Corticosteroid Therapy in Immunoglobulin A Nephropathy: A Friend or Foe?

Immunoglobulin A nephropathy (IgAN) was first described in the late 1960s and is well recognized for its heterogeneity in clinical presentation, histopathology, disease trajectory, and treatment response [1]. IgAN is the most common cause of primary glomerulonephritis worldwide and is a leading cause of kidney failure in young adults, with up to 40% requiring dialysis or transplantation within 20 years after diagnosis [2]. Therefore, the health burden and socioeconomic impact of IgAN is significant [2‒4]. Despite this, there have been limited advances in the development of effective therapeutic agents, with supportive care including optimization of renin-angiotensin system inhibition (RASi), weight management, blood pressure control, smoking cessation, dietary and lifestyle modifications, being the pillar of treatment guidelines for years [3].

More recently, greater understanding around the pathophysiology of IgAN supports a multi-hit hypothesis: (1) production of circulating galactose-deficient IgA1 (Gd-IgA1) by mucosal B lymphocytes, (2) development of glycan-specific IgG or IgA1 autoantibodies, (3) formation of Gd-IgA1-containing immune complexes, and (4) deposition of these complexes in the glomeruli resulting in acute and chronic damage [2, 5] (Fig. 1). The role of complement activation, in particular the alternative and lectin pathways, has also increasingly been recognized to play a pathogenic role in disease progression and is a potential therapeutic target [6]. Therefore, the efficacy of immunosuppressive and immunomodulatory agents, both existing and novel agents, continues to be explored [7].

Current international clinical practice guidelines suggest that patients at high risk of progressive chronic kidney disease (CKD) with IgAN despite optimal supportive care be considered for a course of corticosteroids [3]. However, conflicting data from clinical trials have resulted in ongoing equipoise regarding the role of corticosteroid therapy in IgAN. In particular, there remains uncertainty around optimal treatment dose and duration, which population group is likely to benefit the most, and which group it should be avoided in [3]. This review outlines the latest recommendations for IgAN management and the literature around corticosteroid therapy.

• Are corticosteroids beneficial in IgA nephropathy (IgAN)?

• Corticosteroid therapy can slow down the decline in glomerular filtration decline, reduce proteinuria, and prevent kidney failure in patients with IgAN at high risk for disease progression who have received maximal supportive care for at least 3 months [8].

• Current treatment guidelines suggest patients with persistent proteinuria >1 g/day despite 3 months of maximum RAS blockade could be considered for a 6-month course of corticosteroid therapy [3].

• While greater proteinuria, lower estimated glomerular filtration rate (eGFR), hypertension, and higher kidney histological scoring by Oxford Classification MEST-C scores* at baseline predict a poorer kidney prognosis [10], there is no known correlation with corticosteroid treatment response.

• Are corticosteroids harmful in IgAN?

• Systemic corticosteroids are associated with several adverse effects such as infection including life-threatening sepsis, gastrointestinal haemorrhage, glucose intolerance, avascular necrosis, osteoporosis, and death; therefore, they must be prescribed with caution.

• Current guidelines suggest avoiding corticosteroid therapy in those with an eGFR <30 mL/min/1.73 m², diabetes mellitus, obesity (BMI >30 kg/m²), latent, active peptic ulceration, uncontrolled psychiatric illness, and severe osteoporosis [3].

• High-dose corticosteroids are not recommended in IgAN due to excessive associated adverse effects, particularly infection-related complications. A reduced corticosteroid dose and concurrent Pneumocystis jirovecii pneumonia prophylaxis may mitigate the infection risk associated with corticosteroid therapy [9].

• Unmet needs

• Progressive chronic kidney disease (CKD) (worsening of proteinuria and/or eGFR decline) despite corticosteroid therapy in IgAN suggests additional or alternative therapies are needed.

• Greater long-term follow-up data on outcomes following corticosteroid therapy are required.

• Better tools in identifying individuals at higher risk of progressive CKD and predicting treatment response to corticosteroid therapy will aid management decisions.

The incidence of IgAN is reported to be between 0.2 and 5.7 per 100,000 individuals per year [10] with significant regional and racial variability. The true prevalence of IgAN is likely to be underestimated depending on the clinician’s threshold in performing a kidney biopsy for clinically silent or mild phenotypes [2]. The greatest prevalence is reported in those of East Asian descent, followed by Europeans, and the lowest among those with African heritage [11]. These statistics may be partially influenced by country-specific health practices, such as routine screening for microscopic haematuria and proteinuria in Japanese school children, which is likely to lead to early detection of asymptomatic kidney pathology [12].

Genetic predisposition is recognized to also play a major role in the discrepancies in disease prevalence, clinical presentation, outcomes, and treatment response. IgAN typically presents with mild clinical and histopathological features at the time of diagnosis in Asian populations compared to Caucasians; however, it ultimately leads to poorer outcomes with greater rates of kidney failure [13]. While there are similar rates of males and females with IgAN in Asia, the reported male to female ratio is up to 6:1 in the USA and Europe [14]. These differences may need to be taken into consideration when formulating management plans and clinical trial designs.

The standard of care for IgAN includes RASi with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, blood pressure lowering and lifestyle modifications, which has been the mainstay of IgAN treatment for years. RASi has been shown to improve kidney outcomes independent of blood pressure in individuals with proteinuric IgAN [15, 16] and is well established as first-line treatment. Patients identified as being at high risk of progressing to kidney failure based on persistent proteinuria >0.75–1 g/day despite =3 months of maximal standard of care should be considered for additional treatment, including participation in a clinical trial [3]. While a large study has shown that one in three “high-risk” patients can achieve proteinuria below 0.75 g/day with 6 months of intensive supportive therapy alone [17], those with greater disease severity are less likely to respond; therefore, the residual risk of kidney failure remains high [18].

The Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest that those at high risk of progression of disease could be considered for a 6-month course of corticosteroid therapy (level of evidence 2B) [3]. This recommendation comes with a caveat to highlight the comparatively weak evidence and the recognized risks of treatment-related toxicities such as infection; therefore, the decision to treat should follow an informed discussion between the patient and their clinician. It is advised (as practice points) to concurrently commence those on the equivalence of =0.5 mg/kg/day of prednisone on Pneumocystis jirovecii pneumonia antibiotic prophylaxis, gastroprotection, and bone protection.

Corticosteroids have been used in IgAN for decades with inconsistent results [19‒23] (Table 1). They are cheap, easily accessible, and among the most commonly prescribed immunosuppressant agents outside of supportive therapy to date. Their use has largely been limited to patients with IgAN at high risk of progression and relatively preserved kidney function. A meta-analysis of 29 randomized controlled trials (RCTs) including 2,517 participants with IgAN, >0.75 g/day of proteinuria, and estimated glomerular filtration rate (eGFR) =20 mL/min/1.73 m² or serum creatinine <3.5 mg/dL compared the outcomes of a variety of treatment combinations using RAS blockade, corticosteroids, tonsillectomy, and other corticosteroid-sparing immunosuppressant agents (mycophenolate, azathioprine, cyclosporine) with placebo [24]. Of these, RASi plus corticosteroid therapy was found to be the most effective in inducing clinical remission and preventing kidney failure or doubling of serum creatinine. This regime, however, also came with high rates of serious adverse events (SAEs).

A Cochrane review found that corticosteroid treatment was more effective at delaying major kidney outcomes compared to placebo or standard of care with low-to-moderate certainty evidence; however, the risks of SAE were not well captured [25]. There was a 61% risk reduction of kidney failure, a 57% risk reduction of doubling of serum creatinine, an average of 0.58 g less proteinuria per day, and almost double rates of clinical remission with corticosteroids. Another meta-analysis of 12 RCTs using a variety of corticosteroid regimes reported similar results with a 58% reduction in a primary composite outcome of kidney failure, doubling of serum creatinine, or a 50% reduction in eGFR [26]. The renoprotective effects were not influenced by the type of corticosteroid (prednisone vs. methylprednisolone), dose, or duration of corticosteroid therapy. Individuals treated with corticosteroids had a 15% increased risk for total SAE.

While these data have helped shape today’s guidelines, it is important to note the results from more recent studies which emphasized RAS blockade as standard of care to reflect current clinical practice and the insufficient safety data from earlier studies. Two landmark trials from this era include the STOP-IgAN [17] and TESTING studies [27], and it must be recognized that no meta-analysis conducted to date includes the results from the recently published TESTING trial (Table 2).

STOP-IgAN was a multi-centre open-label RCT conducted in Germany which consisted of a Caucasian population aimed to evaluate whether additional immunosuppressive treatment (corticosteroid monotherapy for patients with an eGFR =60 mL/min/1.73 m² or a combination of prednisolone, cyclophosphamide, and azathioprine for patients with an eGFR between 30 and 59 mL/min/1.73 m²) improves proteinuria remission rates compared to optimized intensive supportive therapy alone [17, 28]. Although it transiently induced remission of proteinuria, additional immunosuppressive therapy did not significantly prevent eGFR decline, compared to intensive supportive therapy. Long-term follow-up over a median of 7.4 years found no difference between either arm in a composite outcome of all-cause death, kidney failure, or decline in eGFR >40% from baseline, or proteinuria [28]. There were greater rates of infectious complications and impaired glucose tolerance or diabetes following immunosuppression (174 vs. 111 events; p = 0.007 and 9 vs. 1 event; p = 0.02, respectively).

The TESTING study was an international multi-centre double-blind RCT and is the largest study in terms of sample size of its kind to date. 503 participants with IgAN were randomized 1:1 to oral methylprednisolone or placebo in China, Australia, India, Canada, and Malaysia [27]. Participants with eGFR 20–120 mL/min/1.73 m² and proteinuria >1 g/day following 3 months of maximum tolerated RAS blockade were randomized to methylprednisolone 0.6–0.8 mg/kg/day tapered over a treatment period of 6–8 months or placebo. Due to an observed number of excess adverse events, the study was halted in November 2015 and a protocol amendment was made by the steering committee. Recruitment recommenced in March 2017 to include participants with a higher eGFR cutoff (30–120 mL/min/1.73 m²), reduction in initiation methylprednisolone dose to 0.4 mg/kg/day (maximum 32 mg/day), and the addition of Pneumocystis jirovecii pneumonia antibiotic prophylaxis. The primary endpoint was a composite of a sustained 40% decline in eGFR, kidney failure, or death due to kidney disease. Following a mean follow-up period of 4.2 years, methylprednisolone therapy was associated with a 47% reduction in primary outcome events compared to placebo and a 41% reduction of kidney failure. Time-averaged proteinuria (mean difference 0.69 g/day, p < 0.001) and annual rate of kidney function decline (mean difference in eGFR 2.46 mL/min/1.73 m²/year, p = 0.002) were also lower with methylprednisolone treatment. 10.9% in the methylprednisolone group compared to 2.8% in the placebo group reported adverse events, and the majority of SAEs were secondary to excess hospitalizations and serious infections. The findings concluded that corticosteroid therapy in patients with IgAN at high risk for progression improved kidney outcomes at the expense of increased SAE, particularly with higher doses.

In a bid to reduce treatment-related adverse effects, a novel corticosteroid, targeted release formulation (TRF)-budesonide, has been developed which allows the targeted release of the drug in the distal ileum where a high density of mucosal B lymphocyte containing Peyer’s patches are located [29]. The NEFIGAN study was a European multi-centre double-blind phase 2b RCT in a largely Caucasian population with IgAN and relatively preserved kidney function (mean baseline eGFR 78.3 mL/min/1.73 m²) that found higher doses of TRF-budesonide were associated with a reduction of proteinuria and stabilization of eGFR following 9 months of therapy compared to placebo [29]. 149 adults with eGFR >45 mL/min/1.73 m² and proteinuria =0.75 g/day following 6 months of optimal RASi were randomized 1:1:1 to TRF-budesonide 16 mg/day, TRF-budesonide 8 mg/day, or placebo. There was a 27.3% reduction in proteinuria from baseline in those who received the higher 16 mg/day dose compared to no significant reduction with the 8 mg/day dose and an increase of 2.7% among the placebo group. eGFR in the TRF-budesonide groups remained stable during the treatment period with a reduction of 9.8% from baseline to 9 months in the placebo arm. TRF-budesonide was associated with greater overall adverse events including hypertension, skin changes, and peripheral oedema compared to placebo. 22% randomized to TRF-budesonide 16 mg/day versus 4% in the placebo arm discontinued therapy due to adverse events, suggesting patients still experience common side effects seen in systemic corticosteroids.

The NefIgaRD study is a 2-part international multi-centre double-blind phase 3 RCT that was conducted following the positive findings from the NEFIGAN study [30]. Part A was recently presented which found that patients with IgAN, >1 g/day proteinuria, and eGFR 35–90 mL/min/1.73 m² despite maximal RAS blockade treated with TRF-budesonide 16 mg/day had a 27% reduction in mean proteinuria and 7% benefit in mean eGFR compared to placebo at 9 months. There were greater rates of SAE including deaths and hospitalization with budesonide (10.4%) compared to placebo (5.3%) [31]. The study has completed recruitment, but the results are yet to be published.

The discrepancy between the STOP-IgAN and TESTING trial findings, particularly the effect of corticosteroids on kidney function, may result from patient selection as they represent populations from varying racial backgrounds with a different risk of disease progression (Table 2). The mean baseline proteinuria was lower in the STOP-IgAN cohort at 1.7 g/day compared to 2.54 g/day in the TESTING cohort [32], and proteinuria is regarded as a reliable surrogate marker that is highly predictive of long-term kidney outcomes in IgAN [33]. In the TESTING trial, approximately 95% of participants were of Pacific Asian origin, who tend to have a greater incidence of active pathological lesions on biopsy and a higher risk of disease progression [34] than the European population included in the STOP-IgAN trial. Participants randomized to supportive therapy in the TESTING study also showed a faster rate of kidney function decline at -4.97 mL/min/1.73 m²/year [27] compared with -2.68 mL/min/1.73 m²/year in the 10-year follow-up of the STOP-IgAN study [28]. The relative “stability” of kidney function in the placebo group in STOP-IgAN can make it more challenging to demonstrate kidney benefits and may also suggest this was a highly selected cohort.

Budesonide has been granted accelerated approval for therapeutic use in IgAN based on promising data using proteinuria reduction as a surrogate marker for kidney protection, but long-term follow-up of hard kidney endpoints is needed. The evidence to support reduced SAE with a TRF despite the initial intentions for development is yet to be verified by the awaited phase 3 data, and all the aforementioned studies confirm higher rates of adverse events related to corticosteroid therapy (Table 2).

The use of corticosteroids is widely accepted as first-line therapy in IgAN with minimal change disease [3]. A small prospective study of 27 participants suggested a good response rate with 100% achieving clinical remission at 8 weeks of treatment and 2/27 (8%) relapsing during the 12-week study period [35]. It has been proposed that the MCN-IgAN variant is a dual glomerulopathy with patients more likely to respond to corticosteroid therapy akin to MCN [36]. As a result, people with MCN-IgA have traditionally been excluded from large clinical trials with evidence derived from prospective studies with limited sample sizes and no placebo control. Similarly, patients with rapidly progressive crescentic IgAN defined as a =50% decline in eGFR over =3 months plus crescents on biopsy are generally excluded from trials, and the data on corticosteroid therapy are less robust. The current guidelines are based on observational data which suggest a combination of corticosteroids and cyclophosphamide, similar to the treatment of ANCA vasculitis [3, 37]. IgA vasculitis is uncommon in adults, and again, proven effective therapy in this condition is an ongoing unmet need. Its presentation is highly variable with cutaneous and systemic involvement and is often severe with higher rates of kidney failure. Management decisions have largely been extrapolated from IgAN guidelines and paediatric studies [3]. There is no evidence to support corticosteroid prophylaxis in extra-renal IgA vasculitis to prevent kidney involvement, and the role of immunosuppressive therapy is inconclusive [3, 38]. There are also no data to support the use of corticosteroids in secondary IgAN including liver cirrhosis, inflammatory bowel disease, mucocutaneous infections, celiac disease, and HIV infection [3]. Current risk prediction tools exclude these conditions in prognostic assessment [39].

The International IgA Nephropathy Network (IIgANN) Risk Prediction Tool is a validated risk calculator derived from the largest and most ethnically diverse dataset and combines various accepted risk factors that enable clinicians to stratify the risk of kidney failure in individuals with IgAN [40]. The latest guidelines incorporate this prediction tool into routine clinical practice to guide decisions in treatment strategy including clinical trial participation or surveillance [3]. While the IIgANN prediction tool is superior to previous models [41‒43], it is not validated to predict treatment response and hence cannot be used to direct management [44]. It has additional limitations in current practice as it does not incorporate the histopathological crescent score and can only be applied in those with a recent kidney biopsy.

Multiple observational studies have demonstrated that the Oxford Classification of IgAN MEST and possibly C scores are associated with a higher risk of disease progression in IgAN [9]. Mesangial hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis have consistently been shown to be associated with poorer kidney outcomes [9, 45]. The latter in particular is an independent risk factor for kidney failure, which is not unexpected as it is a marker of chronic damage and late disease in all causes of CKD [46]. The predictive role of endocapillary proliferation is more contentious where a meta-analysis of 16 retrospective studies evaluating the correlation between the Oxford Classification score and outcomes in IgAN found it was the only component that had no association with higher rates of kidney failure [47]. As this is based on retrospective data, therapeutic intervention can be variable, so the negative predictive values of endocapillary hypercellularity may be confounded by greater rates of corticosteroid use [9]. A study that specifically excluded those treated with immunosuppression found a strong association between endocapillary proliferation and kidney failure (HR 3.34, p < 0.001) [48]. The presence of crescents on kidney biopsy in IgAN has also been shown to correlate with greater rates of kidney failure (HR 2.3, p < 0.001) [47]. This was later confirmed by a larger pooled analysis, which found that crescents were predictive of a higher rate of eGFR decline and kidney failure in those not treated with immunosuppression previously [49]. In a similar fashion, the efficacy of corticosteroid therapy based on histopathological scores has been explored to identify those more likely to benefit from treatment. The TESTING study reported no difference in the primary outcome between corticosteroid therapy and placebo for those with or without endocapillary hypercellularity [27]. Secondary analysis of 70 participants in the STOP-IgAN study also found no difference in clinical remission rates between the treatment arms regardless of mesangial hypercellularity, endocapillary hypercellularity, and segmental glomerulosclerosis [50]. At baseline, patients in the TESTING study had higher rates of mesangial hypercellularity (59.8 vs. 25.7%) and endocapillary hypercellularity (25.2 vs. 17.1%) than those in STOP-IgAN [17, 27].

A number of studies have attempted to elucidate the characteristics of those more likely to clinically respond to corticosteroid therapy based on these prognostic markers with mixed results. Subgroup analyses in the TESTING study found similar outcomes regardless of baseline proteinuria (<3 vs. =3 g/day), kidney function (eGFR <50 vs. =50 mL/min/1.73 m²), histological lesion scoring (absence vs. presence of endocapillary hypercellularity), or age (<50 vs. =50 years old) [27]. The STOP-IgAN study also found no difference in response to immunosuppression based on baseline proteinuria [17]. A retrospective analysis of 368 participants with IgAN in the VALIGA study, however, demonstrated a linear correlation between proteinuria and response to corticosteroids [51]. There was a renoprotective effect on annual rate of eGFR decline in favour of corticosteroids compared to standard of care alone, irrespective of baseline proteinuria, with the greatest benefit observed in individuals with baseline proteinuria =3 g/day.

Although regional and racial variations have been linked to kidney progression and outcomes in IgAN, the impact on corticosteroid response remains unclear. Subgroup analysis in the TESTING study found no difference in the primary outcome between Chinese and non-Chinese populations [27]. Of note, STOP-IgAN [17] was largely conducted in a Caucasian population. It is challenging to draw firm conclusions from this comparison alone, and it is critical to ensure adequate representation from different regions in future clinical trials in IgAN to address this question.

Systemic corticosteroids are well known to be associated with side effects including weight gain, glucose intolerance, osteoporosis, and skin changes, as well as more serious complications such as avascular necrosis, infection, and gastrointestinal haemorrhage. While a few earlier smaller RCTs showed no significant difference in SAEs with corticosteroid therapy compared to placebo [19, 20, 22, 23, 52], these were often inconsistently documented and led to underreporting. Both the STOP-IgAN and TESTING studies reported increased SAE associated with corticosteroid therapy including infections requiring hospitalization, glucose intolerance, and death secondary to sepsis [17, 27]. In the reduced-dose cohort of the TESTING trial, the lower cumulative corticosteroid dose and addition of Pneumocystis jirovecii pneumonia antibiotic prophylaxis reduced but did not completely mitigate treatment-related adverse events, which included one fatality (0.8%). There were three deaths (2.2%) in the full-dose cohort [27].

The TESTING trial showed that the reduced-dose methylprednisolone regimen had a favourable risk-benefit profile compared to the full-dose regimen. For every 100 participants treated, reduced-dose methylprednisolone was estimated to prevent 16.7 individuals from reaching the primary outcome, including 5.8 from reaching kidney failure, at the cost of 2.4 individuals experiencing SAEs over a mean follow-up period of 2.5 years. In comparison, the benefits were less pronounced with the full-dose regimen which resulted in 11.8 fewer primary outcome events, including 5.8 fewer end stage kidney disease events, and 11.7 additional SAEs for every 100 participants treated.

Identifying patients with IgAN who are more likely to receive benefit and experience less harm from corticosteroid therapy remains a clinical conundrum. Several substudies by the TESTING study group are underway to understand this further including the impact of the histopathological MEST-C score on response to methylprednisolone and a collaborative study with the IIgANN to incorporate corticosteroid treatment into the IIgANN Risk Prediction Tool. These studies ultimately aim to provide much needed information and guidance for clinicians to make optimal therapeutic decisions.

In the studies of the novel TRF-budesonide which should theoretically minimize potential side effects compared to systemic corticosteroids due to first-pass metabolism, there were still increased adverse events including gastrointestinal symptoms, peripheral oedema, hypertension, and acne [29, 31]. Although these adverse events are unlikely to directly impact mortality, they are still detrimental to one’s quality of life.

Data around the use of corticosteroids in patients with IgAN with advanced CKD or nephrotic syndrome remain limited. A large retrospective study conducted in China found that SAE secondary to corticosteroid use in IgAN had a positive correlation with older age, higher blood pressure, and lower kidney function, with a rise in SAE rate according to CKD stage [53]. Current evidence supports guideline recommendations to avoid corticosteroid therapy in those with an eGFR <30 mL/min/1.73 m² and the suggestion to exercise cautiously in individuals at high risk of developing corticosteroid-related side effects such as those with diabetes mellitus, obesity (BMI >30 kg/m²), latent infections (e.g., viral hepatitis, tuberculosis), active peptic ulceration, uncontrolled psychiatric illness, and severe osteoporosis based on the known adverse effects of corticosteroids and the likelihood of exacerbating or accelerating certain pre-existing conditions [3].

Steroid-sparing immunosuppressive agents have been explored with largely negative results except for mycophenolate mofetil which has been suggested to be effective in the Chinese population [3]. In the past few years, with the increasing understanding of the pathogenesis of IgAN (Fig. 1), several clinical trials studying the effects of immunomodulatory agents with various targets such as the complement pathway (in particular C5), a proliferation-inducing ligand, and B-cell activating factor have been initiated with promising early data [8, 54].

A pre-specified analysis of the DAPA-CKD trial reported a 71% risk reduction in major kidney events among 270 participants with IgAN treated with dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i) compared to placebo over a median 2-year follow-up duration [55]. The study population had a lower mean baseline eGFR and proteinuria and a greater proportion of patients with type 2 diabetes mellitus compared to those recruited in the corticosteroid therapy trials in IgAN. Since there were no patients in the STOP-IgAN and TESTING studies who received SGLT2i, the effects of corticosteroids with or without SGLT2i on kidney outcomes remain unknown. Endothelin receptor antagonists are another drug class of interest with interim results from the PROTECT study showing proteinuria reduction in IgAN [56]. Given their different mechanisms of action and effects such as haemodynamic benefits, endothelin receptor antagonists and SGT2i have been shown to have additional antiproteinuric properties which are likely to confer long-term renoprotection but unlikely to replace immunosuppressive agents entirely. The discussion around these emerging therapies is beyond the scope of this review, but the need for additional effective treatment options is well recognized.

In summary, the available data consistently support kidney-protective effects of glucocorticoid therapy in individuals with high-risk IgAN across clinical trials overall and a variety of subgroups. It is now equally clear that this benefit comes at the cost of an increased risk of steroid-associated adverse effects, in particular infectious complications and, rarely, death. The TESTING study demonstrated that reduced-dose glucocorticoid therapy was at least as effective as full-dose treatment, with a much lower risk of SAEs. Further dose reductions may be plausible and the budesonide results are encouraging, but longer term follow-up data are awaited. The TESTING-ON post-trial observational study will address long-term outcomes for the reduced-dose methylprednisolone cohort, and current evidence does not support the use of high-dose corticosteroid therapy in individuals with IgAN. Additional important unanswered questions remain: what is the optimal duration of therapy; is there a role for repeated corticosteroid courses; and which high-risk patients are most likely to benefit from or be harmed by corticosteroids.

Although there is a consensus around which characteristics predict poorer kidney outcomes, uncertainties around who is more likely to benefit from corticosteroid treatment persist. It is likely that those at greater risk of poor kidney outcomes with reversible kidney damage and the background to withstand or avoid treatment-related SAE are likely to have the greatest net benefit; however, there is currently no validated tool to guide management decisions. The authors recognize this may not apply to all patients with IgAN, and therefore, as with any therapeutic regime, the use of corticosteroids should involve a doctor-patient discussion to ensure an understanding around the risk-benefit profile and follow an informed choice.

There are a number of unmet needs in the arena of IgAN, and the potential therapeutic options on the horizon are exciting. It is unclear whether these agents will improve kidney outcomes and whether they will replace or augment corticosteroid therapy. However, effective drugs with fewer treatment-related complications should be the focus of future clinical trials. Further prospective studies are also required to help tailor a targeted treatment strategy, and the authors support the current guidelines that recommend that all patients at high risk of progressive disease should be considered for enrolment in a clinical trial [3].

D.K. has no conflicts of interest to declare. M.G.W. served as a member for the TESTING trial steering committee. He has received fees for advisory boards, steering committee roles, or scientific presentations from Travere, Baxter, Amgen, AbbVie, Chinook, Dimerix, Ostuka, GlaxoSmithKline, and CSL-Behring.

The authors certify that there are no sources of financial grants or other funding that are relevant to this manuscript and that should be acknowledged.

D.K. and M.G.W. conceived the manuscript and edited and approved the final version of the manuscript. D.K. collected the literature and drafted the manuscript. M.G.W. provided critical revision of the manuscript.