The alleged dominance of diffuse attenuation of the glomerular basement membrane (GBM) in young children and females with Alport's Syndrome (AS) suggests that it might be the initial ultrastructural manifestation of type IV collagen defects. We carried out a 'blind' review of 130 renal biopsies obtained from 100 patients with AS, emphasizing the electron microscopy changes, and related the findings to the clinical presentation and outcome. The intracapillary distribution of (1) thickened, (2) attenuated and (3) normal GBM was assessed individually as: none (grade 0), <25% (grade 1), 25-50% (grade 2) and >50% (grade 3). Deafness was defined as persistent loss of > or =30 dBs. Proteinuria was measured as protein/creatinine ratios in early morning urine. Heavy proteinuria (> or =200 mg/mmol) correlated significantly with the presence of segmental and global glomerulosclerosis and foam cells. Comparing grades 0+1 vs. 3 GBM changes, using a 2x2 chi(2) test, there were significant correlations between grade 3 GBM thickening and male sex (P =0.005), heavy proteinuria (P =0.02) and deafness (P <0.001). GBM thickening did not correlate with age at the initial biopsy, but repeat biopsies demonstrated increasing thickening with age. The grades of GBM attenuation did not correlate with either age at biopsy or sex. In 11 biopsies with atypical lamina densa changes in thickened GBM segments, there were no differences in clinicopathological correlations compared with classical biopsies. Our data indicate that diffuse GBM attenuation can be an ultrastructural variant of the Alport nephropathy, but do not support the contention that it is the initial lesion.