The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.

T he primary form of membranous nephropathy (MN) is an autoimmune kidney disease in which circulating autoantibodies target podocyte autoantigens, leading to deposition of immune complexes in the glomerular capillary wall, podocyte injury, and proteinuria. 1-3 Overall, MN affects more men than women (sex ratio 2:1), with a peak incidence at 50 to 55 years. 4,5 Clinical outcome varies from spontaneous remission to persistent proteinuria and end-stage renal disease in about 30% of cases.

Background and objectivesPatients with membranous nephropathy can have circulating autoantibodies against membrane-bound (phospholipase A2 receptor 1 [PLA2R1] and thrombospondin type-1 domain containing 7A[THSD7A]) and intracellular (aldose reductase, SOD2, and α-enolase) podocyte autoantigens. We studied their combined association with clinical outcomes.Design, setting, participants, & measurementsSerum levels of anti-PLA2R1, anti-THSD7A, anti-aldose reductase, anti-SOD2, and anti−α-enolase autoantibodies were determined in 285 patients at diagnosis and during follow-up using standardized and homemade assays. An eGFR>60 ml/min per 1.73 m2 and remission of proteinuria (<0.3/<3.5 g per d) after 12 months were the outcomes of interest.ResultsAt diagnosis, 182 (64%), eight (3%), and 95 (33%) patients were anti-PLA2R1+, anti-THSD7A+, and double negative, respectively. The prevalence of a detectable antibody to at least one intracellular antigen was similarly distributed in patients who were anti-PLA2R1+ (n=118, 65%) and double negative (n=64, 67%). Positivity for anti-PLA2R1, anti-SOD2, and anti–α-enolase antibodies and higher titers at diagnosis were associated with poor clinical outcome independently to each other. Combined positivity for anti-PLA2R1, anti-SOD2, and anti−α-enolase was associated with highest risk of poor outcome (odds ratio, 5.5; 95% confidence interval, 1.2 to 24; P=0.01). In Kaplan–Meier analysis, patients who were anti-PLA2R1+/anti-SOD2+ or anti-PLA2R1+/anti−α-enolase+ had lower eGFR at 12 months compared with patients who were anti-PLA2R1+/anti-SOD2− or anti−α-enolase−. Predictive tests (net reclassification index and area under the curve–receiver-operating characteristic analysis) showed that combined assessment of antibodies improved classification of outcome in 22%–34% of cases for partial remission of proteinuria and maintenance of normal eGFR. For patients with nephrotic syndrome at diagnosis, anti-SOD2 positivity and high anti-PLA2R1 titer were associated with a lack of complete remission. Patients who were anti-PLA2R1−/anti-intracellular antigens− had the lowest proteinuria and the highest eGFR at diagnosis and the lowest risk of lower eGFR at 12 months. Epitope spreading was present in 81% of patients who were anti-PLA2R1+ and was associated with increased positivity for intracellular antigens and poor eGFR at diagnosis and 12 months.ConclusionsCombined serological analysis of autoantibodies targeting membrane-bound and intracellular autoantigens identifies patients with poor clinical outcomes.

Henriques-Coelho, Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension, BBA -Molecular Basis of Disease (2015),

Introduction Personalized treatment for patients with membranous nephropathy requires accurate prediction of the disease course at an early stage. In this study, we evaluated the value of baseline anti–phospholipase A2 receptor (PLA2R1) antibody titer as a prognostic biomarker in patients with PLA2R1-associated membranous nephropathy. Methods In this cohort study, we included 168 patients (118 men, 50 women) referred to our nephrology center between February 1995 and November 2016. Mean age was 52 ± 13 years. There were 156 patients with new-onset disease and 12 patients with a relapse ( n = 10) or recent use of immunosuppressive therapy ( n = 2). We measured anti-PLA2R1 titer at baseline and analyzed progression to severe disease (30% increase of serum creatinine or start of immunosuppressive therapy) as a primary study endpoint over 60 months. Results There was a clear association between anti-PLA2R1 antibody titer and severity of the nephrotic syndrome. In univariate analysis, anti-PLA2R1 antibody titer was also associated with disease progression. However, in Cox proportional hazard models that included proteinuria and serum creatinine, anti-PLA2R1 antibody titer was no longer associated with clinical outcome. Results were similar when limiting the analysis to the patients with new-onset disease. Conclusion Our study questions the relevance of single measurement of anti-PLA2R1 antibodies at baseline as a prognostic biomarker in membranous nephropathy. Future studies are needed to determine the possible role of sequential measurements of anti-PLA2R1 antibodies as a prognostic biomarker of disease progression.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. Pulmonary artery smooth muscle cells (PASMCs) play a crucial role in PAH pathophysiology, displaying a hyperproliferative, and apoptotic-resistant phenotype. In the present study, we evaluated the potential therapeutic role of terameprocol (TMP), an inhibitor of cellular proliferation and promoter of apoptosis, in a well-established pre-clinical model of PAH induced by monocrotaline (MCT) and studied the biological pathways modulated by TMP in PASMCs. Wistar rats injected with MCT or saline (SHAM group) were treated with TMP or vehicle. On day 21 after injection, we assessed bi-ventricular hemodynamics and cardiac and pulmonary morphometry. The effects of TMP on PASMCs were studied in a primary culture isolated from SHAM and MCT-treated rats, using an iTRAQ-based proteomic approach to investigate the molecular pathways modulated by this drug. In vivo, TMP significantly reduced pulmonary and cardiac remodeling and improved cardiac function in PAH. In vitro, TMP inhibited proliferation and induced apoptosis of PASMCs. A total of 65 proteins were differentially expressed in PASMCs from MCT rats treated with TMP, some of which involved in the modulation of transforming growth factor beta pathway and DNA transcription. Anti-proliferative effect of TMP seems to be explained, at least in part, by the down-regulation of the transcription factor HMGB1. Our findings support the beneficial role of TMP in PAH and suggest that it may be an effective therapeutic option to be considered in the clinical management of PAH.

Cardiac cachexia is characterized by an imbalance between anabolic and catabolic factors that lead to weight loss. The present study addresses the preventive effect of exercise training on muscle wasting in an animal model of right ventricular failure induced by monocrotaline (MCT) administration. After 4 weeks of training or cage living, male Wistar rats were injected with MCT (60mg/kg) (ExMCT and SedMCT, respectively) or saline (ExC and SedC, respectively), and sacrificed after an additional 4week‐period of movement confined to cage's space. Gastrocnemius and blood samples were collected for biochemical analysis. Sed+MCT showed decreased body weight, cross sectional area and MHC‐I isoform. Total Akt and mTOR protein levels were normal while its phosphorylated forms were increased in exercised groups. Increased Atrogin‐1 protein expression was found only in Sed+MCT, as well as higher serum levels of CRP and IL‐1b. The present study provides evidence that exercise preconditioning prevents cardiac cachexia by averting proteolysis and inflammation.

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