ABSTRACT
BACKGROUND: Percutaneous-transluminal renal angioplasty (PTRA) and stenting aim to halt the progression of kidney disease in patients with renal artery stenosis (RAS), but its outcome is often suboptimal. We hypothesized that a model incorporating markers of renal function and oxygenation extracted using radiomics analysis of blood oxygenation-level dependent (BOLD)-MRI images may predict renal response to PTRA in swine RAS. MATERIALS AND METHODS: Twenty domestic pigs with RAS were scanned with CT and BOLD MRI before and 4 weeks after PTRA. Stenotic (STK) and contralateral (CLK) kidney volume, blood flow (RBF), and glomerular filtration rate (GFR) were determined, and BOLD-MRI R2 * maps were generated before and after administration of furosemide, a tubular reabsorption inhibitor. Radiomics features were extracted from pre-PTRA BOLD maps and Robust features were determined by Intraclass correlation coefficients (ICC). Prognostic models were developed to predict post-PTRA renal function based on the baseline functional and BOLD-radiomics features, using Lasso-regression for training, and testing with resampling. RESULTS: Twenty-six radiomics features passed the robustness test. STK oxygenation distribution pattern did not respond to furosemide, whereas in the CLK radiomics features sensitive to oxygenation heterogeneity declined. Radiomics-based model predictions of post-PTRA GFR (r = 0.58, p = 0.007) and RBF (r = 0.68; p = 0.001) correlated with actual measurements with sensitivity and specificity of 92% and 67%, respectively. Models were unsuccessful in predicting post-PTRA systemic measures of renal function. CONCLUSIONS: Several radiomics features are sensitive to cortical oxygenation patterns and permit estimation of post-PTRA renal function, thereby distinguishing subjects likely to respond to PTRA and stenting.
Subject(s)
Disease Models, Animal , Glomerular Filtration Rate , Magnetic Resonance Imaging , Predictive Value of Tests , Renal Artery Obstruction , Renal Circulation , Stents , Sus scrofa , Renal Artery Obstruction/physiopathology , Renal Artery Obstruction/diagnostic imaging , Renal Artery Obstruction/therapy , Animals , Oxygen/blood , Time Factors , Kidney Cortex/diagnostic imaging , Kidney Cortex/blood supply , Kidney Cortex/physiopathology , Kidney Cortex/metabolism , Furosemide/administration & dosage , Angioplasty, Balloon/instrumentation , Renal Artery/diagnostic imaging , Renal Artery/physiopathology , Female , Male , Diuretics , Image Interpretation, Computer-Assisted , Treatment Outcome , RadiomicsABSTRACT
BACKGROUND The thyroid state significantly influences renal function. However, a direct link between thyroid and kidney dysfunction has not been identified. Thyroid hormones affect cardiac output and vascular resistance, and thus can modify kidney perfusion. This prospective study aimed to test the association between renal cortical perfusion (RCP) estimated in color Doppler sonographic dynamic tissue perfusion measurement (DTPM) with thyroid hormones in 36 patients treated with levothyroxine following total thyroidectomy for resectable thyroid cancer. MATERIAL AND METHODS Blood tests, blood pressure monitoring, and DTPM of the renal cortex were performed. To exclude possible reading errors, the intrarater reliability of the ultrasound perfusion measurement method was estimated. RESULTS The absolute difference between the 2 ultrasound RCP measurements was 5.2±4.4%. RCP correlated significantly with free thyroxine (FT4) (r=0.46; p=0.006) but not with triiodothyronine and thyroid-stimulating hormone. In the adjusted to age backward stepwise multivariable regression analysis model, including estimated glomerular filtration rate, mean arterial pressure, and FT4, only FT4 was independently associated with RCP (R²=0.21; p=0.006). CONCLUSIONS Renal cortical perfusion is independently associated with free thyroxine, which can contribute to renal function abnormalities in the condition of impaired thyroid function. This small prospective study from a single center showed that the renal cortex's color Doppler sonographic dynamic tissue perfusion measurement had very good intraobserver reproducibility.
Subject(s)
Kidney Cortex/diagnostic imaging , Perfusion Imaging/methods , Postoperative Complications/diagnosis , Renal Insufficiency/diagnosis , Thyroid Neoplasms/surgery , Thyroxine/blood , Adolescent , Adult , Feasibility Studies , Female , Glomerular Filtration Rate/physiology , Humans , Kidney Cortex/physiopathology , Male , Middle Aged , Observer Variation , Postoperative Complications/blood , Postoperative Complications/etiology , Postoperative Complications/physiopathology , Prospective Studies , Renal Insufficiency/blood , Renal Insufficiency/etiology , Renal Insufficiency/physiopathology , Reproducibility of Results , Thyroid Function Tests , Thyroid Neoplasms/complications , Thyroidectomy/adverse effects , Thyroxine/administration & dosage , Ultrasonography, Doppler, Color , Young AdultABSTRACT
BACKGROUND: Chronic allograft injury (CAI) is a significant reason for which many grafts were lost. The study was conducted to assess the usefulness of diffusional kurtosis imaging (DKI) technology in the non-invasive assessment of CAI. METHODS: Between February 2019 and October 2019, 110 renal allograft recipients were included to analyze relevant DKI parameters. According to estimated glomerular filtration rate (eGFR) (mL/min/ 1.73 m2) level, they were divided to 3 groups: group 1, eGFR ≥ 60 (n = 10); group 2, eGFR 30-60 (n = 69); group 3, eGFR < 30 (n = 31). We performed DKI on a clinical 3T magnetic resonance imaging system. We measured the area of interest to determine the mean kurtosis (MK), mean diffusivity (MD), and apparent diffusion coefficient (ADC) of the renal cortex and medulla. We performed a Pearson correlation analysis to determine the relationship between eGFR and the DKI parameters. We used the receiver operating characteristic curve to estimate the predicted values of DKI parameters in the CAI evaluation. We randomly selected five patients from group 2 for biopsy to confirm CAI. RESULTS: With the increase of creatinine, ADC, and MD of the cortex and medulla decrease, MK of the cortex and medulla gradually increase. Among the three different eGFR groups, significant differences were found in cortical and medullary MK (P = 0.039, P < 0.001, P < 0.001, respectively). Cortical and medullary ADC and MD are negatively correlated with eGFR (r = - 0.49, - 0.44, - 0.57, - 0.57, respectively; P < 0.001), while cortical and medullary MK are positively correlated with eGFR (r = 0.42, 0.38; P < 0.001). When 0.491 was set as the cutoff value, MK's CAI assessment showed 87% sensitivity and 100% specificity. All five patients randomly selected for biopsy from the second group confirmed glomerulosclerosis and tubular atrophy/interstitial fibrosis. CONCLUSION: The DKI technique is related to eGFR as allograft injury progresses and is expected to become a potential non-invasive method for evaluating CAI.
Subject(s)
Diffusion Magnetic Resonance Imaging/methods , Glomerular Filtration Rate/physiology , Kidney Transplantation , Kidney/diagnostic imaging , Adult , Allografts/diagnostic imaging , Allografts/injuries , Allografts/pathology , Allografts/physiopathology , Biopsy , Creatinine/metabolism , Female , Fibrosis/pathology , Fibrosis/physiopathology , Glomerulosclerosis, Focal Segmental/pathology , Glomerulosclerosis, Focal Segmental/physiopathology , Humans , Kidney/injuries , Kidney/pathology , Kidney/physiopathology , Kidney Cortex/diagnostic imaging , Kidney Cortex/physiopathology , Kidney Medulla/diagnostic imaging , Kidney Medulla/physiopathology , Kidney Tubules/pathology , Kidney Tubules/physiopathology , Male , Middle Aged , Prospective Studies , ROC Curve , Sensitivity and SpecificityABSTRACT
OBJECTIVES: To analyze the outcomes of patients in whom cortical (outer) renorrhaphy (CR) was omitted during robotic partial nephrectomy (RPN). METHODS: We analyzed 1453 patients undergoing RPN, from 2006 to 2018, within a large multi-institutional database. Patients having surgery for bilateral tumors (n = 73) were excluded. CR and no-CR groups were compared in terms of operative and ischemia time, estimated blood loss (EBL), complications, surgical margins, hospital stay, change in estimated glomerular filtration rate (eGFR), and need of angioembolization. Inverse probability of treatment weighting with Firth correction for center code was performed to account for selection bias. RESULTS: CR was omitted in 120 patients (8.7%); 1260 (91.3%) patients underwent both inner layer and CR. There was no difference in intraoperative complications (7.4% CR; 8.9% no-CR group; P = .6), postoperative major complications (1% and 2.8% in CR and no-CR groups, respectively; P = .2), or median drop in eGFR (7.3 vs 10.4 mL/min/m2). The no-CR group had a higher incidence of minor complications (26.7% vs 5.5% in CR group; P < .001). EBL was 100 mL (IQR 50-200) in both groups (P = .6). Angioembolization was needed in 0.7% patients in CR vs 1.4% in no-CR group (P = .4). Additionally, there was no difference in median operative time (168 vs 162 min; P = .2) or ischemia time (18 vs 17 min; P = .7). CONCLUSION: In selected patients with renal masses, single layer renorrhaphy does not significantly improve operative time, ischemia time, or eGFR after RPN. There is a higher incidence of minor complications, but not major perioperative complications after no-CR technique.
Subject(s)
Kidney Cortex/surgery , Kidney Neoplasms/surgery , Nephrectomy/methods , Postoperative Complications/epidemiology , Robotic Surgical Procedures/methods , Aged , Blood Loss, Surgical/statistics & numerical data , Female , Glomerular Filtration Rate/physiology , Humans , Incidence , Kidney Cortex/physiopathology , Male , Middle Aged , Nephrectomy/adverse effects , Operative Time , Postoperative Complications/etiology , Postoperative Complications/physiopathology , Robotic Surgical Procedures/adverse effects , Treatment OutcomeABSTRACT
Kidney regeneration could be classified into 2 groups: kidney generation and kidney repair. We have attempted in vivo nephron generation for kidney repair, as a therapy for chronic renal failure (CRF), by exploiting cellular interactions via conditioned media. In the previous report, we demonstrated the generation of rich nephrons in rat intact kidney cortices through percapsular injection of mesenchymal stem cell (MSC)-differentiated tubular epithelial cells (TECs) after pretreatment of 3-dimensional culture using a small amount of gel complex and condensed medium. In this study, to verify the amelioration of serum creatinine (sCr) levels by regenerated nephrons in rats with CRF, we first created damaged kidneys through systemic administration of adriamycin, and implanted the pretreated MSC-differentiated TECs into unilateral kidney cortices 2 weeks after adriamycin administration (A-2W, that is I-0W). After recovery of acute kidney injury, the control rats without cell implantation showed re-exacerbation of sCr levels, resulting in death within A-12W. Alternatively, the cell-implanted rats had a formation of mature nephrons in I-3W, and showed significant amelioration of sCr levels in I-7W. As a result, these rats could live until euthanization in I-12W or I-16W, indicating the utility of cell injection therapy into a kidney (K-CIT) for CRF. We expect that our K-CIT or the refined methods will be applied to patients with CRF.
Subject(s)
Creatinine/blood , Kidney Cortex/physiopathology , Kidney Failure, Chronic/therapy , Mesenchymal Stem Cell Transplantation , Nephrons/physiopathology , Animals , Cell Differentiation , Cell Line , Doxorubicin , Humans , Kidney Cortex/physiology , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/chemically induced , Kidney Failure, Chronic/physiopathology , Mesenchymal Stem Cells/cytology , Nephrons/physiology , Rats , RegenerationABSTRACT
Voltage-dependent anion channels (VDACs) constitute major transporters mediating bidirectional movement of solutes between cytoplasm and mitochondria. We aimed to determine if VDAC1 plays a role in recovery of mitochondrial and kidney functions after ischemia-induced acute kidney injury (AKI). Kidney function decreased after ischemia and recovered in wild-type (WT), but not in VDAC1-deficient mice. Mitochondrial maximum respiration, activities of respiratory complexes and FoF1-ATPase, and ATP content in renal cortex decreased after ischemia and recovered in WT mice. VDAC1 deletion reduced respiration and ATP content in non-injured kidneys. Further, VDAC1 deletion blocked return of activities of respiratory complexes and FoF1-ATPase, and recovery of respiration and ATP content after ischemia. Deletion of VDAC1 exacerbated ischemia-induced mitochondrial fission, but did not aggravate morphological damage to proximal tubules after ischemia. However, VDAC1 deficiency impaired recovery of kidney morphology and increased renal interstitial collagen accumulation. Thus, our data show a novel role for VDAC1 in regulating renal mitochondrial dynamics and recovery of mitochondrial function and ATP levels after AKI. We conclude that the presence of VDAC1 (1) stimulates capacity of renal mitochondria for respiration and ATP production, (2) reduces mitochondrial fission, (3) promotes recovery of mitochondrial function and dynamics, renal morphology, and kidney functions, and (4) increases survival after AKI.
Subject(s)
Acute Kidney Injury/metabolism , Gene Deletion , Kidney/pathology , Mitochondria/metabolism , Voltage-Dependent Anion Channel 1/metabolism , Acute Kidney Injury/pathology , Acute Kidney Injury/physiopathology , Adenosine Triphosphate/metabolism , Animals , Cell Respiration , Electron Transport , Ischemia/pathology , Ischemia/physiopathology , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Cortex/physiopathology , Kidney Function Tests , Mice , Mitochondrial Dynamics , Proton-Translocating ATPases/metabolism , Survival Analysis , Voltage-Dependent Anion Channel 1/deficiencyABSTRACT
BACKGROUND: Few studies examined the effect of long-acting nitrates on renal function in chronic heart failure (CHF). Thus, we aimed to investigate the effect of long-acting nitrate on the expression of adrenoceptors (AR) and angiotensin II receptor (ATR) subtypes of the renal cortex, in rats with myocardial infarction-induced CHF. METHODS: Rats were randomly divided into the following groups: control, sham-operated, CHF, low- and high-dose nitrate, positive drug control (olmesartan), and high-dose of long-acting nitrate + olmesartan. Ultrasound echocardiography markers were compared, and the levels of AR subtypes, AT1R, and AT2R were measured using reverse transcription-polymerase chain reaction and western blot analysis. Histopathology of the kidney was determined on hematoxylin and eosin-stained sections. RESULTS: CHF significantly increased plasma renin activity (PRA) and angiotensin II levels, upregulated AT1R expression and downregulated α1A-, ß1-, ß2-AR, and AT2R expression compared to the sham control. High-dose nitrate or olmesartan alone, and especially in combination, decreased the levels of PRA and angiotensin II and downregulated the CHF-induced expression of AT1R, α1A-, ß1-, and ß2-AR, and AT2R. CHF resulted in significant impairment of the renal tissue, including inflammatory cells infiltration to the tubular interstitium and surrounding the renal glomerulus, and tubular necrosis, which was alleviated in all treatment groups to different degrees. CONCLUSIONS: Long-acting nitrates could reverse CHF-induced changes in AR and ATR subtypes in the kidney, and improve cardiac function to protect renal function. Compared with monotherapy, the combination of nitrates and olmesartan shows more significant benefits in regulating AR and ATR subtypes.
Subject(s)
Heart Failure/drug therapy , Isosorbide Dinitrate/analogs & derivatives , Kidney Cortex/drug effects , Myocardial Infarction/complications , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Adrenergic, beta/metabolism , Receptors, Angiotensin/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Disease Models, Animal , Drug Therapy, Combination , Heart Failure/etiology , Heart Failure/metabolism , Heart Failure/physiopathology , Imidazoles/pharmacology , Isosorbide Dinitrate/pharmacology , Kidney Cortex/metabolism , Kidney Cortex/physiopathology , Male , Rats, Wistar , Receptors, Adrenergic, alpha-1/genetics , Receptors, Adrenergic, beta/genetics , Receptors, Angiotensin/genetics , Renin-Angiotensin System/drug effects , Tetrazoles/pharmacology , Time FactorsABSTRACT
GLUT9 is generally considered to be associated with the uric acid transport, which plays an important role in the regulation of serum uric acid level. In this study, the expression level of miR-143-3p was significantly decreased in hyperuricemia mice model group compared with the normal control by miRNA microarray, the same results were confirmed in the hyperuricemia patients and the healthy control group. It is predicted that GLUT9 may be the target gene of miR-143-3p by target scan and other net-software. GLUT9 as the downstream target gene of miR-143-3p was determinated by fluorescence enzyme activity assay. Western blotting and qRT-PCR indicated that the expression of GLUT9 in human renal tubular epithelial cells transfected with miR-143-3p mimics was significantly reduced. Meanwhile inflammatory factors IL-1ß and MCP-1 significantly decreased. In conclusion, miR-143-3p can reduce uric acid reabsorption by inhibiting its downstream target gene GLUT9.
Subject(s)
Glucose Transport Proteins, Facilitative/genetics , Hyperuricemia/genetics , Kidney Cortex/metabolism , MicroRNAs/genetics , Uric Acid/blood , Animals , Base Sequence , Case-Control Studies , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Disease Models, Animal , Gene Expression Regulation , Glucose Transport Proteins, Facilitative/metabolism , Humans , Hyperuricemia/blood , Hyperuricemia/chemically induced , Hyperuricemia/physiopathology , Hypoxanthine/administration & dosage , Inflammation , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Kidney Cortex/drug effects , Kidney Cortex/physiopathology , Male , Mice , Mice, Inbred C57BL , MicroRNAs/metabolism , Oligonucleotide Array Sequence Analysis , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Organic Cation Transport Proteins/genetics , Organic Cation Transport Proteins/metabolism , Oxonic Acid/administration & dosage , Renal Reabsorption/drug effects , Renal Reabsorption/physiology , Signal TransductionABSTRACT
Glucotoxicity (high levels of glucose) is a major factor in the pathogenesis of diabetic kidney disease. Cocoa has anti-diabetic effects by lowering glucose levels. However, whether cocoa exerts beneficial effects on the renal cortex glucose homeostasis and the molecular mechanisms responsible for this possible protective activity remain largely unknown. Thus, the potential anti-diabetic properties of cocoa on insulin signalling, glucose transporters and gluconeogenic enzymes were evaluated in the renal cortex of Zucker Diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker Lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed decreased body weight gain, glucose and insulin levels, improved glucose tolerance, insulin resistance and structural alterations in renal cortex. Moreover, cocoa-rich diet ameliorated insulin resistance by reverting decreased tyrosine-phosphorylated-insulin receptor levels and by preventing the inactivation of glycogen synthase kinase-3/glycogen synthase pathway (GSK-3/GS) in the renal cortex of ZDF-Co rats. Cocoa antihyperglycaemic effect also appeared to be mediated through the diminution of phosphoenolpyruvate-carboxykinase (PEPCK), glucose-6-phosphatase (G-6-Pase), sodium-glucose-co-transporter-2 (SGLT-2), and glucose-transporter-2 (GLUT-2) levels in ZDF-Co rat's renal cortex. These findings demonstrate that cocoa alleviates renal injury by contributing to maintain the glucose homeostasis in type 2 diabetic ZDF rats.
Subject(s)
Blood Glucose/metabolism , Cacao , Diabetic Nephropathies/prevention & control , Homeostasis , Animals , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Gluconeogenesis , Insulin/metabolism , Kidney Cortex/enzymology , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Cortex/physiopathology , Male , Monosaccharide Transport Proteins/metabolism , Rats , Rats, Zucker , Signal TransductionABSTRACT
We aimed to determine whether cortical stiffness (CS) values obtained by point shear wave elastography (pSWE) were increased in patients with diabetic kidney disease (DKD) according to increased disease stage and to determine the parameters associated with CS value in the same patient group. A total of 120 patients with Type-II diabetes mellitus who developed DKD and 22 healthy controls were included in the study. In addition to routine laboratory tests and renal ultrasonography (USG), CS levels were measured using pSWE. Carotid intima-media thickness (IMT) and aortic-IMT values were measured. Patients were grouped according to DKD stage (Stage I-II-III-IV-V), then the control group was added and, the six groups were compared within themselves. Renal CS values were found to be significantly higher in all stages of DKD than in the control group and were found to be increased in accordance with the increase in DKD stage (P <0.05). When receiver operating characteristic curve analysis was performed for determining patients with Stage IV-V DKD, it was found that AUC was >70% for parathyroid hormone (PTH), common and internal carotid-IMT, NT-proBNP, cortical thickness, and CS values. It was found that cortical thickness and PTH levels were independently associated with renal CS in DKD patients and independently determined the risk of increased CS (>9.0 kPa) in DKD patients (P <0.05). Renal CS is increased with increasing DKD stage and this is closely related to decreased cortical thickness and serum PTH levels. Renal CS measurement should be used during follow-up of a patient as part of the renal USG.
Subject(s)
Diabetic Nephropathies , Kidney Cortex , Aged , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/diagnostic imaging , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/etiology , Diabetic Nephropathies/physiopathology , Disease Progression , Female , Humans , Kidney Cortex/diagnostic imaging , Kidney Cortex/physiopathology , Male , Middle Aged , UltrasonographyABSTRACT
OBJECTIVE: To estimate postoperative residual renal function after radical nephroureterectomy for upper tract urothelial carcinoma using the preoperative dynamic computed tomography renal cortex enhancement ratio in comparison with the split kidney glomerular filtration rate measured by 99m Tc-diethylenetriaminopentacetic acid renography. METHODS: A total of 47 patients who received radical nephroureterectomy and underwent both preoperative dynamic computed tomography and renography were the model-development cohort; and 109 patients who underwent dynamic computed tomography alone were the validation cohort. Postoperative renal function of the unremoved kidney was estimated using the following formulas: preoperative estimated glomerular filtration rate × the percentage of total renal cortex radiodensity for the intact kidney in Hounsfield units obtained from corticomedullary phase images in the computed tomography-based model, or the percentage of the total glomerular filtration rate measured by renography in the nuclear model. The correlation between observed and estimated postoperative renal function was determined. The computed tomography-based prediction model derived from linear regression analysis was validated externally. RESULTS: The correlation of computed tomography-based split renal function with the observed postoperative estimated glomerular filtration rate (r = 0.80) was equivalent to that of nuclear split renal function (r = 0.78). In the validation cohort, the computed tomography-based prediction model showed an equivalently strong correlation (r = 0.78). CONCLUSIONS: The present study showed that the percentage of total renal cortex radiodensity for the intact kidney is a useful tool for predicting unremoved kidney function in upper tract urothelial carcinoma patients, thereby allowing appropriate patient selection for perioperative cisplatin-based combination chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/therapy , Kidney Cortex/diagnostic imaging , Kidney Neoplasms/therapy , Ureteral Neoplasms/therapy , Aged , Carcinoma, Transitional Cell/diagnostic imaging , Carcinoma, Transitional Cell/pathology , Chemotherapy, Adjuvant/methods , Female , Glomerular Filtration Rate , Humans , Kidney Cortex/physiopathology , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/pathology , Male , Models, Biological , Nephroureterectomy/adverse effects , Patient Selection , Postoperative Period , Predictive Value of Tests , Radioisotope Renography/methods , Retrospective Studies , Technetium Tc 99m Pentetate/administration & dosage , Tomography, X-Ray Computed , Ureteral Neoplasms/diagnostic imaging , Ureteral Neoplasms/pathologyABSTRACT
BACKGROUND: Adenosine-5'-diphosphate (ADP) can influence intrarenal vascular tone and tubular transport, partly through activation of purine P2Y12 receptors (P2Y12-R), but their actual in vivo role in regulation of renal circulation and excretion remains unclear. METHODS: The effects of intravenous ADP infusions of 2-8mg/kg/hour were examined in anesthetized Wistar rats that were untreated or chronically pretreated with clopidogrel, 20mg/kg/24hours, a selective P2Y12-R antagonist. Renal blood flow (transonic probe) and perfusion of the superficial cortex and medulla (laser-Doppler fluxes) were measured, together with urine osmolality (Uosm), diuresis (V), total solute (UosmV), sodium (UNaV) and potassium (UKV) excretion. RESULTS: ADP induced a gradual, dose-dependent 15% decrease of mean arterial pressure, a sustained increase of renal blood flow and a 25% decrease in renal vascular resistance. Clopidogrel pretreatment attenuated the mean arterial pressure decrease, and did not significantly alter renal blood flow or renal vascular resistance. Renal medullary perfusion was not affected by ADP whereas Uosm decreased from 1,080 ± 125 to 685 ± 75 mosmol/kg H20. There were also substantial significant decreases in UosmV, UNaV and UKV; all these changes were attenuated or abolished by clopidogrel pretreatment. Two-weeks' clopidogrel treatment decreased V while UosmUosmV and UNaV increased, most distinctly after 7 days. Acute clopidogrel infusion modestly decreased mean arterial pressure and significantly increased outer- and decreased inner-medullary perfusion. CONCLUSIONS: Our functional studies show that ADP can cause systemic and renal vasodilation and a decrease in mean arterial pressure, an action at least partly mediated by P2Y12 receptors. We confirmed that these receptors exert tonic action to reduce tubular water reabsorption and urine concentration.
Subject(s)
Adenosine Diphosphate/pharmacology , Blood Pressure/drug effects , Clopidogrel/pharmacology , Kidney Cortex , Kidney Medulla , Vascular Resistance/drug effects , Animals , Blood Flow Velocity/drug effects , Clopidogrel/antagonists & inhibitors , Dose-Response Relationship, Drug , Kidney Cortex/blood supply , Kidney Cortex/physiopathology , Kidney Medulla/blood supply , Kidney Medulla/physiopathology , Male , Rats , Rats, Wistar , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2Y12ABSTRACT
AIMS: In this animal study, we tried to test the hypothesis that apocynin could play an anti-inflammation role by inhibiting NLRP3/X-linked inhibitor of apoptosis protein (XIAP) signalling and have an effect on antifibrosis in rats with diabetic nephropathy. MAIN METHODS: Diabetic nephropathy rats were induced by tail-vein injection of streptozotocin at 60â¯mg/kg body weight in sodium citrate buffer (0.01â¯M, pH 4.5) with unrestricted access to food/water for 12 weeks, and rats with blood glucose levels above 18.0â¯mM were considered diabetic; the damage index for glomerular mesangial cells damage index was calculated by morphological examinations; protein and mRNA changes were analysed by western blotting immunohistochemistry and real-time quantitative polymerase chain reaction; interstitial fibrosis was assessed and scored using Masson's staining. KEY FINDINGS: In rats with diabetic nephropathy, apocynin (1) reduced renal injury and improved renal function; (2) downregulated the expression of NLRP3 in renal cortex; (3) downregulated the expression of XIAP in renal cortex; and (4) attenuated renal fibrosis. SIGNIFICANCE: As an inhibitor of reactive oxygen species (ROS), apocynin could downregulate the expression of NLRP3 and XIAP, and alleviate renal fibrosis, which meant not only that ROS was one type of ligands of NLRP3, but also that ROS mechanism and NLRP3 activation might be therapeutic targets in the treatment of diabetic nephropathy in the future.
Subject(s)
Acetophenones/pharmacology , Anti-Inflammatory Agents/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/prevention & control , Inhibitor of Apoptosis Proteins/metabolism , Kidney Cortex/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Animals , Antioxidants/pharmacology , Cytoprotection , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Diabetic Nephropathies/physiopathology , Fibrosis , Inhibitor of Apoptosis Proteins/genetics , Kidney Cortex/metabolism , Kidney Cortex/pathology , Kidney Cortex/physiopathology , Male , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolismABSTRACT
High salt induced renal disease is a condition resulting from the interactions of genetic and dietary factors causing multiple complications. To understand the metabolic alterations associated with renal disease, we comprehensively analyzed the metabonomic changes induced by high salt intake in Dahl salt-sensitive (SS) rats using GC-MS technology and biochemical analyses. Physiological features, serum chemistry, and histopathological data were obtained as complementary information. Our results showed that high salt (HS) intake for 16 weeks caused significant metabolic alterations in both the renal medulla and cortex involving a variety pathways involved in the metabolism of organic acids, amino acids, fatty acids, and purines. In addition, HS enhanced glycolysis (hexokinase, phosphofructokinase and pyruvate kinase) and amino acid metabolism and suppressed the TCA (citrate synthase and aconitase) cycle. Finally, HS intake caused up-regulation of the pentose phosphate pathway (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), the ratio of NADPH/NADP+, NADPH oxidase activity and ROS production, suggesting that increased oxidative stress was associated with an altered PPP pathway. The metabolic pathways identified may serve as potential targets for the treatment of renal damage. Our findings provide comprehensive biochemical details about the metabolic responses to a high salt diet, which may contribute to the understanding of renal disease and salt-induced hypertension in SS rats.
Subject(s)
Kidney Cortex/physiopathology , Kidney Medulla/physiopathology , Sodium Chloride, Dietary/adverse effects , Animal Feed , Animals , Blood Pressure/drug effects , Body Weight , Fatty Acids/metabolism , Gas Chromatography-Mass Spectrometry , Glycolysis , Hypertension/metabolism , Kidney Cortex/metabolism , Kidney Medulla/metabolism , NADP/metabolism , Oxidative Stress , Oxygen/chemistry , Pentose Phosphate Pathway , Phenotype , Rats , Rats, Inbred DahlABSTRACT
Renal tissue hypoxia is a final pathway in the development and progression of chronic kidney disease (CKD), but whether renal oxygenation predicts renal function decline in humans has not been proven. Therefore, we performed a prospective study and measured renal tissue oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in 112 patients with CKD, 47 with hypertension without CKD, and 24 healthy control individuals. Images were analyzed with the twelve-layer concentric objects method that divided the renal parenchyma in 12 layers of equal thickness and reports the mean R2* value of each layer (a high R2* corresponds to low oxygenation), along with the change in R2* between layers called the R2* slope. Serum creatinine values were collected to calculate the yearly change in estimated glomerular function rate (MDRD eGFR). Follow up was three years. The change in eGFR in CKD, hypertensive and control individuals was -2.0, 0.5 and -0.2 ml/min/1.73m2/year, respectively. In multivariable regression analysis adjusted for age, sex, diabetes, RAS-blockers, eGFR, and proteinuria the yearly eGFR change correlated negatively with baseline 24 hour proteinuria and the mean R2* value of the cortical layers, and positively with the R2* slope, but not with the other covariates. Patients with CKD and high outer R2* or a flat R2* slope were three times more likely to develop an adverse renal outcome (renal replacement therapy or over a 30% increase in serum creatinine). Thus, low cortical oxygenation is an independent predictor of renal function decline. This finding should stimulate studies exploring the therapeutic impact of improving renal oxygenation on renal disease progression.
Subject(s)
Glomerular Filtration Rate , Kidney Cortex/diagnostic imaging , Magnetic Resonance Imaging , Oxygen Consumption , Oxygen/metabolism , Renal Insufficiency, Chronic/diagnostic imaging , Adult , Aged , Biomarkers/blood , Case-Control Studies , Cell Hypoxia , Creatinine/blood , Disease Progression , Female , Humans , Kidney Cortex/metabolism , Kidney Cortex/physiopathology , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/physiopathology , Renal Insufficiency, Chronic/therapy , Renal Replacement Therapy , Reproducibility of Results , Risk Assessment , Risk Factors , Time FactorsABSTRACT
OBJECTIVE: Low-energy shockwave (SW) therapy attenuates damage in the stenotic kidney (STK) caused by atherosclerotic renal artery stenosis (ARAS). We hypothesized that magnetic resonance elastography (MRE) would detect attenuation of fibrosis following SW in unilateral ARAS kidneys. MATERIALS AND METHODS: Domestic pigs were randomized to control, unilateral ARAS, and ARAS treated with 6 sessions of SW over 3 consecutive weeks (n = 7 each) starting after 3 weeks of ARAS or sham. Four weeks after SW treatment, renal fibrosis was evaluated with MRE in vivo or trichrome staining ex vivo. Blood pressure, single-kidney renal-blood-flow (RBF) and glomerular-filtration-rate (GFR) were assessed. RESULTS: MRE detected increased stiffness in the STK medulla (15.3 ± 2.1 vs. 10.1 ± 0.8 kPa, p < 0.05) that moderately correlated with severity of fibrosis (R2 = 0.501, p < 0.01), but did not identify mild STK cortical or contralateral kidney fibrosis. Trichrome staining showed that medullary fibrosis was increased in ARAS and alleviated by SW (10.4 ± 1.8% vs. 2.9 ± 0.2%, p < 0.01). SW slightly decreased blood pressure and normalized STK RBF and GFR in ARAS. In the contralateral kidney, SW reversed the increase in RBF and GFR. CONCLUSION: MRE might be a tool for noninvasive monitoring of medullary fibrosis in response to treatment in kidney disease.
Subject(s)
Atherosclerosis/diagnostic imaging , Elasticity Imaging Techniques , Ischemia/diagnostic imaging , Kidney/diagnostic imaging , Magnetic Resonance Imaging , Animals , Atherosclerosis/physiopathology , Constriction, Pathologic , Disease Models, Animal , Female , Fibrosis , Glomerular Filtration Rate , Ischemia/pathology , Kidney/pathology , Kidney Cortex/diagnostic imaging , Kidney Cortex/physiopathology , Renal Artery/diagnostic imaging , Renal Artery/physiopathology , Renal Artery Obstruction/diagnostic imaging , Renal Artery Obstruction/physiopathology , Renal Circulation , Sus scrofa , SwineABSTRACT
BACKGROUND: Contrast-enhanced CT is necessary before donor nephrectomy and is usually combined with a Tc-99m-mercapto-acetyltriglycine (MAG3) scan to check split renal function (SRF). However, all transplant programs do not use MAG3 because of its high cost and exposure to radiation. We examined whether CT volumetry of the kidney can be a new tool for evaluating SRF. METHODS: Sixty-three patients underwent live donor nephrectomy. Patients without a 1.0 mm slice CT or follow-up for <12 months were excluded leaving 34 patients' data being analyzed. SRF was measured by MAG3. Split renal volume (SRV) was calculated automatically using volume analyzer software. The correlation between SRF and SRV was examined. The association between the donor's postoperative estimated glomerular filtration rate (eGFR) and predicted eGFR calculated by MAG3 or CT volumetry was analyzed at 1, 3, and 12 months post nephrectomy. RESULTS: Strong correlations were observed preoperatively in a Bland-Altman plot between SRF measured by MAG3 and either CT cortex or parenchymal volumetry. In addition, eGFR after donation correlated with SRF measured by MAG3 or CT volumetry. The correlation coefficients (R) for eGFR Mag3 split were 0.755, 0.615, and 0.763 at 1, 3 and 12 months, respectively. The corresponding R values for cortex volume split were 0.679, 0.638, and 0.747. Those for parenchymal volume split were 0.806, 0.592, and 0.764. CONCLUSION: Measuring kidney by CT volumetry is a cost-effective alternative to MAG3 for evaluating SRF and predicting postoperative donor renal function. Both cortex and parenchymal volumetry were similarly effective.
Subject(s)
Kidney Cortex/diagnostic imaging , Kidney Cortex/transplantation , Kidney Function Tests/methods , Kidney Transplantation/methods , Living Donors , Nephrectomy , Parenchymal Tissue/diagnostic imaging , Parenchymal Tissue/transplantation , Tomography, X-Ray Computed , Adult , Aged , Aged, 80 and over , Donor Selection , Female , Glomerular Filtration Rate , Humans , Imaging, Three-Dimensional , Kidney Cortex/physiopathology , Kidney Transplantation/adverse effects , Male , Middle Aged , Nephrectomy/adverse effects , Parenchymal Tissue/physiopathology , Predictive Value of Tests , Radiographic Image Interpretation, Computer-Assisted , Radiopharmaceuticals/administration & dosage , Reproducibility of Results , Retrospective Studies , Software , Technetium Tc 99m Mertiatide/administration & dosage , Time Factors , Treatment OutcomeABSTRACT
Glomerular mesangial cell (MC) apoptosis is one of the important mechanisms of glomerulosclerosis, which induces an increased severity of albuminuria and promotes the development of diabetic nephropathy (DN). However, the mechanism by which high glucose (HG) induces MCs apoptosis is not fully understood. In the present study, we investigated the effects of mTOR signalling on apoptosis in cultured MCs exposed to HG and in type I diabetes, and tried to clarify the specific mechanisms underlying these effects. In vitro, exposure of MCs to HG stimulated ROS production, decreased the antioxidant enzyme superoxide dismutase (SOD) activity and glutathione (GSH) level, increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, upregulated P53 expression and Bax/Bcl-2 ratio and enhanced cleavage of caspase 3, resulting in an increase in programmed cell death. Pretreatment of the cells with rapamycin ameliorated oxidative stress, reduced the number of apoptotic cells induced by HG and caused the downstream effects of mTOR activation. In vivo, compared with control rats, diabetic rats had more apoptotic cells in glomeruli. Induction of diabetes increased the level of MDA and NADPH oxidase activity, decreased the SOD activity and GSH level, elevated the Bax/Bcl ratio and P53 expression and activated caspase 3. mTOR inhibitor rapamycin treatment prevented these changes further alleviated albuminuria and improved renal function. Taken together, our data suggest that mTOR plays a key role in mediating ROS-induced MC apoptosis in diabetic nephropathy, and these effects have been associated with the promotion of ROS production by upregulating the antioxidant enzyme and downregulating the NADPH oxidase activity.
Subject(s)
Apoptosis , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Mesangial Cells/metabolism , Mesangial Cells/pathology , Oxidative Stress , TOR Serine-Threonine Kinases/metabolism , Animals , Apoptosis/drug effects , Cell Line , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/physiopathology , Diabetic Nephropathies/physiopathology , Glucose/toxicity , Kidney Cortex/drug effects , Kidney Cortex/pathology , Kidney Cortex/physiopathology , Kidney Function Tests , Male , Mesangial Cells/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Models, Biological , NADPH Oxidase 4/metabolism , Oxidative Stress/drug effects , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
BACKGROUND: Albuminuria is an early sign but not a strong predictor of diabetic kidney disease (DKD). Owing to their high stability, urinary exosomal miRNAs can be useful predictors of the progression of early-stage DKD to renal failure; fluid biopsies are ideal for detecting abnormalities in these miRNAs. The aim of this study was to identify novel differentially expressed miRNAs as urine biomarkers for type 2 DKD by comparing between patients of type 2 diabetes (T2D) with and without macroalbuminuria. METHODS: Ten patients with T2D, including five who had no renal disease and five with macroalbuminuria (DKD G1-2A3), were selected for this study. Exosome- (UExo-) derived miRNA profiles were used to identify candidate biomarkers, a subset of which was verified using quantitative reverse transcription PCR. RESULTS: A total of 496 UExo-derived miRNA species were found to be differentially expressed (>2-fold) in patients with DKD, compared to those with T2D. A validation analysis revealed that three miRNAs (miR-362-3p, miR-877-3p, and miR-150-5p) were upregulated and one (miR-15a-5p) was downregulated. These miRNAs might regulate DKD through p53, mTOR, and AMPK pathways. CONCLUSIONS: In conclusion, UExo-derived miRNAs were altered in type 2 DKD. MiR-362-3p, miR-877-3p, miR-150-5p, and miR-15a-5p might be novel biomarkers for incipient DKD.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/urine , Exosomes/metabolism , Kidney/physiopathology , MicroRNAs/urine , Renal Insufficiency, Chronic/urine , Animals , Biomarkers/urine , Cohort Studies , Computational Biology , Cross-Sectional Studies , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/physiopathology , Exosomes/ultrastructure , Female , Gene Expression Profiling , Gene Expression Regulation , Gene Ontology , Glomerular Filtration Rate , Humans , Kidney/metabolism , Kidney Cortex/metabolism , Kidney Cortex/physiopathology , Male , Mice, Inbred C57BL , MicroRNAs/metabolism , Microscopy, Electron, Transmission , Middle Aged , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/physiopathologyABSTRACT
PURPOSE:: To investigate the glomerular number after different warm ischemia times. METHODS:: Thirty two pigs were assigned into four groups. Three groups (G10, G20, and G30) were treated with 10, 20, and 30 minutes of left renal warm ischemia. The sham group underwent the same surgery without renal ischemia. The animals were euthanized after 3 weeks, and the kidneys were collected. Right kidneys were used as controls. The kidney weight, volume, cortical-medullar ratio, glomerular volumetric density, volume-weighted mean glomerular volume, and the total number of glomeruli per kidney were obtained. Serum creatinine levels were assessed pre and postoperatively. RESULTS:: Serum creatinine levels did not differ among the groups. All parameters were similar for the sham, G10, and G20 groups upon comparison of the right and left organs. The G30 group pigs' left kidneys had lower weight, volume, and cortical-medullar ratio and 24.6% less glomeruli compared to the right kidney. A negative correlation was found between warm ischemia time and glomerular number. CONCLUSIONS:: About one quarter of glomeruli was lost after 30 minutes of renal warm ischemia. No glomeruli loss was detected before 20 minutes of warm ischemia. However, progressive glomerular loss was associated with increasing warm ischemia time.