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.