Glomerular localization of thrombomodulin in human glomerulonephritis.

Abstract

Thrombomodulin (TM), a glycoprotein expressed on the surface of endothelial cells, transforms protein C into a potent anticoagulant by binding thrombin. TM may be an important regulator of intraglomerular coagulation because functional TM activity was demonstrated in glomeruli isolated from normal human and rat kidneys. The role of TM in glomerulonephritis is unknown. Sections from 4 normal human kidneys and from kidneys of 100 patients with various forms of glomerulonephritis were studied by light and transmission electron microscopy, and by light and electron immunohistochemical techniques using polyclonal antibodies to recombinant human TM, and monoclonal antibodies to the membrane attack complex of the complement system. The expression of TM was graded from 0 to 4 according to the intensity and extent of the distribution, and the results were compared with the clinicopathologic findings. In normal glomeruli and in glomeruli with minimal abnormalities, a small amount of TM was localized at the vascular pole only (grade 0-1). In membranoproliferative glomerulonephritis and lupus glomerulonephritis, the amount of TM found on the plasma membrane of endothelial cells was significantly increased (grades 2 to 4). The expression of TM was directly correlated with proteinuria (p < 0.001), glomerular hypercellularity (p < 0.01), and number of subendothelial immune deposits (p < 0.01). In contrast, in other forms of glomerular diseases, TM was not increased and no correlation was found with the clinicopathologic parameters. In membranoproliferative glomerulonephritis and lupus glomerulonephritis, the amount of TM expressed by the plasma membranes of glomerular endothelial cells is increased, and this finding is a marker of disease activity. The significance of an increased expression of an endothelial anticoagulant glycoprotein in diseases characterized by pathologic intraglomerular coagulation is unknown, and requires further studies.