The phenomenon of focal segmental glomerulosclerosis post-transplantation—a one-hit wonder?

Steroid-resistant nephrotic syndrome (SRNS), also termed focal segmental glomerulosclerosis (FSGS), is one of the most difficult conditions for the nephrologist to manage, particularly when the disease recurs post-transplantation. This syndrome is extremely interesting from the biological perspective as the non-genetic form is most likely caused by an as yet unknown disorder of the circulating plasma. This elusive ‘plasma factor’ has been the focus of researchers for several decades. Many hypotheses have been proposed and tested, but none have yet passed the test of clinical utility. However, the search appears to be narrowing, facilitated by landmark discoveries in the molecular properties of the glomerular filtration barrier, as well as by improved experimental tools. In the therapeutic/clinical setting, the targeting of specific molecules in treatments has improved, of which one example is treatment with specific monoclonal antibodies. In this context, our report on the effects of tumor necrosis factor-alpha (TNF-α) on podocytes is instructive as it demonstrates that this cytokine can have directly deleterious effects on podocytes in vivo and that this effect can be targeted clinically, potentially halting or reversing the disease process. As with all thought-provoking research, this result raises several interesting questions. Is TNF-α the elusive ‘plasma factor’ or is it one of several? Does it directly affect the glomerular filtration barrier, or does it modulate the immune response? And could this technique be used as a cell-based assay for disease activity? Our report adds another potential candidate to the growing list of candidates that need to be tested in a wider population of well-phenotyped patients with SRNS.