Background: The identification of nephrin and CD2AP, podocyte proteins which modulate the properties of glomerular barrier selectivity, has made it possible to unravel the mechanisms undergoing foot process effacement and proteinuria. Here we explored the role of nephrin and CD2AP together with the integrity of the slit diaphragm in the pathogenesis of proteinuria in patients with acquired glomerular diseases. Methods: Nephrin mRNA and protein expression were systematically evaluated in 28 renal biopsy samples from adult patients with primary glomerular disease and proteinuria by in situ hybridization and immunohistochemistry using antibodies directed against extra- and intracellular nephrin and compared with biopsy samples from normal controls. CD2AP protein expression by immunohistochemistry was also assessed. Morphometrical analysis of the filtration slit was performed by transmission electron microscopy. Results: Nephrin mRNA and expression of the extracellular nephrin were markedly reduced in IgA nephropathy. No changes were found in patients with minimal change nephrosis and focal segmental glomerulosclerosis. The staining of intracellular nephrin and CD2AP did not change among patients. A comparable frequency of the filtration slits was observed in all patient groups, except in minimal change disease patients, due to extensive foot process effacement. The percentage of slit diaphragms with a filamentous image was markedly reduced in IgA nephropathy, but was comparable to controls in minimal change disease. Slit pore width showed a tendency to decrease both in patients with minimal change disease and IgA nephropathy. Conclusions: These results indicate that the ultrastructure of the filtration slit diaphragm is altered in patients with IgA nephropathy as a consequence of targeted downregulation of extracellular nephrin. Further studies are needed to evaluate the pathophysiological meaning of nephrin abnormality in IgA nephropathy and how these changes can be modulated by antiproteinuric therapy.