Plasma renin, aldosterone, and urinary prostaglandin E2 levels in children with hypocalcemia due to vitamin D deficiency rickets.

We investigated the effect of hypocalcemia on plasma renin, aldosterone, and urine PGE2 levels in children with vitamin D deficiency rickets (VDDR). In the study group, 25 patients with VDDR-induced hypocalcemia were treated with a single dose of 150,000-300,000 IU cholecalciferol and 50 mg/kg/day elemental Ca for 10 days. On any day between 21th and 30th days after the treatment, the patients' clinical, biochemical and radiologic findings were re-evaluated. The healthy children with the same sex and similar age as the study group comprised the control group. Plasma sodium (Na), potassium (K), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), 25- hydroxy vitamin D (25OHD), renin, aldosterone; and urinary Ca, creatinine (Cr) and prostaglandin E2 (PGE2) levels were measured in both the study (pre-treatment and post-treatment) and the control group. Plasma Ca, P, 25OHD and renin levels and urinary PGE2/Cr ratio in the post-treatment group were significantly higher than those in the pre-treatment group while K, ALP, and PTH concentrations were significantly lower. Plasma ALP and PTH levels in pre-treatment group were significantly higher than in the control group while Ca, P, 25OHD, aldosterone and renin concentrations and urinary PGE2/Cr ratio were significantly lower. Post-treatment plasma Ca level was significantly decreased in normal limits compared to the control group while other biochemical parameters were not different from the control group. Plasma Ca concentration was positively correlated with renin level and urinary PGE2/Cr ratio. The findings suggest that hypocalcemia may inhibit the production of renin, aldosterone and PGE2 and a blunt aldosterone secretion may develop even after recovery from hypocalcemia.

Comparison between Prostaglandin E-major urinary metabolite and C-reactive protein levels to reflect endoscopic scores in patients with ulcerative colitis.

Prostaglandin E-major urinary metabolite (PGE-MUM) and C-reactive protein (CRP) are useful biomarkers in patients with ulcerative colitis. However, whether changes in endoscopic scores over time are reflected in the values of these biomarkers has not been verified. This prospective observational study aimed to assess the relationship between changes in biomarker levels and endoscopic scores in patients with ulcerative colitis. A total of 100 colonoscopy intervals of patients with ulcerative colitis were enrolled. The relationship between variations in the Mayo endoscopic subscore over time and the accompanying changes in biomarker values were investigated. PGE-MUM levels showed a significant rise in the increased endoscopic score group (P = 0.007) and a decrease with reduced endoscopic score group (P = 0.023). CRP levels showed a significant decline with lower endoscopic values (P < 0.001); however, there was no corresponding increase with higher endoscopic scores (P = 0.141). Biomarker levels remained unchanged with stable endoscopic scores (P = 0.090 and P = 0.705). PGE-MUM levels varied significantly, and corresponded to the mucosal healing state (P = 0.019 and P = 0.009). The correlation between changes in PGE-MUM and the endoscopic score was stronger than that for CRP (r = 0.518, P < 0.001 vs. r = 0.444, P < 0.001, respectively). PGE-MUM reflected changes in endoscopic scores more accurately than CRP.

Performance of candidate urinary biomarkers for pancreatic cancer - Correlation with pancreatic cyst malignant progression?

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) are precursors of pancreatic cancer. Potential biomarkers of IPMN progression have not been identified in urine. A few urinary biomarkers were reported to be predictive of pancreatic ductal adenocarcinoma (PDAC). Here, we seek to assess their ability to detect high-risk IPMN. METHODS: Urine was collected from patients undergoing pancreatic resection and healthy controls. TIMP-1(Tissue Inhibitor of Metalloproteinase-1), LYVE-1(Lymphatic Vessel Endothelial Receptor 1), and PGEM(Prostaglandin E Metabolite) levels were determined by ELISA and analyzed by Kruskal-Wallis. RESULTS: Median urinary TIMP-1 levels were significantly lower in healthy controls (n = 9; 0.32 ng/mg creatinine) compared to PDAC (n = 13; 1.95) but not significantly different between low/moderate-grade (n = 20; 0.71) and high-grade/invasive IPMN (n = 20; 1.12). No significant difference in urinary LYVE-1 was detected between IPMN low/moderate (n = 16; 0.37 ng/mg creatinine) and high/invasive grades (n = 21; 0.09). Urinary PGEM levels were not significantly different between groups. CONCLUSIONS: Urinary TIMP-1, LYVE-1, and PGEM do not correlate with malignant potential of pancreatic cysts.

Prostaglandin E-major urinary metabolite as a noninvasive surrogate marker for infantile necrotizing enterocolitis.

BACKGROUND: Early definitive diagnosis of necrotizing enterocolitis (NEC) based on Bell's staging criteria is difficult because there are few observable changes on abdominal imaging and blood chemistry tests at the onset of the disease. PURPOSE: To investigate whether prostaglandin E-2 major urinary metabolite (PGE-MUM) can be a useful surrogate marker reflecting the disease state and severity of NEC in infants. METHODS: Infants were enrolled in this study between January 2014 and December 2016. NEC diagnosis was based on Bell's staging criteria > Stage II or necrotic bowel observed at surgery. After diagnosis, PGE-MUM level was measured and compared with that of the other disease and healthy infant groups. RESULTS: Median PGE-MUM value was highest in the NEC group (576 [65-3672] µg/g•Cre/BSA × 1000), followed by the other disease group (94 [57-296] µg/g•Cre/BSA × 1000) and the healthy infant group (19 [10-44] µg/g•Cre/BSA × 1000) (sensitivity: 92.3%, specificity: 81.5%, accuracy: 85.0%; p < 0.01). PGE-MUM level correlated with improved status of NEC, length of necrotic intestine, and Bell's staging criteria. CONCLUSIONS: PGE-MUM level may be a useful surrogate biomarker reflecting the disease state of NEC. The method of urine sample collection is also advantageous, being noninvasive for infants. This is the first study reporting PGE-MUM level in NEC. TYPE OF STUDY: Study of diagnostic test. LEVEL OF EVIDENCE: LEVEL II.

The effects of ivacaftor on CF fatty acid metabolism: An analysis from the GOAL study.

BACKGROUND: Ivacaftor has produced significant improvement in certain individuals with cystic fibrosis (CF), though the full metabolic effects of treatment remain unknown. Abnormalities in fatty acid metabolism have previously been shown to be a characteristic of CFTR dysfunction. We hypothesized that as a reflection of this clinical improvement, ivacaftor would improve plasma fatty acid levels and decrease urine prostaglandin E metabolite levels. METHODS: This study analyzed plasma fatty acid levels and urine prostaglandin E metabolites (PGE-M) in 40 subjects with CF participating in the G551D observational (GOAL) study who demonstrated response to the medication by a significant decrease in sweat Cl levels. Paired samples were analyzed before and after 6months of ivacaftor treatment. RESULTS: Linoleic acid and docosahexaenoic acid levels, which are typically low in individuals with CF, did not significantly increase with ivacaftor treatment. However, arachidonic acid levels did decrease with ivacaftor treatment and there was a significant decrease in the arachidonic acid metabolite PGE-M as measured in the urine [median: before treatment 17.03ng/mg Cr; after treatment 9.06ng/mg Cr; p<0.001]. Furthermore, there were fatty acid age differences observed, including pediatric participants having significantly greater linoleic acid levels at baseline. CONCLUSION: Ivacaftor reduces inflammatory PGE without fully correcting the plasma fatty acid abnormalities of CF. Age-related differences in fatty acid levels were observed, that may be a result of other clinical factors, such as diet, clinical care, or drug response.

Significant increase of prostaglandin E-major urinary metabolite in male smokers: a screening study of age and gender differences using a simple radioimmunoassay.

BACKGROUND: For the assessment of inflammatory status, we have developed a simple, reliable radioimmunoassay (RIA) of prostaglandin E-major urinary metabolite (PGE-MUM), which remains stable in urine after it is metabolized. Using this method, we conducted a screening study to compare standard values of PGE-MUM to serum C-reactive protein (CRP) levels in health check volunteers. METHODS: PGE-MUM (micrograms per gram creatinine) was measured in normal urine samples obtained from 797 samples in volunteers for health check, using a newly developed RIA, and analyzed in relation to age, gender, smoking, and drinking habits. Results were compared to serum CRP. RESULTS: PGE-MUM was significantly higher in males than in females. It was significantly higher in smoking males, compared to males who had never smoked (nonsmokers), particularly in those above 40 years of age. In nonsmokers, PGE-MUM declined in males with advancing age, while it rose in females. Although PGE-MUM reflected current smoking status, independent of smoking index (SI), serum CRP indicated both current and former smoking condition, rather dependent upon SI. CONCLUSIONS: PGE-MUM increases in smokers, as suggested by possible inflammatory injury of pulmonary tissue. This RIA method for PGE-MUM may be thus a sensitive and reliable biomarker for current inflammation, different from serum CRP.

Total dietary fat and fatty acid content modifies plasma phospholipid fatty acids, desaturase activity indices, and urinary prostaglandin E in women.

Compared with diets high in fat, low-fat diets are associated with reduced risk of cardiovascular disease. We hypothesized that a low-fat (LF) (20% fat) and an LF high-omega-3 (n-3) fatty acid diet (LFn3) (23% fat with 3% as α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid [DHA]) would enhance n-3 composition of plasma phospholipid fatty acid and reduce urinary prostaglandin E(2) (PGE(2)) relative to a high-fat diet (HF) (40% fat) and that these changes would be associated with alterations in δ5 desaturase (D5D) and δ6 desaturase (D6D) activity. Phospholipid fatty acids and urinary PGE(2) were measured, and D5D and D6D activity indices calculated in a crossover trial in 17 postmenopausal women fed each of 3 test diets (HF, LF, and LFn3) for 8-week feeding periods. Desaturase activity indices were calculated as D5D, 20:4n-6/20:3n-6, and D6D, 20:3n-6/18:2n-6. Plasma phospholipid fatty acid, α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid (DPA), DHA, and total n-3 fatty acids increased, whereas linoleic acid and arachidonic acid decreased with consumption of LFn3. The LF resulted in enhanced arachidonic acid and DHA. High fat reduced D6D, whereas both HF and LF increased D5D. Urinary PGE(2) was reduced in response to both the LF and LFn3 diets. Low-fat diets, with or without long-chain n-3 fatty acids, promote positive health effects due in part to favorable alteration of plasma phospholipid fatty acid profiles and modification in desaturase activity indices, suggesting that the type and amount of fat consumed are modifiable risk factors for the prevention of cardiovascular disease.

Urinary prostaglandin E2 was increased in patients with suprapontine brain diseases, and associated with overactive bladder syndrome.

OBJECTIVE: To investigate the association between the urinary levels of prostaglandins (PGE(2) and PGF(2α)), nerve growth factor (NGF) and substance P, and overactive bladder (OAB) symptoms in patients with suprapontine brain diseases. MATERIALS AND METHODS: The subjects were 114 patients in the chronic phase of a brain disease and 27 healthy controls with no brain disease or lower urinary tract symptoms (LUTS). The OAB symptoms were assessed with the OAB symptom score and the subjects were then classified into 5 groups: healthy control, patients without LUTS, increased bladder sensation (IBS), OAB dry, and OAB wet. Urinary mediator concentrations were measured using enzyme-linked immunosorbent assay and normalized to the urinary creatinine concentration, and then compared among the 5 groups. RESULTS: The urinary PGE(2) level was significantly higher in patients with brain diseases than in healthy controls, even in the patients without any OAB symptoms, and compared with patients without LUTS, a significant increase in the urinary PGE(2) was observed in patients with OAB dry or wet (P = .004 or .015, respectively). The PGF(2α) level showed a significant increase in OAB wet compared with patients without LUTS (P = .001). The urinary levels of NGF and substance P were not significantly associated with OAB as a result of this type of brain disease. CONCLUSION: The urinary PGE(2) level was putatively elevated in patients with suprapontine brain diseases and associated with the presence of OAB. The PGF(2α) level may also be associated with OAB.

Ibuprofen use during extreme exercise: effects on oxidative stress and PGE2.

PURPOSE: Oxidative stress was examined with use (N = 29) or nonuse (N = 25) of ibuprofen in ultramarathoners after the Western States Endurance Run. METHODS: Oxidative stress was assessed by measuring plasma and urinary F2-isoprostanes, plasma nitrite, and plasma urate. A urinary prostaglandin E2 metabolite (PGE-M) was used as an end point to assess ibuprofen use. Ibuprofen users consumed 600 and 1200 mg of ibuprofen the day before and on race day, respectively, and nonusers avoided all antiinflammatory medications. Blood and urine were collected in the morning before the race and immediately after the race. RESULTS: Use compared with nonuse of ibuprofen significantly increased plasma (P

Levels of prostaglandin E metabolite, the major urinary metabolite of prostaglandin E2, are increased in smokers.

PURPOSE: Increased levels of cyclooxygenase-2 and prostaglandin E2 (PGE2) have been observed in tobacco-related malignancies of the upper aerodigestive tract. Moreover, exposure to tobacco smoke can stimulate the synthesis of PGE2. Recent evidence suggests that urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE2 production. In this study, we investigated whether levels of urinary PGE-M were increased in smokers and in patients with head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Fifty-eight HNSCC cases and 29 age- and gender-matched healthy controls were prospectively enrolled in the study. A detailed smoking history and single void urine specimen were obtained from each participant. Levels of urinary PGE-M were quantified in a blinded fashion using mass spectrometry and compared with smoking history and tumor status. RESULTS: Adjusted for case-control matching, median urinary PGE-M levels were significantly higher in ever smokers (15.7 ng/mg creatinine) compared with never smokers (9.9 ng/mg creatinine) for the entire study population (n = 87, P = 0.005). Concentrations of urinary PGE-M were nearly doubled in ever smokers (15.2 ng/mg creatinine) versus never smokers (7.8 ng/mg creatinine) among healthy controls (P = 0.001). Higher PGE-M levels were observed in current versus former smokers and in those with greater pack-year exposure. A significant difference in amounts of PGE-M was not observed in patients with HNSCC versus healthy controls. CONCLUSIONS: Increased levels of urinary PGE-M were observed in smokers. Urinary PGE-M may have use as a noninvasive biomarker of the effects of tobacco smoke exposure.

Pathogenetic role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome: therapeutic use of the cyclooxygenase-2 inhibitor nimesulide.

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E(2), thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX-2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E(2) formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B(2) synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F(1alpha), reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E(2) is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.

Prostanoid formation during feeding of a preterm formula with long-chain polyunsaturated fatty acids in healthy preterm infants during the first weeks of life.

The objective of this study was to evaluate the effect of conventional and long-chain polyunsaturated fatty acids (LCP)-enriched preterm formula on prostanoid formation in preterm infants during their first weeks of life. In a prospective, randomized, double-blind study, healthy infants received either formula enriched with LCP (n = 10), standard preterm formula (n = 10), or (expressed) breast milk (n = 10). Urine was sampled, and anthropometric measurements were taken at study entry and after the study period of 3 wk. In vivo formation of prostaglandin E2, thromboxane A2, and prostacyclin was evaluated by measuring the urinary excretion of the respective index metabolities by gas chromatography-mass spectrometry. There were no significant differences in urinary prostanoid excretion and anthropometric data between the groups at the end of the study period. We conclude that neither conventional formula nor supplementation of a preterm formula with LCP for a period of 3 wk substantially influence prostanoid formation in healthy preterm infants.

Pre-pubertal growth in the hyperprostaglandin E syndrome.

Pre-pubertal body growth was followed in eight children with the hyperprostaglandin E syndrome (neonatal Bartter syndrome) treated with indomethacin over a period of 5-12 years. When corrected for prematurity, the general growth pattern was normal, with the exception of a child with delayed therapy. From the first observation (usually at birth) to the start of indomethacin, the mean height standard deviation score (SDS) corrected for prematurity changed from -0.2 to -2.8. During the first 2 years of therapy rapid catch-up growth occurred, followed by a slow adaptation of the growth pattern to that of healthy children born at term. At last observation the mean corrected height SDS was -0.5 (range -1.9 to +0.9) and the mean target height -0.9 SDS (range -1.8 to +0.1). Weight, body mass index and bone maturation also reached the normal range. No correlation was found between height SDS per year and serum potassium levels or calcium excretion. We conclude that under indomethacin treatment long-term skeletal growth of children with the hyperprostaglandin E syndrome is similar to that of other preterm children.

Humoral determinants of Na+ excretion after intravenous NaCl loading in normal volunteers.

1. Twelve healthy volunteers maintained on a 100 mmol/day Na+ diet, were given an intravenous infusion of 2L saline (0.9%) between 10.00 h on 2 study days at least 1 week apart. Urine collections (90 min) were made from 08.30 to 16.00 h. Either carbidopa 100 mg or indomethacin 50 mg was given orally at 07.45 h on one study day and placebo was given on the other (in random order). 2. On the placebo day, saline infusion caused significant decreases in plasma albumin concentration, plasma renin activity (PRA), plasma aldosterone concentration and urinary aldosterone excretion, with 2 to 3-fold increases in plasma atrial natriuretic peptide (ANP) concentration and urinary dopamine: noradrenaline ratio (DA:NA), whereas mean urinary kallikrein and prostaglandin E2 (PGE2) excretion rates were unchanged. Carbidopa decreased urinary DA:NA and indomethacin decreased urinary PGE2 excretion, compared with the placebo day. Excretion of sodium (Na+) decreased below baseline in two out of six carbidopa-treated subjects and in three out of six indomethacin-treated subjects, but showed little or no change in the remainder. 3. These preliminary observations suggest that some subjects in the early phase of natriuresis after an intravenous Na+ load can be identified as having prostaglandin-dependent or dopamine-dependent mechanisms for Na+ excretion.

Calcium kinetics in the hyperprostaglandin E syndrome.

Metabolic investigations, including the use of stable isotopes of calcium, were used to study calcium kinetics in three children with the hyperprostaglandin E syndrome. The studies were performed both during indomethacin treatment and in the absence of therapy. Off therapy, each child had hypercalciuria (mean urinary calcium excretion 0.478 mM/kg/d), hyperprostaglandinuria, and elevated serum calcitriol concentration. All had diminished bone density and were euparathyroid. Indomethacin treatment was associated with a marked reduction in serum calcitriol concentration, as well as decreased prostaglandin E excretion. Mean urinary calcium excretion fell to 0.135 mM/kg/d. The stable isotope studies defined two components to the hypercalciuria of this disease: an indomethacin-sensitive dietary contribution and a relatively indomethacin-resistant bone resorptive element. Bone densitometry confirmed the presence of the resorptive element by demonstrating skeletal demineralization.

Effect of prostaglandin synthesis inhibition on glomerular filtration rate in renal transplant recipients.

To determine the influence of prostaglandin (PG) synthesis inhibition on the renal function in renal transplant recipients, we carried out a crossover, double-blind, placebo controlled study of 18 ambulatory patients. Glomerular filtration rate (GFR) was measured using 51-Cr EDTA, before and after indomethacin (50 mgr. three times a day for three days), and placebo. Overnight urinary PGE excretion decreased 88.9 +/- SEM 4.81% after indomethacin, but remained unchanged following placebo. GFR decreased 15.3 +/- SEM 3.94% (p = 0.0139) after indomethacin. There was no correlation between PGE urinary excretion and GFR changes. Pre-existing renal functional impairment was not a significant risk factor. Caution should be exercised when using non-steroidal anti-inflammatory drugs in renal transplant patients.

[Senile pyelonephritis with the arterial hypertension syndrome: the use of trental]. / Starcheskii pielonefrit s sindromom arterial'noi gipertenzii: primenenie trentala.

Eighteen patients with senile pyelonephritis and nephrogenic arterial hypertension were examined for the effect of trental monotherapy (600 mg/day) on intrarenal hemodynamics, the rate of glomerular filtration (effective renal blood flow, the intensity of blood flow in the medullary layer of the kidney), activity of the renin-angiotensin-aldosterone system (plasma renin activity, plasma and urine aldosterone), prostaglandin synthetic capacity of the kidneys (PGE and PGF2 alpha), water-electrolyte balance (circulating blood volume, sodium content in the serum and its excretion with urine), and on arterial pressure and general vascular peripheral resistance. Prolonged administration of the drug (from 3 weeks to 6 months) led to a significant improvement of the medullary blood flow, increase (p less than or equal to 0.05) of excretion of natriuretic PGE [correction of RGE] and lowering (p less than or equal to 0.05) of diurnal excretion of PGF2 alpha, which was accompanied by a rise of natriuresis (p less than or equal to 0.05) and diuresis.

[The effects of thromboxane A2 synthetase inhibitor on chronic rejection of kidney transplantation].

There has been no useful treatments for chronic vascular rejection (CVR) after kidney transplantation until now. Recently, however, some reports have suggested that the thromboxane A2 synthetase inhibitor, OKY-046, is useful in reducing proteinuria in nephrotic syndrome and preventing progression of CVR. Five patients with CVR (serum creatinine range: 1.7-2.6 mg/dl) were treated with OKY-046 for over one year and the effect of OKY-046 was evaluated. One patient developed acute rejection and another renal hypertension during this study. Except for the cases of acute rejection and renal hypertension, serum creatinine slightly decreased in 1 case and remained unchanged in 2 cases. Urinary excretion of protein and thromboxane B2 decreased significantly but prostaglandin E2 did not change in the treatment of the deterioration with OKY-046. We concluded that OKY-046 was effective in preventing graft function and decreasing urinary protein excretion in kidney transplant recipients with CVR.