Free heme and hemopexin in acute kidney injury after cardiopulmonary bypass and transient renal ischemia.

Free heme is released from hemoproteins during hemolysis or ischemia reperfusion injury and can be pro-inflammatory. Most studies on nephrotoxicity of hemolysis-derived proteins focus on free hemoglobin (fHb) with heme as a prosthetic group. Measurement of heme in its free, non-protein bound, form is challenging and not commonly used in clinical routine diagnostics. In contrast to fHb, the role of free heme in acute kidney injury (AKI) after cardiopulmonary bypass (CPB) surgery is unknown. Using an apo-horseradish peroxidase-based assay, we identified free heme during CPB surgery as predictor of AKI in patients undergoing cardiac valve replacement (n = 37). Free heme levels during CPB surgery correlated with depletion of hemopexin (Hx), a heme scavenger-protein. In mice, the impact of high levels of circulating free heme on the development of AKI following transient renal ischemia and the therapeutic potential of Hx were investigated. C57BL/6 mice were subjected to bilateral renal ischemia/reperfusion injury for 15 min which did not cause AKI. However, additional administration of free heme in this model promoted overt AKI with reduced renal function, increased renal inflammation, and reduced renal perfusion on functional magnetic resonance imaging. Hx treatment attenuated AKI. Free heme administration to sham operated control mice did not cause AKI. In conclusion, free heme is a predictor of AKI in CPB surgery patients and promotes AKI in transient renal ischemia. Depletion of Hx in CPB surgery patients and attenuation of AKI by Hx in the in vivo model encourage further research on Hx therapy in patients with increased free heme levels during CPB surgery.

Parametric Imaging of Biologic Activity of Atherosclerosis Using Dynamic Whole-Body Positron Emission Tomography.

BACKGROUND: For molecular imaging of atherosclerotic vessel wall activity, tracer kinetic analysis may yield improved contrast versus blood, more robust quantitative parameters, and more reliable characterization of systems biology. OBJECTIVES: The authors introduce a novel dynamic whole-body positron emission tomography (PET) protocol that is enabled by rapid continuous camera table motion, followed by reconstruction of parametric data sets using voxel-based Patlak graphical analysis. METHODS: Twenty-five subjects were prospectively enrolled and underwent dynamic PET up to 90 minutes after injection of 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Two sets of images were generated: 1) the established standard of static standardized uptake value (SUV) images; and 2) parametric images of the metabolic rate of FDG (MRFDG) using the Patlak plot-derived influx rate. Arterial wall signal was measured and compared using the volume-of-interest technique, and its association with hematopoietic and lymphoid organ signal and atherosclerotic risk factors was explored. RESULTS: Parametric MRFDG images provided excellent arterial wall visualization, with elimination of blood-pool activity, and enhanced focus detectability and reader confidence. Target-to-background ratio (TBR) from MRFDG images was significantly higher compared with SUV images (2.6 ± 0.8 vs 1.4 ± 0.2; P < 0.0001), confirming improved arterial wall contrast. On MRFDG images, arterial wall signal showed improved correlation with hematopoietic and lymphoid organ activity (spleen P = 0.0009; lymph nodes P = 0.0055; and bone marrow P = 0.0202) and increased with the number of atherosclerotic risk factors (r = 0.49; P = 0.0138), where signal from SUV images (SUVmaxP = 0.9754; TBRmaxP = 0.8760) did not. CONCLUSIONS: Absolute quantification of MRFDG is feasible for arterial wall using dynamic whole-body PET imaging. Parametric images provide superior arterial wall contrast, and they might be better suited to explore the relationship between arterial wall activity, systemic organ networks, and cardiovascular risk. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of arterial wall disease.

A Single Oral Dose of Diclofenac Causes Transition of Experimental Subclinical Acute Kidney Injury to Chronic Kidney Disease.

Nephrotoxic drugs can cause acute kidney injury (AKI) and analgesic nephropathy. Diclofenac is potentially nephrotoxic and frequently prescribed for pain control. In this study, we investigated the effects of single and repetitive oral doses of diclofenac in the setting of pre-existing subclinical AKI on the further course of AKI and on long-term renal consequences. Unilateral renal ischemia-reperfusion injury (IRI) for 15 min was performed in male CD1 mice to induce subclinical AKI. Immediately after surgery, single oral doses (100 mg or 200 mg) of diclofenac were administered. In a separate experimental series, repetitive treatment with 100 mg diclofenac over three days was performed after IRI and sham surgery. Renal morphology and pro-fibrotic markers were investigated 24 h and two weeks after the single dose and three days after the repetitive dose of diclofenac treatment using histology, immunofluorescence, and qPCR. Renal function was studied in a bilateral renal IRI model. A single oral dose of 200 mg, but not 100 mg, of diclofenac after IRI aggravated acute tubular injury after 24 h and caused interstitial fibrosis and tubular atrophy two weeks later. Repetitive treatment with 100 mg diclofenac over three days aggravated renal injury and caused upregulation of the pro-fibrotic marker fibronectin in the setting of subclinical AKI, but not in sham control kidneys. In conclusion, diclofenac aggravated renal injury in pre-existing subclinical AKI in a dose and time-dependent manner and already a single dose can cause progression to chronic kidney disease (CKD) in this model.

First experiences and results after cryoablation of prostate cancer with histopathological evaluation and imaging-based follow-up.

Aim: To share our experience after 28 cryoablation treatments for prostate cancer (PCa) with histopathology, clinical data and MRI as the follow-up methods. Methods: Clinical follow-up comprised prostate-specific antigen (PSA)-measurements, PSA-density and quality of life-parameters. multi-parametric (mp)MRI pre- and post-cryoablation were retrospectively re-analyzed in 23 cases using Likert scores. Follow-up-histopathology was performed via MRI/ultrasound fusion-guided and/or systematic biopsy. Receiver operating characteristic curve analysis was performed. Results: 17 PCa (61%) were diagnosed within 12-month post-cryotherapy (infield and out-of-field disease). PSA levels and PSA density were not significantly different between patients with or without PCa recurrence. mpMRI can characterize the decrease in prostate volume and necrosis. Area under the curve for the detection of PCa was 81% (global Likert scores), 74-87% (T2), 78% (diffusion weighted imaging) and 57-78% (dynamic contrast enhanced imaging; Youden-selected cutoff ≥3). Conclusion: Besides histopathological evaluation and control biopsy, MRI might have the potential to accurately detect PCa after cryotherapy. Clinical data and interdisciplinary communication are required for efficient monitoring after cryoablation treatments for PCa.

Skeletal muscle derived Musclin protects the heart during pathological overload.

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

Diffusion-Weighted Imaging and Mapping of T1 and T2 Relaxation Time for Evaluation of Chronic Renal Allograft Rejection in a Translational Mouse Model.

We hypothesized that multiparametric MRI is able to non-invasively assess, characterize and monitor renal allograft pathology in a translational mouse model of chronic allograft rejection. Chronic rejection was induced by allogenic kidney transplantation (ktx) of BALB/c-kidneys into C57BL/6-mice (n = 23). Animals after isogenic ktx (n = 18) and non-transplanted healthy animals (n = 22) served as controls. MRI sequences (7T) were acquired 3 and 6 weeks after ktx and quantitative T1, T2 and apparent diffusion coefficient (ADC) maps were calculated. In addition, in a subset of animals, histological changes after ktx were evaluated. Chronic rejection was associated with a significant prolongation of T1 time compared to isogenic ktx 3 (1965 ± 53 vs. 1457 ± 52 ms, p < 0.001) and 6 weeks after surgery (1899 ± 79 vs. 1393 ± 51 ms, p < 0.001). While mean T2 times and ADC were not significantly different between allogenic and isogenic kidney grafts, histogram-based analysis of ADC revealed significantly increased tissue heterogeneity in allografts at both time points (standard derivation/entropy/interquartile range, p < 0.05). Correspondingly, histological analysis showed severe inflammation, graft fibrosis and tissue heterogeneity in allogenic but not in isogenic kidney grafts. In conclusion, renal diffusion weighted imaging and mapping of T2 and T1 relaxation times enable detection of chronic renal allograft rejection in mice. The combined quantitative assessment of mean values and histograms provides non-invasive information of chronic changes in renal grafts and allows longitudinal monitoring.

Diffusion Weighted Imaging and T2 Mapping Detect Inflammatory Response in the Renal Tissue during Ischemia Induced Acute Kidney Injury in Different Mouse Strains and Predict Renal Outcome.

To characterize ischemia reperfusion injury (IRI)-induced acute kidney injury (AKI) in C57BL/6 (B6) and CD1-mice by longitudinal functional MRI-measurement of edema formation (T2-mapping) and inflammation (diffusion weighted imaging (DWI)). IRI was induced with unilateral right renal pedicle clamping for 35min. 7T-MRI was performed 1 and 14 days after surgery. DWI (7 b-values) and multiecho TSE sequences (7 TE) were acquired. Parameters were quantified in relation to the contralateral kidney on day 1 (d1). Renal MCP-1 and IL-6-levels were measured by qPCR and serum-CXCL13 by ELISA. Immunohistochemistry for fibronectin and collagen-4 was performed. T2-increase on d1 was higher in the renal cortex (127 ± 5% vs. 94 ± 6%, p < 0.01) and the outer stripe of the outer medulla (141 ± 9% vs. 111 ± 9%, p < 0.05) in CD1, indicating tissue edema. Medullary diffusivity was more restricted in CD1 than B6 (d1: 73 ± 3% vs. 90 ± 2%, p < 0.01 and d14: 77 ± 5% vs. 98 ± 3%, p < 0.01). Renal MCP-1 and IL-6-expression as well as systemic CXCL13-release were pronounced in CD1 on d1 after IRI. Renal fibrosis was detected in CD1 on d14. T2-increase and ADC-reduction on d1 correlated with kidney volume loss on d14 (r = 0.7, p < 0.05; r = 0.6, p < 0.05) and could serve as predictive markers. T2-mapping and DWI evidenced higher susceptibility to ischemic AKI in CD1 compared to B6.

Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure.

[Figure: see text].

Plasma Metabolome Signature Indicative of BRCA1 Germline Status Independent of Cancer Incidence.

Individuals carrying a pathogenic germline variant in the breast cancer predisposition gene BRCA1 (gBRCA1+) are prone to developing breast cancer. Apart from its well-known role in DNA repair, BRCA1 has been shown to powerfully impact cellular metabolism. While, in general, metabolic reprogramming was named a hallmark of cancer, disrupted metabolism has also been suggested to drive cancer cell evolution and malignant transformation by critically altering microenvironmental tissue integrity. Systemic metabolic effects induced by germline variants in cancer predisposition genes have been demonstrated before. Whether or not systemic metabolic alterations exist in gBRCA1+ individuals independent of cancer incidence has not been investigated yet. We therefore profiled the plasma metabolome of 72 gBRCA1+ women and 72 age-matched female controls, none of whom (carriers and non-carriers) had a prior cancer diagnosis and all of whom were cancer-free during the follow-up period. We detected one single metabolite, pyruvate, and two metabolite ratios involving pyruvate, lactate, and a metabolite of yet unknown structure, significantly altered between the two cohorts. A machine learning signature of metabolite ratios was able to correctly distinguish between gBRCA1+ and controls in ~82%. The results of this study point to innate systemic metabolic differences in gBRCA1+ women independent of cancer incidence and raise the question as to whether or not constitutional alterations in energy metabolism may be involved in the etiology of BRCA1-associated breast cancer.

Application of MR diffusion imaging for non-invasive assessment of acute kidney injury after lung transplantation.

To assess whether MR diffusion imaging may be applied for non-invasive detection of renal changes correlating with clinical diagnosis of acute kidney injury (AKI) in patients after lung transplantation (lutx).Fifty-four patients (mean age 49.6, range 26-64 years) after lutx were enrolled in a prospective clinical study and underwent functional MR imaging of the kidneys in the early postoperative period. Baseline s-creatinine ranged from 39 to 112 µmol/L. For comparison, 14 healthy volunteers (mean age 42.1, range 24-59 years) underwent magnetic resonance imaging (MRI) using the same protocol. Renal tissue injury was evaluated using quantification of diffusion and diffusion anisotropy with diffusion-weighted (DWI) and diffusion-tensor imaging (DTI). Renal function was monitored and AKI was defined according to Acute-Kidney-Injury-Network criteria. Statistical analysis comprised one-way ANOVA and Pearson correlation.67% of lutx patients (36/54) developed AKI, 47% (17/36) had AKI stage 1, 42% (15/36) AKI stage 2, and 8% (3/36) severe AKI stage 3. Renal apparent diffusion coefficients (ADCs) were reduced in patients with AKI, but preserved in transplant patients without AKI and healthy volunteers (2.07 ±â€Š0.02 vs 2.18 ±â€Š0.05 vs 2.21 ±â€Š0.03 × 10 mm/s, P < .05). Diffusion anisotropy was reduced in all lutx recipients compared with healthy volunteers (AKI: 0.27 ±â€Š0.01 vs no AKI: 0.28 ±â€Š0.01 vs healthy: 0.33 ±â€Š0.02; P < .01). Reduction of renal ADC correlated significantly with acute loss of renal function after lutx (decrease of renal function in the postoperative period and glomerular filtration rate on the day of MRI).MR diffusion imaging enables non-invasive assessment of renal changes correlating with AKI early after lutx. Reduction of diffusion anisotropy was present in all patients after lutx, whereas marked reduction of renal ADC was observed only in the group of lutx recipients with AKI and correlated with renal function impairment.

Early antihypertensive treatment and ischemia-induced acute kidney injury.

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.

[Structured chest X-ray imaging training with OSCE examination : Results of a feasibility study and follow-up survey]. / Training zur strukturierten Befundung von Radiographien des Thorax mit OSCE-Prüfung : Ergebnisse einer Machbarkeitsstudie und Follow-up-Befragung.

BACKGROUND: The structured diagnosis of chest radiographs is an important basic competence in radiology and will be required in the student teaching with the implementation of the National Competency-Based Learning Catalog Medicine (NKLM) in Germany. AIM: The aim was to evaluate the extent to which second-year students gain confidence in the diagnosis of chest radiographs through a new curricular training for the diagnosis of chest radiographs with subsequent objective structured clinical examination (OSCE) and how confident they feel about meeting the expectations of the supervising medical colleagues during the clinical clerkship. METHODS: The training included four lectures and ten commented instructional films on the diagnosis of radiographs. Two years later, the students were asked how often and in what form they had contact with chest radiographs in their clinical clerkship. They were also asked how confident they felt in dealing in different areas. The students with training were also asked to what extent the lectures and the instructional films were helpful. The results of students in the last year without and the first year with training and OSCE were compared using the Mann-Whitney U test for independent samples. RESULTS: The frequency of dealing with chest radiographs was comparably high among students with and without training. The students with training and OSCE felt more confident and better prepared in dealing with chest radiographs than the students without training (varying between p < 0.001 and p = 0.148). They rated the educational films as more helpful than the lectures (mean 2.85 ± 0.76 vs. 3.41 ± 0.68 on a four-point scale). DISCUSSION: With early training, students' confidence in dealing with chest radiographs can be sustainably increased.

Correction to: Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI.

The article Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI.

Liposomal Delivery Improves the Efficacy of Prednisolone to Attenuate Renal Inflammation in a Mouse Model of Acute Renal Allograft Rejection.

BACKGROUND: Systemic exposure to high-dose corticosteroids effectively combats acute rejection after kidney transplantation, but at the cost of substantial side effects. In this study, a murine acute renal allograft rejection model was used to investigate whether liposomal-encapsulated prednisolone (LP) facilitates local exposure to enhance its therapeutic effect. METHODS: Male BalbC recipients received renal allografts from male C57BL/6J donors. Recipients were injected daily with 5 mg/kg cyclosporine A and received either 10 mg/kg prednisolone (P), or LP intravenously on day 0, 3, and 6, or no additional treatment. Functional magnetic resonance imaging (fMRI) was performed on day 6 to study allograft perfusion and organs were retrieved on day 7 for further analysis. RESULTS: Staining of polyethylene-glycol-labeled liposomes and high performance liquid chromatography analysis revealed accumulation in the LP treated allograft. LP treatment induced the expression of glucocorticoid responsive gene Fkbp5 in the allograft. Flow-cytometry of allografts revealed liposome presence in CD45 cells, and reduced numbers of F4/80 macrophages, and CD3 T-lymphocytes upon LP treatment. Banff scoring showed reduced interstitial inflammation and tubulitis and fMRI analysis revealed improved allograft perfusion in LP versus NA mice. CONCLUSIONS: Liposomal delivery of prednisolone improved renal bio-availability, increased perfusion and reduced cellular infiltrate in the allograft, when compared with conventional prednisolone. Clinical studies should reveal if treatment with LP results in improved efficacy and reduced side effects in patients with renal allograft rejection.

Multimodality Imaging of Inflammation and Ventricular Remodeling in Pressure-Overload Heart Failure.

Inflammation contributes to ventricular remodeling after myocardial ischemia, but its role in nonischemic heart failure is poorly understood. Local tissue inflammation is difficult to assess serially during pathogenesis. Although 18F-FDG accumulates in inflammatory leukocytes and thus may identify inflammation in the myocardial microenvironment, it remains unclear whether this imaging technique can isolate diffuse leukocytes in pressure-overload heart failure. We aimed to evaluate whether inflammation with 18F-FDG can be serially imaged in the early stages of pressure-overload-induced heart failure and to compare the time course with functional impairment assessed by cardiac MRI. Methods: C57Bl6/N mice underwent transverse aortic constriction (TAC) (n = 22), sham surgery (n = 12), or coronary ligation as an inflammation-positive control (n = 5). MRI assessed ventricular geometry and contractile function at 2 and 8 d after TAC. Immunostaining identified the extent of inflammatory leukocyte infiltration early in pressure overload. 18F-FDG PET scans were acquired at 3 and 7 d after TAC, under ketamine-xylazine anesthesia to suppress cardiomyocyte glucose uptake. Results: Pressure overload evoked rapid left ventricular dilation compared with sham (end-systolic volume, day 2: 40.6 ± 10.2 µL vs. 23.8 ± 1.7 µL, P < 0.001). Contractile function was similarly impaired (ejection fraction, day 2: 40.9% ± 9.7% vs. 59.2% ± 4.4%, P < 0.001). The severity of contractile impairment was proportional to histology-defined myocardial macrophage density on day 8 (r = -0.669, P = 0.010). PET imaging identified significantly higher left ventricular 18F-FDG accumulation in TAC mice than in sham mice on day 3 (10.5 ± 4.1 percentage injected dose [%ID]/g vs. 3.8 ± 0.9 %ID/g, P < 0.001) and on day 7 (7.8 ± 3.7 %ID/g vs. 3.0 ± 0.8 %ID/g, P = 0.006), though the efficiency of cardiomyocyte suppression was variable among TAC mice. The 18F-FDG signal correlated with ejection fraction (r = -0.75, P = 0.01) and ventricular volume (r = 0.75, P < 0.01). Western immunoblotting demonstrated a 60% elevation of myocardial glucose transporter 4 expression in the left ventricle at 8 d after TAC, indicating altered glucose metabolism. Conclusion: TAC induces rapid changes in left ventricular geometry and contractile function, with a parallel modest infiltration of inflammatory macrophages. Metabolic remodeling overshadows inflammatory leukocyte signal using 18F-FDG PET imaging. More selective inflammatory tracers are requisite to identify the diffuse local inflammation in pressure overload.

Consensus-based technical recommendations for clinical translation of renal diffusion-weighted MRI.

OBJECTIVES: Standardization is an important milestone in the validation of DWI-based parameters as imaging biomarkers for renal disease. Here, we propose technical recommendations on three variants of renal DWI, monoexponential DWI, IVIM and DTI, as well as associated MRI biomarkers (ADC, D, D*, f, FA and MD) to aid ongoing international efforts on methodological harmonization. MATERIALS AND METHODS: Reported DWI biomarkers from 194 prior renal DWI studies were extracted and Pearson correlations between diffusion biomarkers and protocol parameters were computed. Based on the literature review, surveys were designed for the consensus building. Survey data were collected via Delphi consensus process on renal DWI preparation, acquisition, analysis, and reporting. Consensus was defined as ≥ 75% agreement. RESULTS: Correlations were observed between reported diffusion biomarkers and protocol parameters. Out of 87 survey questions, 57 achieved consensus resolution, while many of the remaining questions were resolved by preference (65-74% agreement). Summary of the literature and survey data as well as recommendations for the preparation, acquisition, processing and reporting of renal DWI were provided. DISCUSSION: The consensus-based technical recommendations for renal DWI aim to facilitate inter-site harmonization and increase clinical impact of the technique on a larger scale by setting a framework for acquisition protocols for future renal DWI studies. We anticipate an iterative process with continuous updating of the recommendations according to progress in the field.

Consensus-based technical recommendations for clinical translation of renal ASL MRI.

OBJECTIVES: This study aimed at developing technical recommendations for the acquisition, processing and analysis of renal ASL data in the human kidney at 1.5 T and 3 T field strengths that can promote standardization of renal perfusion measurements and facilitate the comparability of results across scanners and in multi-centre clinical studies. METHODS: An international panel of 23 renal ASL experts followed a modified Delphi process, including on-line surveys and two in-person meetings, to formulate a series of consensus statements regarding patient preparation, hardware, acquisition protocol, analysis steps and data reporting. RESULTS: Fifty-nine statements achieved consensus, while agreement could not be reached on two statements related to patient preparation. As a default protocol, the panel recommends pseudo-continuous (PCASL) or flow-sensitive alternating inversion recovery (FAIR) labelling with a single-slice spin-echo EPI readout with background suppression and a simple but robust quantification model. DISCUSSION: This approach is considered robust and reproducible and can provide renal perfusion images of adequate quality and SNR for most applications. If extended kidney coverage is desirable, a 2D multislice readout is recommended. These recommendations are based on current available evidence and expert opinion. Nonetheless they are expected to be updated as more data become available, since the renal ASL literature is rapidly expanding.

Applicability of readout-segmented echoplanar diffusion weighted imaging for prostate MRI.

To evaluate readout-segmented echoplanar (rsEPI) diffusion weighted imaging (DWI) for multiparametric (mp) magnetic resonance imaging (MRI) of the prostate compared to the established single-shot echoplanar imaging (ssEPI) sequence.One hundred ten consecutive patients with clinical suspicion of prostate cancer underwent mp prostate MRI using both, the ssEPI and the rsEPI DWI sequence. For an objective assessment, delineation of the prostate shape on both DWI sequences was compared to T2-weighted images by measuring organ diameters. Apparent diffusion coefficient (ADC) values, image contrast and contrast-to-noise ratio (CNR) were compared between the 2 sequences on a region-of-interest-based analysis. Diagnostic accuracy for quantitative ADC-values was calculated. Histopathology from MRI/ultrasound fusion-guided biopsy was used as reference standard. For a subjective assessment, 2 independent readers visually assessed image quality of both sequences using Likert-scales.Delineation of the prostate shape was more accurate with rsEPI compared to ssEPI. ADC values in target lesions were not significantly different but significantly higher in the surrounding normal prostatic tissue of the transition zone. CNR was comparable between ssEPI and rsEPI. Sensitivity and specificity were good for both sequences with 84/84% and 82/73% with a Youden selected cut-off of ADC = 0.971*10 mm/s for rsEPI and 1.017*10 mm/s for ssEPI. Anatomic artifacts were significantly less and SNR was lower on rsEPI compared to ssEPI in the subjective analysis.Delineation of the prostate shape was more accurate with rsEPI DWI than with ssEPI DWI with less anatomic artifacts and higher subjective SNR and image quality on rsEPI DW images. Diagnostic ability of quantitative ADC-values was not significantly different between the 2 sequences. Thus, rsEPI DWI might be more suitable for prostate MRI with regard to MRI-guided targeted biopsy and therapy planning.

Single-dose diclofenac in healthy volunteers can cause decrease in renal perfusion measured by functional magnetic resonance imaging.

OBJECTIVES: We investigated changes of renal perfusion after topical and oral diclofenac administration in healthy volunteers using functional magnetic resonance imaging (MRI) with arterial spin labelling (ASL). METHODS: Twenty-four healthy human participants (21-51 years) underwent 1.5T MRI before and 1 h after a single oral dose of diclofenac (50 mg). Twelve of 24 participants underwent an additional MRI examination following 3-day topical diclofenac administration. For renal perfusion imaging, a flow-sensitive alternating inversion-recovery TrueFISP ASL sequence was applied. Plasma concentrations of diclofenac and serum concentrations of thromboxane were determined. KEY FINDINGS: After oral diclofenac application, large interindividual differences in plasma concentrations were observed (range <3-4604 nm). Topical diclofenac application did not result in relevant systemic diclofenac levels (range 5-75 nm). MRI showed a significant reduction of renal perfusion in individuals with diclofenac levels ≥225 nm (baseline: 347 ± 7 vs diclofenac: 323 ± 8 ml/min/100 g, P < 0.01); no significant differences were observed in participants with diclofenac levels <225 nm. Diclofenac levels correlated negatively with thromboxane B2 levels pointing towards target engagement. CONCLUSIONS: Single-dose diclofenac caused a decrease in renal perfusion in participants with diclofenac levels ≥225 nm. We demonstrated that even a single dose of diclofenac can impair renal perfusion, which could be detrimental in patients with underlying chronic kidney disease or acute kidney injury.

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection.

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.