The Pathological Mechanisms and Therapeutic Molecular Targets in Arteriovenous Fistula Dysfunction.

The number of patients with end-stage renal disease (ESRD) requiring hemodialysis is increasing worldwide. Although arteriovenous fistula (AVF) is the best and most important vascular access (VA) for hemodialysis, its primary maturation failure rate is as high as 60%, which seriously endangers the prognosis of hemodialysis patients. After AVF establishment, the venous outflow tract undergoes hemodynamic changes, which are translated into intracellular signaling pathway cascades, resulting in an outward and inward remodeling of the vessel wall. Outward remodeling refers to the thickening of the vessel wall and the dilation of the lumen to accommodate the high blood flow in the AVF, while inward remodeling is mainly characterized by intimal hyperplasia. More and more studies have shown that the two types of remodeling are closely related in the occurrence and development of, and jointly determining the final fate of, AVF. Therefore, it is essential to investigate the underlying mechanisms involved in outward and inward remodeling for identifying the key targets in alleviating AVF dysfunction. In this review, we summarize the current clinical diagnosis, monitoring, and treatment techniques for AVF dysfunction and discuss the possible pathological mechanisms related to improper outward and inward remodeling in AVF dysfunction, as well as summarize the similarities and differences between the two remodeling types in molecular mechanisms. Finally, the representative therapeutic targets of potential clinical values are summarized.

Endothelial-to-Mesenchymal Transition in an Hereditary Hemorrhagic Telangiectasia-like Pediatric Case of Multiple Pulmonary Arteriovenous Malformations.

Pulmonary arteriovenous malformations (PAVMs) are vascular anomalies resulting in abnormal connections between pulmonary arteries and veins. In 80% of cases, PAVMs are present from birth, but clinical manifestations are rarely seen in childhood. These congenital malformations are typically associated with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that affects 1 in 5000/8000 individuals. HHT disease is frequently caused by mutations in genes involved in the TGF-ß pathway. However, approximately 15% of patients do not have a genetic diagnosis and, among the genetically diagnosed, more than 33% do not meet the Curaçao criteria. This makes clinical diagnosis even more challenging in the pediatric age group. Here, we introduce an 8-year-old patient bearing a severe phenotype of multiple diffuse PAVMs caused by an unknown mutation which ended in lung transplantation. Phenotypically, the case under study follows a molecular pattern which is HHT-like. Therefore, molecular- biological and cellular-functional analyses have been performed in primary endothelial cells (ECs) isolated from the explanted lung. The findings revealed a loss of functionality in lung endothelial tissue and a stimulation of endothelial-to-mesenchymal transition. Understanding the molecular basis of this transition could potentially offer new therapeutic strategies to delay lung transplantation in severe cases.

Downregulation of the endothelial histone demethylase JMJD3 is associated with neointimal hyperplasia of arteriovenous fistulas in kidney failure.

Jumonji domain-containing protein-3 (JMJD3), a histone H3 lysine 27 (H3K27) demethylase, promotes endothelial regeneration, but its function in neointimal hyperplasia (NIH) of arteriovenous fistulas (AVFs) has not been explored. In this study, we examined the contribution of endothelial JMJD3 to NIH of AVFs and the mechanisms underlying JMJD3 expression during kidney failure. We found that endothelial JMJD3 expression was negatively associated with NIH of AVFs in patients with kidney failure. JMJD3 expression in endothelial cells (ECs) was also downregulated in the vasculature of chronic kidney disease (CKD) mice. In addition, specific knockout of endothelial JMJD3 delayed EC regeneration, enhanced endothelial mesenchymal transition, impaired endothelial barrier function as determined by increased Evans blue staining and inflammatory cell infiltration, and accelerated neointima formation in AVFs created by venous end to arterial side anastomosis in CKD mice. Mechanistically, JMJD3 expression was downregulated via binding of transforming growth factor beta 1-mediated Hes family transcription factor Hes1 to its gene promoter. Knockdown of JMJD3 enhanced H3K27 methylation, thereby inhibiting transcriptional activity at promoters of EC markers and reducing migration and proliferation of ECs. Furthermore, knockdown of endothelial JMJD3 decreased endothelial nitric oxide synthase expression and nitric oxide production, leading to the proliferation of vascular smooth muscle cells. In conclusion, we demonstrate that decreased expression of endothelial JMJD3 impairs EC regeneration and function and accelerates neointima formation in AVFs. We propose increasing the expression of endothelial JMJD3 could represent a new strategy for preventing endothelial dysfunction, attenuating NIH, and improving AVF patency in patients with kidney disease.

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

Filum terminale arteriovenous shunt with nidus structure: a report of rare condition and treatment consideration.

BACKGROUND:  In the literature, filum terminale arteriovenous shunts (FTAVSs) always feature a single shunt point. Nidus-type FTAVSs have rarely been reported, and the best treatment strategy is unclear. This is a report of one exceptional case of a nidus-type FTAVS and surgical treatment of the lesion. CASE DESCRIPTION: The patient suffered from cauda equina syndrome for 9 months. Magnetic resonance imaging and spinal angiography revealed a nidus-type FTAVF at the L2 level. Surgical resection was performed in the hybrid operating room, and the nidus was completely resected with the assistance of intraoperative methylene blue angiography and neurophysiological monitoring. The postoperative neurological function was stable. CONCLUSIONS: A nidus-type arteriovenous shunt could originate from the FT, and in such cases, complete surgical resection with intraoperative neurophysiological monitoring in a hybrid operating room should be suggested.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

Rates of arteriovenous fistula maturation failure are still high, especially when suboptimal size veins are used. During successful maturation, the vein undergoes lumen dilatation and medial thickening, adapting to the increased hemodynamic forces. The vascular extracellular matrix plays an important role in regulating these adaptive changes and may be a target for promoting fistula maturation. In this study, we tested whether a device-enabled photochemical treatment of the vein prior to fistula creation facilitates maturation. Sheep cephalic veins were treated using a balloon catheter coated by a photoactivatable molecule (10-8-10 Dimer) and carrying an internal light fiber. As a result of the photochemical reaction, new covalent bonds were created during light activation among oxidizable amino acids of the vein wall matrix proteins. The treated vein lumen diameter and media area became significantly larger than the contralateral control fistula vein at 1 week (p = 0.035 and p = 0.034, respectively). There was also a higher percentage of proliferating smooth muscle cells in the treated veins than in the control veins (p = 0.029), without noticeable intimal hyperplasia. To prepare for the clinical testing of this treatment, we performed balloon over-dilatation of isolated human veins and found that veins can tolerate up to 66% overstretch without notable histological damage.

Inhibition of ß-catenin signaling attenuates arteriovenous fistula thickening in mice by suppressing myofibroblasts.

BACKGROUND: Arteriovenous fistula (AVF) is the most important vascular access for hemodialysis; however, preventive treatment to maintain the patency of AVFs has not been developed. In endothelium, ß-catenin functions in both the intercellular adherens complex and signaling pathways that induce the transition of endothelial cells to myofibroblasts in response to mechanical stimuli. We hypothesize that mechanical disturbances in the AVF activate ß-catenin signaling leading to the transition of endothelial cells to myofibroblasts, which cause AVF thickening. The present study aimed to test this hypothesis. METHODS: Chronic kidney disease in mice was induced by a 0.2% adenine diet. AVFs were created by aortocaval puncture. Human umbilical vein endothelial cells (HUVECs) were used in the cell experiments. A pressure-culture system was used to simulate mechanical disturbances of the AVF. RESULTS: Co-expression of CD31 and smooth muscle alpha-actin (αSMA), loss of cell-cell adhesions, and the expression of the myofibroblast marker, integrin subunit ß6 (ITGB6), indicated transition to myofibroblasts in mouse AVF. Nuclear translocation of ß-catenin, decreased axin2, and increased c-myc expression were also observed in the AVF, indicating activated ß-catenin signaling. To confirm that ß-catenin signaling contributes to AVF lesions, ß-catenin signaling was inhibited with pyrvinium pamoate; ß-catenin inhibition significantly attenuated AVF thickening and decreased myofibroblasts. In HUVECs, barometric pressure-induced nuclear localization of ß-catenin and increased expression of the myofibroblast markers, αSMA and ITGB6. These changes were attenuated via pretreatment with ß-catenin inhibition. CONCLUSIONS: The results of this study indicate that mechanical disturbance in AVF activates ß-catenin signaling to induce the transition of endothelial cells to myofibroblasts. This signaling cascade can be targeted to maintain AVF patency.

Pathological Analysis of Vascularization of the Arterialized Veins in Failed Arteriovenous Fistulae.

PURPOSE: To assess venous wall vascularization and its correlation with neointimal hyperplasia (NIH) in failed arteriovenous fistulae (AVFs). MATERIALS AND METHODS: A total of 43 uremic patients who underwent de novo AVF creation and 39 patients who underwent reconstruction of failed fistulae were enrolled in the study. A 5-10-mm vein segment adjacent to the future fistula creation or reconstruction site was surgically removed and assessed using histopathological analyses and stained by immunohistochemistry to quantify vasa vasorum density (VVD). RESULTS: Both the intimal thickness (70.68 [28.81-99.54] vs 4.53 [2.69-7.30] µm, P < .001) and the intimal thickness-to-medial thickness ratio (2.20 [0.77-4.36] vs 0.15 [0.10-0.30], P < .001) were higher in failed AVFs than in preaccess veins. CD31- and factor VIII-marked VVDs in both the intima (6.31 [1.62-12.53] vs 0.0 [0.0-0.0], P < .001; 7.82 [3.33-11.61] vs 0.0 [0.0-0.0], P < .001) and media (10.0 [7.59-12.95] vs 3.71 [2.44-4.87], P < .001; 8.33 [5.55-13.0] vs 3.57 [2.53-4.82], P < .001) as well as the intimal VVD:medial VVD ratio (0.67 [0.19-1.08] vs 0.0 [0.0-0.0], P < .001; 0.71 [0.39-1.14] vs 0.0 [0.0-0.0], P < .001) were significantly higher in failed AVFs than in preaccess veins. Moreover, there was a positive relationship between the intimal VVD:medial VVD ratio and the intimal thickness:medial thickness ratio (P < .001). In addition, the vascular endothelial cell growth factor A expression was higher in failed AVFs than in preaccess veins. CONCLUSIONS: Vascularization of the vessel wall was noticeably more developed in the arterialized veins, especially at the NIH regions in failed AVFs.

IN.PACT AV Access Trial: Economic Evaluation of Drug-Coated Balloon Treatment for Dysfunctional Arteriovenous Fistulae Based on 12-Month Clinical Outcomes.

PURPOSE: To study, from a U.S. payer's perspective, the economic consequences of drug-coated balloon (DCB) versus standard percutaneous transluminal angioplasty (PTA) use for the treatment of stenotic lesions in dysfunctional hemodialysis arteriovenous fistulae. MATERIALS AND METHODS: Cost differences between DCBs and PTA at year 1 and beyond were calculated via 2 methods. The first approach used the mean absolute number of trial-observed access circuit reinterventions through 12 months (0.65 ± 1.05 vs 1.05 ± 1.18 events per patient for DCBs and PTA, respectively) and projected treatment outcomes to 3 years. The second approach was based on the trial-observed access circuit primary patency rates at 12 months (53.8% vs 32.4%) and calculated the cost difference on the basis of previously published Medicare cost for patients who maintained or did not maintain primary patency. Assumptions regarding DCB device prices were tested in sensitivity analyses, and the numbers needed to treat were calculated. RESULTS: Using the absolute number of access circuit reinterventions approach, the DCB strategy resulted in an estimated per-patient savings of $1,632 at 1 year and $4,263 at 3 years before considering the DCB device cost. The access circuit primary patency approach was associated with a per-patient cost savings of $2,152 at 1 year and $3,894 at 2.5 years of follow-up. At the theoretical DCB device reimbursement of $1,800, savings were $1,680 and $2,049 at 2.5 and 3 years, respectively. The one-year NNT of DCB compared to PTA was 2.48. CONCLUSIONS: Endovascular therapy for arteriovenous access stenosis with the IN.PACT AV DCB can be expected to be cost-saving if longer follow-up data confirm its clinical effectiveness.

Long-term outcomes of Spetzler-Martin grade IV and V arteriovenous malformations: a single-center experience.

OBJECTIVE: This study aimed to explore whether intervention can benefit Spetzler-Martin (SM) grade IV-V arteriovenous malformations (AVMs). METHODS: Eighty-two patients with SM grade IV-V AVMs were retrospectively reviewed from 2015 to 2018. Patients were divided into two groups: those who received conservative management (22 cases [26.8%]) and intervention (60 cases [73.2%], including 21 cases of microsurgery, 19 embolization, and 20 hybrid surgery). Neurofunctional outcomes were assessed with the modified Rankin Scale (mRS). The primary outcome was long-term neurofunctional status, and the secondary outcomes were short-term neurofunctional status, long-term obliteration rate, seizure control, and risk of subsequent hemorrhage. RESULTS: Regarding the primary outcome, after an average of 4.7 years of clinical follow-up, long-term neurofunctional outcomes were similar after conservative management or intervention (absolute difference -0.4 [95% CI -1.5 to 0.7], OR 0.709 [95% CI 0.461-1.090], p = 0.106), whereas intervention had an advantage over conservative management for avoidance of severe disability (defined as mRS score > 3) (1.7% vs 18.2%, absolute difference 16.5% [95% CI -23.6% to 56.6%], OR 0.076 [95% CI 0.008-0.727], p = 0.025). Regarding the secondary outcomes, intervention was conducive to better seizure control (Engel class I-II) (70.0% vs 0.0%, absolute difference 70.0% [95% CI 8.6%-131.4%], p = 0.010) and avoidance of subsequent hemorrhage (1.4% vs 6.0%, absolute difference 4.6% [95% CI -0.4% to 9.6%], p = 0.030). In the subgroup analysis based on different intervention modalities, microsurgery and hybrid surgery achieved higher complete obliteration rates than embolization (p < 0.001), and hybrid surgery resulted in significantly less intraoperative blood loss than microsurgery (p = 0.041). CONCLUSIONS: Intervention is reasonable for properly indicated SM grade IV-V AVMs because it provides satisfactory seizure control with decreased risks of severe disability and subsequent hemorrhage than conservative management. Clinical trial registration no.: NCT04572568 (ClinicalTrials.gov).

Natural History and Clinical Outcomes of Paravertebral Arteriovenous Shunts.

BACKGROUND AND PURPOSE: Paravertebral arteriovenous shunts (PVAVSs) are rare. Whether the intradural venous system is involved in drainage may lead to differences in clinical characteristics through specific pathophysiological mechanisms. This study aims to comprehensively evaluate the natural history and clinical outcomes of PVAVSs with or without intradural drainage. METHODS: Sixty-four consecutive patients with PVAVSs from 2 institutes were retrospectively reviewed. Lesions were classified as type A (n=28) if the intradural veins were involved in drainage; otherwise, they were classified as type B (n=36). The clinical course from initial presentation to the last follow-up was analyzed. RESULTS: The patients with type A shunts were older at presentation (52.5 versus 35.5 years, P<0.0001) and more likely to have lower spinal segments affected than patients with type B PVAVSs (67.8% versus 13.9%, P=0.00006). After presentation, the deterioration rates related to gait and sphincter dysfunction were significantly higher in patients with type A than type B shunts (gait dysfunction: 71.8%/y versus 17.0%/y, P=0.0006; sphincter dysfunction: 63.7%/y versus 11.3%/y, P=0.0002). According to the angiogram at the end of the latest treatment, 79% of type A and 75% of type B PVAVSs were completely obliterated. If the lesions were partially obliterated, a significantly higher clinical deterioration rate was observed in patients with type A shunts than those with type B shunts (69.9%/y versus 3.2%/y, P=0.0253). CONCLUSIONS: Type A PVAVSs feature rapid progressive neurological deficits; therefore, early clinical intervention is necessary. For complex lesions that cannot be completely obliterated, surgical disconnection of all refluxed radicular veins is suggested.

Clinical and molecular characterization of patients with hereditary hemorrhagic telangiectasia: Experience from an HHT Center of Excellence.

In this retrospective single-center study, we evaluated whether/how pathogenic/likely pathogenic variants of three hereditary hemorrhagic telangiectasia (HHT)-associated genes (ENG, ACVRL1, and SMAD4) are associated with specific clinical presentations of HHT. We also characterized the morphological features of pulmonary arteriovenous malformations (AVMs) in patients with these variants. Pathogenic or likely pathogenic variants were detected in 64 patients. Using nonparametric statistical tests, we compared the type and prevalence of specific HHT diagnostic features associated with these three variants. Pathogenic variants in these genes resulted in gene-specific HHT clinical presentations. Epistaxis was present in 93%, 94%, and 100% of patients with ENG, ACVRL1, and SMAD4 variants, respectively (p = 0.79). Pulmonary AVMs were more common in patients with the ENG variant (p = 0.034) compared with other subgroups. ACVRL1 variant was associated with the lowest frequency of pulmonary AVMs (p = 0.034) but the highest frequency of hepatic AVMs (p = 0.015). Patients with the ACVRL1 variant did not have significantly more pancreatic AVMs compared with the other groups (p = 0.72). ENG, ACVRL1, and SMAD4 pathogenic or likely pathogenic variants are associated with gene-specific HHT presentations, which is consistent with results from other HHT centers.

High-flow arteriovenous fistula is not associated with increased extracellular volume or right ventricular dysfunction in haemodialysis patients.

BACKGROUND: High-output congestive heart failure secondary to high-flow arteriovenous fistula (AVF) has been reported in haemodialysis (HD) patients. As high-flow AVF (HFA) would be expected to result in fluid retention, we conducted an observational study to characterize the relationship between AVF flow (Qa) and extracellular water (ECW) in HD patients. METHODS: We measured Qa by ultrasound dilution in prevalent HD outpatients with an AVF in two dialysis centres. The ECW:total body water (TBW) ratio was measured both pre- and post-dialysis by multifrequency bioimpedance analysis. Transthoracic echocardiograms (TTEs) were performed as part of routine clinical management. RESULTS: We included 140 patients, mean age 62.7 ± 15.7 years, 60.7% male, 47.9% diabetic and 22.9% with coronary revascularization. Mean Qa was 1339 ± 761 mL/min and 22 (15.7%) patients had HFA defined as Qa >2.0 L/min. Qa was positively associated with an upper arm AVF (P = 0.005), body mass index (P = 0.012) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P = 0.047) and negatively associated with diabetes (P < 0.001) and coronary revascularization (P = 0.005). The ECW:TBW ratio was positively associated with age (P < 0.001), Davies comorbidity index (P = 0.034), peripheral vascular disease (P = 0.030) and NT-proBNP (P = 0.002) and negatively associated with serum albumin (P < 0.001). Qa was not associated with the ECW:TBW ratio (P = 0.744). TTE parameters were not associated with Qa. CONCLUSIONS: In our outpatient HD cohort, high AVF flow was not associated with ECW expansion, either pre- or post-dialysis when accounting for potential confounders. By controlling ECW, high access flow should not necessarily be perceived as a threat to cardiovascular physiology.

Secondary stabbing headache associated with intracranial tumors, aneurysms, and arteriovenous malformation: An alarming warning sign.

BACKGROUND: Stabbing headache (SH) is considered as a pure primary headache, but according to a few clinical observations it could also be secondary. Over the past decades, we have been observing the complaint of SH in patients with intracranial vascular and neoplastic lesions. OBJECTIVE: To describe a series of patients with intracranial lesions who experienced SH. METHODS: This is a cross-sectional, retrospective study of 34 patients with intracranial lesions associated with SH, admitted at Hospital das Clínicas, Federal University of Pernambuco, Brazil. RESULTS: In this series of 34 patients [29 women, 44 ± 12 years (mean ± SD)] with secondary SH, the causes were intracranial neoplasms (n = 31), cerebral aneurysms (n = 2), or arteriovenous malformation (n = 1). Pituitary tumor (n = 18), meningioma (n = 6), and vestibular schwannomas (n = 4) were the most prevalent types of intracranial neoplasms. All these lesions had intimate contact with the dura mater, including an oligodendroglioma, the only intra-axial tumor in the series. A characteristic in the secondary SH is the crescendo pattern (12/34, 35%), progressing from infrequent attacks to recurrent crises occurring several times a day. The SH lasted from 5 days to 60 months (15 ± 18 months, mean ± SD) until the correct diagnosis [16/34 (47%) of the patients ≤6 months]. The SH was triggered by the movement of the head (5/34, 15%) or Valsalva maneuver (1/34). After surgery, suppression of the SH was observed. In a few of the patients to whom dexamethasone was prescribed, the SH subsided within a few days. CONCLUSION: This study was able to identify clinical red flags associated with intracranial lesions and secondary SH, for example, recent onset of SH, exclusively unilateral (ipsilateral) at the same location, crescendo pattern, triggered by head movements, or Valsalva maneuver.

Effect of galectin-3 in the pathogenesis of arteriovenous fistula stenosis formation.

OBJECTIVE: This study sought to investigate the effect of local expression of galectin-3 in the development of stenotic arteriovenous fistula (AVF). METHODS: We collected stenotic venous tissues, adjacent nonstenotic venous tissues, and blood samples from end-stage renal disease (ESRD) patients with AVF stenosis, while normal venous tissues and blood samples were collected from ESRD patients before AVF creation as controls. Also blood samples were collected from ESRD patients with nonstenosis functional AVF. Galectin-3, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase-9 (MMP-9), and α-SMA expression in the venous tissues were examined by immunohistochemistry, and the ERK1/2 pathway activity in the intima was accessed by western blot. Serum galectin-3 level was measured by ELISA. Thereafter, human pulmonary arterial smooth muscle cells (HPASMCs) were cultured in vitro, and the interaction between Galectin-3 and ERK1/2 pathway in HPASMCs was estimated by western blot. RESULTS: ESRD patients with stenotic AVF had a significant higher serum galectin-3 level than normal controls, and patients with non-stenotic functional AVF. The expression levels of galectin-3, phosphorylated ERK1/2, PCNA, MMP-9, and α-SMA in the stenotic venous tissues were higher than that in the normal venous tissues or the adjacent nonstenotic AVF venous tissues. Correlation analysis showed that the expression of galectin-3 of the neointima was positively correlated with PCNA and α-SMA in the stenotic AVF venous tissues. In HPASMCs, galectin-3 can increase the activity of phosphorylated ERK1/2 and promote the expression of α-SMA. CONCLUSION: In the stenotic AVF of ESRD patients, expression of the galectin-3 was significantly increased, showing a positive relation with neointima development.

The impact of location and patency of the arteriovenous fistula on quality of life of kidney transplant recipients.

BACKGROUND: Arteriovenous fistulae (AVFs) may remain patent after kidney transplantation (KTx), contributing to maladaptive cardiac remodeling. The flow in AVFs is associated with the diameter of its vessels and thus with the AVF location. The main objective of this study is to assess the influence of AVF location and its patency on the self-reported quality of life (QOL) of kidney transplant recipients (KTRs) with past history of hemodialysis. METHODS: To gain clinical data, during a scheduled visit, 353 KTRs were asked to fill out an anonymous questionnaire. From this group, 284 respondents were found eligible for analysis. The outcome was defined as prevalence of symptoms and health status, measured with the Left Ventricular Dysfunction-36 (LVD-36) Questionnaire in symptomatic patients. RESULTS: The hemodialysis patients (n = 243) were divided into two groups according to AVF location, i.e., DAVF - distally located AVF - (n = 174) and PAVF - proximally located AVF - (n = 69). The proportion of patients with heart failure (HF) was higher in PAVF group (24% vs. 12%, p = 0.0482). In the multivariable regression, PAVF, serum creatinine levels, and the presence of HF or coronary artery disease (CAD) remained independent predictors of lower functional capacity. Among patients with heart disease, the presence of active AVF was independently associated with worse functional outcome (higher LVD-36 scores). CONCLUSIONS: The influence of persistent PAVF in KTRs seems to be unfavorable, especially when coexisting with CAD or HF. Abbreviations: AVF arteriovenous fistula; BMI body mass index; CAD coronary artery disease; D-AVF distally-located arteriovenous fistula; EC exercise capacity; HD hemodialysis; HF heart failure; KTx kidney transplantation; KTR kidney transplant recipient; LVD-36 Left Ventricle Disfunction - 36; LVEF left ventricle ejection fraction; LVH left ventricle hypertrophy; NYHA New York Heart Association; P-AVF proximally located arteriovenous fistula; PD peritoneal dialysis; PRO patient-reported outcomes; QOL quality of life.

Are There Differences in Arteriovenous Fistulae Created for Hemodialysis between Nephrologists and Vascular Surgeons?

OBJECTIVE: Many studies have reported insufficient support from surgical services, resulting in nephrologists creating arteriovenous fistulas in many centers. The aim of this study was to compare risk factors of arteriovenous fistula dysfunction in patients whose fistulas were created by nephrologists versus vascular surgeons. METHODS: This was a retrospective, analytical study of interventions by nephrologists and vascular surgeons during a period of 15 years. Out of a total of 1,048 fistulas, 764 (72.9%) were created by nephrologists patients, while vascular surgeons were responsible for 284 (27.1%) fistulae. Laboratory, demographic, and clinical parameters which might affect functioning of these arteriovenous fistulae were analyzed. RESULTS: Patients whose arteriovenous fistula was formed by nephrologists differed significantly from those created by vascular surgeons in relation to the preventive character of the arteriovenous fistula (p = 0.011), lumen of the vein (p < 0.001) and systolic blood pressure (p = 0.047). Multivariate logistic regression of arteriovenous fistula dysfunction showed that risk factors were female gender (odds ratio [OR] = 1.56, 95% CI 1.16-2.07), whether the fistulae were created by vascular surgeons or nephrologists (OR = 1.38; 95% CI 1.01-1.89) and the site of the arteriovenous fistula (OR = 0.64; 95% CI 0.48-0.85). CONCLUSIONS: Arteriovenous fistulae created by vascular surgeons, female gender, and the location are risk factors of dysfunction.

Mesenchymal Behavior of the Endothelium Promoted by SMAD6 Downregulation Is Associated With Brain Arteriovenous Malformation Microhemorrhage.

BACKGROUND AND PURPOSE: In unruptured brain arteriovenous malformations (bAVMs), microhemorrhage portends a higher risk of future rupture and may represent a transitional state along the continuum of destabilization. Exploration of the molecular and cellular mechanisms of microhemorrhage will provide a possible target for medical treatment to prevent bAVM bleeding. METHODS: We performed RNA sequencing analysis on 34 unruptured bAVM surgical samples. Functional pathway analysis was performed to identify potential signals associated with the microhemorrhagic phenotype. Candidate gene was then investigated in bAVM specimens by immunohistochemical staining. Several functional assays were used to investigate the effects of candidate genes on the phenotypic properties of cultured human umbilical vein endothelial cells. Then, Masson trichrome staining and immunofluorescence staining were used to evaluate the phenotypic and molecular changes in bAVM tissue. RESULTS: Via RNA sequencing, we identified differential gene expression between 18 microhemorrhagic bAVMs and 16 nonmicrohemorrhagic bAVMs. TGFß (transforming growth factor-beta)/BMP (bone morphogenetic protein) signaling was associated with the bAVM microhemorrhage group when SMAD6 (SMAD family member 6) was downregulated. Immunohistochemical staining showed that the vascular endothelium of microhemorrhagic bAVMs exhibited decreased SMAD6 expression. Functional assays revealed that SMAD6 downregulation promoted the formation of endothelial cell tubes with deficient cell-cell junctions and facilitated the acquisition of mesenchymal behavior by endothelial cells. Masson trichrome and immunofluorescence staining demonstrated that mesenchymal phenotype of endothelial cells is promoted in microhemorrhagic bAVMs. CONCLUSIONS: TGFß/BMP signaling mediated by SMAD6 in vascular endothelial cells is associated with microhemorrhagic bAVMs, and mesenchymal behavior of endothelial cells induced by SMAD6 downregulation is related with bAVM microhemorrhage.

Effect of sex differences in treatment response to angioplasty in a murine arteriovenous fistula model.

Failure to mature and venous neointimal hyperplasia formation are the two major causes of hemodialysis arteriovenous fistula (AVF) vascular access failure. Percutaneous transluminal angioplasty (PTA) is the firstline treatment for both of these conditions, but, clinically, women have decreased patency rates compared with men. The hypothesis to be tested in the present study was that female mice after PTA of venous areas of higher intimal thickening have increased gene expression of transforming growth factor-ß1 (TGF-ß1) and TGF-ß receptor 1 (TGFß-R1) accompanied with histological changes of fibrosis compared with male mice. Seventeen male and eighteen female C57BL/6J mice were used in this study. Chronic kidney disease was induced by partial nephrectomy, and, 28 days later, an AVF was created to connect the left carotid artery to the right jugular vein. Two weeks later, the higher intimal thickening area was treated with PTA, and mice were euthanized 3 days later for gene expression analysis or 14 days later for histopathological analysis. Doppler ultrasound was performed weekly after AVF creation. At day 3, female AVF had significantly higher average gene expression of TGF-ß1 and TGFß-R1 compared with male AVF. At day 14, female outflow veins had a smaller venous diameter, lumen vessel area, decreased wall shear stress, lower average peak systolic velocity, and an increased neointima area-to-media area ratio. Moreover, female outflow veins showed a significant increase in α-smooth muscle actin and fibroblast-specific protein-1. There was a decrease in M1/M2 with an increase in CD68.

The Role of MicroRNA-21 in Venous Neointimal Hyperplasia: Implications for Targeting miR-21 for VNH Treatment.

The molecular mechanism of hemodialysis access arteriovenous fistula (AVF) failure due to venous neointimal hyperplasia (VNH) is not known. The role of microRNA-21 (miR-21) in VNH associated with AVF failure was investigated by performing in vivo and in vitro experiments. In situ hybridization results revealed that miR-21 expression increased and was associated with fibroblasts in failed AVFs from patients. In a murine AVF model, qRT-PCR gene expression results showed a significant increase in miR-21 and a decrease in miR-21 target genes in graft veins (GVs) compared to contralateral veins in mouse AVF. miR-21 knockdown in GVs was performed using a lentivirus-mediated small hairpin RNA (shRNA), and this improved AVF patency with a decrease in neointima compared to control GVs. Moreover, loss of miR-21 in GVs significantly decreased the Tgfß1, Col-Ia, and Col-Iva genes. Immunohistochemistry demonstrated a significant decrease in myofibroblasts and proliferation with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining in miR-21-knockdown vessels, along with a decrease in hypoxia-inducible factor-1 alpha (HIF-1α) and phospho-SMAD2 (pSMAD-2) and phospho-SMAD3 (pSMAD-3) and an increase in phosphatase and tensin homolog (PTEN) staining. Hypoxic fibroblast knockdown for miR-21 showed a significant decrease in Tgfß-1 expression and pSMAD-2 and -3 levels and a decrease in myofibroblasts. These results indicate that miR-21 upregulation causes VNH formation by fibroblast-to-myofibroblast differentiation.