Daily treatment of patients with IgA nephropathy with an oral glucocorticoid, methylprednisolone, led to significant reductions in the rate of kidney failure and a composite tally of adverse incident renal outcomes in a multicenter, randomized trial with more than 500 patients — the largest prospective, controlled study yet reported for this treatment in this population.
“The results clearly demonstrated that oral steroids have a role in preventing kidney failure in the types of patients we enrolled. I think the findings provide very strong evidence of benefit [from oral methylprednisolone] that will change guidelines and change practice,” said Vlado Perkovic, MBBS, PhD, during a press briefing before he presented the results at virtual Kidney Week 2021.
Until now, while there has been “lots of interest in glucocorticoid treatment [for IgA nephropathy] there have been no properly powered trials with clinically relevant endpoints,” added Perkovic, a professor at the University of New South Wales in Sydney and a nephrologist at The George Institute for Global Health in Newtown, Australia.
Two Different Doses Studied in TESTING
While providing new support for a treatment already cited in a guideline as the best option following inadequate response to initial supportive therapy, the efficacy results from the TESTING trial were muddied because the study included two different doses of methylprednisolone that produced sharply different safety profiles, although they appeared to have roughly similar efficacy results.
“I’m disappointed that the data from the low-dose steroid were not presented and analyzed separately from the higher dose,” commented Jonathan Barratt, MChB, PhD, a nephrologist and professor at Leicester University, UK.
In the TESTING trial, which began in 2012, 262 patients had received immunoglobulin (Ig) A plus a “full” oral methylprednisolone dose of 0.6-0.8 mg/kg/day or placebo, for a maximum of 48 mg/day of the steroid, for 2 months, which was then tapered down by 8 mg/day/month for a total treatment duration of 6-9 months. In late 2015, the safety-monitoring committee for the trial pulled the plug on the regimen because of excess serious adverse events, primarily infections.
An interim report from TESTING with results from the first 262 patients was published in JAMA in 2016. The investigators said at the time that the early stop to enrollment made definitive conclusions about efficacy impossible.
TESTING continued with a reduced-dose methylprednisolone regimen that started patients on 0.4 mg/kg/day for a maximum of 24-32 mg/day, which was tapered down by 4 mg/day/month. Other safety measures included routinely treating all patients with antibiotic prophylaxis against pneumocystis pneumonia and increasing the required level of kidney function in enrolled patients from the original minimum of an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.73m2 to an eGFR of 30 mL/min/1.73m2.
Another 241 patients were enrolled and received the modified regimen. A final primary analysis included all 503 patients from both study phases.
This analysis showed that, during an overall average follow-up of 4.2 years, treatment with methylprednisolone cut the primary composite endpoint by a significant 47% compared with placebo, Perkovic reported. The endpoint included incident kidney failure, death due to renal causes, or at least a 40% decline in eGFR from baseline.
Treatment with the steroid also cut the incidence of kidney failure by a significant 41% compared with placebo in the full analysis.
Two Doses Had Similar Efficacy, Different Safety
Perkovic also reported the efficacy outcomes during each of the study’s two phases. During the high-dose phase, patients on methylprednisolone had a significant 42% reduction in the primary endpoint compared with controls during an average 5.7 years of follow-up. During the low-dose phase, patients on the corticosteroid had a significant 73% relative reduction in the primary endpoint compared with controls during an average follow-up of 2.5 years.
There was no significant difference in the primary outcome between the two study phases.
The new report also documented the contrast in safety between the original full dose and the substitute reduced dose plus the other measures taken to reduce adverse effects.
Overall, 28 patients on methylprednisolone had a total of 37 serious adverse events compared with seven patients with eight events in the control group. Thirty of the serious adverse events from methylprednisolone occurred in 22 patients on the full-dose regimen, while just six of the patients on the lower-dose regimen had a total of seven serious adverse events, said Perkovic.
But Barratt said this efficacy analysis was inconclusive.
“The high-dose regimen is unsafe, and therefore, other than telling us that clinicians should not use this dose, it does not give any clinically useful information about the low-dose regimen. The data [from the two different doses] should not be combined,” Barratt maintained in an interview.
He added that Perkovic reported “no formal assessment of significance of efficacy for the low-dose treatment that I could see, just a test for heterogeneity, which in my view is not good enough. The two [phases] should be viewed as completely separate and analyzed as such,” Barratt suggested.
Barratt also faulted the absence of information on changes in body mass index (BMI) and on development of Cushingoid features and other features of steroid toxicity in patients taking methylprednisolone, “the main things that patients complain about when taking these drugs,” he explained.
Number Needed to Treat With Low-Dose Methylprednisolone
TESTING ran at 66 sites in Australia, Canada, and China, and roughly three quarters of patients were enrolled in China. Key inclusion criteria for enrollment were biopsy-proven IgA nephropathy, daily proteinuria of more than 1 g, and at least 3 months on a stable supportive regimen including a maximally tolerated dose of a renin-angiotensin system blocker.
Patients were an average age of 38 years old, and 61% were men. Average eGFR at entry was about 62 mL/min/1.73m2, and average proteinuria was about 2.4 g/day. The analyses showed no heterogeneity linked to whether patients were treated in China or elsewhere, nor heterogeneity linked to any other analyzed variable including age and severity of proteinuria at baseline.
The number needed to treat was six patients to prevent a primary outcome event and the number needed to harm was 41 patients to produce a serious adverse event over 2.5 years with the low-dose regimen, Perkovic said.
The 2021 update to the KDIGO Clinical Practice Guideline for the Management of Glomerular Diseases states that the “primary focus” of managing IgA nephropathy should be multifaceted, optimized supportive care, including as much renin-angiotensin system blockade as tolerated or allowed, blood pressure control, cardiovascular risk minimization, and adherence to lifestyle advice, including dietary counseling, smoking cessation, weight control, and exercise.
The 2021 update also states that “if proteinuria stays above 0.75-1 g/day 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 (Grade 2B), or preferably the opportunity to take part in a therapeutic clinical trial.”
“Because the clinical benefit of glucocorticoids in IgA nephropathy is not established, they should be given with extreme caution or avoided entirely” in patients with risk factors including diabetes, obesity, or an eGFR of less than 30 mL/min/1.73m2, the guideline further states.
TESTING was primarily funded by several government agencies. Seed funding and study drug were provided by Pfizer. Perkovic has reported receiving honoraria from or being an advisor to a number of companies. Barratt has reported being a consultant to or receiving research funding from a number of companies.
Kidney Week 2021. Presented November 5, 2021.
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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