Frank De Geeter

Reevaluation of Formulas for Predicting Creatinine Clearance in Adults and Children, Using Compensated Creatinine Methods

In clinical practice, glomerular filtration rate (GFR) is the most important marker for evaluation of renal function (1). Dosages of drugs that are eliminated by glomerular filtration are often based on GFR. At present, the most reliable methods for accurate assessment of overall GFR require intravenous administration of exogenous compounds and are both cumbersome and expensive. In clinical practice, creatinine clearance (CrCl) is widely accepted as a simple measure of GFR. However, CrCl systematically overestimates GFR because creatinine is freely filtered by the glomerulus and is also secreted by the proximal tubule. In the earliest methods, serum creatinine was assayed by the Jaffe reaction after deproteinization, eliminating the pseudo-chromogen effect of proteins (2). Similarly, the first automated methods used dialysis membranes to prevent interference from plasma proteins. Today, however, analyzers use undiluted serum and plasma, making them subject to the so-called “protein error” (3). This produces a positive difference of ∼27 μmol/L creatinine compared with HPLC methods (4)(5)(6)(7). Because urine contains relatively little or no protein, the protein error affects only creatinine determinations in serum. Therefore, CrCl is underestimated when creatinine methods affected by protein error are used. This underestimation has been stated to be compensated by the overestimation attributable to tubular secretion of creatinine. However, studies confirming this statement are lacking. In compensated Jaffe methods, the values assigned to the calibrator set point are adjusted to minimize the pseudo-creatinine contribution of proteins. The result is that compensated methods produce lower creatinine values. Alternatively, the protein error can be avoided by use of enzymatic creatinine methods. Collection of timed urine for CrCl is often a major source of error; therefore, simple formulas have been introduced to estimate GFR based on serum creatinine concentration, age, gender, body weight, and body length (8)(9) …

Digital Tomosynthesis in the Detection of Urolithiasis: Diagnostic Performance and Dosimetry Compared With Digital Radiography With MDCT as the Reference Standard

OBJECTIVE The purpose of this study was to evaluate the diagnostic performance of digital tomosynthesis in comparison with digital radiography in the detection of urinary stones with MDCT as the reference standard. SUBJECTS AND METHODS Fifty consecutively enrolled patients (32 men, 18 women; mean age, 51.5 years; range, 19-83 years) referred for unenhanced MDCT of the abdomen with suspicion of urinary stones also underwent digital tomosynthesis and digital radiography (anteroposterior and bladder inlet views). Images from all examinations were randomly read by three blinded radiologists. The mean effective doses for digital tomosynthesis, digital radiography, and low- and high-dose MDCT were measured on a male phantom. Free-response receiver operating characteristics and receiver operating characteristics analyses were used to compare the diagnostic performance of digital radiography with that of digital tomosynthesis. RESULTS Both types of analysis showed significantly better performance of tomosynthesis over digital radiography for all urinary stones (p < 0.05). No such improvement was found for ureteral stones. The gain in sensitivity with tomosynthesis was largest for stones between 2 and 5 mm in diameter. The mean effective dose was 0.5 mSv for digital radiography, 0.85 mSv for tomosynthesis, 2.5 mSv for low-dose MDCT, and 12.6 mSv for high-dose MDCT. CONCLUSION Use of digital tomosynthesis of the abdomen results in improved detection of urinary stones in general over digital radiography with only a slight increase in effective dose. Use of tomosynthesis, however, was not associated with major improvement in the diagnosis of ureteral stones. The technique has potential as an alternative imaging technique in the detection and follow-up of urinary stones.

Optimal collimator choice for sequential iodine-123 and technetium-99m imaging

Dual-isotope studies with technetium-99m and iodine-123 may be useful for various organs, including brain and myocardium. For the images obtained with each of the tracers to be comparable, it is important that activity ratios (activity in one part of the image/reference activity in the image) are preserved by the imaging method. We have used a Rollo phantom to study how collimator response affects such ratios. All investigations were performed with123I(p,5n) and on a Siemens Orbiter 3700 camera fitted with either a low-energy high-resolution (LEHR) or a medium-energy (ME) collimator. Images were made of a Rollo phantom filled with an aqueous solution of either99Tc or123I, and placed on the collimator surface with 8 cm of methyl-methacrylate interposed. Count densities were measured in ROIs drawn in each cell of the phantom, and normalised to the maximal ROI value in the image. The mean square error (MSE) was used to assess how well the ratios of count densities approximated the known activity ratios based on the dimensions of the cells of the phantom. For99mTc, regardless of the collimator used, the count density ratios approximated the activity ratios fairly well (LEHR: MSE=0.008; ME: MSE=0.020). For123I, count density ratios obtained with the LEHR were consistently higher than activity ratios (MSE=0.235), whereas the differences between the measured and the theoretical values were less with the ME collimator (MSE=0.013). Contrast fidelity of the123I images obtained with the LEHR collimator could be improved with Jaszczak scatter correction withk=1, but this led to unfavourable signal-to-noise ratios. For sequential99mTc/123I studies with extended sources, ME is to be preferred because of its higher contrast accuracy. Spatial resolution is less for the ME than for the LEHR collimator (FWHM with scatter: LEHR/99mTc=6.9 mm, LEHR/123I=7.4 mm, ME/99mTc=10.1 mm, ME/123I=11.1 mm), but remains similar for both tracers when the ME is used.

Glomerular Filtration Rate Is a Confounder for the Measurement of Soluble Mesothelin in Serum

The mesothelin gene encodes a 71-kDa precursor protein that is subsequently cleaved into a soluble megakaryocyte potentiating factor and a membrane-bound part, mesothelin. Mesothelin can be shed as “soluble mesothelin” or “soluble mesothelin-related protein” (SMRP),1 which is an approximately 40-kDa biomarker of malignant mesothelioma, an asbestos-related cancer (1). Mesothelioma typically occurs in middle-aged men, and the renal function or the glomerular filtration rate (GFR) can occasionally decrease in these patients and in individuals at risk of developing mesothelioma. Renal impairment leads to the accumulation of low molecular weight proteins in the blood [e.g., cystatin C (13 kDa) and β-trace protein (BTP) (23–29 kDa)], and these proteins have been used as markers of the GFR. Such renal impairment can also cause the accumulation of soluble mesothelin, as has previously been reported for a limited number of cases(2). Our aim, therefore, was to thoroughly investigate the impact of renal function on serum SMRP concentrations. We enrolled 66 individuals (49 men and 17 women; median age, 58 years; range, 24–80 years), who were referred for measurement of 51Cr-EDTA clearance to estimate the GFR. We excluded patients with asbestos-related diseases/malignancies, patients with endometrial, ovarian, cervix, lung, breast, pancreatic, or gastrointestinal cancer, and patients with leukemia, because these conditions can overexpress mesothelin (3)(4). The study was approved by the ethics committee of both participating hospitals, and participants gave written informed consent. …

Rapid hepatic clearance of 99mTc-TMEOP: a new candidate for myocardial perfusion imaging

BACKGROUND (99m)Tc labeled radiotracers used in clinical practice lack the perfect characteristics for myocardial perfusion imaging. In particular, the high liver uptake can interfere in the interpretation of the inferior myocardial wall. Within the tricarbonyl approach, we used tris(pyrazolyl)methane (99m)Tc organometallic complexes as a lead structure. Herein we present the production, in vivo and in vitro metabolic studies in rats and the first in vivo biodistribution in rats for tri-methoxy-tris-pyrazolyl-(99m)Tc-(CO)(3) ((99m)Tc-TMEOP), compared with (99m)Tc-sestamibi and (99m)Tc-tetrofosmin. METHODS The chemical identity of (99m)Tc-TMEOP was characterized by RP-HPLC. The octanol-water partition coefficient was determined under physiological conditions. In vitro stability and protein binding were determined using RP-HPLC. In vivo stability was determined in blood, heart, liver and kidney homogenates, intestine and urine using RP-HPLC. In vivo biodistribution was determined using dynamic planar acquisitions. Pinhole gated SPECT images were performed in other animals. Cardiac, liver and lung uptake were expressed as differential uptake ratios by drawing regions of interest in the organs of interest and around the total body. Heart-liver and heart-lung ratios were derived. Cardiac uptake was also expressed as percentage of injected activity. SPECT images were processed to determine the heart-liver ratio on SPECT images, to compare functional parameters between different tracers and to visualize homogeneous intracardiac tracer distribution. RESULTS (99m)Tc-TMEOP is a moderately lipophilic cation, is stable and does not undergo any transformation in vitro. (99m)Tc-TMEOP also shows a high in vivo stability. In vivo imaging shows liver kinetics faster than those of (99m)Tc-sestamibi and (99m)Tc-tetrofosmin. Cardiac uptake and functional analysis of pinhole gated SPECT data are comparable to those of (99m)Tc-sestamibi and (99m)Tc-tetrofosmin. CONCLUSION Although (99m)Tc-TMEOP shows a cardiac uptake between those of (99m)Tc-sestamibi and (99m)Tc-tetrofosmin, a better heart-liver ratio is obtained due to the faster liver washout. These results suggest possible faster cardiac perfusion imaging using (99m)Tc-TMEOP without liver activity interference.

Aspecific Uptake of 68GA-PSMA in Paget Disease of the Bone.

Ga-PSMA plays an increasing role in prostate cancer management, but several instances of false positivity have now been recognized. We present a patient with metastatic prostatic carcinoma who also showed overexpression of PSMA in Paget disease of the humerus on Ga-PSMA PET. This probably relates to bone remodeling and increased vascularity. It is important to be aware of this aspecific uptake because its recognition may avoid overstaging and may alter the therapeutic choice.

Comparison of the prognostic value of dipyridamole and dobutamine myocardial perfusion scintigraphy in hemodialysis patients

Screening for coronary artery disease (CAD) in hemodialysis patients is hampered by contraindications and/or limitations of the available techniques in this population. Myocardial perfusion scintigraphy (MPS) using dipyridamole has been considered inaccurate due to abnormally high basal levels of adenosine in uremia that could blunt the vasodilatory response. Since dobutamine may be more reliable, we directly compared the two in patients on hemodialysis. We performed MPS at rest and after separate dipyridamole or dobutamine stress in 121 chronic hemodialysis patients. More numerous, larger, and more intense reversible lesions were induced with dobutamine than with dipyridamole, mainly in the anteroseptal segments. Reversibility with dipyridamole but not dobutamine MPS was independently and strongly related with mortality associated with CAD and with fatal and non-fatal CAD. We hypothesize that the chronotropic action of dobutamine induced alterations of wall motion, leading to spurious perfusion defects, not unlike artifacts seen with left bundle branch block. Our study shows that even though dobutamine induced more pronounced myocardial ischemia than dipyridamole in chronic hemodialysis patients, dipyridamole MPS more accurately identifies patients at high risk for subsequent cardiac death or non-fatal CAD than dobutamine.

Effect of exercise induced hyperlactatemia on the biodistribution and metabolism of iodine-123-15-(p-iodophenyl)-3-R, S-methyl pentadecanoic acid in normal volunteers

Abstract. We have evaluated the biodistribution and metabolism of iodine-123-15-(p-iodophenyl)-3-R,S-methyl pentadecanoic acid (BMIPP) in the presence of increased lactate levels induced by short-term heavy exercise. Five healthy male subjects received 159 MBq (±13 MBq) 123I-BMIPP at rest and a week later after they performed a maximal exercise test using a bicycle ergometer. Planar and tomographic images were obtained with a dual-head gamma camera up to 4 h after administration of the tracer. Multiple blood samples were taken at different time points for blood clearance, substrate concentration measurements and for HPLC analysis of metabolites. The exercise test did not alter plasma glucose and non-esterified fatty acid concentrations, but blood lactate increased from 1.12 mmol/l at rest to 9.26 mmol/l with maximal exercise. After exercise, BMIPP showed a significantly faster plasma clearance than at rest and the production of PIPA, the end metabolite of BMIPP oxidation, was reduced. Activity in the heart was similar after exercise and at rest on planar images 15 min after injection (4.83±0.50%ID vs 4.80±0.43%ID, P=NS), although the myocardium-to-cavity activity ratio, as determined on the SPET images 20 min after tracer injection, was slightly increased after the exercise test (4.20±0.63 vs 3.78±1.34 at rest, P=NS). Significantly increased activity was observed in a leg muscle region of interest after exercise (4.98±0.50%ID vs 3.93±0.44%ID at rest, P=0.02). Between early and late images, tracer washout from the myocardium increased from 20.72% at rest to 36.72% after exercise (P<0.05), but was unchanged for liver and leg muscles. The metabolic and physiological alterations induced by exercise do not degrade image quality of BMIPP scintigraphy. On the contrary, exercise-induced hyperlactatemia seems to enhance myocardium-to-cavity activity ratios on SPET images, although this effect does not reach statistical significance in this small group of normal subjects. These findings further support the robustness of BMIPP SPET in varied metabolic environments.

18F-FDG PET/CT imaging of an anti-CTLA-4 antibody-associated autoimmune pancolitis.

Ipilimumab (also known as MDX-010; Bristol-Myers Squibb, New York) is a fully human monoclonal antibody that binds to and blocks CTLA-4 (cytotoxic T lymphocyteassociated antigen 4), a receptor molecule on T cells that plays a critical role in regulating natural T-cell immune responses [1]. Ipilimumab improves overall survival in pretreated patients with metastatic melanoma [2]. During ipilimumab treatment, distinct immune-related adverse events may occur, one of the most frequently observed of which is colitis [4], and others include dermatitis, hepatitis, hypophysitis, and hypothyroidism [2, 3]. Endoscopy and histopathological examination of ipilimumab-associated immune-related colitis is characterized by a diffuse active inflammation [4]. We report on the F-FDG PET/CT imaging findings of autoimmune pancolitis in a patient with stage IV-M1c melanoma. Following disease progression despite conventional dacarbazine-based chemotherapy, ipilimumab was initiated at a dose of 3 mg per kilogram of body weight. Two weeks after the fourth ipilimumab administration, the patient developed diarrhoea and abdominal pain. She had no prior history of inflammatory bowel disease. F-FDG PET/CT demonstrated a diffusely increased tracer uptake in the colon (a, c, white arrows), suggesting active pancolitis [5]. Focal tracer uptake in lung and axillary lymph nodes was indicative of metastatic disease (a, arrowheads). Concomitant CT findings of the colon demonstrated a markedly thickened colonic wall and L. Goethals Department of Radiology, Universitair Ziekenhuis Brussel, Brussels, Belgium

Regional quantitative analysis of small animal myocardial sympathetic innervation and initial application in streptozotocin induced diabetes

BACKGROUND In several disease models it is known that heterogeneous dysinnervation occurs in the sympathetic nervous system. We therefore adapted the (123)I-MIBG imaging procedure in small animals to allow quantification of both global and regional uptake and wash-out rate using high specific activity (123)I-MIBG in the myocardium of rats. After evaluation of the image procedure in normal animals, we then applied our imaging protocol to visualize the regional dysinnervation in cardiac autonomic neuropathy occurring in streptozotocin-induced diabetes. METHODS Seven normal Lewis rats underwent (123)I-MIBG pinhole SPECT with low specific activity (123)I-MIBG (lsa MIBG) and high specific activity (123)I-MIBG (hsa MIBG) with a 2 week interval. Twelve normal rats and 12 rats 8 weeks after streptozotocin injection underwent the same hsa MIBG imaging protocol. The imaging protocol consisted of two SPECT acquisitions for every animal. The imaging sequence started at 20 min after tracer injection. The percentage of injected activity (%IA) and the wash-out rate in the global myocardium were measured. Left ventricular regional MIBG kinetics were analyzed in the six midventricular segments of the 17 segment model. RESULTS Compared with lsa MIBG, the wash-out rate of hsa MIBG was significantly slower, in association with a higher cardiac uptake. Regional analysis showed a maximal uptake in the anterolateral segment, without significant differences between segments. We noted a significantly higher global wash-out rate in the streptozotocin group compared to controls (p < 0.05). Regional analysis confirmed the increased wash-out rate, reaching statistical significance in the inferior and the inferoseptal walls. CONCLUSION High-quality (123)I-MIBG images and accurate measurements can be obtained using hsa (123)I-MIBG with image acquisitions performed at relatively early time points. Small animal MIBG SPECT imaging allows for regional analysis of the myocardium. In the streptozotocin group, wash-out of MIBG is globally increased, compatible with a higher sympathetic tonus or decreased reuptake of MIBG. The highest increase is located in the inferior, inferoseptal and anteroseptal walls. These findings further suggest the occurrence of diabetic cardiomyopthy after streptozotocin injection.