Kidney Week

Abstract: SA-PO0728

C3 Nephropathy with Classic Pathway Involvement Responding to Iptacopan

Session Information

• Glomerular Diseases: Complement-Mediated Glomerulopathies and Infection-Related GN
  October 24, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics

Authors

• Kunishi, Ryosuke, Sapporo Tokushukai Byoin, Sapporo, Hokkaido Prefecture, Japan

Ryosuke Kunishi, MD

• Kawata, Yoshihiro, Tomakomai-shi, Tomakomai, Hokkaido Prefecture, Japan

Yoshihiro Kawata, MD

• Yanai, Mitsuru, Sapporo Tokushukai Byoin, Sapporo, Hokkaido Prefecture, Japan

Mitsuru Yanai, MD, PhD

• Ogawa, Yayoi, Sapporo Tokushukai Byoin, Sapporo, Hokkaido Prefecture, Japan

Yayoi Ogawa, MD, PhD

• Araki, Makoto, Sapporo Tokushukai Byoin, Sapporo, Hokkaido Prefecture, Japan

Makoto Araki, MD, PhD

Introduction

C3 glomerulopathy (C3G) is understood primarily as a disease of alternative pathway dysregulation, and therapeutic strategies have accordingly focused on alternative pathway inhibition. However, the initiating and perpetuating pathways of complement activation do not necessarily coincide in C3G. Here we report a case of C3G in which upstream classical pathway involvement was suggested yet the patient responded favorably to iptacopan, a factor B inhibitor targeting the alternative pathway.

Case Description

A 24-year-old woman had persistent hypocomplementemia since age 12, following a diagnosis of post-streptococcal acute glomerulonephritis. At age 20, a kidney biopsy prompted by proteinuria established the diagnosis of C3G. Proteinuria was initially mild and followed conservatively, but increased gradually over the ensuing years, reaching 2.0 g/gCr upon transfer to our institution at age 24. Laboratory evaluation revealed serum creatinine 0.58 mg/dL, C3 16 mg/dL, C4 17.1 mg/dL, and CH50 12 CH50/mL. Autoimmune disease, active infection, and monoclonal gammopathy were excluded.
The biopsy at age 20 demonstrated mesangial expansion, focal GBM duplication, and mesangial and subendothelial electron-dense deposits. Immunofluorescence showed dominant C3 deposition without C4 or C1q, consistent with C3G. A C4b2a generation assay, which probes early classical pathway function, was abnormal, suggesting upstream classical pathway involvement. In addition, markedly depressed AH50 and elevated soluble C5b-9 indicated that alternative pathway amplification was driving terminal complement activation. No quantitative abnormalities of factor B, factor H, or factor I were identified, and anti-factor H antibodies were absent.
Given limited responses to ARB and SGLT2 inhibitor therapy and evidence of ongoing alternative pathway amplification, iptacopan was initiated following vaccination against encapsulated bacteria. Within one month, complement levels normalized and proteinuria decreased by ~50%. By two months, the urine protein-to-creatinine ratio had declined to 0.5 g/gCr.

Discussion

The abnormal C4b2a generation assay suggests that classical pathway dysfunction, such as C4Nef, lies upstream of the complement dysregulation in this case. Nonetheless, the prompt response to iptacopan points to alternative pathway amplification as the principal driver of active disease, supporting factor B inhibition as a viable strategy in C3G.