Abstract
Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, 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 unknown factors. 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 use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living-related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient’s serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyte effacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.
Highlights
Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation
CytoSorb apheresis to treat for treatment resistant and recurrent FSGS
Due to the severity and rapid progression of the primary disease, the early recurrence after transplantation and the past medical history where the disease in the native kidneys was refractory to established treatment regimens, we decided to treat the patient with CytoSorb apheresis as a compassionate use approach
Summary
Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation. Primary focal segmental glomerulosclerosis (FSGS) is a rare disease with an estimated incidence of about 7 per 1 million[1] It is still one of the most prevalent nephropathies causing end-stage renal d isease[2,3]. Soluble urokinase plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF1) and sCD25 have been postulated as such permeability factors in F SGS7–10 It remains to be determined whether these factors are truly pathogenic, specific, sensitive and reproducible in all patients and just like the genetic forms it is likely that this disease category represents only a subgroup of diseases and that one but several different or a combination of circulatory factors exist. Patients who progress to end stage kidney disease and receive a kidney transplant have a 20 to 30% risk of FSGS recurrence in their kidney g raft[11,12]
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