Increased intestinal permeability to oral chromium (51 Cr) -EDTA in human Type 2 diabetes.

OBJECTIVE: In animal models of obesity and Type 2 diabetes, permeability of the intestine is increased because of impairment of tight junction proteins, allowing translocation of bacterial endotoxin and resulting in low-grade systemic inflammation. This has yet to be demonstrated in humans. The objective of this study was the demonstration of increased intestinal permeability in human Type 2 diabetes. METHODS: We examined intestinal permeability using chromium ((51) Cr)-EDTA urinary recovery in twenty well-controlled men with Type 2 diabetes compared with control subjects matched for age, gender and BMI. RESULTS: Intestinal permeability was significantly increased (P = 0.002) in the diabetic group and was correlated to increased levels of systemic inflammatory markers high-sensitivity C-reactive protein (r = 0.694, P = 0.001), interleukin 6 (r = 0.548, P = 0.012) and tumour necrosis factor alpha (r = 0.564, P = 0.010). CONCLUSION: This is the first demonstration that increased intestinal permeability may be a feature of human Type 2 diabetes.

Reliability of 5¹Cr-EDTA plasma and urinary clearance as a measure of residual renal function in dialysis patients.

PURPOSE: In dialysis patients, longer survival is associated with a higher residual renal function. Randomized controlled trials are conducted to clarify how residual renal function can be preserved. However, existing methods for measuring residual renal function are uncertain and there is a need for establishing a standard for measurements of glomerular filtration rate (GFR) in dialysis patients. METHODS: 5¹Cr-EDTA clearances in plasma, urine, and dialysate were evaluated in a sample of 12 hemodialysis and 12 peritoneal dialysis patients. The patients' condition was generally stable, and all patients were investigated twice within 4-10 days. RESULTS: Plasma clearances of 5¹Cr-EDTA for all patients ranged between 2.1 and 30.8 mL/min/1.73 m², whereas urinary 5¹Cr-EDTA clearances ranged from 0.7-20.0 mL/min/1.73 m². This difference was statistically significant (p < 0.001). Week-to-week reproducibility expressed as coefficients of variation were below or equal to 10% for plasma clearances and 13% for urinary clearances in hemodialysis patients and 14% in peritoneal dialysis patients. CONCLUSIONS: This study demonstrated a difference between 5¹Cr-EDTA plasma and urinary clearances in dialysis patients. Plasma clearance of 5¹Cr-EDTA had the best reproducibility. For repeated measurements as in clinical prospective trials, we recommend 5¹Cr-EDTA plasma clearance based on blood sampling at 5 + 24 hours with subtraction of 5¹Cr-EDTA dialysate clearance in peritoneal dialysis patients. Further studies are needed to corroborate our findings.

New Model for Estimating Glomerular Filtration Rate in Patients With Cancer.

Purpose The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing; however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method. Methods We obtained data on age, sex, height, weight, serum creatinine concentrations, and results for GFR from chromium-51 (51Cr) EDTA excretion measurements (51Cr-EDTA GFR) from white patients ≥ 18 years of age with histologically confirmed cancer diagnoses at the Cambridge University Hospital NHS Trust, United Kingdom. We developed a new multivariable linear model for GFR using statistical regression analysis. 51Cr-EDTA GFR was compared with the estimated GFR (eGFR) from seven published models and our new model, using the statistics root-mean-squared-error (RMSE) and median residual and on an internal and external validation data set. We performed a comparison of carboplatin dosing accuracy on the basis of an absolute percentage error > 20%. Results Between August 2006 and January 2013, data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE, 15.00 mL/min; 95% CI, 14.12 to 16.00 mL/min) compared with all published models. Body surface area (BSA)-adjusted chronic kidney disease epidemiology (CKD-EPI) was the most accurate published model for eGFR (RMSE, 16.30 mL/min; 95% CI, 15.34 to 17.38 mL/min) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose absolute percentage error > 20% to 14.17% in contrast to 18.62% for the BSA-adjusted CKD-EPI and 25.51% for the Cockcroft-Gault formula. The results were externally validated. Conclusion In a large data set from patients with cancer, BSA-adjusted CKD-EPI is the most accurate published model to predict GFR. The new model improves this estimation and may present a new standard of care.

Application of the 51Cr-EDTA urinary recovery test for assessment of intestinal permeability in the horse.

Altered intestinal permeability is implicated in the pathogenesis of diverse equine medical conditions including alimentary laminitis and protein-losing enteropathies associated with parasitic infection. The aims of this study were to assess the feasibility of applying the 51Cr-EDTA absorption test for the assessment of intestinal permeability in the horse, and to apply this test in horses with experimentally induced alterations in gastrointestinal function. Four healthy ponies were administered 36 MBq of 51Cr-EDTA via naso-gastric tube, and urine samples were collected into polythene bags strapped to the pony's abdomen. Total urine voided every 6 h was collected during each test, and 1 ml samples were taken for measurement of gamma-radiation. Urinary recovery of 51Cr-EDTA was measured following intravenous atropine sulphate or bethanecol, and following 22 and 46 days of administration of 250,000 third-stage cyathostome larvae. There was no significant difference in urinary 51Cr-EDTA recovery following the control treatment, and following atropine or bethanecol administration, but significant increases were detected in the animals with experimental cyathostome infection consistent with increased permeability of the intestinal membrane. Motility modifying agents (bethanecol and atropine) did not affect absorption of 51Cr-EDTA, suggesting that subtle changes in motility might not affect the ability of this test to detect altered intestinal permeability. The finding of increased urinary recovery of 51Cr-EDTA in ponies with cyathostome infection suggests that 51Cr-EDTA may be a useful marker for assessment of intestinal permeability in the horse.

Validation and impact of a new technique for assessment of glomerular filtration rate in patients with liver disease.

OBJECTIVES: Previously we have proposed a technique for the measurement of plasma clearance in patients with ascites. The impact of using the technique was assessed and the results compared with those from a reference technique in 111 patients having glomerular filtration rate measurements as part of their workup for liver transplantation. METHODS: Results of calculations using the new technique were compared with plasma clearance measurements obtained using a conventional slope-intercept technique and with clearance measurements based on urine collection. Discrepancies between the results of plasma clearance and urinary clearance assessments were investigated by using an uncollimated gamma camera to measure the total retention of the tracer. RESULTS: Conventional slope-intercept calculations overestimated clearance compared with the new technique by more than 20% in 21% of the patients. Significant differences between the results of the two methods were more likely in patients with more severe ascites. Results of urine collection-based measurements of Cr-51 EDTA clearance were frequently significantly lower than measurements using the new technique, whereas measurements of urinary clearance of creatinine were higher. Gamma camera measurements suggest that discrepancies between total and urinary clearance of Cr-51 EDTA are due to incomplete urine collection. CONCLUSION: The new technique is a practical method for assessment of kidney function and should be used in patients with liver disease who have or may have ascites.

In vivo cross-match by chromium-51 urinary excretion from labeled erythrocytes: a case of anti-Gerbich.

We studied a patient with an alloantibody to the high-frequency red blood cell (RBC) antigen Gerbich. A nationwide search for rare Gerbich-negative blood (less than 1:45,000 donors) located only seven units, and our supply was quickly exhausted. By using an in vivo cross-matching method, we demonstrated that this anti-Gerbich did not cause RBC destruction. Regular Gerbich-positive transfusions could then proceed without hemolysis. This cross-match test was based on the determination of the urinary excretion rates of injected radioactive chromium-labeled donor erythrocytes by which it was possible to determine compatibility only 24 hr after the test was begun. The procedure provides an easy and accurate means for in vivo cross-matching of conventionally incompatible donor blood.

Evaluation of gastrointestinal toxicity of ibuprofen using surrogate markers in rats: effect of formulation and route of administration.

OBJECTIVE: To elucidate the mechanism of gastrointestinal (GI) toxicity of ibuprofen and to examine the effect of altered site of drug release using gastroduodenal and intestinal permeability tests in the rat model. METHODS: Adult male Sprague-Dawley rats were administered (n = 6 per group) either: (1) 100 mg/kg immediate or sustained release ibuprofen; (2) 100 mg/kg immediate release and ibuprofen lysinate; or (3) 100 mg/kg or 200 mg/kg ibuprofen po or s.c. Upper and lower GI permeability as a surrogate marker of toxicity were determined at pre-determined times using the urinary excretion of orally administered sucrose and 51Cr-EDTA permeability probes, respectively. RESULTS: Ibuprofen administration resulted in a dose-dependent increase in both upper and lower permeability of the GI tract. Both immediate and sustained release preparations of ibuprofen increased upper and lower GI permeability with no shift of toxicity to the site of drug release. Ibuprofen lysinate also induced significant increased upper and lower GI permeability comparable to immediate release ibuprofen. Oral doses were not more toxic than s.c. doses. CONCLUSION: Ibuprofen-induced increased GI permeable appears to be independent of the type of formulation and route of administration. This indicates that, contrary to some other nonsteroidal anti-inflammatory drugs, ibuprofen's effect on GI permeability is mainly systemic and the direct local effect contributes minimally to its overall GI toxicity. Ibuprofen may be a suitable candidate for sustained release formulations since its effect may be prolonged without the danger of a shift of side effect from the upper to the lower GI tract.

Intestinal permeability in strongyloidiasis.

The objective of the present study was to assess intestinal permeability in patients with infection caused by Strongyloides stercoralis. Twenty-six patients (16 women and 10 men), mean age 45.9, with a diagnosis of strongyloidiasis were evaluated. For comparison, 25 healthy volunteers (18 women and 7 men), mean age 44.9, without digestive disorders or intestinal parasites served as normal controls. Intestinal permeability was measured on the basis of urinary radioactivity levels during the 24 h following oral administration of chromium-labeled ethylenediaminetetraacetic acid ((51)Cr-EDTA) expressed as percentage of the ingested dose. The urinary excretion of (51)Cr-EDTA was significantly reduced in patients with strongyloidiasis compared to controls (1.60 +/- 0.74 and 3.10 +/- 1.40, respectively, P = 0.0001). Intestinal permeability is diminished in strongyloidiasis. Abnormalities in mucus secretion and intestinal motility and loss of macromolecules could explain the impaired intestinal permeability.

51Cr-EDTA absorption blood test: an easy method for assessing small intestinal permeability in dogs.

The 51Cr-EDTA test is a valuable clinical tool for screening intestinal diseases in dogs. The test is performed by calculating the percentage of recovery from urine of a PO-ingested dose of 51Cr-EDTA after 6 or 24 hours. Careful urine collection is a practical limitation of this test in dogs, and our goal was to develop a simpler test that measures 51Cr-EDTA in blood. A 51Cr-EDTA absorption test was simultaneously performed on urine and serum 43 times in healthy Beagle Dogs. Timed blood samples were withdrawn, and urine was collected during a 6-hour period. Percentages of the ingested dose were then calculated in urine and serum. The mean +/- standard deviation (range) percentage in urine after 6 hours was 14.07 +/- 8.72% (3.81-34.18%), whereas results in serum from samples taken at 2, 3, 4, 5, and 6 hours were 0.49 +/- 0.45% (0.02-2.13%), 0.75 +/- 0.52% (0.03-1.89%), 0.82 +/- 0.57% (0.13-2.21%), 0.70 +/- 0.53% (0.12-1.99%), and 0.47 +/- 0.44% (0.11-1.79%), respectively. The results for blood specimens showed good concordance with those for urine, especially for the samples taken at 4 hours (r = 0.89). Moreover, the correlation between urine and blood was better when the sum of the percentages of the recovered analyte from various blood samples was compared with urine. The correlation coefficient when summing 4 blood samples was excellent (r = 0.97) and remained excellent when summing only 2 blood samples taken at 3 and 5 hours (r = 0.95) or at 3 and 4 hours (r = 0.94). We conclude that a serum 51Cr-EDTA test determined by summing successive blood samples provides an easier means of estimating small intestinal permeability in dogs and gives results comparable to those of the 6-hour urine test.

Interleukin-1alpha-induced changes in chromium-51 absorption, tissue retention, and urinary excretion in rats.

The effects of interleukin-1 alpha (IL-1alpha) on chromium-51 absorption, tissue retention, and urinary excretion were studied in adult male Sprague-Dawley rats. Ten rats were deprived of food for 12 h, injected intraperitoneally with mouse recombinant IL-1alpha (1 microg/kg of body weight in phosphate-buffered saline [PBS]) or control (0.1% bovine serum albumin [BSA] in PBS). Two hours after dosing with the IL-1alpha, rats were fed 50 microL (200 microCi, 0.36 microg Cr) of 51CrCl3 by micropipet. Blood was collected from the tail at 0.25, 0.5, 1, 2, and 4 h. Six hours after dosing with 51CrCl3, rats were exsanguinated and blood and tissues were sampled. The IL-1alpha significantly decreased chromium-51 in blood, urine, and some tissues compared to the control. The decreased absorption, retention, and urinary excretion of chromium-51 from 51CrCl3 in this study may be due to IL-1alpha-mediated increases in the production of prostaglandins and/or decreased production of gastric acid.

A simple method for measuring severely reduced glomerular filtration rate.

OBJECTIVE: The purpose of this study was to develop a simpler method to measure severely reduced glomerular filtration rate (GFR) for patients with a GFR below 30 mL/min. METHOD: The GFR was measured in 24 patients using both the 51Cr EDTA slope-intercept method (the conventional method) and 99mTc-DTPA with our proposed simpler GFRn method. RESULTS: The correlation coefficient was 0.92 between the 2 methods, with a slope of 0.97 and an intercept of 2 mL/min. CONCLUSION: Our simplified method for measuring GFR is accurate for most patients with severely reduced GFR. Errors are acceptably small in patients with severely reduced GFR when edema or dehydration are present. If extrarenal (liver) clearance is significant, however, a urine sampling method is required for an accurate GFR measurement.

Metabolism of 51Cr, 54Mn, 59Fe and 60Co in lactating dairy cows.

Different radionuclides which can be released by nuclear installations (Na2(51) CrO4 , 54MnCl2 , 59FeCl3 and 60CoCl2 ) were given to lactating dairy cows either orally or by intravenous (i.v.) injection. Excretion into feces and urine as well as secretion into milk were followed for several weeks. Distribution of activity in organs was determined at sacrifice 102 days after oral and 70 days after i.v. administration. After ingestion, excretion of chromate followed a three-term exponential function with half-lives of 0.88, 3.7 and 26 days. Intestinal absorption was on the order of 0.1-0.2%. About 63% of injected chromate was excreted into urine, about 18% into feces and about 3.6% into milk. Orally administered chromate was concentrated in liver, intestine and spleen. The transfer coefficient into milk was about 1 X 10(-5) days/1. Less than 1% of an ingested dose of manganese was absorbed. Excretion occurred mainly into feces and followed a three-term exponential function. Very little manganese was excreted into urine or secreted into milk. Manganese is concentrated in brain, pancreas, kidney and heart but the differences in concentration are small. The body burden is, therefore, mainly determined by manganese in muscle, skin and bone. The transfer coefficient of manganese into milk is about 3 X 10(-5). Excretion of iron into feces after oral administration follows a three-term exponential function with a small component having a half-life of 72 days. Intestinal absorption is on the order of 0.5-2% of the dose. After i.v. administration, 7% of the dose is excreted in the feces displaying two components of turnover. Very little iron is excreted into urine. Secretion into milk also follows a two-term exponential function. The transfer coefficient of iron into milk is about 3 X 10(-5). About 0.6% of an oral and about 94% of an i.v. dose were recovered from the cows at sacrifice. Most activity was present in blood, liver and spleen. Excretion of radiocobalt into feces after oral administration is described by a three-term exponential function, while excretion into milk and urine is described by two-term exponential functions. Long-lived components in urine and milk represent about 5-10% of the activity absorbed. Only 1-2% of an oral cobalt dose is absorbed and 0.05% of an oral and 5.85% of an i.v. dose is recovered from the cow at sacrifice where concentrations are highest in kidney and thyroid. The body burden depends mainly on cobalt in muscle, skin and bone. The transfer coefficient of cobalt into milk is about 7.5 X 10(-5).

[Increased intestinal permeability to 51 Cr-EDTA among children with persistent diarrhea]. / Aumento da permeabilidade intestinal ao 51Cr-EDTA em crianças com diarréia persistente.

Persistent diarrhea, a condition highly prevalent in developing countries, causes different morphological and functional alterations of the mucosa of the small intestine, including increased permeability to different test molecules. In the present study we investigate for the first time the intestinal permeability to 51Cr-EDTA of Brazilian children with persistent diarrhea. The test of 51Cr-EDTA absorption was performed in 13 control children and in 14 children with persistent diarrhea by offering 50 microCi of the test substance by the oral route, with later detection of radioactivity excreted in 24-hour urine. There was a statistically significant difference between the control group (median = 1.26; range = 0.20-3.31%) and the group with persistent diarrhea (median = 4.68; range = 1.40-10.29%). Using the minimum and maximum values detected in the control group as the normal reference standard for the test of urinary 51Cr-EDTA absorption, we observed that 61.5% of the patients with persistent diarrhea showed altered results. Among the patients with persistent diarrhea, 51Cr-EDTA excretion was significantly higher in the group fed a protein hydrolysate diet and/or total parenteral nutrition than in the group that did not receive this diet. In four patients with persistent diarrhea, the test was performed after clinical recovery, with a fall in the excretion levels in all cases. On the basis of these data, we may conclude that: 1) in persistent diarrhea there must be alteration of intestinal permeability that might permit an increased entry of local alimentary antigens, with subsequent sensitization and allergic enteropathy, contributing to the perpetuation of the diarrhea, malabsorption and malnutrition cycle; 2) the 51Cr-EDTA test may be useful as an indicator of severity in persistent diarrhea; 3) alteration of intestinal permeability is a secondary phenomenon in persistent diarrhea, with normalization occurring after reconstruction of the intestinal barrier.

Intestinal permeability to [51Cr]EDTA in children with cystic fibrosis.

Intestinal permeability was investigated in 14 children with cystic fibrosis making use of [51Cr]EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of [51Cr]EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001).

Radiochromium distribution in aged rats.

Fragmentary studies suggest that tissue chromium (Cr) levels decrease with age. Regardless of the mechanism for such a decline, decreased tissue exchange with administered radiochromium (51Cr) should result. Accordingly, body retention, urinary excretion, and serum (plasma) and tissue levels of 51Cr were determined in 2-month-old male control rats and in 9-18-month-old experimental male rats 3 days after the intravenous injection of high specific activity trivalent 51Cr. The older rats retained relatively less 51Cr than the 2-month-old rats in comparison to body weight but had similar urinary excretions of 51Cr. Serum (plasma) 51Cr levels were generally higher and tissue 51Cr levels generally lower in the older rats, with the exception of spleen 51Cr content, which increased. Skeletal 51Cr content was markedly decreased, by 30-85%. These data suggest that aging alters 51Cr distribution by decreasing cellular Cr content and transport. Other mechanisms must be operative in bone since skeletal Cr is primarily extracellular.

The leaky gut of alcoholism: possible route of entry for toxic compounds.

Intestinal permeability was investigated with a chromium-51-EDTA (edetic acid) absorption test in 36 non-intoxicated alcoholic patients without liver cirrhosis or overt clinical evidence of malabsorption or malnutrition. Patients abstaining from alcohol for less than 4 days almost invariably had higher intestinal permeability than controls, and in many the abnormality persisted for up to 2 weeks after cessation of drinking. The presence of gastritis did not correlate with the presence of increased permeability. The site of altered intestinal permeability was shown by an in-vitro permeability test to be the small bowel. The increased intestinal permeability to toxic "non-absorbable" compounds of less than 5000 molecular weight may account for some of the extraintestinal tissue damage common in alcoholic patients.

Fate of labeled albumin and erythrocytes following injection into amniotic cavity of sheep.

We have previously described a method to measure the amniotic fluid (AF) volume and fetal swallowing rate in near-term sheep by use of 125I-labeled albumin (RISA) and 51Cr-labeled red blood cells (51Cr-RBC). However, when we measured these volumes on consecutive days, reentry of the radionuclides into the amniotic cavity from fetal urine affected the calculated values of AF volume and swallowing rates. In an attempt to clarify the recirculation problem, we injected RISA and Cr-RBC daily for 9 days into the AF of five chronically catheterized pregnant sheep (124 days gestation on the 1st experimental day). We calculated AF volume and fetal swallowing rate, comparing those values to the values corrected for fetal urine isotopic counts. The mean AF volume and fetal swallowing rate measured by RISA were 808 +/- 48 ml (mean +/- SE) and 559 +/- 29 ml/day, respectively. These values were only slightly different from the corrected volumes, 808 +/- 48 ml and 561 +/- 29 ml/day, respectively, because fetal urine 125I activity reached only 4.8% of AF activity even on the 9th day. In contrast, 51Cr-activity in fetal urine on the 9th day showed 47% of the activity of AF. The mean uncorrected AF volume (785 +/- 44 ml) and swallowing rate (561 +/- 31 ml/day) measured by Cr-RBC were different from the corrected values (790 ml and 570 ml/day, respectively). After the 4th day these differences were particularly conspicuous.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison between the lactulose/mannitol and 51Cr-ethylenediaminetetraacetic acid/14C-mannitol methods for intestinal permeability. Frequency distribution pattern and variability of markers and marker ratios in healthy subjects.

Urinary excretion of lactulose and mannitol, determined by gas-liquid chromatography, was compared with that of 51Cr-ethylenediaminetetraacetic acid (EDTA) and 14C-mannitol for measurement of intestinal permeability in 28 healthy humans. The 0- to 6-h excretion values for unlabelled and labelled mannitol (marker of transcellular permeability) were normally distributed, whereas excretion values for lactulose and 51Cr-EDTA (markers of paracellular permeability) were skewly distributed, as were the lactulose to mannitol and 51Cr-EDTA to 14C-mannitol ratios. Excretion of the transcellular markers but not of the paracellular markers was significantly correlated to urinary volume; correction for urinary volume resulted in decreased test variability. Significant correlation was found between lactulose and 51Cr-EDTA excretion (p < 0.01) and between mannitol and 14C-mannitol excretion (p < 0.001) but not between the lactulose to mannitol and 51Cr-EDTA to 14C-mannitol ratios (p = 0.11). Inter- and intraindividual test variability was greater for each chemically determined marker than for the corresponding isotope-labelled marker. Similarly, variability was greater for each paracellular marker than for the corresponding transcellular marker and for each paracellular/transcellular marker ratio than for the transcellular marker alone. Variability of mannitol excretion was increased by the frequent presence of food-derived mannitol in the urine.