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.

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).