Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial

Abstract

Importance: Guidelines recommend corticosteroids in patients with IgA nephropathy and persistent proteinuria, but the effects remain uncertain.

Objective: To evaluate the efficacy and safety of corticosteroids in patients with IgA nephropathy at risk of progression.

Design, setting, and participants: The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study was a multicenter, double-blind, randomized clinical trial designed to recruit 750 participants with IgA nephropathy (proteinuria greater than 1 g/d and estimated glomerular filtration rate [eGFR] of 20 to 120 mL/min/1.73 m2 after at least 3 months of blood pressure control with renin-angiotensin system blockade] and to provide follow-up until 335 primary outcomes occurred.

Interventions: Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) (n = 136) or matching placebo (n = 126) for 2 months, with subsequent weaning over 4 to 6 months.

Main outcomes and measures: The primary composite outcome was end-stage kidney disease, death due to kidney failure, or a 40% decrease in eGFR. Predefined safety outcomes were serious infection, new diabetes, gastrointestinal hemorrhage, fracture/osteonecrosis, and cardiovascular events. The mean required follow-up was estimated to be 5 years.

Results: After randomization of 262 participants (mean age, 38.6 [SD, 11.1] years; 96 [37%] women; eGFR, 59.4 mL/min/1.73 m2; urine protein excretion, 2.40 g/d) and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events. Serious events occurred in 20 participants (14.7%) in the methylprednisolone group vs 4 (3.2%) in the placebo group (P = .001; risk difference, 11.5% [95% CI, 4.8%-18.2%]), mostly due to excess serious infections (11 [8.1%] vs 0; risk difference, 8.1% [95% CI, 3.5%-13.9%]; P < .001), including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (hazard ratio, 0.37 [95% CI, 0.17-0.85]; risk difference, 10.0% [95% CI, 2.5%-17.9%]; P = .02).

Conclusions and relevance: Among patients with IgA nephropathy and proteinuria of 1 g/d or greater, oral methylprednisolone was associated with an increased risk of serious adverse events, primarily infections. Although the results were consistent with potential renal benefit, definitive conclusions about treatment benefit cannot be made, owing to early termination of the trial.

Trial registration: clinicaltrials.gov Identifier: NCT01560052.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lv reported receiving grant funding from Pfizer. Dr Zhang reported receiving grant funding from Peking University Health Central Clinical Research Project and Pfizer during the conduct of the study and receiving personal fees for steering committee membership from Janssen. Dr Wong reported receiving grant funding from the Diabetes Australia Research Trust and giving scientific presentation supported by Astra Zeneca, Roche, and Amgen. Dr Jardine reported receiving grant funding from the National Health and Medical Research Council of Australia and the National Heart Foundation, Cardiovascular Research Network, Gambro, Amgen, Eli Lilly, Merck, Rebecca L. Cooper Medical Research Foundation grant and KHA Project grant; and receiving fees from Boehringer Ingelheim, Fresenius, and Amgen directed to clinical research programs. Dr Hladunewich reported receiving grants from the Canadian Institute of Health Research. Dr Jha reported receiving grant funding from Baxter Healthcare and GSK. Dr Barbour reported receiving grants from the Canadian Institute of Health Research. Dr Reich reported receiving grants and personal fees from Amgen. Dr Cattran reported receiving unrestricted research funding from Genentech; grant funding from the Canadian Institutes of Health; research funding and personal support from the National Institute of Diabetes and Digestive and Kidney Diseases; personal funding for serving on scientific advisory board from Chemocentryx, Omerus, Mallinckrodt; and serving without compensation on the scientific board of Nephcure. Dr Woodward reported receiving personal fees from Amgen. Dr Wheeler reported receiving honoraria from Akebia, Astra Zeneca, Amgen, Boehringer Ingelheim, Janssen, and Vifor Fresenius Medical Care. Dr Johnson reported receiving grant funding from Baxter Healthcare, Fresenius Medical Care, and the National Health and Medical Research Council of Australia; and receiving personal fees from Baxter Healthcare, Fresenius Medical Care, and Astra Zeneca. Dr Floege reported consulting on IgA nephropathy for Pharmalink, Omeros, and Chugai and giving scientific presentations supported by Amgen and Vifor. Dr Remuzzi reported receiving personal fees from Janssen Research and Development. Dr Agarwal reported receiving personal fees from Janssen, Boehringer Ingelheim, Relypsa, Opko, Astra Zeneca, Amgen, Sanofi, Akebia, Bayer, and UpToDate. Dr Perkovic reported consulting on IgA nephropathy for Pharmalink, Eli Lilly, and Novartis; giving scientific presentations supported by Pfizer; and having a policy of honoraria being paid to his institution.

Figures

Figure 1.. Enrollment, Randomization, and Follow-up of Study Participants

eGFR indicates estimated glomerular filtration rate. aPatients were prescreened by the local investigator for eligibility, and 523 patients signed consent and entered the run-in phase; prescreening data were not collected. bOne participant moved overseas and could not be contacted; a second could not be contacted despite many attempts.

Figure 2.. Time From Randomization to First Serious Adverse Event, by Treatment Group

Median at-risk duration of follow-up was 19.7 (interquartile range, 9.2-30.1) months for methylprednisolone and 25.2 (interquartile range, 14.8-32.7) months for placebo. Relative risk, 4.63 (95% CI, 1.63-13.2); P = .001 by Fisher exact test. SAE indicates serious adverse event.

Figure 3.. Time From Randomization to First Primary Composite Outcome of 40% eGFR Decrease, ESKD, or Death Due to Kidney Failure, by Treatment Group

Hazard ratio, 0.37 [95% CI, 0.17-0.85]; P = .02. Median at-risk duration of follow-up was 22.2 (interquartile range, 14.9-30.4) months for methylprednisolone and 22.4 (interquartile range, 14.3 to 30.9) months for placebo. eGFR indicates estimated glomerular filtration rate; ESKD, end-stage kidney disease.

Figure 4.. Effect of Methylprednisolone Therapy on eGFR and Proteinuria During Follow-up

Randomization proteinuria and estimated glomerular filtration rate (eGFR) data are not available for 4 participants who were therefore excluded from this analysis. Error bars indicate 95% confidence intervals. A, Mean difference in eGFR was 5.14 (95% CI, 1.90 to 8.37) mL/min/1.73 m2 at month 3; 6.74 (95% CI, 3.40 to 10.09) mL/min/1.73 m2 at month 6; 4.62 (95% CI, 1.16 to 8.09) mL/min/1.73 m2 at month 12; 5.43 (95% CI, 1.37 to 9.48) mL/min/1.73 m2 at month 24; and 7.67 (95% CI, 1.91 to 13.43) mL/min/1.73 m2 at month 36 (P < .01 for all). The annual rate of eGFR decline was lower in the methylprednisolone group (−1.79 vs −6.95 mL/min/1.73 m2 per year; mean difference, 5.15 [95% CI, 0.42 to 9.89]; P = .03). B, Mean difference in proteinuria was −0.83 (95% CI, −1.18 to −0.47) g/d at month 3; −1.00 (95% CI, −1.37 to −0.63) g/d at month 6; −1.20 (95% CI, −1.59 to −0.81) g/d at month 12; −1.03 (95% CI, −1.49 to −0.56) g/d at month 24; and −0.93 (95% CI, −1.60 to −0.25) g/d at month 36 (P < .01 for all). Time-averaged proteinuria was significantly lower in the methylprednisolone group than in the placebo group (1.37 vs 2.36 g/d; mean difference, −0.99 [95% CI, −1.34 to −0.64]; P < .001).