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The Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) study found that, compared to supportive care, 6-9 months of corticosteroids reduced the risk of major kidney events in people with IgA nephropathy (IgAN) at high risk of disease progression but resulted in a greater number of serious adverse events (SAEs). Higher levels of proteinuria and lower estimated glomerular filtration rate (eGFR) at the time of IgAN diagnosis are predictors of kidney failure, but it is uncertain whether these prognostic markers modify treatment response. This post-hoc analysis of the TESTING study aims to determine the association between baseline proteinuria and eGFR and the effects of corticosteroids on kidney and safety outcomes in IgA nephropathy.
503 participants with IgAN and proteinuria >1g/day despite 3 months of maximal renin-angiotensin system blockade were randomised to full- or reduced-dose oral methylprednisolone (0.6-0.8mg/kg/day or 0.4mg/kg/day) versus placebo. The median follow-up period was 3.5 years. Baseline urinary protein excretion and eGFR were categorised by increasing severity (proteinuria [g/day]; group 1: 1-<1.5, group 2: 1.5-<3, group 3 ≥3 and eGFR [ml/min/1.73m2]; group 1: 60-120, group 2: 45-<60, group 3: 30-<45, group 4: 20-<30). A Cox proportional hazards model was used to analyse the effects of methylprednisolone on kidney outcomes according to baseline proteinuria and eGFR. The primary outcome was a composite of 40% decline in eGFR, kidney failure or death due to kidney disease. In addition, Poisson regression was used to estimate the absolute effects of methylprednisolone on kidney outcomes and SAE by subgroups.
There were 137, 240 and 126 participants in proteinuria groups 1-3, and 228, 127, 123 and 25 participants in eGFR groups 1-4 respectively. The baseline characteristics were well matched between proteinuria subgroups. Across lower eGFR levels, participants were more likely to be older, have hypertension and have greater degrees of tubular atrophy on kidney biopsy. The incidence of the primary outcome in the placebo arm was 24/63 (38%), 44/122 (36%) and 38/61 (62%) in proteinuria groups 1-3 and 31/119 (26%), 29/54 (54%), 31/58 (53%), and 15/15 (100%) in eGFR groups 1-4. Methylprednisolone lowered the risk of the primary composite outcome compared to placebo (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P <0.001), with consistent findings regardless of baseline proteinuria (P=0.53) and eGFR (P=0.68) (Figure 1). Sensitivity analyses performed by fitting proteinuria and eGFR as continuous variables also showed consistent effects (P= 0.32 and 0.50 respectively). Overall, 14 primary composite outcome events (95% CI; 6-21) were prevented including 7 kidney failure events (95% CI; 1-12) per 100 participants treated over 2.5 years in exchange for 5 additional SAEs (95% CI 2-8). There was no difference in the absolute risk reduction for kidney outcomes across baseline proteinuria and eGFR levels. There was also no difference in the absolute effect on safety outcomes but the reported number of SAEs in each subgroup was small.
A 6-9 month course of methylprednisolone improves kidney outcomes however increases SAEs in individuals with high-risk IgAN compared to placebo with consistent effects across different levels of proteinuria and eGFR at baseline.
On behalf of the TESTING trial steering committee.