Addition of Azathioprine to Corticosteroids Does Not Benefit Patients with IgA Nephropathy

The optimal treatment for IgA nephropathy (IgAN) remains unknown. Some patients respond to corticosteroids, suggesting that more aggressive treatment may provide additional benefit. We performed a randomized, multicenter, controlled trial to determine whether adding azathioprine to steroids improves renal outcome. We randomly assigned 207 IgAN patients with creatinine ≤2.0 mg/dl and proteinuria ≥1.0 g/d to either (1) a 3-day pulse of methylprednisolone in months 1, 3, and 5 in addition to both oral prednisone 0.5 mg/kg every other day and azathioprine 1.5 mg/kg per day for 6 months (n = 101, group 1) or (2) steroids alone on the same schedule (n = 106, group 2). The primary outcome was renal survival (time to 50% increase in plasma creatinine from baseline); secondary outcomes were changes in proteinuria over time and safety. After a median follow-up of 4.9 years, the primary endpoint occurred in 13 patients in group 1 (12.9%, 95% CI 7.5 to 20.9%) and 12 patients in group 2 (11.3%, CI 6.5 to 18.9%) (P = 0.83). Five-year cumulative renal survival was similar between groups (88 versus 89%; P = 0.83). Multivariate Cox regression analysis revealed that female gender, systolic BP, number of antihypertensive drugs, ACE inhibitor use, and proteinuria during follow-up predicted the risk of reaching the primary endpoint. Treatment significantly decreased proteinuria from 2.00 to 1.07 g/d during follow-up (P < 0.001) on average, with no difference between groups. Treatment-related adverse events were more frequent among those receiving azathioprine. In summary, adding low-dose azathioprine to corticosteroids for 6 months does not provide additional benefit to patients with IgAN and may increase the risk for adverse events.IgA nephropathy (IgAN) causes ESRD in a significant percentage of patients.^1–3 None of the treatment strategies currently used in clinical practice have proved to be more effective than another, although corticosteroids give some results.^4–6In 1999, we found that a 6-month steroid course significantly decreased the risk of a 50% increase in plasma creatinine from baseline at 5 years in comparison with supportive therapy; proteinuria also decreased.⁷ However, 6 months of steroid therapy may not be enough to ensure stable remission in some patients. Thus, we hypothesized that more aggressive treatment may lead to better results, especially in the long term. Previous studies have suggested the possibility that adding immunosuppressants (particularly azathioprine) to corticosteroids may be more effective in preserving renal function^8,9 and reducing proteinuria.¹⁰ However, azathioprine has mainly been given in combination with other drugs.⁸ Moreover, the sample size⁸ and study design⁹ were inadequate in two of three studies.The aim of this trial was to assess the efficacy and safety of adding low-dose azathioprine for 6 months to steroids in adult IgAN patients.¹¹ We decided to use azathioprine at low dose and for a relatively short period to decrease the risk of serious side effects of this immunosuppressant in relatively young and healthy subjects.