Carboplatin dosing based on measurement of renal function — experience at the Peter MacCallum Cancer Institute

Background: Carboplatin is used in treating many types of cancer. Because renal excretion is the major variable determining the pharmacokinetics of this drug, a dosing formula based on glomerular filtration rate (GFR) has been proposed and is being increasingly used in carboplatin dosing. This method of dosing is critically dependent on accurate measurement of GFR. Aims: To report the experience at a single major oncology centre of carboplatin dosing based on GFR, and comparisons of different methods of measuring renal function for use in this dosing method. Methods: An initial group of patients (n=24) was studied where GFR was measured by Cr⁵¹EDTA clearance and compared to Tc^99mDTPA clearance, measured 24 hour urine creatinine clearance and the Cockcroft and Gault formula. The carboplatin area under the plasma concentration versus time curve (AUC) was calculated using total platinum measured in a single blood sample assayed by flameless atomic absorption spectrophotometry. A subsequent patient group (n=16) was then studied using Tc^99mDTPA clearance to measure GFR. Results: Carboplatin dosing using Cr⁵¹EDTA clearance to measure GFR was accurate (<25% difference between planned and measured AUC) in 87% of samples. Estimation of renal function using the Cockcroft and Gault formula correlated with Cr⁵¹EDTA clearance only in patients with GFR <100 mL/minute. The measured 24 hour urine creatinine clearance did not correlate with Cr⁵¹EDTA clearance. Using Tc^99mDTPA clearance to measure GFR, carboplatin dosing was accurate in 81% of samples. Across a GFR range of 42–239 mL/minute, the Cr⁵¹EDTA and Tc^99mDTPA clearances were closely correlated (r=0.98, slope of regression line=1.02). Conclusions: Carboplatin dosing using a pharmacological formula based on GFR produces accurate targeting of the carboplatin AUC. Tc^99mDTPA clearance can be used to measure GFR instead of Cr⁵¹EDTA clearance, which is both more convenient and has potential cost savings. Estimates of renal function using the Cockcroft and Gault formula or measured 24 hour creatinine clearance are insufficiently accurate to use for carboplatin dosing.     

Comparison of prediction equations to estimate glomerular filtration rate in Chinese patients with chronic kidney disease

Aim: We sought to evaluate the applicability of formulae based on serum creatinine (SC) levels in Chinese patients with chronic kidney disease (CKD). Materials and methods: Three hundred and twenty‐seven patients with CKD who had undergone ^99mTc‐DTPA glomerular filtration rate (GFR) estimation were enrolled. The Cockcroft–Gault equation, SC‐reciprocal equation, Gate equation, Hull equation, Jelliffe‐1973 equation, Jelliffe‐1971 equation, Mawer equation, Bjornsson equation, reexpressed 6‐variable MDRD equation and reexpressed 4‐variable MDRD equation were compared. Using the ^99mTc‐DTPA GFR as the standard GFR (sGFR), the accuracy of estimated GFR was compared with sGFR in various stages of CKD. Results: Median per cents of the absolute difference ranged from 28.16% to 39.39%, accuracy with a deviation less than 30% ranging from 39.4% to 53.5%, accuracy with a deviation less than 50% ranging from 63.0% to 80.7%. None of the equations had accuracy up to the 70% level with a deviation less than 30% from sGFR. Bland–Altman analysis demonstrated that mean difference ranged from ?2.42 to 16.39 mL/min/1.73 m², whereas precision ranged from 82.66 to 106.15 mL/min/1.73 m². However, the agreement limits of all the equations exceeded the prior acceptable tolerances defined as 60 mL/min/1.73 m². Linear regression showed that the slopes of regression line ranged from 0.37 to 0.54 and intercepts ranged from ?12.10 to 3.86. When the overall performance as well as bias and accuracy were compared in different stages of CKD, GFR estimated by Jelliffe‐1973 equation, Cockcroft–Gault equation and Bjornsson equation showed promising results. Conclusion: When SC was measured by the enzymatic method, GFR estimation equations showed great bias in Chinese CKD patients. At present, the Jelliffe‐1973 equation and Cockcroft–Gault equation may be more accurate in the Chinese ethnic group.     

Evaluation of [14C] aminopyrine breath test,peripheral clearance of [99mTc]EHIDA,and serum bile acid levels in liver function and disease

The purpose of this study is to evaluate the diagnostic value of the following tests in the assessment of patients with chronic liver disease (CLD) and cholestatic syndrome (CS):(1) aminopyrine breath test, measuring¹⁴CO₂ excretion in the expired air, (2) peripheral clearance of [^99mTc]EHIDA, and (3) postprandial levels of glycocholic acid (GCA) and glycochenodeoxycholic acid (GCDCA). The results indicate that: (1)¹⁴CO₂ 2-hr excretion rate is a specific and sensitive marker of liver function, with good correlation with postprandial bile acid levels, [^99mTc]EHIDA retention, and the conventional tests of serum albumin and prothrombin time. (2) Peripheral clearance and retention of [^99mTc]EHIDA increased in both groups of CLD and CS vs controls, but it does not discriminate between the two. (3) Postprandial bile acids were elevated in CLD, particularly those of GCDCA, whereas GCA levels were significantly elevated in CS compared with CLD. This may be due to increased synthesis and entry into the blood. (4) The combination of [¹⁴C]aminopyrine breath test and postprandial levels of GCDCA enhance the diagnostic value, specificity, and sensitivity in the assessment of patients with CLD.     

Noninvasive detection ofHelicobacter pylori colonization in stomach using [11C]urea

Summary Helicobacter pylori is associated with chronic type B gastritis. Diagnosis can be made on gastric biopsy specimens and noninvasively using [¹³C]-or [¹⁴C]urea breath tests. Both breath tests require meticulous breath collection, and false positive results are possible from urease producing oral-pharyngeal flora. We used [¹¹C]urea, a positronemitting radionuclide allowing dynamic imaging, to measure metabolism of urea in the stomach of biopsy documentedH. pylori-positive patients. [¹¹C]urea was synthesized from¹¹CO₂ produced using a Van de Graaff accelerator and administered with [^99mTc]DTPA to control for loss of radioactivity via gastric emptying. Images were obtained externally by gamma camera every minute and¹¹CO₂ was monitored in the breath continuously for 30 min. AnH. pylori-positive patient exhibited a^99mTc/¹¹C activity ratio of 2.1 in the stomach 10–20 min following administration, compared to a 11 ratio in a negative control, indicating metabolism of urea to¹¹CO₂ with subsequent diffusion of¹¹C activity out of the stomach. The¹¹C activity in the breath peaked at 10–20 min in theH. pylori-positive patients. The short half-life of carbon-11 (20.4 min) alleviates radiation safety concerns and results in low absorbed radiation doses to patients.This work was supported in part by the National Science Foundation (grant R11-8110671), the Commonwealth of Kentucky through the Kentucky EPSCoR program, a grant from the University of Kentucky Association for Medical Research, and the Veterans Administration.     

A comparison of the plasma disappearance of iohexol and 99m Tc-DTPA for the measurement of glomerular filtration rate (GFR) in diabetes

Background: Changes in glomerular filtration rate (GFR) provide a valuable indicator of the progression of diabetic nephropathy. GFR is most commonly measured by the plasma clearance of radioisotopes, however, use of iohexol, a non-ionic radiocontrast medium, is a recently described alternative and has shown good agreement with inulin clearance. A one-compartment model is used for calculating GFR in most Australian centres but a two-compartment model is more accurate. Aims: To set up a non-radioisotopic method for assessment of GFR using iohexol, and to compare this with the currently used ^99mTc-diethylene-triamine-penta-acetic acid (DTPA) method. Secondly, to compare GFR results using an unmodified one-compartment model with a one-compartment model subjected to the Brochner-Mortensen modification. Methods: Twenty-one patients with diabetes had assessment of GFR with simultaneous measurements of ^99mTc-DTPA and iohexol plasma clearance. Plasma clearance was determined by the slope intercept method and then modified according to the Brochner-Mortensen equation. Plasma iohexol concentrations were determined by capillary electrophoresis. Results: There was no significant difference between iohexol and ^99mTc-DTPA derived GFR values, difference 4.3±7.7 mL/minute (mean±SD). This was despite ^99mTc-DTPA protein binding demonstrated in the range of 5–10%. Comparison of GFR results using an unmodified one-compartment model with a Brochner-Mortensen corrected one-compartment model showed higher GFR values with the former, in the range of 20–30% for GFR values > 100 mL/minute. Conclusion: Iohexol provides an efficient alternative to radioisotopic methods for serial measurement of GFR in diabetic patients with hyperfiltration, incipient and overt nephropathy. A one-compartment model with its inherent overestimation of GFR should be replaced by the Brochner-Mortensen modified one-compartment model.     

Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia

Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by ^99mTc‐DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long‐term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long‐term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty‐three children with SCA (median age 7.5 years, range, 2.5–14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3–30.6 mg/kg/day). After 3 years of treatment, GFR measured by ^99mTc‐DTPA decreased significantly from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m² (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA. Am. J. Hematol., 88:116–119, 2013. © 2012 Wiley Periodicals, Inc.     

Evaluation of gallbladder function before and after gastrectomy using a double-isotope method

The motor function of the gallbladder after partial distal gastrectomy for gastric carcinoma (Billroth-I reconstruction) and its relationship to the motor function of the stomach was investigated using a double-isotope method. In this method, [^99mTc]N-54-pyridoxyl-5-methyltryptophan ([^99mTc]PMT) was utilized as a tracer for the biliary tract and [¹¹¹In]diethyl-triaminopontacetic acid ([¹¹¹In]DTPA) mixed with a liquid test meal was used as a tracer for the digestive tract. Gastric emptying half-time (GET1/2) was measured, since this was used historically as the physiologic indicator of gallbladder contractile stimulus. The volume of test meal that emptied from the stomach into the duodenum per minute (VOL/MIN) was measured, as was the gastric emptying duration (GED). A series of gallbladder emptying phenomena were analyzed using three different criteria: gallbladder emptying half-time (GBET1/2), retention rate of bile in the gallbladder (RR), and the start of gallbladder bile ejection into the duodenum after ingestion (TL: time lag). While GET1/2 was reduced (P<0.01) and VOL/MIN was increased (P<0.01) after gastrectomy, GED was shortened remarkably (P<0.01). GBET1/2 showed no significant change, RR increased (P<0.05), and TL was prolonged (P<0.01). The postoperative dysfunction of the gallbladder was caused by the short and intense stimulus on the biliary tract during the duodenal phase and by intraoperative injury to the innervation of the gallbladder. In particular, the hepatic branch of the left vagus nerve was injured during the right paracardiac lymph node dissection performed as a component of the radical gastrectomy.     

Renal changes and estimation of glomerular filtration rate using different equations in morbidly obese Egyptian patients

Background and aimsObesity is a worldwide pandemic with multiple consequences including kidney affection. This study aimed to assess the effects of obesity on renal functions and to detect the most reliable formula of estimated glomerular filtration rate (eGFR) in morbidly obese patients.MethodsA cross-sectional, observational study was conducted on 82 morbidly obese patients. Anthropometric measurements were done for all patients and body adiposity (BAI) and visceral adiposity (VAI) indices were calculated after assessment of abdominal fat tissue analysis by computerized tomography (CT). Serum creatinine was incorporated into six different formulae of eGFR, then eGFR was compared with the 24-h measured creatinine clearance (CL_cr) values.ResultsThe mean body mass index was 55.8 ± 9.5 kg/m². Proteinuria and glomerular hyperfiltration (CL_cr > 130 ml/min/1.73 m²) were detected in 68.3% and 91.5% of the patients, respectively. Cockcroft–Gault formula using total (CCG-TBW-eGFR) and adjusted body water (CCG-AjBW-eGFR) had the nearest values to measured CL_Cr. These two formulae had a moderate reliability and the lowest percentage of error (30% and 23%, respectively). Visceral and total abdominal fat tissue surface area and volume assessed by CT were directly correlated to the 24-h urinary protein excretion (r = 0.32, 0.24, 0.37 and 0.34, respectively; p = 0.02, 0.03, 0.004 and 0.002, respectively).ConclusionsGlomerular hyperfiltration and proteinuria are highly prevalent in morbidly obese patients. There is no ideal formula for GFR estimation in morbidly obese patients, however, TBW and AjBW incorporated into the Cockcroft–Gault can be helpful in those patients.     

Validity of creatinine clearance from serum creatinine in subjects over 80 years old

In clinical practice, the Cockcroft and Gault formula (CG) is used to evaluate creatinine clearance from serum creatinine in the elderly. Its validity in a very old nondebilitated population over 80 years of age has not been investigated. In our study, we compared the calculated creatinine clearance with the glomerular filtration rate (GFR) measured using the clearance of 99m-diethyleenetriamine pentaacetic acid (99m Tc TDPA), isotopic method which avoids urinary collection in 25 patients over 80 years old. The CG clearance largely underestimates the isotopic GFR: mean calculated creatinine clearance is 37.6 ± 9.8 ml/min/1.73 m2 and the mean isotope GFR is 57.8 ± 15 ml/min/1.73 m2. The mean underestimation is the same in the subgroup of 11 patients with plasma creatininemia below 100 μmol/l and in the subgroup of 14 patients with creatininemia over 100 μmol/1.     

Effect of isolated portal hypertension on kupffer cell function

The increased incidence of infection in cirrhotics may in part be attributable to dysfunction of the reticuloendothelial system (RES) in removing pathogens from the circulation. The portosystemic shunting (PSS) that results from portal hypertension in cirrhotics may compromise RES function by allowing enteric pathogens to be shunted away from the Kupffer cells. A well-characterized model of portal hypertension induced by partial portal vein ligation (PVL), in which there is no hepatic parenchymal cell damage, was used. Kupffer cell function is unaltered and the effect of PSS alone on overall RES function can be evaluated. In addition to the usual immunologically inert [^99mTc]sulfur colloid, an actual pathogen was also evaluated. PVL and sham-ligated rats were given either [^99mTc]sulfur colloid orE. coli via the ileocolic vein. The right femurs, lungs, livers and spleens of the animals receiving^99mTc were excised and the radioactivity counted. The lungs, livers, and spleens of the animals receivingE. coli were liquefied and the bacteria were quantified. For both groups the ratios of^99mTc orE. coli in the lung, spleen, and femur to liver were calculated. PVL rats had significantly more^99mTc in the lung, spleen, and femur than the sham rats. There were also significantly moreE. coli in the lungs for PVL rats but no significant difference in the spleen counts. These results imply that even in the absence of Kupffer cell dysfunction, PSS alters reticuloendothelial system function by causing a greater distribution of pathogens to the periphery. This altered distribution may contribute to an increased susceptibility to infection in cirrhotics.     

Evaluation of Hepatobiliary Excretion and Enterobiliary Reflux in Rats with Biliary Obstruction Submitted to Bilioduodenal or Biliojejunal Anastomosis

Bilioduodenal and biliojejunal anastomoses are effective for the treatment of biliary obstruction. The objective of this study was to compare the effects of these anastomoses on hepatobiliary excretion and enterobiliary reflux. Enterobiliary reflux and biliary excretion were evaluated respectively after oral administration of technetium (^99mTc) in combination with sodium phytate and intravenous infusion of ^99mTc with diisopropyl-iminodiacetic acid. Enterobiliary reflux occurred to an equal degree in the bilioduodenal and biliojejunal groups. Maximum hepatic activity time (T_max) and radiotracer clearance half-time (T^1/2) were similar in both groups. However, when compared with that found for the sham-operated group, T_max, and T^1/2 were higher in the biliojejunal group (P = 0.02 and P = 0.01, respectively). Histopathological analysis showed marked reduction in ductal proliferation in both groups. These data undermine the theoretical advantages attributed to biliojejunal anastomosis and further the understanding of the pathophysiology of cholangitis that occurs even with patent anastomosis.     

Inflammatory Bowel Disease Activity Assessment Using Technetium-99m-HMPAO Leukocytes

Aim of the study was to evaluate[^99mTc]hexamethyl-propylamine-oxime (HMPAO)leukocyte scintigraphy for the assessment of diseaseactivity and extent in inflammatory bowel diseasepatients. Results and scores of scintigraphy using[⁹⁹Tc]HMPAO-labeled leukocytes wereretrospectively compared with the activity index of vanHees, laboratory parameters, and gastroenterologists'assessment of disease using endoscopy, radiology, and histology plusclinical parameters in 136 patients with Crohn's disease(115) and ulcerative colitis (21) and in 29 controls.There were 114 positive and 22 negative[⁹⁹Tc]HMPAO leukocyte scintigrams. Sensitivities for activedisease at 1 and 3 hr were 98% and 98% and specificitieswere 100% and 83%, respectively. [^99mTc]HMPAOleukocyte scintigraphy is superior to the activity index and the gastroenterologists' clinicalassessment of active inflammation in IBD patients.Scintigraphy allows assessment of the existence, extent,and intensity of active inflammation in IBD patients in one examination with highaccuracy.     

Preliminary experience of 99mTc-Aprotinin scintigraphy in amyloidosis

Background and aim: Radio‐labelled Aprotinin has been shown to bind with amyloid fibrils in vitro as well as in vivo. The aim was to test the usefulness of ^99mTc‐Aprotinin imaging in systemic amyloidosis. Methods: Thirty‐five cases who had ^99mTc‐Aprotinin scans for the assessment of systemic amyloidosis were reviewed retrospectively. Eighteen had biopsy‐proven amyloidosis and 17 were controls (amyloidosis was excluded by negative biopsies and non‐invasive tests). Five of 18 patients with amyloidosis had final diagnosis of cardiac amyloid. Results: Physiological uptake of ^99mTc‐Aprotinin was noted in the urinary tract (kidneys and bladder) and in the liver of all patients and controls; and non‐specific uptake of ^99mTc‐Aprotinin was visualised in the spleen and oro‐facial structures in the majority of both groups. Myocardial ^99mTc‐Aprotinin uptake was noted in all five patients with final diagnosis of cardiac amyloidosis and in none of the 30 subjects who did not have cardiac amyloid. The median heart to background uptake ratio was 2.0 in cardiac amyloid patients and 1.1 in subjects without cardiac amyloid (P = 0.0004). Single Photon Emission Tomography (SPECT) studies of the thorax confirmed that the site of uptake lay within the myocardium. In the amyloidosis group, site‐specific ^99mTc‐Aprotinin uptake was also identified in the subcutaneous tissue of the legs and in a breast nodule shown to be positive for amyloidosis on biopsy. Conclusions: ^99mTc‐Aprotinin imaging may be a useful non‐invasive method for the assessment of the presence and extent of extra‐abdominal amyloid, particularly cardiac amyloidosis. It has little role in diagnosis of amyloidosis involving the oro‐facial and abdominal structures.     

Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus

Aims/hypothesis: The pathogenesis of fasting hyperglycaemia in Type II (non-insulin-dependent) diabetes mellitus has yet to be clarified. Rates of glucose production (R _a), utilization and metabolic clearance rate were therefore measured during an extended fast, in control subjects and in Type II diabetic patients. Methods: Nine subjects with newly-diagnosed or diet-treated diabetes and seven control subjects matched for age and weight (BMI 36.0 ± 2.4 and 35.3 ± 3.1 kg/m² respectively) underwent an overnight fast followed by a 10-h unprimed infusion of [6-³H]glucose. Plasma tracer concentrations were fitted by a single-compartment model. Results: The metabolic clearance rate was near-constant [61.7 + 2.4 ml/(min-m²)] in diabetic patients and [75.5 ± 3.3 ml/(min-m²)] in control subjects (p < 0.05). It was correlated to the glucose concentrations both at t = 0 (r = –0.752, p = 0.0008) and t = 10 h (r = –0.675, p = 0.004). The calculated volume of distribution was 17.3 ± 1.4 l (18.2 % weight, diabetes), 19.6 ± 2.4 l (18.4 % weight, control). Glycaemia fell from 10.7 ± 0.8 mmol/l to 6.5 ± 0.3 mmol/l by 10 h (p < 0.05) in diabetes and from 5.6 ± 0.6 to 4.8 ± 0.1 mmol/l in control subjects (p < 0.05). The rate of glucose production decreased in parallel, from 563 ± 33 to 363 ± 23 μmol/(min-m²) (p < 0.05) in diabetes from 419 ± 20 to 347 ± 32 μmol/(min-m²) in control subjects. Initial R _a was higher in diabetic patients than in control subjects (p < 0.05) and was highly correlated to glycaemia (r = 0.836, p = 0.0001). By 10 h, R _a had converged in diabetic patients and control subjects and all correlation with glycaemia was lost (r = 0.0017, p = 0.95). Conclusions/interpretation: In relatively early diabetes, the more “labile” portion of fasting hyperglycaemia, which subsequently decreased, was closely related to the simultaneously decreasing R _a. The 25 % increase in glucose concentrations which persisted as stabilized R _a, resulted from about a 20 % lower metabolic clearance rate. [Diabetologia (2001) 44: 983–991] Received: 28 February 2001 and in revised form: 17 April 2001     

Adalimumab treatment in patients with rheumatoid arthritis with renal insufficiency

Objective

To elucidate the safety of adalimumab for rheumatoid arthritis (RA) patients with renal insufficiency, including those with end‐stage renal disease undergoing hemodialysis.

Methods

Sixty‐five RA patients, including 2 patients undergoing hemodialysis, treated with adalimumab in our hospital from December 1, 2008 to June 30, 2011 were retrospectively analyzed. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) calculated from the Cockcroft‐Gault formula at the start and end of followup after adalimumab treatment. The proportion of the patients who discontinued or switched adalimumab treatment and the change of the eGFR were compared between patients with (n = 39) and without (n = 26) renal insufficiency, defined as an eGFR <60 ml/minute/1.73 m².

Results

There was no significant difference between the 2 groups in the proportion of the patients who discontinued or switched adalimumab treatment (51.3% versus 50.0%; P = 0.53). The mean ± SD changes of eGFR were from 41.6 ± 13.3 to 43.4 ± 17.9 ml/minute/1.73 m² in patients with renal insufficiency and from 83.6 ± 17.5 to 83.0 ± 16.8 ml/minute/1.73 m² in patients without renal insufficiency, and the differences in each group were not statistically significant (P = 0.92 and P = 0.78, respectively). No severe infections or other severe adverse events were observed in either group during adalimumab treatment.

Conclusion

Our data indicate that adalimumab does not worsen renal function and has no serious adverse events even for RA patients with renal insufficiency, including those undergoing hemodialysis, and suggest that it could be a potential therapeutic option for them.     

Human adipose tissue glucose uptake determined using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET in combination with microdialysis

Aims/hypothesis: To determine the lumped constant (LC), which accounts for the differences in the transport and phosphorylation between [¹⁸F]-2-fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) and glucose, for [¹⁸F]FDG in human adipose tissue. Methods: [¹⁸F]FDG-PET was combined with microdialysis. Seven non-obese (29 ± 2 years of age, BMI 24 ± 1 kg/m²) and seven obese (age 32 ± 2 years of age, BMI 31 ± 1 kg/m²) men were studied during euglycaemic hyperinsulinaemia (1 mU/kg · min^–1 for 130 min). Abdominal adipose tissue [¹⁸F]FDG uptake (rGU_FDG) and femoral muscle glucose uptake were measured using [¹⁸F]FDG-PET. Adipose tissue perfusion was measured using [¹⁵O]-labelled water and PET, and interstitial glucose concentration using microdialysis. Glucose uptake (by microdialysis, rGU_MD) was calculated by multiplying glucose extraction by regional blood flow. The LC was determined as the ratio of rGU_FDG to rGU_MD. Results: Rates of adipose tissue glucose uptake (rGU_MD) were 36 % higher in the non-obese than in the obese patients (11.8 ± 1.7 vs 7.6 ± 0.8 μmol/kg · min^–1, p < 0.05, respectively) and a correlation between rGU_MD and rGU_FDG was found (r = 0.82, p < 0.01). The LC averaged 1.14 ± 0.11, being similar in the obese and the non-obese subjects (1.01 ± 0.15 vs 1.26 ± 0.15, respectively, NS). Muscle glucose uptake was fourfold to fivefold higher than adipose tissue glucose uptake in both groups. Conclusion/interpretation: [¹⁸F]FDG-PET seems a feasible tool to investigate adipose tissue glucose metabolism in human beings. Direct measurements with [¹⁸F]FDG-PET and microdialysis suggest a LC value of 1.14 for [¹⁸F]FDG in human adipose tissue during insulin stimulation and the LC does not appear to be altered in insulin resistance. Furthermore, the obese patients show insulin resistance in both adipose tissue and skeletal muscle. [Diabetologia (2001) 44: 2171–2179] Received: 10 May 2001 and in revised form: 29 August 2001     

Detecting alveolar epithelial injury following volatile anesthetics by (99m)Tc DTPA radioaerosol inhalation lung scan

BACKGROUND: Many volatile anesthetics have long been thought to affect alveolar epithelial permeability. OBJECTIVE: The purpose of this study was to examine the acute effects of volatile anesthetics on the permeability of the alveolocapillary barrier to (99m)Tc DTPA. METHODS: Twenty-seven patients (24 females, 3 males, age 29-73 years) undergoing operation were enrolled in this study and grouped according to the type of anesthesia received. Group 1 patients were administered 1% halothane. Group 2 patients were given 1.5% isoflurane. Intravenous anesthesia without volatile anesthetics were used for group 3 patients. Before and after anesthesia, (99m)Tc DTPA radioaerosol inhalation lung scans were performed to detect alveolar epithelial injury due to volatile anesthetics. The negative slope of the regression line was designated as the (99m)Tc DTPA pulmonary clearance rate and was expressed in terms of percentage decrease in radioactivity per minute. RESULTS: In group 1, the (99m)Tc DTPA clearance rates were 1.26 +/- 0.34 and 1.29 +/- 0.38 before and after anesthesia, respectively. The difference was not significant (p > 0.05). In group 2, the rates were 0.76 +/- 0.20 and 1.10 +/- 0. 37, before and after anesthesia, respectively. The difference was significant (p < 0.05). In group 3, the clearance rates were 1.07 +/- 0.38 and 1.21 +/- 0.48, before and after anesthesia, respectively. The difference was not significant. CONCLUSIONS: Following isoflurane administration, the more rapid pulmonary clearance of (99m)Tc DTPA indicates that isoflurane increases the permeability of the alveolo-capillary barrier. Copyright Copyright 1999 S. Karger AG, Basel     

Kidney function and discrimination of cardiovascular risk in middle‐aged men

Objective. To define the optimal glomerular filtration rate (GFR) cut off for discriminating the risk of myocardial infarction or cardiovascular death. Design. Prospective longitudinal observational study. Setting. A community‐based cohort. Participants. A total of 2176 nondiabetic 50‐year‐old men without cardiovascular disease. Methods. The men were followed until age 70. GFR was estimated at baseline using the Cockcroft–Gault formula. The optimal GFR cut‐off points for discriminating risk of a fatal or nonfatal myocardial infarction and cardiovascular death were defined as the GFR levels maximizing integrated discrimination improvement (IDI). Main outcome measures. Fatal or nonfatal myocardial infarction, cardiovascular death. Results. During follow‐up, 264 men experienced a fatal or nonfatal myocardial infarction, and 218 died of cardiovascular disease. The IDI‐defined optimal GFR cut offs in this study were 98 mL min^?1 for discriminating myocardial infarction risk and 92 mL min^?1 for discriminating risk of cardiovascular death. In Cox proportional hazard models adjusting for established risk factors, the myocardial infarction risk was substantially higher in men with GFR below versus above 98 mL min^?1 [hazard ratio (HR) 1.7, 95% confidence interval (CI) 1.3–2.3, P < 0.001], and the risk of cardiovascular death was doubled in men with GFR below versus above 92 mL min^?1 (HR 2.1, 95% CI 1.5–3.0, P < 0.001). Conclusion. The GFR cut‐off point for optimal discrimination of cardiovascular risk in the general population may be higher than previously suggested.     

Acute Effect of Nicotine Patch on Gastric Emptying of Liquid and Solid Contents in Healthy Subjects

The effect of nicotine on gastric emptyingremains controversial. Gastric emptying is delayed inchronic smokers after smoking high-dose nicotinecigarettes, but it is unchanged after chewing nicotinegums. No information is available on the effect oftransdermal nicotine patches on the gastric emptying ofsolid and liquid contents in healthy nonsmokers. Ourobjective was to prospectively evaluate the effect of the nicotine patch on gastric emptying ofliquid and solid contents in healthy nonsmokers. Tenhealthy nonsmoking volunteers under-went a baselinedual-isotope gastric scintigraphy with[¹¹¹In]-diethylenetriaminepantaacetic acid (DTPA) and [^99mTc]sulfurcolloid isotopes to evaluate prospectively the gastricemptying of liquid and solid contents, respectively. Thegastric scintigraphy was repeated after placing a transdermal nicotine patch (Habitrol) for 12 hrdesigned to deliver 14 mg of nicotine per day. Plasmanicotine level was measured prior to baseline gastricscintigraphy and after 12 hr placing the nicotine patch. Plasma nicotine was absent in allsubjects at baseline and but was significantly elevatedafter 12 hr of nicotine patch (P < 0.009). The meanhalf-emptying times (T_1/2) for the gastricemptying of liquids before and after nicotine patchplacement were 31.2 ± 23.3 and 25.6 ± 8.4min, respectively (P = 0.498). The mean T_1/2sfor the gastric emptying of solids before and afternicotine patch placement were 70.1 ± 34.0 and 59.7± 31.4 min, respectively (P = 0.202). There wasno correlation between the plasma nicotine level andgastric emptying of liquid and solid contents(correlation coefficient = –0.23 and –0.01, respectively).In conclusion, acute transdermal delivery of nicotinedoes not affect the gastric emptying of solid and liquidcontents in healthy nonsmoking subjects.     

Estimating glomerular filtration rate in diabetes: a comparison of cystatin-C- and creatinine-based methods

Aims/hypothesis We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes.Subjects, materials and methods In a cross-sectional study of 251 consecutive clinic patients, the mean reference (plasma clearance of ^99mTc-diethylene-triamine-penta-acetic acid) GFR (iGFR) was 88±2 ml min⁻¹ 1.73 m⁻². A regression equation describing the relationship between iGFR and 1/cystatin C levels was derived from a test population (n=125) to allow for the estimation of GFR by cystatin C (eGFR-cystatin C). The predictive performance of eGFR-cystatin C, the Modification of Diet in Renal Disease 4 variable formula (MDRD-4) and Cockcroft–Gault (C–G) formulas were then compared in a validation population (n=126).Results There was no difference in renal function (ml min⁻¹ 1.73 m⁻²) as measured by iGFR (89.2±3.0), eGFR-cystatin C (86.8±2.5), MDRD-4 (87.0±2.8) or C–G (92.3±3.5). All three estimates of renal function had similar precision and accuracy.Conclusions/interpretation Estimates of GFR based solely on serum cystatin C levels had the same predictive potential when compared with the MDRD-4 and C–G formulas.