Distribution of α‐chains of type IV collagen in glomerular basement membranes with ultrastructural alterations suggestive of Alport syndrome
2001
In Alport syndrome (AS) impaired production and or assembly of col IV α-chain isoforms results in abnormal structure of glomerular basement membrane (GBM), haematuria and, frequently, progressive renal disease. We investigated the relationship between col IV α-chains expression and morphology of GBM, as a possible key to the better understanding of the pathogenesis of renal disease in AS. Methods. GBM distribution of col IV α1-, α3-, and α5-chain was investigated by immunohistochemistry in 32 patients (21 males and 11 females, mean age at biopsy of 11.5 years) with ultrastructural findings suggestive of AS. Ten patients had a proven COL4A5 mutation. Based on the severity of ultrastructural findings, the biopsies were grouped in three (I-III) electron microscopy (EM) classes. Significant EM changes of GBM (thinning, thickening, splitting, basket weaving of the lamina densa) were singularly evaluated using a semiquantitative scale (0-3). Results. Col IV α1-chain was demonstrated in GBM of all patients. Three patterns of staining for col IVα3-and α5-chains were observed: positive, negative, and α3(IV)-positive/α5(IV)-negative. By X2 -test, EM class III lesions and complete loss of α3(IV)- and α5(IV)-antigen were significantly more frequent (P < 0.05 and P < 0.01) in male patients, but no significant relation was observed between EM classes and immunohistochemical patterns. GBM alterations did not correlate with staining for α5(IV)-chain. Intensity of α3(IV)-chain staining, however, had a negative correlation (P < 0.05) with the severity of GBM basket weaving. Conclusions. Our results suggest that the α3(IV)-chaincontaining col IV-network plays a fundamental role in structural and, possibly, functional organization of GBM. Absence of α3(IV)-chain in GBM could indicate a more severe renal disease in AS.
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