Kamei et al. [1] have recently described favorable long-term outcomes in pediatric IgA nephritis patients treated with warfarin, dipyridamole, prednisone and azathioprine. Likely, this work will revive interest in ‘combination’ therapy in the management of progressive IgA nephritis. We suggest, however, that this interest needs to be interpreted in light of a recently recognized mechanism of acute kidney injury (AKI), which we have termed warfarin-related nephropathy (WRN) [2–5]. We suggest that WRN, which is relatively common in chronic kidney disease (CKD) patients [3, 4], likely confounds the interpretation of the original randomized trials of combination therapy in adults with progressive IgA nephritis [6–8]. In these studies, the immunosuppressant was oral cyclophosphamide given in the usual doses >6 months. These studies have been interpreted as showing little or no benefit by combination therapy in progressive IgA nephritis [9]. However, since then, Ballardie has reported a randomized trial showing that, compared to the usual supportive therapy, oral cyclophosphamide at 1.5 mg/kg for 3 months followed by azathioprine therapy for 1–3 years was strongly beneficial in preventing end-stage renal disease in adults with progressive IgA nephritis [10].

Despite Ballardie’s work, there continues to be reluctance to recommend cyclophosphamide therapy for progressive IgA nephritis. The rationale is that of the three randomized trials of oral cyclophosphamide [6, 7, 10], only the Ballardie study [10] showed clear evidence of benefit. We suggest that the apparent conflict among these studies can be resolved by taking into account the likelihood that WRN occurred in some of the patients assigned to the combination therapy of the Walker [6] and Woo studies [7], but in none of the patients assigned to cyclophosphamide …

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