Principles for Optimal Drug Selection in IgA Nephropathy—Time for Integrating Pathogenesis and Clinical Markers to Guide Therapy

ABSTRACT

IgA nephropathy is a progressive glomerular disease with a variable clinical course and a substantial risk of progression to end‐stage kidney failure. While proteinuria has long been the central therapeutic target, insights into disease pathogenesis indicate that haematuria should also guide treatment decisions. Based on the pathophysiology of IgA nephropathy—particularly the deposition of galactose‐deficient IgA1 (GdIgA1)‐containing immune complexes and subsequent complement activation—haematuria reflects active glomerular capillaritis. In this context, haematuria serves as a dynamic marker of immunologic injury, whereas proteinuria without haematuria may reflect irreversible breakdown of the glomerular filtration barrier. Therefore, the presence or absence of haematuria helps clarify the underlying mechanisms of proteinuria and informs the selection of appropriate therapeutic strategies. This review proposes a practical framework for drug selection tailored to both disease stage and clinical phenotype. In early, inflammation‐predominant stages marked by haematuria, therapies targeting B/plasma cell function and GdIgA1 production, or complement activation—such as antibodies against APRIL/BAFF or their receptors, and complement inhibitors—may be most effective. In later stages without haematuria, management should focus on chronic structural damage with agents such as RAS inhibitors, SGLT2 inhibitors, and endothelin receptor antagonists. With multiple novel therapies on the horizon, distinguishing between haematuria‐positive and haematuria‐negative proteinuria—each reflecting distinct pathogenic processes—provides critical guidance for selecting and positioning soon‐to‐be‐available new drugs. Integrating this clinical–pathological understanding into treatment planning enables more precise, individualised therapy for IgA nephropathy.

Summary at a Glance

IgA nephropathy is a progressive glomerular disease. While proteinuria has been a key target, haematuria—reflecting active inflammation—should also guide therapy. Recognising haematuria helps distinguish disease mechanisms and clinical stage and thus select appropriate emerging drugs. This review proposes a practical framework based on disease stage and clinical phenotype.

1. Introduction

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. If left untreated, it is a disease with a poor prognosis, with around 40% of cases thought to progress to end‐stage kidney failure [1]. In recent years, the development of new drugs for IgAN has been progressing rapidly. Moreover, multiple new drugs from different classes have been developed, and international clinical trials are underway for each of them. Considering that there have not been enough drugs and treatments for IgAN, these many new drugs will be a great blessing for patients. However, when all the new drugs are on the market, there has not been enough discussion to date about which new drug should be administered to which patient at which disease stage, based on the patient's condition. In this review, treatment approaches will be discussed based on the pathogenesis and disease stage of IgAN.

2. Background to the Development of New Drugs and Basic Therapeutic Strategies

One of the reasons why treatments for IgAN have been developed so rapidly in recent years is that the basic pathogenesis of IgAN has been clarified. For many years, it has been unclear whether the deposition of IgA in the glomerulus is the cause of nephritis or a collateral result in this disease. However, in the past 20 years, various studies have revealed that in IgAN, galactose‐deficient IgA1 (GdIgA1), which has abnormal O‐linked glycosylation at the hinge region of the IgA1 molecule, especially the absence of galactose, triggers the formation of immune complexes (ICs), which in turn induce inflammation in the glomeruli [2, 3, 4, 5]. As a result, the multi‐hit pathological hypothesis, in which GdIgA1 is Hit 1, IgG/IgM autoantibodies against GdIgA1 are Hit 2, and GdIgA1 IC is Hit 3, has become widely accepted [6].

This has made it clear that the basic therapeutic strategy for IgAN can be divided into three main pillars (Figure 1): (1) controlling the production of GdIgA1/GdIgA1‐IC, (2) controlling the acute inflammation that occurs after their deposition in the renal glomeruli, and (3) controlling the progression of glomerular sclerosis/loss of nephrons after repeated inflammation. As shown in Table 1, new drugs related to these three types are being developed. For the first, anti‐APRIL/BAFF drugs are being considered as candidates for controlling the abnormal IgA production programme [7, 8, 9, 10, 11, 12]. Furthermore, development of anti‐CD38 antibodies is also progressing. This is because the responsible cells are thought to be plasma cells of CD38‐positive, more mature and differentiated B‐cell lineage [13, 22]. Intestinal‐action steroids (Nefecon) may also be included in this category [14]. Regarding the second one, at the moment, the focus is on drugs that control the complement pathway activation [15, 16, 17, 18, 19]. For the last one, while RAS inhibitors were the only agents that could be used long‐term, SGLT2 inhibitors [23], MRBs [24] and most recently, endothelin receptor antagonists [20, 21] have been considered as candidates for so‐called CKD management drugs.

FIGURE 1.

Three pillars of pathogenesis‐based therapy in IgA nephropathy. CKD, chronic kidney disease; GdIgA1, galactose‐deficient; IgA1, IC, immune complex.

TABLE 1.

New drugs for IgA nephropathy, including those under development.

Drug	Target	Clinical trial	References
I. B/Plasma cell targeting
Sibeprenlimab	APRIL	P3/accelerated approval	[7, 8]
Zigakibart	APRIL	P3	[9]
Atacicept	APRIL/BAFF	P3	[10]
Telitacicept	APRIL/BAFF	P3	[11]
Povetacicept	APRIL/BAFF	P3	[12]
Mezagitamab	APRIL/BAFF	P3
Felzartamab	APRIL/BAFF	P3	[13]
Nefecon	GALT	Approved	[14]
II. Complement targeting
Iptacopan	Factor B	Approved	[15]
Sefaxersen	Factor B	P3	[16]
ARO‐C3	C3	P1/2
Ravulizumab	C5	P3	[17]
Cemdisiran	C5	P2/completed	[18]
Avacopan	C5aR	P2/completed	[19]
III. CKD management
Sparsentan	ER/AR	Approved	[20]
Atrasentan	ER	P3	[21]

Abbreviations: APRIL, a proliferation ligand; AR, angiotensin receptor; BAFF, B‐cell‐activating factor; C5aR, C5a receptor; ER, endothelin receptor; GALT, gut‐associated lymphoid tissue.

While the treatment targets are becoming clearer, the extremely slow clinical course of IgAN over 20 years has been a major barrier to the development of new drugs. However, the development of this drug was accelerated by the finding that a reduction in urinary protein at 9 months after treatment initiation and the slope of eGFR at 2 years were useful surrogate endpoints for evaluating the therapeutic efficacy of IgAN [25, 26, 27].

3. Clinical Course of IgAN and the Disease Stage

In some Asian countries, medical screening systems, including urinalysis, have been well developed. Particularly in Japan, urinalysis is carried out almost every year from early childhood to the university student stage and even after starting work, and it has contributed greatly to the early diagnosis of kidney and urinary tract diseases [1, 28, 29]. As a result, it is easy to retrace the history of the onset of glomerular diseases such as IgAN. From such clinical experience, it is generally thought that in IgAN, haematuria is the first symptom, and proteinuria appears as the disease progresses [28, 29].

On the other hand, the gross haematuria that is a clinical hallmark of IgAN appears in about 30% of all cases, and most of these cases appear after an upper respiratory tract infection [1, 30]. The frequency of this is reported to be the same in Japan and Europe [30]. However, recently, multiple cases of patients with IgAN presenting with gross haematuria after mRNA vaccination for the new coronavirus have been reported from around the world [31, 32], and the relevance of gross haematuria to the pathogenesis of this disease became the focus of attention again.

Reports on the analysis of donor kidneys in cases of kidney transplants and autopsies have shown that, in 10%–15% of cases, IgA deposition is observed in the glomeruli, even though there are no abnormalities in the urine findings or renal function, or only very slight intermittent haematuria is observed [33, 34]. Because of this, it has been discussed that there may be a stage of IgA‐deposition disease or subclinical IgAN in IgAN [35] (Figure 2a). The possibility of qualitative changes in GdIgA1, such as auto‐reactivity of GdIgA1, has been discussed recently as a factor in the transition from IgA‐deposition disease to IgAN [36, 37, 38].

FIGURE 2.

(a) Clinical and pathophysiological progression in IgA nephropathy. Following an initial asymptomatic stage (subclinical stage), IgA nephropathy typically progresses slowly over the subsequent 15–20 years from an immunologically active stage (characterised by glomerular GdIgA1/IC deposition and complement activation) to an immunologically inactive stage (dominated by glomerular sclerosis and nephron loss, with reduced GdIgA1/IC deposition). Haematuria in IgA nephropathy is thought to result from acute inflammation/glomerular capillaritis due to glomerular deposition of GdIgA1/IC. Therefore, the pathophysiological stage of IgA nephropathy can be inferred from urinary findings. Stage A, accompanied by proteinuria and haematuria, represents the immunologically active phase, while Stage B, proteinuria without haematuria, represents the immunologically inactive phase. These stages require distinct treatment approaches. (b) Treatment algorithm for IgA nephropathy. This stage‐based treatment pathway is structured based on the clinical stages defined in (a). Stage A, characterised by proteinuria and haematuria, is an immunologically active phase driven by persistent glomerular inflammation due to Gd‐IgA1/IC deposition and complement activation. Therefore, it is essentially treated with ‘B/plasma cell targeted agents’, with the addition of ‘complement pathway targeted agents’ considered based on severity, such as progression to RPGN. Stage B, which has proteinuria without haematuria, is an immunologically inactive phase. Therefore, treatment should primarily focus on ‘CKD management drugs’. For Stage A cases with CKD Stage 3 or higher, where advanced glomerulosclerosis is anticipated, consider adding ‘CKD management drugs’ to the ‘B/plasma cell targeted drugs’.

Over many years, chronic deposition (attack) of GdIgA1/GdIgA1IC in the glomerulus leads to glomerular sclerosis, tubulointerstitial fibrosis, and nephron loss. After passing the ‘point of no remission’, the point at which urinary protein no longer disappears due to the increase in sclerotic lesions, irreversible lesions increase further and progress to the ‘point of no return’, the point at which spontaneous renal failure progresses (Figure 2a). Therefore, renal prognosis depends on the timing of diagnosis and intervention during this clinical course, making early diagnosis and treatment ideal. At the same time, it is crucial to determine the disease stage based on this pathophysiology and select appropriate therapeutic agents accordingly.

4. Proteinuria and Haematuria as Indicators of Disease Activity and Staging

4.1. Proteinuria

Proteinuria is caused by structural and functional breakdown of the glomerular filtration barrier [39]. The protein that leaks from the glomerulus is reabsorbed in the renal tubule, and in the process of reabsorption, combined with tubular ischaemia due to decreased post‐glomerular flow, it causes further renal tubular damage. In other words, urinary protein is the result of glomerular damage, but it can also be the cause of tubular damage/fibrosis and the subsequent nephron loss. In fact, in IgAN, the degree of average urinary protein is correlated with renal prognosis [40, 41], and it is widely accepted that the goal of treatment for this disease is to reduce urinary protein as much as possible.

Recently, Yano et al. analysed the detailed clinical course of approximately 900 Japanese patients with IgAN using the J‐CKD database, which has over 150 000 registered CKD patients in Japan [42]. The progression of urinary findings was divided into four trajectories for both proteinuria and haematuria. As shown in Figure 3, this analysis showed that even if the amount of high stable urinary protein was the same, the risk of a 50% or greater decline in eGFR after 4 years was more than twice as high in the presence of haematuria. This means that even if the degree of high urinary protein is the same, there are different types of urinary protein based on different pathologies in IgAN. Multiple cohorts have demonstrated that persistent and time‐averaged haematuria is an independent risk factor for eGFR decline and end‐stage kidney failure in IgAN, supporting this idea [43, 44, 45, 46].

FIGURE 3.

Different types of proteinuria depending on the presence or absence of haematuria in IgA nephropathy. This heat map showing the 4‐year risk of events of a ≥ 50% eGFR decline by both haematuria and proteinuria trajectories in IgA nephropathy patients was referred from [42] and modified. Even in patients with the same high stable urine protein group, the risk of a 50% or greater decline in eGFR after 4 years differs twofold depending on the presence or absence of haematuria. This suggests the presence of different types of proteinuria depending on the pathological stage of the disease.

4.2. Haematuria

What kind of qualitative differences occur in urinary protein depending on whether or not there is haematuria? Pathological haematuria is generally defined as the presence of five or more red blood cells (RBCs) in urine sediment (under a microscope at 400× magnification) or 20 RBC/mL or more in uncentrifuged urine by flow cytometry. Haematuria in IgAN is further characterised by persistent glomerular haematuria, including dysmorphic RBC and acanthocytes [1, 39]. Although haematuria is the first symptom of IgAN, the mechanism is not yet fully understood.

The diameter of albumin is 8 nm. On the other hand, the diameter of RBC is 8 μm, which is 1000 times larger than albumin. Considering that the glomerular filtration barrier has a size barrier mechanism that does not even allow albumin to pass through [39], it is easy to imagine that there must be a very large hole in the glomerular basement membrane for RBC to pass from the glomerulus into the urine.

It is thought that a certain amount of RBC leaks into the urine physiologically and that approximately 10 000 RBC leak into the urine per millilitre of urine [47, 48, 49]. It is reported that this increases to three times this amount when exercising strenuously [47, 48]. In the case of thin basement membrane syndrome, it is thought that 2 × 10⁸ RBC leak into the urine per day, which is about 10 times more than the physiological leakage [50, 51]. In the case of thin basement membrane syndrome, the extracellular matrix component of the basement membrane is reduced [52], and it is thought that small holes called “gaps” of about 2.5 μm form in the thinned basement membrane and that RBC leak out through these gaps, possibly in combination with podocyte injury [51, 53].

In the case of gross haematuria, known as a clinical feature of IgAN, it is thought that 1 × 10¹⁰ RBC are leaking per day, which means that approximately 5000 RBC are leaking per glomerulus per day [49]. This is about 50 times the amount of the thin basement membrane syndrome and 500 times the amount of the normal condition. Considering that such a large amount of RBC can leak out in such a short period of time after an upper respiratory tract infection, and that this is also a transient phenomenon, it is assumed that the RBC are leaking out due to a breakdown of the basement membrane caused by a different mechanism than the thin basement membrane syndrome. It has been reported that there is no decrease in matrix components in the basement membrane of patients with IgAN and that there is high gelatinolytic activity [52]. Given the above, it is reasonable to think that the gross haematuria seen in IgAN is due to the rapid breakdown of the basement membrane caused by powerful proteases derived from inflammatory white blood cells in the glomerular capillaries. We recently reconstructed and analysed whole glomeruli [54] from renal biopsy specimens of IgAN patients presenting with gross haematuria. This revealed extensive leukocyte infiltration and significant leakage of RBCs through the disrupted basement membrane (paper currently under revision). Although macroscopic haematuria is an extreme example of haematuria in IgAN, the mechanism of microscopic haematuria in this disease should be basically the same. Therefore, the haematuria in this disease is considered to be the result of acute inflammation in the glomerular capillaries. Indeed, in both adults and children with IgAN, haematuria strongly correlates with the E (endocapillary hypercellularity) and C (crescents) scores representing acute inflammatory lesions in the Oxford classification [54, 55, 56]. Conversely, the lack of correlation between haematuria and the T (tubulointerstitial fibrosis) score, which reflects chronic lesions, is important for considering the clinical stage of haematuria [55, 56, 57] (Figure 2a).

Complement activity in IgAN, particularly the alternative pathway, lectin pathway, and terminal pathway, has been well established. Accumulating research indicates that this activity plays a crucial role in the pathology of IgAN [58, 59]. It is thus reasonable to think that this acute inflammation is due to complement activation caused by the deposition of GdIgA1IC in the glomeruli [59]. A recent large‐scale systematic review reported on the association between complement activation and Oxford classification MEST‐C lesions in IgAN. This systematic review analysed 34 studies involving 10 082 patients published between 2016 and 2023 and found that all complement‐related molecules were significantly associated with the C score (C 1 and 2). Specifically, Factor B, Factor H‐related proteins, MASP, C5a, and C5b9 were reported as complement system factors associated only with C lesions, strongly suggesting that complement activation due to glomerular GdIgA1/GdIgA1IC deposition is closely involved in the pathogenesis of IgAN with crescent formation and the rapidly progressive renal type [60]. This is consistent with the efficacy of recent anti‐complement pathway drugs in this disease [15, 16, 17, 18, 19, 58].

In other words, the qualitative difference in proteinuria depending on the presence or absence of haematuria may be due to glomerular capillaritis, which is an acute immunological inflammation caused by glomerular GdIgA1‐IC deposition and complement activation, or it may be due to non‐immunological irreversible breakdown of the filtration barrier, such as glomerulosclerosis. At the same time, the presence or absence of haematuria may be considered a useful biomarker for real‐time glomerular GdIgA1‐IC deposition.

5. A Treatment Approach Taking Into Account the Stage of the Disease

IgAN initially presents with haematuria, but we often see cases where haematuria disappears during the course of the disease, leaving only proteinuria. Considering the pathogenesis, the disease state differs between Stages A and B (Figure 2a), and the treatment options should also differ. If haematuria is an indicator of glomerular capillaritis caused by GdIgA1‐IC deposition and the resulting complement activation, then in Stage A, we should consider therapeutic agents that control the production of GdIgA1 (B/plasma cell‐targeting drugs) and that control complement pathway activation after their deposition (complement pathway‐targeting drugs) (Figure 2b) (Table 1). It is known that 5%–10% of cases in Stage A progress to RPGN [1, 61, 62]. In such cases, excessive inflammation is thought to be triggered by GdIgA1/GdIgA‐IC, so it is probably a good idea to consider complement pathway‐targeting drugs in particular (Figure 2b) (Table 1).

On the other hand, in Stage B (Figure 2b), when haematuria has disappeared, RAS inhibitors, SGLT2 inhibitors [23], MRB [24] and endothelin receptor antagonists currently under development [20, 21] (Table 1), which suppress the progression of glomerular sclerosis and the loss of nephrons, should be considered as CKD management agents. However, in the later phase of stage A, immunological damage coexists with non‐immunological damage accompanied by significant degrees of glomerulosclerosis, and it is assumed that the condition has progressed to CKD Stage 3 or higher. Therefore, the combination of drugs used in Stages A and B is desirable for patients with CKD Stage 3 or higher who are positive for both haematuria and proteinuria (Figure 2b). In addition, the severity of chronic renal lesions (especially the T score and S score of the MEST‐C score if a kidney biopsy has been performed in the past few years) may also serve as a useful criterion for decision‐making.

The treatment goal in Stage A is to achieve the disappearance of haematuria, a result of glomerular capillaritis, using B/plasma cell‐targeting drugs or complement pathway‐targeting drugs, and to reduce proteinuria, a result of acute inflammation, as much as possible, thereby suppressing the decline in eGFR slope (Figure 2b). On the other hand, the treatment goal in stage B without haematuria is to reduce proteinuria as much as possible, which results from glomerulosclerosis, disruption of the glomerular filtration barrier and hyperfiltration accompanying nephron loss, and to suppress and stabilise the decline in eGFR slope as much as possible (Figure 2b).

6. Conclusion

Recent developments in new drugs have given us access to multiple drugs with different mechanisms of action (Table 1). We need to use these drugs and combinations of them according to the pathological condition of the patient. At the same time, we should be aware of the clinical stage of the patient's disease. In this disease, the goal of treatment is to reduce urinary protein, but we need to consider that there are different types of urinary protein. One of the clinical indicators of this differentiation is haematuria, which reflects glomerular capillaritis that occurs after GdIgA1/GdIgA1‐IC deposition. In other words, the difference in urinary protein can be considered to reflect the difference between damage caused by immunological acute inflammation and non‐immunological damage. In the future, the use and selection of new drugs may be complicated by drug prices, but decisions based on the condition and stage of the disease must be the basis.

Funding

This work was supported by the Ministry of Health (23FC1048) and the Japan Agency for Medical Research and Development (JP25ek0109833, JP24ek0109706).

Conflicts of Interest

The author has received grants for research funding from Travere Therapeutics, Argenx, Teijin Pharma, Novartis, Tokiwa, Aurinia, Pfizer and Rona Bioscience; consulting fees from Otsuka, Chinook (Novartis), Novartis, Argenx, Alexion, Renalys Japan, BioCryst, Alpine Immune Sciences, Takeda, Biogen, Vera, Viatris, Chugai, Bayer and George Clinical (Emerald Clinical Trials); and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from Kyowa Kirin, Novartis, Daiichi Sankyo, Tanabe Pharma, Boehringer Ingelheim, Otsuka, AstraZeneca, Calliditas and Chinook (Novartis) within the past 36 months.

Suzuki Y., “Principles for Optimal Drug Selection in IgA Nephropathy—Time for Integrating Pathogenesis and Clinical Markers to Guide Therapy,” Nephrology 31, no. 2 (2026): e70168, 10.1111/nep.70168.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.