SummaryBackground and objectives The aims of this study were to determine the frequency of venous thromboembolic events in a large cohort of patients with idiopathic membranous nephropathy and to identify predisposing risk factors.Design, setting, participants, & measurements We studied patients with biopsy-proven membranous nephropathy from the Glomerular Disease Collaborative Network (n=412) and the Toronto Glomerulonephritis Registry (n=486) inception cohorts. The cohorts were pooled after establishing similar baseline characteristics (total n=898). Clinically apparent and radiologically confirmed venous thromboembolic events were identified. Potential risk factors were evaluated using multivariable logistic regression models.Results Sixty-five (7.2%) subjects had at least one venous thromboembolic event, and this rate did not differ significantly between registries. Most venous thromboembolic events occurred within 2 years of first clinical assessment (median time to VTE = 3.8 months). After adjusting for age, sex, proteinuria, and immunosuppressive therapy, hypoalbuminemia at diagnosis was the only independent predictor of a venous thromboembolic event. Each 1.0 g/dl reduction in serum albumin was associated with a 2.13-fold increased risk of VTE. An albumin level ,2.8 g/dl was the threshold below which risk for a venous thromboembolic event was greatest.Conclusions We conclude that clinically apparent venous thromboembolic events occur in about 7% of patients with membranous nephropathy. Hypoalbuminemia, particularly ,2.8 g/dl, is the most significant independent predictor of venous thrombotic risk.

The risk of venous thromboembolic events is thought to be highest in patients with membranous nephropathy. This association has been recently questioned, and it is not known whether this simply reflects the severity of proteinuria. To better understand the relationship between histologic diagnosis and the risk of venous thromboembolic events we evaluated patients in the Toronto Glomerulonephritis Registry. Of 1313 patients with idiopathic glomerulonephritis, 395 were diagnosed with membranous nephropathy, 370 with focal segmental glomerulosclerosis (FSGS), and 548 with immunoglobulin-A nephropathy (IgAN). Risk factors were evaluated by Cox proportional hazards for 53 image-confirmed venous thromboembolic events in 44 patients during a median follow-up of 63 months. The risk was highest in patients with membranous nephropathy and FSGS (hazard ratios of 22 and 7.8, respectively) referenced to patients with IgAN. Following adjustment for gender, cancer history, proteinuria, and serum albumin by multivariable analysis, the histologic subtype remained an independent risk for venous thromboembolic events. This risk was still highest in patients with membranous nephropathy followed by FSGS with adjusted hazard ratios of 10.8 and 5.9, respectively. Thus, in this large cohort, histologic diagnosis was an independent risk factor for venous thromboembolic events. Further studies are needed to discover mechanisms responsible for this high risk in patients with membranous nephropathy.

Monocytes are one of the key inflammatory cells recruited to xenografts and play an important role in delayed xenograft rejection. Previous studies have demonstrated the ability of monocytes to bind to the major xenoantigen Gal-α(1,3)Gal-β(1,4)GlcNAc-R; however, the receptor that mediates this interaction has yet to be identified. We provide evidence that it is Galectin-3, a ∼30-kDa lectin that recognizes β-galactosides (Gal-β(1–3/4)GlcNAc) and plays diverse roles in many physiological and pathological events. Human monocyte binding is strikingly increased on porcine aortic endothelial cells (PAEC), which express high levels of Gal-α(1,3)Gal-β(1,4)GlcNAc-R, compared with human aortic endothelial cells. Human monocytes obtained from healthy donors bind to Gal-α(1,3)Gal-β(1,4)GlcNAc-R at variable intensities. This variation of binding intensity was consistent and reproducible in individual donors. Galectin-3 is mainly expressed in human monocytes, not lymphocytes. Purified Galectin-3 is able to bind directly to Gal-α(1,3)Gal-β(1,4)GlcNAc-R. Galectin-3 can also be affinity isolated from monocytes (and not lymphocytes) using an Gal-α(1,3)Gal-β(1,4)GlcNAc-R-biotin/streptavidin-bead pull-down system. Soluble Galectin-3 binds preferentially to PAEC vs human aortic endothelial cells, and this binding can be inhibited by lactose, indicating dependence on the carbohydrate recognition domain of Galectin-3. Gal-α(1,3)Gal-β(1,4)GlcNAc-R is at least partly responsible for this phenomenon, as binding decreased after digestion of PAEC with α-galactosidase. Furthermore, monocytes pretreated with a blocking anti-Galectin-3 Ab show decreased adhesion to PAEC when compared with isotype control in a parallel plate flow chamber perfusion assay. Thus, we conclude that Galectin-3 expressed in human monocytes is a receptor for the major xenoantigen (Gal-α(1,3)Gal-β(1,4)GlcNAc-R), expressed on porcine endothelial cells.