mTORC Pathway Affects Vascular Changes in Antiphospholipid Syndrome

The vascular changes of antiphospholipid syndrome nephropathy involve activation of the mammalian target of rapamycin complex (mTORC) pathway, suggesting a potential benefit of sirolimus after kidney transplantation, according to a study in the New England Journal of Medicine.

The investigators performed a series of studies to assess activation of the mTORC pathway in patients with antiphospholipid syndrome nephropathy, including autopsy specimens from patients who died of catastrophic antiphospholipid syndrome. In both primary and secondary disease, evidence of mTORC pathway activation was observed in proliferating intrarenal vessels. The autopsy specimens likewise showed signs of mTORC activation in blood vessels. In vitro, IgG antibodies from affected patients stimulated mTORC in vascular endothelial cells through the phosphatidylinositol 3-kinase—protein kinase B pathway.

The researchers also evaluated the effects of the mTORC inhibitor sirolimus after kidney transplantation. Out of 37 transplant recipients with antiphospholipid antibodies, 10 received immunosuppressive therapy including sirolimus. These patients had no recurrent vascular lesions, and they also had reduced vascular proliferation, compared with antiphospholipid antibody-positive recipients not treated with sirolimus. At 12 years’ follow-up, 7 of 10 sirolimus-treated patients had a functioning transplant compared with 3 of 27 patients not receiving sirolimus.

Although thrombosis is regarded as the main feature of antiphospholipid syndrome, chronic vascular lesions are commonly present and may recur after kidney transplantation. The new study provides evidence that activation of mTORC pathways is involved in the vascular lesions seen in antiphospholipid syndrome nephropathy. The results suggest that in kidney transplant recipients with antiphospholipid antibodies, giving sirolimus to inhibit the mTORC pathway “protects the transplanted graft and, more important, prevents graft loss by preventing the development of intimal hyperplasia” [Canaud G, et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N Engl J Med 2014;371:303–312].