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The proteasome to immunoproteasome (iPS) switch consists of β1, β2 and β5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/β5 and LMP2/β1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/β5 (P 75th centile, i.e. −1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/β5 mRNA (P = 0.04) and low CD46 mRNA expression (P

Treatment of systemic lupus erythematosus (SLE) with severe diffuse proliferative nephritis is often challenging, particularly in small children in whom a genetic conditioning is likely to play a role. The effectiveness of standard therapy based on glucocorticoid and immunosuppressive drugs is often unsatisfactory.A 4 year-old girl, whose parents were first-grade cousins of Moroccan ancestry, developed SLE that progressed to severe renal involvement despite standard therapy. She had persistently undetectable serum C4 levels and very low C3 levels (30 mg/dl), and extremely high anti-DNA titers (1:640) that remained unmodified during 2 years of follow-up. No mutations of genes encoding for complement inhibitors were detected. Despite aggressive therapy based on prednisone, plasma exchanges, and cyclosporine, the child worsened and eventually developed features of atypical hemolytic uremic syndrome (aHUS). Treatment with eculizumab provided prompt remission of vasculitis, proteinuria, and hematuria, with normalization of renal function. Two attempts to withdraw eculizumab were followed by severe relapses and rescued by reinstating treatment. The child has been treated with eculizumab for17 months without relevant side effects.C5 inhibition by eculizumab completely reversed clinical symptoms and laboratory renal signs of severe lupus nephritis. Blocking complement-system activation with the use of targeted drugs may be a new and exciting strategy to treat SLE patients unresponsive to conventional therapy.

Neonatal sepsis due to E. coli is often complicated by multiple organ failure (MOF) and a high mortality risk. We report the case of a term newborn discharged in good condition who suddenly fell into septic shock after 11 days and required immediate resuscitation, volume expansion and a high-dosage amine infusion. Extremely severe metabolic acidosis, disseminated intravascular coagulation (DIC) with diffuse bleeding, and unstable hemodynamic status with oliguria turned into strict anuria, and the patient became anuric. The presence of DIC, with gastric and intestinal bleeding, rendered peritoneal dialysis impossible. Continuous renal replacement therapy (CRRT) was started with the new dialysis machine CARPEDIEM® (Cardio-Renal Pediatric Dialysis Emergency Machine), available on a trial-basis in our center, after the surgical placement of jugular double-lumen central venous catheters. A ‘ready to use' neonatal kit with a low-priming volume of the extracorporeal circuit allowed a prompt hemofiltration start. The filtration CRRT was continuously performed for 48 h, then intermittently (12 h/day) for 2 more days and interrupted on day 5 for diuresis reprisal. Acute kidney injury and multi-organ failure resolved after 5 days. The child survived without neurological damage, with a normal renal function and a normal development at 9 months follow-up. In conclusion, a prompt CRRT start with this specifically designed neonatal device allowed a progressive stabilization of hemodynamics, a better control of acidosis, a reduction of amine requirement, a gradual control of fluid overload and a rapid improvement of MOF, DIC as well as a resolution of the acute kidney injury. The device also allowed the extension of CRRT in the neonatal age.

The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/β1, p = 0.039; LPM7/β5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin–proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.

Henoch-Schönlein purpura (HSP) nephritis and primary IgA nephropathy (pIgAN) present with glomerular IgA deposits, but differ with regard to clinical features. The suspected involvement of different immune system pathways is largely unknown.This study was aimed at investigating some of the immunological features including Toll-like receptors (TLR), proteasome (PS)/immunoproteasome (iPS) switch, and the regulatory T cell system (Treg/Th17 cells) in 63 children with HSP with/without renal involvement and in 25 with pIgAN. Real-time PRC (Taqman) was used to quantify mRNA levels in peripheral blood mononuclear cells (PBMC).The expression of mRNAs encoding for TLR4 in both HSP and pIgAN was higher than in controls (HC) and in both diseases FoxP3mRNA and TGF-β1mRNA expression was significantly lower than in HC. A switch from PS to iPS (LMP2/β1) was detected only in PBMC of HSP and it correlated with the level of TLR2mRNA, which was selectively increased only in children with HSP.Children with HSP and pIgAN present with similar signs of engagement of the innate immunity and regulatory T cell depression. The increased immunoproteasome switch, which correlated with TLR2 activation, may suggest an innate immunity pathway peculiar to HSP vasculitic presentation. This research area also deserves further investigation for possible therapeutic applications.