Elevated Excretion Research Articles

Increased urinary zinc excretion after thermal injury.

Urinary zinc excretion normally plays a minor role in zinc homeostasis; however, urinary zinc excretion is markedly elevated after trauma or surgery, and mechanism(s) for this zinc loss are poorly defined. In this study we evaluated multiple potential mechanisms for increased urinary zinc excretion in patients with thermal injury. We documented that patients with severe thermal injury had markedly elevated urinary zinc excretion. Above 20% total body surface area burn, however, the severity of thermal injury did not correlate with urinary zinc excretion. Serum zinc concentrations were depressed on initial evaluation and gradually increased during the hospital course, whereas peak urinary zinc excretion occurred 2 to 5 weeks after injury. Thus the depression in serum zinc concentration did not temporally relate to the observed pattern of hyperzincuria. Increased urinary zinc excretion also did not temporally relate to urinary excretion of the amino acids cysteine and histidine (both of which tightly bind zinc) nor to urinary 3-methylhistidine excretion, a marker of muscle breakdown. Urinary amylase excretion, a marker of renal tubular dysfunction, did follow the pattern of urinary zinc loss to some extent, although this correlation was not perfect. Increased oral intake of zinc via zinc supplements resulted in significantly increased urinary zinc excretion. Patients receiving total parenteral nutrition (TPN) did not have significantly increased urinary zinc excretion when compared with people receiving their total nutrient intake by mouth.(ABSTRACT TRUNCATED AT 250 WORDS)

Two Japanese cases with aspartylglycosaminuria: clinical and morphological features

Two members of a consanguineous Japanese family with a clinical picture of aspartylglycosaminuria (AGU) are described. Both patients exhibited mental retardation, coarse facial features, angiokeratoma and myoclonic seizures. Biochemical studies showed elevated excretion of urinary sialyloligosaccharides and decreased activity of aspartylglycosaminidase in lymphoblasts. Morphologic studies of skin biopsy specimens showed many clear vacuoles mainly in the vascular endothelial cells and secretory cells of the sweat glands. Osmiophilic lamellar cytoplasmic inclusions were also noted in the ganglion cells in rectal biopsy. The ethnic distribution of AGU may be more widespread than previously suspected and appears not to be restricted to Finnish populations. Ours are the first Japanese patients diagnosed as AGU. We conclude that AGU should also be included in the differential diagnosis of mentally retarded patients in Asian countries.

Diabetic nephropathy in insulin-dependent diabetes mellitus patients: How to measure progression of disease and effect of treatment

Medical Department M (Diabetes and Endocrinology), Aarhus Kommunehospitai, Aarhus, Denmark Usually, diabetic nephropathy with end-stage renal disease (ESRD) takes between 25 and 30 years to develop (Figure l), and three main stages may be defined,’ each lasting about a decade, starting with the acute changes (stage I) at diagnosis of diabetes, which also involve abnormalities in the kidney, probably not predictive of subsequent disease.’ Stage II usually lasts 10 years and is characterized by renal hyperfunction and hypertrophy without any clinical or laboratory signs of disease, but structural changes in glomeruli are developing. Longterm follow-up studies have shown, however, that patients with most severe early renal involvement (hyperfiltration) are those most prone to development of late nephropathy.3 In the next decade (stage Ill), a very characteristic abnormality develops, namely microalbuminuria (MA),4 which is defined as an elevated urinary albumin excretion rate (UAER), below the proteinuric range. Usually this too is a slow process, and the increase in albuminuria from normal to the proteinuric level may also last about 10 years, although with considerable variations in rate of progression. In the third decade (stage IV) diabetic nephropathy, well known since the thirties, becomes clinically apparent with proteinuria and eventually end-stage renal failure (ESRF) after a fairly linear decrease in glomerular filtration rate (GFR), lasting approximately 10 years, as shown in Figure 1.

Measurement of the cortisol production rate in two sisters with 17α-hydroxylase deficiency using [1,2,3,4- 13C]cortisol and isotope dilution mass spectrometry

[1,2,3,4- 13C]cortisol was i.v. administered to two sisters aged 11 yr (patient I) and 3 yr (patient II) who suffer from 17α-hydroxylase deficiency. This is the first time that the cortisol production rate (CPR) in patients with 17α-hydroxylase deficiency has been measured with a stable labelled tracer using the urinary method. The urine was collected for 3 days. High-performance liquid chromatography (HPLC) of ≈100 ml urine extracts was carried out to isolate the small amount of cortisol metabolites excreted. The cortisol metabolites were oxidized to 11-oxo-aetiocholanolone. The isotope dilution in the methyl oxime tert-butyldimethylsilyl ether derivatives was measured by selected ion monitoring gas chromatography/mass spectrometry (GC/MS). The CPR calculated from tetrahydrocortisone (THE) and the cortolones was 765 and 536 nmol/day, respectively in patient I. The CPR in patient II was only calculated from THE and was 62 nmol/day. If radioactive labelled cortisol had been used, much larger quantities of urine would have been needed for isolation of sufficient mass of metabolites, even then purification may have been difficult. Steroid profiling of 1 ml urine samples by GC and identification by GC/MS revealed high concentrations of pregnenolone, progesterone, 11β-hydroxy progesterone and corticosterone metabolites. Tetrahydrocorticosterone and 5α-tetrahydrocorticosterone were found in urine at elevated excretions of 2.5 and 5.7, 0.9 and 2.0 μmol/24h, in patients I and II respectively. No cortisol metabolites were detected by routine GC or GC/MS as the low amounts excreted co-eluted with the relatively abundant corticosterone metabolites.

Transferrinuria in Type 2 Diabetes: The Effect of Glycaemic Control

Urinary excretion rates of transferrin, albumin, N-acetyl-beta-D-glucosaminidase (NAG) and alpha-1-microglobulin (A1M) were measured in type 2 (non-insulin-dependent) diabetic patients at diagnosis and after 6 and 12 weeks treatment. Initially 21 (53%) patients had elevated transferrin excretion rates. The proportion of patients with raised transferrin excretion rates fell to 30% at 6 weeks and 20% at 12 weeks with treatment of diabetes. At diagnosis 11 (28%) patients had elevated albumin excretion rates and 10 of these had elevated transferrin excretion rates. After 6 weeks treatment only six (15%) had elevated albumin excretion rates and by 12 weeks this number had fallen to four (10%). NAG and A1M levels also fell with treatment of diabetes. There were correlations between the transferrin excretion rate and albumin excretion rate (r = 0.86, P less than 0.0001), transferrin excretion rate and NAG (r = 0.46, P less than 0.0001), and transferrin excretion rate and A1M (r = 0.55, P less than 0.0001) at each visit. There were weaker correlations between the albumin excretion rate and A1M and NAG at each visit. The correlations between the transferrin excretion rate and markers of tubular function (NAG and A1M) suggest that tubular dysfunction may play a part in renal loss of transferrin in diabetes mellitus. There were no differences in transferrin excretion rates between patients with and without evidence of complications.

Elevated Urinary C-Peptide Excretion in Multiple Trauma Patients

A simple, indirect method of estimating integrated insulin secretion is the measurement of C-peptide, a byproduct of insulin biosynthesis, in plasma and in 24-hr urine samples. We determined, in 29 severely injured hypermetabolic and highly catabolic multiple trauma patients, the plasma level and daily excretion rate of C-peptide, 48-72 hrs postinjury. Data from a set of eight patients who underwent glucose-based total parenteral feeding for 6 days were analyzed for the course of changes in the excretory pattern of C-peptide and catecholamines. The molar ratio of plasma C-peptide to insulin in the trauma patients was similar to that in unstressed controls, indicating that the rate of hepatic insulin extraction is not appreciably altered due to trauma. This is also evident from a significant correlation (p = 0.001) between the plasma C-peptide and insulin levels. The excretion of C-peptide was elevated to three times the normal both in absolute terms and when normalized to creatinine excretion. This was also accompanied by a twofold increase in the plasma levels, indicating an enhanced secretion rate of C-peptide and hence of insulin in response to trauma. Injury-induced insulin resistance does not seem to be due to a decreased insulin secretion. An increase in insulin output would appear to be a significant and desirable response for a continued anabolic stimulus coexistent with the net catabolic phase. Parenteral feeding augmented the excretion of C-peptide and catecholamines and this effect peaked on the fourth day of nutritional therapy.

The Munich Wistar Frömter Rat: Proteinuria and Blood Pressure in Correlation to the Number of Superficial Glomeruli

Rats with a high number of superficial nephrons (MWF/Ztm) also show an elevated urinary protein excretion and a high systolic blood pressure. To investigate a possible correlation between the number of superficial glomeruli and these physiological changes, MWF/Ztm rats were crossed and backcrossed to Wistar cryptorchic (WC/Ztm) animals with no superficial nephrons in order to produce genotypes with differing numbers of superficial glomeruli. In the parental strains, the F1 hybrids and the 8 possible backcrosses, the number of superficial glomeruli, the distance of the 10 most superficial glomeruli to the renal surface, and the diameter of Bowman's capsules were determined by morphometric analysis. The excretion of total protein, in detail low molecular weight proteins, albumin, and high molecular weight proteins were measured quantitatively in 5 males of each genotype. Systolic blood pressure was determined by a tail-cuff method in conscious rats. Means of each variate of the 12 available genotypes were linearly correlated and demonstrate a close correlation between the amount of superficial nephrons and the observed physiological changes, i.e. the more superficial the glomeruli the higher the urinary protein excretion, especially albumin, and the higher the systolic blood pressure.

Impaired left-ventricular function in insulin-dependent diabetic patients with increased urinary albumin excretion

Cardiac function was studied in 30 patients with insulin-dependent diabetes mellitus. Three groups, matched for age and diabetes duration, were defined as: group I (n = 10), normal urinary albumin excretion less than 30 mg 24 h-1; group II (n = 10), incipient diabetic nephropathy (urinary albumin excretion in the range of 30-300 mg 24 h-1); and group III (n = 10), clinical diabetic nephropathy (urinary albumin excretion greater than 300 mg 24 h-1). Ten non-diabetic subjects matched for sex and age served as controls. The left-ventricular end-diastolic volume measured by radionuclide cardiography was, at rest and during exercise, lower in group II and III compared with controls (p less than 0.05), while intermediate values were found in group I. The cardiac output was similar in the control group and group I; it was reduced, but not significantly so (p = 0.10), in group III and was significantly lower in group II (p less than 0.05). Stroke volume was also lower in group II and III than in controls (p less than 0.05), but not so in group I. These differences could not be explained by differences in metabolic control, blood pressure, blood volume status, degree of autonomic neuropathy or frequency of coronary heart disease. Our results might suggest that insulin-dependent diabetic patients with slightly but persistently elevated urinary albumin excretion have reduced diastolic compliance of the left-ventricle leading to impaired cardiac performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Smoking alters thromboxane metabolism in man

Chronic smoking is a major risk factor of atherosclerosis and coronary heart disease. The measurement of three major thromboxane A 2 metabolites, 11-dehydrothromboxane B 2, 2,3-dinorthromboxane B 2 and thromboxane B 2, in the urines of 13 apparently healthy smokers (average 39 years, range 27–56 years) showed significantly elevated excretion rates for all thromboxane A 2 metabolites as compared to 10 apparently healthy age-matched non-smokers (average 37 years, range 26–56 years). Importantly, characteristic alterations in the thromboxane A 2 metabolite pattern were found in the urines of smokers. The contribution of 2,3-dinorthromboxane B 2 to total measured excretion of thromboxane A 2 metabolites was 59.2% in smokers (404.0 ± 53.0 pg/mg creatinine) versus 19.4% in non-smokers (85.2 ± 8.3 pg/mg creatinine), that of 11-dehydrothromboxane B 2 35.7% in smokers (673.2 ± 88.9 pg/mg creatinine) as compared to 75.5% in non-smokers (332.6 ± 30.9 pg/mg creatinine). The contribution of thromboxane B 2 (57.5 ± 7.7 pg/mg creatinine in smokers versus 21.9 ± 1.5 pg/mg creatinine in non-smokers) was similar at 5.1%. The excretion of cotinine, the major urinary metabolite of nicotine that correlates well with the reported daily cigarette consumption ( r = 0.97, P < 0.0001), showed a good correlation to thromboxane A 2 metabolite excretion (2,3-dinorthromboxane B 2: r = 0.92, P < 0.0001; 11-dehydrothromboxane B 2; r = 0.87, P < 0.0001).

Screening for Hypercalciuria

Reference values for the urinary calcium/creatinine ratio (Ca/Cr ratio) in the first morning urine were established in 361 healthy children aged 5 to 15 years, on unrestricted diets. The urinary Ca/Cr ratio in the urine upon arising was independent of sex but dependent upon age. The measurement of the urinary Ca/Cr ratio in the urine upon arising while on unrestricted diets may be a reasonable screening test for elevated calcium excretion. On the basis of the urinary Ca/Cr ratios in the urine upon arising during unrestricted diets and the calciuric response to calcium restricted diets and the oral calcium loading test, idiopathic hypercalciuria (IH) was subclassified into three groups: (1) absorptive hypercalciuria; (2) renal hypercalciuria; (3) dietary hypercalciuria. The pathogenesis of IH is controversial. Our data suggest that disordered 1,25 (OH)2 vitamin D metabolism with excessive urinary phosphate excretion occurs in absorptive hypercalciuria.

Correlation of Urinary Albumin andβ-2-Microglobulin and Growth Hormone Excretion in Patients with Diabetes Mellitus and Short Stature*

We examined the correlation between urinary GH, urinary albumin, and beta-2-microglobulin excretion to determine how the excretion of GH relates to markers of renal glomerular and tubular function. Urinary albumin and GH excretion was determined in timed daytime and nighttime urine collections obtained from both subjects with diabetes mellitus and subjects with short stature. For subjects with diabetes, urinary GH excretion rate correlated highly with urinary albumin concentration and excretion rate in both the range of 0 to 1.6 g/L (r = 0.75), P less than 0.001) and in the microalbuminuria range, 0 to 0.4 g/L (r = 0.53, P less than 0.001). Changes in GH and albumin excretion occurred in parallel in 71% of the subjects with diabetes and elevated albumin excretion. The mean GH excretion rate was higher in the group with elevated albumin excretion rate (AER) during both day and night compared to the group with microalbuminuria during the day and normal AER at night. For subjects with short stature, the mean albumin excretion rate was 0.7 +/- 1.3 micrograms/min (range 0.05-8.3 micrograms/min) using a sensitive enzyme-linked immunosorbent assay to measure albumin concentration. The correlation of GH and albumin excretion rates for the subjects with short stature was not statistically significant (r = 0.14, P less than 0.5). About half of the subjects with diabetes and elevated AER (greater than 10 micrograms/min) had a GH excretion rate within the range observed in subjects with short stature. The GH and albumin excretion rate were not correlated in this group. There was a positive correlation of both albumin and GH excretion rate with age in the subjects with diabetes. Urinary GH and beta-2-microglobulin excretion rates were determined in a larger group of subjects with diabetes and a separate group with short stature. Urinary GH and beta-2-microglobulin excretion were correlated both in subjects with diabetes (r = 0.46, P less than 0.001) and with short stature (r = 0.64, P less than 0.001). The association was present in urine collected either during the day or night. The mean GH excretion rate of the group with diabetes was greater than the group with short stature. In conclusion, there was an association of urinary GH and albumin excretion rate in subjects with abnormal glomerular function as indicated by elevated albumin excretion rate. An association of urinary GH and beta-2-microglobulin excretion was observed in subjects with normal tubular function.(ABSTRACT TRUNCATED AT 400 WORDS)

7 Defects of fatty-acid oxidation in muscle

Long-chain fatty acids (LCFA) are oxidized by muscle mitochondria after transport in the cytosol by fatty-acid-binding protein(s) and their activation by a thiokinase. Carnitine, two forms of carnitine palmitoyltransferase(s) and carnitine acylcarnitine translocase are involved in LCFA gating. A primary genetic carnitine deficiency occurs in children with dilated cardiomyopathy, hypoglycaemia and low carnitine content in plasma, liver and muscle, owing to a defect in a common high-affinity transport system. This high-affinity transport in muscle differs from a low-affinity transport that has modifications during muscle maturation. The genetic enzyme defects of beta-oxidation (long-chain acyl-CoA dehydrogenase, medium- and short-chain acyl-CoA-dehydrogenase) present with Reye-like attacks that may lead to non-ketotic hypoglycaemia, coma and sudden infant death syndrome. There is elevated urinary excretion of dicarboxylic acids, acylcarnitines and acylglycines. Secondary carnitine deficiency may occur. ETF and ETF dehydrogenase deficiencies may present in a neonatal form with congenital anomalies, or in a later-onset form with ethylmalonic adipic aciduria. A still-unidentified defect leads to LCFA accumulation in fibroblasts, bone marrow, liver and muscle cells in a multisystem triglyceride disorder.

Elevated thromboxane excretion does not indicate MI

Elevated thromboxane excretion does not indicate MI

Opiate Withdrawal Presenting as Posttraumatic Stress Disorder

Patients with posttraumatic stress disorder (PTSD) frequently present with signs ofautonomic nervous system hyperactivity, as has been demonstrated recently by a number of investigators (1,2). These patients can appear anxious, agitated, tremubus, and diaphoretic, and their pulse and blood pressure can be elevated. When exposed to combat-associated stimuli such as gunfire, traumatized veterans tend to respond with greaten increases in autonomic parameters (heart rate, respiratory rate, galvanic skin response, and muscle tension seen on electromyogram [EMGD, than do controls. Additionally, studies in our laboratory have shown chronically elevated 24-hour urinary epinephnine and norepinephnine excretion in patients with PTSD and marked down-regulation of platelet alpha2-adrenergic receptons consistent with increased cmculating catecholamines (3,4).

Atriopeptin Does Not Augment the Transvascular Flux of Macromolecules in the Hamster Cheek Pouch

Natriuretic peptides elaborated by atrial myocytes promote marked renal sodium and water excretion as a mechanism for fluid and electrolyte balance. Recent evidence suggests that atriopeptin (ANP) also targets the non-renal vasculature as a site for enhanced fluid exchange. It remains unclear whether ANP alters microvascular integrity to facilitate the efflux of both plasma and proteins across the endothelial barrier, or if fluid exchange is selectively enhanced. This study evaluated the influence of ANP on macromolecular transport through the direct observation of microvessels in the hamster cheek pouch using fluorescent intravital microscopy. Fluorescein isothiocyanate conjugated to either bovine serum albumin or dextran 150,000 Mw was utilized as a permeability probe. Macromolecular efflux was quantified as fluorochrome clearance. The clearance of fluorescein-conjugated bovine serum albumin (57.94 +/- 7.03) or fluorescein-conjugated dextran 150 (4.09 +/- 1.35) remained unaltered by intravascular injection of 1 microgram/kg ANP. Topical application of 40 ng to cheek pouch microvessels produced similar results. All pouches demonstrated positive leakage response to histamine 2.5 x 10(-6) M, increasing fluorochrome clearance approximately 2- to 11-fold. Bolus injection of 1 microgram/kg ANP reduced mean arterial pressure, increased urine flow from 6.63 +/- 2.59 microliters/min to 8.20 +/- 6.13 microliters/min, and elevated sodium excretion from 1.37 +/- 0.49 microEq/min to 2.54 +/- 0.99 microEq/min. These results suggest that ANP fails to significantly alter the integrity of the protein-transporting channels in the microvascular exchange barrier.

Influence of parenteral nutrition on rates of net substrate oxidation in severe trauma patients

Optimal nutritional support should use a patient's energy expenditure as a guide for administering sufficient but not excessive caloric intake. Eight patients requiring parenteral nutrition were evaluated, using indirect calorimetry measurements, to determine the nutritional influence on the rates of substrate utilization in the critical period of catabolic illness due to accidental trauma. Five days of total parenteral nutrition, providing calories to match the measured basal resting energy expenditure and N to replace the initial urinary losses a) shifted the RQ from 0.74 +/- 0.03 to 0.81 +/- 0.03, b) improved but could not reverse negative N balance, c) decreased net fat oxidation, d) increased carbohydrate and protein oxidation, e) elevated daily norepinephrine and epinephrine excretion rates, and f) attained positive energy balance. The results suggest that positive energy balance could be achieved in trauma patients by providing total energy intake matching their basal measured energy expenditure plus 7% to 10% for activity energy expenditure. To prevent further loss of lean body mass, an N intake of 350 mg/kg.day was needed in these catabolic ICU patients.

The role of hypertension in the development of nephropathy in type 1 (insulin-dependent) diabetes mellitus

Which comes first when developing clinical diabetic nephropathy, the blood pressure rise or the increasing urinary albumin excretion? This issue is discussed based on recent literature of studies in humans with Type 1 (insulin-dependent) diabetes mellitus. We conclude that hypertension has a central role in the progression of diabetic nephropathy and has deleterious effects on the life expectancy of patients who already have signs of diabetic renal disease in terms of elevated urinary albumin excretion. However, blood pressure is preceded by small increments of urinary albumin excretion rates, an indicator of universally increased vascular leakiness, and thus does not seem to be the cause of diabetic nephropathy.

Stress, depression, and mania: relationship between perceived role of stressful events and clinical and biochemical characteristics

We investigated the perceived role of stressful events in episodes of major affective disorder in patients studied in the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression (Biological Studies). Using items from the Schedule for Affective Disorders and Schizophrenia (SADS), episodes were divided into environment-sensitive (high perceived role of stressful events) and autonomous (minimal or no perceived role of stressful events). Patients with environment-sensitive episodes had fewer previous episodes and a longer index episode. The groups did not differ with respect to age, gender, education, socioeconomic group, diagnosis, severity of illness, or eventual response to treatment. Unipolar depressed patients with environment-sensitive episodes had lower CSF 5-HIAA than those with autonomous episodes. Among bipolar depressed patients, those with autonomous episodes had elevated excretion of O-methylated catecholamine metabolites and of epinephrine, while those with environment-sensitive episodes had normal excretion of catecholamines and metabolites. Manic subjects with environment-sensitive episodes had elevated norepinephrine excretion, while this was normal in manics with autonomous episodes. Relationships between environmental sensitivity of affective episodes and neurotransmitter function therefore appear to be related to the type of episode.

Dual Column HPLC Analysis of Modified Ribonucleosides as Urinary Pathobiochemical Markers in Clinical Research

Abstract The quantitative determination of the urinary ribonucleosides m1Ado, m22Guo and t6Ado of breast cancer patients was performed by use of an automated high performance liquid chromatography analyzer with on-line sample processing and analysis by a dual column switching technique. M22Guo and t6Ado showed elevated excretion values (normalized to creatinine) in all of our 24 perioperatively examined breast cancer patients. Studies of these two urinary ribonucleosides 3 years after primary surgery showed markedly reduced excretion values in case that no relapse had occurred.

High-Normal Blood Pressure and Early Diabetic Nephropathy

The relationship between high-normal blood pressure (BP) levels and early diabetic nephropathy is currently unknown. Blood pressure levels were checked longitudinally for a mean of 6.6 years in 230 subjects to determine their relationship to early diabetic nephropathy as monitored by microalbuminuria. High-normal BP level correlated with the presence of microalbuminuria. Microalbuminuria was 2.8 times as common in subjects with high-normal BP levels compared with those subjects with BP levels below the 90th percentile for their age. The elevated microalbumin excretion was primarily associated with high-normal diastolic BP levels. Our data suggest that either microalbuminuria or high-normal BP levels can precede the other. In a logistics model, diastolic BP and mean HbA1 (over 6.6 years) entered the model at similar levels, followed by duration of diabetes. When the influence of mean HbA1 was removed using logistic regression, the diastolic BP level remained a significant associated factor for the presence of microalbuminuria.