In this single center retrospective review of 17 children transplanted due to FSGS, 15 or 88% had recurrent disease and were treated for their recurrence with a protocol using PLEX and augmentation of immunosuppression. Of the children with recurrence, 15 or 88% were able to enter a long-lived complete remission. In all but one case, the remissions occurred quickly after institution of therapy for recurrence, and only one child required supplemental therapy with the addition of rituximab after not fully remitting after PLEX and cyclophosphamide provision.
Although a large meta-analysis of patients with FSGS recurrence demonstrated a similar 71% rate of response with PLEX-based therapies, nearly 30% achieved only a partial remission, and the number of PLEX sessions and the duration of PLEX therapy was often substantial. In comparison, the children described in our report tended to have rapid and complete responses, and there were no subsequent relapses during long-term follow up. Moreover, eGFR remained acceptable long-term, with eGFR decline over time like rates seen more generally in children.
There is currently no consensus about the best overall approach for the treatment of recurrent FSGS in children [2, 6, 7], largely due to the lack of prospective randomized controlled trials. Moreover, although PLEX is quite often used as a first-line therapy for recurrence, it is almost always provided in the setting of other additional therapies, and there is little data to guide clinicians as to the specific efficacy of individual components of such multi-tiered management .
The decision to augment immunosuppression in FSGS recurrence in children is further complicated since most of these children have already had significant pre-transplant exposure to immunosuppression as part of attempts to reverse FSGS in their native kidneys. Concerns for cumulative toxicity of certain medications, such as cyclophosphamide, may lead to decisions to forgo the use of what may be an efficacious therapy, especially when there is not clarity as to the best overall therapy or the best population for that drug’s efficacy. In the patient with colorectal cancer, the time between the use of cyclophosphamide and the appearance of colorectal cancer was 3 years. A cause-effect relationship cannot be confirmed or ruled out.
The paucity of prospective controlled studies not only exacerbates the lack of clarity as to best current management strategies but also complicates the assessment of novel therapies as they become available. For instance, rituximab and LDL-apheresis have both been used increasingly to treat FSGS recurrence, but their utility in children with recurrent disease in general is difficult to assess when there has been little formal assessment of current therapies to allow baseline levels of expectation.
The importance of identifying the best therapies is underscored by long-term outcomes in successfully transplanted patients as compared to those with failed allografts. FSGS recurrence that does not respond to treatment leads to early graft loss and return to dialysis, and most often pretends future episodes of recurrence with subsequent transplantation. The long-term reliance on dialysis for renal replacement therapy adversely affects quality of life, requires more health care resources and is more costly, and results in significantly shorter life expectancy. In our own cohort, despite the successful treatment of recurrence in almost all patients, those who went on to lose graft function for other reasons and then required chronic dialysis as young adults all had limited life spans.
This study has some limitations. First, among patients with nephrotic syndrome, there is a low incidence of FSGS that leads to chronic kidney failure and requires a transplant, which explains the low number of patients presented in this study . Second, due to the lengthy collection time, the patients were subjected to different types of management and different clinical concept, which may lead to information bias. However, this study has strengths. The study was conducted in a tertiary care center. Long-term follow-up was possible in these patients from their nephrotic syndrome diagnosis.
Although the conclusions that can be drawn from our results may not be generalizable to all children with recurrent FSGS, our report does show that in some children an aggressive approach to recurrence that uses PLEX and immunosuppression augmentation including cyclophosphamide can lead to rapid, complete, long-term remission. Rigorous assessment of proposed protocols and their effectiveness in children with FSGS should help to determine what therapies need to be studied in a randomized, controlled fashion in children and underscore the importance of sharing results such as described with this reported cohort to the pediatric nephrology community at large.