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Background We carried out a study to determine the impact of prematurity on kidney development in the first 2 years of life. Methods In this prospective study, extremely preterm neonates (gestation Results Fifty-three premature and 31 term neonates (control) were recruited. At the age of 24 months (corrected age), infants born preterm had significantly smaller TKV (56.1 (9.4) vs. 64.8 (10.2) mL; P = 0.006). There was no difference in eGFR. These preterm infants were smaller (11.25 (1.53) vs. 12.9 (1.8) kg; P = 0.002) and shorter (83.8 (3.0) vs. 86.3 (3.4) cm; P = 0.02) when compared with the control group. At 6, 12, and 18 months respectively, preterm infants had, relative to their height, significantly smaller kidney volumes (0.54 (0.1) vs. 0.59 (0.1) mL/cm, P = 0.05; 0.61 (0.1) vs.0.71 (0.1) mL/cm, P = 0.003; and 0.67 (0.1) vs.0.76 (0.1) mL/cm, P = 0.006). Conclusions Relative to body length, TKV in premature infants is smaller. Since length reflects adult body proportions more accurately than BSA, TKV to height ratio may be a more important measure in the child. Despite smaller TKV (and therefore fewer nephrons), infants born prematurely achieve similar eGFRs in the first 24 months of life, probably due to single-nephron hyperfiltration.

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Suboptimal nutrition during pregnancy is recognised as a significant modifiable determinant in the development of chronic disease in offspring in later life. The current study aimed: (i) to assess the dietary intakes of pregnant Indigenous Australian women against national recommendations and (ii) to investigate the associations between maternal nutrition during pregnancy and the growth of the offspring, including kidney development in late gestation in the Gomeroi gaaynggal cohort (n = 103). Maternal dietary intake in the third trimester was assessed using the Australian Eating Survey Food Frequency Questionnaire. Estimated fetal weight (EFW) and kidney size were obtained by ultrasound. Birth weight was retrieved from hospital birth records. Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving the nutrient reference values (NRVs) were zinc (75.7%) and folate (57.3%), whereas iron was the lowest. Only four people achieved all NRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. Sodium and saturated fat intake exceeded recommended levels and diet quality was low, with a median score of 28 out of 73 points. After adjusting for smoking and pre-pregnancy body mass index, only maternal intake of retinol equivalents and the proportion of energy from nutrient-dense or energy-dense, nutrient-poor (EDNP) foods were associated with fetal growth. EFW decreased by 0.13 g and birth weight decreased by 0.24 g for every µg increase in maternal dietary retinol intake. Interestingly, EFW, but not actual birth weight, was positively associated with percentage energy from nutrient dense foods and negatively associated with percentage energy from EDNP foods. Dietary supplement usage was associated with increased birthweight, most significantly iron and folate supplementation. Current dietary intakes of pregnant Australian women from this cohort do not align with national guidelines. Furthermore, current findings show that maternal retinol intake and diet composition during pregnancy can influence fetal growth, but not fetal kidney growth in late gestation. Strategies that aim to support and optimise nutrient intakes of Indigenous pregnant women are urgently needed. Future studies with long-term follow-up of the children in the current cohort to assess renal damage and blood pressure are imperative.

The (pro)renin receptor ((P)RR) is a multi-functional protein that can be proteolytically cleaved and released in a soluble form (s(P)RR). Recently, the (P)RR and s(P)RR have become of interest in pregnancy and its associated pathologies. This is because the (P)RR not only activates tissue renin angiotensin systems, but it is also an integral component of vacuolar-ATPase, activates the wingless/integrated (Wnt)/β-catenin and extracellular signal regulated kinases 1 and 2/mitogen-activated protein kinase signalling pathways, and stabilises the β subunit of pyruvate dehydrogenase. Additionally, s(P)RR is detected in plasma and urine, and maternal plasma levels are elevated in pregnancy complications including fetal growth restriction, preeclampsia and gestational diabetes mellitus. Therefore, s(P)RR has potential as a biomarker for these pregnancy pathologies. Preliminary functional findings suggest that s(P)RR may be important for regulating fluid balance, inflammation and blood pressure, all of which contribute to a successful pregnancy. The (P)RR and s(P)RR regulate pathways that are known to be important in maintaining pregnancy, however their role in the physiological context of pregnancy is poorly characterised. This review summarises the known and potential functions of the (P)RR and s(P)RR in pregnancy, and how their dysregulation may contribute to pregnancy complications. It also highlights the need for further research into the source and function of s(P)RR in pregnancy. Soluble (P)RR levels could be indicative of placental, kidney or liver dysfunction and therefore be a novel clinical biomarker, or therapeutic target, to improve the detection and treatment of pregnancy pathologies.

Introduction An imbalance in angiotensin (Ang) peptides could contribute to the pathophysiology of preeclampsia (PE) and poor fetal growth. Methods We measured maternal plasma levels of Ang peptides and converting enzymes in non-pregnant women (n = 10), in normal pregnant women (n = 59), women delivering small for gestational age babies (SGA, n = 25) across gestation (13-36 weeks) and in women with PE (n = 14) in their third trimester. Results Plasma ACE, ACE2, and Ang-(1-7) levels, and ACE2 activity were significantly higher in normal pregnant women compared with non-pregnant women; neprilysin (NEP) levels were not changed. In SGA pregnancies, ACE and ACE2 levels were higher in early-mid pregnancy compared with normal pregnant women. In women with PE, plasma ACE, ACE2, NEP, and Ang-(1-7) levels and ACE2 activity were lower than levels in normal pregnant women. Conclusion The higher plasma ACE2 levels and activity in pregnancy could be driving the higher Ang-(1-7) levels. The early gestation increases in ACE and ACE2 levels in SGA pregnancies highlights the possibility that these enzymes could be used as potential early biomarkers of poor fetal growth. In women with PE, the reduced ACE2 and NEP levels at term, could be contributing to the reduction in Ang-(1-7) levels. These findings suggest that dysfunctional relationships between two key enzymes in the circulating RAS are involved in the pathogenesis of PE and SGA. Since soluble ACE2 can prevent binding of the novel coronavirus, SARS-CoV-2, to membrane bound ACE2, the interplay between ACE2 and the coronavirus and its impact in pregnancy requires further investigation.

Angiotensin-converting enzyme 2 (ACE2) is the receptor for COVID-19 (SARs-CoV-2). ACE2 protects the lung and heart from acute respiratory distress syndrome (ARDS) and acute myocarditis and arrhythmias, because it breaks down Angiotensin II, which has inflammatory effects in the lung and heart as well as in the kidney. When SARS-CoV-2 binds to ACE2, it suppresses it, so this protective action of ACE2 is lost. Death from COVID-19 is due to ARDS and also heart failure and acute cardiac injury. Drugs that prevent the inflammatory actions of Angiotensin II (i.e., Angiotensin receptor blockers, ARBs) prevent acute lung injury caused by SARS-CoV. Clinical trials are underway to test the risks and benefits of ARBs and angiotensin-converting enzyme inhibitors (ACEIs) in COVID-19 patients requiring hospitalization. Other potential treatments are also discussed.

Chronic kidney disease (CKD) can have an insidious onset because there is a gradual decline in nephron number throughout life. There may be no overt symptoms of renal dysfunction until about two thirds or more of the nephrons have been destroyed and glomerular filtration rate (GFR) falls to below 25% of normal (often in mid-late life) (Martinez-Maldonaldo et al., 1992). Once End Stage Renal Disease (ESRD) has been reached, survival depends on renal replacement therapy (RRT). CKD causes hypertension and cardiovascular disease; and hypertension causes CKD. Albuminuria is also a risk factor for cardiovascular disease. The age of onset of CKD is partly determined during fetal life. This review describes the mechanisms underlying the development of CKD in adult life that results from abnormal renal development caused by an adverse intrauterine environment. The basis of this form of CKD is thought to be mainly due to a reduction in the number of nephrons formed in utero which impacts on the age dependent decline in glomerular function. Factors that affect the risk of reduced nephron formation during intrauterine life are discussed and include maternal nutrition (malnutrition and obesity, micronutrients), smoking and alcohol, use of drugs that block the maternal renin-angiotensin system, glucocorticoid excess and maternal renal dysfunction and prematurity. Since CKD, hypertension and cardiovascular disease add to the disease burden in the community we recommend that kidney size at birth should be recorded using ultrasound and those individuals who are born premature or who have small kidneys at this time should be monitored regularly by determining GFR and albumin:creatinine clearance ratio. Furthermore, public health measures aimed at limiting the prevalence of obesity and diabetes mellitus as well as providing advice on limiting the amount of protein ingested during a single meal, because they are all associated with increased glomerular hyperfiltration and subsequent glomerulosclerosis would be beneficial.

KEY POINTS Preterm infants often have poor cardiovascular function that is associated with adverse neurodevelopmental outcomes. Preterm infants may be vulnerable to hypovolaemia due to excessive vasodilatation and leaky capillaries. Following reduction in blood volume, cardiac output and mean arterial pressure were reduced to the same extent in term and preterm piglets. Cerebral blood flow was maintained following blood volume reduction in term but not in preterm piglets. Effective detection and treatment of functional hypovolaemia may reduce the risk of brain injury in preterm infants. ABSTRACT Preterm infants often have impaired cardiovascular function that may contribute to poor neurodevelopmental outcomes. The study aimed to determine the effects of reduced blood volume on cardiovascular function, including cerebral blood flow, in preterm and term piglets. In preterm (97/115 days) and term piglets, up to 10% of the estimated blood volume was removed. Removal of blood was stopped if MAP dropped below 20 mmHg. Heart rate, cardiac contractility and relaxation, cardiac output, mean arterial pressure (MAP), and cerebral blood flow were measured at baseline and again after blood volume reduction. The volume of blood removed was less in preterm piglets than in term piglets (5.1 ± 1.8 vs. 7.7 ± 0.9 mL kg-1 , mean ± SD, P

The intrarenal renin-angiotensin system (iRAS) is implicated in the pathogenesis of hypertension, chronic kidney disease and diabetic nephropathy. Urinary angiotensinogen (uAGT) levels reflect the activity of the iRAS and are altered in women with preeclampsia. Since Indigenous Australians suffer high rates and early onset of renal disease, we hypothesised that Indigenous Australian pregnant women, like non-Indigenous women with pregnancy complications, would have altered uAGT levels. The excretion of RAS proteins was measured in non-Indigenous and Indigenous Australian women with uncomplicated or complicated pregnancies (preeclampsia, diabetes/gestational diabetes, proteinuria/albuminuria, hypertension, small/large for gestational age, preterm birth), and in non-pregnant non-Indigenous women.Non-Indigenous pregnant women with uncomplicated pregnancies, had higher uAGT/creatinine levels than non-Indigenous non-pregnant women (P < 0.01), and levels increased as pregnancy progressed (P < 0.001). In non-Indigenous pregnant women with pregnancy complications, uAGT/creatinine was suppressed in the third trimester (P < 0.01). In Indigenous pregnant women with uncomplicated pregnancies, there was no change in uAGT/creatinine with gestational age and uAGT/creatinine was lower in the 2nd and 3rd trimesters than in nonIndigenous pregnant women with uncomplicated pregnancies (P < 0.03, P < 0.007, respectively). The uAGT/creatinine ratios of Indigenous women with uncomplicated or complicated pregnancies were the same.A decrease in uAGT/creatinine with advancing gestational age was associated with increased urinary albumin/creatinine, as is seen in preeclampsia, but it was not specific for this disorder. The reduced uAGT/creatinine in Indigenous pregnant women may reflect subclinical renal dysfunction which limits the ability of the kidney to maintain sodium balance and could indicate an increased risk of pregnancy complications and/or future renal disease.

No other physiological state is characterized by such high levels of renin, angiotensinogen, angiotensin II and aldosterone as occurs in pregnancy. Increased activity of the circulating renin-angiotensin-aldosterone system (cRAAS) and possibly the intrarenal renin-angiotensin system (RAS) counteract the effects of pregnancy on maternal cardiovascular and renal function caused by ovarian hormones. Of particular importance is the early activation of the cRAAS by estrogen-stimulated production of angiotensinogen, freeing it from feedback control of active renin release. This leads to increased salt and water retention that fills the maternal cardiovascular system, which is expanding under the influence of relaxin and other factors. The ovarian RAS plays key roles in ovulation and steroidogenesis. Placental and decidual RASs may play important roles in placentation and in regulating the timing of parturition. Thus, increased activity of tissue and circulating renin-angiotensin systems in pregnancy and their coordinated control are required to maintain pregnancy and ensure a healthy outcome.

Maternal obesity during pregnancy has a detrimental impact on offspring renal development and function. This is pertinent to Indigenous Australians as they are twice as likely as non‐Indigenous Australians to develop chronic kidney disease (CKD). The aim of this study was to examine whether there was an association between maternal adiposity and fetal kidney growth in late gestation (>28 weeks) and kidney function in infants, 28 weeks gestation by bioelectrical impedance analysis. Fetal kidney structure was assessed by ultrasound. Renal function indicators (urinary albumin:creatinine and protein:creatinine) were measured in infants from a spot urine collection from nappies. Multiple linear regression and multi‐level mixed effects linear regression models with clustering were used to account for repeated measures of urine. 147 mother–child pairs were examined. Estimated fetal weight (EFW), but not fetal kidney size, was positively associated with maternal adiposity and pre‐pregnancy BMI. When adjusted for smoking, combined kidney volume relative to EFW was negatively associated with maternal percentage body fat. Infant kidney function was not influenced by maternal adiposity and pre‐pregnancy BMI (n = 84 observations). Current findings show that Indigenous babies born to obese mothers have reduced kidney size relative to EFW. We suggest that these babies are experiencing a degree of glomerular hyperfiltration in utero, and therefore are at risk of developing CKD in later life, especially if their propensity for obesity is maintained. Although no impact on renal function was observed at

The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 µg/kg/h), and high (20 µg/kg/h) dose infusions. At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope. In order to provide better cardiovascular support, it may be necessary to develop treatments that target receptors with a more mature profile than adrenoceptors in the preterm newborn.

Endometrial cancer (EC) is the most common gynaecological malignancy and its incidence is increasing. Dysregulation of the endometrial renin–angiotensin system (RAS) could predispose to EC; therefore, we studied the prevalence of RAS single nucleotide polymorphisms (SNPs) in Australian women with EC. SNPs assessed were AGT M235T (rs699); AGTR1 A1166C (rs5186); ACE A240T and T93C (rs4291, rs4292) and ATP6AP2 (rs2968915). They were identified using TaqMan SNP Genotyping Assays. The C allele of the AGTR1 SNP (rs5186) was more prevalent in women with EC (odds ratio (OR) 1.7, 95% confidence interval (CI) (1.2–2.3), P=0.002). The CC genotype of this SNP is associated with upregulation of the angiotensin II type 1 receptor (AGTR1). The G allele of AGT rs699, which is associated with higher angiotensinogen (AGT) levels, was less prevalent in women with EC (OR 0.54, 95% CI (0.39–0.74), PAGTR1 SNP (rs5186) and the ACE SNPs (rs4291 and rs4292) was greater than in women who had no record of HRT; SNP rs4291 is associated with increased plasma ACE activity. These data suggest there is an interaction between genotype, oestrogen replacement therapy and EC. In conclusion, the prevalence of two SNPs that enhance RAS activity was different in women with EC compared with healthy controls. These genetic factors may interact with obesity and hyperoestrogenism, predisposing ageing, obese women to EC.

Background: Male circumcision (MC) is proven to substantially reduce men's risk of a number of sexually transmitted infections (STIs). We conducted a detailed systematic review of the scientific literature to determine the relationship between MC and risk of STIs and associated conditions in women. Methods: Database searches by "circumcision women" and "circumcision female" identified 68 relevant articles for inclusion. Examination of bibliographies of these yielded 14 further publications. Each was rated for quality using a conventional rating system. Results: Evaluation of the data from the studies retrieved showed that MC is associated with a reduced risk in women of being infected by oncogenic human papillomavirus (HPV) genotypes and of contracting cervical cancer. Data from randomized controlled trials and other studies has confirmed that partner MC reduces women's risk not only of oncogenic HPV, but as well Trichomonas vaginalis, bacterial vaginosis and possibly genital ulcer disease. For herpes simplex virus type 2, Chlamydia trachomatis, Treponema pallidum, human immunodeficiency virus and candidiasis, the evidence is mixed. Male partner MC did not reduce risk of gonorrhea, Mycoplasma genitalium, dysuria or vaginal discharge in women. Conclusion: MC reduces risk of oncogenic HPV genotypes, cervical cancer, T. vaginalis, bacterial vaginosis and possibly genital ulcer disease in women. The reduction in risk of these STIs and cervical cancer adds to the data supporting global efforts to deploy MC as a health-promoting and life-saving public health measure and supplements other STI prevention strategies.

Adverse pregnancy outcomes including prematurity and low birth weight (LBW) have been associated with life-long chronic disease risk for the infant. Stress during pregnancy increases the risk of adverse pregnancy outcomes. Many studies have reported the incidence of adverse pregnancy outcomes in Indigenous populations and a smaller number of studies have measured rates of stress and depression in these populations. This study sought to examine the potential association between stress during pregnancy and the rate of adverse pregnancy outcomes in Australian Indigenous women residing in rural and remote communities in New South Wales. This study found a higher rate of post-traumatic stress disorder, depression and anxiety symptoms during pregnancy than the general population. There was also a higher incidence of prematurity and LBW deliveries. Unfortunately, missing post-traumatic stress disorder and depressive symptomatology data impeded the examination of associations of interest. This was largely due to the highly sensitive nature of the issues under investigation, and the need to ensure adequate levels of trust between Indigenous women and research staff before disclosure and recording of sensitive research data. We were unable to demonstrate a significant association between the level of stress and the incidence of adverse pregnancy outcomes at this stage. We recommend this longitudinal study continue until complete data sets are available. Future research in this area should ensure prioritization of building trust in participants and overestimating sample size to ensure no undue pressure is placed upon an already stressed participant.

Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother–child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight (P=0.005) and GROW customized birth weight centiles (P=0.008). There was a significant association between maternal percentage body fat (P=0.02) and visceral fat area (P=0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term (P=0.03). GROW customized birth weight centiles was significantly associated with body weight (P=0.01), BMI (P=0.007) and abdominal circumference (P=0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women.

Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. This study examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P < 0.0001). In non-Indigenous Australians, the A allele at position 204 of ACE rs4291 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (as shown in a previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. These studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines.

Objectives:The newborn circulating, cardiac and renal renin–angiotensin systems (RASs) are essential for blood pressure control, and for cardiac and renal development. If cardiac and renal RASs are immature this may contribute to cardiovascular compromise in preterm infants. This study measured mRNA expression of cardiac and renal RAS components in preterm, glucocorticoid (GC) exposed preterm, and term piglets.Methods:Renal and cardiac RAS mRNA levels were measured using real-time polymerase chain reaction (PCR). Genes studied were: (pro)renin receptor, renin, angiotensinogen, angiotensin converting enzyme (ACE), ACE2, angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptor (AT2R).Results:All the genes studied were expressed in the kidney; neither renin nor AT2R mRNA were detected in the heart. There were no gestational changes in (pro)renin receptor, renin, ACE or AT1R mRNA levels. Right ventricular angiotensinogen mRNA levels in females were lower in preterm animals than at term, and GC exposure increased levels in male piglets. Renal angiotensinogen mRNA levels in female term piglets were lower than females from both preterm groups, and lower than male term piglets. Left ventricular ACE2 mRNA expression was lower in GC treated preterm piglets. Renal AT2R mRNA abundance was highest in GC treated preterm piglets, and the AT1R/AT2R ratio was increased at term.Conclusions:Preterm cardiac and renal RAS mRNA levels were similar to term piglets, suggesting that immaturity of these RASs does not contribute to preterm cardiovascular compromise. Since preterm expression of both renal and cardiac angiotensin II-AT1R is similar to term animals, cardiovascular dysfunction in the sick preterm human neonate might be effectively treated by agents acting on their RASs.

Uterine arteries from pregnant animals are one of only a few adult blood vessels which express predominantly AT2 receptors. Fetal systemic arteries also contain a high density of AT2 receptors. To assess whether fetal systemic arteries, like uterine arteries from pregnant animals, were relatively insensitive to angiotensin II (Ang II), we compared the contractile responses of fetal carotid arteries, as well as the receptor binding properties of fetal aortae, with those of uterine arteries from pregnant ewes. Ang II receptor binding properties were measured in arterial membrane preparations using 125I [Sar1Ile8] Ang II. Proportions of AT1 and AT2 receptors were determined by inhibiting 125I [Sar1Ile8] Ang II with losartan (AT1 antagonist) or PD 123319 (AT2 antagonist). Both fetal aortae and uterine arteries contained predominantly AT2 receptors. However, the AT2 receptor in fetal aortae had a higher affinity than that of the AT2 receptor in uterine arteries (P

Introduction: Indigenous Australians experience higher rates of renal disease and hypertension than non-Indigenous Australians. Low birth weight is recognized as a contributing factor in chronic disease and has been shown to increase the risk of renal failure in adulthood. A smaller kidney volume with fewer nephrons places an individual at risk of hypertension and renal failure. Indigenous Australians have fewer nephrons than non-Indigenous Australians. In this study, intrauterine fetal and kidney growth were evaluated in 174 Indigenous Australian babies throughout gestation in order to record and evaluate fetal growth and kidney size, within a population that is at high risk for chronic illness.Methods: Pregnant women that identified as Indigenous, or non-Indigenous women that were pregnant with a partner who identified as an Indigenous Australian were eligible to participate. Maternal history, smoking status, blood and urine samples and fetal ultrasounds were collected throughout pregnancy. Fetal kidney measurements were collected using ultrasound. Statistical analysis was performed using the Stata 14.1 software package.Results: 15.2% of babies were born prematurely. 44% of the mothers reported smoking in pregnancy. The median birth weight of this cohort was 3,240 g. Male fetuses had higher kidney to body weight ratios than female fetuses (P = 0.02). The birth weights of term neonates whose mothers smoked during pregnancy were lower (327 g, P < 0.001) than the birth weights of term babies from non-smoking mothers. The kidney volumes of babies whose mothers smoked were also smaller (P = 0.02), but were in proportion to body weight.Conclusion: In this cohort of Indigenous women smoking was associated with both increased number of preterm births and with a reduction in birth weights, even of term infants. Since kidney volume is a surrogate measure of nephron number and nephrogenesis is complete at birth, babies whose mothers smoked during pregnancy must have fewer nephrons than those from non-smoking mothers. Previous studies have shown that glomerular filtration rate is not related to birth weight, thus infants with smaller kidney volumes are hyperfiltering from birth and therefore are likely to be more susceptible to early onset renal disease in later life.

Objective We carried out a study to determine the impact of prematurity on renal development. The primary outcomes measured were nephrinuria and albuminuria; renal volume and glomerular filtration rate were the secondary outcomes. Methods Preterm neonates born at less than 28 weeks of gestation, with birth weight between 10th and 90th centile (appropriate for gestational age), were recruited and underwent assessments at 28, 32 and 37 weeks postmenstrual age (PMA). Results Fifty-three premature neonates and 31 term neonates (control) were recruited. The median gestational age of the premature neonates was 26.4 [24.7–27.4] weeks, with a mean birth weight of 886 (179) g. The mean gestational age of term neonates was 39.1 (1.2) weeks and the mean birth weight was 3406 (406) g. The median age of the term neonates was 6.5 [3.0–12.5] days. The total kidney volume (TKV) almost doubled from 10.3 (2.9) cm3 at 28 weeks PMA to 19.2 (3.7) cm3 at 37 weeks PMA (P = 0.0001). TKV at 37 weeks PMA was significantly smaller compared to term neonates (19.2 (3.7) vs 26.3 (7.0) cm3; P = 0.0001). However, there was no significant difference in estimated glomerular filtration rate (eGFR) between premature neonates (at 37 weeks PMA) and term neonates (control) (43.5 [39.7–48.9] vs. 42.0 [38.2–50.0] mL/min/1.73 m2; P = 0.75). There was a statistically significant decline in nephrin-creatinine ratio and albumin-creatinine ratio from 32 to 37 weeks PMA. Conclusions Despite having a smaller renal volume (and fewer nephrons), extremely premature neonates achieve similar eGFRs at corrected term as term-born neonates, likely through single nephron hyperfiltration. Extremely premature neonates also show evidence of glomerular injury.

Background Nephron number in humans is determined during fetal life. The objective of this study was to investigate the effects of preterm birth on nephron number using renal volume as a surrogate for nephron number. Methods This observational study was conducted over 12 months in a tertiary perinatal center. Preterm babies less than 32 weeks of gestation were recruited and followed until discharge. Term infants were recruited for comparison. The babies underwent renal sonography and renal function measurements at 32 and 38 weeks corrected age. The primary outcome measurement was total kidney volume at 38 weeks and the secondary outcome was estimated glomerular filtration rate (eGFR). Results Forty-four preterm infants and 24 term infants were recruited. At 38 weeks corrected age, premature infants had lower total kidney volume than term infants (21.6 ± 5.7 vs. 25.2 ± 5.7 ml; p = 0.02) and a significantly lower eGFR (73.6 [IQR 68.1–77.6] vs. 79.3 [IQR 72.5–86.6] ml·min−1·1.73 m−2; p = 0.03). There was a significant correlation between total kidney volume and eGFR in premature and term babies. Conclusions Premature infants have smaller kidney volume and likely decreased nephron number and lower estimated glomerulofiltration rate relative to infants born at term.

Hypothesis: There are fetal sex-associated differences in the circulating maternal renin–angiotensin system (RAS) in early pregnancy. Methods: Plasma prorenin, angiotensin (Ang) II, Ang 1-7 and angiotensin-converting enzyme (ACE) concentrations were measured at 15 weeks’ gestation in 131 women with uncomplicated pregnancies from the Adelaide SCOPE cohort. Uterine and umbilical artery Doppler sonography was performed at 20 weeks’ gestation. Results: At 15 weeks, women bearing female fetuses had higher maternal Ang II concentrations ( p = 0.017 ) and lower Ang 1-7 to Ang II ratios ( p = 0.016 ) than women bearing males. In women with male fetuses, Ang II positively correlated with birth weight ( p = 0.028 ) and prorenin negatively correlated with placental weight ( p = 0.014 ). Female fetuses had higher umbilical artery resistance indices ( p = 0.019 ) that were related to maternal prorenin concentrations ( p = 0.007 ). Conclusions: In early human pregnancy, the maternal RAS is influenced by fetal sex. The lower Ang 1-7 to Ang II ratios in women with female fetuses may contribute to the lower maternal peripheral microvascular flow as described previously and the lack of any positive effect of Ang II on fetal growth, as seen in women with male fetuses.

A dysfunctional endometrial renin–angiotensin system (RAS) could aid the growth and spread of endometrial cancer. To determine if the RAS is altered in endometrial cancer, we measured RAS gene expression and protein levels in 30 human formalin-fixed, paraffin-embedded (FFPE) endometrioid carcinomas and their adjacent endometrium. All components of the RAS were expressed in most tumours and in adjacent endometrium; mRNA levels of (pro)renin receptor (ATP6AP2), angiotensin II type 1 receptor (AGTR1), angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were greater in tumour tissue than adjacent non-cancerous endometrium (P = 0.023, 0.008, 0.004 and 0.046, respectively). Prorenin, ATP6AP2, AGTR1, AGTR2 and ACE2 proteins were abundantly expressed in both cancerous and adjacent non-cancerous endometrium. Staining was most intense in cancerous glandular epithelium. One potential target of the endometrial RAS, transforming growth factor beta-1 (TGFB1), which is essential for epithelial-to-mesenchymal transition, was also upregulated in endometrial cancer tissue (P = 0.001). Interestingly, TGFB1 was strongly correlated with RAS expression and was upregulated in tumour tissue. This study is the first to characterise the mRNA and protein expression of all RAS components in cancerous and adjacent non-cancerous endometrium. The greater expression of ATP6AP2, AGTR1 and ACE1, key elements of the pro-angiogenic/proliferative arm of the RAS, suggests that the RAS plays a role in the growth and spread of endometrial cancer. Therefore, existing drugs that inhibit the RAS and which are used to treat hypertension may have potential as treatments for endometrial cancer.

Background: Pregnancy can be a stressful time for many women. There is ample evidence of numerous physical and mental health inequities for Indigenous Australians. For those Indigenous women who are pregnant, it is established that there is a higher incidence of poor physical perinatal outcomes when compared with non-Indigenous Australians. However, little evidence exists that examines stressful events and post-traumatic stress disorder (PTSD) symptoms in pregnant women who are members of this community.Aims: To quantify the rates of stressful events and PTSD symptoms in pregnant Indigenous women.Methods: One hundred and fifty rural and remote Indigenous women were invited to complete a survey during each trimester of their pregnancy. The survey measures were the stressful life events and the Impact of Events Scale.Results: Extremely high rates of PTSD symptoms were reported by participants. Approximately 40% of this group exhibited PTSD symptoms during their pregnancy with mean score 33.38 (SD = 14.37) significantly higher than a study of European victims of crisis, including terrorism attacks (20.6, SD = 18.5).Conclusions: The extreme levels of PTSD symptoms found in the women participating in this study are likely to result in negative implications for both mother and infant. An urgent response must be mounted at government, health, community development and research levels to address these findings. Immediate attention needs to focus on the development of interventions to address the high levels of PTSD symptoms that pregnant Australian Indigenous women experience.

AIM To determine whether recent evidence-based United States policies on male circumcision (MC) apply to comparable Anglophone countries, Australia and New Zealand. METHODS Articles in 2005 through 2015 were retrieved from PubMed using the keyword “circumcision” together with 36 relevant subtopics. A further PubMed search was performed for articles published in 2016. Searches of the EMBASE and Cochrane databases did not yield additional citable articles. Articles were assessed for quality and those rated 2+ and above according to the Scottish Intercollegiate Grading System were studied further. The most relevant and representative of the topic were included. Bibliographies were examined to retrieve further key references. Randomized controlled trials, recent high quality systematic reviews or meta-analyses (level 1++ or 1+ evidence) were prioritized for inclusion. A risk-benefit analysis of articles rated for quality was performed. For efficiency and reliability, recent randomized controlled trials, meta-analyses, high quality systematic reviews and large well-designed studies were used if available. Internet searches were conducted for other relevant information, including policies and Australian data on claims under Medicare for MC. RESULTS Evidence-based policy statements by the American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) support infant and later age male circumcision (MC) as a desirable public health measure. Our systematic review of relevant literature over the past decade yielded 140 journal articles that met our inclusion criteria. Together, these showed that early infant MC confers immediate and lifelong benefits by protecting against urinary tract infections having potential adverse long-term renal effects, phimosis that causes difficult and painful erections and “ballooning” during urination, inflammatory skin conditions, inferior penile hygiene, candidiasis, various sexually transmissible infections in both sexes, genital ulcers, and penile, prostate and cervical cancer. Our risk-benefit analysis showed that benefits exceeded procedural risks, which are predominantly minor, by up to 200 to 1. We estimated that more than 1 in 2 uncircumcised males will experience an adverse foreskin-related medical condition over their lifetime. Wide-ranging evidence from surveys, physiological measurements, and the anatomical location of penile sensory receptors responsible for sexual sensation strongly and consistently suggested that MC has no detrimental effect on sexual function, sensitivity or pleasure. United States studies showed that early infant MC is cost saving. The evidence supporting early infant MC has further strengthened since the positive AAP and CDC reviews. CONCLUSION Affirmative MC policies are needed in Australia and New Zealand. Routine provision of accurate, unbiased education, and access in public hospitals, will maximize health and financial benefits.

Indigenous Australians have high rates of chronic diseases, the causes of which are complex and include social and environmental determinants. Early experiences in utero may also predispose to later-life disease development. The Gomeroi gaaynggal study was established to explore intrauterine origins of renal disease, diabetes and growth in order to inform the development of health programmes for Indigenous Australian women and children. Pregnant women are recruited from antenatal clinics in Tamworth, Newcastle and Walgett, New South Wales, Australia, by Indigenous research assistants. Measures are collected at three time points in pregnancy and from women and their children at up to eight time points in the child’s first 5 years. Measures of fetal renal development and function include ultrasound and biochemical biomarkers. Dietary intake, infant feeding and anthropometric measurements are collected. Standardized procedures and validated tools are used where available. Since 2010 the study has recruited over 230 women, and retained 66 postpartum. Recruitment is ongoing, and Gomeroi gaaynggal is currently the largest Indigenous pregnancy-through-early-childhood cohort internationally. Baseline median gestational age was 39.1 weeks (31.5–43.2, n=110), median birth weight was 3180 g (910–5430 g, n=110). Over one third (39.3%) of infants were admitted to special care or neonatal nursery. Nearly half of mothers (47.5%) reported tobacco smoking during pregnancy. Results of the study will contribute to knowledge about origins of chronic disease in Indigenous Australians and nutrition and growth of women and their offspring during pregnancy and postpartum. Study strengths include employment and capacity-building of Indigenous staff and the complementary ArtsHealth programme.

Here we review the international evidence for benefits and risks of infant male circumcision (MC) and use this to develop an evidence-based policy statement for a developed nation setting, focusing on Australia. Evidence from good quality studies that include meta-analyses and randomized controlled trials showed that MC provides strong protection against: urinary tract infections and, in infancy, renal parenchymal disease; phimosis; paraphimosis; balanoposthitis; foreskin tearing; some heterosexually transmitted infections including HPV, HSV-2, trichomonas, HIV, and genital ulcer disease; thrush; inferior hygiene; penile cancer and possibly prostate cancer. In women, circumcision of the male partner protects against HPV, HSV-2, cervical cancer, bacterial vaginosis, and possibly Chlamydia. MC has no adverse effect on sexual function, sensitivity, penile sensation or satisfaction and may enhance the male sexual experience. Adverse effects are uncommon (

Background In pregnancy, the decidualised endometrium expresses high levels of prorenin and other genes of the renin-angiotensin system (RAS) pathway. In this study we aimed to determined if the RAS was present in endometrial stromal cells and if decidualisation upregulated the expression of prorenin, the prorenin receptor ((P)RR) and associated RAS pathways. Immortalised human endometrial stromal cells (HESCs) can be stimulated to decidualise by combined treatment with medroxyprogesterone acetate (MPA), 17β-estradiol (E2) and cAMP (MPA-mix) or with 5-aza-2’-deoxycytidine (AZA), a global demethylating agent. Methods HESCs were incubated for 10 days with one of the following treatments: vehicle, MPA-mix, a combination of medroxyprogesterone acetate (MPA) and estradiol-17β alone, or AZA. Messenger RNA abundance and protein levels of prorenin (REN), the (P)RR (ATP6AP2), angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), vascular endothelial growth factor (VEGF), and plasminogen activator inhibitor-1 (PAI-1) were measured by real-time PCR and ELISA’s, respectively. Promyelocytic zinc finger (PLZF) and phospho-inositol-3 kinase (PIK3R1) mRNA abundances were also measured. Results HESCs expressed the prorenin receptor (ATP6AP2), REN, AGT, ACE and low levels of AGTR1. MPA-mix and AZA stimulated expression of REN. Prorenin protein secretion was increased in MPA-mix treated HESCs. E2 + MPA had no effect on any RAS genes. MPA-mix treatment was associated with increased VEGF (VEGFA) and PAI-1 (SERPINE1) mRNA and VEGF protein. Conclusions An endometrial prorenin receptor/renin angiotensin system is activated by decidualisation. Since (P)RR is abundant, the increase in prorenin secretion could have stimulated VEGF A and SERPINE1 expression via Ang II, as both ACE and AGTR1 are present, or by Ang II independent pathways. Activation of the RAS in human endometrium with decidualisation, through stimulation of VEGF expression and secretion, could be critical in establishing an adequate blood supply to the developing maternal placental vascular bed.

Right (RVFW) and left (LVFW) ventricular free wall cardiac myocytes were collected from 25 fetal sheep aged 77–146 days gestation (term = 150 days gestation), six saline-infused catheterized fetal sheep (129 GD), and five lambs to measure gestational changes in uni- and binucleated cardiac myocyte numbers and cell volumes by confocal microscopy. At 77 days gestation, 2% of the myocytes were binucleated, which increased to 50% at 135 days gestation and 90% at 4–6 weeks after birth. RVFW uni- and binucleated myocytes were larger than those in the LVFW, and cell volumes of RVFW uni- and binucleated and LVFW binucleated myocytes (but not LVFW uninucleated myocytes) increased with gestation. Before birth, the approximate number of myocytes was greater in the LVFW than in the RVFW (P < 0.001). Before 110 GD, cardiac growth appeared to be due to myocyte hyperplasia, as approximate myocyte numbers and VFW weight increased at the same rate. After 110 days gestation, the approximate myocyte number/g VFW weight decreased, which suggests that myocyte hypertrophy, as well as hyperplasia, was occurring in association with the appearance of a greater proportion of binucleated cells after that time. By 4–6 weeks of age, there was marked hypertrophy of myocytes and an apparent reduction in myocyte number. Anat Rec Part A 274A:952–961, 2003. © 2003 Wiley-Liss, Inc.

A pregnant woman participated in cycling events in the 2000 Olympics. Recently there was concern about the participation of a pregnant woman in the Australian netball team. More and more women are anxious to pursue sports during their pregnancies and to maintain condition. For the clinician or sports physician caring for women who want to maintain a high-level of physical activity there is no simple exercise prescription. It is probable that continuing exercise by women who are already conditioned will not result in foetal compromise, unless there are hidden or unknown complications of pregnancy. Pregnant women should probably exercise within limits that do not cause severe discomfort and should, as pregnancy progresses, be prepared to moderate the intensity and duration of their exercise programs to avoid risks and injury. It is probably not advisable for women to begin high intensity exercise programs when pregnant, although moderate exercise is beneficial to both mother and baby. The type of activity that is undertaken has to be taken into consideration and in particular the adverse effects of supine activity in late gestation recognised.

Endometrial cancer is the most common gynaecological malignancy and its incidence is increasing. Tissue renin angiotensin systems (RAS) are known to stimulate angiogenesis, cell proliferation and migration. All of these actions potentiate cancer growth and spread. We have previously demonstrated that endometrioid endometrial cancers express both prorenin and prorenin receptor ((P)RR) mRNA and have significantly greater levels of these proteins than normal adjacent endometrial tissue. Prorenin acting via the (P)RR can activate both RAS dependent and independent signalling pathways. Therefore we hypothesized that endometrial cancer growth can be inhibited by drugs that block Ang II/AT1R interactions and prorenin/(P)RR mediated signaling pathways. To determine the functional role of (P)RR in endometrial cancer growth, we used siRNA transfection to knock down (P)RR expression in three endometrial cancer cell lines (Ishikawa, HEC-1A and AN3CA) at 24h, 48h, 72h & 96h. The effect of RAS blockers on cell viability was also assessed by Resazurin assay at 48h in the three endometrial cancer cell lines. All three of the endometrial cancer cell lines examined (Ishikawa, HEC-1A and AN3CA) expressed (P)RR and prorenin mRNA, however levels of (P)RR were much higher in Ishikawa cells. Transfection of the three cell lines with a (P)RR siRNA resulted in 90% knockdown of (P)RR mRNA expression and reduced the cell viability of both Ishikawa and AN3CA but not HEC-1A cells, as measured by a resazurin assay after 48h incubation. Aliskiren (a renin inhibitor) inhibited Ishikawa cell growth by 20%. There was no effect of Aliskiren on cell viability in HEC-1A and AN3CA cell lines. Perindoprilat (an ACE inhibitor) and Losartan (an angiotensin II type 1 receptor (AT1R) inhibitor) had no effect on cell viability in any cell line. Another AT1R antagonist, telmisartan, which also acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), did however significantly reduce cell viability in all cell lines (Ishikawa 75%, HEC-1A 50% and AN3CA 60%). Removal of the prorenin receptor inhibits the growth and development of some endometrial cancer cell lines. Only telmisartan, which has properties additional to Ang II antagonism, was effective in inhibiting endometrial cancer cell growth. (P)RR knockdown and telmisartan are therefore potential therapeutic drugs for the treatment of endometrial cancer. Citation Format: Riazuddin Mohammed, Sarah J. Delforce, Yu Wang, Nicole M. Verrills, Eugenie R. Lumbers, Kirsty G. Pringle. Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4136. doi:10.1158/1538-7445.AM2017-4136

Previous studies in fetal sheep have concluded that (a) the vascular AT(1) angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT(1) specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT(1) receptors first appear. We measured AT(1) and AT(2) receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65-144 days (term approximately 150 days), and in hearts and aortae from lambs, and adult pregnant and non-pregnant ewes. Both AT(1) and AT(2) receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT(2) receptors were found. The proportion of carotid artery and aortic AT(1) receptors increased with age, while the proportion of AT(2) receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT(1) receptors. The highest density of Ang II receptors was found in the fetal heart where the AT(2) subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r = -0.44, P < 0.02) due to the decrease in the AT(2) subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT(1) receptors, and we have documented for the first time that the appearance of AT(1) receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT(1) receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels. Experimental Physiology (2001) 86.1, 71-82.

1. The effects of cold saline (25 mL) injected over the fetal skin on fetal heart rate (HR) and HR variability (HRV), measured as the coefficient of variation (CV) in pulse interval (PI) and by power spectral analysis (PSA), were measured in 10 chronically catheterized fetal sheep aged 140-144 days. To determine the extent to which effects on HR and HRV were mediated by the sympathoadrenal neuroendocrine axis and the cardiac vagus, experiments were performed before and after beta-adrenoreceptor blockade with propranolol (n = 12 fetuses) or before and after cardiac vagal blockade with atropine (n = 4 fetuses). 2. Injection of ice-cold saline over the skin caused an immediate rise in mean arterial pressure (MAP) from 46+/-1 to 55+/-1 mmHg (P < 0.001) and HR from 156+/-2 to 182+/-2 b.p.m. (P < 0.001). Heart rate variability, measured as CV of PI, rose from 3.5+/-0.2 to 8.0+/-0.2% (P < 0.001) and total power spectral density (PSD) increased from 78+/-6 to 278+/-16 units (P < 0.001) as measured by PSA. Within 100s, MAP, HR and HRV had returned to baseline. 3. Beta-adrenoreceptor blockade abolished all these changes in HR, HRV and PSD, but had no effect on changes in MAP. Atropine had no demonstrable effect on the responses to cold. 4. Therefore, the increase in fetal MAP, HR and HRV that occurred with stimulation of peripheral thermoreceptors was the result of increased activity of the sympathetic nervous system. Alterations in efferent cardiac vagal tone were not involved in the cardiac response to cold.

Numerous epidemiological studies, together with mounting evidence from studies in animals, point to a correlation between an adverse intrauterine environment and the early onset of cardiovascular and metabolic diseases later in life. We were the first to show that sheep exposed to dexamethasone (0.28 mg⋅kg-1⋅day-1 for only 2 days) at the end of the first month of pregnancy (PTG1), but not those exposed at the end of the second month of pregnancy (PTG2), had a higher basal mean arterial pressure (MAP) 19 months after birth. In the present study we report the MAP, cardiovascular haemodynamics and baroreflex sensitivity in these animals at 40 months of age. MAP in the PTG1 group was significantly higher than in the control group (91±1 mmHg and 81±1 mmHg respectively; P< 0.001) and also when compared with the PTG2 group (82±1 mmHg; P< 0.001). There was a significant increase in cardiac output in the PTG1 group compared with the control group (108±2 and 96±4 ml⋅min-1⋅kg-1 respectively; P< 0.05). The increase in cardiac output in the PTG1 group was due to an increase in stroke volume (1.82±0.08 ml⋅kg-1⋅beat-1, compared with 1.46±0.06 ml⋅kg-1⋅beat-1 in the control group; P< 0.05), but not in heart rate. In the hypertensive group of animals (PTG1), there was a rightward shift of the baroreflex curve. In group PTG2 (the normotensive group of animals), a lower gain was found before and during propranolol treatment. The decrease in gain of the baroreflex was not associated with changes in heart rate range, suggesting an impairment in the central processing of the baroreceptor signals. Thus sheep fetuses exposed to dexamethasone for only 2 days at the end of the first month of gestation have high blood pressure (dependent upon the increase in cardiac output) and a reset of the baroreflex at 40 months of age. Animals that have received prenatal dexamethasone closer to mid-gestation, although normotensive with normal cardiac output, showed an altered baroreceptor-heart rate response.

1. The cardiac baroreflex was measured in four non-pregnant and six pregnant ewes before and during beta-adrenoreceptor blockade with propranolol and before and during vagal blockade with atropine. Arterial pressure was raised by phenylephrine and lowered by sodium nitroprusside. The relationships between mean arterial pressure (MAP) and heart rate (HR), between MAP and heart rate variability (HRV) measured as the coefficient of variation (c.v.) of the mean pulse interval (PI), and between MAP and HRV measured by power spectral analysis were determined. 2. The MAP-HR relationship showed that in pregnant ewes the gain of the cardiac baroreflex was reduced when compared with non-pregnant ewes. Threshold and saturation pressures were higher, maximum achievable HR was lower and there was a decrease in the operating range. 3. V-shaped relationships were obtained between MAP and HRV (measured as the c.v. of PI) and between MAP and power spectral density in the frequency range 0.04-0. 08 Hz. Using selective autonomic blockade the negative, or downward, slope of the V shape was shown to be a measure of baroreceptor-induced, sympathetically mediated effects on HRV. The upward, or positive, slope of the V shape was a measure of baroreceptor-induced, vagally mediated effects. Similar results were also obtained from the cardiac power spectrum, but it was less sensitive. The MAP at which the two slopes intersected was the same as the resting MAP. 4. In pregnant ewes, the slope of the downward limb of the V-shaped relationship between HRV (when measured as the c.v. of PI) and MAP was less than in non-pregnant ewes. 5. The relationship between MAP and the coefficient of variation of the mean pulse interval can therefore be used to measure the degree to which baroreceptor-induced sympathetic and parasympathetic activity affects the heart. 6. The resting MAP is the pressure at which the net effect of these sympathetic and parasympathetic influences on the heart is at a minimum. Studies of both the MAP-HR and MAP-HRV relationships in pregnant and non-pregnant sheep show that in pregnant sheep, there is attenuation of baroreceptor-mediated sympathetic effects on the heart.

To study the effects of elevated maternal levels of adrenocorticotropic hormone (ACTH) on the fetus, nine chronically catheterized pregnant ewes (132 ± 0.9 days of gestation) were infused intravenously for 3 days with Synacthen (5 μg ⋅ kg−1 ⋅ day−1). Four ewes were given 0.15 M saline intravenously over the same period. ACTH induced hypertension in the ewe. Mean arterial pressure (MAP) increased from 101 ± 4.4 to 114 ± 3.9 mmHg at 48 h ( P < 0.05); cardiac output increased from 8.6 ± 0.5 to 10.4 ± 1.0 l/min after 24 h ( P < 0.05). Within 2–4 h, maternal cortisol levels increased from 24.6 ± 6.3 to 287 ± 30 nM ( P < 0.05) and remained high. Fetal plasma cortisol levels increased from 20 ± 4.5 to 60 ± 4.5 nM ( P < 0.05) within 2–4 h and then increased further. Fetal MAP was increased at 24 h. There was no effect on fetal blood gases or pH. Ewes became hyperglycemic and lactacidemic by 24 h ( P < 0.05), and the fetuses were also hyperglycemic and lactacidemic ( P < 0.05) at this time. There were no changes in fetuses carried by saline-infused ewes. Both ewes and fetuses had raised plasma osmolalities and, since hematocrit fell, retained fluid. Ewes became hypokalemic; the fetuses did not, but there was an increase in fetal K excretion. Thus ACTH-induced hypertension in the ewe had minimal effects on fetal MAP, fetal blood gas status, and pH. The fetus, however, did show many of the other effects of maternal glucocorticoid and mineralocorticoid excess, partly because its cortisol levels were increased but also as a consequence of metabolic and endocrine changes in the ewe.

To determine the effects of sustained high levels of arginine vasopressin (AVP) on the fetus and whether these effects were the same as those found during acute infusion of AVP, chronically catheterized fetal sheep aged 121-136 days were infused for 3 days with either AVP (45 mU x kg(-1) x h(-1)) or saline. The bradycardia, acidemia, and failure of glomerulotubular balance that occurred with acute AVP infusion were reversed by day 3 of AVP (P < 0.005) and the acute rise in arterial pressure was attenuated (P < 0.005). By contrast, the rise in the glomerular filtration rate was sustained (P < 0.005) and urinary osmolality increased further to 426 +/- 30 mosmol/kg (P < 0.01). Although placental blood flow did not change acutely with AVP, it had fallen by day 3 (P < 0.01). In addition, with AVP but not saline extracellular volume fell from 588 +/- 28 to 493 +/- 29 ml/kg (P < 0.002) and the plasma/interstitial volume ratio rose from 0.18 +/- 0.01 to 0.21 +/- 0.01 (P = 0.001). These findings suggest that although release of AVP may be beneficial in acute stress in utero, sustained high levels may be detrimental to fetal health and sodium balance.

In 16 chronically catheterized fetal sheep the effects of reducing and restoring maternal renal blood flow (RBF) and thus inducing and reversing hypertension were studied in uninephrectomized pregnant ewes; controls were 3 fetuses that were carried by uninephrectomized ewes in which RBF was not reduced and that did not become hypertensive. Within 24-72 h of maternal RBF reduction, fetal arterial PO2 had fallen (P < 0.001) and PCO2 had increased (P < 0.025); fetal arterial pressure also increased (P < 0.005). These effects persisted, despite restoration of maternal RBF and reversal of maternal hypertension. Within 24-72 h of reduction of maternal RBF, fetal urine flow had increased (P < 0.005), and it remained elevated over the first 3 h after RBF was restored; 24-72 h later it was lower (P < 0.025) and returned to control levels. The excretion of sodium, potassium, and chloride showed a similar increase when maternal RBF was reduced (P < 0.001), with return to control values 24-72 h after RBF had been restored. Fetal glomerular filtration rate did not change; thus the natriuresis and diuresis that occurred were due to reduced tubular solute and water reabsorption (P < 0.025). These changes in fetal renal function may be related, in part, to changes in fetal PO2 and PCO2, but they are most likely due to reduced maternal renal function due to the restriction in maternal RBF, inasmuch as they were reversed when RBF was restored.

The renin-angiotensin system (RAS) plays a critical role in placentation and nephrogenesis. Failure to thrive during intrauterine life, possibly related to placental dysfunction and impaired expression of the renal RAS, as well as prematurity, results in smaller kidneys at birth and reduced nephron number. The remaining nephrons are therefore hyperfiltering from birth. Hyperfiltration, infections and Type 2 diabetes cause glomerular and tubular fibrosis, leading to further reductions in nephron number. The intrarenal RAS plays a key role in promoting tubulointerstitial fibrosis. Low birth weight and a high incidence of preterm birth program Indigenous children for early onset renal disease in adult life. Indigenous Australians have 404 000 fewer nephrons than non-Indigenous Australians. This, coupled with the high incidence of infectious diseases (particularly acute post-streptococcal glomerulonephritis) and the increasing prevalence of Type 2 diabetes, explains why end-stage renal disease is of epidemic proportions in Indigenous Australians. The existence of RAS gene polymorphisms and inflammatory cytokines may further potentiate susceptibility to renal disease in Indigenous Australians.

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To determine the effects on the fetus of high maternal levels of noradrenaline, experiments were carried out in 17 pregnant ewes (123–137 days gestation). Intravenous infusion of 40 mg/min of norepinephrine to the ewe for 1.5 h increased maternal arterial pressure and significantly decreased maternal placental blood flow (p

There are fetal sex-specific differences in the balance between angiotensin (Ang) II and Ang-(1-7) in the maternal circulation during pregnancy. To determine whether at 15 weeks' gestation plasma levels of Ang II and Ang-(1-7), as well as levels of prorenin and Ang-converting enzyme (ACE), predicted the development of gestational hypertension (GH) or preeclampsia (PreE) and were associated with estimates of fetal and maternal health, women who later developed GH (n=50) or PreE (n=50) were compared with body mass index-matched controls (n=100). Women who subsequently developed PreE or GH had increased Ang-(1-7) levels at 15 weeks' gestation compared with women with normal pregnancies. When separated by fetal sex, this difference was seen only in women carrying a female fetus. Prorenin and ACE concentrations were not useful biomarkers for the prediction of either PreE or GH at 15 weeks' gestation. Women with a male fetus who developed PreE and women who subsequently developed GH had increased blood pressures at 15 weeks' gestation compared with women with normal pregnancies, suggesting that these women were on an early trajectory for the development of hypertension. We propose that measurement of Ang-(1-7) during early gestation could be useful in predicting, those women who will go on to develop new-onset hypertension in pregnancy. Refereed/Peer-reviewed

Low systemic blood flow occurs in up to 30% of infants born at less than 30 wk gestation. It is associated with increased morbidity and mortality, and current treatments are ineffective in 40% of cases. The aim of this study was to assess the ability of the preterm heart to respond to the acute shifts in preload and afterload that occur at the time of birth. Myocardial and coronary vascular function was assessed using an isolated working heart model in term (115 days) and preterm (92 days) piglets. Cardiac output/kg body wt in preterm hearts was ∼50% lower than that of term hearts ( P = 0.001). Pressure development was similar in term and preterm hearts. Elevations in preload increased cardiac output and aortic flow similarly in term and preterm hearts, demonstrating significant preload “reserve”. By contrast, elevations in afterload markedly depressed aortic flow, with a greater proportion of cardiac output being distributed to coronary flow in preterm hearts at high afterloads. The demands of increased workload were associated with greater increases in coronary flow in preterm hearts compared with term hearts. In preterm hearts, exposure to maternal glucocorticoids resulted in increased aortic flow when afterload was below 25 mmHg. These data suggest the preterm heart lacks the functional capacity to acutely adapt to postnatal afterload. To maximize systemic blood flow in preterm infants, treatments limiting afterload, while harnessing significant preload reserve, should be further explored.

Background: Low birth weight (LBW), defined as birth weight below 2,500 g, is an important risk factor for the development of hypertension and renal disease in adult life. LBW is associated with a reduced nephron number, which results in hyperfiltration. The objective of this study was to compare the glomerular filtration rates (GFRs) of LBW and normal-birth-weight (NBW) term infants relative to their kidney volumes. Methods: Term infants (born after 37 weeks of gestation) who had been admitted to Townsville Hospital's neonatal unit were recruited for this study. Serum cystatin C was used to calculate GFR. A kidney ultrasound was used to measure renal volume. All assessments were performed during the first week of life. Results: Data from 39 infants (17 male, 22 female; 13 LBW, 26 NBW) were analyzed. There were no significant differences in the median cystatin C (1.36 mg/L, inter quartile range [IQR] = 1.12 - 1.41, vs. 1.17 mg/L, IQR = 1.10 - 1.39; p = 0.39) and gestational age. There was no significant difference in the median GFR (53.0 ml/min per 1.73 m2, IQR = 50.8-66.9, vs. 63.2 ml/min per m2, IQR = 51.8-69.5; p = 0.39) between LBW and NBW infants, but LBW infants had smaller total renal volume compared with NBW infants (18.0 ± 4.7 mL vs. 24.4 ± 6.2 mL; p = 0.002). Conclusion: Within 6 days, LBW infants achieved a similar GFR to NBW infants, despite 25% smaller kidney volumes. Thus, the single-nephron glomerular filtration rate must be increased in LBW infants. Prior to this study, it was unclear when hyperfiltration begins, but our results demonstrate that hyperfiltration begins in early life.

Introduction This study aimed to determine the association of AGTR1 and AGTR2 polymorphisms with preeclampsia and whether these are affected by environmental factors and fetal sex. Methods Overall 3234 healthy nulliparous women, their partners and babies were recruited prospectively to the SCOPE study in Adelaide and Auckland. Data analyses were confined to 2121 Caucasian parent-infant trios, among whom 123 had preeclamptic pregnancies. 1185 uncomplicated pregnancies served as controls. DNA was extracted from buffy coats and genotyped by utilizing the Sequenom MassARRAY system. Doppler sonography on the uterine arteries was performed at 20 weeks' gestation. Results Four polymorphisms in AGTR1 and AGTR2 genes, including AGTR1 A1166C , AGTR2 C4599A , AGTR2 A1675G and AGTR2 T1134C , were selected and significant associations were predominately observed for AGTR2 C4599A . When the cohort was stratified by maternal BMI, in women with BMI ≥ 25 kg/m 2 , the AGTR2 C4599A AA genotype in mothers and neonates was associated with an increased risk for preeclampsia compared with the CC genotype [adjusted OR 2.1 (95% CI 1.0–4.2) and adjusted OR 3.0 (95% CI 1.4–6.4), respectively]. In the same subset of women, paternal AGTR2 C4599A A allele was associated with an increased risk for preeclampsia and uterine artery bilateral notching at 20 weeks' gestation compared with the C allele [adjusted OR 1.9 (95% CI 1.1–3.3) and adjusted OR 2.1 (95% CI 1.3–3.4), respectively]. Conclusion AGTR2 C4599A in mothers, fathers and babies was associated with preeclampsia and this association was only apparent in pregnancies in which the women had a BMI ≥ 25 kg/m 2 , suggesting a gene–environment interaction.

The effects of high salt intake on blood pressure and renal function were studied in nine subtotally nephrectomized pregnant ewes (STNxP) and seven intact pregnant ewes (IntP) in late gestation and in eight subtotally nephrectomized nonpregnant ewes (STNxNP) and seven intact nonpregnant ewes (IntNP). STNxP had higher mean arterial pressures ( P < 0.02) and plasma creatinine levels ( P < 0.001) than IntP. High salt (0.17 M NaCl as drinking water for 5 days) did not change blood pressure in either STNxP or IntP. STNxNP had higher mean arterial pressures ( P = 0.03) and plasma creatinine levels ( P < 0.001) than IntNP. In STNxNP, blood pressure increased with high salt intake and there was a positive relationship between diastolic pressure and sodium balance ( r = 0.497, P = 0.05). This relationship was not present in IntNP, STNxP, or IntP. Because high salt intake did not cause an increase in blood pressure in STNxP, it is concluded that they were protected by pregnancy from further rises in blood pressure. The observed increase in glomerular filtration rate ( P < 0.03) and depression of fractional proximal sodium reabsorption ( P = 0.003) that occurred in STNxP, but not in STNxNP, in response to high salt may have contributed to this protection. As well, the increased production of vasorelaxants in pregnancy may selectively protect against the occurrence of salt-sensitive hypertension in pregnancy.