The 2025 KDIGO IgA nephropathy guideline update: an ERA Immunonephrology Working Group perspective

INTRODUCTION

Immunoglobulin A nephropathy (IgAN) is the most prevalent form of glomerulonephritis worldwide, carrying a substantial lifetime risk of kidney failure. Since the publication of the last Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline update for the management of glomerular diseases in 2021 [1], much has changed in the field of IgAN. New successful studies have introduced more targeted, safer and pathophysiology-based therapeutic approaches, rendering parts of the earlier KDIGO guideline outdated (Table 1). The present article focuses on the 2025 KDIGO IgAN guideline update [2] from a European perspective and incorporates important new European data on the prevalence of IgAN, the speed of progression and the prognosis of IgAN and discusses how to best use the new drugs approved for IgAN, including their affordability.

Table 1:

Comparison of KDIGO 2021 versus 2025 IgA nephropathy Guideline.

Topic	KDIGO 2021	KDIGO 2025
Diagnosis	Kidney biopsy remains the gold standard for diagnosis unchanged from 2021. Indications: sustained proteinuria >0.5 g/day
Prognosis and risk stratification	High risk : >0.75–1 g/day after supportive care	At risk ≥0.5 g/day Dynamic risk assessment: continuous re-evaluation of risk and therapy escalation without waiting
	IgAN Prediction Tool (adults)	IgAN Prediction Tool (adults + children); emphasis on limitations
Treatment—supportive care	ACEi/ARB therapy for all patients (maximize dose) to reduce proteinuria; strict BP control	ACEi/ARB therapy for all patients (maximize dose) to reduce proteinuria; strict BP control (<120/70 mmHg)
		Addition of SGLT2i and new dual angiotensin-/endothelin-receptor blockade option (sparsentan)
Treatment—immunosuppressive therapy	Systemic glucocorticoids suggested for persistent proteinuria >≈1 g/day despite ≥3–6 of supportive care—use lowest effective dose (TESTING low-dose regimen) to mitigate side effects No other immunosuppressants recommended for general use	Targeted budesonide (nefecon) 9-month course now recommended first-line for high-risk IgAN (proteinuric, progressive cases)If Nefecon unavailable, use reduced-dose methylprednisolone regimen (≈0.4 mg/kg/day with taper) plus prophylaxis instead of high-dose steroids
Monitoring	Aim for proteinuria <1 g/day. Routine follow-up; no standard for relapse surveillance	Target proteinuria <0.5 g/day (ideally <0.3). Continuous risk reassessment; monitor for relapse, even after remission
Paediatrics	RAS inhibitor if proteinuria >0.2–0.5 g/day. Steroids considered in nephrotic-range or declining GFR	Refer to IPNA 2025 guideline
Pregnancy	Preconception counselling is vital: discontinue ACEi/ARB (teratogenic) and switch to pregnancy-safe antihypertensives	Pre-pregnancy planning: stop RAS blockers, SGLT2i, sparsentan and budesonide prior to conception; use alternative BP meds. If immunosuppression required, use glucocorticoids

ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; BP: blood pressure; SGLZ2i: SGLT2 inhibitor.

IGAN PREVALENCE IN EUROPE: SHOULD WE ADOPT A MORE LIBERAL BIOPSY APPROACH?

In Europe, the estimated point prevalence of IgAN varies across different countries. A comprehensive study reported a pooled IgAN point prevalence of 2.53 per 10 000 individuals, with country-specific rates ranging from 1.14 per 10 000 in Spain to 5.98 per 10 000 in Lithuania [3]. The incidence of IgAN is estimated at 0.76 per 100 000 individuals per year [4]. These variations are influenced by factors such as healthcare access and regional genetic predispositions, but particularly by the frequency of kidney biopsies [5]. Indeed, the later study demonstrated an almost linear correlation of national IgAN prevalences and the kidney biopsy rate per population.

The 2025 KDIGO IgAN guideline continues to emphasize the critical role of kidney biopsy in diagnosing IgAN [1]. Currently, a kidney biopsy is recommended when there is a clinical constellation consistent with possible IgAN, evidence of proteinuria >0.5 g/day or decreased estimated glomerular filtration rate (eGFR). In contrast, the presence of isolated microhaematuria with a proteinuria <0.5 g/day and normal eGFR is generally not considered an indication, as it rarely impacts treatment decisions.

Many measures that constitute part of the supportive care or ‘CKD bundle’ (see below) in a proteinuric patient with or without decreased eGFR are not restricted to a biopsy-confirmed diagnosis of IgAN. These measures include lifestyle advice, blockade of the renin–angiotensin system (RAS) and the administration of a sodium–glucose co-transporter 2 inhibitor (SGLT2i). However, other novel therapies, such as nefecon and sparsentan [6, 7], are only approved for use in Europe when primary IgAN has been confirmed by a biopsy and when proteinuria is >0.8 g/g (or 1 g/day). Consequently, at least in patients with proteinuria levels around this threshold, a liberal biopsy policy should be adopted. Without biopsy, close monitoring of proteinuria and eGFR remains mandatory, given the often-progressive nature of IgAN [8].

PROGRESSION OF IGAN: RISK FACTORS AND RATES OF PROGRESSION

In patients with IgAN, the KDIGO guideline has shifted its focus from reducing proteinuria to <1 g/day to aiming for complete remission. Previously, a proteinuria threshold of <1 g/day was considered a ‘safe’ target [1]. However, recent large European cohort studies have shown that lower levels of proteinuria or albuminuria also carry a significant risk for long-term kidney failure [9–11]. Even proteinuria in the range of 0.3–0.5 g/g increased the risk of kidney events in IgAN, resulting in the KDIGO recommendation to reduce proteinuria to <0.5 g/day, ideally <0.3 g/day.

Beyond proteinuria, stable eGFR with an annual loss of no more than 1 ml/min/1.73 m²/year is an important if not central aim of treatment in IgAN. A study involving multiple European centres categorized patients in tertiles as fast, intermediate and slow progressors and reported annual eGFR changes ranging from −6.4 to +3.4 ml/min/1.73 m² in the fast and slow group, respectively [12]. A British study in a large cohort of adult patients included in the Rare Diseases Registry (RaDaR) indicated a relatively fast overall progression of patients with a mean annual eGFR loss of −3.7 ml/min/1.73 m² [9]. This later annual eGFR loss corresponds to that observed, for example, in the control group of the PROTECT trial (NCT03875729; all patients were on 300 mg irbesartan; the annual eGFR decrease was −3.7 ml/min/1.73 m²) [6]. Interestingly, however, in high-risk patients included in the STOP-IgAN trial (NCT00554502), where most patients reached a kidney endpoint, the annual eGFR decrease was only 1.5 ml/min/1.73 m² [13, 14]. Other European observational cohorts of IgAN patients, such as the German Chronic Kidney Disease cohort or the pan-European Rare Kidney Disease Registry cohort of IgAN patients, have also shown relatively slow disease progression with annual eGFR decreases between 1.5 and 2.5 ml/min/1.73 m² in most patients [11, 15]. At present, the reasons underlying these remarkable differences in progression rates between the various IgAN cohorts are not well understood.

Finally, the extent of microhaematuria is associated with IgAN progression, and its resolution may have a favourable impact on IgAN outcomes [16–18]. Additionally, recent clinical trials observed the disappearance of microhaematuria with newer immunomodulatory therapies, suggesting that resolution of haematuria could become an achievable therapeutic goal in IgAN management [7, 19, 20].

ASSESSING PROGNOSIS IN PATIENTS WITH IGAN: THE INTERNATIONAL IGAN PREDICTION TOOL

The International IgAN Prediction Tool quantifies the 80-month risk of a 50% decrease in eGFR or progression to kidney failure from the time of the biopsy by combining clinical and histopathological factors, including the Oxford MEST score [21, 22]. However, it falls short in capturing long-term risks, as demonstrated by the RaDaR cohort [9], where most IgAN patients, particularly those with low degrees of proteinuria, progressed to kidney failure within 10–15 years, far beyond the tool’s prediction window. Although Norwegian observational studies confirmed the prediction tool’s validity over longer time periods [23]. In addition, the tool is based on increasingly historical cohorts with increasingly different treatment patterns compared with those of today, and it now shows limited performance in patients receiving novel therapies [24]. In the future, a dynamic risk prediction model, adjusting for clinical changes over time, would be more useful. For example, analysis of a Swedish cohort showed that proteinuria changes during the first year are critical prognostic indicators [10], and RaDaR found that an eGFR decrease of >1 ml/min/year is predictive of kidney failure within 10–15 years [9].

Importantly, the prediction tool has not been prospectively validated for treatment decisions, especially for immunomodulatory therapy, in clinical trials or daily practice. Therefore, both the old and the updated KDIGO guidelines discourage its use for this purpose. Additionally, its limited sensitivity to significant changes in laboratory parameters or clinical parameters, such as blood pressure, sometimes limits its adoption in clinical practice.

ASSESSING PROGNOSIS IN PATIENTS WITH IGAN: THE HISTOLOGICAL MEST-C SCORE

The prognostic MEST-C scoring system for kidney biopsies in IgAN consists of three proliferative and inflammatory parameters (mesangial proliferation, endocapillary hypercellularity and crescents) and two fibrotic parameters (segmental glomerulosclerosis and tubulointerstitial atrophy and fibrosis) [25]. Conceptually, fibrotic changes are permanent and stable or progressive [26], whereas preclinical data show that even pronounced inflammatory changes, including crescents, can fully resolve within days. Therefore concerns with the use of MEST-C scores in predicting the prognosis are that several components of the score relate to potentially highly dynamic snapshots, even the absence of inflammatory lesions does not necessarily indicate inactive disease [27], reproducibility among different nephropathologists is only good for the fibrotic parameter [28] and MEST-C scores have only been established and validated retrospectively [26, 28]. Consequently, both the 2021 and 2025 KDIGO guidelines emphasize that the MEST-C score can be used to assess prognosis but should not be used to determine the choice of any particular treatment regimen [1, 2]. In striking contrast, the 2025 International Pediatric Nephrology Association (IPNA) guideline for the treatment of children with IgAN places a central weight on the MEST-C score in deciding which therapy to use [29].

Whether newer histological parameters, such as podocytopathic changes [30] or extensive morphometric analyses (‘pathomics’) [31], augmented by semi- or unsupervised artificial intelligence models, can improve the prognostic power of kidney biopsies remains to be determined. In addition, we need clinical studies to determine whether biopsy findings can indeed direct the choice of therapy. The first trials in this direction are ongoing (NCT04662723, NCT05528991, NCT03188887).

TREATMENT OF PATIENTS WITH IGAN

The mainstay of IgAN therapy consists of optimized CKD management and immunomodulatory/anti-inflammatory measures [32].

CKD therapy

Almost all patients first diagnosed with IgAN have established and in many cases already relatively advanced CKD. Thus optimized supportive therapy or ‘CKD therapy’ is of paramount importance in all patients to slow the progression of kidney damage [33] (Fig. 1). RAS inhibition remains a cornerstone of this approach [34–36] and, in fact, trials enforcing the use of maximum recommended doses of RAS blockers, such as the STOP-IgAN and PROTECT trials, noted relatively little loss of annual eGFR compared with other trials [37]. Trials are ongoing to evaluate newer mineralocorticoid receptor antagonists (MRAs) in this context [38].

Figure 1:

Pathway-directed therapy in IgAN. Future therapy for IgAN is expected to combine agents that blunt each of the three key drivers of nephron loss. Aberrant upstream immune dysregulation can be mitigated by targeted-release budesonide (nefecon), APRIL- or BAFF-directed biologics and emerging anti-CD38 antibodies, while active glomerular inflammation and the transition to fibrosis can be controlled with systemic glucocorticoids, iptacopan or other complement inhibitors currently in development. These disease-specific interventions must be layered onto optimized supportive care that tackles generic CKD progression. This includes lifestyle modifications and maximized renin–angiotensin–aldosterone system blockade, SGLT2 inhibition and, where appropriate, add-on endothelin–angiotensin receptor antagonists (ERAs), MRAs or glucagon-like peptide-1 receptor agonists in obese patients. Items outlined in red denote therapies with current regulatory approval at the time of writing; items without a red outline are under investigation.

Beyond RAS inhibitors, CKD therapy in IgAN should now include SGLT2is [39], which can further mitigate the risk of progressive eGFR loss in IgAN. Most contemporary clinical trials in IgAN now allow the use of SGLT2is on top of a RAS blocker as long as the dosage remains stable throughout the trial. SGLT2is are recommended for IgAN patients with proteinuria, regardless of diabetes and obesity status, provided the eGFR is >20 ml/min. Of note, very recent data raise the possibility of body mass index–related heterogeneity [40]; however, caution is needed as these are retrospective data.

CKD therapy can be extended to blocking not only the RAS but also the endothelin-1 system via dual endothelin angiotensin receptor antagonists (DEARAs) [6] or selective endothelin receptor antagonists (ERAs) [41, 42]. Fluid retention is a relatively common adverse event with endothelin-1 antagonists, and this can be alleviated by combining sparsentan, for example, with an SGLT2i [43]. The combination therapy can enhance the antiproteinuric effect of sparsentan in proteinuric IgAN patients as evidenced by the first real-life data [44].

Even with lifestyle measures, good blood pressure control and a DEARA plus an SGLT2i, very few patients reach full remission, particularly proteinuria <0.3 g/day [44]. A fundamental change in the treatment paradigm of IgAN patients at risk for kidney failure is therefore the guideline proposal to simultaneously initiate both CKD therapy and immunomodulatory/anti-inflammatory measures [37, 45]. This change remains to be tested in clinical practice, as there certainly are IgAN patients at risk with a benign clinical course and excellent long-term prognosis. For these patients, a uniform treatment strategy may result in overtreatment and unnecessary healthcare costs. In such cases, a more individualized, stepwise approach might be more appropriate. Therefore an important task for the future is to be able to prospectively identify such patients and to develop strategies that avoid irreversible loss of eGFR by targeting CKD as well as immune-mediated pathophysiology.

Corticosteroids

The 2025 KDIGO guidelines for IgAN management emphasize two primary treatment goals: reducing pathogenic forms of IgAN and controlling inflammation (Fig. 1). While anti-inflammatory actions of systemic glucocorticoids are well established, their effect on pathogenic forms of IgA are still not fully understood. A small European study showed minimal effect on IgA-producing B cells [46]. In contrast, data from the TESTING trial (which included almost exclusively patients from Southeast Asia), demonstrated dose-dependent reductions in total IgA and galactose-deficient IgA1 levels over 6 months that decreased by 12 months with a reduced dose of systemic methylprednisolone [47].

The STOP-IgAN trial, conducted in a Caucasian German population, showed higher rates of transient disease remission with systemic immunosuppression (high-dose corticosteroid regimen) but did not improve long-term kidney outcomes such as the need for dialysis or a 40% decrease in eGFR [13, 14]. Moreover, increased infection rates were observed, raising significant safety concerns. Recent retrospective analyses from Romania, the UK and Norway also found no significant benefit of systemic corticosteroids on long-term kidney outcomes in Caucasian patients, while again reporting increased adverse events [48–50]. In the TESTING trial, high and reduced doses of methylprednisolone had nephroprotective effects, but serious safety issues led to early termination of the high-dose methylprednisolone arm of the trial [51]. This finding suggests potential geographic or ethnic differences in treatment response, possibly related to more aggressive disease progression and higher baseline proteinuria in Asian cohorts compared with European populations [52]. While reduced regimens of corticosteroids continue to be considered in IgAN management in the 2025 KDIGO guidelines, their role should be critically assessed in European populations, where the risks may outweigh the potential benefits. When corticosteroids are used, the 2025 KDIGO guidelines recommend prophylaxis to reduce steroid-related complications, including against Pneumocystis jirovecii pneumonia.

An exception are patients with crescentic IgAN and a rapid loss of eGFR over a few months. The KDIGO advises that such patients receive immunosuppressive therapy with corticosteroids and cytotoxic drugs, analogous to anti-neutrophil cytoplasmic antibody vasculitis. However, this is mostly opinion-based and large retrospective series do not strongly support this approach [53].

Nefecon and other budesonide preparations

Nefecon, a targeted-release formulation of budesonide, has been developed to specifically target the gut–kidney axis. Results from the phase 3 NefigArd trial (NCT03643965) demonstrated that it effectively reduces proteinuria and stabilizes eGFR in high-risk patients [7, 54]. However, after tapering the nefecon dose after 9 months, eGFR began decreasing again and proteinuria increased 3 months later [54, 55]. This raises the question of whether repeated or maintenance therapy with nefecon will be necessary to sustain long-term kidney benefits. Although no head-to-head trial compares nefecon with moderate-dose systemic corticosteroids, we favour nefecon based on a more favourable safety profile alongside demonstrated efficacy in reducing proteinuria and attenuating eGFR decline. Systemic corticosteroids remain a reasonable option in selected patients (e.g. where nefecon is unavailable or contraindicated), but require vigilant risk mitigation. Shared decision-making is essential. Safety concerns regarding prolonged or repeated therapy with nefecon remain largely unresolved, emphasizing the need for real-world data to better understand its long-term application. Additional data are also awaited in special populations like transplant patients with recurrent IgAN. The 2025 KDIGO guidelines positions targeted-release budesonide as the preferred option where available; if unavailable, reduced regimens of systemic corticosteroids may be considered in carefully selected high-risk cases (Fig. 2). Notably, in Europe, nefecon prescribing is currently restricted to patients with primary IgAN and proteinuria >1 g/day [56].

Figure 2:

Stepwise framework of aspects to consider when choosing mono- or combination therapy in IgAN at risk of progression. Panels are ordered by decision priority: (1) safety/monitoring → (2) efficacy → (3) trial data versus real-life (match age, race, eGFR and background meds to the trial setting) → (4) cost/availability (label, access, reimbursement). GI: gastrointestinal; AE: adverse event; ERAs: endothelin receptor antagonists; PJP: Pneumocystis jirovecii pneumonia; RASi: renin–angiotensin system inhibitor; SGLT2i: sodium–glucose co-transporter 2 inhibitor.

The cost of new IgAN therapies like nefecon and sparsentan is high. While these innovative treatments offer promising results, their significant costs may lead to restricted use or approval, especially in countries with universal healthcare. European countries will likely face pressure to balance the clinical efficacy of these drugs with cost-effectiveness, possibly through strategies such as long-term studies demonstrating effects on hard endpoints such as a 40% decrease in eGFR or progression to kidney failure, negotiating drug prices, capped reimbursement policies or applying stricter guidelines for patient eligibility. In fact, in the rare cases in which hard kidney outcomes are studied (as in the STOP-IgAN trial), despite higher rates of transient disease remission with systemic immunosuppression, no long-term improvement (such as the need for dialysis or a 40% decrease in eGFR) was observed.

Other enteric formulations of budesonide have also shown promise in reducing proteinuria, although they have not been tested in randomized clinical trials [57, 58]. The BUDIGAN study (ISRCTN47722295) from Romania using conventional budesonide reported significant proteinuria reductions and stable kidney function over 3 years even though the dosage was reduced to 30% at 1 year and completely stopped at 2 years [59]. However, this study has been met with scepticism, necessitating cautious interpretation and further validation through larger, more rigorous studies.

Complement inhibitors

Ample evidence supports the involvement of the alternative pathway of complement in the pathogenesis of IgAN [60]. Iptacopan (LNP023), which targets this pathway, is currently under evaluation in the APPLAUSE-IgAN phase 3 RCT (NCT04578834) [61]. Interim results of this trial demonstrated that iptacopan effectively reduces proteinuria and maintains a good safety profile, leading to its accelerated approval by the US Food and Drug Administration [62]. Despite iptacopan’s proven effectiveness, its high cost—≈$500 000 per year in the USA—remains a substantial barrier for its integration into IgAN treatment, particularly as long-term benefit outcomes are still awaited. Terminal pathway (C5) blockade with ravulizumab reduced proteinuria significantly in the phase 2 SANCTUARY trial (NCT04564339) at 26 weeks (≈30% relative treatment effect), with signals toward eGFR stabilization and sustained effect to week 50 [63]; a global phase 3 study in adults with IgAN [I CAN (NCT06291376)] is under way.

PREGNANCY

The 2025 KDIGO IgAN guideline includes a dedicated section on pregnancy planning, reflecting a welcome recognition that this disease predominantly affects young adults and recommending preconception counselling for all women of childbearing age. The new recommendations emphasize proactive pregnancy planning and detail how to safely adjust therapy to protect both maternal and kidney health. From a clinical perspective, this patient-centred guidance is a long-awaited addition, as it directly addresses young female patients’ concerns that a new IgAN diagnosis could endanger their future motherhood.

FUTURE PERSPECTIVES

The landscape of IgAN treatment is rapidly evolving, with a clear shift toward disease modification using multitargeted therapeutic approaches. Emerging treatments such as anti-APRIL antibodies, combined APRIL–BAFF inhibitors or antibodies targeting long-lived CD38⁺ plasma cells have provided early evidence suggesting the possibility of achieving full remission and maintaining stable kidney function in phase 2 clinical trials [20, 64–66]. However, cost, long-term efficacy and especially safety of these newer therapies remain to be evaluated.

The traditional stepwise treatment model in IgAN, where therapies are added sequentially depending on the clinical response, may soon be replaced by a more aggressive, simultaneous approach. This approach targets both the CKD elements and the immunological factors contributing to nephron loss from the time of diagnosis, aiming to mitigate inflammation, reduce pathogenic IgA production and counteract maladaptive responses to nephron injury. However, a simultaneous CKD and immunomodulatory approach carry the risk of overtreatment in some patients. Despite considerable efforts to identify diagnostic and prognostic biomarkers, proteinuria and eGFR remain the only validated markers; consequently, reliable biomarkers to guide therapy selection are still lacking and cost remains a major unresolved issue, particularly in resource-limited settings. Now that IgAN is considered a treatable disease, with both better disease-modifying and anti-nephropathic drugs in place, new treatment strategies need to be developed given the relatively young age of most IgAN patients. These include initiating aggressive treatment early, followed by tapering based on clinical response, potentially guided by biomarkers in the future. Furthermore, trials exploring treatment discontinuation strategies are urgently needed.

FUNDING

None declared.

DATA AVAILABILITY STATEMENT

No new data were generated or analysed in support of this research.

CONFLICT OF INTEREST STATEMENT

E.S., A.B. and K.I.S. are members of the CKJ Editorial Board. J.F. is the CKJ Editor-in-Chief.