Reduced-Dose Methylprednisolone Improves Kidney Outcomes, Delays Renal Failure in High-Risk IgAN

A reduced-dose oral methylprednisolone regimen tapered over 6 to 9 months improves kidney outcomes in patients with high-risk IgA nephropathy (IgAN), according to findings from a prespecified secondary analysis of the reduced-dose cohort of the therapeutic effects of steroids in IgAN global (TESTING) trial.¹

Results showed a 0.4 mg/kg/d methylprednisolone regimen is associated with a 76% reduced risk of the primary composite kidney outcome compared to supportive care alone, additionally highlighting a delay in the progression to kidney failure for patients already established on maximal supportive care.¹

“Whereas other drugs that target specific immunological and hemodynamic pathways in IgAN are being studied in trials, systemic corticosteroids are currently the only immunosuppressant agents in widespread use worldwide, including low resource settings,” Muh Geot Wong, MBBS, PhD, a renal physician, senior staff specialist, and head of the renal clinical trial unit at the Royal North Shore Hospital, and colleagues wrote.¹ “Therefore, it is important to define the balance of risks versus benefits of the reduced-dose regimen to inform the safe use of corticosteroids in clinical practice.”

The renal pipeline has seen many developments pertaining to IgAN, beginning in early 2023 with the accelerated approval of sparsentan (Filspari), the full approval of budesonide (Tarpeyo) at the end of 2023, and the recent accelerated approval of iptacopan (Fabhalta) on August 7, 2024.^2,3 However, corticosteroids remain a mainstay for treatment for many patients with high-risk IgAN who experience proteinuria > 1 g/d despite maximal supportive care.

Although an interim analysis revealed methylprednisolone 0.6 to 0.8 mg/kg/d was associated with 4-fold increased severe adverse events in the TESTING trial, the largest randomized controlled trial to assess the effect of corticosteroids in IgAN to date, protocol amendments were later enacted to include a reduction in methylprednisolone dose to 0.4 mg/kg/d. The present prespecified analysis examined the risk-benefit balance of this reduced-dose methylprednisolone regimen.¹

For inclusion, patients were required to be ≥ 18 years of age with primary IgAN confirmed on kidney biopsy, have an eGFR between 30 and 120 ml/min per 1.73 m2, and a 24-hour urinary protein excretion ≥ 1 g/d while receiving maximum tolerated renin-angiotensin system blockade. Eligible participants entered a run-in period of 4 to 12 weeks and received optimal supportive care with maximally tolerated renin-angiotensin system inhibitor therapy for a minimum of 12 weeks. Those with persistent proteinuria > 1 g/d and demonstrated treatment adherence were randomly assigned in a 1:1 ratio to receive oral methylprednisolone or matching placebo.¹

Participants in the intervention arm received 0.4 mg/kg/d of oral methylprednisolone at a maximum dose of 32 mg/d for 2 months, followed by a tapering regimen of 4 mg/d each month for a total duration of 6 to 9 months. Supportive background therapy was continued throughout the study period.¹

Study visits were conducted monthly for the first 3 months and every 3 months thereafter until the study completion date. The primary outcome was a composite of a 40% eGFR decline, kidney failure requiring kidney replacement therapy, or death due to kidney disease.¹

A total of 427 potentially eligible patients were screened across 42 sites in China, Australia, India, Canada, and Malaysia. Of these, 241 participants were included in the study and followed up for a median of 2.5 years, with 121 randomized to reduced-dose oral methylprednisolone and 120 randomized to placebo. Among the cohort, the mean age was 36.7 years, 42% were female, and 47% were recruited from sites based outside of China.¹

Methylprednisolone was associated with fewer primary outcome events compared to placebo (6% vs 18%; hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.10 to 0.58; P = .002). Additionally, investigators pointed out the mean change in proteinuria from baseline was 1.15 g/d lower (50.4% reduction) in the methylprednisolone group compared to 0.03 g/d lower in the placebo group at 6 months, with a mean difference of 1.14 g/d (95% CI, 0.48 to 1.80; P = .002). Of note, the proteinuria-lowering effect was predominantly observed in the first 12 months and was lost over time.¹

With methylprednisolone, investigators noted an increase in eGFR from baseline of 4.7 ml/min per 1.73 m2 and 5.0 ml/min per 1.73 m2 at 6 and 12 months, respectively, compared to a decrease of 3.2 ml/min per 1.73 m2 and 3.0 ml/min per 1.73 m2 with placebo. The mean differences between the 2 arms were 7.6 ml/min per 1.73 m2 at 6 months (95% CI, 3.8 to 11.4; P <.001) and 7.9 ml/min at 12 months (95% CI, 4.3 to 11.5; P <.001).¹

Investigators called attention to the greater number of severe adverse events observed in the methylprednisolone group compared to the placebo group (7 vs 3; HR, 1.97; 95% CI, 0.49 to 7.90; P = .34). Severe infection requiring hospitalization affected 5 (4%) participants in the methylprednisolone arm compared to 2 (2%) in the placebo arm, and there was a single death in the methylprednisolone group related to serious infection. Additionally, 2 participants developed new onset diabetes following methylprednisolone therapy. There were no major cardiovascular events, fractures, or gastrointestinal bleed in either group during the study.¹

Investigators outlined potential limitations to these findings, including the low power in detecting differences between the intervention arms due to the limited number of kidney failure events and SAEs in the cohort; the short follow-up period compared to the full-dose cohort; the limited number of Caucasian participants; and the insufficient power of the TESTING study to compare the full-dose and reduced-dose cohorts.¹

“The reduced-dose TESTING study demonstrates that a 6 to 9 month reduced-dose methylprednisolone regimen is associated with improved kidney outcomes and a delay in the progression toward kidney failure for individuals with high risk IgAN already established on maximal supportive care. However, some increased risk of SAEs likely remains, albeit at a lower rate than with the full-dose regimen,” investigators concluded.¹

References

1. ^{Kim D, Lv J, Hladunewich M, et al. The Efficacy and Safety of Reduced-Dose Oral Methylprednisolone in High-Risk Immunoglobulin A Nephropathy. KI Reports. https://doi.org/10.1016/j.ekir.2024.03.032}
2. ^{Brooks, A. FDA Awards Full Approval to Budesonide (Tarpeyo) in Treatment of IgA Nephropathy. HCPLive. December 20, 2023. Accessed August 8, 2024. https://www.hcplive.com/view/fda-awards-full-approval-to-budesonide-tarpeyo-in-treatment-of-iga-nephropathy}
3. ^{Campbell, P. Iptacopan Receives Accelerated Approval for Reducing Proteinuria in IgA Nephropathy. HCPLive. August 7, 2024. Accessed August 8, 2024. https://www.hcplive.com/view/iptacopan-receives-accelerated-approval-for-reducing-proteinuria-in-iga-nephropathy}