Dataset Information

Diagnostic Indicators of Superimposed Preeclampsia in Women With CKD.

ABSTRACT:

Introduction

Diagnosis of superimposed preeclampsia in women with chronic kidney disease (CKD) is complicated by the presence of hypertension and proteinuria due to renal disease. The aims of this study were to determine mechanistic links between superimposed preeclampsia and renin-angiotensin system activation, endothelial pathology, complement dysfunction, and tubular injury, and to explore the role of diagnostic indicators of superimposed preeclampsia.

Methods

Plasma and urinary biomarkers derived from the renin-angiotensin system (active renin, angiotensinogen), endothelial glycocalyx (hyaluronan, intercellular adhesion molecule, vascular cell adhesion molecule [VCAM], P-selectin, E-selectin), complement activation (C3a, C5a, complement factor H, C5b-9), and tubular injury (kidney injury molecule-1, urinary lipocalin-2) were quantified in 60 pregnant women with CKD including 15 women at the time of superimposed preeclampsia diagnosis and 45 women who did not develop superimposed preeclampsia, 18 women with preeclampsia, and 20 normal pregnancies. Correlation with placental growth factor was assessed.

Results

Plasma concentrations of hyaluronan (67.5 ng/ml vs. 27.5 ng/ml, P = 0.0017, receiver operating characteristic area 0.80) and VCAM (1132 ng/ml vs. 659 ng/ml, P < 0.0001, receiver operating characteristic area 0.86) distinguished women with CKD and superimposed preeclampsia from those without superimposed preeclampsia, and correlated with placental growth factor concentration. The diagnostic discrimination of markers of the renin-angiotensin system was reduced by adjustment for chronic hypertension, antihypertensive drug use, and black ethnicity. Other markers offered limited or no diagnostic discrimination for superimposed preeclampsia.

Conclusion

This study suggests that endothelial dysfunction contributes to the pathophysiology of superimposed preeclampsia and a diagnostic role for plasma hyaluronan and VCAM is hypothesized.

SUBMITTER: Wiles K

PROVIDER: S-EPMC6551530 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Diagnostic Indicators of Superimposed Preeclampsia in Women With CKD.

Wiles Kate K Bramham Kate K Seed Paul T PT Kurlak Lesia O LO Mistry Hiten D HD Nelson-Piercy Catherine C Lightstone Liz L Chappell Lucy C LC

Kidney international reports 20190326 6

<h4>Introduction</h4>Diagnosis of superimposed preeclampsia in women with chronic kidney disease (CKD) is complicated by the presence of hypertension and proteinuria due to renal disease. The aims of this study were to determine mechanistic links between superimposed preeclampsia and renin-angiotensin system activation, endothelial pathology, complement dysfunction, and tubular injury, and to explore the role of diagnostic indicators of superimposed preeclampsia.<h4>Methods</h4>Plasma and urinar ...[more]

PMID: 31194119

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Project description:BackgroundPatients with chronic hypertension are at increased risk for superimposed preeclampsia. The 2016 American College of Obstetricians and Gynecologists guideline recommended initiating 81 mg of daily aspirin for all pregnant women with chronic hypertension to prevent superimposed preeclampsia.Objective(1) To evaluate the rates of implementation of the 2016 American College of Obstetricians and Gynecologists guideline over time; and (2) to evaluate the effectiveness of aspirin for the prevention of superimposed preeclampsia and other adverse maternal and neonatal outcomes in women with chronic hypertension before and after this guideline.Study designThis is a retrospective study of women with chronic hypertension who delivered at Thomas Jefferson University Hospital from January 2014 through June 2018. This cohort of women with chronic hypertension was divided into 2 groups, before and after the American College of Obstetricians and Gynecologists recommendation published in September 2016. Daily 81 mg of aspirin was initiated between 12 and 16 weeks. We excluded multiple gestations and incomplete records. The primary outcome was incidence of superimposed preeclampsia, and secondary outcomes were incidence of superimposed preeclampsia with or without severe features, small for gestational age, and preterm birth <37 weeks. Subgroup analysis based on risk stratification was evaluated in women with chronic hypertension requiring antihypertensive medication, history of preeclampsia, and pregestational diabetes.ResultsWe identified 457 pregnant women with chronic hypertension, 203 in the post-American College of Obstetricians and Gynecologists group and 254 in the pre-American College of Obstetricians and Gynecologists group. Aspirin 81 mg was offered to 142 (70%) in the post-American College of Obstetricians and Gynecologists group and 18 (7.0%) in the pre-American College of Obstetricians and Gynecologists group. Maternal demographics were not significantly different. The overall incidence of superimposed preeclampsia was not significantly different: 87 (34.3%) vs 72 (35.5%), P=.79, in the pre- and post-American College of Obstetricians and Gynecologists guideline groups, respectively. Superimposed preeclampsia with severe features significantly increased: 32 (12.6%) vs 9 (4.4%), P<.01, whereas superimposed preeclampsia without severe features significantly decreased: 55 (21.7%) vs 63 (31.0%), P=.03. There were no significant differences in small for gestational age neonates or preterm birth <37 weeks incidences between groups. There were no significant differences in the subgroup analysis based on the severity of chronic hypertension requiring antihypertensive medication, history of preeclampsia, or pregestational diabetes.ConclusionAfter the adoption of the American College of Obstetricians and Gynecologists guidelines in 70% of the cohort, superimposed preeclampsia, small for gestational age, and preterm birth were not significantly decreased after implementation of aspirin 81 mg initiated between 12 and 16 weeks of gestation.

Project description:Preeclampsia (PE), a multifactorial pregnancy-specific syndrome accounting for up to 8% of pregnancy complications, is a leading cause of maternal and fetal morbidity and mortality and PE is also associated with long-term risk of hypertension and stroke for both the mother and fetus. Currently, the only “cure” is delivery of the baby and placenta, largely because the pathogenesis of preeclampsia is not yet fully understood. Preeclampsia is associated with impaired vascular remodeling at the maternal-fetal interface and placental insufficiency; however, the specific factors that contribute to this impairment have not been identified. To identify potential contributing pathways, we examined temporal transcriptomic changes occurring within the uterus, uterine implantation sites, and placentae from the Dahl salt-sensitive (Dahl S) rat model of superimposed preeclampsia compared to Sprague Dawley (SD) rats. We hypothesized that the Dahl S maternal-fetal interface would exhibit a unique temporal transcriptomic profile unveiling novel biomarkers, therapeutic targets, and mechanistic pathways regarding the development of PE. Our initial study focused on evaluation of genes previously linked to the development PE from using real time quantitative PCR (RT qPCR) and total RNA was isolated from uterus (day 0), uterine implantation sites (days 7, 10, 14), and placenta (days 14 and 20). Subsequently, an unbiased transcriptome analysis was performed at each time point using whole genome microarray to identify novel factors involved in PE. 624, 332, 185 , and 366 genes were found to be differentially expressed on days 0, 7, 10 and 14 respectively, with a Reactome Pathway enrichment for “Fatty acid metabolism, Metabolism of water-soluble vitamins and cofactors, Metabolism, Synthesis of substrates in N-glucan biosynthesis on Day 7”; ”Glycerophospholipid biosynthesis, Phospholipid metabolism, and Metabolism of lipids on Day 10”; and “Metabolism of lipids, Phospholipid metabolism, degradation of the extracellular matrix, Fatty acid metabolism, and Collagen degradation on Day 14” in the Dahl S rat vs. SD. Our data revealed numerous pathways that may play a role in the pathophysiology of spontaneous superimposed PE and allow for further investigation of novel therapeutic targets and biomarker development.

Project description:Animal models that recapitulate human diseases and disorders are widely used to investigate etiology, diagnosis, and treatment of those conditions in people. Disorders during pregnancy are particularly difficult to explore as interventions in pregnant women are not easily performed. Therefore, models that allow for pre-conception investigations are advantageous for elucidating the mechanisms involved in adverse pregnancy outcomes that are responsible for both maternal and fetal morbidity, such as preeclampsia. The Blood Pressure High (BPH)/5 mouse model has been used extensively to study the pathogenesis of preeclampsia. The female BPH/5 mouse is obese with increased adiposity and borderline hypertension, both of which are exacerbated with pregnancy making it a model of superimposed preeclampsia. Thus, the BPH/5 model shares traits with a large majority of women with pre-existing conditions that predisposes them to preeclampsia. We sought to explore the genome of the BPH/5 female mouse and determine the genetic underpinnings that may contribute to preeclampsia-associated phenotypes in this model. Using a whole genome sequencing approach, we are the first to characterize the genetic mutations in BPH/5 female mice that make it unique from the closely related BPH/2 model and the normotensive background strain, C57Bl/6. We found the BPH/5 female mouse to be uniquely different from BPH/2 and C57Bl/6 mice with a genetically complex landscape. The majority of non-synonymous consequences within the coding region of BPH/5 females were missense mutations found most abundant on chromosome X when comparing BPH/5 and BPH/2, and on chromosome 8 when comparing BPH/5 to C57Bl/6. Genetic mutations in BPH/5 females largely belong to immune system-related processes, with overlap between BPH/5 and BPH/2 models. Further studies examining each gene mutation during pregnancy are warranted to determine key contributors to the BPH/5 preeclamptic-like phenotype and to identify genetic similarities to women that develop preeclampsia.

Project description:Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. KEY MESSAGES: The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

Project description:Hypertensive disorders of pregnancy are the second leading cause of maternal deaths worldwide. Superimposed preeclampsia is an increasingly common problem and often associated with impaired placental perfusion. Understanding the underlying mechanisms and developing treatment options are crucial. The pregnant stroke-prone spontaneously hypertensive rat has impaired uteroplacental blood flow and abnormal uterine artery remodeling. We used Ang II (angiotensin II) infusion in pregnant stroke-prone spontaneously hypertensive rats to mimic the increased cardiovascular stress associated with superimposed preeclampsia and examine the impact on the maternal cardiovascular system and fetal development. Continuous infusion of Ang II at 500 or 1000 ng/kg per minute was administered from gestational day 10.5 until term. Radiotelemetry and echocardiography were used to monitor hemodynamic and cardiovascular changes, and urine was collected prepregnancy and throughout gestation. Uterine artery myography assessed uteroplacental vascular function and structure. Fetal measurements were made at gestational day 18.5, and placentas were collected for histological and gene expression analyses. The 1000 ng/kg per minute Ang II treatment significantly increased blood pressure (P<0.01), reduced cardiac output (P<0.05), and reduced diameter and increased stiffness of the uterine arteries (P<0.01) during pregnancy. The albumin:creatinine ratio was increased in both Ang II treatment groups (P<0.05; P<0.0001). The 1000 ng/kg per minute-treated fetuses were significantly smaller than vehicle treatment (P<0.001). Placental expression of Ang II receptors was increased in the junctional zone in 1000 ng/kg per minute Ang II-treated groups (P<0.05), with this zone showing depletion of glycogen content and structural abnormalities. Ang II infusion in pregnant stroke-prone spontaneously hypertensive rats mirrors hemodynamic, cardiac, and urinary profiles observed in preeclamptic women, with evidence of impaired fetal growth.

Dataset Information

Diagnostic Indicators of Superimposed Preeclampsia in Women With CKD.

Introduction

Methods

Results

Conclusion

Publications

Diagnostic Indicators of Superimposed Preeclampsia in Women With CKD.

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