Dystroglycan in the Diagnosis of FSGS

Abstract

Background and objectives: ␣-and ␤-dystroglycan (DG), which link the actin cytoskeleton of the podocyte to the glomerular basement membrane, are maintained in FSGS but decreased in minimal change disease (MCD). Fibrosis has been linked to increased fibroblast-specific protein-1 (FSP1) and epithelial-mesenchymal transition. We studied DG, FSP1, and podocyte differentiation in FSGS variants and cases of suspected FSGS.Design, setting, participants, & measurements: We studied renal biopsies with FSGS, not otherwise specified (NOS), tip lesion, or collapsing variants (COLL), versus secondary FSGS or cases without segmental sclerotic lesions where a diagnosis of MCD versus FSGS could not be established (undefined [UNDEF]) and compared the expression of DG, FSP1, and podocyte Wilms' tumor antigen (WT1).Results: WT1 is markedly decreased in NOS versus normal and correlates with the extent of sclerosis. ␣-and ␤-DG are maintained in most primary and secondary FSGS cases. In contrast, ␣-DG is significantly decreased in UNDEF, supporting a diagnosis of MCD. Furthermore, follow-up shows remission or decreased proteinuria in four of six of these UNDEF cases in response to therapy. Interstitial FSP1 is numerically highest in COLL but is only rarely found in tubules or podocytes in any other forms of FSGS.Conclusions: We conclude that increased FSP1 may be a marker of the aggressive course of collapsing FSGS. Furthermore, DG staining is a useful adjunct to assist in distinction of FSGS versus MCD in biopsies without defining lesions.

Detection of Activated Parietal Epithelial Cells on the Glomerular Tuft Distinguishes Early Focal Segmental Glomerulosclerosis from Minimal Change Disease

“…These efforts are to improve the diagnosis and subsequent treatment of the diseases and to obtain a better understanding of the pathomechanisms of both diseases. It was proposed that differences in the podocyte expression of dystroglycans could discriminate between MCD and FSGS because only in MCD the expression of b-dystroglycan 24 and a-dystroglycan 25 was reduced. This would also suggest that the pathomechanism underlying MCD may be different from that of FSGS.…”

“…However, these studies have been debated because the findings in later studies by the same group 26 and other groups 27,28 were not consistent with the previous studies. 24,25 More recently it was found that urinary soluble CD80 (B7.1) is elevated in MCD and not in FSGS, which could be promising for both diagnosis and pathogenesis of the disease. 29 To discriminate MCD from FSGS, we focused on the role of PECs in the development and progression of FSGS.…”

Dystroglycan in the Molecular Diagnosis of the Podocytopathies

“…Furthermore, they found that in minimal-change nephropathy (MCN), protein expression was reduced by 75% for ␣-dystroglycan and by 50% for ␤-dystroglycan, whereas expression of both dystroglcyans was normal or slightly increased in FSGS. In this issue of CJASN, Giannico et al (2) extend these findings to a somewhat different clinical setting, namely, seven patients with findings typical of MCN, including extensive foot process effacement and nephrotic proteinuria (with the exception that one patient had subnephrotic proteinuria). Because of limitations in the number of glomeruli present on these biopsies, the diagnosis of unsampled FSGS could not be safely excluded, and this group is therefore described as "undefined."…”

“…It is also possible that dystroglycan gene expression will add useful information, perhaps assessed as part of a molecular profiling approach, as has been described by Kretzler and colleagues (14). A fairly common clinical dilemma, similar to that studied by Giannico et al (2), is a renal biopsy obtained from a patient with nephrotic range proteinuria that manifests nondiagnostic abnormalities such as focal global glomerulosclerosis and/or focal tubular atrophy, interstitial inflammation, or interstitial fibrosis. Does this individual have MCN, or does this the patient have FSGS, unsampled because of the limitations of the biopsy sample?…”

“…A presentation of the semiquantitative scoring of ␣-dystroglycan staining carried out by Giannico et al (2) is shown in Figure 2. Using a threshold score of 0.3 arbitrary units (which will of course vary from laboratory to laboratory and observer to observer), the sensitivity is 0.86, the specificity is 0.88, the positive predictive value is 0.67, and the negative predictive value is 0.95.…”