Longitudinal evaluation of perfusion changes in acute and chronic renal allograft rejection using arterial spin labeling in translational mouse models.

PURPOSE: To examine the longitudinal changes of renal perfusion due to acute and chronic renal allograft rejection by using arterial spin labeling (ASL) MRI in translational mouse models of isogenic and allogenic kidney transplantation (ktx). MATERIALS AND METHODS: Acute rejection was induced by allogenic ktx of C57BL/6 (B6)-kidney grafts to BALB/c-recipients with prolonged cold ischemia (CIT) of 60 minutes (n = 13). To induce chronic rejection BALB/c-kidneys were transplanted into B6-recipients with short CIT of 30 minutes (n = 22). Isogenic grafts without rejection (n = 14 with prolonged, n = 9 with short CIT) and normal kidneys (n = 22) were used for comparison. Perfusion was measured on a 7T small-animal magnetic resonance imaging (MRI) scanner using flow-sensitive alternating inversion recovery (FAIR) ASL-sequences at day 1 and 6 (acute) or at week 3 and 6 (chronic) after surgery. Histological analyses of grafts included inflammation, vascular changes, and fibrosis. RESULTS: In the acute ktx model, ASL showed perfusion impairment in isogenic and allogenic kidney grafts. Perfusion of allografts further decreased until day 6 and remained stable in isografts without rejection (allogenic ktx 62 ± 21 vs. isogenic ktx 181 ± 39 ml/min/100g, P < 0.01). In the chronic ktx model, perfusion in isografts was similar to normal kidneys over the entire observation period. Perfusion was severely reduced in allografts compared to isografts (week 3: 28 ± 7 vs. 310 ± 46 ml/min/100g, P < 0.001, week 6: 32 ± 5 vs. 367 ± 72 ml/min/100g, P < 0.001). Histological analysis revealed severe inflammation, vascular occlusion, and rejection in allografts. Chronic rejection grafts showed endothelialitis, peritubular capillaritis, interstitial fibrosis, and tubular atrophy. CONCLUSION: ASL allows longitudinal assessment of renal perfusion impairment due to acute and chronic renal allograft rejection in translational mouse models. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1664-1672.

Maternal and pregnancy-related death: causes and frequencies in an autopsy study population.

BACKGROUND: Maternal deaths during pregnancy, both from pregnancy-related or other causes, are rare in Western industrialized countries. In this study we report maternal and pregnancy-related deaths in a large autopsy population focusing on medical history, autopsy findings and histological examinations. MATERIALS AND METHODS: Medico-legal autopsy files (n = 11,270) from the Institute of Legal Medicine and Forensic Sciences, University Medical Centre Charité, University of Berlin, and the State Institute of Legal and Social Medicine, Berlin, from 2005 to 2010 were reviewed. All female cases between 15 and 49 years were checked for maternal and pregnancy-related death, and deaths of pregnant women from non-natural causes were also included. Fatalities that met the chosen criteria were classified as "direct gestational death," "indirect gestational death" or "non-gestational death." RESULTS: 13 female fatalities (0.12 %) met the chosen criteria (median age 28 years ± 6.87 SD). Eight (61.5 %) women died in-hospital, four (30.8 %) at home, and one woman died in public. Three cases (23.1 %) were "non-gestational deaths," and one case (7.7 %) remained unclear after autopsy and additional examinations. Of the remaining nine cases, six cases (46.5 %) were "direct gestational deaths," and two cases (15.4 %) were "indirect gestational deaths." One case (7.7 %) was not to be defined as "late maternal death," but the cause of death seemed to be directly related to previous gestation ["(very) late maternal death"]. CONCLUSION: Maternal deaths during pregnancy, both from pregnancy-related or other causes, remain an uncommon event in routine forensic autopsy practice. We report on the collection and analysis of maternal and pregnancy-related deaths in a large autopsy population, with particular attention to the phenomenology of pregnancy, pathophysiological changes in different organ systems and their detection, and the forensic autopsy assessment.

Classification of Diverticular Disease (CDD) - assessment of the intra- and interobserver agreement in abdominal CT scans.

PURPOSE: Along with ultrasound, computed tomography (CT) is one of the imaging modalities of choice in patients with suspected diverticular disease (DD). Recently, a newer Classification of Diverticular Disease (CDD) has been proposed. However, its reliability in daily radiological practice has never been proven. Therefore, our aim was to evaluate the intra- and interobserver agreement of the CDD in abdominal CT scans. METHODS: In this retrospective study, 481 CT scans of patients with suspected DD were included. Two readers (one board-certified radiologist with 6 years of experience, one 3 rd year radiology resident) individually evaluated all CTs in two reading sessions using the CDD. A composite endpoint of a prior consensus reading, follow-up, and intraoperative findings served as the reference. Intra- and interobserver agreement were calculated using Cohen-k statistic. RESULTS: DD was present in 317 cases (66 %), mostly classified as CDD stage 0, 1b, and 2a (28 %, 30 %, und 14 %). Intraobserver agreement was almost perfect for both readers (kappa 0.93 and 0.88). Interobserver agreement was high and improved from substantial (kappa 0.77) in the first reading session to almost perfect (kappa 0.84) in the second reading session. The interobserver agreement was best for CDD types 0 (diverticulosis) and 2c (free perforated diverticulitis) (mean kappa 0.83 and 0.86) and poorest for CDD types 1a (diverticulitis without phlegmon) and 2b (covered diverticulitis with macroabscess) (mean kappa 0.17 and 0.38). Intra- and interobserver agreement of acute uncomplicated (CDD type 1) and acute complicated diverticulitis (CDD type 2) were substantial to almost perfect (mean kappa 0.63-0.86). Agreement with the reference was almost perfect for both observers (mean kappa 0.86 and 0.82). Administration of rectal contrast did not significantly improve the diagnosis. CONCLUSION: The CDD is a classification based on relatively clear imaging characteristics, which can be readily applied by radiologists with different expertise. In our study, the CDD had a high intra- and interobserver agreement, enabling a reliable therapy-related categorization of DD. KEY POINTS: · The Classification of Diverticular Disease (CDD) is an easy-to-use classification for diverticular disease based on relatively clear image features.. · The CDD can be applied equally by radiologists with different levels of experience in the clinical routine.. · The high intra- and interobserver agreement indicates high reliability in the therapy-relevant classification of diverticulitis on CT..

Impact of the COVID-19 Pandemic on Interventional Radiology in Germany. / Auswirkung der COVID-19-Pandemie auf die Interventionelle Radiologie in Deutschland.

PURPOSE: To investigate the effect of the ongoing COVID-19 pandemic on interventional radiology (IR) in Germany in 2020 and 2021. MATERIALS UND METHODS: This retrospective study is based on the nationwide interventional radiology procedures documented in the quality register of the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR-QS-Register). The nationwide volume of interventions in the pandemic years 2020 and 2021 was compared with the pre-pandemic period (Poisson-test, Mann-Whitney test). The aggregated data were additionally evaluated by intervention type with differentiated consideration of the temporal epidemiological infection occurrence. RESULTS: During the two pandemic years 2020 and 2021, the number of interventional procedures increased by appr. 4 % compared to the same period of the previous year (n = 190 454 and 189 447 vs. n = 183 123, respectively, p < 0.001). Only the first pandemic wave in spring 2020 (weeks 12-16) showed a significant temporary drop in the number of interventional procedures by 26 % (n = 4799, p < 0.05). This primarily involved interventions that were not immediately medically urgent, such as pain treatments or elective arterial revascularization. In contrast, interventions in the field of interventional oncology, such as port catheter implantations and local tumor ablations, remained unaffected. The decline of the first wave of infection was accompanied by a rapid recovery and a significant, partly compensatory, 14 % increase in procedure numbers in the second half of 2020 compared to the same period of the previous year (n = 77 151 vs. 67 852, p < 0.001). Subsequent pandemic waves had no effect on intervention numbers. CONCLUSION: The COVID-19 pandemic in Germany led to a significant short-term decrease in interventional radiology procedures in the initial phase. A compensatory increase in the number of procedures was observed in the subsequent period. This reflects the adaptability and robustness of IR and the high demand for minimally invasive radiological procedures in medical care. KEY POINTS: · The study shows the nationwide pandemic-related effects on interventional radiology in Germany.. · In quantitative terms, the ongoing pandemic caused a significant, temporary decline in intervention cases only in the initial phase.. · Subsequent waves of infections had no effect on the scope of services provided by interventional radiology.. · Short-term deficits, especially in elective interventions, could be partially compensated.. CITATION FORMAT: · Schmidbauer M, Busjahn A, Paprottka P et al. Impact of the COVID-19 Pandemic on Interventional Radiology in Germany. Fortschr Röntgenstr 2023; 195: 597 - 604.

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.

Impact of the COVID 19 Pandemic on Radiological Imaging in Germany. / Auswirkung der COVID-19-Pandemie auf die radiologische Bildgebung in Deutschland.

PURPOSE: To analyze the impact of the COVID-19 pandemic in 2020 on the radiological imaging volume in Germany. MATERIALS UND METHODS: In this retrospective multicenter study, we analyzed CT and MRI examinations of 7 radiology institutes across Germany from January to December 2020. The imaging volume was compared to 2019 (Wilcoxon-Mann-Whitney test). Modality, patient service locations, and examined body parts were assessed in consideration of time periods of the pandemic. In addition, correlation with the incidence of SARS-CoV-2 cases and associated death was performed (Spearman-test). RESULTS: In total, in 2020, imaging volume declined by 4 % (n = 8314) compared with 2019 (p < 0.05). The hard lockdown during the first pandemic wave (calendar week 12-16, March 22 - April 19) revealed the highest decrease with 29 % (n = 894, p < 0.01), with the greatest decrease in CT (36 % vs. MRI 26 %), outpatients (38 %, p < 0.01), and imaging of the spine and extremities (51-72 %, < 0.05 - p < 0.01). Examinations referred from the emergency department (-13 %, p < 0.05) and CT of the chest (-16 %, p < 0.05) were least affected. With the end of the first wave, gradual normalization of the imaging volume was observed and persisted until the end of the observation period. A reduction of imaging volume negatively correlated with the incidence of SARS-CoV-2-positive cases and associated deaths (r = 0.28 and 0.49, p < 0.05 and p < 0.001). CONCLUSION: The COVID-19 pandemic was associated with a significant temporary decline in imaging volume. After the first lockdown period, a quick recovery was observed with radiologic imaging examinations steadily approaching prior-year figures. KEY POINTS: · This study assesses the impact of dynamic pandemic activity on radiological imaging in a multicenter analysis in Germany.. · The COVID-19 pandemic was associated with a temporary decline in CT and MRI scans.. · Relaxation of restrictions was associated with fast normalization of imaging volumes to prior-year levels, which persisted until the end of the year.. · Significant catch-up effects were not observed.. CITATION FORMAT: · Schmidbauer M, Grenacher L, Juchems MS et al. Impact of the COVID 19 Pandemic on Radiological Imaging in Germany. Fortschr Röntgenstr 2022; 194: 625 - 633.

To Fill or Not to Fill? - Value of the Administration of Positive Rectal Contrast for CT Evaluation of Diverticular Disease of the Colon.

PURPOSE: To assess the value of the administration of positive rectal contrast at CT in patients referred for suspected diverticular disease (DD) of the colon. MATERIALS AND METHODS: 460 patients (253 male, 207 female; median age 62 years; interquartile range 24) with clinical suspicion of DD of the colon were included in this retrospective IRB-approved study. CT was performed with i. v. contrast only (n = 328, group M1), i. v. + positive rectal contrast (n = 82, group M2), neither i. v. nor rectal contrast (n = 32, group S1), or positive rectal contrast only (n = 19, group S2). Two readers in consensus evaluated all CT datasets concerning diagnosis of DD (yes/no) and categorized findings (classification of diverticular disease (CDD)). Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values for the diagnosis of DD were calculated for all groups, using either clinical follow-up (n = 335) or intraoperative findings (n = 125) as the reference standard. In patients undergoing surgery, radiological staging of DD was correlated with the histopathology (weighted Cohen-k). RESULTS: 224 patients (48.7 %) were diagnosed with DD. The sensitivity, specificity, PPV, and NPV were as follows. Group M1 / M2: 92 %/92 %, 97 %/94 %, 96 %/96 %, 94 %/89 %, respectively; group S1 / S2: 94 %/86 %, 93 %/80 %, 94 %/92 %, 93 %/67 %, respectively. Radiological staging and histopathology correlated substantially in all groups (k = 0.748-0.861). CONCLUSION: Abdominal CT had a high sensitivity and specificity for the diagnosis of DD. Disease staging correlated well with the findings at surgery. Additional positive rectal contrast administration did not have a significant advantage and may therefore be omitted in patients with suspected DD. KEY POINTS: · CT has a high sensitivity and specificity for diagnosis of DD.. · CT staging using the CDD algorithm correlates very well with surgery.. · Positive rectal contrast administration does not improve diagnosis and radiological staging.. CITATION FORMAT: · Meyer S, Schmidbauer M, Wacker FK et al. To Fill or Not to Fill? - Value of the Administration of Positive Rectal Contrast for CT Evaluation of Diverticular Disease of the Colon. Fortschr Röntgenstr 2021; 193: 804 - 812.

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.

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.

Analysis of the genomic architecture of a complex trait locus in hypertensive rat models links Tmem63c to kidney damage.

Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein Tmem63c as a novel potential target. Tmem63c is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for tmem63c in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as Tmem63c for further translational investigation.

Usability of Functional MRI in Clinical Studies for Fast and Reliable Assessment of Renal Perfusion and Quantification of Hemodynamic Effects on the Kidney.

The purpose of this study was to evaluate contrast-media-free arterial spin labeling, a technique of functional magnetic resonance imaging (MRI), for assessment of kidney perfusion in a clinical study. We examined renal perfusion by arterial spin labeling in 15 healthy adults using a clinical 1.5-T MRI system, twice under baseline conditions and 60 minutes after a single oral dose of 50 mg captopril. Data evaluation included assessment of interstudy and interrater reproducibility in addition to the pharmacological effect of captopril on kidney perfusion and a sample size calculation for potential application of the technique in pharmacological intervention studies. Interstudy reproducibility of cortical and medullary kidney perfusion was excellent (intraclass correlation coefficients 0.77 and 0.83, respectively). Interrater reproducibility was excellent in the cortex and good in the medulla (intraclass correlation coefficients 0.97 and 0.66, respectively). Ingestion of 50 mg captopril was associated with an 11% drop of systolic blood pressure and a rise in kidney perfusion by 22% in the cortex (369 ± 48 vs 452 ± 56 mL/[min·100 g], P < .001) and 26% in the medulla (157 ± 39 to 198 ± 45 ml/[min·100 g]; P < .01). Statistical power analysis revealed that a small sample size of only 6 participants is needed in a clinical trial to capture an equal change in kidney perfusion to the one induced by 50 mg captopril with a statistical power of 82% and an α error of 0.05. In conclusion, funtional MRI with arterial spin labeling is a reliable method for quantification of kidney perfusion and for fast assessment of pharmacologically induced renal perfusion changes, allowing low case numbers.

Multiparametric Functional MRI: Non-Invasive Imaging of Inflammation and Edema Formation after Kidney Transplantation in Mice.

BACKGROUND: Kidney transplantation (ktx) in mice is used to learn about rejection and to develop new treatment strategies. Past studies have mainly been based on histological or molecular biological methods. Imaging techniques to monitor allograft pathology have rarely been used. METHODS: Here we investigated mice after isogenic and allogenic ktx over time with functional MRI with diffusion-weighted imaging (DWI) and mapping of T2-relaxation time (T2-mapping) to assess graft inflammation and edema formation. To characterize graft pathology, we used PAS-staining, counted CD3-positive T-lymphocytes, analyzed leukocytes by means flow cytometry. RESULTS: DWI revealed progressive restriction of diffusion of water molecules in allogenic kidney grafts. This was paralleled by enhanced infiltration of the kidney by inflammatory cells. Changes in tissue diffusion were not seen following isogenic ktx. T2-times in renal cortex were increased after both isogenic and allogenic transplantation, consistent with tissue edema due to ischemic injury following prolonged cold ischemia time of 60 minutes. Lack of T2 increase in the inner stripe of the inner medulla in allogenic kidney grafts matched loss of tubular autofluorescence and may result from rejection-driven reductions in tubular water content due to tubular dysfunction and renal functional impairment. CONCLUSIONS: Functional MRI is a valuable non-invasive technique for monitoring inflammation, tissue edema and tubular function. It permits on to differentiate between acute rejection and ischemic renal injury in a mouse model of ktx.