What is new in the pathogenesis and treatment of IgA glomerulonephritis

Abstract

Recently, new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis. The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease. All these new genes apply to each of the four hits. Additionally, new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis. The IgA treatment is also changed included the future possibilities. The treatment of the chronic kidney disease, associated with the nephropathy, is mandatory, since the beginning of the disease. The classical immunosuppressive agents have poor effect. The corticosteroids remain an important cornerstone in any phase of the disease. More effect is related to the treatment of B cells and plasma cells. In particular, in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents. Most of these studies are to date in phase II/III. Finally, new agents targeting complement are arising. These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.

Key Words: IgA nephropathy; Anti IgA autoantibodies; Genetic wide association studies; Microbiota; Anti B cell-activating factor agents; Anti A proliferation-inducing ligand agents; Anti complement agents

Core Tip: Genetic wide association studies (GWAS) and studies on microbiota allowed finding new aspects in pathogenesis of IgA nephropathy. GWAS allowed finding new genes related to the different IgA nephropathy phases. Microbiota allowed finding new roles exerted by microbes in mucosa immune system and in IgA pathogenesis. Treatment of chronic kidney disease must be always associated to the immune treatment. In the latter fundamental role is exerted by steroids. Recent studies found the relevance of anti B cell-activating factor and anti A proliferation-inducing ligand agents even if the majority of these studies are still in phases II/III. Similarly in premarketing studies are the anti-complement agents.

INTRODUCTION

The aim of this study has been to check what is new in the pathogenesis and treatment of the IgA glomerulonephritis, one of the most common nephropathies in the world. Indeed, genetic wide association studies (GWAS) have allowed to confirm the old hypothesis of the four hits pathogenesis, but added several genes involved in the pathogenesis. Similarly, new findings have been found in the fields of microbiota, as important causes of the disease. The treatment also has been reviewed. The necessity to add to the immune therapy, the treatment of the chronic kidney disease (CKD) has been confirmed. Concerning the immunological therapy, in addition to the corticosteroids, new drugs anti B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) and anti-complement cascade are in trials. Some of them are already in phase III and ready to enter the marketing.

IgA glomerulonephritis is the most common form of primary glomerulonephritis worldwide. Up to 50% of patients with IgA nephropathy (IgAN) develop end-stage kidney disease (ESKD) and require dialysis, and 10% of patients on dialysis have IgAN. Sixty percent of IgAN patients with ESKD receive one or more kidney transplants. Overall, 200000 people in the United States have IgAN, and 200000 people in Europe have IgAN. Most likely, in Asia, this glomerulonephritis is more common, 130000 people in Japan have IgAN, and 800000 people in China have IgAN.

IgAN is characterized by high heterogeneity and high-unmet medical needs. It is characterized by dominant IgA glomerular deposits, highly variable clinical presentation[1] and different histological features such as interesting glomeruli, tubules, interstitial and vessels. In addition, the clinical course may be highly variable[1]. The mechanisms responsible for the presentation and development of IgAN are incompletely understood, and the development of highly targeted therapies for this disease has been limited[2].

PATHOGENESIS

Under normal conditions, the hinge region is unique to IgA1. Indeed, it consists of repeating sequences of proline, serine and threonine, and it carries multiple O-linked carbohydrate side chains. Each O-glycan chain is based on a core N-acetyl galactosamine unit that is O-linked to serine or threonine. Moreover, abnormalities in O-glycosylation represent hit 2 of the development of IgA nephritis.

The interactions of different pathogenic elements are required to produce IgAN. The fraction of total serum IgA that has a propensity for mesangial deposition is small, and the fraction capable of initiating glomerulonephritis is still small[3]. The response of the mesangium, particularly the mesangial cells, to the deposited IgA is critical for the development of IgAN. Failure of mesangial cell clearance mechanisms could contribute to mesangial IgA accumulation, whereas mesangial cell activation with the release of proinflammatory cytokines and extracellular matrix components drives glomerulonephritis and glomerulosclerosis. Without an appropriate genetic predisposition to develop IgAN, IgA deposition can be a benign process with little to no risk of triggering glomerulonephritis; however, given an appropriate genetic background, serum IgA responses favor mesangial IgA deposition, and the mesangial response takes on a proinflammatory phenotype, resulting in clinically significant IgAN of varying severity.

A multi-hit mechanism has been proposed to clarify the pathways involved in the pathogenesis of IgAN.

Accordingly, in hit 1, galactose-deficient IgA1 is produced by a subpopulation of IgA1-secreting cells. IgA1 production may be affected by the IgAN-associated locus on chromosome 22q12.2[4]. Hit 2 includes the formation of antiglycan antibodies with specific characteristics of the variable region of the heavy chain that recognize galactose-deficient IgA1. In hit 3, immune complexes are formed from autoantigens (galactose-deficient IgA1) and O-glycan-specific antibodies. Hits 2 and 3 may be regulated by the three major histocompatibility complex loci on chromosome 6p21 associated with the risk of IgAN[4]. In hit 4, there is the deposition of pathogenic immune complexes in the mesangium, activation of mesangial cells and induction of glomerular injury. Hits 3 and 4 may be affected by the genotype at the complement factor H locus on chromosome 1q32, which regulates the alternative complement cascade. One pathway involves the formation of immune complexes in the circulation and their subsequent mesangial deposition[5-8]. In an alternative pathway, some aberrantly glycosylated IgA1 molecules are in the mesangium as lanthanide deposits and are later bound by newly generated antiglycan antibodies to form immune complexes in situ, which activate mesangial cells[9] (Table 1).

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.

According to the data shown, there are different pathogenic processes according to the hit considered, different putative environmental factors, different putative genetic factors, different potential clinical biomarkers and, therefore, different potential novel therapeutic approaches[10].

The importance of genetics in determining IgAN and high serum galactose deficient (Gd)-IgA1 levels has been documented by several GWAS, as documented by the review of Xu et al[11] and as shown in Table 2[11-19]. One of the most important cited studies is the one conducted by Kiryluk et al[20], in 2023. This study was conducted on a large population (10146 kidney biopsy-diagnosed IgAN patients and 28751 matched controls across 17 international cohorts). Additionally, the study defined 30 independent risk loci in IgAN.

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)

Overall, the review of Xu et al[11] supported the multi-hit hypothesis. Indeed, genes responsible for the dysregulation of mucosal innate immunity (DEFA, CARD 9, TNFSF 13), genes responsible for immune cell proliferation and abnormal IgA production (LYN, FCRL3, CD28; TNFGF12/13), genes responsible for the production of galactose-deficient IgA1 (CIGALT1, GALNT12) and, at the circulatory level, genes responsible for the formation of autoantibodies against galactose-deficient IgA1 (HLA-DRA) have been identified. Finally, at the kidney level, genes responsible for the activation of the complement system and cytokine production have been identified (ITGAM-ITGAX).

Genetics alone are important in promoting the development of IgA glomerulonephritis, but the abnormal handling of the microbiota and the inflammatory phenotype are similarly important factors[20].

Alterations in the gut microbiome are considered novel factors involved in the pathogenesis of IgAN. Dysbiosis ultimately results in changes in microbial functions, including changes in biochemical processes and fermentation. Loss of immune equilibrium could increase the susceptible of the host to intestinal infections. Intestinal infections prime the class switch of B cells, leading to the overproduction of Gd-IgA1. Excess Gd-IgA1 acts as an autoantigen and is bound to autoantibodies such as IgG or IgA. These immune complexes are deposited in the glomerular mesangium, where they are involved in processes such as mesangial proliferation. A series of downstream pathways, including the complement system, are activated, leading to inflammation and glomerular injury[21-28]

Mucosal infections are implicated in the pathogenesis of IgAN through three hypotheses. According to one hypothesis, specific pathogens are believed to be involved in the initiation and progression of IgAN. Several pathogens can be directly detected in renal tissue. Several other pathogens, such as Helicobacter pylori and poliovirus, affect the production of IgA1 and the hypogalactosylation process[29,30]. According to another hypothesis, the occurrence of tonsillitis is believed to be related to IgAN. Clinically there is a close relationship between upper respiratory tract infections and hematuria. Morphologic analyses have shown that tonsils are important producing sites of Gd-IgA1. Additional evidence includes microbiome analysis of tonsillar crypts in IgAN, genetic association analysis (HORMAD2) and the effectiveness of population-based tonsillectomy[31]. Thus, chronic and persistent tonsillitis might be involved in disease pathogenesis. According to a third hypothesis, intestinal infections caused by alterations in the gut microbiome have been recognized as critical inducers of the pathogenesis of IgAN[32]. Indeed, persistent antigenic stimulation causes aberrant mucosal immune responses, affecting the class switch of B-cell and the overproduction of IgA. Additionally, the gut microbiota post-translational modifies IgA1 in autoimmune glomerulonephritis[33].

A recent study from He et al[34] analyzed the potential roles of the oral microbiota in the pathogenesis of IgAN. In this study, saliva samples from 31 patients affected by IgAN and 30 controls were collected and analyzed via 16S rRNA gene sequencing. Microbial diversity was reduced in IgAN patients and microbes, such as Capnocytophaga and Haemophilus were associated with increased levels of proteinuria. In addition, in IgAN, metabolic pathways such as glycosphingolipid synthesis and N-glycan biosynthesis were enriched. The authors conclude that alterations in the oral microbiota are associated with IgAN. In another study, Currie et al[35] characterized the tonsil microbiota of patients affected by IgAN. These authors reported an elevated presence of the genus Neisseria. In vitro the authors found that in mice affected by IgAN, with the enzyme-linked immune spot assay, the kidneys of these mice contained anti Neisseria-specific IgA secreting cells.

For many years, the relevance of the microbiota in IgAN has been recognized[36]. In 2011, the first description of the gut microbiota in animal models of IgAN was published. By the beginning of 2020, disturbance of the intestinal microflora was recognized to be important for the severity of IgAN, as was the potential of the gut microbiota as a specific biomarker in the pathogenesis of IgAN. More recently, microbial profiles have been shown to be useful for distinguishing IgAN patients, and the gut microbiota in newly diagnosed IgAN patients with CKD stages 1-2 is different from that in healthy controls.

In a recent study, Zhu et al[37] reported that in IgAN, the gut microbiome regulates the production of hypoglycosylated IgA1 via the TLR4 signaling pathway. Indeed, the overproduction of Gd-IgA1 correlated with gut dysbiosis, and TLR4 and B-cell stimulators and the TLR4 inhibitor; TAK242 inhibited the overproduction of Gd-IgA1 and B-cell stimulators in peripheral blood mononuclear cells from IgAN patients and controls. In another recent study from Cai et al[38], systematic microbiome dysbiosis was associated with IgAN. The study enrolled 505 participants and performed 16S rRNA gene sequencing on samples from the mouth, pharynx, gut and urine. The microbial abundance in the samples was used to predict IgAN, and an accuracy of 0.879 was obtained.

In addition to genetics and the microbiome, other factors intervene in the genesis of IgAN.

Toll-like receptor 9 and 7 stimulation induces aberrant expression of a proliferation-inducing ligand by tonsillar germinal center B cells in IgAN[39], and (Myotubularin-related protein 3 gene) MTMR risk alleles increase Toll-like receptor 9-induced IgA immunity in IgAN[40]. Therefore, targeting IgA-regulating genes has therapeutic importance as shown in Figure 1.

Figure 1 Targeting regulating genes. MTMR3: Myotubularin related protein 3; TLR9: Toll like receptor 9.

Another important factor is the existence of a mucosa bone marrow axis in patients with IgAN[41]. As shown in Figure 2, IgAN patients have an impaired IgA immune response in the mucosa that causes impaired elimination/exclusion of mucosal antigens. Therefore, there is an increased level of immunologic memory for IgA1 production in bone marrow or other lymphoid tissues. This ultimately causes IgAN1 hyporesponsiveness to recall antigens and increased production of nephritogenic IgA1.

Figure 2 Induction of IgA nephropathy.

Figure 3 shows the potential therapeutic targets for IgAN based on the findings of GWASs[42]. Basing on what is described, it can be stated that: IgAN is a heterogeneous disease with complex underlying pathophysiology, and current options are variable and often not sufficient. The evolving understanding of the pathogenic pathways of IgAN has led to the discovery and development of new treatments for more targeted therapies. Identifying better biomarkers and establishing evaluative systems for new treatments may help in identify more precise targeted treatments for patients with IgAN.

Figure 3 Potential targets for IgA nephropathy based on findings from genetic wide association studies. ETAR: Endothelin angiotensin inhibitor; SGLT2: Sodium-glucose cotransporter; MRA: Mineralocorticoid receptor antagonists; AP: Alternative pathway; LP: Lectin pathway; CP: Classical pathway.

TREATMENT

Figure 3 shows the different treatments according to the four hit theories confirmed by GWAS. From the clinical point of view is better to distinguish the different treatments according Figure 4. One the one hand, we have to address treatment against immune inflammation; on the other hand, we have to address different stages of CKD. In all patients, these treatments should be addressed simultaneously.

Figure 4 Treatment for IgA nephropathy. SGLT2: Sodium-glucose cotransporter; MRA: Mineralocorticoid receptor antagonists; GLP-1: Glucagon-like peptide-1; CKD: Chronic kidney disease; DEARA: Dual endothelial angiotensin receptor antagonist.

Like CKD of different origins, IgAN is essential to prevent or control CKD if it is present.

This can be addressed in different ways, as shown in Figure 4. First, optimal control of blood pressure and proteinuria is essential. These factors delay CKD progression in patients with any type of renal disease (including IgAN)[43].The optimal control of blood pressure includes several aspects of lifestyle modification, such as salt restriction, dietary modification, weight reduction, smoking cessation and physical activity. Medications may include angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs)[44-47].

Sodium-glucose cotransporter inhibitors (SGLT2is) inhibit glucose reabsorption from the proximal tubule and cause glycosuria and natriuresis. Glycosuria is essential in controlling prediabetes and diabetes, whereas natriuresis contributes to a reduction in plasma volume and in preload. Additionally, intraglomerular pressure and glomerular hyperfiltration are reduced with a nephroprotective action[48]. Two studies[49,50] documented a protective effect in CKD patients. A different molecule still belonging to SGLT2 (empaglifozin) has been used in the EMPA-KIDNEY trial. Among 6609 CKD patients, 817 patients with IgAN were included in the trial. Overall, empaglifozin was associated with a reduction in kidney disease progression[51].

In prediabetic patients with IgAN, the efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists has been proven. In a meta-analysis by Salamah et al[52], its efficacy was proven in 2903 patients with prediabetes and CKD. Unfortunately, how many patients are affected by IgAN has not been clarified, but owing to the good results of the study, GLP-1 may be added to the drugs used in CKD patients.

In the HAKA multicenter retrospective study on patients affected by advanced CKD[53], the efficacy of other drugs, such as renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists, was proven to be affected principally by heart complications when given in association with SGLT2. Sparsentan is a molecule that targets dual endothelin angiotensin receptor antagonist. In addition to the vascular effect, it ameliorates glomerular hypercellularity and inflammatory-gene networks. In a recent mouse model, its efficacy in IgAN was documented[54]. The study PROTECT is designed to determine the long-term antiproteinuric and nephroprotective potential of treatment with sparsentan compared head-to-head with active control irbesartan, an ARB, in patients with IgAN. There is a strong scientific rationale for the dual antagonism of endothelin and angiotensin receptors in IgAN, which is supported by extensive preclinical data. The PROTECT study interim analysis clearly revealed the superiority of sparsentan in reducing proteinuria compared with the active control irbesartan.

Immunosuppressive treatment

Immunosuppressive treatment for IgAN should principally be considered for patients at high risk of evolution because of the clinical, pathogenetic and evolution of renal function. Several immunosuppressive treatments (cyclophosphamide, azathioprine, calcineurin inhibitors) have not been shown to be effective in treating IgAN[55]. Uniform data concerning the use of mycophenolate mofetil are not available[56-58]. In these patients, corticosteroids in combination with supportive care are recommended.

Among the different glucocorticoids, the target-release formulation of budesonide should be considered. Budesonide is a drug that is released in the distal ileum and acts on IgA1 released from Peyer patches. Budesonide acts on IgA1 produced by the mucosa, which is the main source of undergalactosylated IgA1.

Budesonide has been studied in an randomized controlled trial (RCT) phase 3 trial (NefIgArd)[59]. A total of 199 patients were enrolled. At 9 months, a reduction in proteinuria and a reduction in the epidermal growth factor receptor (EGFR) were observed. These results were confirmed by other controlled and uncontrolled studies[60-62]. Overall, the principal studies with corticosteroids are reported in Table 3.

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

In the largest RCT on glucocosteroids in IgA nephritis (TESTING)[64], 503 patients were enrolled. Proteinuria greater than 1 g /day was present in all patients, and oral methylprednisolone was given at dosage of 0.6/0.8 mg/kg/day. A reduction in proteinuria and a reduction in the loss of EGFR were observed, but there was an excess of infection. The study was repeated by the same authors with a reduced corticosteroid dose (0.4 mg/kg/daily)[63], obtaining similar results with a lower rate of infection. Another study by Manno et al[65] and Lv et al[66] reported good results with the use of prednisone in combination with ACE inhibitors. Pozzi et al[67] obtained similarly good results with a different strategy. The patients were given 1 g of IV methylprednisolone for 3 days at the beginning of months 1, 3 and 5, followed by 0.5 mg of prednisone orally every other day. Finally, Rauen et al[68] obtained very good results in the STOP-IgAN trial[68], who administered prednisolone or prednisone at the dose of 0.5 mg/kg orally every other day in addition to complete supportive care (Table 3).

As B cells are responsible for producing Gd-IgA1, targeting B cells is considered an optimal treatment to improve renal outcomes in patients with IgAN. Rituximab, a chimeric monoclonal agent that targets CD20, was used in a controlled trial to control IgAN[69]. A study of 34 patients documented a lack of efficacy. Since then, several other drugs have been used to control IgAN. The majority are still in clinical development and are shown in Table 4.

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.

We have previously described the beneficial effect of Sparsentan, which is among the no- immunosuppressive drugs, on IgAN[70]. Atresantan is a selective endothelin A receptor antagonist used in IgAN patients in the ALIGN trial[71] for the treatment of IgAN with deterioration of renal function. Felzartamab is a monoclonal IgG1 antibody that targets CD38 on plasma cells[72]. It is used in a phase II trial (NCT05065970) with decreasing renal function. Bortezomib, a proteasome inhibitor, depletes plasma cells and, in addition to multiple myeloma has been used for to reduce proteinuria in a pilot trial[73]. TNF ligand superfamily member 13 B (BAFF and APRIL) are important triggers of autoimmunity and are involved in several types of glomerulonephritis, included IgAN. These data indicate that alterations in the BAFF/APRIL system affect the capacity of the innate immune system to regulate B-cell activation. BAFF and type I interferons function together in different forms of glomerulonephritis pathogenesis in both Toll-like receptor-dependent and Toll-like receptor-independent manners.

BAFF and APRIL are type II transmembrane proteins located on myeloid cells, lymphocytes and epithelial cells. BAFF can be processed into a soluble cytokine after cleavage at a furin protease site. APRIL is soluble and has been cleaved intracellularly. Both BAFF and APRIL are responsible for B-cell maturation, proliferation and survival after binding to their receptors. BAFF receptors include B-cell maturation antigen (BCMA) and BAFF receptor. The APRIL receptors are BCMA and transmembrane activator and cyclophilin ligand interactor (TACI). Another receptor for APRIL is heparan sulfate proteoglycan, which is responsible for the homing of plasma cells to the bone marrow[74].

Both APRIL[75] and BAFF[76] are extremely elevated in IgAN patients with respect to controls. Most likely, according to Schrezenmeier et al[77], APRIL is more active than BAFF in IgAN. According to the already cited GWAS of Kiryluk et al[20], the gene TNFSF13 encodes APRIL as a susceptibility gene. According to the study of Zhai et al[75], there is a correlation between GdIgA1 and APRIL According to a study from Han et al[78], the serum and mucosal levels of APRIL correlate with the severity and prognosis of IgAN. APRIL, rather than BAFF, is involved in IgAN recurrence after transplantation. Indeed, a study from Martín-Penagos et al[79] reported that this increase in the expression of proliferation-inducing ligands precedes the recurrence of IgAN in kidney transplant recipients. Kim et al[80], have reported a pathogenic role of APRIL in murine IgAN. Therefore, Myette et al[81] reported that an antibody targeting APRIL is a safe and effective treatment for murine IgAN.

Recently, several drugs have been used to control BAFF and APRIL in human patients affected by IgAN. All these studies are to date in different phases of RCTs. Blisibimob is a monoclonal antibody against both soluble and membrane BAFF. In a phase II/III study (BRIGHT-SC study) (NCT020 62684)[82], Blisibimob reduced proteinuria in IgAN patients. Sibenprelimab is a monoclonal IgG2k antibody that targets APRIL. In a phase II trial conducted by Mathur et al[83] (NCT05248646), the 24-hour urinary protein-to-creatinine ratio decreased significantly, and the decrease was dose-dependent. Zigakibart (BION-1301) is a monoclonal IgG4 antibody that targets APRIL In a phase I/II, a multicenter trial investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of BION-1301[84] (NCT03945318) was conducted in 40 healthy volunteers and adults with IgAN.

Recently, the same drug was the subject of a phase III RCT (NCT05852938) (BEYOND study)[85]. This study will document and confirm the beneficial effects on proteinuria, the EGFR and key safety measures in IgAN patients at risk of progressive loss of kidney function. Atacicept is a BAFF/APRIL dual inhibitor in a phase III study (ORIGIN 3) (NCT04716231)[86]. It is a soluble TACI immunoglobulin fusion protein. This study aimed to asses to check the reduction in Gd-IgA1 antibody levels and proteinuria in IgAN patients. Telitacicept, another BAFF/APRIL inhibitor (NCT049505212)[87], is in a phase II trial and, given to 44 patients affected by IgAN, is associated with a dose related reduction in IgA and proteinuria and a reduction in the EGFR. Povetacicept (ALPN-303) is an enhanced dual APRIL/BAFF antagonist in a phase I/II trial (NCT05732402). In a study conducted by Evans et al[88], multiple dose levels were evaluated in patients with IgAN, membranous nephropathy, lupus nephritis and ANCA vasculitis. Povatacicept has been shown to be effective in improving the clinical outcomes of patients with autoantibody-related autoimmune diseases.

Inhibitors of immune-complex-activated complement activity constitute the last group of agents. These agents operate on the fourth hit after immune complex deposition in the mesangium and consequent complement activation. Both the lectin pathway and alternative pathway are activated, and glomerular inflammation is generated by interleukin 6 and tumor growth factor beta 1[89]. Glomerular C3 deposition leads to a poor clinical outcome[90]. Several phase II/III studies to date are ongoing, targeting different phases of complement activation. Avacopan is an anti-C5ab receptor antagonist that has been proven to improve the protein-creatinine ratio[91]. Ravalizumab is a long-acting C5-blocking antibody. Its efficacy is under investigation by the SANCTUARY study, NCT04564339[92]. Cemdisaran is a small interfering RNA that targets C5. To date, this agent is in a phase 2, randomized, double-blind, placebo-controlled trial in adult patients with IgAN (NCT03841448)[93].

APL-2 is a cyclic peptide inhibitor of C3 and C3b. To date, a phase 2 study (NCT03453619)[94] was performed to evaluate the safety and biological activity in patients with IgAN, lupus nephritis membranous nephropathy and C3 glomerulopathy.

Similarly, Iptacopan is a small-molecule inhibitor of complement factor B. This agent reduces proteinuria in IgAN patients and will be further evaluated in a phase III APPLAUSE-IgAN trial (NCT04578834)[95]. IONIS-B-LRx is an antisense inhibitor of complement factor B messenger ribonucleic acid. In phase II, its effect on plasma factor B levels and serum AH50, and CH50 activity in patients with IgAN is being evaluated (NCT04014335)[96]. Narsoplimab is a human monoclonal antibody against mannan-associated lectin-binding serine protease-2 that inhibits the lectin pathway. In a phase II trial, Narsoplimab reduced proteinuria[97]. The safety and efficacy of the agent is currently being evaluated in the phase III ARTEMIS-IGAN trial (NCT03608033)[98].

In conclusion, the vast majority of these agents are still in different phases of randomized clinical trials. Obviously, we have selected the ongoing, enrolling and more promising trials. B-cell modulation with anti-APRIL or with the combination of anti-BLYS/BAFF and APRIL appears promising. Early signals suggest tolerable administration and limited adverse effects, with no significant concerns for infection to date. These agents seem to have potent, stable effects on the EGFR while maintaining a reduction in the Gd-IgA level, proteinuria and likely hematuria. We are waiting to see if phase III can identify differences between agents and classes.

Since a long time[99] the main limitation in evaluating the drug efficacy in IgAN has been the few controlled randomized studies. This fact is true also to date, also because of the new agents on trial. A revision of the main limitations and gaps of the drug used has been recently made by Caster et al[100]. According this study tonsillectomy may be used, but is limited by the geographic genes. The use of SGLT2 inhibitors is still awaiting the results of controlled studies, in particular the analysis of the empagliflozin study. Main problem with the use of the targeted release budesonide are that long-term outcomes are still pending and the high cost of the treatment. Studies on the use of corticosteroids are the STOP IgAN and the TESTING trial. The first has the limitation that the ongoing study did not document differences in the kidney outcomes between the two groups on study. The second documented a high incidence of adverse effects. The principal agent on study against B-Cell, is the anti-April. Concerning this agent we are still awaiting the phase 3 results, checking in particular the infections rate and the infusion reaction. Similarly, infections and infuse reactions concern the use of anti plasma-cell agents. Recently, several agents inhibiting complement have been proposed in the treatment of IgAN. The main knowledge gap is the evaluation of the relative contribution to the disease of the lectin and the alternative pathways and the importance of determining the dominant pathway driving IgAN progression[101]. In addition, all these studies are still in phase 2 or 3.

CONCLUSION

Following the still valid four hit hypotheses, new recent studies allowed finding new aspects in the pathogenesis and in the treatment of IgAN. Several GWAS studies found genes responsible for the dysregulation of mucosal immunity, gene responsible for the immune cell proliferation, genes responsible for the production of galactose-deficient IgA1 and genes responsible for the activation of complement. For the treatment is essential to associate the classic CKD treatment to the more specific immune treatment. Standard immunosuppressive therapy has poor utility, except for the corticosteroids treatment. Targeting B cells and plasma cells seems to be essential. Among these agents, those targeting BAFF and APRIL have the higher utility. These agents are still in phase II or III, but their results seem to be important in several nephropathies, included the IgAN. Other new agents, still in RCTs are the anti-complement agents, which acts principally in the fourth hit stage.