inhibitor sirolimus prevents renal allograft loss and improves survival in patients with antiphospholipid-associated nephropathy.

Antiphospholipid syndrome (APS) is an acquired autoimmune disorder characterized by venous and arterial thrombotic events and pregnancy complications. Patients can also develop vascular hyperplasia leading to arterial stenosis in the coronary, carotid, mesenteric, and renal arteries; those with renal involvement often progress to renal failure. The mainstay of treatment is anticoagulation, but this does not address the arterial complication causing organ deterioration.

The mammalian target of rapamycin complex (mTORC) pathway regulates cell proliferation and survival, and the mTORC inhibitor sirolimus is used to prevent the arterial stenosis that occurs after stenting. To determine whether the mTORC pathway is involved in the vascular lesions found in APS-associated nephropathy, investigators obtained renal biopsy specimens from patients with antiphospholipid antibodies and nephropathy, as well as from controls without antiphospholipid antibodies.

Immunostaining of the samples demonstrated increased mTORC activity and increased proliferation of the vascular endothelium in APS patients compared with controls. A cohort of 37 renal-transplant recipients with antiphospholipid antibodies was compared with 74 posttransplant patients without antiphospholipid antibodies. Of the 37 transplant recipients, the 10 who were receiving sirolimus demonstrated significantly less mTORC activation than the 27 not receiving sirolimus and no hyperplasia of the endothelium or vascular smooth muscle. At 82 months, a significant improvement in allograft survival was observed in APS patients treated with sirolimus versus alternative immunosuppressive regimens.

Citation(s):

Canaud G et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med 2014 Jul 24; 371:303.