Increased urinary albumin leakage is related to injuries of glomerular glycocalyx and podocytes, and associated with tubular dysfunction in preeclampsia.

OBJECTIVE: The pathogenesis of preeclampsia (PE) is known to be endothelial cell damage; however, the existence of dysfunction in glomerular endothelial glycocalyx, podocytes and tubules remains unclear. The glomerular endothelial glycocalyx, basement membrane, podocytes, and tubules are permeability barriers against albumin excretion. This study aimed to assess the relationship between urinary albumin leakage and injuries of the glomerular endothelial glycocalyx, podocytes, and tubules in patients with PE. METHODS: A total of 81 women with uncomplicated pregnancies (control, n = 22), PE (PE, n = 36), or gestational hypertension (GH) (GH, n = 23) were enrolled. We assessed urinary albumin and serum hyaluronan for glycocalyx injuries, podocalyxin for podocytes injuries, and urinary N-acetyl-ß-d-glucosaminidase (NAG) and liver-type fatty acid-binding protein (l-FABP) for renal tubular dysfunctions. RESULTS: The serum hyaluronan and the urinary podocalyxin levels were higher in the PE and GH groups. The urinary NAG and l-FABP levels were higher in the PE group. Urinary NAG and l-FABP levels positively correlated with urinary albumin excretion. CONCLUSIONS: Our findings suggest that increased urinary albumin leakage is related to injuries of the glycocalyx and podocytes, and associated with tubular dysfunction in pregnant women with PE. The clinical trial described in this paper was registered at the UMIN Clinical Trials Registry under registration number UMIN000047875. URL of registration: https://centre6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000054437.

Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

Amount of proteinuria as associated with severity classification of pregnant women with preeclampsia.

OBJECTIVE: This study aimed to verify whether the severity classification of preeclamptic women differed by the presence or absence of proteinuria exceeding 2.0 g/24 h. METHODS: In this retrospective cohort study, data were collected from women with singleton pregnancies who presented with preeclampsia and proteinuria at Aichi Medical University Hospital between April 1, 2008 and September 30, 2021. Participants were divided into two groups (high proteinuria and low proteinuria) based on whether or not their proteinuria exceeded 2.0 g/24 h. Between the two groups, severity of maternal was assessed using the American College of Obstetricians and Gynecologists (ACOG) severity classification (Severe Features) and perinatal and neonatal outcomes were compared. RESULTS: Relative to preeclamptic women with lower proteinuria group, those with higher proteinuria group delivered and were diagnosed with preeclampsia at an earlier gestational week. The latter group also exhibited higher rates of pleural effusion or ascites, preterm birth, and early preterm birth, in addition to lower birth weight and birth weight SD. Rates of admission to the NICU were also higher for neonates born to preeclamptic women in the higher proteinuria group. The percentage of women classified as 'severe' was higher in the higher proteinuria group relative to that in the lower proteinuria group. The percentage of those with severe hypertension and new-onset headache was higher in the higher proteinuria group compared to the lower proteinuria group. The optimal proteinuria cutoff value that distinguished between severe and non-severe maternal cases was determined to be 2.2 g/24 h. CONCLUSIONS: Severity classifications were more common among preeclamptic women with proteinuria exceeding 2.0 g/24 h, particularly with regard to the percentage of those with severe hypertension and new-onset headache.

Hypoalbuminemia is related to endothelial dysfunction resulting from oxidative stress in parturients with preeclampsia.

Serum albumin levels are inversely related with oxidative stress, but positively related with endothelial function, in pregnant women. However, it is unclear whether hypoalbuminemia in pregnant women with preeclampsia (PE) increases the production of oxygen-derived free radicals and impacts endothelial function. The present study aimed to assess the relationship between serum albumin, oxidative stress, and endothelial dysfunction in pregnant women with PE. A total of 75 women with control pregnancy (Control group, n = 30), PE (PE group, n = 24), or gestational hypertension (GH) (GH group, n = 21) were enrolled. We assessed serum albumin levels, diacron-reactive oxygen metabolites (d-ROMs) as an oxygen-derived free radical marker, and flow-mediated dilation (FMD) as a readout for vascular endothelial function during the gestational period and at one month after delivery. During the gestational period, FMD was lower, but d-ROM levels were higher, in the PE and GH groups compared with the Control group. Serum albumin levels were lower in the PE group compared with the Control and GH groups. d-ROM levels were inversely correlated with serum albumin levels (r = -0.54, p < 0.05) and FMD (r = -0.56, p < 0.05) in the PE group, and negatively correlated with FMD, but not serum albumin levels, in the GH group. Serum levels of d-ROMs and albumin, as well as FMD, were similar between groups after delivery. Our findings suggest that reduced serum albumin levels enhance the production of oxygen-derived free radicals, resulting in impaired maternal vascular endothelial function in parturients with PE.

Placental hypoplasia and maternal organic vascular disorder in pregnant women with gestational hypertension and preeclampsia.

Objective: This study aimed to investigate the etiology and pathology of preeclampsia (PE), a two-stage disorder involving uteroplacental dysfunction resulting from abnormal implantation and placentation, and gestational hypertension (GH), for which maternal organic vascular disorder is often an underlying factor.Methods: We assessed concentrations of oxygen free radicals (d-ROMs), maternal angiogenic factor (PlGF), and antiangiogenic factor (sFlt-1), placental hypoxic changes, oxidative DNA damage, and maternal organic vascular disorders in 23 women with PE (PE group), 13 with GH (GH group), and 16 with uncomplicated pregnancies (normal group). Intima-media thickness (IMT) of the carotid artery was assessed as a proxy for maternal organ vascular disorder. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for hypoxia-inducible factor-1α (HIF-1α), which reflects hypoxic changes, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which reflects oxidative DNA damage.Results: Maternal serum d-ROM concentrations were significantly increased in both GH and PE groups relative to the normal group. Maternal serum d-ROM concentrations were significantly increased in both GH and PE groups relative to the normal group. Maternal serum sFlt-1 concentrations, ratio of sFlt-1/PlGF, and proportions of HIF-1α-positive nuclei and 8-OHdG-positive nuclei were significantly higher in the PE group compared to GH and normal groups. IMT was significantly greater in GH and PE groups compared to the normal group, and was higher in the GH group compared to the PE group.Conclusions: Our findings suggest that placental hypoxic changes and oxidative DNA damage are severe in patients with PE and accompanied by an increase in antiangiogenic factors. Moreover, maternal organ vascular disorder was more severe in patients with GH compared to those with PE, as assessed by IMT.Key message: PE is a two-stage disorder that involves uteroplacental dysfunction, and organic vascular disorder underlies GH.