The impact of chronic kidney disease Stages 3-5 on pregnancy outcomes.

BACKGROUND: Contemporaneous data are required for women with chronic kidney disease (CKD) Stages 3-5 to inform pre-pregnancy counselling and institute appropriate antenatal surveillance. METHODS: A retrospective cohort study in women with CKD Stages 3-5 after 20 weeks' gestation was undertaken in six UK tertiary renal centres in the UK between 2003 and 2017. Factors predicting adverse outcomes and the impact of pregnancy in accelerating the need for renal replacement therapy (RRT) were assessed. RESULTS: There were 178 pregnancies in 159 women, including 43 women with renal transplants. The live birth rate was 98%, but 56% of babies were born preterm (before 37 weeks' gestation). Chronic hypertension was the strongest predictor of delivery before 34 weeks' gestation. Of 121 women with known pre-pregnancy hypertension status, the incidence of delivery before 34 weeks was 32% (31/96) in women with confirmed chronic hypertension compared with 0% (0/25) in normotensive women. The risk of delivery before 34 weeks doubled in women with chronic hypertension from 20% [95% confidence interval (CI) 9-36%] to 40% (95% CI 26-56%) if the gestational fall in serum creatinine was <10% of pre-pregnancy concentrations. Women with a urinary protein:creatinine ratio >100 mg/mmol prior to pregnancy or before 20 weeks' gestation had an increased risk for birthweight below the 10th centile (odds ratio 2.57, 95% CI 1.20-5.53). There was a measurable drop in estimated glomerular filtration rate (eGFR) between pre-pregnancy and post-partum values (4.5 mL/min/1.73 m2), which was greater than the annual decline in eGFR prior to pregnancy (1.8 mL/min/1.73 m2/year). The effect of pregnancy was, therefore, equivalent to 1.7, 2.1 and 4.9 years of pre-pregnancy renal disease in CKD Stages 3a, 3b and 4-5, respectively. The pregnancy-associated decline in renal function was greater in women with chronic hypertension and in those with a gestational fall in serum creatinine of <10% of pre-pregnancy concentrations. At 1 year post-partum, 46% (58/126) of women had lost ≥25% of their pre-pregnancy eGFR or required RRT. Most women with renal transplants had CKD Stage 3 and more stable renal function prior to pregnancy. Renal transplantation was not independently associated with adverse obstetric or renal outcomes. CONCLUSIONS: Contemporary pregnancies in women with CKD Stages 3-5 are complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension, pre- or early pregnancy proteinuria and a gestational fall in serum creatinine of <10% of pre-pregnancy values are more important predictors of adverse obstetric and renal outcome than CKD Stages 3-5. Pregnancy in women with CKD Stages 3-5 advances the need for dialysis or transplantation by 2.5 years.

Remote post-mortem radiology reporting in disaster victim identification: experience gained in the 2017 Grenfell Tower disaster.

On 14 June 2017 at 00:54 h, the worst residential fire since the conclusion of the Second World War broke out in Flat 16, 4th floor of the 24-storey residential Grenfell Tower Block of flats, North Kensington, West London, UK. Seventy-one adults and children died, including one stillbirth. All victims of the Grenfell Tower disaster who died at the scene underwent post-mortem computed tomography (PMCT) imaging using a mortuary-sited mobile computed tomography scanner. For the first time, to the authors' knowledge, the disaster victim identification (DVI) radiology reporting was undertaken remote to the mortuary scanning. Over an 11-week period, 119 scans were undertaken on 16 days, with up to 18 scans a day. These were delivered to a remote reporting centre at Leicester on 13 days with between 2 and 20 scans arriving each day. Using a disaster-specific process pathway, a team of 4 reporters, with 3 support staff members, trialled a prototype INTERPOL DVI radiology reporting form and produced full radiology reports and supporting image datasets such that they were able to provide 96% of prototype DVI forms, 99% of image datasets and 86% of preliminary reports to the DVI teams in London within one working day of image receipt. This paper describes the first use of remote radiology reporting for DVI and exemplifies how remote PMCT reporting can be used to support a DVI process of this scale.

Pregnancy in chronic kidney disease and kidney transplantation.

Chronic kidney disease (CKD) affects up to 6% of women of childbearing age in high income countries, and is estimated to affect 3% of pregnant women. Advanced renal dysfunction, proteinuria, hypertension, and poorly controlled underlying primary renal disease are all significant risks for adverse maternal, fetal, and renal outcomes. In order to achieve the best outcomes, it is therefore of paramount importance that these pregnancies are planned, where possible, to allow the opportunity to counsel women and their partners in advance and to optimize these risks. These pregnancies should be deemed high risk and they require close antenatal monitoring from an expert multidisciplinary team. We discuss the effect of pregnancy on CKD, and also current guidelines and literature with specific reference to transplantation, autoimmune disease, and medication use in pregnancy. We also discuss the benefits of prepregnancy counseling and give practical recommendations to advise pregnant women with renal disease.

Diagnostic and predictive biomarkers for pre-eclampsia in patients with established hypertension and chronic kidney disease.

Women with chronic kidney disease (CKD) and chronic hypertension (CHT) frequently develop superimposed pre-eclampsia, but distinction from pre-existing disease is challenging. Plasma placental growth factor (PlGF), B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), and serum relaxin concentrations were quantified in a longitudinal prospective cohort of 121 women with CKD: 44 with chronic hypertension, and 79 healthy controls. Biomarker concentrations were compared with 32 women with pre-eclampsia without pre-existing disease. Test performance was evaluated for diagnosis of superimposed pre-eclampsia requiring delivery within 14 days of sampling. PlGF was evaluated as a promising marker in a validation cohort of women with suspected pre-eclampsia (29 with CKD; 94 with chronic hypertension; 29 with superimposed pre-eclampsia requiring delivery within 14 days) and compared with women without pre-existing disease (290 with no pre-eclampsia and 176 with pre-eclampsia requiring delivery within 14 days). From 20 and up to 42 weeks of gestation, lower maternal PlGF concentrations had high diagnostic accuracy for superimposed pre-eclampsia requiring delivery within 14 days (receiver operator characteristic 0.85) and confirmed in the validation cohort. The other plasma and serum biomarkers were not discriminatory. Thus, plasma PlGF concentrations could potentially help guide clinical decision making regarding admission and delivery for superimposed pre-eclampsia.

Malignancies confined to disused arteriovenous fistulae in renal transplant patients: an important differential diagnosis.

BACKGROUND: Swelling in an arteriovenous fistula (AVF) is commonly caused by thrombosis, aneurysm and infection. However, due to the increased risk of malignancy after transplantation, this should also be considered. PATIENTS: We discuss 4 patients with malignancy confined to an AVF after renal transplantation presenting in a 2-year period. Angiosarcoma was diagnosed in 3 patients and the other had post-transplant lymphoproliferative disorder (PTLD). Angiosarcoma behaves aggressively and 2 of our patients died within 6 months of diagnosis. There are 6 previous cases and 5 died within 16 months of diagnosis. PTLD at AVFs has not been documented previously. CONCLUSION: Malignancy at an AVF is a rare but important differential that can impact significantly on patient morbidity and mortality. Predilection for malignancy at an AVF is not understood. We review the literature and discuss possible aetiologies.

LUMI-PCR: an Illumina platform ligation-mediated PCR protocol for integration site cloning, provides molecular quantitation of integration sites.

BACKGROUND: Ligation-mediated PCR protocols have diverse uses including the identification of integration sites of insertional mutagens, integrating vectors and naturally occurring mobile genetic elements. For approaches that employ NGS sequencing, the relative abundance of integrations within a complex mixture is typically determined through the use of read counts or unique fragment lengths from a ligation of sheared DNA; however, these estimates may be skewed by PCR amplification biases and saturation of sequencing coverage. RESULTS: Here we describe a modification of our previous splinkerette based ligation-mediated PCR using a novel Illumina-compatible adapter design that prevents amplification of non-target DNA and incorporates unique molecular identifiers. This design reduces the number of PCR cycles required and improves relative quantitation of integration abundance for saturating sequencing coverage. By inverting the forked adapter strands from a standard orientation, the integration-genome junction can be sequenced without affecting the sequence diversity required for cluster generation on the flow cell. Replicate libraries of murine leukemia virus-infected spleen samples yielded highly reproducible quantitation of clonal integrations as well as a deep coverage of subclonal integrations. A dilution series of DNAs bearing integrations of MuLV or piggyBac transposon shows linearity of the quantitation over a range of concentrations. CONCLUSIONS: Merging ligation and library generation steps can reduce total PCR amplification cycles without sacrificing coverage or fidelity. The protocol is robust enough for use in a 96 well format using an automated liquid handler and we include programs for use of a Beckman Biomek liquid handling workstation. We also include an informatics pipeline that maps reads, builds integration contigs and quantitates integration abundance using both fragment lengths and unique molecular identifiers. Suggestions for optimizing the protocol to other target DNA sequences are included. The reproducible distinction of clonal and subclonal integration sites from each other allows for analysis of populations of cells undergoing selection, such as those found in insertional mutagenesis screens.

Author Correction: Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates.

The original version of this Article contained an error in the hyperlink for the online repository http://mulvdb.org which was incorrectly given as http://mulv.lms.mrc.ac.uk. This has been corrected in both the PDF and HTML versions of the Article.

Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates.

Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of murine leukemia virus-driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel statistical approaches for identifying selected mutations and yields a high-resolution, genome-wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening of two BCL2 transgenic models confirmed known drivers of human non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features independently of local variance in mutation density also provides support for weakly evidenced cancer genes. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.

A complicated multisystem flare of systemic lupus erythematosus during pregnancy.

We report a case of systemic lupus erythematosus (SLE) in a young woman who became pregnant amid a severe flare. She continued to have active disease in the face of aggressive treatments complicated by several side effects of immunosuppressive drugs including recurrent sepsis and gestational diabetes. Her fetus was at risk for congenital heart block during the second and third trimesters. Despite an extremely guarded prognosis, she delivered a healthy baby girl. This case highlights the complexities of SLE management during pregnancy. We discuss the therapeutic options available in pregnancy, and highlight the importance of cross-specialty multidisciplinary care in these women.

A Multicenter Cohort Study of Histologic Findings and Long-Term Outcomes of Kidney Disease in Women Who Have Been Pregnant.

BACKGROUND AND OBJECTIVES: For many women pregnancy is the first contact with health services, thus providing an opportunity to identify renal disease. This study compares causes and long-term renal outcomes of biopsy-proven renal disease identified during pregnancy or within 1 year postpartum, with nonpregnant women. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Native renal biopsies (1997-2012), in women of childbearing age (16 to <50 years), from 21 hospitals were studied. The pregnancy-related diagnosis group included those women with abnormal urinalysis/raised creatinine identified during pregnancy or within 1 year postpartum. Pregnancy-related and control biopsies were matched for age and ethnicity (black versus nonblack). RESULTS: One hundred and seventy-three pregnancy-related biopsies (19 antenatal, 154 postpregnancy) were identified and matched with 1000 controls. FSGS was more common in pregnancy-related biopsies (32.4%) than controls (9.7%) (P<0.001) but there were no differences in Columbia classification. Women with a pregnancy-related diagnosis were younger (32.1 versus 34.2 years; P=0.004) and more likely to be black (26.0% versus 13.3%; P<0.001) than controls, although there were no differences in ethnicities in women with FSGS. The pregnancy-related group (excluding antenatal biopsies) was more likely to have a decline in Chronic Kidney Disease Epidemiology Collaboration eGFR in the follow-up period than the control group (odds ratio, 1.67; 95% confidence interval, 1.03 to 2.71; P=0.04), and this decline appeared to be more rapid (-1.33 versus -0.56 ml/min per 1.73 m2 per year, respectively; P=0.045). However, there were no differences between groups in those who required RRT or who died. CONCLUSIONS: Pregnancy is an opportunity to detect kidney disease. FSGS is more common in women who have been pregnant than in controls, and disease identified in pregnancy or within 1 year postpartum is more likely to show a subsequent decline in renal function. Further work is required to determine whether pregnancy initiates, exacerbates, or reveals renal disease.

Characterizing the pH-dependent stability and catalytic mechanism of the family 11 xylanase from the alkalophilic Bacillus agaradhaerens.

The xylanase, BadX, from the alkalophilic Bacillus agaradhaerens was cloned, expressed and studied in comparison to a related family 11 xylanase, BcX, from B. circulans. Despite the alkaline versus neutral conditions under which these bacteria grow, BadX and BcX both exhibit optimal activity near pH 5.6 using the substrate o-nitrophenyl beta-xylobioside. Analysis of the bell-shaped activity profile of BadX yielded apparent pK(a) values of 4.2 and 7.1, assignable to its nucleophile Glu94 and general acid Glu184, respectively. In addition to having an approximately 10-fold higher k(cat)/K(m) value with this substrate at pH 6 and 40 degrees C, BadX has significantly higher thermal stability than BcX under neutral and alkaline conditions. This enhanced stability, rather than a shift in its pH-optimum, may allow BadX to hydrolyze xylan under conditions of elevated temperature and pH.

Fimag: the United Kingdom disaster victim/forensic identification imaging system.

Imaging is an integral diagnostic tool in mass fatality investigations undertaken traditionally by plain X-rays, fluoroscopy, and dental radiography. However, little attention has been given to appropriate image reporting, secure data transfer and storage particularly in relation to the need to meet stringent judicial requirements. Notwithstanding these limitations, it is the risk associated with the safe handling and investigation of contaminated fatalities which is providing new challenges for mass fatality radiological imaging. Mobile multi-slice computed tomography is an alternative to these traditional modalities as it provides a greater diagnostic yield and an opportunity to address the requirements of the criminal justice system. We present a new national disaster victim/forensic identification imaging system--Fimag--which is applicable for both contaminated and non-contaminated mass fatality imaging and addresses the issues of judicial reporting. We suggest this system opens a new era in radiological diagnostics for mass fatalities.