To further define the clinicopathologic spectrum and pathogenetic mechanism of the nephropathy associated with alpha 1-antitrypsin (A1AT) deficiency, we evaluated renal specimens from 34 patients with chronic hepatic disease, including 20 with A1AT deficiency (study patients), and correlated these findings with urinalysis evaluation. Glomerular lesions were noted in 79% (15 of 19) of A1AT patients with the PiZZ phenotype, including seven with mesangio-capillary glomerulonephritis (MPGN and focal segmental MPGN), six with mesangial proliferative glomerulonephritis (Mes GN), one with diffuse endocapillary proliferative glomerulonephritis (DPGN), and one with focal segmental mesangial proliferative glomerulonephritis with segmental necrosis (FS Nec GN). One A1AT patient with the PiMZ phenotype did not demonstrate glomerular abnormalities. Focal segmental Mes GN was found in 43% (six of 14) of patients in an age-matched group with chronic hepatic failure unrelated to A1AT deficiency. In nine study patients, glomerular pathology was noted in the presence of a normal urinalysis. Immunofluorescence studies revealed the presence of immunoproteins and the A1AT protein isoelectric forms, PiM and PiZ, in the subendothelial region of glomerular basement membranes in A1AT patients with MPGN, Mes GN, and DPGN. Our results emphasize the heterogeneity of glomerular lesions associated with A1AT deficiency and hepatic disease and the relatively high incidence of MPGN in these children. The presence of abnormal PiZ protein in the subendothelial region of the glomerular basement membrane in A1AT patients with glomerulonephritis suggests a possible role for this protein in the pathogenesis of this lesion.