Still mysterious: the elusive circulating factor for FSGS

201 4

Important new findings were recently published in relation
to proteinuria and FSGS, which are definitely of interest to our community.
First, the punch line:
There is new evidence
for a “circulating factor” in recurrent FSGS in a fascinating case of a
re-transplanted kidney
(here)
BUT
There is growing
evidence that suPAR is a non-specific marker of kidney disease and therefore not likely to be the “circulating
factor.”
(here)
In fact, it appears that it is non-specifically found in CKD,
and correlates with a declining GFR.
Now for some details:
The re-transplanted
kidney
A letter to the NEJM editor (here)
describes an amazing case of resolution of recurrent FSGS after
re-transplantation. 
A 27 year old patient with primary FSGS receiving a kidney
from his healthy 24 year old sister developed proteinuria in the nephrotic
range (up to 25 g/day!) within 2 days of transplantation, and had no
improvement after plasmapheresis and standard immunosuppressive treatment. A
renal biopsy confirmed foot process effacement, the first hallmark of recurrent
podocyte damage heralding recurrent FSGS. Incredibly, with all appropriate
consents and institutional approval, the transplant team removed the allograft
from Patient 1 and re-transplanted it into another patient who had ESRD due to
diabetes. Within 3-4 days, the proteinuria resolved and a repeat biopsy showed
resolution of foot process effacement and re-establishment of a normal podocyte
architecture. Eight months later, Patient 2 is reported to be doing very well,
with good allograft function and no proteinuria.
This case demonstrates in a remarkable way that recurrent
FSGS results from an elusive “factor” rapidly produced by the recipient (with
primary FSGS), and that the allograft itself can remain fully functional if
removed from the influence of this “factor” and placed in another patient.
suPAR is not suPER specific
What may have seemed to be exciting news in 2011, namely the
notion that soluble uPAR may be predictive of recurrent FSGS (here),
appears to be unfortunately evolving into yet another unsuccessful attempt to
identify the ever elusive circulating factor.
Recent work published in Kidney International by Maas et al.
(here) confirms that suPAR is not able to distinguish between idiopathic
FSGS, secondary FSGS or minimal change disease. 
This is actually not
surprising, because a closer look at the clinical data in Wei et al. (here)
reveals that the admittedly arbitrary cut-off for separating primary FSGS from
all other glomerular disease (3000 pg/ml) did not hold up when tested among
their patient cohorts with idiopathic, recurrent versus non-recurrent FSGS (all
had suPAR> 3000 pg/ml, thus suPAR could not predict the recurrent from the non-recurrent
cases). 
The second figure in the Maas et al. paper may help explain this
conundrum: they show a negative correlation between suPAR and eGFR, meaning
that as GFR drops, suPAR levels rise, which essentially means that suPAR is
simply a marker of CKD.
Future work will no doubt continue to address these issues,
but the apparent lack of specificity of suPAR for FSGS casts serious
doubt on its proposed role as the circulating factor.
So, the search is still on!!!

4 comments

  1. Enough is enough Dr. Reiser!

  2. We have collaborated with Reiser and his team. His lab measured suPAR on
    large number of samples obtained from our patients with or without FSGS.
    His team was absolutely blinded to our study population. Our suPAR
    results were completely in agreement with what they have published so far
    and correlated significantly with FSGS.

  3. As became apparent at the ASN Renal Week 2012, the field requires independent confirmation of suPAR measurements, which has not been possible in the hands of many investigators. Those of us who are clinicians believe in the importance of blinded, independent confirmation of clinical data by multiple groups before it has any clinical validity or utility.

  4. Reiser has just published measurements of suPAR in two large cohorts of FSGS (JASN), would you care to coment on that?

Leave a Reply