Management of congenital nephrotic syndrome: consensus recommendations of the ERKNet-ESPN Working Group

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin–angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant

Tree water relations can trigger monoterpene emissions from Scots pine stems during spring recovery

Tree canopies are known to emit large amounts of VOCs( volatile organic compounds) such as monoterpenes into the surrounding air. High VOC emission rates from bo-real forests have been observed during the transition from winter to summer activity. The most important sources of these are considered to be the green foliage, understory vegetation and soil organisms, but emissions from the living stand woody compartments have so far not been quantified. We analyzed whether the non-foliar components could partially explain the springtime high emission rates. We measured the monoterpene emissions from Scots pine( Pinus sylvestris L.) stem and shoots during the dehardening phase of trees in field conditions in two consecutive springs. We observed a large, transient monoterpene burst from the stem, while the shoot monoterpene emissions remained low. The burst lasted about 12 h. Simultaneously, an unusual nighttime sap flow and a non-systematic diurnal pattern of tree diameter were detected. Hence, we suggest that the monoterpene burst was a consequence of the recovery of the stem from wintertime, and likely related to the refilling of embolized tracheids and/or phenological changes in the living cells of the stem. This indicates that the dominant processes and environmental drivers triggering the monoterpene emissions are different between the stem and the foliage.Peer reviewe

A single dose of the gamma-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans

Background: In Alzheimer’s disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose. Methods: Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification. Results: Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner. Conclusions: These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD00307

Normal growth and intravascular volume status with good metabolic control during peritoneal dialysis in infancy

Peer reviewe

Management of children with congenital nephrotic syndrome: challenging treatment paradigms

Background: Management of children with congenital nephrotic syndrome (CNS) is challenging. Bilateral nephrectomies followed by dialysis and transplantation are practiced in most centres, but conservative treatment may also be effective. / Methods: We conducted a 6-year review across members of the European Society for Paediatric Nephrology Dialysis Working Group to compare management strategies and their outcomes in children with CNS. / Results: Eighty children (50% male) across 17 tertiary nephrology units in Europe were included (mutations in NPHS1, n = 55; NPHS2, n = 1; WT1, n = 9; others, n = 15). Excluding patients with mutations in WT1, antiproteinuric treatment was given in 42 (59%) with an increase in S-albumin in 70% by median 6 (interquartile range: 3–8) g/L (P < 0.001). Following unilateral nephrectomy, S-albumin increased by 4 (1–8) g/L (P = 0.03) with a reduction in albumin infusion dose by 5 (2–9) g/kg/week (P = 0.02). Median age at bilateral nephrectomies (n = 29) was 9 (7–16) months. Outcomes were compared between two groups of NPHS1 patients: those who underwent bilateral nephrectomies (n = 25) versus those on conservative management (n = 17). The number of septic or thrombotic episodes and growth were comparable between the groups. The response to antiproteinuric treatment, as well as renal and patient survival, was independent of NPHS1 mutation type. At final follow-up (median age 34 months) 20 (80%) children in the nephrectomy group were transplanted and 1 died. In the conservative group, 9 (53%) remained without dialysis, 4 (24%; P < 0.001) were transplanted and 2 died. / Conclusion: An individualized, stepwise approach with prolonged conservative management may be a reasonable alternative to early bilateral nephrectomies and dialysis in children with CNS and NPHS1 mutations. Further prospective studies are needed to define indications for unilateral nephrectomy

Unprecedented staining of polar lipids by a luminescent rhenium complex revealed by FTIR microspectroscopy in adipocytes.

Fourier transform infrared (FTIR) microspectroscopy and confocal imaging have been used to demonstrate that the neutral rhenium(i) tricarbonyl 1,10-phenanthroline complex bound to 4-cyanophenyltetrazolate as the ancillary ligand is able to localise in regions with high concentrations of polar lipids such as phosphatidylethanolamine (PE), sphingomyelin, sphingosphine and lysophosphatidic acid (LPA) in mammalian adipocytes

Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides

BACKGROUND: Evaluation of microbicides for prevention of HIV-1 infection in macaque models for vaginal infection has indicated that the concentrations of active compounds needed for protection by far exceed levels sufficient for complete inhibition of infection in vitro. These experiments were done in the absence of seminal plasma (SP), a vehicle for sexual transmission of the virus. To gain insight into the possible effect of SP on the performance of selected microbicides, their anti-HIV-1 activity in the presence, and absence of SP, was determined. METHODS: The inhibitory activity of compounds against the X4 virus, HIV-1 IIIB, and the R5 virus, HIV-1 BaL was determined using TZM-bl indicator cells and quantitated by measuring β-galactosidase induced by infection. The virucidal properties of cellulose acetate 1,2-benzene-dicarboxylate (CAP), the only microbicide provided in water insoluble, micronized form, in the presence of SP was measured. RESULTS: The HIV-1 inhibitory activity of the polymeric microbicides, poly(naphthalene sulfonate), cellulose sulfate, carrageenan, CAP (in soluble form) and polystyrene sulfonate, respectively, was considerably (range ≈ 4 to ≈ 73-fold) diminished in the presence of SP (33.3%). Formulations of micronized CAP, providing an acidic buffering system even in the presence of an SP volume excess, effectively inactivated HIV-1 infectivity. CONCLUSION: The data presented here suggest that the in vivo efficacy of polymeric microbicides, acting as HIV-1 entry inhibitors, might become at least partly compromised by the inevitable presence of SP. These possible disadvantages could be overcome by combining the respective polymers with acidic pH buffering systems (built-in for formulations of micronized CAP) or with other anti-HIV-1 compounds, the activity of which is not affected by SP, e.g. reverse transcriptase and zinc finger inhibitors

Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism

Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37(-/-)) model for MUL. Trim37(-/-) mice were viable and had normal weight development until approximately 12 months of age, after which they started to manifest increasing problems in wellbeing and weight loss. Assessment of skeletal parameters with computer tomography revealed significantly smaller skull size, but no difference in the lengths of long bones in Trim37(-/-) mice as compared with wildtype. Both male and female Trim37(-/-) mice were infertile, the gonads showing germ cell aplasia, hilus and Leydig cell hyperplasia and accumulation of lipids in and around Leydig cells. Male Trim37(-/-) mice had elevated levels of follicle-stimulating and luteinizing hormones, but maintained normal levels of testosterone. Six-month-old Trim37(-/-) mice had elevated fasting blood glucose and low fasting serum insulin levels. At 1.5 years Trim37(-/-) mice showed non-compaction cardiomyopathy, hepatomegaly, fatty liver and various tumors. The amount and morphology of liver peroxisomes seemed normal in Trim37(-/-) mice. The most consistently seen phenotypes in Trim37(-/-) mice were infertility and the associated hormonal findings, whereas there was more variability in the other phenotypes observed. Trim37(-/-) mice recapitulate several features of the human MUL disease and thus provide a good model to study disease pathogenesis related to TRIM37 deficiency, including infertility, non-alcoholic fatty liver disease, cardiomyopathy and tumorigenesis