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Antiphospholipid syndrome involves both blood vessel damage and thrombosis. A new study reveals the molecular pathway that causes the former, and a drug that inhibits it.
Canaud, G, BienaimÃ© F, Tabarin F, et al. Inhibition of the mTORC Pathway in the Antiphospholipid SyndromeN Engl J Med (2014)371:303-312. doi: 10.1056/NEJMoa1312890
Eikelboom JW and Weitz JI. Editorial: The mTORC Pathway in the Antiphospholipid Syndrome N Engl J Med (2014) 371:369-371 doi: 10.1056/NEJMe1406870
The antiphospholipid syndrome (APS) looks like a coagulopathy, but anti-coagulation is often not enough to save kidneys – and other organs.
This new study reveals that APS also involves intimal hyperplasia, and that sirolimus, a drug used to prevent hyperplasia and restenosis in coronary stents, seems to prevent this in APAS and to spare kidneys.
APS is an acquired immune disorder characterized by elevation of antiphospholipid antibodies, thrombosis, and sometimes vasculopathy. Although mechanisms in the pathogenesis of the thrombosis have been clarified, the cause of the vasculopathy is less clear.
This study clarifies the vasculopathy. Researchers in Paris have found evidence that when antiphospholipid antibodies bind to vascular endothelial cells in the kidneys, brain or other organs, they activate the signaling pathway of mammalian target of rapamycin complex (mTORC). This triggers the vasculopathy.
They support this hypothesis by showing that IgG antiphospholipid antibodies upregulate mTORC in renal vascular endothelial cells in biopsy specimens from kidneys obtained from patients with nephropathy, with or without APS, and also from controls without nephropathy.
These include patients with primary APS, patients with secondary APS superimposed on systemic lupus erythematosus (SLE), patients with SLE but not APS, and control patients with kidney cancers.
Autopsy specimens from patients with catastrophic APS also showed activation of mTORC.
Finally, they compared the results of patients with APS who had kidney transplants and were receiving sirolimus, which inhibits mTOR, with those of patients who were not.
Patients with transplants who were receiving sirolimus had no recurrence of vascular lesions and had decreased vascular proliferation on biopsy.
Among 10 patients taking sirolimus, 7 (70%) had a functioning renal allograft 144 months after transplantation, versus only three of 27 untreated patients (11%).