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1.
J Am Soc Nephrol ; 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893223

RESUMO

BACKGROUND: Fractalkine receptor 1 (CX3CR1) mediates macrophage infiltration and accumulation, causing venous neointimal hyperplasia (VNH)/venous stenosis (VS) in arteriovenous fistula (AVF). The effect of blocking CX3CR1 using an anti-human variable VHH molecule (hCX3CR1 VHH, BI 655088) on VNH/VS was determined using a humanized mouse in which the human CX3CR1 (hCX3CR1) gene was knocked in (KI). METHODS: Whole-transcriptomic RNA sequencing with bioinformatics analysis was used on human stenotic AVF samples, C57BL/6J, hCX3CR1 KI mice with AVF and CKD, and in in vitro experiments to identify the pathways involved in preventing VNH/VS formation after hCX3CR1 VHH administration. RESULTS: Accumulation of CX3CR1 and CD68 was significantly increased in stenotic human AVFs. In C57BL/6J mice with AVF, there was increased Cx3cr1, Cx3cl1, Cd68, and Tnf-α gene expression, and increased immunostaining of CX3CR1 and CD68. In hCX3CR1-KI mice treated with hCX3CR1 VHH molecule (KI-A), compared with vehicle controls (KI-V), there was increased lumen vessel area and patency, and decreased neointima in the AVF outflow veins. RNA-seq analysis identified TNF-α and NF-κB as potential targets of CX3CR1 inhibition. In KI-A-treated vessels compared with KI-V, there was decreased gene expression of Tnf- α, Mcp-1, and Il-1 ß; with reduction of Cx3cl1, NF-κB, and Cd68; decreased M1, Ly6C, smooth muscle cells, fibroblast-activated protein, fibronectin, and proliferation; and increased TUNEL and M2 staining. In cell culture, monocytes stimulated with PMA and treated with hCX3CR1 VHH had decreased TNF- α, CD68, proliferation, and migration. CONCLUSIONS: CX3CR1 blockade reduces VNH/VS formation by decreasing proinflammatory cues.

2.
Transl Res ; 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33711514

RESUMO

Iodinated contrast is used for imaging and invasive procedures and it can cause contrast induced acute kidney injury (CI-AKI), which is the third leading hospital-acquired health problem. The purpose of the present study was to determine the effect of α-adrenergic receptor-1b (Adra1b) inhibition by using terazosin on change in kidney function, gene, and protein expression in C57BL/6J male mice, 6-8 weeks with chronic kidney disease (CKD). CKD was induced by surgical nephrectomy. Twenty eight days later, 100-µL of iodinated contrast (CI group) or saline (S group) was given via the carotid artery. Whole-transcriptome RNA-sequencing (RNA-Seq) analysis of the kidneys was performed at day 2. Mice received either 50-µL of saline ip or terazosin (2 mg/kg) in 50-µL of saline ip 1 hour before contrast administration which was continued every 12 hours until the animals were euthanized 2 and 7 days later. The kidneys were removed for gene expression, immunohistochemical analysis, and blood serum analyzed for kidney function. Differential gene expression analysis identified 21 upregulated and 436 downregulated genes (fold change >2; P < 0.05) that were common to all sample (n = 3 for both contrast and saline). We identified Adra1b using bioinformatic analysis. Mice treated with terazosin had a significant decrease in serum creatinine, urinary Kim-1 levels, HIF-1α, apoptosis, and downstream Adrab1 genes including Ece1, Edn1, pMAPK14 with increased cell proliferation. Contrast exposure upregulated Adra1b gene expression in HK-2 cells. Inhibition of Adra1b with terazosin abrogated Ece1, Edn1, and contrast-induced Fsp-1, Mmp-2, Mmp-9 expression, and caspase-3/7 activity in HK-2 cells.

3.
Sci Rep ; 11(1): 4772, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637886

RESUMO

Percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVFs) is performed to maintain optimal function and patency. The one-year patency rate is 60% because of venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation. Immediate early response gene X-1 (Iex-1) also known as Ier3 increases in response to wall shear stress (WSS), and can cause VNH/VS formation in murine AVF. In human stenotic samples from AVFs, we demonstrated increased gene expression of Ier3. We hypothesized that 1α, 25-dihydroxyvitamin D3, an inhibitor of IER3 delivered as 1α, 25-dihydroxyvitamin D3 encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 NP) to the adventitia of the stenotic outflow vein after PTA would decrease VNH/VS formation by reducing Ier3 and chemokine (C-C motif) ligand 2 (Ccl2) expression. In our murine model of AVF stenosis treated with PTA, increased expression of Ier3 and Ccl2 was observed. Using this model, PTA was performed and 10-µL of 1,25 NP or control vehicle (PLGA in hydrogel) was administered by adventitial delivery. Animals were sacrificed at day 3 for unbiased whole genome transcriptomic analysis and at day 21 for immunohistochemical analysis. Doppler US was performed weekly after AVF creation. At day 3, significantly lower gene expression of Ier3 and Ccl2 was noted in 1,25 NP treated vessels. Twenty-one days after PTA, 1,25 NP treated vessels had increased lumen vessel area, with decreased neointima area/media area ratio and cell density compared to vehicle controls. There was a significant increase in apoptosis, with a reduction in CD68, F4/80, CD45, pro-inflammatory macrophages, fibroblasts, Picrosirius red, Masson's trichrome, collagen IV, and proliferation accompanied with higher wall shear stress (WSS) and average peak velocity. IER3 staining was localized to CD68 and FSP-1 (+) cells. After 1,25 NP delivery, there was a decrease in the proliferation of α-SMA (+) and CD68 (+) cells with increase in the apoptosis of FSP-1 (+) and CD68 (+) cells compared to vehicle controls. RNA sequencing revealed a decrease in inflammatory and apoptosis pathways following 1,25 NP delivery. These data suggest that adventitial delivery of 1,25 NP reduces VNH and venous stenosis formation after PTA.

4.
J Am Soc Nephrol ; 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627344

RESUMO

BACKGROUND: Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)2D3 from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model. METHODS: Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF. RESULTS: Encapsulation of 1α,25(OH)2D3 in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)2D3. The 1,25 NP-treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFß1, and apoptotic pathways. CONCLUSIONS: Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.

5.
J Am Heart Assoc ; : e018418, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-33283594

RESUMO

Background Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fistula (AVF) patency in patients with end-stage renal disease. There are limited therapies that prevent VNH/VS. Systemic delivery of simvastatin has been shown to reduce VNH/VS but local delivery may help decrease the side effects associated with statin use. We determined if microparticles (MP) composed of cyclodextrins loaded with simvastatin (MP-SV) could reduce VS/VNH using a murine arteriovenous fistula model with chronic kidney disease. Methods and Results Male C57BL/6J mice underwent nephrectomy to induce chronic kidney disease. Four weeks later, an arteriovenous fistula was placed and animals were randomized to 3 groups: 20 µL of PBS or 20 µL of PBS with 16.6 mg/mL of either MP or MP-SV. Animals were euthanized 3 days later and the outflow veins were harvested for quantitative reverse transcriptase-polymerase chain reaction analysis and 28 days later for immunohistochemistical staining with morphometric analysis. Doppler ultrasound was performed weekly. Gene expression of vascular endothelial growth factor-A (Vegf-A), matrix metalloproteinase-9 (Mmp-9), transforming growth factor beta 1 (Tgf-ß1), and monocyte chemoattractant protein-1 (Mcp-1) were significantly decreased in MP-SV treated vessels compared with controls. There was a significant decrease in the neointimal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP-SV treated outflow veins. MP-SV treated fibroblasts when exposed to hypoxic injury had decreased gene expression of Vegf-A and Mmp-9. Conclusions In experimental arteriovenous fistulas, periadventitial delivery of MP-SV decreased gene expression of Vegf-A, Mmp-9, Tgf-ß1 and Mcp-1, VNH/VS, inflammation, and fibrosis.

6.
Clin Appl Thromb Hemost ; 26: 1076029620982669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33372807

RESUMO

Deep venous thrombosis (DVT) is a severe complication of coronavirus disease 2019 (COVID-19). The purpose of this study was to study the prevalence, risk factors, anticoagulant therapy and sex differences of DVT in patients with COVID-19. The enrolled 121 hospitalized non-ventilator patients were confirmed positive for COVID-19. All suspected patients received color Doppler ultrasound (US) to screen for DVT in both lower extremities. Multivariate logistic regression was performed to identify risk factors related to DVT in COVID-19 patients. DVT was found in 48% of the asymptomatic COVID-19 patients with an increased PADUA or Caprini index using US scanning. The multivariate logistic regression determined that age (OR, 1.05; p = .0306), C-reactive protein (CRP) (OR, 1.02; p = .0040), and baseline D-dimer (OR, 1.42; p = .0010) were risk factors among COVID-19 patients. Although the most common DVT location was infrapopliteal (classes I and II), higher mortality in DVT-COVID-19 patients was confirmed. DVT-COVID-19 patients presented significant increases in CRP, neutrophil count, and D-dimer throughout the whole inpatient period compared to non-DVT-COVID-19 patients. Although anticoagulation therapy accelerated the recovery of lymphocytopenia in DVT patients, men DVT-COVID-19 patients with anticoagulant therapy showed significant higher CRP and neutrophil count vs. lymphocyte count (N/L) ratio, but showed lower lymphocyte counts compared to women DVT-COVID-19 patients. DVT is common in COVID-19 patients with high-risk factors, especially for older age and higher CRP and baseline D-dimer populations. It is important to consider sex differences in anticoagulant therapy among DVT-COVID-19 patients.


Assuntos
/complicações , Trombose Venosa/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Proteína C-Reativa/análise , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Caracteres Sexuais
7.
Sci Rep ; 10(1): 16300, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004888

RESUMO

Tissue fibrosis is an important index of renal disease progression. Diffusion-weighted magnetic resonance imaging's (DWI-MRI) apparent diffusion coefficient (ADC) reveals water diffusion is unobstructed by microstructural alterations like fibrosis. We hypothesized that ADC may indicate renal injury and response to therapy in patients with renovascular disease (RVD). RVD patients were treated with medical therapy (MT) and percutaneous transluminal renal angioplasty (MT + PTRA) (n = 11, 3 bilaterally, n = 14 kidneys) or MT (n = 9). ADC and renal hypoxia (R2*) by blood-oxygen-level-dependent MRI were studied before (n = 27) and 3 months after (n = 20) treatment. Twelve patients underwent renal biopsies. Baseline ADC values were correlated with changes in eGFR, serum creatinine (SCr), systolic blood pressure (SBP), renal hypoxia, and renal vein levels of pro-inflammatory marker tumor necrosis-factor (TNF)-α. Renal oxygenation, eGFR, and SCr improved after MT + PTRA. ADC inversely correlated with the histological degree of renal fibrosis, but remained unchanged after MT or MT + PTRA. Basal ADC values correlated modestly with change in SBP, but not in renal hypoxia, TNF-α levels, or renal function. Lower ADC potentially reflects renal injury in RVD patients, but does not change in response to medical or interventional therapy over 3 months. Future studies need to pinpoint indices of kidney recovery potential.

8.
J Vasc Interv Radiol ; 31(12): 2106-2112, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33023806

RESUMO

This study aimed to better define the safety and efficacy of transjugular renal biopsy (TJRB) based on published studies. Seventeen published articles were included (1,321 biopsies). Complications were classified as major if they resulted in blood transfusion or additional invasive procedures. All other bleeding complications were considered minor. Diagnostic tissue was obtained in 1,193 procedures (90.3%). The total incidence of bleeding complications among 15 articles with complete data was 202 of 892 procedures (22.6%): 162 (18.2%) minor and 40 (4.5 %) major. These results show that TJRB is a feasible procedure for obtaining renal tissue for diagnosis and that most complications are self-limiting.

9.
Lab Anim (NY) ; 49(11): 320-334, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33082594

RESUMO

Percutaneous transluminal angioplasty (PTA) is a very common interventional treatment for treating stenosis in arteriovenous fistula (AVF) used for hemodialysis vascular access. Restenosis occurs after PTA, resulting in vascular lumen loss and a decrease in blood flow. Experimental animal models have been developed to study the pathogenesis of stenosis, but there is no restenosis model after PTA of stenotic AVF in mice. Here, we describe the creation of a murine model of restenosis after angioplasty of a stenosis in an AVF. The murine restenosis model has several advantages, including the rapid development of restenotic lesions in the vessel after angioplasty and the potential to evaluate endovascular and perivascular therapeutics for treating restenosis. The protocol includes a detailed description of the partial nephrectomy procedure to induce chronic kidney disease, the AVF procedure for development of de novo stenosis and the angioplasty treatment associated with progression of restenosis. We monitored the angioplasty-treated vessel for vascular patency and hemodynamic changes for a period of 28 d using ultrasound. Vessels were collected at different time points and processed for histological analysis and immunostaining. This angioplasty model, which can be performed with basic microvascular surgery skills, could be used to identify potential endovascular and perivascular therapies to reduce restenosis after angioplasty procedures.

11.
J Am Heart Assoc ; 9(16): e017420, 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32757791

RESUMO

Background Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex-specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells. Methods and Results Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real-time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of BMP7 (bone morphogenetic protein 7) and downstream IL17Rb (interleukin 17 receptor b), with increased transforming growth factor-ß1 (Tgf-ß1) and transforming growth factor-ß receptor 1 (Tgfß-r1). There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of Tgf-ß1, Tgfß-r1, and Col1 with increased migration. Conclusions In female AVFs, there is decreased gene expression of BMP7 and IL17Rb with increased Tgf-ß1 and Tgfß-r1, and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.

12.
Kidney Med ; 2(3): 326-331, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32734252

RESUMO

Rationale & Objective: Primary patency is variable with arteriovenous fistulas, and many patients require angiographic procedures to obtain patency. Accordingly, we determined postintervention patency rates and contributing factors for fistula failure following intervention to establish secondary patency in non-dialysis-dependent patients with advanced chronic kidney disease following creation of an arteriovenous fistula. Study Design: Observational study from a single referral center. Setting & Participants: 210 non-dialysis-dependent patients with advanced chronic kidney disease who underwent upper-extremity fistula creation for anticipated dialysis between October 1995 and January 2015 and who required subsequent endovascular therapy to establish or maintain patency were reviewed. Exposure: Endovascular therapy for dialysis arteriovenous fistula primary patency failure. Outcomes: Postintervention patency duration following endovascular therapy. Analytical Approach: Descriptive study with outcomes determined using Cox proportional hazards models. Results: Multiple fistula configurations were reviewed: 138 (65.7%) brachiocephalic, 39 (18.6%) radiocephalic, 30 (14.3%) brachiobasilic, 2 (1.0%) ulnocephalic, and 1 (0.5%) radiobasilic. There were 261 initial stenoses treated. Postintervention primary patency is defined as the time from the index intervention to repeat intervention for stenosis. Postintervention primary-assisted patency is the time from the index intervention to thrombectomy for fistula thrombosis or change in modality. Postintervention secondary patency is the time from the index intervention to fistula abandonment. Median postintervention primary patency, postintervention primary-assisted patency, and secondary patency were 2.7, 3.2, and 3.6 years, respectively. The overall 1-year primary, primary-assisted, and secondary patency rates in this cohort were 53.0%, 87.7%, and 83.5%, respectively. Compared with radiocephalic fistulas, brachiocephalic fistulas had higher risk for postintervention primary patency loss (HR, 1.90; 95% CI, 1.13-3.20; P = 0.02). Limitations: Dialysis fistula revascularization techniques varied. Conclusions: The radiocephalic fistula configuration had the best postintervention primary patency in this cohort. Postintervention primary-assisted patency and secondary patency were not significantly different among different fistula configurations.

14.
J Am Soc Nephrol ; 31(8): 1781-1795, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32587073

RESUMO

BACKGROUND: Percutaneous transluminal angioplasty (PTA) is the first line of treatment for stenosis in the arteriovenous fistula (AVF) created to provide access for hemodialysis, but resenosis still occurs. Transplants of adipose-derived mesenchymal stem cells (AMSCs) labeled with green fluorescent protein (GFP) to the adventitia could reduce pro-inflammatory gene expression, possibly restoring patency in a murine model of PTA for venous stenosis. METHODS: Partial nephrectomy of male C57BL/6J mice induced CKD. Placement of the AVF was 28 days later and, 14 days after that, PTA of the stenotic outflow vein was performed with delivery of either vehicle control or AMSCs (5×105) to the adventitia of the vein. Mice were euthanized 3 days later and gene expression for interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha TNF-α) analyzed, and histopathologic analysis performed on day 14 and 28. GFP (+) AMSCs were tracked after transplantation for up to 28 days and Doppler ultrasound performed weekly after AVF creation. RESULTS: Gene and protein expression of IL-1ß and TNF-α, fibrosis, proliferation, apoptosis and smooth muscle actin decreased, and the proportions of macrophage types (M2/M1) shifted in a manner consistent with less inflammation in AMSC-transplanted vessels compared to controls. After PTA, AMSC-treated vessels had significantly higher wall shear stress, average peak, and mean velocity, with increased lumen vessel area and decreased neointima/media area ratio compared to the control group. At 28 days after delivery, GFP (+) AMSC were present in the adventitia of the outflow vein. CONCLUSIONS: AMSC-treated vessels had improved vascular remodeling with decreased proinflammatory gene expression, inflammation, and fibrotic staining compared to untreated vessels.

15.
Circulation ; 141(23): 1859-1869, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32370548

RESUMO

BACKGROUND: Paclitaxel-containing devices (PTXDs) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease. A recent aggregate-data meta-analysis reported increased late mortality in patients with peripheral artery disease treated with PTXDs. We performed an individual patient data meta-analysis to evaluate mortality. METHODS: Manufacturers of US Food and Drug Administration-approved and commercially available devices in the United States provided deidentified individual patient data for independent analysis. Cox proportional hazards 1-stage meta-analysis models using intention-to-treat methods were used for the primary analysis. A secondary analysis of recovered missing vital status data was performed. The impact of control crossover to PTXDs, cause-specific mortality, and drug dose mortality were assessed. RESULTS: A total of 2185 subjects and 386 deaths from 8 PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% CI, 6% to 80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data, the excess relative mortality risk was 27% (95% CI, 3%-58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXDs. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dose-mortality association was identified. CONCLUSIONS: This individual patient data meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.

16.
Am J Physiol Renal Physiol ; 318(5): F1210-F1219, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200666

RESUMO

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem, and more than 70 million patients undergo studies using iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present article was to determine the role of transforming growth factor-ß1 (TGF-ß1)/mothers against decapentaplegic homolog (SMAD)3 and associated collagen expression in a murine model of intra-arterial CI-AKI. The murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease. Twenty-eight days later, 100 µL of contrast agent [iodixanol (320 mg/mL)] or saline were administered via the carotid artery. Two days after contrast administration, compared with saline, average serum creatinine was significantly elevated (P < 0.05). In the cortex, there was a significant increase in phosphorylated SMAD3 and gene expression of TGF-ß1, TGF-ß receptor type I, and TGF-ß receptor type II at day 2 in the contrast group compared with the saline group. Average gene expressions of connective tissue growth factor, matrix metalloproteinase-2 and -9, and collagen type I-α and type IV-α were significantly increased at 2 days after contrast administration (all P < 0.05). Moreover, there was a decrease in Ki-67 staining in the cortex, with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling in the cortex and medulla after contrast administration (P < 0.05). In the murine intra-arterial CI-AKI model, there was increased hypoxia and TGF-ß1/SMAD3 pathway activation and collagen expression, resulting in renal fibrosis. Together, these results suggest that the TGF-ß1/SMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.


Assuntos
Lesão Renal Aguda/etiologia , Meios de Contraste , Rim/metabolismo , Insuficiência Renal Crônica/complicações , Ácidos Tri-Iodobenzoicos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose , Artérias Carótidas , Hipóxia Celular , Proliferação de Células , Colágeno/genética , Colágeno/metabolismo , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Injeções Intra-Arteriais , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Nefrectomia , Fosforilação , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Ácidos Tri-Iodobenzoicos/administração & dosagem
17.
J Am Soc Nephrol ; 31(5): 931-945, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32152232

RESUMO

BACKGROUND: Arteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins' induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the in vivo physiologic and molecular effects of statins on fistula patency and maturation remain poorly understood. METHODS: We randomized 108 C57Bl/6J mice to receive daily atorvastatin 1.14 mg/kg or PBS (control) starting 7 days before end-to-side carotid artery-jugular vein fistula creation and for up to 42 days after fistula creation. We then assessed longitudinally the effects of statin therapy on primary murine fistula patency and maturation. We concomitantly analyzed the in vivo arteriovenous fistula thrombogenic and inflammatory macrophage response to statin therapy, using the fibrin-targeted, near-infrared fluorescence molecular imaging agent FTP11-CyAm7 and dextranated, macrophage-avid nanoparticles CLIO-VT680. RESULTS: In vivo molecular-structural imaging demonstrated that atorvastatin significantly reduced fibrin deposition at day 7 and macrophage accumulation at days 7 and 14, findings supported by histopathologic and gene-expression analyses. Structurally, atorvastatin promoted favorable venous limb outward remodeling, preserved arteriovenous fistula blood flow, and prolonged primary arteriovenous fistula patency through day 42 (P<0.05 versus control for all measures). CONCLUSIONS: These findings provide new in vivo evidence that statins improve experimental arteriovenous fistula patency and maturation, indicating that additional clinical evaluation of statin therapy in patients on dialysis undergoing arteriovenous fistula placement is warranted.

18.
Kidney Int ; 97(4): 793-804, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32093917

RESUMO

Atherosclerotic renovascular disease (ARVD) reduces tissue perfusion and eventually leads to loss of kidney function with limited therapeutic options. Here we describe results of Phase 1a escalating dose clinical trial of autologous mesenchymal stem cell infusion for ARVD. Thirty-nine patients with ARVD were studied on two occasions separated by three months. Autologous adipose-derived mesenchymal stem cells were infused through the renal artery in 21 patients at three different dose levels (1, 2.5 and 5.0 × 105 cells/kg) in seven patients each. We measured renal blood flow, glomerular filtration rate (GFR) (iothalamate and estimated GFR), renal vein cytokine levels, blood pressure, and tissue oxygenation before and three months after stem cell delivery. These indices were compared to those of 18 patients with ARVD matched for age, kidney function and blood pressure receiving medical therapy alone that underwent an identical study protocol. Cultured mesenchymal stem cells were also studied in vitro. For the entire stem cell treated-cohort, mean renal blood flow in the treated stenotic kidney significantly increased after stem cell infusion from (164 to 190 ml/min). Hypoxia, renal vein inflammatory cytokines, and angiogenic biomarkers significantly decreased following stem cell infusion. Mean systolic blood pressure significantly fell (144 to 136 mmHg) and the mean two-kidney GFR (Iothalamate) modestly but significantly increased from (53 to 56 ml/min). Changes in GFR and blood pressure were largest in the high dose stem cell treated individuals. No such changes were observed in the cohort receiving medical treatment alone. Thus, our data demonstrate the potential for autologous mesenchymal stem cell to increase blood flow, GFR and attenuate inflammatory injury in post-stenotic kidneys. The observation that some effects are dose-dependent and related to in-vitro properties of mesenchymal stem cell may direct efforts to maximize potential therapeutic efficacy.

19.
Neuromodulation ; 23(1): 3-9, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31965667

RESUMO

The United States Food and Drug Administration (FDA) ensures that patients in the United States have access to safe and effective medical devices. The division of neurological and physical medicine devices reviews medical technologies that interface with the nervous system, including many neuromodulation devices. This article focuses on neuromodulation devices and addresses how to navigate the FDA's regulatory landscape to successfully bring devices to patients.


Assuntos
Aprovação de Equipamentos/legislação & jurisprudência , Aprovação de Equipamentos/normas , Neuroestimuladores Implantáveis/normas , Estimulação Elétrica Nervosa Transcutânea/normas , Humanos , Estimulação Elétrica Nervosa Transcutânea/instrumentação , Estados Unidos
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