scholarly journals Challenges in primary focal segmental glomerulosclerosis diagnosis: from the diagnostic algorithm to novel biomarkers

2020 ◽  
Author(s):  
Conxita Jacobs-Cachá ◽  
Ander Vergara ◽  
Clara García-Carro ◽  
Irene Agraz ◽  
Nestor Toapanta-Gaibor ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Focal Segmental Glomerulosclerosis ◽  
Graft Function ◽  
Experimental Studies ◽  
Diagnostic Algorithm ◽  
Disease Recurrence ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Stage Renal Disease

Abstract Primary or idiopathic focal segmental glomerulosclerosis (FSGS) is a kidney entity that involves the podocytes, leading to heavy proteinuria and in many cases progresses to end-stage renal disease. Idiopathic FSGS has a bad prognosis, as it involves young individuals who, in a considerably high proportion (∼15%), are resistant to corticosteroids and other immunosuppressive treatments as well. Moreover, the disease recurs in 30–50% of patients after kidney transplantation, leading to graft function impairment. It is suspected that this relapsing disease is caused by a circulating factor(s) that would permeabilize the glomerular filtration barrier. However, the exact pathologic mechanism is an unsettled issue. Besides its poor outcome, a major concern of primary FSGS is the complexity to confirm the diagnosis, as it can be confused with other variants or secondary forms of FSGS and also with other glomerular diseases, such as minimal change disease. New efforts to optimize the diagnostic approach are arising to improve knowledge in well-defined primary FSGS cohorts of patients. Follow-up of properly classified primary FSGS patients will allow risk stratification for predicting the response to different treatments. In this review we will focus on the diagnostic algorithm used in idiopathic FSGS both in native kidneys and in disease recurrence after kidney transplantation. We will emphasize those potential confusing factors as well as their detection and prevention. In addition, we will also provide an overview of ongoing studies that recruit large cohorts of glomerulopathy patients (Nephrotic Syndrome Study Network and Cure Glomerulonephropathy, among others) and the experimental studies performed to find novel reliable biomarkers to detect primary FSGS.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Janina Müller-Deile ◽  
George Sarau ◽  
Ahmed M. Kotb ◽  
Christian Jaremenko ◽  
Ulrike E. Rolle-Kampczyk ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Raman Spectra ◽  
Focal Segmental Glomerulosclerosis ◽  
Disease Recurrence ◽  
Early Recurrence ◽  
Metabolome Analysis ◽  
Novel Technologies ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Living Related

AbstractIdiopathic 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.

scholarly journals Novel Diagnostic and Therapeutic Techniques Reveal Changed Metabolic Profiles in Recurrent Focal Segmental Glomerulosclerosis 

2020 ◽  
Author(s):  
Janina Müller-Deile ◽  
George Sarau ◽  
Christoph Daniel ◽  
Christian Jaremenko ◽  
Ahmed M Kotb ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Raman Spectra ◽  
Focal Segmental Glomerulosclerosis ◽  
Disease Recurrence ◽  
Early Recurrence ◽  
Metabolome Analysis ◽  
Novel Technologies ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis ◽  
Living Related

Abstract Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead 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. We then performed Raman spectroscopy in the <50 kD 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 metabolom 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.

scholarly journals UK experience of ofatumumab in recurrence of focal segmental glomerulosclerosis post-kidney transplant

2021 ◽  
Author(s):  
Ben C. Reynolds ◽  
Angela Lamb ◽  
Caroline A. Jones ◽  
Pallavi Yadav ◽  
Kay S. Tyerman ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Kidney Function ◽  
Focal Segmental Glomerulosclerosis ◽  
Graft Function ◽  
Case Series ◽  
Disease Recurrence ◽  
Post Transplantation ◽  
Segmental Glomerulosclerosis ◽  
Kidney Replacement Therapy ◽  
Risk Of Disease

Abstract Background Steroid-resistant nephrotic syndrome (SRNS), commonly caused by focal segmental glomerulosclerosis (FSGS), is associated with progression to stage 5 chronic kidney disease, requirement for kidney replacement therapy and a risk of disease recurrence post-kidney transplantation. Ofatumumab (OFA) is a fully humanised monoclonal antibody to CD20, with similar mechanisms of action to rituximab (RTX). Methods We report a case series of seven UK patients (five paediatric, two adult), all of whom developed FSGS recurrence after kidney transplantation and received OFA as part of their therapeutic intervention. All also received concomitant plasmapheresis. The 2-year outcome of these seven patients is reported, describing clinical course, kidney function and proteinuria. Results Four patients (all paediatric) achieved complete urinary remission with minimal proteinuria 12 months post-treatment. Three of those four also had normal graft function. Two patients showed partial remission—brief improvement to non-nephrotic proteinuria (197 mg/mmol) in one patient, maintained improvement in kidney function (estimated glomerular filtration rate 76 ml/min/1.73 m2) in the other. One patient did not demonstrate any response. Conclusions OFA may represent a useful addition to therapeutic options in the management of FSGS recurrence post-transplantation, including where RTX has shown no benefit. Concomitant plasmapheresis in all patients prevents any definitive conclusion that OFA was the beneficial intervention.

MO247NOVEL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES REVEAL CHANGED METABOLOMIC PROFILE IN RECURRENT FOCAL SEGMENTAL GLOMERULOSCLEROSIS*

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Janina Müller-Deile ◽  
George Sarau ◽  
Ahmed Kotb ◽  
Christoph Daniel ◽  
Stefan Kalkhof ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Raman Spectroscopy ◽  
Kidney Transplantation ◽  
Raman Spectra ◽  
Focal Segmental Glomerulosclerosis ◽  
Disease Recurrence ◽  
Metabolome Analysis ◽  
Novel Technologies ◽  
Filtration Barrier ◽  
Segmental Glomerulosclerosis

Abstract Background and Aims Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead 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 can allow us to study FSGS from a yet unexplored angle. Method We used novel treatment options, a personalized in vitro and in vivo assay as well as Raman spectroscopy and mass spectrometry for recurrent FSGS. Results 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 (Fig. 1). 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 podocyte’s actin cytoskeleton inducing a functional phenotype (Fig. 2, Fig. 3). We then performed Raman spectroscopy in the &lt;50 kD serum fraction (Fig. 4), on cultured podocytes treated with the FSGS serum (Fig. 5), and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence (Fig. 6). The analysis revealed metabolomic changes in podocytes induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several disturbed Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which corresponded to disturbances in the Raman spectra. Conclusion Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.

scholarly journals Unsuccessful Treatment with Abatacept in Recurrent Focal Segmental Glomerulosclerosis after Kidney Transplantation

2017 ◽  
Vol 7 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Tilde Kristensen ◽  
Per Ivarsen ◽  
Johan Vestergaard Povlsen
Keyword(s):  
Renal Transplantation ◽  
Focal Segmental Glomerulosclerosis ◽  
Case Reports ◽  
Graft Function ◽  
Therapeutic Drug ◽  
Allograft Survival ◽  
Segmental Glomerulosclerosis ◽  
Unsuccessful Treatment ◽  
Stage Renal Disease ◽  
End Stage

Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation occurs in up to 20–50% of FSGS patients and is associated with inferior allograft survival. Treatment of both primary FSGS as well as recurrent FSGS after transplantation with plasma exchange and immunosuppression is often unsuccessful and remains a major challenge as the disease still leads to end-stage renal disease and decreased graft survival. Previous case reports have described patients with recurrent FSGS who were successfully treated with a B7-1 inhibitor (abatacept) inducing partial or complete remission. The rational basis for believing in abatacept as a new therapeutic drug for the treatment of FSGS is the study by Yu et al. [N Engl J Med 2013;369: 2416–2423] showing B7-1 in immunostainings of the podocytes. The authors speculated that B7-1 immunostaining of renal biopsies might identify a subgroup of patients who would benefit from abatacept treatment. We present a case with recurrent FSGS after renal transplantation. The patient was unsuccessfully treated with B7-1 inhibitors. Although the patient was treated with abatacept 10 mg/kg body weight twice, the proteinuria and decreased graft function remained unchanged, and he never reached remission.

scholarly journals Higher Urine Exosomal miR-193a Is Associated With a Higher Probability of Primary Focal Segmental Glomerulosclerosis and an Increased Risk of Poor Prognosis Among Children With Nephrotic Syndrome

2021 ◽  
Vol 9 ◽  
Author(s):  
Lixia Wang ◽  
Jie Wang ◽  
Zhimin Wang ◽  
Jianhua Zhou ◽  
Yu Zhang
Keyword(s):  
Focal Segmental Glomerulosclerosis ◽  
Release Mechanism ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Operating Characteristics ◽  
Glomerular Diseases ◽  
Calcium Dependent ◽  
Segmental Glomerulosclerosis ◽  
Increased Risk ◽  
Stage Renal Disease

Background: In children, focal segmental glomerulosclerosis (FSGS) is one of the most common primary glomerular diseases leading to end-stage renal disease. Exosomes facilitate communication between cells by transporting proteins and microRNAs. We aimed to investigate the utility of urine exosomal miR-193a for diagnosis and prognosis estimation among patients with primary FSGS, and preliminarily explore the regulation mechanism of exosome secretion from podocytes.Methods: Specimens of urine were obtained from patients with primary FSGS, minimal change nephropathy (MCN) and IgA nephropathy (IgAN), followed by exosome isolation. We quantified urine exosomal miR-193a based on quantitative reverse transcription-polymerase chain reaction, and evaluated its applicability using area-under-receiver-operating-characteristics curves (AUROCs). The semiquantitative glomerulosclerosis index (GSI) was used to evaluate the degree of glomerulosclerosis according to the method of Raij et al. We further used FAM-labeled miR-193a-5p to examine exosome shuttling using confocal microscopy for visualization, and explored the regulation mechanism of exosomes release from podocytes using Fluo-3AM dye.Results: Urine exosomal miR-193a levels were significantly higher in patients with primary FSGS than those with MCN and IgAN. The AUROCs for discriminating between primary FSGS and MCN or IgAN were 0.85 and 0.821, respectively. Urine exosomal miR-193a levels positively correlated with GSI in patients with primary FSGS. We further found that kidney tissues from these patients had increased CD63 expression involving podocytes in non-sclerotic tufts. Exosomes from cultured podocytes could transport miR-193a-5p to recipient cells, potentially through a calcium-dependent release mechanism.Conclusion: Urine exosomal miR-193a might be harnessed as a non-invasive marker for diagnosis and outcome assessment among patients with primary FSGS. Exosomes were potential vehicles for miRNAs shuttling between podocytes, and released from podocytes in a calcium-dependent manner.

scholarly journals Update on Recurrent Focal Segmental Glomerulosclerosis in Kidney Transplantation

Nephron ◽  
2020 ◽  
pp. 1-6
Author(s):  
Jun Shoji ◽  
Akiko Mii ◽  
Mika Terasaki ◽  
Akira Shimizu
Keyword(s):  
Kidney Transplantation ◽  
Focal Segmental Glomerulosclerosis ◽  
Rapid Progression ◽  
Segmental Glomerulosclerosis ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
History Of ◽  
Stage Renal Disease ◽  
End Stage

<b><i>Background:</i></b> Focal segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome characterized by nephrotic-range proteinuria with high incidence of progression to end-stage renal disease (ESRD). In primary FSGS, 40–60% of patients develop ESRD within 10–20 years. <b><i>Summary:</i></b> Recurrence of FSGS after kidney transplantation is frequent and is associated with poor allograft survival. The risk factors for recurrent FSGS include onset of FSGS during childhood, rapid progression of primary FSGS to ESRD, history of recurrent FSGS in previous allograft, and diffuse mesangial hypercellularity or collapsing variant of FSGS in the native kidney. The early histological findings of recurrent FSGS consist of unremarkable glomerular changes on light microscopy but significant podocyte effacement on electron microscopy; the loss of foot processes with eventual dropout of podocytes leads to the development of segmental lesions in the glomerulus. Experimental and clinical data suggest the existence of circulating permeability factors, such as soluble urokinase-type plasminogen activator receptor (suPAR), cardiotrophin-like cytokine factor-1 (CLCF-1), CD40 axis, and apolipoprotein A-Ib (ApoA-Ib), in the pathogenesis of recurrent FSGS. These biomarkers including circulating permeability factors may facilitate earlier diagnosis of FSGS posttransplant and may guide in the development of novel therapies that may be more effective and improve long-term outcomes in kidney transplantation. <b><i>Key Messages:</i></b> Several studies have suggested the possible circulating permeability factors, such as suPAR, CLCF-1, CD40 axis, and ApoA-Ib, in the pathogenesis and disease progression of FSGS and recurrent FSGS. Further studies should be performed to elucidate the true essential biomarker(s) associated with the onset and progression of FSGS as well as recurrent FSGS.

scholarly journals A clinical case of using therapeutic plasma exchange for the treatment of recurrent focal segmental glomerulosclerosis in a child after kidney transplantation

2021 ◽  
Vol 23 (2) ◽  
pp. 60-66
Author(s):  
I. A. Miloserdov ◽  
V. S. Bogdanov ◽  
P. M. Gadzhieva ◽  
D. A. Saydulaev ◽  
A. A. Kartashev ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Kidney Transplantation ◽  
Plasma Exchange ◽  
Kidney Transplant ◽  
Focal Segmental Glomerulosclerosis ◽  
Graft Function ◽  
Therapeutic Plasma Exchange ◽  
Kidney Graft ◽  
Graft Dysfunction ◽  
Segmental Glomerulosclerosis

Background. Focal segmental glomerulosclerosis (FSGS) of the graft in kidney recipients is a rare and difficultto-diagnose post-kidney transplant complication, which can lead to graft loss and death of the recipient. A unified protocol is required for the treatment of this disease.Materials and methods. A 15-year-old female patient C. diagnosed with stage 5 chronic kidney disease as a result of steroid-resistant nephrotic syndrome with hematuria underwent a living related-donor kidney transplantation. On the third day after the operation, laboratory and imaging data showed kidney graft dysfunction. Patient examinations established the cause of the graft dysfunction – idiopathic nephrotic syndrome in FSGS.Results. For the treatment of recurrent FSGS, the patient had her immunosuppressive therapy converted from tacrolimus to cyclosporin A, and received two 500 mg rituximab injections. Ten sessions of therapeutic plasma exchange (Plasauto Sigma) were performed to remove antibodies to podocytes. During the therapy, diuresis was restored, creatinine and urea levels decreased. Six months after the kidney transplant, graft function was fully restored. Conclusion. The absence of recurrent FSGS within six months during a single course of therapeutic plasma exchange with its subsequent cancellation after restoration of graft function allows to recommend the developed method for the treatment of FSGS in pediatric patients after kidney transplantation.

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