Treatments for idiopathic membranous nephropathy, a common cause of nephrotic syndrome, can be very toxic. In view of the pathogenic potential of B cells in this disease, we studied the effects of four weekly infusions of rituximab (375 mg/m(2)-- the monoclonal antibody to B-cell antigen CD20--in eight patients who had idiopathic membranous nephropathy with persistent nephrotic syndrome. At weeks 4 and 20, urinary protein decreased from mean (SE) 8.6 g/24 h (1.4) to 3.8 (0.8) and 3.7 (0.9), respectively (p<0.0001). At week 20, albuminuria and albumin fractional clearance decreased by 70% and 65%, and serum albumin increased by 31%. CD20 B lymphocytes fell below normal ranges up to study end. The short-term risk-benefit profile of rituximab seems more favourable to that of any other immunosuppressive drug used to treat idiopathic membranous nephropathy.
sTNF-alpha and sIL-8 are markers of 'systemic' inflammation in severe asthmatics, in conjunction with augmented circulating neutrophils, suggesting the involvement of neutrophil-derived cytokine pattern in severe asthma.
Rituximab effectively reduces proteinuria in patients with idiopathic membranous nephropathy (IMN), but response to treatment may vary from patient to patient. The association between baseline clinical, laboratory, and histology covariates and proteinuria reduction was evaluated retrospectively by multiple linear regression analysis at 3 mo after rituximab therapy in 14 patients with IMN with proteinuria >3.5 g/24 h while on angiotensin-converting enzyme inhibition for at least 6 mo and no previous remissions. The association strength was expressed by standardized  coefficients (SC). Glomerular (SC ؍ 0.48, P ؍ 0.049) and tubulointerstitial (TI) scores (SC ؍ 0.61, P ؍ 0.003) predicted the outcome. Among glomerular and TI score components, tubular atrophy (SC ؍ 0.59, P ؍ 0.003) and interstitial fibrosis (SC ؍ 0.60, P ؍ 0.001) were significantly associated with 3-mo proteinuria. Urinary protein excretion decreased from 9.1 ؎ 4.0 to 4.6 ؎ 3.5 g/24 h (P < 0.001) in eight patients with TI score <1.7 but did not change in six with a score >1.7. Nine additional patients with IMN then were allocated prospectively to rituximab treatment on the basis of a TI score <1.7. Three-month proteinuria decreased in all patients from 8.9 ؎ 5.3 to 4.9 ؎ 3.9 g/24 h (P < 0.001) and serum albumin increased from 2.2 ؎ 0.6 to 2.8 ؎ 0.5 mg/dl (P < 0.01). Changes in serum albumin and cholesterol were inversely correlated (P < 0.02, r ؍ ؊0.44). Rituximab achieved CD 20 and CD 19 depletion in all patients. In patients with IMN and nephrotic proteinuria despite angiotensin-converting enzyme inhibition therapy, renal biopsy findings may help in predicting response to rituximab and defining selection criteria for randomized trials that aim to assess the risk/benefit profile of B cell target therapy as compared with aspecific immunosuppressants and/or conservative therapy alone.
We investigated the effect of hemodynamic shear forces on the expression of adhesive molecules, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells (HUVEC) exposed to laminar (8 dynes/cm2) or turbulent shear stress (8.6 dynes/cm2 average), or to a static condition. Laminar flow induced a significant time-dependent increase in the surface expression of ICAM-1, as documented by flow cytometry studies. Endothelial cell surface expression of ICAM-1 in supernatants of HUVEC exposed to laminar flow was not modified, excluding the possibility that HUVEC exposed to laminar flow synthetize factors that upregulate ICAM-1. The effect of laminar flow was specific for ICAM-1, while E-selectin expression was not modulated by the flow condition. Turbulent flow did not affect surface expression of either E-selectin or ICAM-1. To evaluate the functional significance of the laminar-flow-induced increase in ICAM-1 expression, we studied the dynamic interaction of total leukocyte suspension with HUVEC exposed to laminar flow (8 dynes/cm2 for 6 hours) in a parallel-plate flow chamber or to static condition. Leukocyte adhesion to HUVEC pre-exposed to flow was significantly enhanced, compared with HUVEC maintained in static condition (233 +/- 67 v 43 +/- 16 leukocytes/mm2, respectively), and comparable with that of interleukin-1 beta treated HUVEC. Mouse monoclonal antibody anti-ICAM-1 completely blocked flow-induced upregulation of leukocyte adhesion. Interleukin-1 beta, which upregulated E-selectin expression, caused leukocyte rolling on HUVEC that was significantly lower on flow- conditioned HUVEC and almost absent on untreated static endothelial cells. Thus, laminar flow directly and selectively upregulates ICAM-1 expression on the surface of endothelial cells and promotes leukocyte adhesion. These data are relevant to the current understanding of basic mechanisms that govern local inflammatory reactions and tissue injury.
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