Determinants of Perinatal Outcomes in Dialyzed and Transplanted Women in Australia.

Introduction: Drivers of adverse perinatal outcomes in pregnancies of women receiving chronic kidney replacement therapy (KRT) remain poorly understood. Methods: Births ≥ 20 weeks of gestation in Australian women receiving KRT were analyzed for perinatal outcomes stratified by maternal KRT exposure (dialysis or transplant, analyzed separately), by linking the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and perinatal data sets (1991-2013). Results: Of 2,948,084 babies (1,628,181 mothers), 248 were born to mothers receiving KRT (transplant, n = 211; dialysis, n = 37), with live birth rates ≥ 94%. The perinatal death rate was 162, 62, and 9 per 1000 births in the dialysis, transplant, and non-KRT cohorts, respectively. Babies exposed to KRT had increased odds of prematurity, small-for-gestational age (SGA), poor birth condition, resuscitation, intensive care admission, and longer hospitalization, with the dialysis cohort having worse outcomes. Preterm babies of dialyzed and transplanted mothers (compared with preterm babies with no KRT exposure) experienced 1.6- to 2.7-fold higher odds for all adverse outcomes, except birthweight 10-fold higher odds of preterm birth and low birthweight and 1.8- to 4.6-fold increased odds of other adverse outcomes. In transplanted women, mediation analysis revealed that pregnancy-induced hypertension contributed only a modest proportional effect (2.5%-11.2%) on adverse outcomes. Conclusion: Maternal dialysis and transplantation conferred excess perinatal morbidity, particularly for preterm babies, and even in women with good preconception allograft function. Pregnancy-induced hypertension is not the predominant determinant of perinatal morbidity. Preconception counseling of women with kidney disease should encompass discussion of perinatal complications

Parenthood and pregnancy in Australians receiving treatment for end-stage kidney disease: protocol of a national study of perinatal and parental outcomes through population record linkage.

INTRODUCTION:Achieving parenthood is challenging in individuals receiving renal replacement therapy (RRT; dialysis or kidney transplantation) for end-stage kidney disease. Decision-making regarding parenthood in RRT recipients should be underpinned by robust data, yet there is limited data on parental factors that drive adverse health outcomes. Therefore, we aim to investigate the perinatal risks and outcomes in parents receiving RRT. METHODS AND ANALYSIS:This is a multijurisdictional probabilistic data linkage study of perinatal, hospital, birth, death and renal registers from 1991 to 2013 from New South Wales, Western Australia, South Australia and the Australian Capital Territory. This study includes all babies born ≥20 weeks' gestation or 400 g birth weight captured through mandated data collection in the perinatal data sets. Through linkage with the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, babies exposed to RRT (and their parents) will be compared with babies who have not been exposed to RRT (and their parents) to determine obstetric and fetal outcomes, birth rates and fertility rates. One of the novel aspects of this study is the method that will be used to link fathers receiving RRT to the mothers and their babies within the perinatal data sets, using the birth register, enabling the identification of family units. The linked data set will be used to validate the parenthood events directly reported to ANZDATA. ETHICS AND DISSEMINATION:Ethics approval was obtained from Human Research Ethics Committees (HREC) and Aboriginal HREC in each jurisdiction. Findings of this study will be disseminated at scientific conferences and in peer-reviewed journals in tabular and aggregated forms. De-identified data will be presented and individual patients will not be identified. We will aim to present findings to relevant stakeholders (eg, patients, clinicians and policymakers) to maximise translational impact of research findings

Parenthood With Kidney Failure: Answering Questions Patients Ask About Pregnancy

Achieving parenthood can be an important priority for women and men with kidney failure. In recent decades, the paradigm has shifted toward greater support of parenthood, with advances in our under- standing of risks related to pregnancy and improvements in obstetrical and perinatal care. This review, codesigned by people with personal experience of kidney disease, provides guidance for nephrologists on how to answer the questions most asked by patients when planning for parenthood. We focus on important issues that arise in preconception counseling for women receiving dialysis and postkidney transplant. We summarize recent studies reflecting pregnancy outcomes in the modern era of nephrology, obstetrical, and perinatal care in developed countries. We present visual aids to help clinicians and women navigate pregnancy planning and risk assessment. Key principles of pregnancy management are outlined. Finally, we explore outcomes of fatherhood in males with kidney failure.Shilpanjali Jesudason, Amber Williamson, Brooke Huuskes, and Erandi Hewawasa

Assessing whether early attention of very preterm infants can be improved by an omega-3 long-chain polyunsaturated fatty acid intervention: a follow-up of a randomised controlled trial

Introduction: Docosahexaenoic acid (DHA) accumulates in the frontal lobes (responsible for higher-order cognitive skills) of the fetal brain during the last trimester of pregnancy. Infants born preterm miss some of this in utero provision of DHA, and have an increased risk of suboptimal neurodevelopment. It is thought that supplementing infants born preterm with DHA may improve developmental outcomes. The aim of this follow-up is to determine whether DHA supplementation in infants born preterm can improve areas of the brain associated with frontal lobe function, namely attention and distractibility. Methods and analysis: We will assess a subset of children from the N-3 (omega-3) Fatty Acids for Improvement in Respiratory Outcomes (N3RO) multicentre double-blind randomised controlled trial of DHA supplementation. Infants born <29 weeks’ completed gestation were randomised to receive an enteral emulsion containing 60 mg/kg/day of DHA or a control emulsion from within the first 3 days of enteral feeding until 36 weeks’ postmenstrual age. Children will undergo multiple measures of attention at 18 months’ corrected age. The primary outcome is the average time to be distracted when attention is focused on a toy. Secondary outcomes are other aspects of attention, and (where possible) an assessment of cognition, language and motor development with the Bayley Scales of Infant and Toddler Development, Third Edition. A minimum of 72 children will be assessed to ensure 85% power to detect an effect on the primary outcome. Families, and research personnel are blinded to group assignment. All analyses will be conducted according to the intention-to-treat principal. Ethics and dissemination: All procedures were approved by the relevant institutional ethics committees prior to commencement of the study. Results will be disseminated in peer-reviewed journal publications and academic presentations. Trial registration number: ACTRN12612000503820; Pre-results.Jacqueline F Gould, John Colombo, Carmel T Collins, Maria Makrides, Erandi Hewawasam, Lisa G Smither

Parenthood and pregnancy in Australians receiving treatment for end-stage kidney disease: protocol of a national study of perinatal and parental outcomes through population record linkage.

Introduction Achieving parenthood is challenging in individuals receiving renal replacement therapy (RRT; dialysis or kidney transplantation) for end-stage kidney disease. Decision-making regarding parenthood in RRT recipients should be underpinned by robust data, yet there is limited data on parental factors that drive adverse health outcomes. Therefore, we aim to investigate the perinatal risks and outcomes in parents receiving RRT. Methods and analysis This is a multijurisdictional probabilistic data linkage study of perinatal, hospital, birth, death and renal registers from 1991 to 2013 from New South Wales, Western Australia, South Australia and the Australian Capital Territory. This study includes all babies born ≥20 weeks’ gestation or 400 g birth weight captured through mandated data collection in the perinatal data sets. Through linkage with the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, babies exposed to RRT (and their parents) will be compared with babies who have not been exposed to RRT (and their parents) to determine obstetric and fetal outcomes, birth rates and fertility rates. One of the novel aspects of this study is the method that will be used to link fathers receiving RRT to the mothers and their babies within the perinatal data sets, using the birth register, enabling the identification of family units. The linked data set will be used to validate the parenthood events directly reported to ANZDATA. Ethics and dissemination Ethics approval was obtained from Human Research Ethics Committees (HREC) and Aboriginal HREC in each jurisdiction. Findings of this study will be disseminated at scientific conferences and in peer-reviewed journals in tabular and aggregated forms. De-identified data will be presented and individual patients will not be identified. We will aim to present findings to relevant stakeholders (eg, patients, clinicians and policymakers) to maximise translational impact of research findings.Erandi Hewawasam, Aarti Gulyani, Christopher E Davies, Elizabeth Sullivan, Sally Wark, Philip A Clayton, Stephen P McDonald, Shilpanjali Jesudaso

Misregulation of Scm3p/HJURP Causes Chromosome Instability in Saccharomyces cerevisiae and Human Cells

The kinetochore (centromeric DNA and associated proteins) is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of HJURP, the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed SCM3 and HJURP in Saccharomyces cerevisiae and HJURP in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of SCM3 (GALSCM3) or HJURP (GALHJURP) caused chromosome loss in a wild-type yeast strain, and overexpression of HJURP led to mitotic defects in human cells. GALSCM3 resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of CSE4 or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in GALSCM3 strains. Using mutant alleles of scm3, we identified a domain in the N-terminus of Scm3p that mediates its interaction with CEN DNA and determined that the chromosome loss phenotype of GALSCM3 is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of HJURP and SCM3 expression are critical for genome stability

Stressful situation if CENP-A not front and CENter

The exclusive localization of the histone H3 variant CENP-A to centromeres is essential for accurate chromosome segregation. Ubiquitin-mediated proteolysis helps to ensure that CENP-A does not mislocalize to euchromatin, which can lead to genomic instability. Consistent with this, overexpression of the budding yeast CENP-A(Cse4) is lethal in cells lacking Psh1, the E3 ubiquitin ligase that targets CENP-A(Cse4) for degradation. To identify additional mechanisms that prevent CENP-A(Cse4) misincorporation and lethality, we analyzed the genome-wide mislocalization pattern of overexpressed CENP-A(Cse4) in the presence and absence of Psh1 by chromatin immunoprecipitation followed by high throughput sequencing. We found that ectopic CENP-A(Cse4) is enriched at promoters that contain histone H2A.Z(Htz1) nucleosomes, but that H2A.Z(Htz1) is not required for CENP-A(Cse4) mislocalization. Instead, the INO80 complex, which removes H2A.Z(Htz1) from nucleosomes, promotes the ectopic deposition of CENP-A(Cse4). Transcriptional profiling revealed gene expression changes in the psh1Δ cells overexpressing CENP-A(Cse4). The down-regulated genes are enriched for CENP-A(Cse4) mislocalization to promoters, while the up-regulated genes correlate with those that are also transcriptionally up-regulated in an htz1Δ strain. Together, these data show that regulating centromeric nucleosome localization is not only critical for maintaining centromere function, but also for ensuring accurate promoter function and transcriptional regulation

A validated method for analyzing polyunsaturated free fatty acids from dried blood spots using LC–MS/MS

Omega-3 and omega-6 polyunsaturated free fatty acids (PUFA-FFA) are precursors to potent downstream lipid mediators that are regulators of inflammation. We describe the development and validation of a novel and sensitive method for quantification of individual PUFA-FFA in a dried blood spot using liquid chromatography tandem mass spectrometry (LC-MS/MS). Lipids were extracted from dried blood spot and six individual PUFA-FFA were quantified by LC-MS/MS using stable isotope dilution analysis with deuterated internal standards. PUFA-FFA concentrations in blood samples from 30 subjects were measured using the new method and compared to the traditional approach of thin layer chromatography followed by gas chromatography with flame ionization detection (TLC-GC). Responses for each PUFA-FFA were linear throughout a range of concentrations expected in clinical samples. Intra-day and inter-day variations for all PUFA-FFA were ≤ 16%. The concentrations of all PUFA-FFA measured by LC-MS/MS were positively correlated with measures of the same PUFA-FFA obtained by a traditional TLC-GC method. This novel method for the quantification of PUFA-FFA extracted from dried blood is sensitive and precise, and accurately measures levels of biologically important PUFA-FFA in blood.Erandi Hewawasam, Ge Liu, David W. Jeffery, Beverly S. Muhlhausler, Robert A. Gibso