Protective effect of sacubitril/valsartan (Entresto) on kidney function and filtration barrier injury in a porcine model of partial nephrectomy.

Kidney surgery often includes organ ischaemia with a risk of acute kidney injury. The present study tested if treatment with the combined angiotensin II-angiotensin II receptor type 1 and neprilysin blocker Entresto (LCZ696, sacubitril/valsartan) protects filtration barrier and kidney function after ischaemia and partial nephrectomy (PN) in pigs. Single kidney glomerular filtration rate (GFR) by technetium-99m diethylene-triamine-pentaacetate clearance was validated (n = 6). Next, four groups of pigs were followed for 15 days (n = 24) after PN (one-third right kidney, 60 min ischaemia) + Entresto (49/51 mg/day; n = 8), PN + vehicle (n = 8), sham + Entresto (49/51 mg/day; n = 4) and sham + vehicle (n = 4). GFR, diuresis and urinary albumin were measured at baseline and from each kidney after 15 days. The sum of single-kidney GFR (right 25 ± 6 mL/min, left 31 ± 7 mL/min) accounted for the total GFR (56 ± 14 mL/min). Entresto had no effect on baseline blood pressure, p-creatinine, mid-regional pro-atrial natriuretic peptide (MR-proANP), heart rate and diuresis. After 15 days, Entresto increased GFR in the uninjured kidney (+23 ± 6 mL/min, P < .05) and reduced albuminuria from both kidneys. In the sham group, plasma MR-proANP was not altered by Entresto; it increased to similar levels 2 h after surgery with and without Entresto. Fractional sodium excretion increased with Entresto. Kidney histology and kidney injury molecule-1 in cortex tissue were not different. In conclusion, Entresto protects the filtration barrier and increases the functional adaptive response of the uninjured kidney.

Lymph Nodes Draining Infections Investigated by PET and Immunohistochemistry in a Juvenile Porcine Model.

BACKGROUND: [18F]FDG and [11C]methionine accumulate in lymph nodes draining S. aureus -infected foci. The lymph nodes were characterized by weight, [11C]methionine- and [18F]FDG-positron emissions tomography (PET)/computed tomography (CT), and immunohistochemical (IHC)-staining. METHODS: 20 pigs inoculated with S. aureus into the right femoral artery were PET/CT-scanned with [18F]FDG, and nine of the pigs were additionally scanned with [11C]methionine. Mammary, medial iliac, and popliteal lymph nodes from the left and right hind limbs were weighed. IHC-staining for calculations of area fractions of Ki-67, L1, and IL-8 positive cells was done in mammary and popliteal lymph nodes from the nine pigs. RESULTS: The pigs developed one to six osteomyelitis foci. Some pigs developed contiguous infections of peri-osseous tissue and inoculation-site abscesses. Weights of mammary and medial iliac lymph nodes and their [18F]FDG maximum Standardized Uptake Values (SUVFDGmax) showed a significant increase in the inoculated limb compared to the left limb. Popliteal lymph node weight and their FDG uptake did not differ significantly between hind limbs. Area fractions of Ki-67 and IL-8 in the right mammary lymph nodes and SUVMetmax in the right popliteal lymph nodes were significantly increased compared with the left side. CONCLUSION: The PET-tracers [18F]FDG and [11C]methionine, and the IHC- markers Ki-67 and IL-8, but not L1, showed increased values in lymph nodes draining soft tissues infected with S. aureus. The increase in [11C]methionine may indicate a more acute lymph node response, whereas an increase in [18F]FDG may indicate a more chronic response.

Radiotracers for Bone Marrow Infection Imaging.

INTRODUCTION: Radiotracers are widely used in medical imaging, using techniques of gamma-camera imaging (scintigraphy and SPECT) or positron emission tomography (PET). In bone marrow infection, there is no single routine test available that can detect infection with sufficiently high diagnostic accuracy. Here, we review radiotracers used for imaging of bone marrow infection, also known as osteomyelitis, with a focus on why these molecules are relevant for the task, based on their physiological uptake mechanisms. The review comprises [67Ga]Ga-citrate, radiolabelled leukocytes, radiolabelled nanocolloids (bone marrow) and radiolabelled phosphonates (bone structure), and [18F]FDG as established radiotracers for bone marrow infection imaging. Tracers that are under development or testing for this purpose include [68Ga]Ga-citrate, [18F]FDG, [18F]FDS and other non-glucose sugar analogues, [15O]water, [11C]methionine, [11C]donepezil, [99mTc]Tc-IL-8, [68Ga]Ga-Siglec-9, phage-display selected peptides, and the antimicrobial peptide [99mTc]Tc-UBI29-41 or [68Ga]Ga-NOTA-UBI29-41. CONCLUSION: Molecular radiotracers allow studies of physiological processes such as infection. None of the reviewed molecules are ideal for the imaging of infections, whether bone marrow or otherwise, but each can give information about a separate aspect such as physiology or biochemistry. Knowledge of uptake mechanisms, pitfalls, and challenges is useful in both the use and development of medically relevant radioactive tracers.

Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis: Experiences from a Porcine Model.

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model.

Comparison of simultaneous plasma clearance of 99mTc-DTPA and 51Cr-EDTA: can one tracer replace the other?

Both 99mTc-DTPA and 51Cr-EDTA are widely used to determine glomerular filtration rate (GFR), but few direct comparative studies exist. The shortage of 51Cr-EDTA makes a direct comparison highly relevant. The aim of the study was to investigate if there is any clinically relevant difference between plasma clearance of 99mTc-DTPA and 51Cr-EDTA. Patients ≥18 years of age referred for routine GFR measurement by 51Cr-EDTA were prospectively enrolled. The two tracers (10 MBq 99mTc-DTPA (CaNa3-DTPA) and 2.5 MBq 51Cr-EDTA) were intravenously injected at time zero. A standard 4-sample technique was applied with samples collected at 180, 200, 220 and 240 min, if the estimated GFR (eGFR) was ≥30 mL/min. A comparison of single-sample GFR based on the 200 min sample was also conducted. Fifty-six patients were enrolled in the study. All patients had an estimated GFR >30 mL/min/1.73 m2. No patients suffered from ascites or significant oedema. The mean 51Cr-EDTA plasma clearance was 82 mL/min (range 16-226). The plasma clearances determined by the two methods were highly correlated (r = 0.993). The plasma clearance was significantly higher when measured by 99mTc-DTPA than by 51Cr-EDTA (p = 0.01), but the numerical difference was minimal (mean difference 1.4 mL/min; 95% limits of agreement (LOA) -6.6 to 9.4). The difference between the two methods was independent of the level of renal function. Similar results were found for one-sample GFR. No clinically relevant differences were found between the plasma clearance of 99mTc-DTPA and that of 51Cr-EDTA. Therefore, 99mTc-DTPA can replace 51Cr-EDTA when needed.

An evaluation of phase angle, bioelectrical impedance vector analysis and impedance ratio for the assessment of disease status in children with nephrotic syndrome.

BACKGROUND: Oedema, characterized by accumulation of extracellular water (ECW), is one of the major clinical manifestations in children suffering from nephrotic syndrome (NS). The lack of a simple, inexpensive and harmless method for assessing ECW may be solved by the use of the bioelectrical impedance analysis (BIA) technique. The aims of this study were to examine whether phase angle (PA), bioelectrical impedance vector analysis (BIVA) and the impedance ratio (IR) reflect change in disease status in children with NS. METHODS: Eight children (age range: 2-10 years) with active NS (ANS group) were enrolled. In five of these (ANS* subgroup), impedance was also measured at remission (NSR group). Thirty-eight healthy children (age range: 2-10 years) were included as healthy controls (HC group). Whole-body impedance was measured with a bioimpedance spectroscopy device (Xitron 4200) with surface electrodes placed on the wrist and ankle. RESULTS: Values of PA, BIVA and IR were found to be significantly lower (p-value range < 0.001 to < 0.01) in the ANS patients compared to the HC and NSR groups. No significant differences were observed between the NSR and HC groups. CONCLUSION: The studied parameters can be used to assess change in disease status in NS patients. Data were consistent with NS being associated with expansion of ECW.

Bioimpedance Resistance Indices and Cell Membrane Capacitance Used to Assess Disease Status and Cell Membrane Integrity in Children with Nephrotic Syndrome.

BACKGROUND: Accumulation of extracellular water (ECW) is a major clinical manifestation of nephrotic syndrome (NS) in children. Bioimpedance spectroscopy (BIS) is a simple, noninvasive technique that reflects body water volumes. BIS can further measure cell membrane capacitance (CM), which may be altered in NS. The aims of the study were to explore how BIS measurements could reflect disease status in NS, while avoiding prediction equations which are often only validated in adult populations. METHODS: The study involved 8 children (2-10 years) with active NS (ANS group), 5 of which were also studied at NS remission (NSR group), as well as 38 healthy children of similar age (HC group). BIS measurements determined resistances RINF, RE, and RI (reflecting total body water, extracellular water, and intracellular water) and CM. Also resistance indices based on height (H) were considered, RI = H2/R. RESULTS: It was found that RE and RINF were significantly lower in the ANS group than in both NSR and HC groups (p < 0.001). Corresponding resistance indices were significantly higher in the ANS group than in the NSR (p < 0.01) and the HC (p < 0.05) groups, in accordance with elevated water volumes in NS patients. Indices of intracellular water were not significantly different between groups. CM was significantly lower in the ANS group than in NSR and HC groups (p < 0.05). CONCLUSION: BIS could distinguish children with active NS from well-treated and healthy children. Studies with more children are warranted.

Kinetic Modelling of [68Ga]Ga-DOTA-Siglec-9 in Porcine Osteomyelitis and Soft Tissue Infections.

BACKGROUND: [68Ga]Ga-DOTA-Siglec-9 is a positron emission tomography (PET) radioligand for vascular adhesion protein 1 (VAP-1), a protein involved in leukocyte trafficking. The tracer facilitates the imaging of inflammation and infection. Here, we studied the pharmacokinetic modelling of [68Ga]Ga-DOTA-Siglec-9 in osteomyelitis and soft tissue infections in pigs. METHODS: Eight pigs with osteomyelitis and soft tissue infections in the right hind limb were dynamically PET scanned for 60 min along with arterial blood sampling. The fraction of radioactivity in the blood accounted for by the parent tracer was evaluated with radio-high-performance liquid chromatography. One- and two-tissue compartment models were used for pharmacokinetic evaluation. Post-mortem soft tissue samples from one pig were analysed with anti-VAP-1 immunofluorescence. In each analysis, the animal's non-infected left hind limb was used as a control. RESULTS: Tracer uptake was elevated in soft tissue infections but remained low in osteomyelitis. The kinetics of [68Ga]Ga-DOTA-Siglec-9 followed a reversible 2-tissue compartment model. The tracer metabolized quickly; however, taking this into account, produced more ambiguous results. Infected soft tissue samples showed endothelial cell surface expression of the Siglec-9 receptor VAP-1. CONCLUSION: The kinetics of [68Ga]Ga-DOTA-Siglec-9 uptake in porcine soft tissue infections are best described by the 2-tissue compartment model.

Exploring the radiosynthesis and in vitro characteristics of [68 Ga]Ga-DOTA-Siglec-9.

Vascular adhesion protein 1 is a leukocyte homing-associated glycoprotein, which upon inflammation rapidly translocates from intracellular sources to the endothelial cell surface. It has been discovered that the cyclic peptide residues 283-297 of sialic acid-binding IgG-like lectin 9 (Siglec-9) "CARLSLSWRGLTLCPSK" bind to vascular adhesion protein 1 and hence makes the radioactive analogues of this compound ([68 Ga]Ga-DOTA-Siglec-9) interesting as a noninvasive visualizing marker of inflammation. Three different approaches to the radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 are presented and compared with previously published methods. A simple, robust radiosynthesis of [68 Ga]Ga-DOTA-Siglec-9 with a yield of 62% (non decay-corrected) was identified, and it had a radiochemical purity >98% and a specific radioactivity of 35 MBq/nmol. Furthermore, the protein binding and stability of [68 Ga]Ga-DOTA-Siglec-9 were analyzed in vitro in mouse, rat, rabbit, pig, and human plasma and compared with in vivo pig results. The plasma in vitro protein binding of [68 Ga]Ga-DOTA-Siglec-9 was the lowest in the pig followed by rabbit, human, rat, and mouse. It was considerably higher in the in vivo pig experiments. The in vivo stability in pigs was lower than the in vitro stability. Despite considerable species differences, the observed characteristics of [68 Ga]Ga-DOTA-Siglec-9 are suitable as a positron emission tomography tracer.

First-order compartment model solutions - Exponential sums and beyond.

First-order compartment models are common tools for modelling many biological processes, including pharmacokinetics. Given the compartments and the transfer rates, solutions for the time-dependent quantity (or concentration) curves can normally be described by a sum of exponentials. This paper investigates cases that go beyond simple sums of exponentials. With specific relations between the transfer rate constants, two exponential rate constants can be equal, in which case the normal solution cannot be used. The conditions for this to occur are discussed, and advice is provided on how to circumvent these cases. An example of an analytic solution is given for the rare case where an exact equality is the expected result. Furthermore, for models with at least three compartments, cases exist where the solution to a real-valued model involves complex-valued exponential rate constants. This leads to solutions with an oscillatory element in the solution for the tracer concentration, i.e., there are cases where the solution is not a simple sum of (real-valued) exponentials but also includes sine and cosine functions. Detailed solutions for three-compartment cases are given. As a tentative conclusion of the analysis, oscillatory solutions appear to be tied to cases with a cyclic element in the model itself.

Detecting reduced renal function in children: comparison of GFR-models and serum markers.

BACKGROUND: The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR)-models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results. METHODS: Glomerular filtration rate was measured by plasma clearance of (51)Cr-EDTA (13.7-147.4 mL/min/1.73 m(2)) in 119 children (age range 2.3-14.9 years). Reduced renal function was defined as a GFR of <82 mL/min/1.73 m(2). SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone. RESULTS: The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629-637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221-230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50-57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other variables (P < 0.01), with the BCM-model performing the best (P < 0.05). The SCr-based Schwartz formula and SCr-ratio both performed better than SCr and SCysC. CONCLUSIONS: Among the 119 children enrolled in this study and the renal indicators tested, the BCM-model had the best diagnostic performance in terms of screening for normal or reduced renal function, and the SCr-ratio was a superior diagnostic tool to both SCr and SCysC.

GFR prediction from cystatin C and creatinine in children: effect of including body cell mass.

BACKGROUND: Aiming to develop a more accurate cystatin C-based model for estimation of glomerular filtration rate (GFR) in children, we hypothesized that inclusion of body cell mass (BCM) would increase the accuracy of the GFR estimate in comparison to a well-established GFR reference method. STUDY DESIGN: Diagnostic test accuracy study. SETTINGS & PARTICIPANTS: 119 children (mean age, 8.8; range, 2.3-14.9 years) referred for GFR measurement by chromium 51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) clearance (mean GFR, 98; range, 13.7-147.4 mL/min/1.73 m(2)). INDEX TEST: GFR estimations by the 2 prediction models resulting from theoretical considerations corroborated by forward stepwise variable selection: GFR (mL/min) = 0.542 × (BCM/SCysC)(0.40) × (height × BSA/SCr)(0.65) and GFR (mL/min) = 0.426 × (weight/SCysC)(0.39) × (height × BSA/SCr)(0.64), where SCysC is serum cystatin C level, BSA is body surface area, and SCr is serum creatinine level. The accuracy and precision of these models were compared with 7 previously published prediction models using random subsampling cross-validation. Local constants and coefficients were calculated for all models. Root mean square error, R(2), and percentage of predictions within ±10% and ±30% of the reference GFR were calculated for all models. Based on 1,000 runs of the cross-validation procedure, median values and 2.5th and 97.5th quantiles of the validation parameters were calculated. REFERENCE TEST: GFR measurement by (51)Cr-EDTA clearance. RESULTS: The BCM model predicted 98% within ±30% of reference GFR and 66% within ±10%, which was higher than for any other model. The weight model predicted 97.5% within ±30% of reference GFR and 62% within ±10%. The BCM model had the highest R(2) and the smallest root mean square error. LIMITATIONS: Included only 9 children with GFR <60 mL/min/1.73 m(2). Lack of independent validation cohort. CONCLUSIONS: The novel BCM model predicts GFR with higher accuracy than previously published models. The weight model is almost as accurate as the BCM model and allows for GFR estimation without knowledge of BCM. However, endogenous methods are still not sufficiently accurate to replace exogenous markers when GFR must be determined with high accuracy.

Absorption rate of subcutaneously infused fluid in ill multimorbid older patients.

BACKGROUND: Subcutaneous (SC) hydration is a valuable method for treating dehydration in the very old patients. Data are absent on the absorption rate, and the availability of SC infused fluid in the circulation in this group of patients where SC hydration is particularly relevant. METHODS: We performed an explorative study on ill very old (range 78-84 years old) geriatric patients with comorbidities who received an SC infusion of 235 ml isotonic saline containing a technetium-99m pertechnetate tracer. The activity over the infusion site was measured using a gamma detector to assess the absorption rate from the SC space. The activity was measured initially every 5 minutes, with intervals extended gradually to 15 minutes. Activity in blood samples and the thyroid gland was measured to determine the rate of availability in the circulation. RESULTS: Six patients were included. The mean age was 81 years (SD 2.1), the number of comorbidities was 4.6 (SD 1.3), and the Tilburg frailty indicator was 3.8 (SD 2.4). When the infusion was completed after 60 minutes, 53% (95% CI 50-56%) of the infused fluid was absorbed from the SC space, with 88% (95% CI 86-90%) absorbed one hour later. The absorption rate from the SC space right after the completion of the infusion was 127 ml/h (95% CI 90-164 ml/h). The appearance of the fluid into the blood and the thyroid gland verified the transfer from SC to circulation. CONCLUSION: This first explorative study of absorption of SC infused fluid in the very old found an acceptable amount of fluid absorbed from the SC space into the circulation one hour after infusion had ended. Results are uniform but should be interpreted cautiously due to the low sample size. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04536324.

Beta emitters and radiation protection.

BACKGROUND: Beta emitters, such as (90)Y, are increasingly being used for cancer treatment. However, beta emitters demand other precautions than gamma emitters during preparation and administration, especially concerning shielding. AIM: To discuss practical precautions for handling beta emitters in general, and specifically determine proper shielding for (90)Y, while comparing to (177)Lu and (131)I. The aim is achieved through the application of physical principles combined with results from practical experience. MATERIAL AND METHODS: Typical and maximal electron ranges were calculated for (131)I, (177)Lu, and (90)Y, using data from a freely available database. Bremsstrahlung yields were calculated for (90)Y shielded by lead, aluminium, or perspex. Bremsstrahlung spectrum from (90)Y shielded by perspex was measured, and attenuation of spectrum by lead was calculated. Whole-body and finger doses to persons preparing (90)Y-Zevalin were measured. CONCLUSIONS: Good laboratory practice is important to keep radiation doses low. To reduce bremsstrahlung, (90)Y should not be shielded by lead but instead perspex (10 mm) or aluminium (5 mm). Bremsstrahlung radiation can be further reduced by adding a millimetre of lead on the outside of the primary shielding material. If suitable shielding is used and larger numbers of handlings are divided among several persons, then handling of beta emitters can be a safe procedure.

Reassessment of a classical single injection 51Cr-EDTA clearance method for determination of renal function in children and adults. Part I: Analytically correct relationship between total and one-pool clearance.

BACKGROUND: Total plasma clearance of (51)Cr-EDTA, Cl, is widely used as a measure of GFR. Commonly, only the final part of the plasma concentration curve is measured, and a one-pool clearance (slope-intercept clearance), Cl(1), is computed. Empirically determined second-order polynomials of the general form Cl = b x Cl(1) + c x Cl(1)(2) are usually used to estimate Cl from a measured Cl(1). However, theoretical considerations indicate that such corrections underestimate Cl at high values. AIMS: To derive an analytically correct relationship between Cl and Cl(1) and determine the parameters involved for children and adults. MATERIAL AND METHODS: Cl was determined in 149 subjects (M/F/children: 71/46/32) from a complete plasma concentration curve followed for 4-5 h after injection of (51)Cr-EDTA (range of clearance: 8-183 mL/min/1.73 m(2)). Plasma volume, PV and the "missing" area under the plasma fraction curve, a (minutes), not used for determination of Cl(1), were measured. RESULTS: The true relationship between Cl and Cl(1) is given by Cl = Cl(1)/(1 + f x Cl(1)), where f = a/PV. For men, women and children alike, the equation f = 0.0032 x BSA(-1.3) was applicable (BSA = body surface area in m(2)). Estimation errors on clearance were within +/-8% for adults and +/-13% for children (95% limits of agreement). CONCLUSIONS: The true relationship between Cl and Cl(1) of (51)Cr-EDTA is given, resulting in a common correction equation applicable for children and adults. The new equation has better mathematical behaviour than quadratic equations on very high values of clearance and takes into account dependence on body size.

Reassessment of a classical single injection 51Cr-EDTA clearance method for determination of renal function in children and adults. Part II: Empirically determined relationships between total and one-pool clearance.

BACKGROUND: The one-pool or slope-intercept technique is widely used when determining total (51)Cr-EDTA plasma clearance (Cl). The one-pool clearance (Cl(1)), which always exceeds Cl, has mostly been corrected to Cl by multiplication by a constant factor = 0.80, suggested by Chantler (CH(0.80)), or by using a second-order polynomial originally proposed by Brøchner-Mortensen (BM) and later recommended by the British Nuclear Medicine Society (BM(BNMS)). Theoretical considerations indicate that the CH correction gives a systematic overestimate of Cl, whereas the BM correction may underestimate Cl at high values. OBJECTIVE: To assess the accuracy of Cl as estimated from Cl (1) corrected either by CH(0.80) or by second-order polynomials. MATERIAL AND METHODS: Cl(ref) was determined in 149 subjects (M/F/children: 71/46/32) from a complete plasma curve followed for 4-5 h after injection of (51)Cr-EDTA (range of Cl(ref) : 8-183 mL/min/1.73 m(2)). Cl(est) was determined from Cl(1) subsequently corrected by CH(0.80) and four second-order polynomials. RESULTS: Using CH(0.80) correction, Cl(est) underestimated Cl(ref) (by a maximum of 20%) at Cl(ref) values less than about 100 mL/min/1.73 m(2) in children and 130 mL/min/1.73 m(2) in adults. At higher clearance levels, Cl(ref) was increasingly overestimated. Taking the BM(BNMS) correction as representative of second-order polynomials, Cl(est) increasingly underestimated Cl(ref) at high levels, the error being 10% at a Cl(ref) value of about 175 mL/min/1.73 m(2). CONCLUSIONS: We suggest that the tested correction equations are replaced by the given common correction equation based on the "true" relationship between Cl(1) and Cl thoroughly described in part I of this study.

WITHDRAWN: Erratum to "Derivation and presentation of formulas for drug concentrations in two-, three- and four-compartment pharmacokinetic models" [Journal of Pharmacological and Toxicological Methods 100 (2019), 106621].

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.vascn.2019.106648. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Derivation and presentation of formulas for drug concentrations in two-, three- and four-compartment pharmacokinetic models.

Although compartment models are frequently used in pharmacokinetics, it is difficult to find complete analytical formulas describing the behaviour of drugs in universal simpler compartment models in the accessible literature. The paper presents derivations of formulas for general two- and three-compartment models, including the possibilities of original non-zero quantity in all compartments and elimination from all compartments. Formulas for four-compartment models are also derived with the restriction that original quantity is non-zero in only one compartment. Derivation uses Laplace transformation but does not require prior knowledge of the technique. The derived analytical formulas are verified numerically. These formulas can be easily simplified to less complex cases.

Three-compartment pharmacokinetic models of radiotracers used in the GFR-determination - estimation of their parameters using the time-concentration curves.

BACKGROUND: In GFR measurements with radiotracers, there is evidence that a two-compartment model is unable to describe the full plasma curve, including early time points, but analyses generally focus on two-compartment models. AIMS: To analyze both the mammillary and catenary three-compartment model and to determine empirical relations between model constants and the overall GFR and ECV (extra-cellular volume). MATERIAL AND METHODS: Mathematical analysis of the three-compartment model. Full-curve patient data from 32 adults and 7 children were used to relate model parameters to GFR and ECV. RESULTS: Model volumes were found to be roughly proportional to ECV. In both models, the central (plasma) volume was V1 = 0.24 × ECV and elimination rate from V1 was k10 = 4.2 × GFR/ECV. In the mammillary model, the two parallel volumes were V2 = 0.28 × ECV, V3 = 0.48 × ECV, and intercompartmental clearances were Cl12 [mL/min] = 0.0058 × ECV [mL], Cl13 = 0.042 × ECV. In the catenary model, the serial volumes were V2 = 0.60 × ECV, V3 = 0.16 × ECV, with clearances Cl12 = 0.048 × ECV, Cl23 = 0.0036 × ECV. CONCLUSION: Insight into the three-compartment model was achieved, and empirical relations to ECV and GFR/ECV were determined.

Standardisation of bioelectrical impedance analysis for the estimation of body composition in healthy paediatric populations: a systematic review.

BACKGROUND: Bioelectrical impedance analysis (BIA) requires a high degree of standardisation in order to ensure valid and reproducible impedance measurements. The overall aim of this review was to study the degree to which BIA papers conducted in healthy paediatric populations (aged 0-17 years) were standardised. METHODS: Literature was identified on the basis of a systematic search of internationally-recognised electronic databases and hand searching of the reference lists of the included papers in order to identify additional relevant papers. The review was limited to lead-type BIA devices for whole-body, segmental- and focal impedance measurements. In total, 71 papers published between 1988 and 2016 were included. To evaluate the degree of standardisation of the papers, a recently published review detailing critical factors that may impact on BIA measurements in children was used as a model for structuring and extracting data. RESULTS: There was a general lack of BIA standardisation, or its reporting, in the papers under review, which hinders comparison of data between studies and could potentially lead to erroneous measurements. CONCLUSIONS: If the BIA technique should be accepted clinically for routine use in paediatric populations, there is a need for an increased focus on the importance of improved standardisation and its reporting in future studies. Consequently, this review contains recommendations for performing and reporting BIA measurements in a standardised manner.