In nephrotic syndrome, plasminogen is aberrantly filtered from plasma to the urinary space and activated along the tubular system. In vitro, plasmin increases ENaC current by proteolytic cleavage of the γ-subunit. It was hypothesized that preeclampsia is associated with plasmin-dependent ability of tubular fluid to activate ENaC. Urine was sampled from 16 preeclamptic (PE) patients and 17 normotensive pregnant women (Ctrl). Urine was analyzed for plasmin(ogen), creatinine, albumin, aldosterone, Na
+
, K
+
, proteolytic activity, and for its effect on inward current in cortical collecting duct cells (M1 cells) by whole-cell patch clamp. In PE, urine plasmin(ogen): creatinine ratio was elevated 40-fold (geometric mean, 160 versus 4 µg/g;
P
<0.0001) and urine aldosterone: creatinine ratio was suppressed to 25% of Ctrl (geometric mean, 27 versus 109 µg/g;
P
<0.001). A significant negative correlation was found in PE between urinary plasmin(ogen) and aldosterone (
P
<0.05). In PE, proteolytic activity was detected at 90 to 75 kD by gelatin zymography in 14 of 16 patients and confirmed by serine protease assay. Immunoblotting showed active plasmin in PE urine. Whole-cell inward current increased in M1 cells on exposure to urine from PE (173±21%; n=6;
P
<0.001). The increase in current was abolished by amiloride (2 μmol/L;
P
<0.001), α
2
-antiplasmin (1 μmol/L;
P
<0.001), and heat denaturation (
P
<0.001). Preeclampsia is associated with urinary excretion of plasmin(ogen) and plasmin-dependent activation of ENaC by urine. Proteolytic activation of ENaC by plasmin may contribute to Na
+
retention and hypertension in preeclampsia.
Preeclampsia is characterized by hypertension, proteinuria, suppression of plasma renin-angiotensin-aldosterone, and impaired urine sodium excretion. Aberrantly filtered plasmin in urine may activate proteolytically the γ-subunit of the epithelial sodium channel (ENaC) and promote Na reabsorption and urine K loss. Plasma and urine was sampled from patients with preeclampsia, healthy pregnant controls and non-pregnant women, and from patients with nephrostomy catheters. Aldosterone concentration, urine plasminogen, and protein were determined. Exosomes were isolated by ultracentrifugation. Immunoblotting was used to detect exosome markers; γ-ENaC (two different epitopes within the inhibitory peptide tract), α-ENaC, and renal outer medullary K-channel (ROMK) and compared with human kidney cortex homogenate. Urine total plasmin(ogen) was significantly increased in preeclampsia, plasma and urine aldosterone was higher in pregnancy compared to non-pregnancy, and the urine Na/K ratio was lower in preeclampsia compared to healthy pregnancy. Exosome markers ALIX and AQP-2 were stably associated with exosomes across groups. Exosomal α-ENaC-subunit migrated at 75 kDa and dominantly at 50 kDa and was significantly elevated in pregnancy. In human kidney cortex tissue and two of four pelvis catheter urine, ~90-100 kDa full-length γ-ENaC was detected while no full-length γ-ENaC but 75, 60, and 37 kDa variants dominated in voided urine exosomes. There was no difference in γ-ENaC protein abundances between healthy pregnancy and preeclampsia. ROMK was detected inconsistently in urine exosomes. Pregnancy and preeclampsia were associated with increased abundance of furin-cleaved α-ENaC subunit while γ-subunit appeared predominantly in cleaved form independently of conditions and with a significant contribution from post-renal cleavage.
Preeclampsia is not associated with altered prostasin in placenta or plasma at term, but with increased prostasin in urine. An impact of prostasin-matriptase on placental development is likely to be at the level of activity and not protein abundance.
BACKGROUNDElectronic fetal heart rate (FHR) monitoring, also known as fetal cardiotocography (CTG), monitors the FHR simultaneously with uterine contractions. This is an indirect assessment of the oxygenation and the wellbeing of the fetus during labour. Most commonly, the FHR is monitored externally using an ultrasonic Doppler device and the contractions are monitored concurrently via an external strain-gauge device.During labour, when a more precise record of fetal wellbeing and its capacity to withstand the rigours of labour is required, internal monitoring may provide more accurate monitoring information by applying an electrode to the fetal scalp. The electrode picks up the fetal ECG and the CTG monitor converts it 'beat-to-beat' into the FHR record.
Objective: Midwives in Greenland observe that people give birth faster,
with fewer complications tentatively due to early maternal expulsive
efforts in second stage. Our aim was to quantify these observations and
potential geographical differences. Design: Bicentre observational
prospective cohort study. Method: Between October and December 2020, 50
participants in labour in Aabenraa (Denmark) and Nuuk (Greenland)
participated. Transperineal head-perineum distance was measured with a
handheld ultrasound scanner. Negative binomial regression was used to
calculate incidence rate ratio. Fetomaternal outcome was recorded and
compared Results: The median duration of maternal expulsive efforts was
23 minutes in Denmark compared to 10 minutes in Greenland (p=0.046).
This was adjusted for parity, epidural use and gestational age. In
Denmark 22 % and in Greenland 81 % started maternal expulsive efforts
before the fetal head was at the pelvic floor (p-value<
0.001). Conclusion: Although the duration of maternal expulsive efforts
and head-perineum distance was significantly different in the univariate
analysis, in the multivariate analysis this was not affected by
ethnicity. There was no significant difference in bleeding, perineal
tears, or Apgar scores. There is a tendency of a shorter duration of
maternal expulsive efforts in the active phase of the second stage of
labour distance in Greenland compared to practice in Denmark. However,
it seems that epidural and parity could be the main confounders to
explain the difference between the two groups, but this needs further
investigation.
Objective:The soluble Fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio has been introduced as a biomarker for diagnosing preeclampsia (PE) and the prediction of adverse pregnancy outcome. In a cohort of pregnant women with PE or at high risk of PE, the additive value of the sFlt-1/PlGF ratio for diagnosing PE and prediction of adverse pregnancy outcomes was investigated.Design and method: From September 2011 until August 2013 patients with suspected or confirmed clinical PE were recruited at the Erasmus MC. At time of admission, blood for measurement of sFlt-1 and PlGF was obtained. A sFlt-1/PlGF ratio of >85 was considered suggestive for PE. Clinical characteristics and pregnancy outcomes were retrieved from medical records. The clinical diagnosis of PE was made based on the ISSHP criteria, whereas the fullPIERS definition was used for the rating of adverse pregnancy outcomes.
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