There remains an urgent unmet need to develop new approaches for the treatment of children with SRNS who fail a trial of CNI therapy (3). While investigators have attempted various combinations of immunosuppressive therapies such as MMF (15), ofatumumab (16) and rituximab (8, 17, 18), none have been effective in sustaining remission in a significant proportion of treated children; moreover, some have been associated with potentially life-threatening complications, not to mention their significant cost (19–21). All of these factors have limited their widespread adoption for the treatment of SRNS in children, and recommendations for their use and not based on robust evidence (13). While rituximab has been recommended as the 1st line agent in children with DTT-SRNS (Grade C recommendation), its efficacy in inducing long term remission is low and it is associated with significant potential side effects, is expensive and may need re-dosing when B-cell repopulation occurs (13).
Based on previously referenced data using IV CTX in children of Asian-Indian ethnicity with SRNS, at our center our practice has been to offer this therapy in the setting of SRNS-DTT. IV CTX has also been demonstrated to be of benefit in adults with SRNS; although remission rates are lower compared to CNIs and time to remission longer, unlike patients treated with tacrolimus, CTX was associated with a lower relapse rate after discontinuation of therapy (22). Our current study explored the risks-benefits of its use in children and demonstrates that IV CTX can be a very effective strategy in a subset of children with SRNS-DTT in North-America: those with MCD on biopsy. Fifty-percent (n 4) of the children treated with IV CTX went into CR that was sustained over a considerable period of time, with preserved renal function, which is a heartening observation. These 4 children represent a 100% of those who had ‘pure’ MCD on biopsy and 50% of those who had MCD variants. Only 1 child with an MCD variant was completely unresponsive and subsequently also failed rituximab therapy- he remains edema free and with normal renal function. In contrast, both children with FSGS failed to show any response and both progressed to ESRD. While we cannot draw definitive conclusions due to our small sample size, it is possible that the concomitant use of IV methylprednisolone along with IV CTX may be of benefit in attaining remission (or faster time to remission); 3 of the 4 patients who received IV methylprednisolone went into CR and only 1 child who attained CR had not received IV methylprednisolone (patient #2).
At last follow up, only one of the children who went into CR or PR remains intermittently on steroids; he relapsed after going into CR and has become steroid dependent with normal renal function (patient #5). He too failed rituximab therapy after IV CTX.
Interestingly, the time to remission was quite late (unexpectedly so for us) after start of IV CTX. This is important to realize since failure to respond early on in the course may lead some treating teams to abandon therapy. None of our patients needing hospitalization for any serious illness- no life-threatening infections were noted, nor was hemorrhagic cystitis seen. Transient alopecia was common during the treatment. Clearly longer-term follow-up is needed to assess long term risks such as infertility and malignancies.
Out study is limited by its retrospective nature and small sample size. There was no consistent immunosuppressive protocol that was followed after patients were deemed unresponsive to tacrolimus, and the IV CTX treatment regimen also varied somewhat.