Urinary Epidermal Growth Factor Concentrations Research Articles

Epidermal growth factor and its influencing variables in healthy children and adults

Background & objectiveEpidermal growth factor (EGF) stimulates cell proliferation and differentiation after binding to its receptor. Next to its role in magnesium homeostasis, EGF disturbances have been described in oncology, diabetes and autism spectrum disorders. The aim of this study was to determine EGF serum and urine values for both healthy children and adults. Next, we investigated the relation between several variables and urinary and serum EGF concentrations.MethodsBoth healthy adults (n = 50) and children (n = 78) were included. Serum and urinary EGF concentrations were measured with ELISA technology.ResultsSerum EGF was inversely correlated with age (r = —0.873; p<0.001) and positively correlated with serum magnesium (r = 0.597; p<0.001). The urinary EGF was also inversely correlated with age (r = -0.855; p<0.001). In adults and children older than 13 years of age, the urinary EGF significantly differed between sexes (p = 0.001). Urinary EGF was positively correlated with serum magnesium (r = 0.583; p<0.001) and creatinine clearance (r = 0.524; p<0.001) and negatively correlated with the fractional excretion of magnesium (r = 0.248; p = 0.014). In a multivariate model, age and serum magnesium remained independently related to serum EGF while age, serum EGF and serum magnesium remained independently related to urinary EGF.ConclusionsThis study provides valuable insights in urinary and serum EGF patterns in healthy subjects. By systematically correcting EGF for body surface, significant correlations with age, gender and magnesium were observed.

Longitudinal Study of the Role of Epidermal Growth Factor on the Fractional Excretion of Magnesium in Children: Effect of Calcineurin Inhibitors.

Background: It was shown in animal models and adults that the epidermal growth factor (EGF) is involved in the pathophysiology of calcineurin inhibitor (CNI) induced renal magnesium loss. In children, however, the exact mechanism remains unclear, which was set as the purpose of the present study. Methods: Children with nephrotic syndrome and renal transplant children treated with CNI (n = 50) and non-CNI treated children (n = 46) were included in this study. Urine and serum samples were collected at three time points to determine magnesium, creatinine, and EGF. The magnesium intake was calculated from a food frequency questionnaire. Results: Serum Mg2+ and urinary EGF/creatinine were significantly lower in the CNI treated children, with significantly more CNI-treated children developing hypomagnesaemia. In the latter patients, the fractional excretion of magnesium (FE Mg2+) was significantly higher. Urinary EGF, age, renal function, and serum magnesium were independent predictors of the FE Mg2+. Only 29% of the children reached the recommended daily intake of magnesium. The magnesium intake did not differ between hypomagnesemic and normomagnesemic patients and was not a predictor of the FE Mg2+. Conclusions: In CNI-treated children who developed hypomagnesemia, the FE Mg2+ was increased. The urinary EGF concentration, age, and renal function are independent predictors of the FE Mg2+.

Prediction of the outcome of antenatal hydronephrosis: significance of urinary EGF

Down-regulation of epidermal growth factor (EGF) in the renal parenchyma has been demonstrated in children who underwent pyeloplasty due to ureteropelvic junction obstruction (UPJO). Urine levels of EGF were confirmed to parallel this finding before and after surgery. The aim of our study was to evaluate the relationship between urinary EGF (uEGF) concentrations and Society of Fetal Urology (SFU) high-grade hydronephrosis in infants presenting unilateral antenatal hydronephrosis (ANH). This was a prospective study involving 45 infants (33 in the observational group, 12 in the surgical group) who presented with unilateral ANH. Postnatal evaluation included a clinical examination, renal ultrasonography, and voiding cystourethrography. Diuretic renal scans were performed in infants with an initial SFU grade 3 or 4 hydronephrosis or increasing hydronephrosis during follow-up. Pyeloplasty was performed when a well-tempered renogram showed an obstructive drainage curve with a half-life of >20 min and/or an obstructive washout curve pattern during the diuretic phase. We studied the longitudinal changes in SFU hydronephrosis grade and uEGF in each group and compared concentration levels at three time points in both groups. The enzyme-linked immunosorbent assay (ELISA) method was used to measure EGF concentrations in the urine. The results were normalized with urinary creatinine (Cr). During the first 6 months, from 6 to 12 months, and in the second year of life, median SFU hydronephrosis grade and uEGF levels were 2, 2 (p = 0.015), and 1 (p < 0.01), and 50, 59 (p = 0.015), and 69.5 ng/mg Cr (p < 0.01), respectively, in the observational group. In the first 6 months, preoperatively and at 3-12 months postoperatively, the median SFU hydronephrosis grade and uEGF levels were 4, 4, and 3 (p > 0.05), and 38, 46, (p > 0.05), and 55 ng/mg Cr (p < 0.01), respectively, in the surgical group. uEGF levels in the first 6 months of life were significantly lower in the surgical group than in the observational group (p < 0.01). Patients in the observational group with SFU grade 3-4 hydronephrosis showed higher uEGF levels than those in the surgical group with SFU grade 3-4 in (p = 0.048). Urinary EGF changes over time are associated with inverse changes in SFU hydronephrosis grade, which suggests a role for uEGF as a predictive marker of worsening hydronephrosis grades in infants with ANH. uEGF in the first 6 months of life may predict the need for surgery in infants with ANH.

URINARY EPIDERMAL GROWTH FACTOR IN DIFFERENT RENAL CONDITIONS IN CHILDREN

Several studies have demonstrated the important role of growth factors, particularly epidermal growth factor (EGF) and transforming growth factor α (TGFα), in cellular growth after renal damage. EGF is mainly synthesized by the kidney. Many studies indicate that urinary EGF concentration significantly decreases in patients with acute and chronic renal failure. In this study we determined urinary EGF concentrations in children with renal and/or urological pathologies. We investigated 38 patients, 17 males and 21 females, of 3.34 ± 2.96 years (mean ± standard deviation), who were followed in the Nephrologic Unit of the Pediatric Department of the University of Verona for recurrent urinary tract infections: seven of these had vesicoureteric reflux and 4 had hypodysplasia. The results were compared with those from a healthy age-matched group of 44 children. In all patients, we assessed renal function including an examination of the urine with a microbiological evaluation. Moreover, a renal ultrasound and a voiding cystourethrogram were performed. Urinary EGF was measured by a radioimmunoassay, using polyclonal goat antibodies. In all patients, laboratory parameters were within the normal range. In 34 patients the renal ultrasound was negative and in 4 cases structural alterations of the renal parenchyma were found. Voiding cystourethrography detected 7 instances of vesicoureteric reflux. In controls 10°, 50°, 90° percentile uEGF values were 7.3, 19 and 40.4μg/L, respectively. Mean urinary EGF values were 22.22 ± 16 μg/L. Urinary EGF values were 54 ± 35.2 μg/L in patients with recurrent urinary tract infections and without urinary malformations, 81 ± 29.37 μg/L in patients with vesicoureteric reflux and 22.30 ± 22.90μg/L in patients with hypodysplasia, respectively. There was a statistical significant difference between controls and groups A (p < 0.001) and B (p < 0.001) respectively, while the difference between group C and controls wasn't significant (p = 0.044). Results are reported in Figure . We believe that our results could be helpful for further studies on pathophysiology of growth factors in different renal conditions of children.Figure 1. Urinary epidermal growth factor concentrations (uEGF) in the three groups considered (data are expressed as mean values ± standard deviation) compared with the line of the 90° percentile value calculated in the control group. Unpaired t-test: Group A vs. controls, p < 0.001. Group B vs. controls, p < 0.001. Group C vs. controls, n.s. (p = 0.487). Group A vs. Group B, p = 0.044.

Effect of asphyxia on urinary epidermal growth factor levels in newborns.

Urinary epidermal growth factor (EGF) excretion in normal newborn as well as neonates with asphyxia was investigated by using radioimmunoassay, and serum creatinine (Scr) levels determined at the same time. The results showed that in severe asphyxia group the ratio of urinary EGF to urinary creatinine (Cr) (EGF/Cr), an index reflecting EGF excretion, was decreased on the first day (P < 0.05) and reached the lowest level on the third day (P < 0.01). However, EGF/Cr values were decreased only on the third day in neonates with mild asphyxia (P < 0.05). On the seventh day, EGF/Cr values of neonates with asphyxia rose to normal. There were a negative correlation between urinary EGF/Cr and Scr. It is suggested that EGF may play a role in the repair of acute renal injury after asphyxia and the detection of urinary EGF concentration is useful in the judgment of severity of renal injury and in the evaluation of the recovery of renal tubule after injury.

Effects of extracorporeal shockwave lithotripsy on urinary concentration of epidermal growth factor.

In a prospective study, we tried to determine whether extracorporeal shockwave lithotripsy (SWL) has any effect on urinary epidermal growth factor (EGF) concentrations and to investigate whether EGF can be used as a marker for detecting shockwave-induced impairment of distal tubular cells. A total of 12 patients with renal pelvic or caliceal stones < or = 2 cm undergoing anesthesia-free SWL without ancillary measures and a control group of 10 patients without any urologic symptoms were included in this study. The urinary concentrations of EGF were measured by radioimmunoassay before and 4 hours, 24 hours, and 7 days after SWL. Relative urinary EGF concentrations were expressed as the ratio of EGF to creatinine (ng/mL creatinine). The mean urinary EGF concentration (mean +/- standard error) in control subjects and patients with renal pelvic or caliceal stones before SWL was 23.90 +/- 3.15 ng/mL creatinine and 22.18 +/- 6.85 ng/mL creatinine, respectively (p > 0.05). In patients with stones, we found a decrease in urinary EGF concentration 4 hours, 24 hours, and 7 days after SWL. Indeed, 7 days after SWL, the EGF concentration was on average half of the original value, a biologically significant, although not statistically significant, decrease.

Decreased urinary epidermal growth factor in children with acute renal failure: epidermal growth factor/creatinine ratio not a reliable parameter for urinary epidermal growth factor excretion.

To verify some animal experimental results in humans, we have studied urinary epidermal growth factor (EGF) excretion in normal children as well as children with acute renal failure (ARF). Urinary EGF excretion was expressed as a ratio of urinary EGF to urinary creatinine concentration (EGF/Cr) for random and 24-h urine, and a daily total urinary EGF for 24-h urine. The highest urinary EGF/Cr in children was found at 1 mo to 3 y of age. There was a highly significant correlation between random urine EGF/Cr and 24-h urine EGF/Cr (r = 0.92, p < 0.001), whereas no correlation of urinary EGF/Cr with daily total urine EGF was found. During the course of ARF, a decline in urinary EGF/Cr from the period before peak serum creatinine to the period after the declination of serum creatinine was noted (p = 0.013, n = 13, by repeated measure analysis), with a constant low daily total urine EGF (p value not significant). However, a rise in both urinary EGF/Cr and daily total urine EGF was found between the period of serum creatinine decline and the period of completely normal serum creatinine (p < 0.001). Serum EGF remained unchanged throughout the course of ARF. These results suggest 1) the possible role of EGF in renal growth or maturation during the first 2 or 3 y of life, 2) the possible renal origin of human urinary EGF, and 3) decreased urinary EGF excretion in children with ARF. In particular, EGF/Cr is not a reliable indicator for the expression of actual urinary EGF excretion in ARF. Instead of urinary EGF/Cr, urinary EGF concentration may be used to predict the daily total urinary EGF excretion during ARF. These results provide the pattern of urinary EGF excretion during ARF in children and may be of help for further clinical studies.

Dexamethasone therapy is associated with a rise in urinary epidermal growth factor concentrations in the preterm infant

The effect of glucocorticoid hormones on epidermal growth factor (EGF) concentrations has not been described in the premature infant. We examined this relationship in a group of infants treated with dexamethasone for airway edema (three to five doses) or chronic lung disease (six weeks of a tapering protocol). We collected urinary samples in 45 infants (25 for airway edema, 20 for chronic lung disease) before, during and after the use of dexamethasone. The EGF values were unchanged in infants that were given dexamethasone for airway edema. In contrast, all infants treated for chronic lung disease increased their EGF values by 1 week of therapy. At the end of the dexamethasone taper, ten of the infants had recovered successfully from ventilatory support. This group of infants had post-therapy EGF values that were significantly higher than pretherapy values. In the ten infants that were still ventilator dependent at the end of therapy, EGF values were not different from pretherapy values. We conclude that dexamethasone therapy was associated with an increase in urinary EGF values in the preterm infant treated for at least 1 week. The positive correlation of tapering from ventilatory support with increases in EGF values suggests that EGF may be a marker of dexamethasone effect or an effector of dexamethasone action.

Urinary epidermal growth factor concentration in patients affected by ADPKD.

Urinary epidermal growth factor concentration in patients affected by ADPKD.

Urinary and plasma epidermal growth factor levels are decreased in neonates with intrauterine growth retardation and in their mothers.

Epidermal growth factor (EGF) concentrations in urine and plasma samples collected from pregnant women and neonates were measured by RIA. The EGF concentration of the first voided urine was higher in appropriate-for-date (AFD) neonates (33.9 +/- 23.0 ng/mg creatinine) than in those with intrauterine growth retardation (IUGR; 23.5 +/- 7.7 ng/mg creatinine, p less than 0.05) and heavy-for-date (19.8 +/- 5.2 ng/mg creatinine, p less than 0.05) neonates. The urinary EGF concentration of pregnant women showed no marked changes throughout pregnancy. Urinary EGF concentrations of women with AFD fetuses (45.9 +/- 31.2 ng/mg creatinine) did not differ significantly from those of women with diabetes (39.9 +/- 26.8 ng/mg creatinine) or women with multiple fetuses (44.6 +/- 30.6 ng/mg creatinine). However, women with IUGR fetuses showed lower urinary EGF concentrations (13.8 +/- 7.4 ng/mg creatinine, p less than 0.05) than women with AFD fetuses. Maternal and fetal platelet-poor plasma EGF concentrations at delivery were lower in the IUGR group (mother: 2.62 +/- 0.38 ng/ml, fetus: 2.16 +/- 0.07 ng/ml, respectively, p less than 0.05 and p less than 0.005) than in the AFD group (mother: 3.34 +/- 0.64 ng/ml, fetus: 3.24 +/- 0.93 ng/ml). In the IUGR group, the EGF concentration in fetal blood was always lower than that in maternal blood (p less than 0.05), although the AFD groups showed no such difference. These data suggest that EGF levels are closely related to fetal growth.

Epidermal growth factor (EGF) expression in the congenital polycystic mouse kidney

The mechanisms responsible for renal cyst formation in congenital polycystic kidney disease remain unknown, although abnormalities of cellular metabolism, basement membrane components, and growth factors have been suggested. In the present study, we examined a potential role for epidermal growth factor (EGF) in cyst formation in a mouse model. We measured growth factor activity and concentration in renal cyst fluid, urine, and serum obtained from mice with congenital polycystic kidney disease (cpk). In affected mice, both growth factor activity of urine and the urinary EGF concentration were much lower than unaffected littermate controls even when corrected for creatinine concentration. Although the growth factor activity was much lower in affected mice, there were significant differences in the regional distribution of EGF in animals with cysts. Both growth factor activity and EGF concentration were greater in cyst fluid when compared to urine. Growth factor activity in cysts was completely inhibited by anti-EGF antibody using BALB/MK epithelial keratinocytes as targets. The expression of EGF mRNA in kidneys from affected mice was markedly decreased when compared to littermate controls. These results suggest that decreased EGF production and local differences in EGF concentration may contribute to cyst formation.

Epidermal Growth Factor (Egf) Concentrations in Amniotic Fluid and Maternal Urine During Pregnancy

Epidermal growth factor (EGF) was measured in amniotic fluid and maternal urine from women undergoing amniocentesis for genetic studies (15-22 weeks' gestation, n = 36) and lung maturational studies (35-39 weeks' gestation, n = 20). Amniotic fluid EGF concentrations (mean +/- SD) were higher near term (87 +/- 71 pM) than mid-gestation (35 +/- 8 pM) (p less than 0.0001). Urinary EGF concentrations were higher near mid-gestation (53.9 +/- 30.8 micrograms EGF/g creatinine) than near term (33.4 +/- 14.1 micrograms EGF/g creatinine) (p less than 0.006). There was no correlation between individual amniotic fluid and urinary EGF concentrations. The amniotic fluid EGF concentrations correlated with gestational age. However, there was no relationship between EGF concentrations and pulmonary maturity studies or placental weight from the pregnancies studied near term. We conclude that the concentration of EGF in amniotic fluid increases towards term. The lack of correlation between amniotic fluid and maternal urinary EGF concentrations suggests that there probably is a different source of EGF in the two compartments and that EGF does not cross the placenta to any great extent.

Epidermal growth factor in urine of pregnant women and in amniotic fluid throughout pregnancy

To investigate the role of epidermal growth factor (EGF) in feto-placental development, we measured the urinary and amniotic fluid EGF levels throughout pregnancy. Thirty urinary samples of non-pregnant women, 85 of normal pregnant women, 21 of women with toxemic pregnancy, 17 of postpartum women and 30 of newborns, and 55 amniotic fluid samples of pregnant women with a variety of conditions necessitating amniotomy and amniocentesis at 25-39 weeks of gestation were collected. EGF concentrations were measured by double-antibody radioimmunoassay. Urinary EGF levels of pregnant women reached their peak (24.6 +/- 6.7 ng/mg creatinine) at 19-22 gestational weeks; after that, they slightly decreased. Although there is no significant difference between the urinary EGF levels of non-pregnant women (19.0 +/- 5.1) and those of pregnant women (18.1 +/- 3.2), the EGF levels of toxemic women (12.2 +/- 1.5) were lower than those of normal pregnant women. The levels in puerperium women were similar to those found during pregnancy. However, the neonates had higher urinary EGF concentrations than those in pregnant women. On the other hand, EGF levels in amniotic fluid were higher according to gestational weeks and the levels of intrauterine growth retardation (IUGR) cases lower compared with normal pregnancy. Furthermore, EGF concentrations in amniotic fluid have a significant correlation with the creatinine levels in amniotic fluid. These data suggest that EGF plays an important role in fetoplacental development and it is possible that the measurement of amniotic fluid EGF might become available for the clinical assessment of fetal maturation.

Effect of salivarectomy on the growth of gastrointestinal mucosa and urinary secretion of epidermal growth factor in rats

The effect of salivary epidermal growth factor (EGF) on the growth and metabolism of gastrointestinal mucosa was examined by comparing DNA synthesis, DNA and RNA content, and weight of mucosa of salivarectomized and sham operated male rats. DNA synthesis of gastric mucosa was suppressed at 2 days after salivarectomy. Both weight and DNA content of oxyntic mucosa in the salivarectomized group were significantly lower than that of the sham operated group. Although salivarectomy suppressed DNA synthesis of jejunal mucosa, the difference was not significant statistically. The effect of salivarectomy on colonic mucosa was least in the gastrointestinal tract. Such a result suggested that the gradient-oriented antitrophic effect was brought about by salivarectomy. Urinary EGF excretion after salivarectomy was examined by radioreceptor assay. Although the antitrophic effect of salivarectomy on oxyntic mucosa was highest on day 2, no significant difference of urinary EGF concentration was detected on day 2. From these results it is suggested that the effect of salivarectomy on the gastrointestinal tract was not due to the change of EGF in systemic circulation but due to the change of luminal EGF.

Mouse epidermal growth factor concentrations are altered by gonadectomy and treatments with estradiol and progesterone

In adult male and female mice we compared the epidermal growth factor (EGF) concentrations after gonadectomy and studied the effects of postgonadectomy treatments with estradiol and progesterone. In gonadectomized mice the mean concentration of EGF in the submandibular salivary gland (SMG) was (7-fold) higher in the females than the males. In the kidneys the males had (1.3-fold) higher levels of EGF than the females. Yet, gonadectomized males had higher plasma EGF levels and females higher urinary EGF concentrations. Estradiol treatment clearly decreased the EGF concentration in the SMG and increased it in urine and kidneys. Progesterone decreased male kidney EGF. Combined treatment with estradiol and progesterone increased the EGF concentration in the male urine and SMG, and decreased it in male kidneys.

Growth factors and the thyroid: effects of treatment for hyper- and hypothyroidism on serum IGF-I and urinary epidermal growth factor concentrations

We investigated the impact of thyroid hormone levels on serum concentrations of IGF-I and urinary epidermal growth factor (EGF) in hyper- and hypothyroid patients before and during medical treatment. Serum IGF-I levels measured with radioreceptor-assay decreased in 12 hyperthyroid patients from 1.25 (1.02-1.80) to 1.02 (0.77-1.78) X 10(3) U/l (P less than 0.01), whereas a non-significant increase in 8 hypothyroid patients--from 1.14 (0.85-1.40) to 1.39 (1.08-1.80) X 10(3) U/l was recorded. Urinary EGF, measured with radioimmunoassay decreased in 10 hyperthyroid patients from 68.0 (38.0-122.9) to 40.9 (23.6-100.3) micrograms/g creatinine (P less than 0.001) and increased in 7 hypothyroid subjects from 23.8 (17.5-35.8) to 36.1 (24.7-60.1) micrograms/g creatinine (P less than 0.05). In hyperthyroidism, but not in hypothyroidism, the urinary excretion of creatinine changed significantly from 0.66 (0.26-1.21) to 1.52 (0.81-2.59) g/l (P less than 0.001) during treatment, thus affecting the EGF excretion values. However, a comparison of untreated hyperthyroid with untreated hypothyroid patients showed a highly significant difference in EGF excretion (P less than 0.001) despite a non-significant difference in creatinine excretion between the two groups. FT4 I concentrations correlated significantly (r = 0.83) (P less than 0.001) to EGF values in untreated hyper- and hypo-thyroid patients. Data from the present study thus conform with the view that the growth promoting effect of thyroid hormones involves a stimulated synthesis or release of classic growth factors.

Urinary epidermal growth factor concentrations in various human malignancies.

We determined the concentrations of immunoreactive epidermal growth factor in the urine (U-irEGF) of 97 adult patients with various malignancies, including carcinomas of the urinary bladder, kidney, stomach, colon, rectum, breast, endometrium, uterine cervix, ovary, vagina, prostate, pancreas and thyroid, liposarcoma and skin melanoma. The relative U-irEGF concentrations (ng m-1 creatinine) were higher (P = 0.002) for the whole series of female patients than for healthy controls matched for sex and age. Such difference did not appear for male patients. The only specific group with a statistically supranormal U-irEGF concentration (P = 0.0005) comprised women with endometrial carcinoma of the uterus.

1283 ROLE OF EPIDERMAL GROWTH FACTOR IN THE PHENOTYPIC EXPRESSION OF LEPRECHAUNISM

Epidermal growth factor (EGF) is a polypeptide hormone important in growth and differentiation of multiple cell types. It has a wide range of biological activities including precocious eruption of teeth, gut mucosa hyperplasia, and proliferation of epidermal cells in mice. Despite multiple known biological functions and presence in several body fluids, no disease state has been identified in which there is either a deficiency or excess of EGF. Leprechaunism (L) has many of the characteristics expected in EGF hypersecretion, i.e., severe acanthosis nigricans, hirsutism, pachyderma, precocious breast development and hypertrophy of gut and genitals. We have measured urinary EGF excretion in an 8-year-old patient with L over several years and found a mean concentration to be 151.9±50.4μg/gm cr. In comparison we have measured urinary EGF concentrations in normal children and children with various disease states. EGF excretion was linear with creatinine excretion and not influenced by age. The mean EGF excretion is 26.7±4.3μg/gm cr in control children as compared to 29.6±1.1 and 39.8±1.6μg/gm cr in normal adult males and females respectively. Blood EGF levels in our patient were increased above normal. Measurement of other gut hormones were normal. We conclude that many of the phenotypic manifestations of L are secondary to excessive EGF, thus providing a disease for this well characterized but otherwise orphan hormone.