GLOMERULAR LOCALIZATION OF THROMBOMODULIN IN HUMAN GLOMERULONEPHRITIS

BACKGROUND: Thrombomodulin (TM), a glycoprotein expressed on the surfa ce of endothelial cells, transforms protein C into a potent anticoagul ant by binding thrombin. TM may be an important regulator of intraglom erular coagulation because functional TM activity was demonstrated in glomeruli isolated from normal human and rat kidneys. The role of TM i n glomerulonephritis is unknown. EXPERIMENTAL DESIGN: Sections from 4 normal human kidneys and from kidneys of 100 patients with various for ms of glomerulonephritis were studied by light and transmission electr on microscopy, and by light and electron immunohistochemical technique s using polyclonal antibodies to recombinant human TM, and monoclonal antibodies to the membrane attack complex of the complement system. Th e expression of TM was graded from 0 to 4 according to the intensity a nd extent of the distribution, and the results were compared with the clinicopathologic findings. RESULTS: In normal glomeruli and in glomer uli with minimal abnormalities, a small amount of TM was localized at the vascular pole only (grade 0-1). In membranoproliferative glomerulo nephritis and lupus glomerulonephritis, the amount of TM found on the plasma membrane of endothelial cells was significantly increased (grad es 2 to 4). The expression of TM was directly correlated with proteinu ria (p < 0.001), glomerular hypercellularity (p < 0.01), and number of subendothelial immune deposits (p < 0.01). In contrast, in other form s of glomerular diseases, TM was not increased and no correlation was found with the clinicopathologic parameters. CONCLUSIONS: In membranop roliferative glomerulonephritis and lupus glomerulonephritis, the amou nt of TM expressed by the plasma membranes of glomerular endothelial c ells is increased, and this finding is a marker of disease activity. T he significance of an increased expression of an endothelial anticoagu lant glycoprotein in diseases characterized by pathologic intraglomeru lar coagulation is unknown, and requires further studies.