Inside IgA nephropathy deposits: dimeric IgA with IgG1, and alternative-pathway complement

Design

Proteomic biopsy study (laser microdissection and mass spectrometry)

Population

22 IgA nephropathy biopsies

Primary outcome

Composition of immune and complement deposits

Effect

IgA1 100%, IgA2 82%, J chain 91%, IgG1 100%; predominantly alternative and terminal complement

This study used laser microdissection and mass spectrometry on glomeruli from 22 IgA nephropathy biopsies to identify exactly what the deposits contain.

IgA1 was found in all cases and IgA2 in 82%. J chain, which links IgA into dimers, was present in 91%, but secretory component in only 9%, pointing to dimeric IgA of mucosal origin. IgG1 was in every case and co-localised with IgA. Complement proteins were mainly from the alternative and terminal pathways — C3, C5 to C9 — with less C4, alongside regulators including factor H and its related proteins, particularly CFHR5. Higher C3, C5, C9 and CFHR5 counts were seen in active lesions, though not significantly.

This is a small mechanistic study, but it fits the biology behind the drugs now in trials, which target APRIL and BAFF, which drive IgA production, and alternative or terminal complement.

• Deposits contained dimeric IgA1 and IgA2 with IgG1 in every case studied.
• Complement came mostly from the alternative and terminal pathways.
• This supports the rationale for complement- and APRIL-targeted therapies under study.
• Routine biopsy reporting does not need to change on this evidence.

Why it matters

It links biopsy biology to the treatment classes now reaching phase 3 results.

Don't overread it

Twenty-two biopsies cannot establish that complement levels predict outcome or treatment response.

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