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The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge., (© 2021. The Author(s).)

Primary IgA nephropathy (IgAN) diagnosis is based on IgA-dominant glomerular deposits and histological scoring is done on formalin-fixed paraffin embedded tissue (FFPE) sections using the Oxford classification. Our aim was to use this underexploited resource to extract RNA and identify genes that characterize active (endocapillary-extracapillary proliferations) and chronic (tubulo-interstitial) renal lesions in total renal cortex. RNA was extracted from archival FFPE renal biopsies of 52 IgAN patients, 22 non-IgAN and normal renal tissue of 7 kidney living donors (KLD) as controls. Genome-wide gene expression profiles were obtained and biomarker identification was carried out comparing gene expression signatures a subset of IgAN patients with active (N = 8), and chronic (N = 12) renal lesions versus non-IgAN and KLD. Bioinformatic analysis identified transcripts for active (DEFA4, TNFAIP6, FAR2) and chronic (LTB, CXCL6, ITGAX) renal lesions that were validated by RT-PCR and IHC. Finally, two of them (TNFAIP6 for active and CXCL6 for chronic) were confirmed in the urine of an independent cohort of IgAN patients compared with non-IgAN patients and controls. We have integrated transcriptomics with histomorphological scores, identified specific gene expression changes using the invaluable repository of archival renal biopsies and discovered two urinary biomarkers that may be used for specific clinical decision making.

Deposition of amyloid-beta (Aβ) peptides has been shown to induce the release of inflammatory factors by activated microglia and brain infiltrating monocytes/macrophages. Interestingly, the enzyme transglutaminase 2 (TG2) has been shown to play a key role in neuroinflammation and regulation of transcription factors involved in immunomodulation. In this study, we aimed to better elucidate the mechanisms underlying TG2 involvement in the pro-inflammatory signaling pathway activated by fibrillar Aβ 1-42 in THP-1 monocytes. Cell exposure for 24 h to 500 nM Aβ 1-42 , induced the up-regulation of CD14, CD16, and TG2, suggesting THP-1 cell functional activation. Aβ 1-42 also increased the production of reactive oxygen species, that was reduced by the pre-incubation with genistein (25 µg/ml), a soy isoflavone with antioxidant properties. Moreover, IL-1β and IL-6 mRNA transcript and protein levels were eightfold increased in Aβ 1-42 -treated THP-1 monocytes. Interestingly, these effects were significantly reduced by R283 (~45%), a specific inhibitor of TG activity, and genistein (~40%). Aβ 1-42 induced the activation of p54/p46 JNK, as well as ERK 1/2 at a lower extent. The inactivation of ERK1/2 signalling pathway, but not JNK, by either genistein or U0126, a MEK1/2 inhibitor, was not able to blunt Aβ 1-42 -induced TG2 up-regulation, that, instead, was significantly reduced by R283. Aβ 1-42 also induced AP-1 activation that was not significantly affected by genistein or U0126, while was strongly reduced by R283. Our preliminary findings first suggest that TG2 up-regulation is involved in the pro-inflammatory activation of THP-1 monocytes induced by Aβ 1-42 via AP1/JNK signalling pathways.

Panic disorder (PD) is a disabling anxiety disorder that is characterized by unexpected, recurrent panic attacks, associated with fear of dying and worrying about possible future attacks or other behavioral changes as a consequence of the attacks. The acid-sensing ion channels (ASICs) are a family of proton-sensing channels expressed throughout the nervous system. Their activity is linked to a variety of behaviors including fear, anxiety, pain, depression, learning, and memory. The human analog of ASIC1a is the amiloride-sensitive cation channel 2 (ACCN2). Adenosine A2A receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. In this work we aimed to evaluate the distribution of ACCN2 rs685012 and ADORA2A rs2298383 polymorphisms in PD patients compared with healthy subjects. We found no association between ADORA2A polymorphism and PD. Instead, the C mutated allele for ACCN2 rs685012 polymorphism was significantly more frequent in patients than in controls. On the contrary, the TT homozygous wild-type genotype and also the ACCN2 TT/ADORA2A CT diplotype were significantly more represented in controls. These results are suggestive for a role of ACCN2 rs685012 polymorphism in PD development in Caucasian people.

Flavonoids have been shown to be effective in protecting against age-related cognitive and motor decline in both in vitro and in vivo models. Recently, a flavonoid-rich extract of Citrus bergamia juice (BJe) has been shown to display anti-oxidant and anti-inflammatory properties against LPS-induced activation of human THP-1 monocytes. In the light of these observations, we wondered whether BJe may be beneficial against neuroinflammatory processes, such as those observed in Alzheimer's disease. To this aim we used THP-1 monocytes to investigate the mechanisms underlying the beneficial potential of BJe against amyloid-beta1-42 (Aβ1-42) -mediated inflammation. Exposure of THP-1 cells to Aβ1-42 significantly induced the expression and secretion of IL-6 and IL-1β in THP-1 cells and increased the phosphorylation of ERK 1/2 as well as p46 and p54 members of JNK family. Moreover, Aβ1-42 raises AP-1 DNA binding activity in THP-1-treated cells. Interestingly, all these effects were reduced in the presence of BJe. Our data indicate that BJe may effectively counteract the pro-inflammatory activation of monocytes/microglial cells exposed to amyloid fibrils, suggesting a promising role as a natural drug against neuroinflammatory processes.

Aims: Oxidative stress increase is a key event for development of sensitivity-related illnesses (SRIs). The aim of this work was to evaluate the influence of a genetic variant in the antioxidant enzyme glutathione peroxidase (GPx1) on oxidative stress development in SRIs., Main Methods: GPx1 rs1800668 genotype, as well as glutathione, ubiquinone, and DNA damage were assessed in 34 SRI patients and 36 healthy subjects., Key Findings: Total glutathione, reduced/oxidized glutathione, and ubiquinone were significantly decreased in cases compared with controls, while DNA fragmentation was significantly increased in patients. However, these differences were not associated to GPx1 genetic background., Significance: GPx1 rs1800668 polymorphism does not play a major role in SRI-related oxidative stress development., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Objectives: X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV α5 chain (α5[COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS., Design, Setting, Participants, & Measurements: The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of α1, α3, and α5(COLIV) chains was assessed by immunofluorescence microscopy., Results: GBM distribution of the α5(COLIV) chain was diffuse in 1 and segmental or absent in 21 of the 22 patients; the expression of the α3(COLIV) chain was diffuse in 5 of 22 patients and segmental or absent in 17 of 22 patients. Patients with diffuse staining for the α3(COLIV) chain presented with proteinuria significantly later (median age, 16.9 versus 6.1 years; P=0.02) and reached an estimated GFR < 90 ml/min per 1.73 m(2) at an older age (median age, 27.0 versus 14.9 years; P=0.01) compared with patients with segmental or absent staining. Two thirds of patients with abnormal α3(COLIV) expression by immunofluorescence studies had null or truncating COL4A5 mutations, as opposed to none of the 4 tested patients with diffuse α3(COLIV) chain glomerular distribution., Conclusions: These results indicate that maintained expression of the α3(COLIV) chain is an early positive prognostic marker in patients with X-linked Alport symdrome.

This prospective, multicenter, proof-of-concept study aimed to evaluate the possibility to reduce the ordinary heparin dose and the systemic anti-Xa activity during hemodialysis (HD) sessions using a new heparin-grafted HD membrane. In 45 stable HD patients, the use of a heparin-grafted membrane with the ordinary heparin dose was followed by a stepwise weekly reduction of dose. Reduction was stopped when early signs of clotting (venous pressure, quality of rinse-back) occurred during two out of three weekly HD sessions. Heparin dose was decreased for 67% of patients resulting in the lowering of these patients' anti-Xa activity by 50%. Dose reductions were achieved with both types of heparin (low-molecular-weight heparin: 64 ± 14 to 35 ± 12 IU/kg, P < 0.0001; unfractionated heparin: 82 ± 18 to 46 ± 13 IU/kg, P < 0.0001) resulting in a decrease of anti-Xa activity at dialysis session end (low-molecular-weight heparin: 0.51 ± 0.25 to 0.25 ± 0.11 IU/mL, P < 0.0001; unfractionated heparin: 0.28 ± 0.23 to 0.13 ± 0.07 IU/mL, P < 0.0001). Failure to further decrease heparin dose was related to signs of clotting in blood lines (57% of sessions), in dialyzer (9%), or both (34%). Significant reduction of heparin dose and anti-Xa activity at the end of HD sessions was possible in stable HD patients using heparin-grafted membrane. HD patients who require low anti-Xa activity at the end of HD sessions might benefit from a heparin-grafted membrane to reduce bleeding risk and other heparin adverse events., (© 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.)

Background: The aim of this study was to evaluate indocyanine green angiographic findings in patients with systemic lupus erythematosus (SLE) with or without lupus nephritis. In particular, the presence of choroidal abnormalities at indocyanine green angiography (ICG-A) that could not be detected by fluorescein angiography (FAG) was investigated., Methods: Sixteen patients with SLE underwent simultaneous ICG-A and FAG. Patients were divided into 2 groups based on whether renal disease was present (group A, n=9) or not (group B, n=7)., Results: Drusen-like deposits were ophthalmoscopically evident in only 1 out of 9 group A patients (11.1%). While FAG disclosed the deposits in 4 out of 9 group A patients (44.4%), drusen-like deposits were otherwise found in all group A patients (100%) by ICG-A. FAG and ICG-A did not show choroidal alterations in group B patients., Conclusions: ICG-A can provide information that is not detectable by clinical or FAG examination in patients with lupus nephritis (group A). The findings of choroidopathy by ICG-A represent an indicator of ocular involvement and could be an indirect sign of renal involvement. Given that histological lesions may be present where there are no anomalies in urinary sediment and/or proteinuria, the positivity of ICG-A could help in deciding whether or not to carry out a renal biopsy. Therefore, ICG-A could be useful in the screening of patients with SLE, especially where there are no evident signs of renal involvement.

Mycophenolate mofetil (MMF) has been suggested as a promising therapeutic agent in the treatment of idiopathic nephrotic syndrome. Two patients with persistent nephrotic syndrome, secondary to minimal change disease and idiopathic membranous nephropathy, respectively, who were steroid-, cyclophosphamide- and cyclosporine-resistant, were treated with MMF during a 6-12-month period. In these cases there was no beneficial effect from treatment with MMF. Therapy was stopped after 6 months in case 1 and after 12 months in case 2 due to the persistence of proteinuria.

The authors describe a case of anisakiasis in Sicily. The diagnosis was based on the knowledge that a contaminated fish, Lepidopus caudatus, had probably been absorbed, as well as on clinical intestinal symptoms, intestinal lesions observed by endoscopy and O.G.D.S, duodenal infiltration by eosinophilic polymorphonuclear, positive ELISA anisakis serology and successful treatment by albendazole.