Oral Methylprednisolone Proves Mettle in IgA Nephropathy

Treatment with an oral glucocorticoid offered better outcomes in patients with immunoglobulin A (IgA) nephropathy and proteinuria, according to the TESTING trial, although the study had its fair share of ups and downs.

In the multicenter trial, participants were randomized to receive oral methylprednisolone or placebo and, over a mean 4.2 years of follow-up, the composite primary outcome—40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease—occurred in 28.8% (n=74) in the methylprednisolone group versus 43.1% (n= 106) in the placebo group for a hazard ratio of 0.53 (95% CI 0.39 to 0.72, P<0.001) and an absolute annual event rate difference of −4.8%/year (95% CI −8.0% to −1.6%), reported Hong Zhang, MD, PhD, of Peking University First Hospital in Beijing, and co-authors.

Trial recruitment began in May 2012, but then came to a halt in November 2015 after 262 patients had been randomized, the authors explained in JAMA. Why? Because there were "an excess of serious infections," two of which were fatal, in the study-drug arm. Earlier results from TESTING were reported in 2017 in JAMA and in 2021 in the American Journal of Nephrology.

Despite the unfortunate turn of events, "there were signs of efficacy" with the treatment approach, noted Kirk N. Campbell, MD, at Icahn School of Medicine at Mount Sinai in New York City, in a JAMA editorial accompanying the current study. "The [trial] steering committee resumed the study a year and 4 months after halting, with a revised protocol."

Specifically, the trial’s initial methylprednisolone dose was 0.6-0.8 mg/kg/d, for a maximum dose of 48 mg/d, and weaning by 8 mg/d/mo. For the study’s second go-around, more participants were recruited but with a reduced methylprednisolone dose of 0.4 mg/kg/d, for a maximum 32 mg/d, and weaning by 4 mg/d/mo, along with an add-on antibiotic prophylaxis for pneumocystis pneumonia.

Ultimately, there were 503 total randomized patients at 67 global sites (41 in China; majority men), and 98% completed the trial. "Recruitment began earlier in China and Australia and continued throughout the trial in these countries, whereas in Canada, India, and Malaysia, recruitment commenced only after recruitment to the full-dose protocol had been stopped," the authors noted.

The goal of TESTING was to compare the effects of oral methylprednisolone against matching placebo for the risk of kidney failure events in patients with IgA nephropathy and persistent (≥1 g per day) proteinuria.

Currently, an IgA nephropathy diagnosis requires a "kidney biopsy, as no biomarker sufficiently specific and sensitive is available to supplant the procedure. Patients display significant heterogeneity in the epidemiology, clinical manifestations, renal progression, and long-term outcomes across diverse racial and ethnic populations," wrote Dana V. Rizk, MD, of the University of Alabama at Birmingham, and co-authors in a 2022American Journal of Medical Sciences review.

In a 2021 StatPearls article, Prashanth Rawla, MD, of Sovah Health in Martinsville, Virginia, and Faten Limaiem, MD, of the University of Tunis El Manar in Tunisia, explained that the "feature of IgA nephropathy is mesangial proliferation with significant IgG deposition in the kidney. While primary IgA nephropathy is a limited disorder, it can also be associated with Henoch Schönlein purpura, lupus, dermatitis herpetiformis, and hepatitis."

Eligible TESTING participants had a diagnosis of primary IgA nephropathy proven on kidney biopsy; an estimated glomerular filtration rate (eGFR) between 20 and 120 mL/min/1.73 m²; and 24-hour urinary protein excretion ≥1 g per day.

The dosing breakdown was as follows:

• TESTING group: 131 patients received the original full dose of methylprednisolone and were matched to 122 patients who got full-dose placebo.
• Low-dose TESTING group: 117 patients received a reduced-dose and were matched to 113 patients who got a reduced-dose placebo.
• Nine patients in the study-drug arms, and 11 patients in the placebo arms, did not receive the assigned intervention.

The authors reported that the "effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen," specifically HR 0.58 (95% CI 0.41-0.81) for the full dose and HR 0.27 (95% CI, 0.11-0.65) for the reduced dose (P=0.11 for heterogeneity).

Among multiple secondary outcomes for both TESTING and low-dose TESTING, the risk of kidney failure requiring dialysis or transplant was significantly lower in the methylprednisolone group versus the placebo group (19.5% versus 27.2%, HR 0.59, 95% CI 0.40-0.87, P=0.008) for an annual event rate difference of −2.9%/year (95% CI −5.4% to −0.3%). And proteinuria reduction, evaluated by time-averaged mean proteinuria, was also significantly lower at 1.70 g/d (95% CI 1.54-1.86) versus 2.39 g/d (95% CI 2.15-2.63), respectively, but this difference was no longer apparent by 3 years of follow-up.

As for adverse events (AEs), serious AEs were reported in 10.9% in the study-drug group versus 2.8% in the placebo group, and these were attributed to excess hospitalizations and serious infections. "The excess was primarily observed with the full-dose methylprednisolone regimen compared with participants randomized to receive placebo during that study period (22 versus 4), rather than the reduced-dose regimen compared with participants in the placebo group randomized at that time (6 versus 3)," the authors noted.

In total, there were four infection-related fatalities, all in the study-drug groups (three in TESTING; one in low-dose TESTING).

Besides the start-stop-start nature of the trial, other limitations included the fact that the majority of trial participants were from China and that unblinded participants were recruited to low-dose TESTING. Finally, the reduction in proteinuria in the study-drug arms did not hold up at 36 months, and a post hoc analysis that suggested that the therapy’s benefit on other outcomes may diminish over time, the authors conceded.

"Furthermore, many participants continued to lose kidney function over time, suggesting that additional longer-term therapies may also be required to optimize kidney outcomes in IgA nephropathy," they said.

What might be a major takeaway from the trial? Campbell pointed out that "[a]s a result of the TESTING data, patient physician discussions can now be better informed, particularly around the question of safety."

He explained that when TESTING first got underway, there was no other ongoing research and development involving IgA nephropathy. TESTING laid the groundwork for numerous other trials and studies have been done, one of which (NEFIGAN) supported the FDA approval of budesonide in 2021.

Campbell noted that ongoing studies (NefIgArd, for one) are looking at other treatment options for IgA nephropathy, such as proliferation-inducing ligand and B-cell-activating factor. Also, sodium glucose cotransporter 2 inhibitors (SGLT2i) are now approved for the general indication of chronic kidney disease, including IgA nephropathy, he stated.

Finally, "[a]dvances in genomics and the use of histologic, serologic, and urinary biomarkers may help guide clinicians in the future in identifying patients most likely to benefit from glucocorticoid-based therapies in the evolving IgA nephropathy treatment landscape," Campbell said.

TESTING was funded by the Australian National Health and Medical Research Council, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, China National Funds for Distinguished Young Scientists, National Key Research and Development Program of China, and the Canadian Institutes for Health Research (MOP126078), and Pfizer. Pfizer provided the study drug for the trial.

Zhang reported relationships with, and/or support from, Novartis, Omeros, Calliditas, Chinook, and Pfizer. Co-authors reported relationships with, and/or support from, multiple entities.

Campbell reported relationships with Calliditas, Travere, Chinook, Vera, and Omeros.

Lv J, et al "Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: The TESTING randomized clinical trial" JAMA 2022; 327(19): 1888-1898.

Campbell KN "Oral glucocorticoids for IgA nephropathy" JAMA 2022; 327(19): 1872-1874.