A suPAR breakthrough in FSGS

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As has been mentioned in previous post, the identification of the anti-PLA2R antibody has the potential to revolutionize the diagnosis of membranous GN and is already being used clinically on a small scale. It is found in 70% of patients with idiopathic MN and could replace a renal biopsy in some cases.
Last week, a paper was published in Nature Medicine that may be equally revolutionary. For a long time it has been suspected that a there is a circulating factor that is responsible for at least some cases of primary FSGS. This is suggested by the fact that recurrent FSGS after transplantation can be treated with plasmapheresis. However, up to now, this factor has remained elusive.
In 2008, a paper was published reporting that induction of the urokinase receptor in the podocytes of mice led to foot process effacement and proteinuria. The authors postulated that a circulating, soluble form of this receptor (suPAR), that is normally present in low concentration in the serum, could be responsible for some cases of recurrent FSGS.
They took 78 patients with FSGS and measured their levels of suPAR, comparing them to normal controls and patients with other glomerular diseases including MN, MCD and pre-eclampsia. Elevated suPAR levels were noted in the patients with FSGS and the highest levels were seen in the pre-transplant sera of patients who went on to develop recurrent FSGS after transplantation. Using 3000 pg/ml as a cut-off, 2/3 of the patients with FSGS had an elevated serum suPAR compared to no healthy controls, and no patients with MCD or pre-eclampsia. 4/11 patients with MN had suPAR levels in this range although the mean level was far lower. suPAR levels were also seen to fall significantly following plasmapheresis. Using 3 different models, they then showed that increased levels of suPAR caused foot process effacement and proteinuria in mice.
It is thought that suPAR mediates its effect by depositing in the glomeruli and activating podocyte β3 integrin. This appears to be enough to initiate foot process effacement. Measuring suPAR levels may be a means of guiding therapy for recurrent FSGS and could provide a new target for treatments in the future.


  1. Several new studies confirmed that the measurement of suPAR using currently available assays has absolutely no value at the present time in decision-making in routine clinical practice! For more on this see the following review article from the leading experts in suPAR reseach in Nephrology.

    Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol. 2013 Mar 21. [Epub ahead of print]

  2. Unfortunately this study is so flawed, it is unlikely that it truly represents a long sought breakthrough, and I fear that it will lead to many years of wasted research down the wrong path.
    A review of the clinical literature reveals that suPAR is elevated in various inflammatory conditions, so it is certainly not specific to recurrent FSGS.
    In this particular study by Wei et al. the patient data are highly inconsistent and the levels of suPAR do not correlate with the degree of proteinuria…
    Futhermore, the mouse data are fundamentally flawed and therefore do not support the conclusions of this study.
    – the uPAR used to inject in mice is actually fused to a human Fc receptor, making in an allo-antigen in mice, which most certainly would trigger an immune response similar to serum sickness, leading to proteinuria.
    – the amount of mouse suPAR- human Fc is also a problem: there is no effect at 10 ug, but only at 20 ug, and there are no controls shown! 20 ug of any protein, much less an allo-antigen, injected in a mouse is the equivalent of injecting 10 grams of something in a human!
    The experiments in this study are, I am afraid, so fraught with artifact, that unless repeated by a number of different and reputable scientists, will remain hard to believe…

  3. Two of my children have had kidney transplants due to FSGS caused by identical genetic mutations from both their father and I. Since first diagnosis in 1995, we have seen magnificent progress in the understanding of this disease. I am so thankful to the doctors at The Children's Hospital of Philadelphia and Loma Linda Medical Center, and all of you who are continuing to research this disease and search for answers. This is an incredible breakthrough for all who are affected by FSGS. It gives me hope that my boys will have a better chance of keeping their new kidneys healthy, and that future generations will never have to go through dialysis and transplant. Thank you from all of us!!!
    The Kimbirk boys and family!

  4. I was diagnosed with fsgs 20 years ago, and for all this time, no one on my medical care team has been able to guess what exactly causes it. With fsgs recurrence so prevalent in transplant patients, I did suspect there was something already present in the patient that would cause this recurrence. This is incredibly exciting news; it is actually the first glimmer of hope I've experienced in decades!

    What do you think will be the earliest practical use of this new knowledge?

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