Supportive Therapy Can Be as Good as Immunosuppression in IgA Nephropathy

Optimal supportive therapy (SUP) can obviate the need for immunosuppression in treating progressive IgA nephropathy (IgAN), a new study shows. Among patients with biopsy-proven IgAN, SUP drove 30 percent of them into a low-risk category, slowing their loss of renal function and overcoming the benefits of immunosuppression.

For the prospective Supportive Versus Immunosuppressive Therapy for Progressive IgA Nephropathy (STOP-IgAN) trial, eligible adult patients at 32 nephrology centers underwent a 6-month run-in phase of SUP using antihypertensive, antiproteinuric (ACE inhibitor or angiotensin-receptor blocker), and statin medications as well as dietary counseling. Patients with persistent proteinuria >0.75 g/day at the end of the run-in were randomly assigned in an open-label manner to SUP or to SUP plus immunosuppressive therapy for 3 years.

At the 52nd annual meeting of the European Renal Association—European Dialysis and Transplant Association conference in London in May 2015, Jürgen Floege, MD, Director of the Division of Nephrology at RWTH Aachen University in Germany, reported that of 309 patients who completed the run-in phase, 94 (30%) achieved a reduction of proteinuria to <0.75 g/day on SUP. These patients were therefore “low-risk” for progression and did not enter the randomized treatment phase.

After accounting for patients who dropped out or refused randomization, 80 patients were assigned to SUP and 82 to SUP plus immunosuppression with corticosteroids alone or in combination therapy.

Equivalent proportions progressed regardless of immunosuppression

At 3 years there was no significant difference in the proportion of patients in each arm of the randomized phase of the trial whose disease progressed, defined as loss in estimated glomerular filtration rate (eGFR) of at least 15 mL/min compared to baseline. In the SUP-alone group, 24 patients (30%) had such an eGFR loss vs. 28 patients (34%) in the SUP plus immunosuppression group (p = 0.602).

A minority of patients in each arm of the randomized phase of the trial reached full clinical remission at 3 years, defined as proteinuria <0.2 g/day and an eGFR loss of <5 mL/min, although the group receiving immunosuppression did significantly better. Only 4 patients (5%) in the SUP arm were in remission versus 14 patients (17%) who achieved full clinical remission in the SUP plus immunosuppression arm (p = 0.011).

“There seems to be a benefit of immunosuppresssion for some IgAN patients as indicated by the higher number of patients achieving full clinical remission,” Floege concluded. “However, this benefit is not accompanied by any detectable effect on functional loss,” as measured by eGFR decline. He noted that immunosuppressive treatment was accompanied by more serious adverse effects, including infections, diabetes, and weight gain.

The value of immunosuppression on top of SUP in the treatment of IgAN is controversial. Recent reports of the European Validation Study of the Oxford Classification of IgAN (VALIGA) trial indicated that immunosuppression was associated with significant reductions in proteinuria and in renal functional decline and with increased renal survival. The benefits were seen regardless of initial eGFR and with greater benefit at higher levels of proteinuria.

However, Floege noted that VALIGA was based on a retrospective analysis, “and it would not be the first time that a prospective, randomized study has refuted what was previously indicated by observational studies,” adding that STOP-IgAN is the largest randomized clinical trial that has addressed the question of immunosuppressive therapy in IgAN. A key difference between STOP-IgAN and previous trials also may be that STOP-IgAN achieved “very strict blood pressure control” during the run-in phase and throughout the ensuing 3 years of the trial, he said.

Floege said an implication of STOP-IgAN for clinical practice is that “intensified, supportive therapy” with maximized antihypertensive and antiproteinuric medication “should always be provided initially.” If the desired outcomes are not achieved, then immunosuppression may be considered for patients with proteinuria up to 1.5 g/day. However, his results indicated that higher levels of proteinuria do not seem to benefit from immunosuppression, and these patients should therefore be spared the side effects of such treatment without an adequate prospect of success.