Moderator's view: Treatment of IgA nephropathy-getting comfortable with uncertainty.

A Polar Views discussion by Pozzi and Rauen et al. on the interpretation and clinical application of the recently published Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) trial has elucidated important points concerning potential strengths and weaknesses of this landmark randomized trial. This critical examination of the impact of steroid monotherapy or steroid plus an immunosuppressive (IS) agent compared with 'supportive' therapy with inhibitors of the renin-angiotensin system (RAS) has enhanced our appreciation of the importance of rigorous application of titrated RAS inhibition in high-risk patients with persistent proteinuria >0.75 g/day. At the same time, it brings a new level of uncertainty concerning the overall value and risk of steroid or steroid plus IS therapy in patients failing such 'supportive' therapy. Some of these uncertainties revolve on issues of study design, such as the duration of follow-up, participant stratification (particularly underlying pathology) and dosing regimens. It is hoped that additional trials, better methods of patient selection, improved surrogate end points and safer regimens will lead to less uncertainty over the best treatment practices. On balance, the STOP-IgAN trial raises some key concerns about the merits of steroid alone or steroid plus IS therapy for selected subjects with IgAN, but it does not by itself close the door on the utility of steroid monotherapy in subjects with high-risk IgAN, even as it further degrades the value of steroid plus IS, at least with sequential cyclophosphamide and azathioprine.