Urotensin-II levels in children with minimal change nephrotic syndrome
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- Balat, A., Pakir, I.H., Gok, F. et al. Pediatr Nephrol (2005) 20: 42. doi:10.1007/s00467-004-1716-5
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Human urotensin-II (hU-II) is the most potent mammalian vasoconstrictor identified to date. Although it is expressed mainly in the brain and spinal cord, it is also detected in other tissues, such as the kidney. It has been speculated that U-II might be an important physiological mediator of vascular tone and blood pressure in humans. To our knowledge, no studies have investigated the level of U-II in children with minimal change nephrotic syndrome (MCNS). Considering the renal synthesis and vasoactive role of U-II, we aimed to measure the plasma and urinary levels of U-II in children with MCNS, and investigate the correlation with other clinical and laboratory findings. Twenty-six children with clinical MCNS, ranging in age from 2 to 7 years, were compared with 16 healthy age- and sex-matched controls. The median age of the children was 4.73±2.36 years. U-II level was measured by RIA. Plasma U-II concentrations (pg/ml) were decreased during relapse (20.11±14.43 in relapse, 38.94±23.86 in remission, P <0.05), whereas urinary U-II levels (pg/mg urinary creatinine) were significantly higher in relapse than in remission (37.31±28.43 in relapse, 31.09±21.10 in remission, P <0.05). We could not detect any relationship between U-II levels and other clinical and laboratory parameters. Our data indicate that the important changes in plasma and urinary U-II levels during relapse may be the result of heavy proteinuria rather than playing a role in mediating the clinical and laboratory manifestations of MCNS in children.
KeywordsMinimal change nephrotic syndromeUrotensin-II
Human urotensin-II (hU-II) is a cyclic peptide of 11 amino acids cleaved from a larger prepro-U-II precursor peptide of about 130 amino acids [1, 2]. It is a ligand for the orphan G-protein-coupled receptor, GPR14 . Although human prepro-U-II mRNA is expressed mainly in the brain and spinal cord, it is also detected in other tissues, such as kidney, spleen, small intestine, thymus, prostate, pituitary, and adrenal gland .
U-II is the most potent mammalian vasoconstrictor identified to date , being tenfold more potent than endothelin-I. It circulates in the plasma of healthy individuals, and acts as a circulating vasoactive hormone  and as a locally acting paracrine or autocrine factor in cardiovascular regulation [3, 4]. It may also be detected in urine .
It has been speculated that U-II might be an important physiological mediator of vascular tone and blood pressure in hums and, since its vasoconstrictor effects are modulated by endothelium-dependent vasodilators, that it may be of importance in states of endothelial dysfunction . Although it is a potent mammalian vasoconstrictor , it also has a vasodilatory effect on the small arteries of rats  and on the resistance arteries of humans , through release of endothelium-derived hyperpolarizing factor and nitric oxide. Although it has been recognized as an important hormone of the caudal neurosecretory system of teleost fish for over 30 years , only recently has it become a major focus of clinical research . However, more work is needed to characterize the role of U-II in health and disease.
To our knowledge, no studies have investigated the level of U-II in children with minimal change nephrotic syndrome (MCNS). Considering the renal synthesis and vasoactive role of U-II, we aimed to measure the plasma and urinary levels of U-II in children with MCNS and investigate the correlation with other clinical and laboratory findings.
Patients and methods
Twenty-six children with clinical MCNS, ranging in age from 2 to 7 years, were compared with 16 healthy age- and sex-matched controls. The median age of the children was 4.73±2.36 years. Ten of the patients were girls. Patients were studied in relapse and in remission.
Nephrotic syndrome was defined as heavy proteinuria( >40 mg/m2per hour)or 4+ proteinuria measured by dipstick, hypoalbuminemia (<2.5 g/dl), hypercholesterolemia (>250 mg/dl), and edema. MCNS was diagnosed from the clinical findings. Patients who had onset of nephrosis between 2 and 5 years of age, with normal renal function, absence of hypertension, absence of hematuria on urine microscopy, and complete response to corticosteroids were presumed to have MCNS on clinical grounds.
Remission was defined as serum albumin within normal limits and normal urinary protein excretion (negative by dipsticks). Patients were considered in relapse if heavy proteinuria and low serum albumin levels were present .
Children with nephrotic syndrome were treated with corticosteroids for the initial episode or subsequent relapses of MCNS. None of the patients was being treated with immunosuppressive medications other than corticosteroids. Children with a raised temperature or clinical infection were excluded.
Control subjects who were free of kidney disease had a complete physical examination, tested negative for urinary protein by dipstick, had normal blood urea nitrogen (BUN) and creatinine levels, and were normotensive at the time of the study.
After informed consent had been obtained, blood and 24-h urine samples were collected at the time of the initial diagnosis of nephrotic syndrome, and from children with previously diagnosed MCNS during relapse of their disease before beginning steroids. Additional blood and urine specimens were obtained from the same patients who went into remission. All samples in remission were taken during a period off steroids (for at least 2 weeks).
Blood samples were drawn into tubes containing EDTA, and urine samples into tubes containing sodium tetraboric acid (Na2B4O7, 0.5 g/l). The tubes were gently rocked several times immediately after collection of the specimens, and transferred to centrifuge tubes containing aprotinin (0.6 TIU/ml of blood or urine). These tubes were also gently rocked several times to inhibit the activity of proteinases and centrifuged. The samples were kept at −70oC until the study period.
U-II level was measured by RIA using a hU-II RIA kit (Phoenix Pharmaceuticals, Calif., USA, measured in Bio-rad quality control laboratory code no. 3584-Adana). The results were presented as picograms per milliliter. The urinary U-II levels were corrected using urinary creatinine levels to avoid influence of the concentration of the urine itself.
Determination of other clinical parameters
Serum creatinine, BUN, electrolytes, albumin, cholesterol, and triglycerides, as well as urinary creatinine, electrolytes, and protein, were determined by routine methods. Excretion of urinary protein and creatinine clearance were calculated from urine collected during the 24-h period.
Results are given as mean±SD. Differences between the patients and controls were compared by Mann-Whitney U and the Wilcoxon matched pairs signed-ranks tests. A P level <0.05 was considered statistically significant. Statistical analysis was performed with Statistical Package for the Social Sciences for Windows (SPSS, version 10.0).
Of the 26 patients, 6 were newly diagnosed with MCNS, while 20 were established patients. The serum creatinine concentration and blood pressure were within the normal range in all subjects. Renal function was normal (glomerular filtration rate >90 ml/min per 1.73 m2) in all patients. Tubular reabsorption of phosphorus was within normal limits. There were no statistically significant differences between boys and girls for U-II levels.
Plasma and urinary urotensin (U)-II levels in children with minimal change nephrotic syndrome and controls
Plasma U-II (pg/ml)
Urinary U-II (pg/mg urinary creatinine)
There was no correlation between the extent of proteinuria and plasma/urinary U-II levels (P>0.05). We could not detect any relationship between U-II levels and other clinical and laboratory parameters (such as the age at onset of disease, number of relapses, time to remission, blood pressure, serum creatinine, and hematological parameters).
Recently, some studies have suggested a potential role of U-II in human physiology. In fish, U-II regulates membrane sodium transport, influences lipid and glucose metabolism , and enhances cortisol secretion . It has also been reported as a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney . U-II stimulates vascular smooth muscle cell (VSMC) proliferation , and the mitogenic effect on VSMC is synergistic with oxidized low-density lipoprotein . Interestingly, it has been also shown that U-II acts as a mitogen for the porcine renal epithelial cell line LLCPK1 . Shenouda et al.  demonstrated that U-II was mostly present in the epithelial cells of tubules and ducts, with greater staining intensity in the distal convoluted tubules in normal human kidneys. Moderate U-II immunoreactivity was seen in the endothelial cells of renal capillaries, but only focal immunoreactivity was found in the endothelial cells of the glomeruli. Considering the high expression of prepro-U-II in the human kidney  and the recognition of conservation of function under evolutionary pressures, these would suggest an endocrine role for U-II in sodium handling, and perhaps even in the metabolic syndrome .
In the literature, there is only a study of the possible role of U-II in patients on dialysis. Plasma concentrations were raised in patients with renal dysfunction—twofold in non-dialyzed patients and three-fold in those on hemodialysis . Although U-II has been reported to have a role in vascular permeability in specific organs, including the kidneys , there are no data on the level of this vasoactive peptide in glomerular diseases of childhood.
The present study demonstrated that U-II levels were significantly lower in plasma and elevated in urine of children with MCNS in relapse. We have previously shown similar changes in another vasoactive peptide, adrenomedullin, in children with MCNS . There are a few possible reasons for the high urinary excretion of U-II. One is the loss of U-II in urine, since plasma U-II levels are markedly decreased in relapse and increased in remission for the same patients. Another possible explanation is that the kidney may be one of the major sites of U-II synthesis. Since the distal convoluted tubules and endothelial cells of renal capillaries have been shown to produce U-II , urinary excretion of U-II may be partly derived from renal tissues. However, we cannot determine the exact site(s) of synthesis by the kidney from our study.
Considering the significant positive correlation between plasma U-II level and plasma albumin concentration during remission, we suggest that the high urinary excretion of U-II may also result from tubular protein overload, saturating protein reabsorptive mechanisms during relapse.
Plasma U-II levels during relapse and urinary U-II levels during relapse and remission were lower than in controls. Although we collected the samples during an off-steroid period, most patients (20/26) had established and frequently relapsing disease. Consequently, the lower urinary U-II levels than in controls may be due to the lasting suppressive effect of steroids. However, we cannot conclude from our study that steroids suppress U-II. This hypothesis needs further detailed studies.
Since all of our patients were diagnosed with MCNS, a most-benign form of childhood glomerular diseases, we suggest that the important changes in plasma and urinary U-II levels during relapse may be the result of heavy proteinuria rather than playing a role in mediating the clinical and laboratory manifestations of this disease. However, further studies are required to define the exact role of U-II in children with glomerular diseases other than MCNS..