The renal parenchyma – evaluation of a novel ultrasound measurement to assess fetal renal development

Sonja Brennan used a novel ultrasound measurement of the renal parenchyma to evaluate fetal kidney growth. Normal ranges of fetal renal parenchymal thickness were developed to aid diagnosis of kidney disease and help predict future kidney function. The effects of abnormal fetal growth and diabetes on the developing kidneys was explored

Kidney growth following preterm birth: evaluation with renal parenchyma ultrasonography

Background: Preterm birth impairs nephrogenesis, leading to a reduced nephron endowment which is inextricably linked to hypertension and chronic kidney disease in adults. The aim of this study was to compare nephron endowment between preterm infants to that of intrauterine fetuses at the same gestational age (GA) using a novel indirect ultrasound measurement of the renal parenchymal thickness. We hypothesized that extrauterine and intrauterine renal parenchymal thickness would differ based on altered renal growth environments. Methods: In this observational study, appropriately grown preterm infants (birth weight of between the 5th and 95th percentile) born <32 weeks, admitted to the neonatal department were eligible to participate. Renal parenchymal thickness of the infants was measured at 32- and 37-weeks postmenstrual age (PMA). These measurements were compared to the intrauterine renal parenchymal thickness of appropriately grown fetuses (control). Results: At 32-weeks PMA, the preterm infants had a significantly thinner renal parenchyma compared to fetuses at 32-weeks GA suggesting they had less nephrons, however by 37-weeks there was no significant difference in renal parenchymal thickness. Conclusions: We propose that the differences in the extrauterine growth of the renal parenchyma in preterm infants may be due to a reduced number of nephrons and compensatory hyperfiltration. Impact: This article provides insight into the effects of prematurity on nephrogenesis by comparing extrauterine renal parenchymal growth of born preterm infants to the ideal intrauterine fetal growth. Renal parenchyma thickness measurement using ultrasonography is a novel non-invasive measurement of renal development for the determination of nephron endowment. Differences in the renal parenchymal thickness of the preterm infants may be due to a deficit in nephron number and compensatory hyperfiltration

Fetal renal parenchyma: evaluation of a novel ultrasound measurement to assess kidney development

Introduction: Abnormal fetal growth can adversely impact renal development and is associated with increased risks of developing hypertension and chronic kidney disease later in life. A non-invasive, sensitive method of assessing normal and abnormal fetal kidney development is required. We hypothesise that the fetal renal parenchymal thickness could be used to evaluate the development of the fetal kidneys and provide an indirect estimate of fetal nephron number. This study uses antenatal ultrasound to assess fetal renal parenchymal growth and blood flow to determine if these are affected by abnormal fetal growth. Methods: A longitudinal, observational study was conducted at the Townsville Hospital, Townsville, Australia between May 2017 to December 2018. Mixed risk women with an accurately dated, singleton pregnancy underwent a pregnancy ultrasound scan at least every four weeks between 16 and 40 weeks gestation. Renal parenchymal thickness and echogenicity, renal volume, fetal growth biometries, amniotic fluid measurements, renal artery Doppler and other fetal Dopplers were assessed in appropriately grown, fetal growth restriction or large for gestational age fetuses. Results: 155 participants were recruited, with 7 participants excluded due to fetal abnormalities. Mixed effects modelling was used so that variations between gestational ages within fetuses and between fetuses was considered. A reference graph was developed for normal fetal renal parenchymal growth. In growth restricted fetuses the renal parenchymal thickness was found to be significantly less when compared to the parenchymal thickness of appropriately grown fetuses. Conclusions: Measurement of the renal parenchymal thickness is an innovative method to evaluate the development of the fetal kidneys. This new chart of fetal renal parenchymal thickness may be useful for the diagnosis of nephropathologies and the identification of infants at risk of kidney disease. Fetal growth restriction was found to adversely affect the renal parenchymal growth. This suggests growth restricted fetuses are born with fewer nephrons and are therefore likely to be more susceptible to hypertension and early onset kidney disease later in life

International Communications

Introduction: Disorders of fetal growth, such as intrauterine growth restriction (IUGR) and large for gestational age (LGA), have been found to have a profound effect on the development of the fetal kidney. Abnormal kidney development is associated with hypertension and chronic kidney disease later in life. This study will use a novel ultrasound measurement to assess the renal parenchymal growth and kidney arterial blood flow in the fetus to evaluate the development of the fetal kidneys and provide an indirect estimate of nephron number. Measurements in normally grown, IUGR and LGA fetuses will be compared to determine if changes in renal parenchymal growth can be detected in utero. Methods and analysis: This longitudinal, prospective, observational study will be conducted over 12 months in the Ultrasound Department of the Townsville Hospital, Australia. The study will compare fetal renal parenchymal thickness (RPT) and renal artery Doppler flow between IUGR fetuses and appropriately grown fetuses, and LGA fetuses and appropriately grown fetuses between 16 and 40 weeks. The fetal RPT to renal volume ratio will also be compared, and correlations between RPT, renal parenchymal echogenicity, fetal Doppler indices and amniotic fluid levels will be analysed. Ethics and dissemination: This study was approved by the Townsville Health District Human Research Ethics Committee. The study results will form part of a thesis and will be published in peer-reviewed journals and disseminated at international conferences

Instances and connectors : issues for a second generation process language

This work is supported by UK EPSRC grants GR/L34433 and GR/L32699Over the past decade a variety of process languages have been defined, used and evaluated. It is now possible to consider second generation languages based on this experience. Rather than develop a second generation wish list this position paper explores two issues: instances and connectors. Instances relate to the relationship between a process model as a description and the, possibly multiple, enacting instances which are created from it. Connectors refers to the issue of concurrency control and achieving a higher level of abstraction in how parts of a model interact. We believe that these issues are key to developing systems which can effectively support business processes, and that they have not received sufficient attention within the process modelling community. Through exploring these issues we also illustrate our approach to designing a second generation process language.Postprin

Comprehensive Analysis of 5-Aminolevulinic Acid Dehydrogenase (ALAD) Variants and Renal Cell Carcinoma Risk among Individuals Exposed to Lead

BACKGROUND: Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead. METHODS: The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: The adjusted risk associated with the ALAD variant rs8177796(CT/TT) was increased (OR = 1.35, 95%CI = 1.05-1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles ((GG)OR = 2.68, 95%CI = 1.17-6.12, p = 0.01; (GA)OR = 1.79, 95%CI = 1.06-3.04 with an interaction approaching significance (p(int) = 0.06). No significant modification in RCC risk was observed for the functional variant rs1800435(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results. CONCLUSION: A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure

Phenotypic Detection of Clonotypic B Cells in Multiple Myeloma by Specific Immunoglobulin Ligands Reveals their Rarity in Multiple Myeloma

In multiple myeloma, circulating “clonotypic” B cells, that express the immunoglobulin rearrangement of the malignant plasma cell clone, can be indirectly detected by PCR. Their role as potential “feeder” cells for the malignant plasma cell pool remains controversial. Here we established for the first time an approach that allows direct tracking of such clonotypic cells by labeling with patient-specific immunoglobulin ligands in 15 patients with myeloma. Fifty percent of patients showed evidence of clonotypic B cells in blood or bone marrow by PCR. Epitope-mimicking peptides from random libraries were selected on each patient's individual immunoglobulin and used as ligands to trace cells expressing the idiotypic immunoglobulin on their surface. We established a flow cytometry and immunofluorescence protocol to track clonotypic B cells and validated it in two independent monoclonal B cell systems. Using this method, we found clonotypic B cells in only one out of 15 myeloma patients. In view of the assay's validated sensitivity level of 10−3, this surprising data suggests that the abundance of such cells has been vastly overestimated in the past and that they apparently represent a very rare population in myeloma. Our novel tracing approach may open perspectives to isolate and analyze clonotypic B cells and determine their role in myeloma pathobiology

Regulation of the Escherichia coli HipBA Toxin-Antitoxin System by Proteolysis

Bacterial populations produce antibiotic-tolerant persister cells. A number of recent studies point to the involvement of toxin/antitoxin (TA) modules in persister formation. hipBA is a type II TA module that codes for the HipB antitoxin and the HipA toxin. HipA is an EF-Tu kinase, which causes protein synthesis inhibition and dormancy upon phosphorylation of its substrate. Antitoxins are labile proteins that are degraded by one of the cytosolic ATP-dependent proteases. We followed the rate of HipB degradation in different protease deficient strains and found that HipB was stabilized in a lon- background. These findings were confirmed in an in vitro degradation assay, showing that Lon is the main protease responsible for HipB proteolysis. Moreover, we demonstrated that degradation of HipB is dependent on the presence of an unstructured carboxy-terminal stretch of HipB that encompasses the last 16 amino acid residues. Further, substitution of the conserved carboxy-terminal tryptophan of HipB to alanine or even the complete removal of this 16 residue fragment did not alter the affinity of HipB for hipBA operator DNA or for HipA indicating that the major role of this region of HipB is to control HipB degradation and hence HipA-mediated persistence