IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, leading to end stage
renal disease (ESRD) in up to 30 to 40% of patients with in a few decades after diagnosis.
Several therapeutic options have been used in clinical practice. However, no treatments can
completely stop the progression of IgAN. Given the pathogenic mechanism of IgAN, many
researchers have tried to treat patients with IgAN using immunosuppression such as
corticosteroids. To date, there have been conflicting results on the effects of
immunosuppression in IgAN. Earlier studies from Italian groups showed that corticosteroid
treatment significantly attenuated kidney function decline and decreased the development of
ESRD. Since then, the beneficial effects of corticosteroids have generally been accepted for
treatment of IgAN particularly in patients with high degree of proteinuria > 1.0 g/day
despite maximal conservative care during 3 to 6 months. However, a recent interventional
study by German group, known as the Supportive Versus Immunosuppressive Therapy for the
Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial, showed that immunosuppressive
treatment in addition to intensive supportive care did not significantly improve renal
outcome and resulted in more treatment-related side effects. Moreover, the Therapeutic
Evaluation of Steroids in IgA Nephropathy Global (TESTING) study, another randomized
controlled study from China, was early terminated because of safety concern related to
corticosteroids. Interestingly, the primary composite outcome occurred significantly less in
the methylprednisolone group as compared to the placebo group despite more serious adverse
events in the former group. With this background in mind, we designed a multicenter
prospective randomized controlled open-label trial; a step-wise therapeutic approach with
corticosteroids or add-on cyclophosphamide therapy in IgAN patients with persistent
proteinuria who have preserved eGFR of ≥ 30 ml/min/1.73 m2. A total of 19 hospitals will
participate in this study. During 12 weeks before the enrollment, all patients will receive
maximal supportive care including the use of RAS blockers, blood pressure control with a
target of <130/80 mmHg, and protein restriction diet. If proteinuria does not decrease < 1.0
g/g creatinine, patients will be randomly assigned to continue supportive care, or to receive
corticosteroids. At 3 months after randomization, patients in the corticosteroid arm who have
persistent proteinuria of ≥ 1.0 g/g creatinine, or fast decline in eGFR ≥ 15% from the
baseline value, will additionally receive cyclosphosphamide during the following 3 months.
Patients who have substantial decreased amount of proteinuria < 1.0 g/g creatinine at 3
months will continue protocol-based corticosteroids during the same period. At 6 months after
randomization, patients who receive add-on cyclophosphamide will switch to azathioprine as a
maintenance therapy and those who receive corticosteroids alone will discontinue the
treatment and will be followed up during 24 months thereafter. At least 87 subjects (a total
of 174) would be required for each group to detect 13.5% difference in response rates between
the two groups based on previous studies if type I error rate is 5% and type II error is 20%
given 20% of drop-out rate during the study period. The primary endpoint is the development
of a ≥ 30% decline in eGFR from the baseline or the onset of ESRD. This study will unveil
conflicting results on the effects of immunosuppressive treatment in IgAN patients at high
risk of progression.