Distribution of α‐chains of type IV collagen in glomerular basement membranes with ultrastructural alterations suggestive of Alport syndrome

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.