Background: Preeclampsia is clinically featured by a rise in high blood pressure and reduction in glomerular filtration rate and protein excretion in urine, on the other hand, the fundamental pathophysiological pathways are un clarified. Renalase as a biological marker is a newly revealed protein concerned in manipulation and adjustment of blood pressure levels in human physiology.
Methodology: serum plasma levels of renalase were assayed in healthy Gestations, and gestations with mild and severe PET matched for subject age, gestational age, in the third gestational trimester. Serum renalase levels have been compared in gestations with mild, severe preeclampsia and without preeclampsia gestations as controls. Other laboratory parameters and indices have been assessed and evaluated in correlation with serum renalase.
Results: In healthy gestations serum levels of renalase were statistically significantly higher than in mild and severe preeclampsia cases. Serum levels of renalase had an inverse correlation with blood pressure measurement levels and had a positive correlation with glomerular filtration rate.
Conclusion: The results displayed that the pathophysiological development of preeclampsia in gestations is linked with alteration in levels of serum renalase. Elevated blood pressure levels and renal damage that feature this pathological disorder is impacted by low serum levels of renalase.
Gestation is featured by physiologic adaptations within systemic and renal hemodynamic systems. The initial hemodynamic adaptation in gestation is crucial systemic arterial vasodilatory physiological change . On the other hand, hypertensive illnesses involve up to 10% of all gestations . Preeclampsia the chief and most prominent hypertensive illness of gestation is the most common etiology and cause of various fetal and maternal clinical morbidity and mortality. Even though the clinical effect of the preeclampsia, management protocols of that disorder did not change significantly. This could be due to unclear pathophysiologic pathways of the disease. It is described by raised systemic arterial resistance levels. Failure of vascular refractoriness physiological feature to vasoconstricting agents contribute to the systemic occurrence of vascular vasoconstriction in preeclampsia . A new hypothetical feature that has implied and investigated to elucidate the rise in blood pressure levels in gestations that have hyperadrenergic status may donate to the pathological pathway of preeclampsia.
Prior research studies displayed that amplified sympathetic
vasoconstricting effect is cornerstone pathological mechanism at vascular system level causing a raised vascular resistance [4-6]. Renalase is a variety of monoamine oxidase enzyme and it acts directly to degrade catecholamines (noradrenaline, adrenaline and dopamine). It reduces the blood pressure levels in vivo by inhibiting cardiac contractility feature and heart rate and blocking the compensatory mechanism rise in peripheral levels of vascular tone [7,8]. Consequently serum renalase is considered as a novel biological marker for primary hypertensive disease. It is secreted into the blood by the renal system. Up to date research studies have additionally displayed and revealed that renalase is secreted and synthesized within the peripheral nervous system, hypothalamus and the pituitary . In an experimental research study, renalase expressive features is augmented in ovaries during gestation . In the current research study the main goal to investigate the serum levels of renalase levels in clinically normal gestations and correlations between serum levels of renalase and blood pressure levels, glomerular filtration rate and protein excretion in urine in gestations with mild and severe preeclampsia .
The total cohort recruited for the research, 150 gestations
having an age range between 20-39 yrs (50 normotensive
gestations, 50 gestations with mild preeclampsia and 50
gestations with severe preeclampsia) were enrolled for the
research study. Preeclamptic gestations (10) with a protein
excreted in urine >300mg/l collected at random or >300mg/24
h after 20 gestational weeks were recruited in the research study
for estimation of GFR the following equation has been used
Small for Gestational Age was described as a birth weight
under the 10th centile for gestational age by fetal growth charts
(11). Mean gestational age of gestations with mild preeclampsia
was 35±2 gestational weeks with severe preeclampsia had a mean
gestational age of 34±3 gestational weeks. The 40 normotensive
gestations were recruited from outpatient clinics according to
inclusive research criteria (gestation age above 20 weeks); and
exclusive research criteria ((1) history of preeclampsia in prior
gestations; (2) history of hypertension and renal disorders;
(3) history of cardiovascular disorders). Mean gestational age
of normal gestations have been 34±3 weeks. The demographic
research subjects’ criteria (age, history of hypertensive disorders
and preeclampsia, gestational weeks, BMI) of the whole research
cohort was obtained at the start of the current research study.
Serum levels of creatinine, albumin, and uric acid levels
of gestations were obtained from hospital filing system. The
research study performance has been approved by the Ain Shams
Maternity Hospital Ethical Committee and a written research
consent was obtained from each research study subject.
Blood samples have been collected and centrifuged at 1000
× g for 10 minutes. Serum levels of renalase were assayed
by usage of ELISA kit for renalase. (Aviva Systems Biology
RNLS ELISA Kit (Human) (OKEH00771) is based on standard
sandwich enzyme-linked immuno-sorbent assay technology.
An antibody specific for RNLS has been pre-coated onto a 96-
well plate (12 x 8 Well Strips). Standards or test samples are
added to the wells, incubated and removed. A biotinylated
antibody detector specific for RNLS is added, incubated and then
washed. Avidin-Peroxidase Conjugate is then added, incubated
and unbound conjugate is washed away. An enzyme reaction is
created by adding of TMB substrate which is catalyzed by HRP
that generated a blue color product that converts to yellow
color after adding acidic stop solution. The density of yellow
coloration read by absorbance at 450nm and is quantitatively
proportional to the amount of sample RNLS captured in well)
All samples were measured in duplicate and the average indices
of two measurements was recorded for each patient. The intraassay
coefficient of variation (CV) was < 10%, and inter-assay CV
was < 12%. The detectability range of the renalase assay was 21-
364mcg/mL. Collected 24h urine was used for quantitation of
daily urinary protein excretion.
Urinary protein concentrations have been quantified
using dipstick method. Systolic and diastolic blood pressure
was measured three subsequent times by usage of a
sphygmomanometer after the cases had a period of rest for at
least 15min; the mean of the lowest two readings was obtained.
Blood pressure was measured three times a day in a supine
position, and the means of indices recorded 3 days before the
starting the antihypertensive agent have been obtained.
The SPSS program version 15.0 was used for statistical
analysis. Results are presented as means±SDs values.
Kolmogorov-Smirnov and Levine’s tests were used for
distribution and variance homogeneity. The parameters with
a normal distribution were compared between groups by
parametric tests such as the ANOVA test and t-tests. Parameters
with non-normal distribution were compared between groups
by non-parametric tests such as Mann-Whitney U test or Fisher
Exact Test. Similarly, correlation analyses between parameters
were made by Pearson’s or Spearman’s correlation tests
depending on the distribution of data; a p-value of < 0.05 was
considered statistically significant.
The demographic and laboratory data of the study population
are presented in Table 1. There were no statistically significant
differences in demographic features between normal gestation
as control, mild and severe with preeclampsia. Mean serum uric
acid levels, serum creatinine, and blood pressure measurements
were less in healthy gestations than mild and severe preeclamptic
cases (Table 1). In gestations with preeclampsia, BP levels,
serum levels uric acid, SGOT, SGPT, alkaline phosphatase and
proteinuria/24h were greater than healthy gestations (controls).
Hemoglobin indices were slightly lower in gestations with mild
and severe PE than healthy gestations (Table 1). Birth weight
was statistically significantly lower, and the number of women
with SGA infants were significantly higher in gestations with
mild and severe preeclampsia than healthy gestations.
In healthy pregnant; renalase levels were statistically
significantly higher than in mild and severe preeclampsia
cases. (316+/-23 VS, 223+/-12VS, 152+/-21, consecutively,
p value=0.001). Correlation analysis in research cohort
displayed that levels of serum renalase had an inverse statistical
correlation in a statistically significant manner with systolic and
diastolic blood pressure indices; (p= 0.001, r= -0.41; p= 0.001,
r= -0.39 consecutively). Additionally, serum levels of renalase
had an inverse correlation with 24h protein excretion in urine
(p=0.004, r=-0.22) on the other hand serum, renalase levels were
not correlated statistically with cases age and gestational age.a
The current research study displayed that serum levels
of renalase are raised in healthy gestations and reduced in
gestations with preeclampsia [12,13]. Renalase is secreted
in blood and its serum levels are influenced by three main
factors: renal functional performance, renal perfusion levels
and catecholamine serum levels. Various recent observational
research studies have investigated the correlation between
genetic polymorphisms in the renalase gene and the hazardous
risk of pathological development of hypertensive disorders. In
addition, renalase levels seem to be associated with systolic and
diastolic blood pressure levels, glomerular filtration rate and
urinary protein excretion in pregnant women with preeclampsia.
Since renalase metabolizes catecholamines, it is could be of
clinical value in management protocols in disorders associated
by raised sympathetic activity .
Prior research studies displayed a direct correlation with
the glomerular filtration rate and renal mass. Additionally,
in the isolated perfused animal kidney model infusions of
catecholamine trigger renalase secretion levels in the renal
vein. Systemic vascular resistance in human gestation falls
significantly as a part of physiological pregnancy changes and
leads to a decrease in mean arterial pressure, which causes a
compensatory rise in cardiac output levels. A reduced cardiac
output level or arterial VD causes a reduction in efficient arterial
blood volume indices. This consequently causes the stimulation
of the sympathetic system [15,16].
Additionally, renal VD exists concurrently with systemic VD
and it is also linked with a 30-50% rise in renal blood flow levels
and glomerular filtration rate indices. It is probable that the
revealed elevated serum level of renalase in gestation represents
a response to elevated plasma catecholamines and increased
GFR. In an experimental study, Zhou et al. displayed that renalase
is highly expressed in reproductive/steroidogenic enzymatic
system, particularly in ovaries and adrenal gland and renalase
serum levels can be augmented by gestation [17,18].
Our current research findings displayed that cases with mild
and severe preeclampsia PE gave birth to small for gestational
age newborns than clinically healthy gestations. It is well proven
from prior research studies that preeclampsia is correlated with
raised risk of infants with small for gestational age. This could
clarify the correlation displayed in the current research between
serum renalase levels and birth weight [1,5,11].
Various research studies on animal and human subjects
uncover the pathophysiological fact that renalase regulates
blood pressure. Renalase deficiency is correlated with
hypertensive disorders and raised sympathetic activity [3,8].
Likewise, research studies conducted on cases with resistant
hypertensive disorders reveal and display that arterial plasma
concentrations of renalase are inversely correlated with systolic
blood pressure. Recent research studies have also investigated
the role and therapeutic value of recombinant human renalase
has a powerful antihypertensive pharmacological impact in
rodent animal models of hypertensive disease [4,7].
In another research study conducted in a similar manner
by Zehra et al 2016 in which renalase was assayed in healthy
Research control study subjects, healthy gestations and
gestations having PET matched as regards age, gestational age,
within the third gestational trimester. Renalase serum levels
were statistically analysed and compared in gestations with
and without PET and non-pregnant research control study
subjects. Variables of interest linked with renalase serum levels
in gestation were also assesed. The research group revealed
the following results in which healthy pregnant serum renalase
levels were statistically significantly higher than in study subject
controls. On the other hand, gestations affected by preeclampsia
had decreased serum levels of renalase in comparison to healthy
study subject control group. renalase serum levels had an
inverse correlation with blood pressure measurements and were
positively statistically correlated with GFR. The research team
concluded that development of preeclamptic pathophysiologic
process in pregnancy is associated with alteration and significant
changes in renalase serum levels. High blood pressure indices
and renal affection that clinically feature this disease are affected
at least partially by low serum renalase concentration. These
findings are in great jarmony with the current research findings
Our Research study results is in harmony with the findings
of the prior research experimental models and clinical
data in hypertensive cohorts. Renalase was recommended
hypothetically to have a cornerstone role in the pathological
development of hypertensive disease and renal dysfunction
in general population; therefore this correlation and linkage
could be established in hypertensive and renal disorders in
gestation . Additionally, low serum renalase levels were
correlated with blood pressure indices elevation, and renal
insufficiency, presented by proteinuria and low levels of GFR
in gestations with PE. The current research study findings
uncover the pathophysiological significance of serum renalase in
preeclampsia development . Interestingly an ideal research
zone is very crucial to develop more inderstanding of renalase
levels pathophysiological role in development of hypertensive
disorders in pregnanacies, it could be an agent of potential
diagnostic and curative value. Additional broader scale research
studies are required to clarify the current research study findings.