Posttransplantation relapse of FSGS is characterized by glomerular epithelial cell transdifferentiation

This study examined six cases of idiopathic nephrotic syndrome with primary lesions of focal segmental glomerulosclerosis (FSGS) that relapsed after r enal transplantation. The glomerular lesions comprised the cellular, the co llapsing, and the scar variants of FSGS and showed shedding of large round cells into Bowman's space and within the tubular lumens. Immunohistochemist ry and confocal laser microscopy carried out on kidneys with FSCS relapse d isclosed several phenomena. (I) Some podocytes that expressed podocalyxin, synaptopodin, and glomerular epithelial protein-1 were detached from the tu ft and were free in the urinary space. (2) In the cellular variant, most po docytes had lost podocyte-specific epitopes (podocalyxin, synaptopodin, glo merular epithelial protein-1, Wilm's tumor protein-1, complement receptor-1 , and vimentin). In the scar variant, these podocyte markers were absent fr om cobblestone-like epithelial cells and from pseudotubules. (3) Podocytes had acquired expression of various cytokeratins (CK; identified by the AE1/ AE3, C2562, CK22, and AEL-KS2 monoclonal antibodies) that were not found in the podocytes of control glomeruli. Parietal epithelial cells expressed AE 1/AE3 CK that were faintly, if ever, found on the parietal epithelial cells of normal glomeruli. (4) Numerous cells located at the periphery of the tu ft or free in Bowman's space and within tubular lumens expressed macrophagi c epitopes (identified by PGM1 [CD68], HAM56, and 25F9 monoclonal antibodie s). These macrophage-like cells expressed the activation epitopes HLA-DR an d CD16. (5) A number of these cells coexpressed podocalyxin + AE1/AE3 CK, p odocalyxin + CD68, and CD68 + AE1/AE3. These findings suggest that in prima ry FSGS relapsing on transplanted kidneys, some "dysregulated" podocytes, o ccasionally some parietal epithelial cells, and possibly some tubular epith elial cells undergo a process of transdifferentiation. This process of tran sdifferentiation was especially striking in podocytes that acquired macroph agic and CK epitopes that are absent from normal adult and fetal podocytes.