Primary focal segmental glomerulosclerosis (pFSGS) is one of the leading causes of nephrotic syndrome, and its recurrence after kidney transplantation remains a major challenge in the absence of targeted therapy. The recent identification of autoantibodies directed against nephrin, a protein of the podocyte slit diaphragm, has reshaped the understanding of this disease: it reinforces the notion that minimal change disease and pFSGS are two manifestations of a common molecular mechanism, and provides an immunological argument in favor of a circulating factor underlying the disease. Several retrospective studies have, moreover, established a close link between the presence of anti-nephrin antibodies and early post-transplant recurrence, which often occurs as soon as the first day. To date, a total of 21 patients with post-transplant recurrence associated with these antibodies had been reported, but preventive therapeutic strategies remained unexplored.
The authors describe here the case of an adolescent with pFSGS and positive for anti-nephrin antibodies, monitored prior to kidney transplantation from a living donor. The presence of the antibodies was assessed in sera collected before and after transplantation, using three complementary techniques — ELISA, Western blot, and immunoprecipitation — and three distinct nephrin proteins. The preventive protocol combined two doses of rituximab initiated five weeks before surgery, followed by repeated sessions of therapeutic plasma exchange with antibody measurement before and after each session, continued until a sustained reduction below the detection threshold was achieved. Transplantation was then carried out under conventional immunosuppressive therapy, with daily monitoring of albuminuria for early detection of a possible recurrence.
This regimen achieved an effective and sustained reduction in anti-nephrin antibodies. With more than one year of follow-up, graft function remains excellent and free of albuminuria, in contrast with the typically very early recurrence observed in patients carrying these antibodies. The analysis further revealed cross-reactivity of the antibodies with NEPH3 (filtrin), another key slit diaphragm protein sharing similarities with nephrin; cross-inhibition studies suggest that a single antibody population recognizes both antigens, although the coexistence of two populations cannot be entirely ruled out. This dual reactivity could intensify podocyte injury, a hypothesis that remains to be confirmed.
The authors emphasize the limitations of this work: it is a single case, which will need to be confirmed in other patients and then in prospective multicenter studies; neither the time of antibody appearance, nor the recognized epitopes, nor the course the patient would have experienced without these preventive measures could be determined, and no post-transplant biopsy was performed given the favorable outcome. This management nonetheless illustrates a personalized medicine approach, and monitoring combined with the preventive removal of anti-slit diaphragm antibodies could become a standard strategy in pFSGS patients who are candidates for kidney transplantation.