What is new in the pathogenesis and treatment of IgA glomerulonephritis

Table 1 The summary of the four hits involved in the pathogenesis of IgA nephritis

Hit	Pathogenetic process	Putative environmental factors involved	Putative genetic factors involved	Potential clinical biomarkers	Potential novel therapeutic approaches
1	Hereditary increase in circulating galactose-deficient IgA1	Potential role of mucosal exposure to infectious of dietary antigens	Strong evidence for high heritability of serum galactose-deficient IgA1 level. Potential role of chromosome 22q12.2	Serum galactose-deficient IgA1 level (HAA based ELISA)	Suppression of synthesis of galactose-deficient IgA1. Enzymatic boost of galactose transfer to IgA1 hinge region O-glycans
2	Circulating antibody directed against galactose-deficient IgA1	Potential role of mucosal exposure to infectious or dietary antigens	Potential role of three MHC-II loci in antigen presentation and humoral response to galactose-deficient IgA1 O-glycans	Serum anti-glycan antibodies (dot-blot assay)	Alteration of processing and presentation of galactose-deficient IgA1 O-glycopeptides. Specific B-cell depletion therapy
3	Formation of pathogenic IgA1-containing immune complexes	Unknown	Unknown	Circulating and/or urinary immune complexes	Competitive blockade of immune complex formation by non-cross-linking anti-glycan antibodies or specific glycopeptides
4	Mesangial deposition of IgA1-containing immune complexes, cell activation and initiation of glomerular injury	Unknown	Protective effect of common deletion in CFHR1 and CFHR3	Circulating and/or urinary complement degradation products, or novel markers of glomerular injury	Suppression of the alternative complement pathway. Targeted CFHR1/3 depletion. Blocking mesangial cell signaling induced by nephritogenic IgA1-containing immune complexes

HAA: Helix aspersa agglutinin; ELISA: Enzyme-linked immunosorbent assay; MHC-II: Major histocompatibility complex.

Table 2 The association between genetic wide association studies and new candidate genes

Ref.	Published date	Ancestry	GWAS population	Genome-wide significant loci (candidate gene)
Susceptibility to IgA nephropathy
Feehally et al[12]	2010	European ancestry	244 cases and 4980 healthy controls	6p21 (HLA)
Gharavi et al[4]	2011	Chinese and European ancestry	3144 cases and 2822 healthy controls	6p21 (HL-DQB1/DRB1; PSMB9/TAPI; HLA-DPA1/DPB2), 1q32 (CFHR3/R1), 22q12 (HORMAD2)
Yu et al[13]	2011	Chinese ancestry	1434 cases and 4270 healthy controls	6p21 (HLA), 8p23 (DEFAs), 17p13 (TNFSF13), 22q12 (MTMR3)
Kiryluk et al[14]	2014	European and East Asian ancestry	7658 cases and 12954 healthy controls	6p21 (HLA-DQ-HLA-DR; TAP1-PSMB8; HLA-DP), 1p13 (VAV3), 1q32 (CFHR3-CFHR1 deletion), 8p23 (DEFAs), 9q34 (CARD9), 16p11 (ITGAM-ITGAX), 17p13 (TNFSF13), 22q12 (HORMAD2)
Li et al[15]	2015	Chinese ancestry	1434 cases and 10661 healthy controls	6p21 (HLA), 3q27 (ST6GAL1), 8p23 (DEFA), 8q22 (ODF1-KLF10), 11p11 (ACCS), 16p11 (ITGAX-ITGAM, 22q12 (HORMAD2)
Jeong et al[16]	2019	Korean ancestry	188 cases and 455 healthy controls	10p15 (ANKRD16)
Li et al[17]	2020	Chinese and European ancestry	2628 cases and 11563 healthy controls	6p21 (HLA), 1q23 (FCRL3), 1p36 (PAD14), 6p25 (DUSP22/IRF4), 8p23 (DEFA), 16p11 (ITGAX-ITGAM), 17p13 (TNPSF12-TNPSF13), 22q12 (MTMR3/HORMAD2)
Zhou et al[18]	2021	Chinese ancestry	601 cases and 4076 healthy controls	6p21 (GABBR1), suggestive genes (TGFB1, CCR6, STAT3, CFB)
Li et al[19]	2023	Chinese ancestry	2378 cases and 15642 healthy controls	6p21 (HLA), 6p21.1 (VEGFA), 16q22.2 (PKD1 L3), 17p13 (TNFSF13)
Kiryluk et al[20]	2023	European and East Asian ancestry	10146 cases and 28751 healthy controls	6p21 (HLA), 8 known non-HLA loci (CFH, FCRL3, IRF4/DUSP22, DEFA ¼, CARD9, ITGAM/ITGAX, TNFSF 13/12, MTMR3/HORMAD2/LIF/OSM), 16 new non HLA loci (TNFSF4/18, CD28, REL, PF4V1, LY86, LYN, ANXA13, TNFSF8/15, ZMIZ1, REEP3, OVOL1/RELA, ETS1, IGH, IRF8, TnFRSF13B, and FCAR) CCR6 (only in the East Asian cohorts)
Serum Gd-IgA1 levels
Gale et al[21]	2017	European and Chinese ancestry	513 subsets	7p21 (C1GALT1)
Kiryluk et al[22]	2017	European and East Asian ancestry	2633 subsets	7p21 (C1GALT1), Xq24 (C1GALT1C1)
Wang et al[23]	2021	Chinese ancestry	1127 patients with IgAN	7p22 (C1GALT1), 9q22 (GALNT12)

Table 3 Glucocorticoid regimens used in clinical trials of IgAN

Ref.	Medication	Initial dose	Taper	Total exposure
Lv et al[63]	Methylprednisolone	0.4 mg/kg orally once daily	Reduce daily dose by 4 mg every month	6 months
Lv et al[64]	Methylprednisolone	0.6 to 0.8 mg/kg orally once daily	Reduce daily dose by 8 mg every month	6 months
Manno et al[65]	Prednisone	1 mg/kg orally per day	Reduce daily dose by 0.2 mg/kg every month	6 months
Lv et al[66]	Prednisone	0.8 to 1 mg/kg orally per day	Reduce daily dose by 5 to 10 mg every 2 weeks	6 months
Pozzi et al[67]	Methylprednisolone	Methylprednisolone 1 g IV for 3 days, followed by prednisolone	None	6 months
Rauen et al[68]	Prednisolone/prednisone	Prednisolone or prednisone 05 mg/kg orally ever other day	None	6 months
Fellström et al[59]	TRF- budesonide	16 mg orally daily	Reduce dose to 8 mg once daily for 2 weeks	9 months

Table 4 Investigation agents in clinical development for the treatment of IgAN

Agent	Phase	Registration number	Mechanism of action
Inhibition of endothelin A receptor and angiotensin II subtype 1 receptor inhibitor
Sparsentan	III	NCT03762850	Endothelin A receptor and angiotensin II subtype 1 receptor inhibitor
Atrasentan	III	NCT04573478	Endothelin A receptor antagonist
Plasma cell depletion
Felzartamab	II	NCT05065970	Monoclonal IgG1 antibody targeting CD38
Bortezomib	NA	NCT05383547	Proteasome inhibitor that depletes plasma cells
Inhibition of BAFF/APRIL signaling
Blisibimod	II/III	NCT02062684	Monoclonal antibody against both soluble and membrane BAFF
Sibeprenlimab		NCT05248646	Monoclonal IgG2k antibody targeting APRIL
BION-1301	I/II	NCT03945318	Monoclonal IgG4 antibody targeting APRIL
Atacicept	IIb	NCT04716231	BAFF/APRIL dual inhibitor
Telitacicept	II	NCT04905212	BAFF/APRIL dual inhibitor
Povetacicept	I	NCT05034484	BAFF/APRIL dual inhibitor
Zigakibart (BION-1301)	III	NCT05852938	Monoclonal IgG4 antibody targeting APRIL
Inhibition of immune complex-activated complement activity
Avacopan	II	NCT02384317	Anti-C5ab receptor antagonist
Ravulizumab	II	NCT04564339	Long-acting C5-blocking antibody
Cemdisiran	II	NCT03841448	Small interfering RNA-targeting C5
APL-2	II	NCT03453619	Cyclic peptide inhibitor of C3 and C3b
Iptacopan	III	NCT04578834	Small-molecule inhibitor of complement factor B
IONIS-B-LRx	II	NCT04014335	Antisense inhibitor of complement factor B messenger ribonucleic acid
Narsoplimab	III	NCT03608033	Human monoclonal antibody against MASP-2

MASP-2: Mannan-associated lectin-binding serine protease-2; BAFF: B cell-activating factor; APRIL: A proliferation-inducing ligand.