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Kidney International (2024) 105, 1; https://doi.org/10.1016/j.kint.2023.11.009
Society of Nephrology.
Results of a randomized
double-blind placebo-
controlled Phase 2 study
propose iptacopan as an
alternative complement
pathway inhibitor for IgA
nephropathy
The alternative complement pathway
(AP) blocker iptacopan was tested as a
therapy for IgA nephropathy (IgAN) in a
phase 2 randomized controlled trial.
Iptacopan binds to factor B, an essential
component for the formation of C3
convertase, leading to amplification of
the AP. By blocking factor B activity,
iptacopan prevents complement
component C3 cleavage and all down-
stream events, such as formation of C5a
anaphylatoxin and the membrane attack
complex. Compared with placebo, pa-
tients treated with iptacopan (200 mg
twice daily) achieved a 23% reduction in
proteinuria after 3 months and a 40%
reduction after 6 months. Kidney func-
tion remained stable in the patients with
IgAN. Complement biomarkers declined
rapidly after initiating iptacopan, with
almost complete absence of the mem-
brane attack complex from the urine
within about a week. More important,
there were no safety signals with iptaco-
pan. Confirmation of these findings is
being sought in a large, ongoing phase 3
trial. See page 189
Complement alternative
pathway determines
disease susceptibility and
severity in antineutrophil
cytoplasmic antibody
(ANCA)–associated
vasculitis
A complement inhibitor has been
approved for the treatment of ANCA-
associated vasculitis (AAV). Lucientes-
Continente et al. therefore studied the
complement system for biomarkers of
AAV susceptibility and outcomes. In a
Kidney International (2024) 105
in this issue
Copyright ª 2023, Published by Elsevier, Inc., on behalf of the International
discovery cohort of patients with AAV CD163þ, M2-like myeloid cells in the
with kidney involvement (76% myelope circulation and the allografts. The in-
roxidase-ANCA), the investigators vestigators postulated that multiple Treg
found that genetic variants coding for a infusions directly after kidney transplant
less active complement factor B were may enhance graft survival by stimulating
significantly decreased in patients with production of kidney-infiltrating protec-
AAV. A validation cohort confirmed this tive M2 macrophages. See page 84
finding. During active AAV plasma C3,
factor B, properdin, and factor H levels
were lower, whereas membrane attack IL-22 is secreted by
complex levels were higher, compared proximal tubule cells and
with inactive AAV controls. Higher
alternative pathway activity was associ- regulates DNA damage
ated with worse prognosis. During suc- response and cell death
cessful treatment and longitudinal in acute kidney injury
follow-up, alternative pathway activity The DNA damage response (DDR) can
decreased. Taken together, the weight of protect against acute kidney injury
the evidence suggests that the alternative (AKI), or if overactivated, it can worsen
complement pathway is relevant to AAV AKI. During AKI and DDR activation,
and may be used to predict disease the interleukin-22 (IL-22) receptor A1
course. See page 177 (IL22RA1) is expressed by proximal
tubular cells. Using 2 animal models of
Multiple infusions of AKI, Taguchi et al. found that proximal
tubular cells make IL-22. Furthermore,
ex vivo-expanded the DDR response was amplified by IL-
regulatory T cells 22. Global deletion of IL-22 protected
promote CD163D against AKI, reduced expression of DDR
components, and inhibited proximal
myeloid cells and kidney tubular cell death. These results were
allograft survival in non- replicated in a more specific proximal
lymphodepleted non- tubular cell knockout of IL-22. The in-
vestigators postulated that IL-22 could
human primates be targeted therapeutically to attenuate
Using a non-human primate model of
AKI but not block the DNA repair ac-
human leukocyte antigen–mismatched tivities of the DDR. See page 99
kidney transplantation, Sasaki et al.
studied the consequences of multiple in-
fusions of autologous, ex vivo antigen-
expanded regulatory T cells (Tregs).
During the first 30 days after kidney
transplantation, increasing doses of Tregs
were infused over 8 sessions. The trans-
planted animals were not lymphode-
pleted before this cell therapy was given.
The anti-rejection regimen consisted of
tacrolimus combined with costimulatory
blockade using cytotoxic T-lymphocyte–
associated protein 4 Ig, and was tapered
over time. Allograft survival doubled
(from 35 to 70 days) for the animals who
received Treg therapy. Treg treatment also
resulted in increased presence of Tregs in
secondary lymphoid tissue and increased
1