Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis

Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeabilityfactors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation.In the past three decades, many research endeavors were undertaken to identify these unknownfactors. Even though some potential candidates have been recently discussed in the literature, “the”actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the useof novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we reportthe successful treatment of recurrent FSGS in a patient after living-related kidney transplantationby removal of circulating factors with CytoSorb apheresis. Interestingly, the classical publishedcirculating factors were all in normal range in this patient but early disease recurrence in thetransplantkidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulatingfactors. To proof the functional effects of the patient’s serum on podocytes and the glomerularfiltration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detectpathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyteeffacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on culturedpodocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time oftransplantation and at the time of disease recurrence. The analysis revealed changes in podocytemetabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cellregions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serumand metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, whichweresupported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipidmetabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.