Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial

Abstract

Importance: The effect of glucocorticoids on major kidney outcomes and adverse events in IgA nephropathy has been uncertain.

Objective: To evaluate the efficacy and adverse effects of methylprednisolone in patients with IgA nephropathy at high risk of kidney function decline.

Design, setting, and participants: An international, multicenter, double-blind, randomized clinical trial that enrolled 503 participants with IgA nephropathy, proteinuria greater than or equal to 1 g per day, and estimated glomerular filtration rate (eGFR) of 20 to 120 mL/min/1.73 m2 after at least 3 months of optimized background care from 67 centers in Australia, Canada, China, India, and Malaysia between May 2012 and November 2019, with follow-up until June 2021.

Interventions: Participants were randomized in a 1:1 ratio to receive oral methylprednisolone (initially 0.6-0.8 mg/kg/d, maximum 48 mg/d, weaning by 8 mg/d/mo; n = 136) or placebo (n = 126). After 262 participants were randomized, an excess of serious infections was identified, leading to dose reduction (0.4 mg/kg/d, maximum 32 mg/d, weaning by 4 mg/d/mo) and addition of antibiotic prophylaxis for pneumocystis pneumonia for subsequent participants (121 in the oral methylprednisolone group and 120 in the placebo group).

Main outcomes and measures: The primary end point was a composite of 40% decline in eGFR, kidney failure (dialysis, transplant), or death due to kidney disease. There were 11 secondary outcomes, including kidney failure.

Results: Among 503 randomized patients (mean age, 38 years; 198 [39%] women; mean eGFR, 61.5 mL/min/1.73 m2; mean proteinuria, 2.46 g/d), 493 (98%) completed the trial. Over a mean of 4.2 years of follow-up, the primary outcome occurred in 74 participants (28.8%) in the methylprednisolone group compared with 106 (43.1%) in the placebo group (hazard ratio [HR], 0.53 [95% CI, 0.39-0.72]; P < .001; absolute annual event rate difference, -4.8% per year [95% CI, -8.0% to -1.6%]). The effect on the primary outcome was seen across each dose compared with the relevant participants in the placebo group recruited to each regimen (P for heterogeneity = .11): full-dose HR, 0.58 (95% CI, 0.41-0.81); reduced-dose HR, 0.27 (95% CI, 0.11-0.65). Of the 11 prespecified secondary end points, 9 showed significant differences in favor of the intervention, including kidney failure (50 [19.5%] vs 67 [27.2%]; HR, 0.59 [95% CI, 0.40-0.87]; P = .008; annual event rate difference, -2.9% per year [95% CI, -5.4% to -0.3%]). Serious adverse events were more frequent with methylprednisolone vs placebo (28 [10.9%] vs 7 [2.8%] patients with serious adverse events), primarily with full-dose therapy compared with its matching placebo (22 [16.2%] vs 4 [3.2%]).

Conclusions and relevance: Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the incidence of serious adverse events was increased with oral methylprednisolone, mainly with high-dose therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT01560052.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lv reported receiving grants from the China National Funds for Distinguished Young Scientists and the National Key Research and Development Program of China during the conduct of the study and personal fees from Chinook Therapeutics and KBP Bioscience outside the submitted work. Dr Wong reported receiving fees for advisory boards, steering committee roles, or scientific presentations from Travere, Baxter, Amgen, AbbVie, Chinook, Dimerix, Otsuka, GlaxoSmithKline, and CSL Behring. Dr Hladunewich reported receiving grants from the Canadian Institute for Health Research and study drugs from Pfizer during the conduct of the study and grants from Calliditas for a study in IgA, Ionis for a study in IgA, Pfizer for a study in focal segmental glomerulosclerolsis, and Roche for a study in preeclampsia outside the submitted work and being the medical lead for glomerulonephritis for the Ontario Renal Network. Dr Jha reported receiving grants paid to the institution from Baxter Healthcare and NephroPlus and personal fees paid to the institution from GlaxoSmithKline, AstraZeneca, Bayer, Zydus Cadilla, and Panacea outside the submitted work. Dr Jardine reported receiving grants from the National Health and Medical Research Council during the conduct of the study and other competitively awarded grants from the National Health and Medical Research Council, the Australian government research-funding body, outside the submitted work. Dr Reich reported receiving personal fees from Calliditas, being a clinical trial investigator for Omeros, receiving personal fees from Novartis for providing advisory to and being a speaker at an internal conference, providing advisory to Chinook and being a national coordinating investigator for the ALIGN study, receiving personal fees from Travere for providing advisory, being a site trial co-investigator for Alnylam, being a site trial investigator for Pfizer, and being director of the Glomerulonephritis Fellowship funded by the Louise Fast Foundation outside the submitted work. Dr Cattran reported receiving grants from the Canadian Institute of Health Research for salary support of coordinator during the conduct of the study and personal fees from Calliditis for being on a pharmaceutical scientific advisory board, Alnylam Pharmaceutical Scientific for being on a steering committee, Novartis for being a pharmaceutical data and safety monitoring committee member, Chemocentryx for being a data and safety monitoring committee member, Alexion Pharmaceutical for being an advisory board member, and UpToDate for being an author and being a member of a steering committee for the international IgA nephropathy network outside the submitted work. Dr Glassock reported receiving personal fees from Omeros, Biocryst, Novartis, Calliditas, Chemocentryx, Ionis, Travere, Arrowhead, and Horizon outside the submitted work, being editor of the Nephrology section of UpToDate, and being a contributor to KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Dr Wheeler reported receiving personal fees from Amgen, Astellas, Mundipharma/Napp, Merck Sharp and Dohme, Boehringer Ingelheim, and Vifor for speaker fees, personal fees from AstraZeneca for a consultancy contract, and personal fees from Bayer GlaxoSmithKline, Gilead, Janssen, Tricida, and Zydus for consultancy outside the submitted work. Dr Woodward reported receiving personal fees as a consultant from Amgen, Freeline, and Kyowa Kirin outside the submitted work. Dr Billot reported receiving grants from the Australian National Health and Medical Research Council during the conduct of the study. Dr Johnson reported receiving personal fees from Baxter Healthcare, AstraZeneca, Bayer, AWAK Technologies, and Boehringer Ingelheim and Lilly; grants from Fresenius Medical Care; and travel sponsorship from Ono and Amgen outside the submitted work. Dr Cass reported receiving grants from Australian National Health and Medical Research Council during the conduct of the study. Dr Floege reported receiving personal fees from Calliditas, Idorsia, Omeros, Travere, and Visterra during the conduct of the study and personal fees from Bayer, Boehringer, and AstraZeneca outside the submitted work. Dr Remuzzi reported receiving personal fees from Akebia Pharmaceuticals, Alexion Pharmaceuticals, AstraZeneca, BioCryst Pharmaceuticals, Boehringer Ingelheim, Janssen Research & Development, Menarini Ricerche Spa, Otsuka, and Silence Therapeutics outside the submitted work. Dr Agarwal reported receiving personal fees from Bayer Healthcare Pharmaceuticals, AstraZeneca, Boehringer, Relypsa, Vifor Pharma, Merck, Sanofi, Eli Lilly, Lexicon, Reata, Chinook, Vertex Pharma, Akebia, and Diamedica outside the submitted work and reported being an author for UpToDate. Dr Zhang reported receiving personal fees related to steering committee roles from Novartis, Omeros, Calliditas, and Chinook and grants and funding from Pfizer during the conduct of the study. Dr Perkovic reported receiving grants from Pfizer, which provided study drug and initial seed funding, during the conduct of the study and grants from AbbVie for a clinical trial steering committee; personal fees from Amgen for serving on an advisory board; serving on a clinical trial steering committee for Astellas; receiving personal fees from AstraZeneca Boehringer Ingelheim, Janssen, Novo Nordisk, and Novartis for serving on a steering committee, advisory committee, and scientific presentations; serving on a trial steering committee and advisory committee for Bayer; receiving personal fees from Chinook Therapeutics for serving on an advisory committee; serving on a data and safety monitoring committee for Dimerix; serving on the board of directors for George Clinical; serving on a steering committee and advisory committee for Gilead, GlaxoSmithKline, and Travere; serving on an advisory committee for Medimmune; receiving personal fees from Mitsubishi Tanabe for scientific presentations; receiving personal fees from Mundipharma for advisory committee and scientific presentations; and serving on an advisory committee for Vifor Pharma. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants in a Study of the Effect of Oral Methylprednisolone on Kidney Function Decline in Patients With IgA Nephropathy

eGFR indicates estimated glomerular filtration rate. aDosing of methylprednisolone starting at 0.6-0.8 mg/kg per day (maximum, 48 mg/d) was reduced to a starting dose of 0.4 mg/kg per day (maximum, 32 mg/d) after an interim analysis demonstrated a high rate of adverse events in the intervention group. bA total of 126 participants were randomized to receive placebo during the period when full-dose methylprednisolone was being used for the intervention group and 120 were randomized to receive placebo during the period when reduced-dose methylprednisolone was being used. cA total of 23 participants were still receiving full-dose methylprednisolone or placebo in 2015 when the excess serious adverse events were identified. Based on the advice from the independent data safety monitoring committee, treatment was discontinued for these 23 individuals, but scheduled follow-up was continued and they were included in the primary analysis. dPatients lost to follow-up may have received, completed, or discontinued the assigned intervention.

Figure 2.. Time From Randomization to First Outcome in a Study of the Effect of Oral Methylprednisolone on Kidney Function Decline in Patients With IgA Nephropathy

Component outcome of 40% eGFR reduction is shown in eFigure 4 in Supplement 2; the component outcome of death is not shown because there were only 2 events (after a median [IQR] follow-up of 3.5 [2.4-6.2] y). Hazard ratios, CIs, and P values were estimated using the Cox proportional hazards regression models, stratified according to randomization factors (site, ethnicity, baseline proteinuria, baseline eGFR, and kidney biopsy findings). Included in these analyses are all the participants who were randomized and received at least 1 dose of methylprednisolone or placebo. Analyses were censored at the date when patients died (for causes other than death due to kidney failure), were lost to follow-up, or withdrew from the study or at the end of study visit, whichever occurred first. The log-rank P values were <.001 for the primary outcome in all patients, .03 for kidney failure requiring dialysis or transplant, .002 for the primary outcome in the full-dose cohort, and .004 for the primary outcome in the reduced-dose cohort.

Figure 3.. Primary Outcome in a Study of the Effect of Oral Methylprednisolone on Kidney Function Decline in Patients With IgA Nephropathy

Hazard ratios and CIs were calculated with a Cox proportional hazards model with stratification according to region, baseline proteinuria, baseline estimated glomerular filtration rate, and kidney biopsy findings, with factors for trial group, subgroup, and the interaction between trial group and the subgroup variable. Ancestry was reported by the investigators. Proteinuria was 24-hour urinary protein.