Steroids for IgA Nephropathy: Risks Outweigh Benefits in Some

Diana Phillips

August 07, 2017

A high rate of serious adverse events led to the premature termination of a clinical trial designed to evaluate the efficacy of oral methylprednisolone in patients with immunoglobulin A (IgA) nephropathy despite evidence of a statistically significant clinical benefit.

Jicheng Lv, MD, from the Department of Medicine, Peking University First Hospital, Beijing, China, and colleagues published their findings in the August 1 issue of JAMA.

The researchers with the Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study report recruitment for the multicenter, double-blind, placebo-controlled study, which aimed to enrol 750 patients, was discontinued after randomization of 262 patients.

The TESTING study was designed to be conducted in as many as 100 centers from China, Australia, India, Canada, and Malaysia with 5 years of planned follow-up. At the time of termination, enrolment had occurred in China and Australia only.

The researchers randomly assigned patients with a diagnosis of primary IgA nephropathy based on kidney biopsy who had an estimated glomerular filtration rate (eGFR) between 20 and 120 mL/minute/1.73 m2 and urinary protein excretion greater than 1 g/day, in a 1:1 ratio to receive oral methylprednisolone or matching placebo. Placebo and methylprednisone dosing followed a run-in period during which patients' standard therapy was adjusted to ensure optimal renin-angiotensin system blockade and blood pressure control. Treatment occurred during a period of 6 to 8 months, during which patients received 0.6 to 0.8 mg/kg/day oral methylprednisolone or matching placebo (maximal dose of 48 mg/day) for 2 months, which was tapered by 8 mg/day each month.

Of 136 patients randomly assigned to receive oral methylprednisolone, 20 (14.7%) experienced one or more treatment-related serious adverse events compared with four (3.2%) of the 126 patients in the placebo group.

In total, 28 serious adverse events occurred in the treatment group, including 13 infections, two of which were fatal, in 11 patients, the authors write, noting that no serious infections were reported in the placebo group.

Consistent with the findings of previous research, however, corticosteroid therapy was associated with a reduced risk for composite renal outcomes. During the median 21 months of follow-up, 20 patients in the placebo group progressed to the primary renal composite outcome of a 40% reduction in eGFR or end-stage renal disease or death resulting from kidney disease, and only eight patients in the treatment group experienced similar disease progression, reflecting a nearly threefold reduced risk for kidney failure (hazard ratio, 0.37 [95% confidence interval (CI), 0.17 - 0.85; P = .02]; risk difference, 10.0% [95% CI, 2.5% - 17.9%]).

Similar patterns emerged in prespecified analyses of subgroups defined by baseline proteinuria, kidney function, histological lesion scoring, and dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, although the small number of primary outcomes limited the analysis, the authors write.

The researchers also assessed multiple secondary outcomes, including two composite measures (end-stage kidney disease, 40% decrease in eGFR, and all-cause death, and end-stage kidney disease, 50% decrease in eGFR, and all-cause death), as well as each of the following individually: end-stage kidney disease, death resulting from kidney disease, all-cause death, and proteinuria reduction.

Of particular note with respect to the secondary outcomes, mean proteinuria during follow-up was significantly reduced in the treatment group (1.37 [standard deviation, 1.08] vs 2.36 (standard deviation, 1.67) g/day difference, &minutes;0.99 g/day; 95% CI, −1.34 to −0.64 g/day) and the eGFR in the corticosteroid-treated treatment group increased early and remained significantly higher throughout follow-up. The overall mean difference between the treatment and placebo group was 6.1 mL/minute/1.73 m2; 95% CI, 2.9 - 9.3 mL/minute/1.73 m2; P < .001), the authors report.

"The early increase in eGFR observed in the corticosteroid-treated participants raises the possibility that some of the eGFR effects may be due to sarcopenic effects of corticosteroid leading to reduced creatinine generation or due to corticosteroid-induced hyperfiltration," the authors hypothesize.

There was no clear difference between the two groups regarding end-stage kidney disease, they note.

"While proteinuria and eGFR levels were improved, and suggestions of potential benefit for the primary outcome were observed, there were too few primary outcomes to draw definitive conclusions about treatment efficacy from this trial," the authors state.

The nearly 5 times higher risk for serious adverse events, in contrast, "has implications for clinical decision making and treatment guidelines for the use of corticosteroids in IgA nephropathy," the authors write. "Future studies could also consider the use of prophylactic antibiotic therapy, which has not been used in any of the completed studies and is not recommended in clinical practice guidelines."

"Safety Always Has to Come First in a Disease That Is Not Life-Threatening"

The study findings add fuel to the argument in favor of more judicious use of immunosuppressant therapy in patients with progressive IgA nephropathy, according to coauthor Jürgen Floege, MD, director of the Division of Nephrology and Clinical Immunology, University Hospital, Aachen, Germany.

"Safety always has to come first in a disease that is not life-threatening," Dr Floege told Medscape Medical News. "The TESTING trial findings thus strengthen our plea for a comprehensive supportive care approach, including antihypertensive and antiproteinuric measures as well as lifestyle changes that should always be used to the full extent in such patients before considering immunosuppressive agents," he said, referring to the call to action that he and his colleagues made in an New England Journal of Medicine article reporting the negative findings of the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) study.

"The increased rate of serious adverse events in the treatment group in the TESTING trial begs the question whether the risks of corticosteroid therapy outweigh its potential benefit in IgA nephropathy." Jonathan J. Hogan, MD, clinical director, Penn Glomerular Disease Center, assistant professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia, told Medscape Medical News. "The publication of two consecutive studies showing higher rates of adverse events (STOP-IgA and TESTING) will deter the use of corticosteroids by some nephrologists. However, the improved renal outcome observed in TESTING may prompt the continued use of corticosteroid use in selected patients. Unfortunately, there are limited other treatments for patients with IgA nephropathy who are at risk for progressive kidney disease.

Corticosteroid Therapy May Be Appropriate for Certain Patients

Under certain circumstances, corticosteroid therapy may be appropriate for patients with IgA nephropathy.

"High-dose corticosteroids, starting with 8 weeks at 1 mg/kg/day of prednisolone, may still be indicated in the patient with nephrotic range proteinuria (>3.5 g/day) despite extensive supportive care. In patients with lower proteinuria (ie, 1 - 3 g/day), lower doses of corticosteroids may be indicated," Dr Floege told Medscape Medical News. "More importantly, several other new therapeutic approaches to progressive IgA nephropathy are emerging, such as enteric-coated budesonide, which may be safer than systemic corticosteroids."

Despite some limitations in the study design, including the failure to consider pathological findings in the determination of patient eligibility, which could influence the efficacy of immunosuppressive therapy, the findings "can critically inform clinical practice, guideline development, and the design of future clinical trials in IgA nephropathy," Michelle M. O'Shaughnessy, MB, BCh, and Richard A. Lafayette, MD, from the Glomerular Disease Center at Stanford University School of Medicine, in Palo Alto, California, write in an accompanying editorial.

"From a patient care perspective, findings from the TESTING trial highlight the importance of delivering the right drug, to the right patient, at the right time," the editorial authors write. For example, "[f]or an elderly patient with diabetes, osteoporosis, recurrent infections, and only mild glomerulonephritis, adverse events are likely to be of far greater concern to patient and physician than the remote possibility of [end-stage renal disease]," Dr O'Shaughnessy and Dr Lafayette explain. "Conversely, for a young and otherwise healthy patient with multiple risk factors for rapid progression to [end-stage renal disease], an increased short-term risk for (typically reversible) adverse events might be an acceptable trade-off for the potential to delay or prevent the need for dialysis or kidney transplantation.

"Corticosteroid therapy should still be considered in patients with aggressive clinical presentations and high risk of quickly progressing to end stage kidney disease, such as rapidly progressive glomerulonephritis, and who have dangerous systemic (nonkidney) manifestations of the disease," Dr Hogan told Medscape Medical News.

Until additional research into the timing and use of immunosuppressive drugs and the possibility of concomitant prescribing of prophylactic antibiotics to reduce the occurrence of serious infections is conducted, "an onus is on physicians to effectively translate the adverse event findings from the TESTING trial to their patients with IgA nephropathy," the editorialists write. "Borrowing from guidelines developed for corticosteroid prescribing for patients with rheumatic diseases, embarking on this course of therapy in patients with IgA nephropathy should involve a careful assessment of expected risks and benefits, counseling patients about these potential outcomes, and close monitoring for the development of adverse events if this treatment course is pursued."

This study was supported by the National Health and Medical Research Council of Australia, the Peking University Health Central Clinical Research Project, and the Canadian Institutes of Health Research and the study drug was provided by Pfizer Pharmaceuticals. Some of the study authors disclosed various financial relationships with Pfizer and multiple additional various additional drug companies. Dr Floege reports personal fees from Pharmalink, Amgen, Fresenius/Vifor, Chugai, and Sanofi. Dr Lafayette reports financial relationships with Alexion Inc, Mallinckrodt Inc, the National Institutes of Health, Roche Inc, and Rigel Pharmaceuticals Inc. Dr O'Shaughnessy and Dr Hogan have disclosed no relevant financial relationships.

JAMA. 2017;318(5):429-442. Article abstract, Editorial extract

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