Identification of a Potential Marker of Glomerular Fibrogenesis in Childhood Nephrotic Syndrome.
Mariana M Cajaiba, Rose Ayoob, Ronald Houston, Sheldon I Bastacky, Peter Baker. Nationwide Children's Hospital, Columbus, OH; University of Pittsburgh, PA
Background: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the major causes of pediatric nephrotic syndrome (NS). Most MCD cases respond to steroids, whereas FSGS tends to be resistant and progress to global sclerosis leading to chronic renal disease. The reversible nature of MCD is thought to reflect transient podocyte damage due to increased circulating cytokines, whereas FSGS would correspond to irreversible podocyte damage with activation of TGF-β-mediated apoptosis and fibrogenesis. Markers of fibrogenesis that could help to define the pathogenesis and prognosis in these cases have not been clearly identified. One of the downstream targets of TGF-β signalling is Sox9, a transcription factor involved in normal skeletal development and pathological fibrogenesis. Recent experimental studies showed increased levels of both Sox9 and TGF-β mRNA in FSGS, and increased glomerular collagen IV accumulation triggered by TGF-β-induced Sox9 expression. The aim of this study is to investigate Sox9 as a potential indicator of glomerular fibrogenesis in NS.
Design: 29 renal needle biopsies performed in children with NS were selected; 15 were diagnosed as FSGS and 14 as MCD. 10 renal biopsies from healthy living transplant donors were used as normal controls. Immunohistochemical stains with an antibody against Sox-9 were performed on representative slides from each case. Specimens with sampling of 5 or more glomeruli were considered adequate. Sox9 nuclear staining was recorded as positive/negative in glomeruli (mesangial cells/podocytes), and as percentage of stained cells in parietal and tubular epithelial cells (PEC/TEC).
Results: Ages ranged from 1-18 years, with 14 males and 15 females. 5 cases (3 FSGS and 2 MCD) were excluded due to sampling inadequacy. None (0/10) of the normal controls showed glomerular staining. 7/12 (58.3%) FSGS cases had positive glomerular staining (seen in segmentally sclerotic and non-sclerotic glomeruli) versus 1/12 (8.3%) MCD cases (p=0.0136). Sox9 stained 0-10% of TEC and PEC in all controls (100%) and most MCD (67%), and 10-50% in most FSGS cases (67%).
Conclusions: Glomerular Sox9 expression was significantly more frequent in FSGS than MCD, suggesting a potential use for this protein as a diagnostic/prognostic marker of fibrogenesis in NS. A larger patient sample is needed to confirm these observations, to establish a possible relationship between Sox9 staining and poor outcome in MCD, and an association between tubular Sox9 staining and chronic parenchymal changes.
Category: Kidney (does not include tumors)
Monday, February 28, 2011 1:45 PM
Platform Session: Section H, Monday Afternoon