-
Journal of Medical Case Reports Oct 2023Clopidogrel and ticagrelor are rarely reported to cause vasculitis via drug hypersensitivity reaction, largely mediated by T cells and immunoglobulin E (IgE). Despite... (Review)
Review
BACKGROUND
Clopidogrel and ticagrelor are rarely reported to cause vasculitis via drug hypersensitivity reaction, largely mediated by T cells and immunoglobulin E (IgE). Despite therapeutic advances, the etiology of refractory vasculitides remains incompletely understood. Recently, (non)immunological mechanisms bypassing T cells and IgE have been proposed to explain resistance to standard immunosuppressants. Herein, we report a case of refractory drug-induced systemic small-vessel vasculitis with varied extracutaneous manifestations and incorporate multiple sources of data to provide detailed accounts of complex (non)immunological phenomena involved in this case. Study objectives are to provide an insight about rare presentations of commonly used drugs, upgrade the pathophysiological concepts of drug-induced vasculitis, raise need for further investigation to define causes and risk factors for refractory vasculitis, and discuss most of the current knowledge suggesting novel therapeutic approaches to treat this vasculitis. To our knowledge, this is the first case of the two flares of systemic small-vessel vasculitis in a single patient in response to clopidogrel and ticagrelor exposure, respectively. However, this report is limited by attribution/observer bias.
CASE PRESENTATION
We herein report a 24-year-old Caucasian male student with a medical history of mild seasonal allergic rhinoconjunctivitis, tension-type headaches, posttraumatic arterial stenosis, and previous exposure to ibuprofen, acetylsalicylic acid, and mRNA coronavirus disease 2019 (COVID-19) vaccine who suffered largely from acute urticaria and dyspnea after 20 days of acetylsalicylic acid and clopidogrel introduction. A skin punch biopsy confirmed leukocytoclastic vasculitis. Serologic antibody testing, complement analysis, microbiologic testing, and cancer biomarkers revealed no abnormalities. Regarding the patient's medical history, both acetylsalicylic acid and clopidogrel were exchanged for ticagrelor. Furthermore, the addition of naproxen, cyclosporine, bilastine, prednisolone, and montelukast resulted in complete recovery. After 7 days, diarrhea and hematuria occurred. Urinalysis and computed tomography showed reversible proteinuria with gross hematuria and hypodense changes in kidney medulla, respectively, associated with discontinuation of ticagrelor and naproxen. In addition, the patient recovered completely without any immunosuppression up-titration.
CONCLUSIONS
This case highlights the role of clopidogrel and ticagrelor as possible triggering agents for systemic small-vessel vasculitis and offers an insight into novel therapeutic strategies for refractory vasculitides. Further research is needed to build on the findings of a current report.
Topics: Humans; Male; Young Adult; Aspirin; Clopidogrel; Hematuria; Immunoglobulin E; Naproxen; Ticagrelor; Vasculitis
PubMed: 37885023
DOI: 10.1186/s13256-023-04174-8 -
Frontiers in Physiology 2023Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present...
Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, C-acetoacetate (C-AcAc), in the heart and kidney compared to C-acetate (C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of C-Ac was higher compared to C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with C-Ac. This suggests an equilibrium of C-AcAc with the other ketone, C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of C-AcAc is different compared to C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs.
PubMed: 37869718
DOI: 10.3389/fphys.2023.1280191 -
Diabetes Jan 2024In contrast to the well-defined biological feedback loops controlling glucose, the mechanisms by which the body responds to changes in fatty acid availability are less...
UNLABELLED
In contrast to the well-defined biological feedback loops controlling glucose, the mechanisms by which the body responds to changes in fatty acid availability are less clearly defined. Growth differentiating factor 15 (GDF15) suppresses the consumption of diets high in fat but is paradoxically increased in obese mice fed a high-fat diet. Given this interrelationship, we investigated whether diets high in fat could directly increase GDF15 independently of obesity. We found that fatty acids increase GDF15 levels dose dependently, with the greatest response observed with linolenic acid. GDF15 mRNA expression was modestly increased in the gastrointestinal tract; however, kidney GDF15 mRNA was ∼1,000-fold higher and was increased by more than threefold, with subsequent RNAscope analysis showing elevated expression within the cortex and outer medulla. Treatment of wild-type mice with linolenic acid reduced food intake and body mass; however, this effect disappeared in mice lacking the GDF15 receptor GFRAL. An equal caloric load of glucose did not suppress food intake or reduce body mass in either wild-type or GFRAL-knockout mice. These data indicate that fatty acids such as linolenic acid increase GDF15 and suppress food intake through a mechanism requiring GFRAL. These data suggest that a primary physiological function of GDF15 may be as a fatty acid sensor designed to protect cells from fatty acid overload.
ARTICLE HIGHLIGHTS
The mechanisms by which the body responds to changes in fatty acid availability are less clearly defined. We investigated whether diets high in fat could directly increase growth differentiating factor 15 (GDF15) independently of obesity. Fatty acids increase GDF15 and reduce food intake through a GFRAL signaling axis. GDF15 is a sensor of fatty acids that may have important implications for explaining increased satiety after consumption of diets high in fat.
Topics: Animals; Mice; Eating; Fatty Acids; Glucose; Linolenic Acids; Mice, Knockout; Obesity; RNA, Messenger
PubMed: 37847913
DOI: 10.2337/db23-0495 -
Frontiers in Medicine 2023Xp11.2 translocation/TFE3 gene fusion associated with renal cell carcinoma (Xp11.2 RCC) exhibits unique biological characteristics and is associated with an increased...
BACKGROUND
Xp11.2 translocation/TFE3 gene fusion associated with renal cell carcinoma (Xp11.2 RCC) exhibits unique biological characteristics and is associated with an increased incidence of tumor thrombosis, lymph node metastasis, and advanced disease stages. Multimodality imaging, including US, contrast-enhanced CT, multi-parametric MRI, and F-FDG PET/CT plays a crucial role in the preoperative diagnosis and differentiation of renal tumors.
CASE REPORT
A 15-year-old female presented with lumbar pain worsened, and developed persistent painless hematuria. The CT attenuation values of the scan without contrast, corticomedullary phase, nephrographic phase, and delayed phases were 35 HU, 83 HU, 82 HU, and 75 HU, respectively. The solid component of the mass displayed heterogeneous marked enhancement. Furthermore, MRU indicated that the lesion involved the cortical medulla and infringed on the renal sinus fat. The lesion appeared isosignal in T1WI, slightly low signal in T2WI, and slightly high signal in DWI. The degree of enhancement in the three phases of enhancement scan was lower than that in the renal parenchyma, and hemorrhage and necrosis were observed within the internal part of the lesion. To further clarify the staging, the patient underwent F-FDG PET/CT. PET/CT images showed multiple irregular occupancies in the right kidney with unclear borders, showing a heterogeneous increase in F-FDG uptake, with SUVmax values ranging from 2.3 to 5.2 in the routine imaging phase (60 min post-injection), compared to SUVmax values ranging from 2.8 to 6.9 in the delayed imaging phase (160 min post-injection). Additionally, multiple enlarged and fused lymph nodes were observed in the medial part of the right kidney and the retroperitoneum, exhibiting a heterogeneous increase in F-FDG uptake, with SUVmax values ranging from 4.1 to 8.7 in the routine imaging phase, compared to SUVmax values ranging from 4.4 to 9.1 in the delayed imaging phase. The postoperative pathology, immunohistochemistry, and molecular analysis of histiocytes were consistent with a diagnosis of Xp11.2 RCC. One month after surgery, enhanced-CT examination of the patient revealed lung metastasis, peritoneal metastasis, and multiple lymph node metastases throughout the body, with an overall survival of 16 months.
CONCLUSION
Xp11.2 RCC exhibits unique biological characteristics and is associated with an increased incidence of tumor thrombosis, lymph node metastasis, and advanced disease stages. Long-term follow-up is essential to monitor the likelihood of recurrence and metastasis. F-FDG PET/CT examination can comprehensively visualize the lesion's location and extent, providing a basis for clinical tumor staging and aiding in treatment monitoring and follow-up. To address the limitations of FDG, the utilization of specific tracers designed for RCC or tracers that are not excreted via the urinary system would be ideal. Further advancements in molecular imaging technologies and the development of novel tracers hold great promise in advancing the diagnosis and management of RCC, ultimately contributing to better patient outcomes and overall disease management.
PubMed: 37795411
DOI: 10.3389/fmed.2023.1266630 -
Magnetic Resonance Imaging Dec 2023Accurate segmentation of renal tissues is an essential step for renal perfusion estimation and postoperative assessment of the allograft. Images are usually manually...
Accurate segmentation of renal tissues is an essential step for renal perfusion estimation and postoperative assessment of the allograft. Images are usually manually labeled, which is tedious and prone to human error. We present an image analysis method for the automatic estimation of renal perfusion based on perfusion magnetic resonance imaging. Specifically, non-contrasted pseudo-continuous arterial spin labeling (PCASL) images are used for kidney transplant evaluation and perfusion estimation, as a biomarker of the status of the allograft. The proposed method uses machine/deep learning tools for the segmentation and classification of renal cortical and medullary tissues and automates the estimation of perfusion values. Data from 16 transplant patients has been used for the experiments. The automatic analysis of differentiated tissues within the kidney, such as cortex and medulla, is performed by employing the time-intensity-curves of non-contrasted T-weighted MRI series. Specifically, using the Dice similarity coefficient as a figure of merit, results above 93%, 92% and 82% are obtained for whole kidney, cortex, and medulla, respectively. Besides, estimated cortical and medullary perfusion values are considered to be within the acceptable ranges within clinical practice.
Topics: Humans; Spin Labels; Deep Learning; Kidney Transplantation; Kidney; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Female; Male; Adult; Middle Aged; Renal Circulation; Perfusion
PubMed: 37776961
DOI: 10.1016/j.mri.2023.09.007 -
Theranostics 2023Mesoscopic visualization of the main anatomical structures of the whole kidney plays an important role in the pathological diagnosis and exploration of the etiology of...
Mesoscopic visualization of the main anatomical structures of the whole kidney plays an important role in the pathological diagnosis and exploration of the etiology of hydronephrosis. However, traditional imaging methods cannot achieve whole-kidney imaging with micron resolution under conditions representing perfusion. We used cryofixation (IVCF) to fix acute obstructive hydronephrosis (unilateral ureteral obstruction, UUO), chronic spontaneous hydronephrosis (db/db mice), and their control mouse kidneys for cryo-micro-optical sectioning tomography (cryo-MOST) autofluorescence imaging. We quantitatively assessed the kidney-wide pathological changes in the main anatomical structures, including hydronephrosis, renal subregions, arteries, veins, glomeruli, renal tubules, and peritubular functional capillaries. By comparison with microcomputed tomography imaging, we confirmed that IVCF can maintain the status of the kidney . Cryo-MOST autofluorescence imaging can display the main renal anatomical structures with a cellular resolution without contrast agents. The hydronephrosis volume reached 26.11 ± 6.00 mm and 13.01 ± 3.74 mm in 3 days after UUO and in 15-week-old db/db mouse kidneys, respectively. The volume of the cortex and inner stripe of the outer medulla (ISOM) increased while that of the inner medulla (IM) decreased in UUO mouse kidneys. Db/db mice also showed an increase in the volume of the cortex and ISOM volume but no atrophy in the IM. The diameter of the proximal convoluted tubule and proximal straight tubule increased in both UUO and db/db mouse kidneys, indicating that proximal tubules were damaged. However, some renal tubules showed abnormal central bulge highlighting in the UUO mice, but the morphology of renal tubules was normal in the db/db mice, suggesting differences in the pathology and severity of hydronephrosis between the two models. UUO mouse kidneys also showed vascular damage, including segmental artery and vein atrophy and arcuate vein dilation, and the density of peritubular functional capillaries in the cortex and IM was reduced by 37.2% and 49.5%, respectively, suggesting renal hypoxia. In contrast, db/db mouse kidneys showed a normal vascular morphology and peritubular functional capillary density. Finally, we found that the db/db mice displayed vesicoureteral reflux and bladder overactivity, which may be the cause of hydronephrosis formation. We observed and compared main renal structural changes in hydronephrosis under conditions representing perfusion in UUO, db/db, and control mice through cryo-MOST autofluorescence imaging. The results indicate that cryo-MOST with IVCF can serve as a simple and powerful tool to quantitatively evaluate the pathological changes in three dimensions, especially the distribution of body fluids in the whole kidney. This method is potentially applicable to the three-dimensional visualization of other tissues, organs, and even the whole body, which may provide new insights into pathological changes in diseases.
Topics: Mice; Animals; Kidney Cortex; X-Ray Microtomography; Imaging, Three-Dimensional; Kidney; Hydronephrosis; Ureteral Obstruction; Tomography, Optical
PubMed: 37771780
DOI: 10.7150/thno.86695 -
Analytical Chemistry Oct 2023Detection of small molecule metabolites (SMM), particularly those involved in energy metabolism using MALDI-mass spectrometry imaging (MSI), is challenging due to...
Detection of small molecule metabolites (SMM), particularly those involved in energy metabolism using MALDI-mass spectrometry imaging (MSI), is challenging due to factors including ion suppression from other analytes present (e.g., proteins and lipids). One potential solution to enhance SMM detection is to remove analytes that cause ion suppression from tissue sections before matrix deposition through solvent washes. Here, we systematically investigated solvent treatment conditions to improve SMM signal and preserve metabolite localization. Washing with acidic methanol significantly enhances the detection of phosphate-containing metabolites involved in energy metabolism. The improved detection is due to removing lipids and highly polar metabolites that cause ion suppression and denaturing proteins that release bound phosphate-containing metabolites. Stable isotope infusions of [C]nicotinamide coupled to MALDI-MSI ("Iso-imaging") in the kidney reveal patterns that indicate blood vessels, medulla, outer stripe, and cortex. We also observed different ATP:ADP raw signals across mouse kidney regions, consistent with regional differences in glucose metabolism favoring either gluconeogenesis or glycolysis. In mouse muscle, Iso-imaging using [C]glucose shows high glycolytic flux from infused circulating glucose in type 1 and 2a fibers (soleus) and relatively lower glycolytic flux in type 2b fiber type (gastrocnemius). Thus, improved detection of phosphate-containing metabolites due to acidic methanol treatment combined with isotope tracing provides an improved way to probe energy metabolism with spatial resolution .
Topics: Mice; Animals; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Methanol; Glycolysis; Glucose; Lipids; Solvents; Isotopes; Phosphates; Lasers
PubMed: 37756255
DOI: 10.1021/acs.analchem.3c01875 -
Frontiers in Cell and Developmental... 2023Kidney formation and nephrogenesis are controlled by precise spatiotemporal gene expression programs, which are coordinately regulated by cell-cycle, cell type-specific...
Kidney formation and nephrogenesis are controlled by precise spatiotemporal gene expression programs, which are coordinately regulated by cell-cycle, cell type-specific transcription factors and epigenetic/chromatin regulators. However, the roles of epigenetic/chromatin regulators in kidney development and disease remain poorly understood. In this study, we investigated the impact of deleting the chromatin remodeling factor , a human Wilms tumor-associated gene, in -expressing cells. deficiency led to severe tubular defects and a shortened medulla. Through unbiased single-cell RNA sequencing analyses, we identified multiple types of -labeled interstitial cells, along with nephron-related cells. deficiency increased interstitial cells but markedly reduced tubular cells, resulting in cells with mixed identity and elevated expression of cell-cycle regulators and genes associated with extracellular matrix and epithelial-to-mesenchymal transition/fibrosis. We found that loss induced a significant upregulation of the oncogene and hyperproliferation of -labeled cells. These changes in the cellular state could hinder the cellular transition into characteristic tubular structures, eventually leading to fibrosis. In conclusion, our findings shed light on novel cell types and genes associated with -labeled cells and highlight the critical role of Smarca4 in regulating tubular cell differentiation and the expression of the cancer-causing gene in the kidney. These findings may provide valuable insights into potential therapeutic strategies for renal cell carcinoma resulting from deficiency.
PubMed: 37727504
DOI: 10.3389/fcell.2023.1233317 -
Ultrasonography (Seoul, Korea) Oct 2023The aim of this study was to quantify renal microcirculatory perfusion in braindead donors using contrast-enhanced ultrasonography (CEUS), and to establish an accurate,...
PURPOSE
The aim of this study was to quantify renal microcirculatory perfusion in braindead donors using contrast-enhanced ultrasonography (CEUS), and to establish an accurate, noninvasive, and convenient index for predicting delayed graft function (DGF) post-transplantation.
METHODS
In total, 90 brain-dead donor kidneys (training group, n=60; validation group, n=30) examined between August 2020 and November 2022 were recruited in this prospective study. CEUS was performed on the kidneys of brain-dead donors 24 hours before organ procurement and time-intensity curves were constructed. The main measures were arrival time, time to peak, and peak intensity of the kidney segmental arteries, cortex, and medulla. Recipients were divided into DGF and non-DGF groups according to early post-transplant graft function. The area under the receiver operating characteristic curve (AUC) was used to assess diagnostic performance.
RESULTS
The arrival time of the kidney segmental artery and cortex and the time interval between the time to peak of the segmental artery and cortex were identified as independent factors associated with DGF by multivariate stepwise regression analysis. A new index for the joint prediction model of three variables, the contrast-enhanced ultrasonography/Kidney Donor Profile index (CEUS-KDPI), was developed. CEUS-KDPI showed high accuracy for predicting DGF (training group: AUC, 0.91; sensitivity, 90.5%; specificity, 92.3%; validation group: AUC, 0.84; sensitivity, 75.0%; specificity, 92.3%).
CONCLUSION
CEUS-KDPI accurately predicted DGF after kidney transplantation. CEUS may be a potential noninvasive tool for bedside examinations before organ procurement and may be used to predict early renal function after kidney transplants kidneys from donors after brain death.
PubMed: 37722724
DOI: 10.14366/usg.23006