Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #{"type":"clinical-trial","attrs":{"text":"NCT00981838","term_id":"NCT00981838"}}NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m² intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2–4) to 0.5 (IQR, 0–1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19–0.60) to 0 mg/kg (IQR, 0–0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0–29.2) to 0.5 mg/kg (IQR, 0–9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m² (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.Idiopathic nephrotic syndrome (NS) in children and young adults is almost invariably the clinical counterpart of a continuum of glomerular diseases ranging from the relatively frequent minimal change disease (MCD) and the less frequent mesangial proliferative GN (MesGN), which are predominantly observed in children, to the relatively uncommon FSGS that is observed more frequently in adult patients.¹ In a small minority of patients that are generally resistant to immunosuppressive therapies, the disease is due to molecular defects of one of the podocyte genes.² In all of the other cases, it appears to be immune-mediated, but the pathophysiologic process underlying glomerular injury remains poorly understood.³Independent of the underlying renal pathology, prednisone continues to be the cornerstone treatment at disease onset, achieving remission within 4 weeks in approximately 90% of children with MCD and in 20%–60% of those with FSGS.^4,5 However, 60%–70% of patients relapse after steroid tapering or withdrawal, and most require repeat courses of prednisone to achieve remission of recurrent episodes and/or the addition of other immunosuppressive medications, such as calcineurin inhibitors, mycophenolate mofetil, or alkylating agents, to reduce the number of relapses and prevent major side effects of steroid treatment.⁶ According to their relapse rate, these patients are classically labeled as “steroid-dependent” or “frequently relapsing”. In these patients, serious adverse effects of treatment associate with complications of relapsing episodes of heavy proteinuria. These are the patients in most urgent need of more effective and safer treatment.The possibility of a specific and, hopefully, safer approach to patients with steroid-dependent or frequently relapsing NS emerged in 2004 when the B cell–depleting mAb rituximab was reported to induce remission of proteinuria in a child with frequently relapsing NS secondary to MCD who had received this medication to cure a supervened idiopathic thrombocytopenic purpura.⁷ Subsequent uncontrolled observations found some effect of rituximab in patients with steroid-dependent or frequently relapsing MCD,^8–11 suggesting that B-cell immunity could play a key role in the pathophysiology of the disease. Controlled studies in support of this hypothesis, however, have been both scanty and almost confined to children^12,13 or to patients with MCD who were evaluated in the context of a retrospective, observational design.¹⁴ Indeed, less attention was given to adults and patients with FSGS given difficulties in designing adequately powered trials.Here, we designed a longitudinal, off-on study (ClinicalTrials.gov #{"type":"clinical-trial","attrs":{"text":"NCT00981838","term_id":"NCT00981838"}}NCT00981838) to evaluate the efficacy of rituximab in reducing the incidence of relapses and need for steroid and other immunosuppressive medications in children and adults with steroid-dependent or frequently relapsing NS due to MCD, MesGN, or FSGS. To minimize the side effects and costs of rituximab, we abandoned the standard four-dose protocol originally implemented for the treatment of B-cell lymphomas,¹⁵ and adopted a new B cell–driven regimen we found to achieve remission of NS in patients with idiopathic membranous nephropathy (IMN) as effectively as the standard protocol, but with fewer side effects and less costs.¹⁶     

The effect of colonoscopy on intraocular pressure: an observational prospective study

Graefe's Archive for Clinical and Experimental Ophthalmology - Colonoscopy is an endoscopic examination of the bowel. It requires insufflation of the large bowel lumen with gas which leads to...     

Suppression of hypoxia-inducible factor-1α contributes to the antiangiogenic activity of red propolis polyphenols in human endothelial cells

Polyphenol-enriched fractions from natural sources have been proposed to interfere with angiogenesis in pathological conditions. We recently reported that red propolis polyphenols (RPP) exert antiangiogenic activity. However, molecular mechanisms of this activity remain unclear. Here, we aimed at characterizing molecular mechanisms to explain the impact of RPP on endothelial cells' (EC) physiology. We used in vitro and ex and in vivo models to test the hypothesis that RPP inhibit angiogenesis by affecting hypoxia-inducible factor-1α (HIF1α) stabilization in EC. RPP (10 mg/L) affected angiogenesis by reducing migration and sprouting of EC, attenuated the formation of new blood vessels, and decreased the differentiation of embryonic stem cells into CD31-positive cells. Moreover, RPP (10 mg/L) inhibited hypoxia- or dimethyloxallylglycine-induced mRNA and protein expression of the crucial angiogenesis promoter vascular endothelial growth factor (VEGF) in a time-dependent manner. Under hypoxic conditions, RPP at 10 mg/L, supplied for 1-4 h, decreased HIF1α protein accumulation, which in turn attenuated VEGF gene expression. In addition, RPP reduced the HIF1α protein half-life from ~58 min to 38 min under hypoxic conditions. The reduced HIF1α protein half-life was associated with an increase in the von Hippel-Lindau (pVHL)-dependent proteasomal degradation of HIF1α. RPP (10 mg/L, 4 h) downregulated Cdc42 protein expression. This caused a corresponding increase in pVHL protein levels and a subsequent degradation of HIF1α. In summary, we have elucidated the underlying mechanism for the antiangiogenic action of RPP, which attenuates HIF1α protein accumulation and signaling.     

Assessing pharmacokinetic marker correlates of outcome,with application to antibody prevention efficacy trials

The Antibody Mediated Prevention efficacy trials are the first studies to evaluate whether passive administration of a broadly neutralizing monoclonal antibody can prevent human immunodeficiency virus (HIV) acquisition. The trials randomize 4600 HIV-negative volunteers to receive 10 infusions of the monoclonal antibody VRC01 or placebo. The primary objective compares the incidence of HIV infection between the study groups. The secondary objective assesses whether and how a marker defined as the serum concentration of VRC01 over time associates with the instantaneous rate of HIV infection, using a two-phase sampling design, a pharmacokinetic model for the time-concentration curve, and an estimator of HIV infection times. While a Cox model with a time-dependent covariate constitutes an important approach to this problem, the low interindividual versus intraindividual marker variability limits its power, motivating us to develop two alternative methods that condition on outcome status: (1) an indirect method that checks whether HIV-infected cases have unexpectedly long times from the most recent infusion to the estimated infection date and (2) a direct method that checks whether the marker itself is unexpectedly low at estimated infection dates. In simulations and a pseudo Antibody Mediated Prevention application, we find that method (2) (but not (1)) has greater power than the Cox model. We also find that the quality of the infection time estimator majorly impacts method performance, and thus, incorporating details of an optimized estimator is critical. The methods apply more generally for assessing a time-dependent longitudinal marker as a correlate of risk when the marker trajectory is modeled pharmacokinetically.     

Retinal Layers Measurements following Silicone Oil Tamponade for Retinal Detachment Surgery

This study aimed to investigate the influence of silicone oil on the retinal nerve fiber layer (RNFL) thickness in patients with primary rhegmatogenous retinal detachment who underwent vitreoretinal surgery. The study included 47 patients (eyes), who underwent a pars plana vitrectomy with the silicone oil tamponade. The control group included unoperated eye of all participants. Spectral-domain optical coherence tomography (SD-OCT) was used for the measurements of peripapilar and macular RNFL thickness. The average peripapillary RNFL thickness was significantly higher in the silicone oil filled eyes during endotamponade and after its removal. The eyes with elevated IOP had less thickening of the RNFL in comparison to the eyes with normal IOP. Central macular thickness and macular volume were decreased in the silicone oil filled eyes in comparison to the control eyes. In conclusion, silicone oil caused peripapilar RNFL thickening in the vitrectomized eyes during endotamponade and after silicone oil removal.