So I have been serving as the therapeutic apheresis physician for my colleague (and mentor) Dr. Bruce McLeod (editor of Apheresis: Principles and Practice). Big shoes to fill.
One of our regular patients for plasmapheresis has the diagnosis of focal segmental glomerulosclerosis (FSGS). It has always interested me how we can best follow apheresis patients for therapeutic response. Therefore, it was with great interest that I stumbled on a recent article by Wei et al. published in the August 2011 issue of Nature Medicine in which they identify a circulating permeability factor associated with the development of FSGS in humans and mice: suPAR (soluble urokinase receptor).
FSGS, the most common histologic injury seen in adults with nephrotic syndrome in the U.S., is understood to be caused by podocyte injury. Mutations in several proteins known to be crucial in podocyte structure and/or function have been identified that are associated with FSGS. It has long been suspected that the cause of the vast majority of FSGS cases are due to some circulating factor based on the clinical observations that FSGS can occur immediately after transplant or as a de novo disease in transplanted kidneys--but the identification of this factor has been frustratingly elusive.
Podocyte urokinase receptor (uPAR; encoded by PLAUR) is a GPI-anchored membrane recpetor protein that is a receptor for urokinase but also interacts with a variety of other transmembrane receptors, including integrins. uPAR can be released from the plasma membrane as a soluble molecule (suPAR) by cleavage of the GPI anchor. The authors have recently reported that induced uPAR expression in podocytes can cause podocyte foot process effacement and proteinuria, and so they hypothesized that suPAR might be a candidate circulating factor in FSGS.
Wei et al. have shown that elevated levels of suPAR were present in the plasma of two-thirds of the 78 patients with FSGS that they studied. Further, they found the highest suPAR levels in pretransplant sera from patients with FSGS who later developed FSGS after transplantation. They also found that lowering the levels of suPAR by plasmapheresis led to disease remission.
The paper also sheds light on the pathogenesis of FSGS. Their previous work showed that uPAR is required for activation of beta-3 integrin signaling within the kidney podocyte. In this paper, they demonstrate that suPAR also binds and activates this protein. Increased podocyte beta-3 integrin signaling leads to accelerated podocyte foot process changes that result in effacement, proteinuria, and initiation of FSGS.
A key question is what the source is for increased suPAR. The authors suggest that neutrophils and monocytes may be responsible. This work is an important advance for understanding an enigmatic disease and I highly recommend taking the time to read this as my summary really doesn't do it justice. One can easily envision an ELISA for testing and monitoring people suspected of or having FSGS. But before using suPAR as a diagnostic test or as a way to monitor therapeutic plasmapheresis, further work must be done to validate diagnostic "levels" and correlate falling levels to plasma exchanges.
