**4. Treatment**

The Kidney Disease Improving Global Outcome (KDIGO) working group on glomerulonephritis compiled the first evidence-based guidelines for the treatment of IgAN and IgAV in 2012 [43]. Children and adults were treated in the same way.

In adults and children with IgAN, the particular value of RAAS blockers, as angiotensinconverting-enzyme inhibitors [44,45] or angiotensin-receptor blockers [46] in retarding progression of the disease, has been shown in prospective randomized trials. Supportive care is now the first line of treatment, recommended in IgAN and IgAV, as soon as proteinuria is > 1 g per day (in children 0.5 to 1 g/day per 1.73 m2) with a blood pressure goal < 130/80 mmHg (no BP goals specified for children), and to achieve proteinuria < 1 g per day.

Concerning the use of corticosteroids and other immunosuppressive agents, KDIGO, in 2012 [43], published its guidelines for IgAN and IgAV, in children as in adults, with a quiet low level of proof (no more than 2C) because of the lack of large clinical trials:

The KDIGO practice guidelines have been recently update [47], including several important clinical trials for IgAN published since 2012, either with corticosteroids or other immunosuppressive drugs, mainly mycophenolate mofetil (MMF). Unfortunately, all have excluded patients with IgAV (adult or children) and children with IgAN. No additional recommendation was done for them.

The authors stressed that future guideline recommendations will need to include an assessment of the relative risks and benefits of steroids in individual patients over a broader range of eGFR, with careful consideration of infections and prophylaxis. They emphasize that we must pay particular attention to comorbidities as advanced age, metabolic syndrome, morbid obesity, latent infection as viral hepatitis or HIV, active peptic ulceration or uncontrolled psychiatric illness.

Concerning corticosteroids in adult IgAN, three main clinical studies [48–50] and one meta-analysis [51] are available. They showed that corticosteroids, after optimization supportive treatment (mainly RAAS blockers) and in addition to it, can decrease proteinuria and slow loss of kidney function, particularly in patients with persistent proteinuria more than 1 g/g and preserved renal function (eGFR > 50 mL/min/1.73 m2). The Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) study recently published its follow-up data, available for 149 participants, with a median of 7.4 years, which showed no difference of renal outcomes (in terms of serum creatinine, proteinuria, end-stage kidney disease, and death) between the two groups [49,52]. The Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING) trial was stopped early after an interim analysis revealed a high risk of infectious serious adverse events including the lethal Pneumocystis Jirovecii pneumonia [50]. Patients with IgAN from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort, classified according to the Oxford-MEST classification and medication used, have been retrospectively studied. From the 1147 patients of the cohort, 184 subjects who received corticosteroids and RAAS blockers were matched to 184 patients with a similar risk profile of progression who received only RAAS blockers. Using a propensity score, authors showed that corticosteroids reduced proteinuria and the rate of renal function decline and increased renal survival, even in patients with an eGFR < 50 mL/min per 1.73 m<sup>2</sup> [48].

Although previous studies [53,54] showed that MMF was not effective for treatment of IgAN, recent trials [55,56] add conflicting information. Hou JH and al.'s study reintroduces the possibility that MMF may be useful for IgAN, notably by its steroid-sparing effect.

In adult IgAV, very limited evidence is available regarding the value of corticosteroids, cyclophosphamide or other immunosuppressive agents. Only one RCT is available and shows, in adults with severe IgAV, most of them with nephritis, no additional benefit when cyclophosphamide was added to corticosteroids [57,58]. However, by extrapolating from findings in adults with IgAN, the KDIGO guidelines sugges<sup>t</sup> that a 6-month course of corticosteroid therapy would be effective to treat nephropathy in IgAV, if proteinuria is more than 1 g per day persisting despite RAAS blockade and blood pressure control, whereas it has been shown to be ineffective in IgAN [59], Rituximab seems to be a promising therapy in the managemen<sup>t</sup> of adults with IgAV [60].

In child IgAV, although earlier studies showed some benefit of corticosteroids, these studies were small and poorly designed. Meta-analyses [61] and more recent randomized controlled trials [62,63] have not clearly shown its benefit and confirm that cyclophosphamide therapy is ineffective in severe renal disease. Despite that, based on the opinions of 16 experts in pediatric rheumatology, systemic vasculitis, and nephrology across Europe, the recent SHARE [64] (Single Hub and Access Point for Paediatric Rheumatology in Europe) initiative recommends corticosteroids to be used for treatment of IgAV nephritis in children, regardless of severity. For severe nephritis, the authors drew on experiences with similar forms of systemic vasculitis to recommend intravenous cyclophosphamide in combination with high-dose steroid therapy to induce remission, followed by azathioprine or MMF in combination with low-dose steroid therapy as a maintenance treatment.

Two randomized placebo-controlled prednisone trials [62,65] and one meta-analysis [61] showed that corticosteroids are ineffective to prevent occurrence of nephritis in children with IgAV. One ongoing study (NCT04008316) will evaluate colchicine in adult patients with IgAV limited to skin to prevent skin relapse (primary endpoint) and occurrence of digestive or kidney involvement (secondary endpoint).

A grea<sup>t</sup> quantity of clinical trials concerning IgAN are ongoing (about one hundred registered in ClinicalTrial.gouv), with four molecules particularly attractive (sparsentan, hydrochloroquine, budesomide, glifozine). None of them included IgAV or children. It is therefore not possible to compare the sensitivity to treatment of both diseases in those two populations.
