What is the issue?
IgA vasculitis (IgAV), previously known as Henoch-Schönlein Purpura, causes inflammation of small blood vessels in children and rarely in adults. Symptoms and signs include a skin rash of small red spots and larger bruises, particularly on the bottom and legs, tummy pain, pain and swelling of joints, and occasionally bleeding from the gut. About a third of children have kidney involvement with blood and protein found in the urine on testing. In most children, kidney involvement is mild (small amounts of blood and protein in the urine only), and it resolves completely, but a few children have persistent kidney disease that may progress to kidney failure.
What did we do?
We looked at information from 20 randomised controlled trials (RCT), which included 1963 participants. Eleven studies included children with IgAV with mild or no kidney involvement. Five studies compared prednisone tablets given for 14 to 28 days with placebo tablets or no treatment, five studies compared medications that reduce blood clotting, and one study compared montelukast (a medication usually used in children with asthma) with a placebo. Nine studies included children with moderate or severe kidney involvement. Five studies compared different medications which suppress the immune system (cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporin, leflunomide, azathioprine). One study compared plasma exchange (where the patient's plasma is removed and replaced with normal plasma) and cyclophosphamide and methylprednisolone with cyclophosphamide and methylprednisolone alone. The last study compared fosinopril, which reduces the amount of protein in the urine, with no treatment.
What did we find?
We wanted to see whether the tested treatments prevented or treated persistent kidney disease at six to 12 months after the onset of IgAV. We found no definite benefits of prednisone or other treatments in preventing more serious kidney involvement in children with none or mild kidney involvement at study entry. We did not find any studies which evaluated prednisone in children presenting with IgAV and severe kidney involvement, although it is recommended for such children in treatment guidelines. In children with severe kidney involvement, we found no benefit of any medication that suppresses the immune system or of plasma exchange in treating kidney involvement in IgAV. As in other kidney diseases, we found that the ACE inhibitor, fosinopril, reduced the number of children with protein in the urine.
Conclusions
There are few data from RCTs examining interventions to prevent or treat kidney disease in people with IgAV. We found no evidence that giving prednisone at the onset of IgAV reduces the risk of serious kidney disease subsequently. We found no evidence that some agents are more effective than others in treating kidney involvement when it occurs. However, the numbers of people studied were too small to exclude a benefit of treatment, so further studies are required. No serious side effects were reported.
There are no substantial changes in conclusions from this update compared with the initial review or the previous update despite the addition of five studies. From generally low to moderate certainty evidence, we found that there may be little or no benefit in the use of corticosteroids or antiplatelet agents to prevent persistent kidney disease in children with IgAV in participants with no or minimal kidney involvement at presentation. We did not find any studies which evaluated corticosteroids in children presenting with IgAV and nephritic and/or nephrotic syndrome, although corticosteroids are recommended in such children in guidelines. Though heparin may be effective in reducing proteinuria, this potentially dangerous therapy is not justified to prevent serious kidney disease when few children with IgAV develop severe kidney disease. There may be no benefit of cyclophosphamide compared with no specific treatment or corticosteroids. While there may be no benefit in the efficacy of MMF or tacrolimus compared with IV cyclophosphamide in children or adults with IgAV and severe kidney disease, adverse effects, particularly infections, may be lower in MMF or tacrolimus-treated children. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin, MMF or leflunomide have any role in the treatment of children with IgAV and severe kidney disease. We did not identify any studies which evaluated corticosteroids
IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is the most common vasculitis of childhood but may also occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009 and updated in 2015.
To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for (1) the prevention of severe kidney disease in people with IgAV with or without kidney involvement at onset, (2) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in IgAV, and (3) the prevention of recurrent episodes of IgAV-associated kidney disease.
We searched the Cochrane Kidney and Transplant Register of Studies up to 2 February 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in IgAV compared with placebo, no treatment or other agents were included.
Two authors independently determined study eligibility, assessed the risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model, and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Twenty studies (1963 enrolled participants) were identified; one three-arm study has been assessed as two studies. Nine studies were at low risk of bias for sequence generation (selection bias), and nine studies were at low risk of bias for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and outcome assessment (detection bias) was at low risk of bias in four and seven studies, respectively. Nine studies reported complete outcome data (attrition bias), while 10 studies reported expected outcomes, so were at low risk of reporting bias. Five studies were at low risk of other bias.
Eleven studies evaluated therapy to prevent persistent kidney disease in IgAV with or without kidney involvement at presentation. There was probably no difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32) or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of IgAV compared with placebo or supportive treatment (moderate certainty evidence). There may be no differences in the risk of any persistent kidney disease with antiplatelet therapy (three studies) or heparin (two studies) in children with or without any kidney disease at study entry, although heparin may reduce the risk of proteinuria by three months compared with placebo or no specific treatment (2 studies, 317 children: RR 0.47, 95% CI 0.31 to 0.73). One study comparing montelukast with placebo found no differences in outcomes as assessed by severity scale scores.
Nine studies examined the treatment of severe IgAV-associated kidney disease. In two studies (one involving 56 children and the other involving 54 adults), there may be no differences in efficacy outcomes or adverse effects with cyclophosphamide compared with placebo or supportive treatment. In two studies, there may be no differences in the numbers achieving remission of proteinuria with intravenous (IV) cyclophosphamide compared with mycophenolate mofetil (MMF) (65 children evaluated) or tacrolimus (142 children evaluated). In three small studies comparing cyclosporin with methylprednisolone (15 children), MMF with azathioprine (26 children), or MMF with leflunomide (19 children), it is unclear whether the treatment had any effect on the numbers in remission or the degree of proteinuria between treatment groups because of small numbers of included participants. In one study comparing plasmapheresis, cyclophosphamide and methylprednisolone with cyclophosphamide and methylprednisolone, there may be no difference in the numbers achieving remission. One study compared fosinopril with no specific therapy and reported fosinopril reduced the number of participants with proteinuria. No studies were identified that evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of IgAV.