Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

Abstract. The transmembrane component of the dystroglycan complex, a heterodimer of ␣-and ␤-dystroglycan, was recently localized at the basal cell membrane domain of podocytes, and it was speculated that it serves as a device of the podocyte for maintaining the complex podocyte foot process architecture, and for regulating the exact position of its ligands, the matrix proteins laminin and agrin, in the glomerular basement membrane (GBM). The redistribution of dystroglycan in two experimental rat models of foot process flattening and proteinuria-i.e., podocyte damage induced by polycationic protamine sulfate perfusion, and reactive oxygen species (ROS)-associated puromycin aminonucleoside nephrosiswas examined. In both experimental diseases, aggregation and reduced density of ␣-dystroglycan by endocytosis by podocytes was observed. In in vitro solid-phase binding assays, protamine and ROS competed with the binding of ␣-dystroglycan with purified laminin and a recombinant C-terminal fragment of agrin that contains the dystroglycan-binding domain. These changes were associated with disorder of the fibrillar components of the lamina rara externa of the GBM, as confirmed quantitatively by fractal analysis. These results indicate that both polycation and ROS induce similar changes in the distribution of podocyte ␣-dystroglycan that involve competitive disruption of ␣-dystroglycan/matrix protein complexes, endocytosis of the liberated receptor by podocytes, and disorganization of the matrix protein arrangement in the lamina rara externa. This links functional damage of the dystroglycan complex with structural changes in the GBM.Extensive flattening of podocyte foot processes is the major pathologic feature of minimal change nephrotic syndrome and focal segmental glomerulosclerosis (FSGS), and is thought to be obligatorily associated with increased glomerular permeability and proteinuria (1-3). Experimentally, these pathologic podocyte changes are induced within minutes by kidney perfusion of polycations, such as protamine sulfate, in a complex energy-and actin-dependent fashion (4,5). Injection of puromycin aminonucleoside into rats induces foot process flattening within days that depends on the overproduction of reactive oxygen species (ROS) within the glomerulus (6 -8). Both experimental approaches also induce increased glomerular permeability and proteinuria (6,8,9).Podocyte proteins of potential importance for maintaining the complex podocyte architecture and their interactions and functional hierarchies are currently under intense investigation, and it appears, primarily from genetic knockout experiments, that several podocyte membrane and cytoskeletal proteins are critical for the development of mature foot process organization (reviewed in 10,11). These comprise membrane proteins of the luminal domain of podocytes, such as the sialoglycoprotein podocalyxin (12,13), several membrane proteins of the slit diaphragm domain (14 -17), the cytoskeletal protein ␣-actinin-4 (18), and the scaffolding protein CD2AP (19,20)...

the VEESA Study Group Summary Background and objectives A 1-year multicenter prospective randomized controlled study was conducted on the effects of vitamin E-bonded polysulfone dialyzers on erythropoiesis-stimulating agent response in hemodialysis patients.Design, setting, participants, & measurements Major inclusion criteria were use of high-flux polysulfone dialyzers with 50-70 ml/min b 2 -microglobulin clearance over 3 months, transferrin saturation over 20%, same erythropoiesisstimulating agent for over 3 months, and hemoglobin at 10-12 g/dl. Hemodialysis patients were placed in four interventional groups: two hemoglobin ranges (10.0-10.9 or 11.0-11.9 g/dl) and two dialyzers. Patients were randomly assigned by central registration to a vitamin E-bonded polysulfone dialyzers or polysulfone control group. Primary end point was relative erythropoiesis resistance index at baseline between groups at 12 months. Erythropoiesis resistance index was defined as total weekly erythropoiesis-stimulating agent dose divided by hemoglobin.Results There were no statistically significant differences in age or sex. There was no significant difference in relative erythropoiesis resistance index between vitamin E-bonded polysulfone dialyzers and control groups at 12 months (vitamin E-bonded polysulfone dialyzers: 1.1, control: 1.3). The vitamin E-bonded polysulfone dialyzers group showed better relative erythropoiesis resistance index than the control group at 11.0-11.9 g/dl hemoglobin (vitamin E-bonded polysulfone dialyzers: 1.0, control: 1.4 at 12 months, significant difference) but no difference at 10.0-10.9 g/dl hemoglobin. ConclusionsThe overall relative erythropoiesis resistance index showed no difference between the vitamin Ebonded polysulfone dialyzers and control groups, although the change in relative erythropoiesis resistance index differed according to hemoglobin level.

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