Sirolimus application in patients with autoimmune-associated kidney diseases based on mTORC1 activation: a preliminary exploration and future perspectives.

Background: The mTORC1 pathway drives pathogenesis in autoimmune kidney diseases. We hypothesized that intrarenal mTORC1 activation could identify patients likely to benefit from sirolimus, irrespective of their specific diagnosis. Methods: In this prospective proof-of-concept series, we screened eight patients with active autoimmune kidney disease for mTORC1 activation by immunohistochemistry on renal biopsy. Five positive patients (staining intensity: + to +++) received sirolimus, presenting with lupus nephritis atypical hemolytic uremic syndrome (aHUS), thrombotic microangiopathy (TMA), or IgA nephropathy (IgAN) associated with lung cancer. Results: Over a mean follow-up of 25 months, four patients exhibited improved or stable renal function. All responders demonstrated moderate-to-high (++ to +++) mTORC1 staining, whereas the single non-responder who progressed to end-stage renal disease had only weak (+) staining. Proteinuria declined to <1 g/day in most responders. Sirolimus was well-tolerated. In two patients with concurrent malignancy, sirolimus did not aggravate stable breast cancer but was discontinued due to lung adenocarcinoma progression. Conclusion: This study indicates that intrarenal mTORC1 activation levels may help identify patients more likely to respond to sirolimus across various autoimmune kidney diseases, warranting further investigation as a precision-medicine approach.