Rebiopsy-Guided Long-term Management and Iptacopan Introduction in a Steroid-Dependent Case of C3 Glomerulopathy with Cyclosporine Nephrotoxicity

C3 glomerulopathy (C3G) is a rare glomerular disorder caused by alternative complement pathway dysregulation. Despite partial remission with immunosuppression, long-term management remains challenging due to relapses, cumulative drug toxicity, and the lack of targeted therapeutic options. We present the case of a male patient with C3G complicated by steroid dependence and cyclosporine (CyA)-induced nephrotoxicity, in whom iptacopan was introduced as a targeted complement inhibitor for steroid-sparing therapy.

At onset, proteinuria (0.86 g/gCr), microscopic hematuria (>100 RBC/HPF), and hypocomplementemia (C3 7 mg/dL, C4 15 mg/dL, and CH50 < 12 U/mL) were present, with preserved renal function. Kidney biopsy revealed a membranoproliferative pattern with isolated C3 deposition in the glomeruli. Electron microscopy revealed electron-dense deposits in the mesangium, extending to the subendothelial and occasional subepithelial areas with mild mesangial interposition, findings typical of C3G. Three courses of pulse methylprednisolone followed by oral prednisolone (30 mg/day) induced partial remission. At 2 years, CyA was introduced, allowing for temporary tapering of steroids. However, when prednisolone was reduced to 5 mg on alternate days, a relapse occurred. Four years after the initial biopsy, a second biopsy revealed early interstitial fibrosis with arteriolar hyalinosis, consistent with CyA nephrotoxicity. CyA was reduced, and prednisolone was increased to 30 mg/day, resulting in near-complete remission. However, after tapering prednisolone to 7.5 mg/day at 6 years, proteinuria increased to 1.0 g/gCr, necessitating steroid escalation to 30 mg/day, which again induced a partial remission. Subsequently, mycophenolate mofetil (MMF 1–1.5 g/day) was added. At 8.5 years, pathological re-evaluation revealed mild interstitial fibrosis, consistent with CyA nephrotoxicity.

At year 9, prednisolone (15 mg/day), MMF (1500 mg/day), and CyA (100 mg/day) were maintained. Proteinuria stabilized at 0.4–0.7 g/gCr with normal kidney function (estimated glomerular filtration rate >100 ml/min/1.73 m2), while complement activity (C3 ≈ 30-40 mg/dL, CH50 ≈ 15-20 U/mL) remained low, consistent with persistent activation of the alternative pathway. Given persistent complement dysregulation refractory to intensive multi-agent immunosuppression, iptacopan (200 mg twice daily) was initiated 10 years after the initial biopsy to facilitate steroid reduction. Preliminary outcomes following iptacopan initiation will be presented at WCN’26.

In this C3G case, serial biopsies confirmed progressive complement-mediated glomerular injury with CyA nephrotoxicity, despite preserved renal function. Over ten years, persistent hypocomplementemia (C3, CH50 low) and relapsing proteinuria under triple immunosuppression underscored the need for complement-directed therapy. Iptacopan, an oral factor B inhibitor, reduced proteinuria by ~40% and normalized complement activity within 12 months in the phase 3 APPEAR-C3G trial, supporting both its mechanistic rationale and clinical applicability in this case. The transition marks a strategic shift toward targeted factor B inhibition aiming for sustained disease control with minimized exposure to conventional immunosuppression.