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While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

In recent years, migration and the social changes associated with it have increasingly become the focus of scientific interest. The diversity of cultures in hospitals poses a major challenge. Medical teams are often confronted with language barriers and different concepts of illness, health, and healing. The field is wide, and in addition to foreign language skills, primarily human skills such as self-awareness, communication, and empathy are demanded. Religion also plays a role in medical care for patients with a foreign cultural background. This work is intended to provide an overview of the scientifically based necessary skills in dealing with this patient clientele and to give an insight into the personal experiences of the authors. After many years of dealing with intercultural care of patients, this experience has shown one thing above all: Sometimes, it is beyond language and just needs humanity.

The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30–300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75–187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7; p < 0.05); it was “only” about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5; p < 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6; p = 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104).

Familial hypercholesterolemia (FH) is an inherited metabolic defect leading to increased total cholesterol and low-density cholesterol (LDL) from birth onwards. Homozygous FH, presenting with clear clinical features, has a prevalence of ~ 1 per million. Prevalence of heterozygous FH is 1/500 European population. Atherosclerotic burden depends on the degree and duration of high LDL exposure. In severe cases, early detection is critical, and aggressive lipid-lowering therapies should begin in early childhood to reduce coronary heart disease risk. Pediatric therapeutic concepts correspond to adults and are orientated at LDL plasma concentration. Mean LDL plasma target value during treatment is

Mycophenolate Mofetil (MMF) has an established role as a therapeutic agent in childhood nephrotic syndrome. While other immunosuppressants have been shown to positively affect podocytes, direct effects of MMF on podocytes remain largely unknown. The present study examines the effects of MMF’s active component Mycophenolic Acid (MPA) on the transcriptome of podocytes and investigates its biological significance. We performed transcriptomics in cultured murine podocytes exposed to MPA to generate hypotheses on podocyte-specific effects of MPA. Accordingly, we further analyzed biological MPA effects on actin cytoskeleton morphology after treatment with bovine serum albumin (BSA) by immunofluorescence staining, as well as on cell survival following exposure to TNF-α and cycloheximide by neutral red assay. MPA treatment significantly (adjusted p

Export of sinking particles from the surface ocean is critical for carbon sequestration and to provide energy to the deep biosphere. The magnitude and spatial patterns of this export have been estimated in the past by in situ particle flux observations, satellite-based algorithms, and ocean biogeochemical models; however, these estimates remain uncertain. Here, we use a recent machine learning reconstruction of global ocean particle size distributions (PSDs) from Underwater Vision Profiler 5 measurements to estimate carbon fluxes by sinking particles (35 μm–5 mm equivalent spherical diameter) from the surface ocean. We combine global maps of PSD properties with empirical relationships constrained against in situ flux observations to calculate particulate carbon export from the euphotic zone (5.8 ± 0.1 Pg C y−1) and annual maximum mixed layer depths (6.1 ± 0.1 Pg C y−1). The new flux reconstructions suggest a less variable seasonal cycle in the tropical ocean and a more persistent export in the Southern Ocean than previously recognized. Smaller particles (less than 418 μm) contribute most of the flux globally, while larger particles become more important at high latitudes and in tropical upwelling regions. Export from the annual maximum mixed layer exceeds that from the euphotic zone over most of the low-latitude ocean, suggesting shallow particle recycling and net heterotrophy in the deep euphotic zone. These estimates open the way to fully three-dimensional global reconstructions of particle fluxes in the ocean, supported by the growing database of in situ optical observations.

Objectives To assess the spectrum of underlying pathologies, the intrauterine course and postnatal outcome of 46 fetuses with megacystis that underwent intrauterine vesico-amniotic shunting (VAS) with the Somatex® shunt in a single center. Methods Retrospective analysis of 46 fetuses with megacystis that underwent VAS either up to 14 + 0 weeks (early VAS), between 14 + 1 and 17 + 0 weeks (intermediate VAS) or after 17 + 0 weeks of gestation (late VAS) in a single tertiary referral center. Intrauterine course, underlying pathology and postnatal outcome were assessed and correlated with the underlying pathology and gestational age at first VAS. Results 46 fetuses underwent VAS, 41 (89%) were male and 5 (11%) were female. 28 (61%) fetuses had isolated and 18 (39%) had complex megacystis with either aneuploidy (n = 1), anorectal malformations (n = 6), cloacal malformations (n = 3), congenital anomalies overlapping with VACTER association (n = 6) or Megacystis–Microcolon Intestinal–Hypoperistalsis Syndrome (MMIHS) (n = 2). The sonographic ‘keyhole sign’ significantly predicted isolated megacystis (p Conclusions Our data suggest that VAS is feasible from the first trimester onward. Early intervention has the potential to preserve neonatal kidney function in the majority of cases and enables neonatal survival in up to 87% of cases. Despite successful fetal intervention, parents should be aware of the potential of mid- or long-term kidney failure and of additional health impairments due to concomitant extra-renal anomalies that cannot be excluded at time of intervention.

CA extern

Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluation of tumor genomic evolution. We characterize changes in tumor fraction (TFx), somatic copy number alterations (SCNAs), and somatic mutations over time in patients (pts) with and without BRCA1/2 mutations and metastatic breast cancer (mBC) who received a PARP inhibitor (PARPi) or platinum chemotherapy. Specifically, we seek to identify the frequency of BRCA1/2 reversion mutations. Methods: Pts with mBC and germline or somatic BRCA1/2 mutations were identified on a banking protocol of prospectively-collected serial samples of blood and plasma. Control pts without a BRCA1/2 mutation were matched 2:1 by age and hormone receptor (HR) status. Ultra-low-pass whole genome sequencing (ULPWGS) with 0.1x depth was performed on all plasma samples (n=103) and the ichorCNA algorithm was used to determine TFx and SCNAs. Targeted panel sequencing (TPS) of 402 cancer-related genes was performed at 10,000x depth on plasma samples, and one blood sample per pt. The panel includes BRCA1/2 and 38 other DNA damage repair (DDR) genes. Somatic mutations were identified by joint calling with Mutect2 across plasma timepoints with paired pt normal blood. Germline variant calling from TPS on blood with HaplotypeCaller was used to confirm germline mutations in BRCA1/2. Results: We identified 10 pts with mBC with a germline (n=7) or somatic (n=3) BRCA1 (n=2) or BRCA2 (n=8) mutation and banked blood and plasma samples at 2-9 timepoints at a median of 8 weeks apart (range 1-43). The control cohort of 20 pts with mBC and wildtype BRCA1/2 was well matched by age and HR status. All pts with BRCA1/2 mutations received a PARPi and/or platinum chemotherapy at some point during sample collection. Half of control pts received platinum chemotherapy. Germline BRCA1/2 mutations were confirmed in all 7 pts with known germline mutations. Somatic BRCA2 mutations were confirmed in ctDNA in 2 of 3 patients. Among all samples, median TFx was 0.05 (range 0-0.80) with 35% of samples having TFx >0.10. There was no significant difference in TFx by age, receptor status, or active treatment with a PARPi or platinum. There was no significant change in the percent of genome with a SCNA over time. A reversion mutation of a germline BRCA2 mutation, restoring the open reading frame of BRCA2, was discovered at the last timepoint from 1 pt while receiving carboplatin. She had radiographic progression 4 weeks later. A germline BRCA1/2 reversion mutation in this cohort occurred in 2.3% of samples, 14.3% of pts. The somatic mutation landscape and clonal evolution of TPS using PyClone will be presented. Clonal evolution can show emerging and responding clusters of variants. For pts with available tissue specimens, somatic variants in ctDNA will be compared to somatic mutations detected in tissue with TPS. Conclusions: Evaluation of serial ctDNA samples for TFx, SCNAs, and somatic mutations from banked plasma and blood from pts with mBC is feasible. SCNAs were stable over time. The frequency of reversion mutations in BRCA1/2 was low, suggesting that either their incidence is low or ctDNA TPS is not sensitive enough to detect them. Citation Format: Katharine A Collier, David Tallman, Zachary T. Weber, Marcy Haynam, Elizabeth J. Adams, Janet Jenison, Sarah Asad, Maryam Lustberg, Mathew Cherian, Bhuvaneswari Ramaswamy, Sagar Sardesai, Nicole Williams, Robert Wesolowski, Jeffrey Vandeusen, Margaret E. Gatti-Mays, Ashley Pariser, Amir Mortazavi, Daniel G. Stover. Serial circulating tumor DNA from patients with metastatic breast cancer with and without BRCA1/2 mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-09.

The purpose of this update is to summarize current knowledge on the pathophysiology of immunglobulin A (IgA) vasculitis nephritis (IgAVN) as well as to critically review evidence for established therapeutic regimes and available biomarkers. An additional purpose is to raise the discussion what could be done to further improve our understanding of IgAVN, identify patients at risk for adverse outcome and increase the evidence for therapy recommendations.Clinical and experimental studies have established the concept of a multilevel pathogenesis. Toll-like-receptor activation, B cell proliferation, micro-RNAs and complement activation have been identified or confirmed as potential therapeutic targets which can modify the course of the disease. Currently, kidney injury molecule-1, monocyte chemotactic protein-1, N-acetyl-β-glucosaminidase, and angiotensinogen are the most promising urinary biomarkers for early diagnosis of renal involvement in IgA vasculitis.Close surveillance of all IgAV patients for renal involvement is recommended. Given the multilevel pathogenesis, early treatment of even mild cases should be initiated. Further therapeutic options should be considered in case first-line therapy (mostly corticosteroids) has no effect. The evidence supporting current therapeutic regimes is predominantly based on expert opinion. Prospective studies are needed and should involve substances inhibiting B cell proliferation and complement activation.