Successful Management of C3 Glomerulopathy Recurrence Post-Kidney Transplantation with Iptacopan: A Case Report

Abstract

C3 glomerulopathy (C3G) is the predominant cause of complement-mediated membranoproliferative glomerulonephritis and is considered a rare disorder caused by genetic or acquired dysregulation of the alternative complement pathway. There are no established treatment guidelines for treating kidney-transplanted recipients with C3G recurrence, as they are already on immunosuppressive protocols. Furthermore, non-complement-specific immunosuppressive drugs appear to offer limited benefits for patients with C3G in native kidneys. Therefore, modulating the complement system appears to be the most effective strategy for this specific patient population. We describe the use of Iptacopan in a 38-year-old kidney-transplanted patient with C3G recurrence. Iptacopan was associated with a significant and striking improvement in the patient's clinical and laboratories status. A follow-up kidney biopsy performed 5 months after the initiation of Iptacopan revealed a reduction in endocapillary, extracapillary and mesangial hypercellularity, along with a decreased extent of parietal proteinaceous deposits observed on light microscopy. The direct control of the complement dysregulation underlying the pathogenesis of C3G with Iptacopan was accompanied by improvements in clinical, laboratory and histological features, with demonstrated reduced disease activity and slowed disease progression. Therefore, the case report described is intended to shed light on the potential role of new AP complement blockers in the treatment of C3G.

Keywords: C3 glomerulopathy; Iptacopan; complement system; innate immunity.

Figure 1

Pathological findings of the first kidney biopsy. (A): Membranoproliferative pattern. Double contours of the glomerular basement membranes with cellular interposition and proteinaceous subendothelial deposits (arrows). (Methenamine Silver). (B): IgG deposits in the mesangium and, globally distributed, along the glomerular basement membranes, coarsely granular, “sausage”-shaped (anti-IgG,×400). (C,D): C3 and C1q deposits in the mesangium and along the glomerular basement membranes.

Figure 2

Timeline of interventions before first dose of Iptacopan. The figure illustrates timeline and clinical course between interventions and Iptacopan initiation. Created in BioRender. Troise, D. (2025), https://BioRender.com/z1hiq62 (accessed on 19 May 2025).

Figure 3

Laboratory measures before and after the first dose of Iptacopan. The figure illustrates the trajectories of key laboratory values for the subject of the study in relation to the first administration of Iptacopan. The vertical green arrow indicates the initiation of Iptacopan treatment at a dose of 200 mg administered orally twice a day.

Figure 4

(A,B) Comparison between the first kidney biopsy and the follow-up biopsy at low magnification. (A): Low magnification from the first biopsy showing diffuse MPGN pattern of glomerular injury along with diffuse endocapillary proliferation and extracellular proliferation with cellular crescent formation (Periodic Acid Shiff). (B): Low magnification from the second biopsy showing persistence of MPGN pattern of glomerular injury with slightly less endocapillary and mesangial hypercellularity. (C–H) Comparison between the first kidney biopsy and the follow-up biopsy at high magnification. (C–E): High magnification from the first biopsy showing diffuse MPGN pattern of glomerular injury along with diffuse endocapillary proliferation (black arrow) and extracellular proliferation with cellular crescent formation (white arrow). Proteinaceous material is observed in the subendothelial region (arrowheads). (C,D): Periodic Acid Shiff, (E) Methenamine Silver). (F–H): High magnification from the second biopsy showing persistence of MPGN pattern of glomerular injury with slightly less endocapillary and mesangial hypercellularity.

Figure 5

Iptacopan mechanism of action. The initiation of the alternative pathway (AP) occurs spontaneously via a process known as “tickover”, where the protein C3 undergoes a low rate of hydrolysis in the fluid phase. Subsequently, C3 binds to factor B, a key component of the alternative pathway, which is then cleaved into Ba and Bb, leading to the formation of the AP C3 convertase (C3Bb). Additionally, C3b from Classical and Lectin pathways can contribute to the amplification of the AP, facilitating cross-talk between pathways. Then, C3b leads to the generation of C5 convertases, which cleave C5 into C5a and C5b. C5b initiates the assembly of the membrane attack complex (MAC), a structure composed of C5b, C6, C7, C8 and C9. The MAC forms transmembrane pores on the cell surfaces, ultimately leading to cell lysis. The mechanism of action of Iptacopan is based on the inhibition of the enzymatic activity of factor B. This inhibition suppresses the formation of both C3 and C5 convertases, thereby regulating the AP at both upstream (C3 activation) and downstream (C5 activation) levels. As a result, the generation and subsequent deposition of C3 breakdown products in the glomeruli and the formation of the MAC are effectively prevented. Created in BioRender. Troise, D. (2025), https://BioRender.com/arm1qbp (accessed on 14 May 2025).