Plasma Disappearance Research Articles

Extracellular Fluid Volume and Mortality after Kidney Transplantation.

High extracellular fluid volume (ECV) is associated with an increased risk of death in non-transplanted patients with chronic kidney disease (CKD). By contrast, both the determinants and the prognosis value of ECV in kidney transplant recipients (KTR) remain unclear. We studied a bicentric prospective cohort of 2057 KTR, who underwent glomerular filtration rate measurement (mGFR) three months after transplantation. We calculated ECV from iohexol plasma disappearance curve and analyzed its association with patient's characteristics and outcomes. Mean ECV and mGFR were 14.6±2.6L/1.73m2 and 52±16mL/min/1.73m2, respectively. Multiple linear regression identified male gender, older donor and recipient ages, deceased donor, non-preemptive transplantation, diabetes, cardiac arrhythmia, heart failure, proteinuria and higher mGFR as independent factors associated with increased ECV. In multivariable cause specific cox analyzes, higher tertiles of ECV were associated with increased mortality [tertile 1 as reference; hazard ratio (95% confidence interval) for tertile 2: 1.65 (1.11-2.47); tertile 3: 1.80 (1.18-2.74)] but not graft loss. Increased ECV, 3 months after transplantation, was a predictor of reduced mGFR at 12 months after adjusting for three months mGFR and other confounding factors (β coefficient: -0.06; 95%CI [-0.09 to -0.02]). an elevated ECV 3 months after KT is independently associated with increased mortality and decreased mGFR at 12 months, but not with graft loss.

Use of noninvasive measurement of the indocyanine green plasma disappearance rate in patients with septic shock.

Our aim was to analyse the relation between serial values of the indocyanine green plasma disappearance rate (ICG-PDR) with hospital mortality in the first 48 hours of ICU admission in patients with septic shock. A prospective observational study was carried out over 12 months of patients admitted to the ICU with septic shock. Each patient underwent noninvasive determination of ICG-PDR at 24 and 48 hours with the LiMON® module. Follow-up was performed until hospital discharge or exitus. 63 patients. Age 61.1±12.3 years. 60.3% men. SOFA score on admission 8.7±3.3, APACHE II score was 27.9±10.7 points. A total of 44.4% of patients died. The ICG-PDR values in the first 24 hours of ICU admission were lower in nonsurvivors: 10.5 (5.7-13.0)%/min vs. 15.9 (11.4-28.0)%/min, p <0.001. Furthermore, in nonsurvivors, there was no improvement in ICG-PDR between 24 h and 48 h, while in survivors, there was an increase of 25%: 15.9 (11.4-28.0)%/min and 20.9 (18.0-27.0)%/min, p=0.020. The silhouette measure of ICG-PDR cohesion and separation for the clusters analysed (nonsurvivors and survivors) was satisfactory (0.6). ICG-PDR<11.7%/min was related to in-hospital mortality, ICG-PDR> 18%/min to survival, and the interval between 11.7% and 18%/min covered a range of uncertainty. In the two-stage cluster, ICG-PDR, SOFA and APACHE II present satisfactory predictive scores 24 hours after patient admission. ICG-PDR in our setting is a useful clinical prognostic tool and could optimise the decision tree in patients with septic shock.

Use of Fluorescence Imaging in Liver Transplant Surgery.

Liver transplant surgery is a complex procedure that demands high knowledge of surgical anatomy and the precise recognition and preservation of structures. To address this, the use of fluorescence imaging has facilitated the identification of anatomical structures such as biliary ducts, arteries, and liver segmentation. Indocyanine green is among the most commonly utilized fluorescent agents, not just during surgery but also in the pre- and postoperative phases, where it is used to assess graft failure by measuring the plasma disappearance rate. New advancements such as artificial intelligence paired with fluorescence imaging have the potential to enhance patient outcomes. Additionally, technologies such as augmented reality and mixed reality could be integrated into surgical procedures, broadening the scope of possibilities for improving patient safety.

InVivo Inhibition of Dipeptidyl Peptidase 4 Allows Measurement of GLP-1 Secretion in Mice.

Dipeptidyl peptidase (DPP)-4 and neprilysin (NEP) rapidly degrade glucagon-like peptide 1 (GLP-1) in mice. Commercially available sandwich ELISA kits may not accurately detect the degradation products, leading to potentially misleading results. We aimed to stabilize GLP-1 in mice allowing reliable measurement with sensitive commercially available ELISA kits. Non-anesthetized male C57Bl/6JRj mice were subjected to an oral glucose tolerance test (OGTT; 2 g/kg glucose), and plasma total and intact GLP-1 were measured (Mercodia and Alpco ELISA kits, respectively). No GLP-1 increases were seen in samples taken beyond 15 minutes after the glucose load. Samples taken at 5 and 10 minutes after the OGTT showed a minor increase in total, but not intact GLP-1. We then administered saline (control), or a DPP-4 inhibitor (valine pyrrolidide or sitagliptin) with or without a NEP-inhibitor (sacubitril) 30 minutes before the OGTT. In the inhibitor groups only, intact GLP-1 increased significantly during the OGTT. After injecting male C57Bl/6JRj mice with a known dose of GLP-1(7-36)NH2, peak GLP-1 levels were barely detectable after saline, but 5-10-fold higher during sitagliptin and the combination of sitagliptin/sacubitril. The half-life of the GLP-1 plasma disappearance increased up to 7-fold during inhibitor treatment. We conclude that reliable measurement of GLP-1 secretion is not possible in mice in vivo with commercially available sandwich ELISA kits, unless degradation is prevented by inhibition of DPP-4 and perhaps neprilysin. The described approach allows improved estimates of GLP-1 secretion for future studies, although it is a limitation that these inhibitors additionally influence levels of insulin and glucagon.

Analysis of indocyanine green plasma disappearance rate in clinical practice

To justify the optimal method for determining indocyanine green plasma disappearance rate (PDRICG). We analyzed PDRICG in intensive care units. Indocyanine green was administered intravenously at a dose of 0.25 mg/kg. PDRICG was analyzed simultaneously by using of three methods: 1) PDD (PiCCO2 LiMON device), 2) SBS with analysis of plasma samples on precise spectrophotometer, 3) SBS with analysis of plasma samples on simple experimental photometer. PDD method was used for 346 PDRICG tests in 256 patients. Of these, 14.3% of measurements were erroneous. Paired tests using PDD and SBS methods were performed in 299 cases. SBS method resulted erroneous data in 0.6% of cases. Certain correlation (r=0.79, p<0.001) was found between the reference method (SBS with spectrophotometry) and the PDD method. Bland-Altman plot for these two methods showed that proportional bias of mean difference was caused by extremely high PDRICG of the PDD method (for example, more than 30%/min). Comparison of two SBS variants (spectrophotometer and experimental photometer) revealed good correlation (r=0.91, p<0.001). SBS method for measuring PDRICG ensures accurate results under mechanical interferences in patients with impaired capillary blood flow. This eliminates the need for redo measurement. Duplication of the PDD and SBS methods is recommended when repeating the test is not possible (organ donors).

Indocyanine green clearance test as a predictor of linezolid overexposure in septic patients

Hepatic impairment increases the risk of drug overexposure in septic patients. However, there is a lack of effective indicators to predict overexposure risk. The indocyanine green (ICG) clearance test is a helpful method for dynamically assessing hepatic function and perfusion. This study aimed to investigate whether the ICG test could serve as a potential predictor of linezolid trough concentration (Cmin) and to compare its efficacy with that of conventional liver function markers. A total of 35 consecutive septic patients treated with linezolid were grouped into either linezolid Cmin of ≤7 µg/mL or >7 µg/mL. Correlations between linezolid Cmin and ICG-PDR (plasma disappearance rate), ICG-R15 (retention ratio after 15 min) and other traditional indicators were analysed by Spearman's rank test. A multivariable regression model was employed to discern factors contributing independently to overexposure. Statistical differences were observed between groups for APACHE II score (P=0.031), SOFA score (P=0.018), creatinine clearance (CLCr) (P=0.003), thrombocytes (P=0.039), lactate (P=0.003), ICG-PDR (P < 0.001) and ICG-R15 (P < 0.001). Moreover, linezolid Cmin was correlated with ICG-PDR (ρ=-0.628, P < 0.001), ICG-R15 (ρ=0.676, P < 0.001) and CLCr (ρ=-0.503, P=0.002). ICG-PDR was identified as an independent predictor of linezolid overexposure, with an optimal cut-off value of 17.70%/min (93.3% sensitivity, 85.0% specificity; P < 0.001). This pilot clinical trial represents the first investigation of potential of the ICG test to predict linezolid overexposure in septic patients.

Successful two-stage transplant hepatectomy using the ALPPS procedure for advanced hepatocellular cancer

In the presented case, after liver transplantation (LT) for hepatocellular cancer (HCC), the disease progressed in the graft, left lung and bronchopulmonary lymph nodes after 16 months, according to the Milan criteria. Against the background of combined treatment – hepatic artery chemoembolization (HAC), systemic targeted therapy and stereotactic radiotherapy for metastatic node of the left lung – HCC in the extrahepatic foci was stabilized. In this situation, we considered resection of the liver transplant as the only therapeutic option that provides a chance for significant prolongation of the patient’s life. However, extensive resection of the right liver lobe seemed unsafe due to a number of limiting factors – borderline functional residual capacity of the remaining liver: future liver remnant (FLR), 599 cm3 (32%); plasma disappearance rate (PDR), 12.3%/min; tumor invasion of the middle hepatic vein basin. In this case, right portal vein branch (RPVB) embolization could promote vicarious hypertrophy of the remaining part of the liver, but the waiting period usually exceeds three to four weeks, and the RPVB was already partially blocked by the tumor at that time. The only option for surgical intervention was, in our opinion, two-stage hepatectomy according to the Associated Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS) procedure, despite the absence of literature data on the performance of such operations on a liver transplant. On postoperative day 5 from the first stage, a 799 cm3 FLR hypertrophy was achieved, which allowed to perform the second stage of intervention relatively safely. Competent tactics regarding medication in the intensive care unit (ICU) and renal replacement therapy allowed to cope with sepsis and acute renal failure – the prevailing postoperative complications.

Diagnostic Accuracy of Indocyanine Green Clearance Test for Different Stages of Liver Fibrosis and Cirrhosis.

(1) Background: This study aimed to correlate the indocyanine green clearance (ICG) test with histopathological grades of liver fibrosis and liver cirrhosis to assess its diagnostic accuracy in differentiating normal liver parenchyma from liver fibrosis and liver cirrhosis. (2) Methods: A total of 82 patients who received a histopathological liver examination, imaging, and ICG test within three months were included in this retrospective study. The histopathological level of fibrosis was graded using the Ishak scoring system, and the patients were divided into five categories: no liver fibrosis (NLF), mild liver fibrosis (MLF), advanced liver fibrosis (ALF), severe liver fibrosis (SLF), and liver cirrhosis (LC). The non-parametric Kruskal-Wallis test with post hoc pairwise comparison utilizing Mann-Whitney U tests and Bonferroni adjustment was used to analyze differences in the ICG test results between the patient groups. Cross correlation between the individual fibrosis/cirrhosis stages and the score of the ICG test was performed, and the sensitivity, specificity, and positive and negative predictive values were calculated for each model predicting liver fibrosis/cirrhosis. (3) Results: A significant difference (p ≤ 0.001) between stages of NLF, LF, and LC was found for the ICG parameters (ICG plasma disappearance rate (ICG-PDR) and ICG retention percentage at 15 min (ICG-R15)). The post hoc analysis revealed that NLF significantly differed from SLF (ICG-PDR: p = 0.001; ICG-R15: p = 0.001) and LC (ICG-PDR: p = 0.001; ICG-R15: p = 0.001). ALF also significantly differed from SLF (ICG-PDR: p = 0.033; ICG-R15: p = 0.034) and LC (ICG-PDR: p = 0.014; ICG-R15: p = 0.014). The sensitivity for detection of an initial stage of liver fibrosis compared to no liver fibrosis (Ishak ≥ 1) was 0.40; the corresponding specificity was 0.80. The differentiation of advanced liver fibrosis or cirrhosis (Ishak ≥ 4) compared to other stages of liver fibrosis was 0.75, with a specificity of 0.81. (4) Conclusions: This study shows that the ICG test, as a non-invasive diagnostic test, is able to differentiate patients with no liver fibrosis from patients with advanced liver fibrosis and liver cirrhosis. The ICG test seems to be helpful in monitoring patients with liver fibrosis regarding compensation levels, thus potentially enabling physicians to both detect progression from compensated liver fibrosis to advanced liver fibrosis and cirrhosis and to initiate antifibrotic treatment at an earlier stage.

Unsupervised Machine Learning of MRI Radiomics Features Identifies Two Distinct Subgroups with Different Liver Function Reserve and Risks of Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma

Objective: To identify subgroups of patients with hepatocellular carcinoma (HCC) with different liver function reserves using an unsupervised machine-learning approach on the radiomics features from preoperative gadoxetic-acid-enhanced MRIs and to evaluate their association with the risk of post-hepatectomy liver failure (PHLF). Methods: Clinical data from 276 consecutive HCC patients who underwent liver resections between January 2017 and March 2019 were retrospectively collected. Radiomics features were extracted from the non-tumorous liver tissue at the gadoxetic-acid-enhanced hepatobiliary phase MRI. The reproducible and non-redundant features were selected for consensus clustering analysis to detect distinct subgroups. After that, clinical variables were compared between the identified subgroups to evaluate the clustering efficacy. The liver function reserve of the subgroups was compared and the correlations between the subgroups and PHLF, postoperative complications, and length of hospital stay were evaluated. Results: A total of 107 radiomics features were extracted and 37 were selected for unsupervised clustering analysis, which identified two distinct subgroups (138 patients in each subgroup). Compared with subgroup 1, subgroup 2 had significantly more patients with older age, albumin–bilirubin grades 2 and 3, a higher indocyanine green retention rate, and a lower indocyanine green plasma disappearance rate (all p &lt; 0.05). Subgroup 2 was also associated with a higher risk of PHLF, postoperative complications, and longer hospital stays (&gt;18 days) than that of subgroup 1, with an odds ratio of 2.83 (95% CI: 1.58–5.23), 2.41(95% CI: 1.15–5.35), and 2.14 (95% CI: 1.32–3.47), respectively. The odds ratio of our method was similar to the albumin–bilirubin grade for postoperative complications and length of hospital stay (2.41 vs. 2.29 and 2.14 vs. 2.16, respectively), but was inferior for PHLF (2.83 vs. 4.55). Conclusions: Based on the radiomics features of gadoxetic-acid-enhanced MRI, unsupervised clustering analysis identified two distinct subgroups with different liver function reserves and risks of PHLF in HCC patients. Future studies are required to validate our findings.

An Individualized Low-Pneumoperitoneum-Pressure Strategy May Prevent a Reduction in Liver Perfusion during Colorectal Laparoscopic Surgery.

High intra-abdominal pressure (IAP) during laparoscopic surgery is associated with reduced splanchnic blood flow. It is uncertain whether a low IAP prevents this reduction. We assessed the effect of an individualized low-pneumoperitoneum-pressure strategy on liver perfusion. This was a single-center substudy of the multicenter 'Individualized Pneumoperitoneum Pressure in Colorectal Laparoscopic Surgery versus Standard Therapy II study' (IPPCollapse-II), a randomized clinical trial in which patients received an individualized low-pneumoperitoneum strategy (IPP) or a standard pneumoperitoneum strategy (SPP). Liver perfusion was indirectly assessed by the indocyanine green plasma disappearance rate (ICG-PDR) and the secondary endpoint was ICG retention rate after 15 min (R15) using pulse spectrophotometry. Multivariable beta regression was used to assess the association between group assignment and ICG-PDR and ICG-R15. All 29 patients from the participating center were included. Median IAP was 8 (25th-75th percentile: 8-10) versus 12 (12,12) mmHg, in IPP and SPP patients, respectively (p < 0.001). ICG-PDR was higher (OR 1.42, 95%-CI 1.10-1.82; p = 0.006) and PDR-R15 was lower in IPP patients compared with SPP patients (OR 0.46, 95%-CI 0.29-0.73; p = 0.001). During laparoscopic colorectal surgery, an individualized low pneumoperitoneum may prevent a reduction in liver perfusion.

Indocyanine green clearance predicts outcome in patients undergoing transcatheter valve intervention for severe atrio-ventricular valve regurgitation.

Severe mitral regurgitation (MR) and tricuspid regurgitation (TR) aggravate haemodynamic stress leading to congestive heart failure with impaired hepatic function, also known as cardiohepatic syndrome (CHS). Current perioperative risk calculators do not sufficiently consider CHS and serum liver function parameters lack sensitivity to diagnose CHS. Indocyanine green and its elimination (measured by the LIMON® test) represent a dynamic and non-invasive test which correlates with the hepatic function. Nevertheless, its utility in the setting of transcatheter valve repair/replacement (TVR) to predict CHS and outcome remains unknown. We analysed liver function and outcomes of patients undergoing TVR for MR or TR between August 2020 and May 2021 at the Munich University Hospital. Out of a total of 44 patients treated at the University Hospital of Munich, 21 (48%) were treated for severe MR, 20 (46%) for severe TR and 3 (7%) for both diseases. Procedural success defined as MR/TR ≤2+ was 94% among MR patients and 92% among TR patients. While classical serum liver function parameters did not change after TVR, there was a significant improvement in liver function as assessed by the LIMON® test (P ≤ 0.001). Patients with baseline indocyanine green plasma disappearance rate <12.95%/min showed significantly increased 1-year mortality (hazard ratio: 1.54, 95% confidence interval: 1.05-2.25, P = 0.027) and lower New York Hear Association class improvement (P = 0.05). Especially in the context of the recently stressed importance of a careful patient selection prior to the interdisciplinary treatment of valvular heart disease, the LIMON® test may provide further real-time information on the patients' cardiohepatic injury and prognosis.

Relative enhancement index can be used to quantify liver function in cirrhotic patients that undergo gadoxetic acid-enhanced MRI.

To evaluate MRI with gadoxetic acid to quantify liver function in cirrhotic patients using the relative enhancement index (REI) compared with Child-Pugh score (CPS), MELD score, and indocyanine green plasma disappearance rate (ICG-PDR) and to establish cutoffs for REI to stratify cirrhotic patients into good and poor liver function groups. We prospectively evaluated 60 cirrhotic patients and calculated CPS, MELD score, ICG-PDR, and REI for each patient. Spearman's correlation coefficient was used to assess correlation between REI, CPS, MELD, and ICG-PDR. Good and poor liver function groups were created by k-means clustering algorithm using CPS, MELD, and ICG-PDR. ROC curve analysis was performed and optimal cutoff was identified for group differentiation. Good correlations were found between REI and other liver function biomarkers: REI and CPS (rho = - 0.816; p < 0.001); REI and MELD score (rho = - 0.755; p < 0.001); REI and ICG-PDR (rho = 0.745; p < 0.001)]. REI correlation was stronger for patients with Child-Pugh A (rho = 0.642, p = 0.002) and B (rho = 0.798, p < 0.001) than for those with Child-Pugh C (rho = 0.336, p = 0.148). REI is significantly lower in patients with poor liver function (p < 0.001). ROC curve showed an AUC 0.94 to discriminate patients with poor liver function (REI cutoff < 100; 100% sensitivity; 76% specificity). REI is a valuable non-invasive index for liver function quantification that has good correlations with other liver function biomarkers. REI can be easily calculated and can be used to estimate liver function in clinical practice in the routine evaluation of cirrhotic patients that undergo MR imaging with gadoxetic acid contrast. • REI is a valuable non-invasive index for liver function quantification that has good correlations with other liver function biomarkers. • REI can be easily calculated in the routine evaluation of cirrhotic patients that undergo gadoxetic acid-enhanced MRI. • The REI enables stratification of cirrhotic patients into good and poor liver function groups and can be used as additional information, together with morphological and focal liver lesion evaluation.

Usefulness of Indocyanine Green Plasma Disappearance Rate in Liver Donors and Recipients: A Prospective Observational Study

Determination of indocyanine green (ICG) plasma disappearance rate (PDR) is a simple, inexpensive, and noninvasive tool to assess liver perfusion, absorption, and elimination. Its application in the liver transplant process has not been widely incorporated in clinical practice. This study aims to assess the usefulness of ICG PDR in the donor selection setting and in the early post-transplant phase and to analyze its variation between these 2 time points. We performed a single-center prospective observational study. ICG clearance test was performed in 50 brain-dead donors (T0-PDR) to assess concordance with graft suitability. Rejected grafts biopsy specimens were analyzed to correlate histology with T0-PDR. In the recipients, ICG PDR was performed before wound closure (T1-PDR). The association of T0, T1, and T0-T1 variation with the development of early allograft dysfunction (EAD) was investigated. A total of 23 of 50 grafts were discarded because of poor macroscopic quality. A T0-PDR below 15.5%/min could predict graft rejection with 100% specificity and 69.6% sensitivity. All the biopsy specimens from donors with PDR < 10 %/min showed liver fibrosis. A total of 25 of the remaining 27 grafts were implanted; 5 patients (20%) developed EAD. T1-PDR performed better than T0-T1 variation to predict dysfunction. ICG PDR could be used in the donors as a filter to discard poor-quality grafts before procurement and, in the early post-transplant phase, to predict EAD.

Resveratrol therapy improves liver function via estrogen-receptors after hemorrhagic shock in rats.

BackgroundResveratrol may improve organ dysfunction after experimental hemorrhagic or septic shock, and some of these effects appear to be mediated by estrogen receptors. However, the influence of resveratrol on liver function and hepatic microcirculation after hemorrhagic shock is unknown, and a presumed mediation via estrogen receptors has not been investigated in this context.MethodsMale Sprague-Dawley rats (200-300g, n = 14/group) underwent hemorrhagic shock for 90 min (MAP 35±5 mmHg) and were resuscitated with shed blood and Ringer’s solution. Animals were treated intravenously with vehicle (1% EtOH), resveratrol (0.2 mg/kg), the unselective estrogen receptor antagonist ICI 182,780 (0.05 mg/kg) or resveratrol + ICI 182,780 prior to retransfusion. Sham-operated animals did not undergo hemorrhage but were treated likewise. After 2 hours of reperfusion, liver function was assessed either by plasma disappearance rate of indocyanine green (PDRICG) or evaluation of hepatic perfusion and hepatic integrity by intravital microscopy, serum enzyme as well as cytokine levels.ResultsCompared to vehicle controls, administration of resveratrol significantly improved PDRICG, hepatic perfusion index and hepatic integrity after hemorrhagic shock. The co-administration of ICI 182,780 completely abolished the protective effect only with regard to liver function.ConclusionsThis study shows that resveratrol may improve liver function and hepatocellular integrity after hemorrhagic shock in rats; estrogen receptors mediate these effects at least partially.

α-Tocopherol Pharmacokinetics in Adults with Cystic Fibrosis: Benefits of Supplemental Vitamin C Administration.

Background: Numerous abnormalities in cystic fibrosis (CF) could influence tocopherol absorption, transportation, storage, metabolism and excretion. We hypothesized that the oxidative distress due to inflammation in CF increases vitamin E utilization, which could be positively influenced by supplemental vitamin C administration. Methods: Immediately before and after receiving vitamin C (500 mg) twice daily for 3.5 weeks, adult CF patients (n = 6) with moderately advanced respiratory tract (RT) disease consumed a standardized breakfast with 30% fat and a capsule containing 50 mg each hexadeuterium (d6)-α- and dideuterium (d2)-γ-tocopheryl acetates. Blood samples were taken frequently up to 72 h; plasma tocopherol pharmacokinetics were determined. During both trials, d6-α- and d2-γ-tocopherols were similarly absorbed and reached similar maximal plasma concentrations ~18–20 h. As predicted, during vitamin C supplementation, the rates of plasma d6-α-tocopherol decline were significantly slower. Conclusions: The vitamin C-induced decrease in the plasma disappearance rate of α-tocopherol suggests that vitamin C recycled α-tocopherol, thereby augmenting its concentrations. We conclude that some attention should be paid to plasma ascorbic acid concentrations in CF patients, particularly to those individuals with more advanced RT inflammatory disease and including those with severe exacerbations.

Glomerular filtration rate in critically ill neonates and children: creatinine-based estimations versus iohexol-based measurements

BackgroundAcute kidney injury (AKI) and augmented renal clearance (ARC), both alterations of the glomerular filtration rate (GFR), are prevalent in critically ill children and neonates. AKI and ARC prevalence estimates are based on estimation of GFR (eGFR) using serum creatinine (SCr), which is known to be inaccurate. We aimed to test our hypothesis that AKI prevalence will be higher and ARC prevalence will be lower in critically ill children when using iohexol-based measured GFR (mGFR), rather than using eGFR. Additionally, we aimed to investigate the performance of different SCr-based eGFR methods.MethodsIn this single-center prospective study, critically ill term-born neonates and children were included. mGFR was calculated using a plasma disappearance curve after parenteral administration of iohexol. AKI diagnosis was based on the KDIGO criteria, SCr-based eGFR, and creatinine clearance (CrCL). Differences between eGFR and mGFR were determined using Wilcoxon signed-rank tests and by calculating bias and accuracy (percentage of eGFR values within 30% of mGFR values).ResultsOne hundred five children, including 43 neonates, were included. AKI prevalence was higher based on mGFR (48%), than with KDIGO or eGFR (11–40%). ARC prevalence was lower with mGFR (24%) compared to eGFR (38–51%). eGFR equations significantly overestimated mGFR (60–71 versus 41 ml/min/1.73 m2, p < 0.001–0.002). Accuracy was highest with eGFR equations based on age- and sex-dependent equations (up to 59%).ConclusionIohexol-based AKI prevalence was higher and ARC prevalence lower compared to standard SCr-based eGFR methods. Age- and sex-dependent equations for eGFR (eGFR-Smeets for neonates and eGFR-Pierce for children) best approached measured GFR and should preferably be used to optimize diagnosis of AKI and ARC in this population.Graphical A higher resolution version of the Graphical abstract is available as Supplementary information

Indocyanine green clearance test in liver transplantation: defining cut-off levels for graft viability assessment during organ retrieval and for the prediction of post-transplant graft function recovery - the Liver Indocyanine Green (LivInG) Trial Study Protocol

IntroductionViability assessment of the graft is essential to lower the risk of liver transplantation (LT) failure and need for emergency retransplantation, however, this still relies mainly on surgeon’s experience. Post-LT...

Automated multicolor mesoscopic imaging for the 3-dimensional reconstruction of fluorescent biomarker distribution in large tissue specimens.

Research in translational medicine often requires high-resolution characterization techniques to visualize or quantify the fluorescent probes. For example, drug delivery systems contain fluorescent molecules enabling in vitro and in vivo tracing to determine biodistribution or plasma disappearance. Albeit fluorescence imaging systems with sufficient resolution exist, the sample preparation is typically too complex to image a whole organism of the size of a mouse. This article established a mesoscopic imaging technique utilizing a commercially available cryo-microtome and an in-house built episcopic imaging add-on to perform imaging during serial sectioning. Here we demonstrate that our automated red, green, blue (RGB) and fluorescence mesoscope can generate sequential block-face and 3-dimensional anatomical images at variable thickness with high quality of 6 µm × 6 µm pixel size. In addition, this mesoscope features a numerical aperture of 0.10 and a field-of-view of up to 21.6 mm × 27 mm × 25 mm (width, height, depth).

51Cr-EDTA plasma clearance in children: One, two, or multiple samples?

Plasma disappearance curves using multiple blood samples are a recognized reference method for measuring glomerular filtration rate (GFR). However, there is no consensus on the protocol for this type of measurement. A two-compartment model is generally considered acceptable for the mathematical description of the concentration–time decay curve. The impact of the fitting procedure on the reported GFR has not been questioned.We defined 8 different fitting procedures to calculate the area under the curve, and from this area under the curve, the GFR. We applied the 8 fitting methods (all considering a full concentration–time curve) on the multiple sample data (8 samples) of 20 children diagnosed with Duchenne muscular dystrophy. We evaluated the effect (variability) on the reported GFR from the different fitting methods and compared these results with GFR-values calculated from late samples only (samples after 120 minutes) and from one-sample methods.In 6 out of 20 cases, the fitting methods on the full concentration–time curve resulted in very different reported GFR-values, mainly because some methods were not able to fit the data, or methods resulted in GFR-values ranging from 0 to 120 mL/min. The reported GFR-result therefore strongly depends on the fitting method, making the full concentration–time method less robust than expected. Compared with a consensus reference GFR, the late sample models did not show fitting issues and may therefore be considered as more robust. Also the one-sample methods showed acceptable accuracy.The late sample methods (using 3 time-points) provide robust and reliable methods to determine GFR.

Physiologically Based Modeling of the Effect of Physiological and Anthropometric Variability on Indocyanine Green Based Liver Function Tests.

Accurate evaluation of liver function is a central task in hepatology. Dynamic liver function tests (DLFT) based on the time-dependent elimination of a test substance provide an important tool for such a functional assessment. These tests are used in the diagnosis and monitoring of liver disease as well as in the planning of hepatobiliary surgery. A key challenge in the evaluation of liver function with DLFTs is the large inter-individual variability. Indocyanine green (ICG) is a widely applied test compound used for the evaluation of liver function. After an intravenous administration, pharmacokinetic (PK) parameters are calculated from the plasma disappearance curve of ICG which provide an estimate of liver function. The hepatic elimination of ICG is affected by physiological factors such as hepatic blood flow or binding of ICG to plasma proteins, anthropometric factors such as body weight, age, and sex, or the protein amount of the organic anion-transporting polypeptide 1B3 (OATP1B3) mediating the hepatic uptake of ICG. Being able to account for and better understand these various sources of inter-individual variability would allow to improve the power of ICG based DLFTs and move toward an individualized evaluation of liver function. Within this work we systematically analyzed the effect of various factors on ICG elimination by the means of computational modeling. For the analysis, a recently developed and validated physiologically based pharmacokinetics (PBPK) model of ICG distribution and hepatic elimination was utilized. Key results are (i) a systematic analysis of the variability in ICG elimination due to hepatic blood flow, cardiac output, OATP1B3 abundance, liver volume, body weight and plasma bilirubin level; (ii) the evaluation of the inter-individual variability in ICG elimination via a large in silico cohort of n = 100,000 subjects based on the NHANES cohort with special focus on stratification by age, sex, and body weight; (iii) the evaluation of the effect of various degrees of cirrhosis on variability in ICG elimination. The presented results are an important step toward individualizing liver function tests by elucidating the effects of confounding physiological and anthropometric parameters in the evaluation of liver function via ICG.