Steroids Cut Risk for Serious Renal Events in IgA Nephropathy

Oral steroids helped reduce the risk of major kidney outcomes for patients with immunoglobulin A (IgA) nephropathy, the TESTING study found.

In a randomized trial of 503 participants, those who received oral methylprednisolone saw a 47% risk reduction for a composite kidney outcome — defined as a 40% eGFR decline or kidney failure resulting in dialysis, transplantation, or kidney disease-related death — meeting the primary endpoint (event rate 7.0 vs 11.8/100 patient-years; HR 0.53, 95% CI 0.39-0.72, P<0.0001), reported Vlado Perkovic, MBBS, PhD, of the University of New South Wales in Sydney.

Looking just at the effect on kidney failure, those on steroids saw a 41% risk reduction (HR 0.59, 95% CI 0.40-0.87, P=0.008).

On top of that, patients on this steroid regimen saw a 41% drop in the risk for progression to end-stage kidney disease during the average 4.2-year follow-up period, which was one of the secondary endpoints (HR 0.59, 95% CI 0.40-0.87, P=0.008), Perkovic explained in a presentation at the American Society of Nephrology virtual Kidney Week.

Those on the steroid regimen also saw a risk reduction in most of the other secondary outcomes, including a 30%, 40%, or 50% eGFR reduction.

Death due to kidney failure and death due to any cause weren’t significantly different between the two groups, though.

When the trial was first initiated several years ago, participants randomized to the active treatment arm received a dose of oral methylprednisolone between 0.6-0.8 mg/kg/day, capped at a maximum dose of 48 mg/day for 2 months, and were subsequently weaned by 8 mg/day/month.

However, during the early months of the trial, some safety concerns arose — particularly a spike in serious infections among the steroid arm participants — leading to a change in trial protocol.

In 2016, Perkovic’s group reviewed the dosing, reducing it to 0.4 mg/kg/day, capped at a maximum dose of 32 mg/day, and weaning by 4 mg/day/month. At this time, pneumocystis jirovecii prophylaxis for 12 weeks was also added to this reduced dose protocol. The researchers also limited the study to only patients with an eGFR between 30 to 120 mL/min/1.72m² at entry, slightly higher than the previous allowance of patients with an eGFR of 20 mL/min/1.72m² at entry.

The risk reduction in kidney events was significant among both dose protocols: full dose group followed for a mean of 5.7 years (HR 0.58, 95% CI 0.41-0.81) and reduced dose group followed for a mean of 2.5 years (HR 0.27, 95% CI 0.11-0.65. P=0.11 for heterogeneity).

For inclusion in the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study, all participants had to have biopsy-proved IgA nephropathy with a proteinuria level above 1 g/day.

“The immunological basis [of IgA nephropathy] has been elucidated over recent years, suggesting a possible role for immunosuppressive therapy,” Perkovic noted.

Among the total cohort, the average participant age was 38 and less than 40% were female. Being a multicenter, multicountry study, more than 75% of participants were Chinese, with another 13% South Asian. Only 5% of the total cohort was not Asian. The average BMI was 25 and about half the cohort also had hypertension.

Because of the geographic breakdown of the cohort, Perkovic’s group did a subanalysis separating the cohort by location. Looking exclusively at non-Chinese participants, the primary composite kidney outcome was reduced by 76% (HR 0.24, 95% CI 0.10-0.56, P=0.046 for heterogeneity). And among just participants residing in China, there was a 39% risk reduction for the primary outcome (HR 0.61, 95% CI 0.44-0.84).

Not surprisingly, patients on methylprednisolone saw a higher rate of serious adverse events (AE), largely driven by hospitalization for severe infection (16 vs 3 in placebo, P=0.004). There was also a significantly higher number of patients on methylprednisolone who experienced one or more serious AEs (28 vs 7 in placebo).

There were four deaths in the methylprednisolone group and none in the placebo, but this difference was not statistically significant (P=0.12). Likewise, there was a higher rate of hospitalization for gastrointestinal bleeding, new diabetes cases, and fracture or osteonecrosis in the steroid arm, but none of these differences were statistically significant.

Kidney Week session moderator Kirk Campbell, MD, of the Icahn School of Medicine at Mount Sinai in New York City, asked Perkovic how these findings fit into the KDIGO 2021 guidelines, which state: “If proteinuria stays above 0.75-1 g/d despite at least 90 days of optimized supportive care, the patient has a high risk of progressive loss of kidney function and may be considered for a 6-month course of glucocorticoid therapy.”

“The guidelines currently already suggest that conversations should be had with individuals at high risk about the potential benefits and risks of steroids,” Perkovic pointed out. “I think these data would support that approach and…add strength to it, in some degree, making the benefits a little clearer,” adding that the data “will help to inform those conversations by providing more precision about both the risks and benefits of different approaches.”

“But I think they suggest that this treatment should be offered to high risk people,” he concluded.