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C3 glomerulopathy is a rare disease caused by fluid phase dysregulation of the alternative complement pathway. Currently, treatment depends on clinical and histological severity and includes nephroprotection, unspecific immunosuppression, and terminal complement blockers (C5), without having an etiological treatment approved. C3 glomerulopathy has high recurrence rates after kidney transplantation with a high risk of graft loss. Fortunately, new molecules are being developed that specifically target the proximal alternative complement pathway, such as iptacopan, a factor B inhibitor that showed promising results in native kidneys and cases of transplant recurrence in a phase 2 clinical trial. We present 2 “real-world” cases of C3 glomerulopathy recurrence in kidney allografts treated with iptacopan, with initial excellent clinical response and safety profile, especially with early introduction. We also present follow-up biopsies that showed no C3 deposition during factor B inhibition. Our cases suggest that proximal blockade of the alternative complement pathway can be effective and safe in the treatment of C3 glomerulopathy recurrence in kidney transplantation, bringing other questions such as dual blockade (eg, in C3 and C5), the optimal patient profile to benefit from factor B inhibition or treatment duration and its potential use in other forms of membranoproliferative glomerulonephritis (eg, immune complex-mediated).

The complement system causes kidney injury in a variety of different diseases, and clinical evaluation of the complement system is an important part of the diagnostic workup of patients with glomerulonephritis. In cases of ongoing, uncontrolled complement activation, the kidney is susceptible to complement hyperactivation, and thrombotic microangiopathy associated kidney injury can occur. Two principle modes of complement-mediated kidney injury have been proposed: classical pathway mediated injury in immune complex diseases and/or alternative pathway mediated renal injury causing atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathy in patients with abnormalities in alternative pathway regulation. Recent advances have also provided new insights into the pathogenesis of glomerular and tubulointerstitial injury associated with aberrant complement activation. Complement inhibition is effective for treatment of aHUS, and there is growing evidence of the favourable effect of the anti-C5 monoclonal antibody eculizumab. Measurement of ex vivo serum-induced endothelial C5b-9 deposits is supposed to be a sensitive tool to monitor complement activation and eculizumab effectiveness. Although understanding the role of the complement system in the pathogenesis of many kidney diseases is improved, there is not a simple algorithm for identifying which patients should be treated with complement inhibitors or for how long complement inhibition should be continued.