Background
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.
Glomerular Filtration Barrier and the Pathophysiology of FSGS
Podocytes are the site of damage in FSGS. These highly differentiated epithelial cells of renal glomeruli consist of a cell body and foot processes which make contact with the glomerular basement membrane. The actin-based cytoskeleton is critical in maintaining an effective glomerular filtration barrier to prevent proteinuria. The disruption of podocyte cytoskeleton and slit diaphragm with subsequent foot process efiacement, podocyte hypertrophy, detachment from the glomerular basement membrane, and the loss with migration into the Bowman space leads to the development of FSGS.
Histological Findings of Recurrent FSGS
Podocytes in recurrent FSGS undergo profound changes in adhesion molecules and transdifferentiate into macrophage-like cells. In advanced stages of FSGS, there is a disappearance of both α5 integrin and α3β3 integrin. The relevance of Columbia classiffcation of the histological variants of FSGS is equivocal since studies have not shown a consistent pattern of recurrence postransplant.
The Columbia classification of FSGS includes (1) tip lesion variant, (2) cellular variant, (3) collapsing variant, (4) perihilar variant, and (5) FSGS not other wise specified (NOS).
Circulating Permeability Factors of FSGS
Experimental and clinical data have strongly suggested the existence of circulating permeability factors that likely contribute to podocyte injury and development of proteinuria in idiopathic FSGS. The recurrence of proteinuria posttransplant in recurrent FSGS and improvement of proteinuria after treatment with plasmapheresis also support the existence of circulating permeability factors. 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.
suPAR and FSGS
One of the first circulating permeability factors that have been identied as a possible culprit in FSGS is suPAR. It is generated by the cleavage of the glycosylphosphatidy linositol anchor of urokinase receptor or secreted directly from cells as an alternative transcript. After treatment with plasmapheresis and rituximab, suPAR levels were noted to decrease. Since the suPAR level reduction is transient and rebounds after treatment, it is not shown to predict the clinical outcome in recurrent FSGS. Although these studies have shown ambivalent results, it is unlikely that FSGS and suPAR are entirely unrelated . Despite suPAR or anti-CD40 antibody alone has not caused podocyte damage and proteinuria, the coadministration of suPAR and anti-CD40 antibody in mice has led to podocyte damage and proteinuria.
CLCF-1 in FSGS
Another potential permeability factor in primary FSGS that has been isolated via galactose affnity chromatography and mass spectrometry is CLCF-1, a member of the IL-6 family of B-cell-stimulating cytokine with a predicted molecular weight of 22 kDa. In patients with recurrent FSGS, levels of CLCF-1 were found to be 100 times higher than in controls. CLCF-1 likely causes FSGS due to destabilization of the actin cytoskeleton of podocytes. CLCF-1 is secreted and forms heterodimers with either cytokine receptor-like factor 1 or soluble ciliaric neurotrophic receptor alpha, and the heterodimer composed of CLCF-1 and CRLF1 aftenuated the increase in albumin permeability caused by CLCF-1 or FSGS serum.
CD40-CD40L Axis in the Pathogenesis of Recurrent FSGS
CD40-CD40L Axis in the Pathogenesis of Recurrent FSGS In renal pathophysiology, CD40-CD40L signaling pathway blockade has been shown to be protective in multiple models of glomerulonephritis. Autoantibodies that have been identified to possibly predict postransplant FSGS recurrence with 92% accuracy, pretransplant elevation of CD40 autoantibody has the highest correlation with postransplant recurrence of FSGS.
SuPAR infusion followed by the infusion of CD40 from patients with recurrent FSGS has led to proteinuria in mice, and podocyte efiacement was seen on electron microscopy. Activation of CD40 on podocytes with soluble CD40L has shown to cause rearrangement of the actin cytoskeleton and loss of slit diaphragm proteins including nephfirin and podocin.
ApoA-Ib in Recurrent FSGS
ApoA-I is a component of HDL particle that is absent in the urine of healthy population. ApoA-Ib is a high molecular weight form of ApoA-I that may be associated with a misprocessed form of ApoA-I precursor with no genetic variations in the ApoA-I gene. Amongst the several modified ApoA-I forms, ApoA-1b is noted to be present in the urine of recurrent FSGS. This elevation was not found in non relapsing FSGS and non-FSGS nephrotic patients. The urinary biomarker may serve as both diagnostic and prognostic marker for recurrent FSGS.
One study performed a proteomic analysis of serum and urine samples of transplant patients with history of primary FSGS; the results showed the existence of ApoA-Ib exclusively in patients with relapsing FSGS.
Conclusion
Recurrent FSGS is a primary glomerular disease with significant impact on allograft and patient survival. As a disease that is due to the disruption of the podocyte cytoskeleton, treatments have targeted culprits that destabilize this structure. Identifying biomarkers that may serve to diagnose and predict outcomes of recurrent FSGS may facilitate rapid diagnosis of FSGS postransplant. It may also guide the development of novel therapies that may be more effective and improve long-term outcomes in kidney transplantation. Based on the recent results, further studies should be
performed for searching the involvement of possible circulating permeability factors in pathogenesis and disease progression of FSGS.
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