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Methods in Molecular Biology (Clifton,... 2021The kidney is a complex organ involved in the excretion of metabolic products as well as the regulation of body fluids, osmolarity, and homeostatic status. These...
The kidney is a complex organ involved in the excretion of metabolic products as well as the regulation of body fluids, osmolarity, and homeostatic status. These functions are influenced in large part by alterations in the regional distribution of blood flow between the renal cortex and medulla. Renal perfusion is therefore a key determinant of glomerular filtration. Therefore the quantification of regional renal perfusion could provide important insights into renal function and renal (patho)physiology. Arterial spin labeling (ASL) based perfusion MRI techniques, can offer a noninvasive and reproducible way of measuring renal perfusion in animal models. This chapter addresses the basic concept of ASL-MRI.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This introduction chapter is complemented by two separate chapters describing the experimental procedure and data analysis.
Topics: Animals; Arteries; Biomarkers; Blood Flow Velocity; Contrast Media; Diffusion Magnetic Resonance Imaging; Humans; Image Enhancement; Image Processing, Computer-Assisted; Kidney; Monitoring, Physiologic; Perfusion; Renal Circulation; Software; Spin Labels
PubMed: 33476003
DOI: 10.1007/978-1-0716-0978-1_13 -
PloS One 2022Blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) can measure deoxyhemoglobin content. This study aims to evaluate the capacity of BOLD-MRI, which is...
AIM
Blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) can measure deoxyhemoglobin content. This study aims to evaluate the capacity of BOLD-MRI, which is possible to evaluate the oxygenation state of kidneys with renal artery stenosis (RAS).
MATERIALS AND METHODS
We performed BOLD-MRI for 40 patients with RAS and for 30 healthy volunteers. We then performed post-scan processing and analysis of manually drawn regions of interest to determine R2* values (relaxation rates) for the renal cortex and medulla. We compared R2* values in patients with RAS with those in the control group, and also compared these values for subgroups with varying degrees of stenosis.
RESULTS
Medulla R2* values were higher than cortex R2* values in the control group. There was no significant difference in R2* values for different segments (upper, middle, lower) of the kidneys. Both cortex and medulla R2* values in patients with RAS were significantly higher than corresponding R2* values in the control group (P < 0.05), and BOLD-MRI was more sensitive to changes in the R2* values in the medulla than in the cortex. Among different subgroups in the RAS group, the medulla R2* values were significantly higher in kidneys with severe stenosis than in those with no obvious obstruction, mild stenosis, or moderate stenosis (P < 0.05).
CONCLUSION
BOLD-MRI is an effective, noninvasive method for evaluating kidney oxygenation, which is important for proper treatment in RAS. It is sufficiently sensitive for detecting medulla ischemia and anoxia of the kidneys.
Topics: Constriction, Pathologic; Female; Humans; Kidney; Magnetic Resonance Imaging; Male; Oxygen; Renal Artery Obstruction
PubMed: 35271618
DOI: 10.1371/journal.pone.0264630 -
Journal of Veterinary Science Jul 2020Quantitative evaluation of renal cortical echogenicity (RCE) has been tried and developed in human and veterinary medicine.
BACKGROUND
Quantitative evaluation of renal cortical echogenicity (RCE) has been tried and developed in human and veterinary medicine.
OBJECTIVES
The objective of this study was to propose a method for evaluating RCE quantitatively and intuitively, and to determine associations between ultrasonographic renal structural distinction and estimated glomerular filtration rate (eGFR) in canine chronic kidney disease (CKD).
METHODS
Data were collected on 63 dogs, including 27 with normal kidney function and 36 CKD patients. Symmetric dimethylarginine and creatinine concentrations were measured for calculating eGFR. RCE was evaluated as 3 grades on ultrasonography images according to the distinction between the renal cortex and outer medulla. The RCE grade of each kidney was measured.
RESULTS
There was a significant difference in eGFR between the group normal and CKD ( < 0.001). As mean of RCE grades (the mean values of each right and left kidney's RCE grade) increases, the proportion of group CKD among the patients in each grade increases ( < 0.001). Also, severity of RCE (classified as "high" if any right or left kidney evaluated as RCE grade 3, "low" otherwise) and eGFR is good indicator for predicting group CKD ( < 0.001).
CONCLUSIONS
The degree of distinction between the renal cortex and the outer medulla is closely related to renal function including eGFR and the RCE grade defined in this study can be used as a method of objectively evaluating RCE.
Topics: Animals; Dog Diseases; Dogs; Glomerular Filtration Rate; Kidney Cortex; Kidney Medulla; Renal Insufficiency, Chronic; Ultrasonography
PubMed: 32735096
DOI: 10.4142/jvs.2020.21.e58 -
Magnetic Resonance in Medicine Mar 2020Renal function is characterized by concentration of urea for removal in urine. We tested urea as a CEST-MRI contrast agent for measurement of the concentrating capacity...
PURPOSE
Renal function is characterized by concentration of urea for removal in urine. We tested urea as a CEST-MRI contrast agent for measurement of the concentrating capacity of distinct renal anatomical regions.
METHODS
The CEST contrast of urea was examined using phantoms with different concentrations and pH levels. Ten C57BL/6J mice were scanned twice at 7 T, once following intraperitoneal injection of 2M 150 µL urea and separately following an identical volume of saline. Kidneys were segmented into regions encompassing the cortex, outer medulla, and inner medulla and papilla to monitor spatially varying urea concentration. Z-spectra were acquired before and 20 minutes after injection, with dynamic scanning of urea handling performed in between via serial acquisition of CEST images acquired following saturation at +1 ppm.
RESULTS
Phantom experiments revealed concentration and pH-dependent CEST contrast of urea that was both acid- and base-catalyzed. Z-spectra acquired before injection showed significantly higher CEST contrast in the inner medulla and papilla (2.3% ± 1.9%) compared with the cortex (0.15% ± 0.75%, P = .011) and outer medulla (0.12% ± 0.58%, P = .008). Urea infusion increased CEST contrast in the inner medulla and papilla by 2.1% ± 1.9% (absolute), whereas saline infusion decreased CEST contrast by -0.5% ± 2.0% (absolute, P = .028 versus urea). Dynamic scanning revealed that thermal drift and diuretic status are confounding factors.
CONCLUSION
Urea CEST has a potential of monitoring renal function by capturing the spatially varying urea concentrating ability of the kidneys.
Topics: Algorithms; Animals; Contrast Media; Female; Humans; Hydrogen-Ion Concentration; Image Interpretation, Computer-Assisted; Image Processing, Computer-Assisted; Kidney; Kidney Cortex; Kidney Function Tests; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Normal Distribution; Phantoms, Imaging; Reproducibility of Results; Urea
PubMed: 31483529
DOI: 10.1002/mrm.27968 -
Cellular Physiology and Biochemistry :... Oct 2022Acute kidney injury (AKI) carries high morbidity and mortality, and the inducible nitric oxide synthase (iNOS) is a potential molecular target to prevent kidney...
BACKGROUND/AIMS
Acute kidney injury (AKI) carries high morbidity and mortality, and the inducible nitric oxide synthase (iNOS) is a potential molecular target to prevent kidney dysfunction. In previous work, we reported that the pharmacological inhibitions of iNOS before ischemia/reperfusion (I/R) attenuate the I/R-induced AKI in mice. Here, we study the iNOS inhibitor 1400W [N-(3-(Aminomethyl)benzyl] acetamide, which has been described to be much more specific to iNOS inhibition than other compounds.
METHODS
We used 30 minutes of bilateral renal ischemia, followed by 24 hours of reperfusion in Balb/c mice. 1400w (10 mg/kg i.p) was applied before I/R injury. We measured the expression of elements associated with kidney injury, inflammation, macrophage polarization, mesenchymal transition, and nephrogenic genes by qRT-PCR in the renal cortex and medulla. The Periodic Acid-Schiff (PAS) was used to study the kidney morphology.
RESULTS
Remarkably, we found that 1400W affects the renal cortex and medulla in different ways. Thus, in the renal cortex, 1400W prevented the I/R-upregulation of 1. NGAL, Clusterin, and signs of morphological damage; 2. IL-6 and TNF-α; 3. TGF-β; 4. M2(Arg1, Erg2, cMyc) and M1(CD38, Fpr2) macrophage polarization makers; and 5. Vimentin and FGF2 levels but not in the renal medulla.
CONCLUSION
1400W conferred protection in the kidney cortex compared to the kidney medulla. The present investigation provides relevant information to understand the opportunity to use 1400W as a therapeutic approach in AKI treatment.
Topics: Animals; Mice; Acetamides; Acute Kidney Injury; Clusterin; Disease Models, Animal; Fibroblast Growth Factor 2; Interleukin-6; Ischemia; Kidney; Kidney Cortex; Lipocalin-2; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Reperfusion Injury; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vimentin
PubMed: 36259161
DOI: 10.33594/000000577 -
Current Medical Science Dec 2022The aim of this study was to explore the effect of norepinephrine (NE) on renal cortical and medullary blood flow in atherosclerotic rabbits without renal artery...
OBJECTIVE
The aim of this study was to explore the effect of norepinephrine (NE) on renal cortical and medullary blood flow in atherosclerotic rabbits without renal artery stenosis.
METHODS
Atherosclerosis was induced in 21 New Zealand white rabbits by feeding them a cholesterol-rich diet for 16 weeks. Thirteen healthy New Zealand white rabbits were randomly selected as controls. After atherosclerosis induction, standard ultrasonography was performed to confirm that there was no plaque or accelerated flow at the origin of the renal artery. Contrast-enhanced ultrasound (CEUS) was performed at baseline and during intravenous injection of NE. The degree of contrast enhancement of renal cortex and medulla after the injection of contrast agents was quantified by calculating the enhanced intensity.
RESULTS
The serum nitric oxide (NO) level in atherosclerotic rabbits was higher than that in healthy rabbits (299.6±152 vs. 136.5±49.5, P<0.001). The infusion of NE induced a significant increase in the systolic blood pressure (112±14 mmHg vs. 84±9 mmHg, P=0.016) and a significant decrease in the enhanced intensity in renal cortex (17.78±2.07 dB vs. 21.19±2.03 dB, P<0.001) and renal medulla (14.87±1.82 dB vs. 17.14±1.89 dB, P<0.001) during CEUS. However, the enhanced intensity in the cortex and medulla of healthy rabbits after NE infusion showed no significant difference from that at baseline.
CONCLUSION
NE may reduce renal cortical and medullary blood flow in atherosclerotic rabbits without renal artery stenosis, partly by reducing the serum NO level.
Topics: Animals; Rabbits; Atherosclerosis; Hemodynamics; Kidney Cortex; Norepinephrine; Renal Artery Obstruction; Case-Control Studies
PubMed: 36083378
DOI: 10.1007/s11596-022-2626-0 -
Kidney360 Sep 2020Kidney tissue hypoxia is detected in various kidney diseases and is considered to play an important role in the pathophysiology of both AKI and CKD. Because of the... (Review)
Review
Kidney tissue hypoxia is detected in various kidney diseases and is considered to play an important role in the pathophysiology of both AKI and CKD. Because of the characteristic vascular architecture and high energy demand to drive tubular solute transport, the renal medulla is especially prone to hypoxia. Injured kidneys often present capillary rarefaction, inflammation, and fibrosis, which contribute to sustained kidney hypoxia, forming a vicious cycle promoting progressive CKD. Hypoxia-inducible factor (HIF), a transcription factor responsible for cellular adaptation to hypoxia, is generally considered to protect against AKI. On the contrary, consequences of sustained HIF activation in CKD may be either protective, neutral, or detrimental. The kidney outcomes seem to be affected by various factors, such as cell types in which HIF is activated/inhibited, disease models, balance between two HIF isoforms, and time and methods of intervention. This suggests multifaceted functions of HIF and highlights the importance of understanding its role within each specific context. Prolyl-hydroxylase domain (PHD) inhibitors, which act as HIF stabilizers, have been developed to treat anemia of CKD. Although many preclinical studies demonstrated renoprotective effects of PHD inhibitors in CKD models, there may be some situations in which they lead to deleterious effects. Further studies are needed to identify patients who would gain additional benefits from PHD inhibitors and those who may need to avoid them.
Topics: Biology; Humans; Hypoxia; Kidney; Oxygen; Renal Insufficiency, Chronic
PubMed: 35369554
DOI: 10.34067/KID.0001302020 -
Kidney International Apr 2024Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due...
Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.
Topics: Humans; Middle Aged; Nephritis, Interstitial; Amyloidosis; Mutation; Renal Insufficiency, Chronic; Apolipoproteins A
PubMed: 38096951
DOI: 10.1016/j.kint.2023.11.021 -
Quantitative Imaging in Medicine and... Sep 2023Acute kidney injury (AKI) is frequently found in deceased donors; however, few studies have reported the use of imaging to detect and identify this phenomenon. The...
BACKGROUND
Acute kidney injury (AKI) is frequently found in deceased donors; however, few studies have reported the use of imaging to detect and identify this phenomenon. The purpose of this study was to detect renal microcirculatory perfusion in brain-dead donors using contrast-enhanced ultrasonography (CEUS), investigate the value of CEUS in identifying AKI, and analyze the correlation between CEUS and preimplantation biopsy results and early post-transplant renal function of grafts.
METHODS
This prospective study recruited 94 kidneys from brain-dead donors (AKI =44, non-AKI =50) from August 2020 to November 2022. The inclusion criteria were age ≥18 years and brain death. The exclusion criteria encompassed donors maintained with extracorporeal membrane oxygenation (ECMO) and the presence of irregular kidney anatomy. The mean age of the donors was 45.1±10.4 [standard deviation (SD)] years, and the majority were male (86.2%). CEUS was performed prior to organ procurement, and time-intensity curves (TICs) were constructed. The time to peak (TTP) and peak intensity (PI) of kidney segmental artery (KA), kidney cortex (KC), and kidney medulla (KM) were calculated using TIC analysis.
RESULTS
Arrival time (AT) of KA (P<0.001) and TTP of kidney cortex (TTPKC) (P<0.001) of the non-AKI group were significantly shorter than those of the AKI group. The PI of the KA (P=0.003), KM (P=0.005), and kidney cortex (PIKC; P<0.001) of the non-AKI group were significantly higher than those of the AKI group. Multivariable logistic regression analysis showed that serum creatinine [odds ratio (OR) =1.06; 95% CI: 1.03-1.1; P<0.001], TTPKC (OR =1.38; 95% CI: 1.03-1.84; P=0.03), and PIKC (OR =0.95; 95% CI: 0.91-1; P=0.046) were the independent factors of AKI. The area under the receiver operating characteristic curve (AUC) for identifying AKI for TTPKC and PIKC was 0.73 and 0.71, respectively. TTPKC showed a weak correlation with interstitial fibrosis (r=0.23; P=0.03), PIKC showed a weak correlation with arterial intimal fibrosis ((r=-0.29; P=0.004) and arteriolar hyalinosis (r=-0.27; P=0.008), and PIKC showed the strongest correlation with eGFR on postoperative day 7 (r=-0.46; P=0.046) in the donor kidneys with AKI.
CONCLUSIONS
CEUS can be used to identify AKI in brain-dead donors. Furthermore, there is a correlation between CEUS-derived parameters and pretransplant biopsy results and early preimplantation renal function of grafts.
PubMed: 37711792
DOI: 10.21037/qims-23-207 -
Scientific Reports Dec 2021Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has become a massive global health burden. Despite considerable efforts, the underlying...
Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has become a massive global health burden. Despite considerable efforts, the underlying mechanisms have not yet been comprehensively understood. In this study, a systematic approach was utilized to identify the microRNA signature in DN and to introduce novel drug targets (DTs) in DN. Using microarray profiling followed by qPCR confirmation, 13 and 6 differentially expressed (DE) microRNAs were identified in the kidney cortex and medulla, respectively. The microRNA-target interaction networks for each anatomical compartment were constructed and central nodes were identified. Moreover, enrichment analysis was performed to identify key signaling pathways. To develop a strategy for DT prediction, the human proteome was annotated with 65 biochemical characteristics and 23 network topology parameters. Furthermore, all proteins targeted by at least one FDA-approved drug were identified. Next, mGMDH-AFS, a high-performance machine learning algorithm capable of tolerating massive imbalanced size of the classes, was developed to classify DT and non-DT proteins. The sensitivity, specificity, accuracy, and precision of the proposed method were 90%, 86%, 88%, and 89%, respectively. Moreover, it significantly outperformed the state-of-the-art (P-value ≤ 0.05) and showed very good diagnostic accuracy and high agreement between predicted and observed class labels. The cortex and medulla networks were then analyzed with this validated machine to identify potential DTs. Among the high-rank DT candidates are Egfr, Prkce, clic5, Kit, and Agtr1a which is a current well-known target in DN. In conclusion, a combination of experimental and computational approaches was exploited to provide a holistic insight into the disorder for introducing novel therapeutic targets.
Topics: Algorithms; Animals; Chemistry, Pharmaceutical; Cluster Analysis; Computational Biology; Diabetic Nephropathies; Drug Design; Epigenesis, Genetic; Gene Expression Profiling; Gene Regulatory Networks; Global Health; Humans; Kidney Cortex; Kidney Medulla; Linear Models; Machine Learning; Male; Mice; Mice, Inbred DBA; MicroRNAs; Microarray Analysis; Oligonucleotide Array Sequence Analysis; Principal Component Analysis; Regression Analysis; Signal Transduction; Support Vector Machine; Systems Biology
PubMed: 34873190
DOI: 10.1038/s41598-021-02282-3