Targeting the alternative complement pathway by iptacopan abrogates C3 and strongly reduces C5b-9 deposition within glomeruli in IgA nephropathy recurrence after kidney transplantation

Abstract

Current trials are exploring complement blockade in IgA nephropathy (IgAN) of native kidneys. No data are available on IgAN recurrence. Here, we report on the first small case series (n = 5) treated with iptacopan, a factor B inhibitor targeting the alternative complement pathway, for this condition, providing biopsy findings after treatment. All patients underwent indication biopsies for proteinuria increase, graft function deterioration, and subsequent posttreatment biopsies. Three of 5 were treated with iptacopan-only between the biopsies, whereas in 2 of 5, iptacopan treatment was preceded by either a steroid pulse or a steroid pulse plus plasmapheresis. Within 6 to 12 months, iptacopan led to a marked reduction in terminal complement component deposition (C5b-9) and almost disappearance of C3. In contrast, IgA deposition was slightly reduced. There was no consistent improvement in proteinuria. No major adverse events (AE) occurred. In conclusion, to our knowledge, this is the first report of iptacopan use for recurrent IgAN in kidney transplant recipients. In addition, it demonstrates in vivo modulation of glomerular complement deposition, specifically preventing C3 deposition and C5b-9 fixation, which is considered a major effector mechanism of tissue injury. Large cohorts are required to define its impact on clinical outcomes in long-term transplant settings.

Keywords: IgA nephropathy; complement cascade; iptacopan; kidney transplant.