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Hemodialysis is the predominant treatment modality for chronic kidney disease, with arteriovenous fistula (AVF) being considered to be the preferred type of long-term vascular access. Implantation of the external anastomotic VasQ™ support device during AVF creation has been suggested to improve the functional outcomes of AVFs. In the current study, we report the clinical outcomes when using the device with radial-cephalic AVF (RCAVF) creation in a large cohort over 3 years.One hundred fifty RCAVFs were created between June 2018 and August 2021 with implantation of VasQ™. Time to maturation, cannulation characteristics, and assisted (AP) and secondary patency (SP) rates were analyzed.In this predominantly male (68%), median 64 years old cohort, 150 VasQ™ devices were implanted. Physiological maturation was achieved in 142/150 (95%) and was unassisted in 133/150 (89%). Of those, 129 matured within 1 month and four additional AVFs within 165 days. Eight AVFs achieved maturation following percutaneous transluminal angioplasty, and one required surgical patch angioplasty. The median time from creation to first successful cannulation in dialysis patients was 41 days. AP at 6, 12, 18, 24, and 30 months was 89%, 81%, 78%, 73%, and 73%, and SP was 94%, 87%, 86%, 84%, and 84%, respectively.Consistent use of the VasQ™ device in RCAVF creation demonstrates excellent AVF maturation and patency rates with very low frequency of assisted maturation and interventions for maintenance. The VasQ™ device appears a suitable aid in increasing the creation of functional RCAVFs.

Radiocephalic arteriovenous fistulas have been historically perceived as requiring multiple follow-up procedural interventions to achieve maturation and maintain patency. Recent clinical practice guidelines from the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) emphasize a patient-centered hemodialysis access strategy with new maximum targets for intervention rates, potentially conflicting with concomitant recommendations to prioritize autogenous forearm hemodialysis access creation. The present descriptive study seeks to assess whether radiocephalic fistulas can meet the KDOQI guideline benchmarks for interventions following access creation, and to elucidate clinical and anatomic characteristics associated with the timing and frequency of interventions following radiocephalic arteriovenous fistula creation.Prospective patient-level data from the multicenter PATENCY-1 and PATENCY-2 randomized trials, which enrolled patients undergoing new radiocephalic arteriovenous fistula creation, was analyzed (ClinicalTrials.gov NCT02110901 and NCT02414841). The primary outcome was the rate of interventions at one year postoperatively. Incidence rates were calculated, and time to surgical or endovascular intervention following fistula creation was modeled using recurrent event extensions of the Cox proportional hazards model. Confidence intervals at the 95% level were calculated using non-parametric bootstrapping.The cohort consisted of 914 patients; mean (SD) age was 57 (13) years and 22% were female. Median followup was 707 days (IQR 447-1066). The incidence of interventions per person-year (95% CI) was 1.04 (0.95-1.13) overall; 1.10 (0.98-1.21) before fistula use, and 0.96 (0.82-1.11) after fistula use. The most common interventions overall were balloon angioplasty (54.9% of all interventions), venous side-branch ligation (16.4%), and open revisions (e.g., proximalization from snuffbox to wrist, 16.4%). The locations requiring balloon angioplasty included the juxta-anastomotic segment (51.7% of angioplasties), the outflow vein (29.2%), the inflow artery (14.8%), the central veins (3.8%), and the cephalic arch (0.5%). Common indications were to restore or maintain patency (75.6% of all interventions), assist maturation (14.9%), improve depth (4.4%), or improve augmentation (3.0%). In the multivariable regression analysis, female sex (adjusted hazard ratio [HR] 1.21, 95% CI 1.05-1.45), diabetes (HR 1.21, 95% CI 1.01-1.46), and intraoperative vein diameter3.0mm (vs. ≥4.0mm, HR 1.33, 95% CI 1.02-1.66) were associated with earlier and more frequent interventions. Patients not on hemodialysis at the time of fistula creation underwent less frequent interventions (HR 0.69, 95% CI 0.59-0.81).Patients with radiocephalic arteriovenous fistulas can expect to undergo one intervention, on average, in the first year after creation, which aligns with current KDOQI guidelines. Patients already requiring hemodialysis, female patients, patients with diabetes, and patients with intraoperative vein diameters3.0mm were at increased risk for repeated intervention. No subgroup exceeded guideline-suggested maximum thresholds for recurrent interventions. Overall, the results demonstrate that creation of radiocephalic arteriovenous fistula remains a guideline-concordant strategy when part of an end-stage kidney disease life-plan in appropriately selected patients.

Brachiocephalic arteriovenous fistulas (AVF) makeup approximately one third of prevalent dialysis vascular accesses. The most common cause of malfunction with this access is cephalic arch stenosis (CAS). The accepted requirement for treatment of a venous stenosis lesion is ⩾50% stenosis associated with hemodynamically abnormalities. However, the correlation between percentage stenosis and a clinically significant decrease in access blood flow (Qa) is low. The critical parameter is the absolute minimal luminal diameter (MLD) of the lesion. This is the parameter that exerts the key restrictive effect on Qa and results in hemodynamic and functional implications for the access. CAS is the result of low wall shear stress (WSS) resulting from the effects of increased blood flow and the unique anatomical configuration of the CAS. Decrease in WSS has a linear relationship to increased blood flow velocity and neointimal hyperplasia exhibits an inverse relationship with WSS. The result is a stenotic lesion. The presence of downstream venous stenosis causes an inflow-outflow mismatch resulting in increased pressure within the access. Qa in this situation may be decreased, increased, or within a normal range. Over time, the increased intraluminal pressure can result in marked aneurysmal changes within the AVF, difficulties with cannulation and the dialysis treatment, and ultimately, increasing risk of access thrombosis. Complete characterization of the lesion both hemodynamically and anatomically should be the first step in developing a strategy for management. This requires both access flow measurement and angiographic imaging. Patients with CAS present a relatively broad spectrum as relates to both of these parameters. These data should be used to determine whether primary treatment of CAS should be directed toward the anatomical lesion (small MLD and low Qa) or the pathophysiology (large MLD and high Qa).

Background: Catheter-associated bacteremia (CAB) often leads to removal of tunneled dialysis catheters with delayed insertion (RDI). Exchange over a guidewire (ExW) can be considered for access site preservation. Fibrin sheath disruption (FSD) during exchange is not standard practice for infected catheters. Here we present the first analysis of outcomes after such exchanges (ExW-FSD). Methods: Retrospective analysis of catheter exchanges and removals performed by interventional nephrology for bacteremia in 2008–2011 observed for 20.5 months. Charts were reviewed for recurrent or new bacteremia and death at 3 months, and for occurrence of thrombosis or stenosis along the catheter site. Catheter exchange with central venogram and fibrin sheath disruption was our standard of care in all patients presenting for CAB. RDI was performed either for tunnel infection, non-clearing of infection or at the request of referring physicians. Results: Over 4 years, 66 patients were treated for CAB. Forty-two patients underwent ExW-FSD, which was performed even for Staph. aureus, gram negative bacteremia or candidemia. RDI was performed in 24 cases. Bacteremia recurred in 3 (7%) patients after ExW-FSD, and in 7 (30%) cases after RDI ( p = 0.02). There was no significant difference in new infections: 5 (12%) after ExW-FSD and 2 (8%) after RDI. There was no death within 3 months after ExW-FSD and 4 (27%) ( p = 0.005) deaths in the RDI group. There was one new central venous stenosis in the ExW-FSD group (2%) with no loss of access site, and 8 (33%) patients developed thrombosis/stenosis along the prior catheter track after RDI (33%) ( p = 0.006) with loss of access site in (21%). Conclusions: In this retrospective analysis of treatment of CAB, ExW-FSD was associated with lower recurrence of bacteremia, lower death rate and a lower incidence of access site loss compared to RDI. These data support ExW-FSD use in patients with CAB.

Point-of-care ultrasound (POCUS) is increasingly being used in nephrology as a diagnostic tool, and there is a growing interest among physicians and nursing staff to learn how to use POCUS for the evaluation of the dialysis vascular access (DVA). The goal of POCUS is to extend the physical examination and more closely evaluate the DVA at bedside. Typically, POCUS quickly answers yes-no questions (ie, Is the vein too deep? Y/N). It is not the goal of POCUS of the vascular access to extensively investigate the entire fistula or graft. In conjunction with a good physical examination, brightness-mode ultrasound alone can answer most questions regarding the DVA, such as depth and diameter of the vessel. With some additional training, a limited color Doppler can be added to the standard evaluation to check flow direction and pseudoaneurysms. With more extensive training and an understanding of Doppler physics, access flow volumes can also be determined using spectral Doppler-mode ultrasound.

Background: The inability of a newly created arteriovenous fistula to support hemodialysis due to non-maturation results in increased complications secondary to catheter dependence. Methods: In view of the highly variable approaches by providers with heterogenous backgrounds (general surgery, vascular surgery, interventional radiology and interventional nephrology, urology, transplant surgery, etc.) we sought to describe a collection of algorithms that have functioned well in our hands to manage this challenging clinical problem and guide trainees and practicing clinicians alike. Results: Physical examination along with selective duplex ultrasound and fistulogram can identify most pathologies underlying non-maturation. Conclusion: Both endovascular and open techniques can be employed to optimize maturation rates in this complex population.

Endovascular salvage plays an important role in dialysis access care. Angioplasty using standard high- and ultrahigh-pressure balloon is the mainstay of therapy, while the use of cutting balloons and balloons designed to deliver pharmacologically active agents to the site of recurrent stenosis is demonstrating improved performance for specific targets that have to be further defined. Stents and stent grafts are additional tools for use at access segments predisposed for inward remodeling such as the cephalic arch or basilic swing point. The juxta-anastomotic segment has particular relevance in maturation of autogenous accesses as well as maintenance of access flow volume. Depending on the location of the access in the forearm or upper arm, and which artery is feeding into the access vein, any type of balloon angioplasty and stent or stent graft placement may be used to establish and maintain patency. Successful management of dialysis access options relies on preservation of venous real estate during the chronic kidney disease phase of kidney disease as well as on knowledgeable evaluation of arm veins and the access by physical examination, bed side ultrasound, and angiographic studies.

Objective: High-flow hemodialysis accesses are a well-recognized source of patient morbidity. Among available management strategies inflow constriction based on real-time physiologic flow monitoring offers a technically straightforward data-driven approach with potentially low morbidity. Despite the benefits offered by this approach, large contemporary series are lacking. Methods: A retrospective review of a prospectively maintained clinical database was undertaken to capture patients undergoing precision banding within a signal tertiary care institution between 2010 and 2019. Multivariable logistic regression modeling of thrombosis within 30 days and re-banding within 1 year were performed. Results: In total, 297 patients underwent banding during the study period for a total number of 398 encounters. Median [IQR] follow-up was 157 [52–373] days. Most accesses were upper arm with brachial artery inflow (84%) and half of the banding procedures were performed for flow imbalance based on exam, duplex, or fistulogram. Median flow rate reduction was 58%. The 30-day thrombosis rate after banding was 15 of 397 (3.8%) with a median time to event of 5.5 days (2–102). The re-banding rate within a year was 54 of 398 (14%) with a median time to re-banding of 134 days [56–224]. Multivariate logistic regression analysis using a univariate screen did not identify any predictors of 30-day thrombosis. Having a forearm radial-cephalic AVF compared to all other access types was protective against need for rebanding at 1 year (OR 0.12 95% CI 0.02–0.92, p = 0.04), as was flow imbalance as the indication for banding (OR 0.43 95% 0.23-0.79, p = 0.006). Conclusions: Precision banding offers an effective, low-morbidity approach for high-flow hemodialysis accesses. Early thrombosis is a rare event after precision banding, although in the long term, one in four patients will require re-banding to maintain control of flow volumes.

Background: When hemodialysis arteriovenous accesses fail, autogenous options are often limited. Non-autogenous conduit choices include bovine carotid artery xenografts (BCAG) and expanded polytetrafluoroethylene (PTFE), yet their comparative effectiveness in hemodialysis access revision remains largely unknown. Methods: A cohort study was performed from a prospectively collected institutional database from August 2010 to July 2021. All patients undergoing an arteriovenous access revision with either BCAG or PTFE were followed for up to 3 years from their index access revision. Revision was defined as graft placement to address a specific problem of an existing arteriovenous access while maintaining one or more of the key components of the original access (e.g. inflow, outflow, and cannulation zone). Outcomes were measured starting at the date of the index revision procedure. The primary outcome was loss of secondary patency at 3 years. Secondary outcomes included loss of post-intervention primary patency, rates of recurrent interventions, and 30-day complications. Pooled logistic regression was used to estimate inverse probability weighted marginal structural models for the time-to-event outcomes of interest. Results: A total of 159 patients were included in the study, and 58% received access revision with BCAG. Common indications for revision included worn out cannulation zones (32%), thrombosis (18%), outflow augmentation (16%), and inflow augmentation (13%). Estimated risk of secondary patency loss at 3 years was lower in the BCAG group (8.6%, 3.9–15.1) compared to the PTFE group (24.8%, 12.4–38.7). Patients receiving BCAG experienced a 60% decreased relative risk of secondary patency loss at 3 years (risk ratio 0.40, 0.14–0.86). Recurrent interventions occurred at similar rates in the BCAG and PTFE groups, with 1.86 (1.31–2.43) and 1.60 (1.07–2.14) interventions at 1 year, respectively (hazard ratio 1.22, 0.74–1.96). Conclusions: Under the conditions of this contemporary cohort study, use of BCAG in upper extremity hemodialysis access revision decreased access abandonment when compared to PTFE.

Fragmentation of outpatient care is a substantial barrier to creation and maintenance of hemodialysis access. To improve patient accessibility, satisfaction, and multidisciplinary provider communication, we created a monthly Saturday multidisciplinary vascular surgery and interventional nephrology access clinic at a tertiary care hospital in a major urban area for the complicated hemodialysis patient population. The study included patients presenting for new access creation as well as those who had previously undergone access surgery. Staffing included two to three interventional nephrologists, two to three vascular surgeons, one medical assistant, one research assistant, and one practice assistant. Patient satisfaction and perception of the clinic was measured using surveys during six of the monthly Saturday hemodialysis clinics. A total of 675 patient encounters were completed (18.2 average/clinic ±6.3 standard deviation) from August 2016 to August 2019. All patients were seen by both disciplines. The average no-show rate was 19.9% throughout the study period. Patient satisfaction in all measures was consistently high with the Saturday clinic. Providers were also assayed, and they generally valued the real-time, multidisciplinary care plan generation, and its subsequent efficient execution. Saturday multidisciplinary hemodialysis access clinics offer high provider and patient satisfaction and streamlined patient care. However, no-show rates remain relatively high for this challenging patient population.

Purpose: Thoracic central venous obstruction is a common clinical complication in dialysis patients utilizing hemodialysis catheters. Thoracic central venous obstruction can lead to inability to utilize affected veins for catheter placement and sequential use of less preferred alternative venous access sites. The latter can affect the ability to create and/or mature permanent arteriovenous access and contribute to the future loss of thoracic veins for venous access. While alternative procedures exist for gaining venous access in patients who have exhausted routine venous access options, these procedures are complex, time-consuming, and associated with high patient risk. The Surfacer System provides a new approach in patients with right-sided thoracic central venous obstruction, enabling the ability to establish repeated access from the right side of the neck to the right atrium. Methods: We describe the use of the Surfacer System to facilitate placement of hemodialysis catheters in a series of nine patients with thoracic central venous obstruction involving one or more central veins. Patient characteristics and procedure-related outcomes were recorded for all patients. Results: Central venous access was successfully achieved in eight of nine patients using the Surfacer System. Significant venous tortuosity resulted in the inability to achieve venous access in one patient and prolonged procedural time to achieve access in another patient. The mean time required for Surfacer-related procedural steps and associated fluoroscopy time in the remaining seven patients was 13.3 and 3.7 min, respectively. Conclusion: The Surfacer System provides an efficient low-complexity alternative for gaining repeated right-sided central venous access in hemodialysis patients with obstructed thoracic veins.

Objective The Society for Vascular Surgery guidelines for permanent hemodialysis (HD) access creation recommend prioritizing the most distal possible autogenous access to minimize complications and preserve more proximal options. The "snuffbox" arteriovenous fistula (AVF) is the most distal radial artery–cephalic vein AVF. Despite the theoretical benefits of the snuffbox approach, recent trends have been toward upper arm access. Our study sought to investigate the feasibility of a snuffbox-first strategy for HD access in all anatomically appropriate candidates. Methods From January 2016 to August 2019, all patients with end-stage renal disease (ESRD) or pre-ESRD under consideration for HD access were evaluated for a snuffbox-first approach by a team of vascular surgeons and nephrologists at a single, urban academic medical center in the United States. Data were collected prospectively and supplemented by medical record review. A survival analysis was performed to evaluate primary unassisted and secondary patency and clinical and functional maturation. Patients were censored if they had received a kidney transplant or had died. Cox proportional hazards regression was used to determine the risk factors for prolonged clinical maturation and functional maturation. Results A total of 55 snuffbox AVFs were created. The median patient age was 60 years (interquartile range [IQR], 52-70 years), and 52.7% of the patients were men. The median follow-up was 369 days (IQR, 166-509 days). The median survival for primary unassisted patency was 90 days (95% confidence interval [CI], 79-111). Secondary patency at 1 year was 92.3% (95% CI, 85.3%-99.9%). The clinical maturation rate at 1 year was 83.7% (n = 55; 95% CI, 66.8%-91.9%), and the functional maturation rate at 1 year was 85.6% (n = 40; 95% CI, 63.3%-94.4%). Of the patients who were pre-ESRD at AVF creation and had initiated HD during the study period, 87.5% had successfully received incident HD with their snuffbox AVF. Twenty-four patients were receiving HD via a catheter at snuffbox creation. Of those patients, the functional maturation rate at 1 year was 82.5% (95% CI, 44.8%-94.4%). The patients had undergone a median of two interventions (IQR, zero to seven interventions) in the first year. Of these, 46.9% were percutaneous angioplasty and 31.2% were side-branch ligation. Diabetes was associated with slower AVF clinical maturation (multivariate hazard ratio, 0.35; 95% CI, 0.15-0.82; P = .016). A larger artery diameter was associated with earlier AVF clinical maturation (multivariate hazard ratio, 6.64; 95% CI, 2.11-20.9). Conclusions A snuffbox-first approach to HD access is a viable option for distal access creation in a cohort of patients requiring HD in the United States. Subsequent ancillary interventions to facilitate access maturation were required for most patients.

Brachial-cephalic arteriovenous fistulas (BCFs) are associated with high-flow volumes, leading to potential risks such as arm swelling, steal syndrome, pseudoaneurysm (due to a pressurized access), and cephalic arch stenosis. We hypothesized that a proximal radial-cephalic fistula (prRCF) configuration mitigates these risks because a lower flow state is created. Furthermore, we also hypothesized that despite these lower flows, patencies (primary, primary assisted, secondary) are sustained.Leveraging a prospectively collected database supplemented with detailed medical record data, analyses of patients undergoing BCF and prRCF were completed (November 2008 through March 2016). Preoperative clinical and imaging characteristics, operative variables, and postoperative complications were reviewed. The primary end point was a composite of arm swelling, steal, and pseudoaneurysm at 2 years. Fistulograms and interventions (surgical revision, thrombectomy, endovascular treatment of cephalic arch stenosis) censored at 2 years were compared between configurations. Patencies were plotted using Kaplan-Meier techniques and compared using Cox proportional hazards.During the study period, 345 arteriovenous fistulas and 72 prosthetic grafts were primarily placed; 56 patients underwent BCF and 50 patients underwent prRCF with a mean follow-up of 1.8 ± 1.7 (standard deviation) years. Except for prRCF patients being older, there was no difference between the groups with regard to preoperative characteristics. The artery diameter used for anastomosis was significantly larger in the BCF group (4.0 ± 1.1 mm vs 2.6 ± 0.8 mm; P .001), with higher flow volumes at 6-week ultrasound examination (1060 ± 587 mL/min vs 735 ± 344 mL/min; P .001). Complications (arm swelling, steal, pseudoaneurysm) were significantly more common in the BCF group (P = .02). There was a trend, albeit statistically insignificant, for the BCF group to require more cephalic arch stenosis interventions. Of those patients needing dialysis within 1 year, both BCF and prRCF were successfully used in the majority of patients (n = 27 [66%] vs n = 25 [63%]; P = 1.0). Unadjusted and adjusted primary, primary assisted, and secondary patency rates were similar between the groups.prRCFs have fewer complications yet similar midterm durability compared with BCFs. When it is anatomically feasible, prRCFs should be constructed over BCFs because of their superior physiology and clinical outcomes.

Although not common, hemodialysis access-induced distal ischemia is a serious condition resulting in significant hemodialysis patient morbidity. Patients with signs and symptoms suggestive of hand ischemia frequently present to the general and interventional nephrologist for evaluation. In order to care for these cases, it is necessary to understand this syndrome and its management. Most cases can be managed conservatively without intervention. Some cases requiring intervention may be treated using techniques within the scope of practice of the interventional nephrologists while other cases require vascular surgery. In order for the interventional nephrologists to evaluate and manage these cases in a timely and appropriate manner, practice guidelines are presented.

Thoracic central venous obstruction is a common clinical complication in dialysis patients utilizing hemodialysis catheters. Thoracic central venous obstruction can lead to inability to utilize affected veins for catheter placement and sequential use of less preferred alternative venous access sites. The latter can affect the ability to create and/or mature permanent arteriovenous access and contribute to the future loss of thoracic veins for venous access. While alternative procedures exist for gaining venous access in patients who have exhausted routine venous access options, these procedures are complex, time-consuming, and associated with high patient risk. The Surfacer System provides a new approach in patients with right-sided thoracic central venous obstruction, enabling the ability to establish repeated access from the right side of the neck to the right atrium.We describe the use of the Surfacer System to facilitate placement of hemodialysis catheters in a series of nine patients with thoracic central venous obstruction involving one or more central veins. Patient characteristics and procedure-related outcomes were recorded for all patients.Central venous access was successfully achieved in eight of nine patients using the Surfacer System. Significant venous tortuosity resulted in the inability to achieve venous access in one patient and prolonged procedural time to achieve access in another patient. The mean time required for Surfacer-related procedural steps and associated fluoroscopy time in the remaining seven patients was 13.3 and 3.7 min, respectively.The Surfacer System provides an efficient low-complexity alternative for gaining repeated right-sided central venous access in hemodialysis patients with obstructed thoracic veins.

Objective The results of preoperative ultrasound (pre-US) vein mapping for hemodialysis access creation can be affected by environmental and clinical factors, such as ambient temperature, acute illness, recent phlebotomy, and hypovolemia. These factors may inadvertently exclude otherwise viable veins as options for access creation. We hypothesized that repeating the ultrasound vein mapping immediately preoperatively after anesthesia administration (post-US) identifies additional veins not appreciated by pre-US, thereby altering the operative plan and producing more preferred accesses, particularly more forearm accesses. Methods We performed a retrospective cohort study of patients (N = 323) at one institution who underwent pre-US followed by creation of a permanent dialysis access (fistula or graft) between January 2008 and December 2013. By applying the Silva criteria to pre-US vein mapping reports, a preoperative surgical plan was established. There were 99 patients who underwent only pre-US (group I); an additional post-US was performed in 224 patients (group II). Using multivariable logistic regression, we tested the association of post-US (group II) with pre-US alone (group I) with a change in operative plan and placement of a more preferred access (ie, more distal and autogenous). We also analyzed access survival using multivariable Cox proportional hazards regression and determined maturation rates for accesses in groups I and II. Results In group II, there were more changes in operative plan after controlling for potential confounders (adjusted odds ratio, 1.96; 95% confidence interval, 1.18-3.25), and more preferred accesses were created (adjusted odds ratio, 1.82; 95% confidence interval, 1.01-3.27). In addition, more autogenous accesses were created in group II when initially only upper arm graft options had been identified (P = .01); overall, more forearm accesses were created in group II (P = .03). There was no significant difference in access maturation and patency in comparing accesses in group I and group II, despite creation of autogenous accesses in group II that are usually associated with higher rates of access failure. In fact, forearm radial-cephalic autogenous accesses created in group II had secondary patency rates of 91% at 2 years. Conclusions Our study supports the hypothesis that the use of post-US in addition to pre-US leads to placement of more preferred accesses while maintaining maturation and patency rates. Ultrasound evaluation after anesthesia should be considered a step in the process of care for hemodialysis access creation to improve outcomes.

Vascular access is the Achilles’ heel of hemodialysis. This was true for the first patient with CKD treated repeatedly by Willem Kolff in 1943, who ran out of access sites. It remains a challenge today; creation of autogenous accesses (arteriovenous fistulas [AVFs]) is characterized by high

Hypertension is one of the major risk factors for chronic kidney disease. Using quantitative trait loci analysis, we identified the gene of the F-BAR protein NOSTRIN in the center of an overlapping region in rat and human quantitative trait loci that are associated with hypertension. Immunohistochemical analysis revealed a predominantly podocytic expression pattern of NOSTRIN in human and mouse glomeruli. Further, NOSTRIN colocalizes with cell–cell contact–associated proteins β-catenin and zonula occludens-1 and interacts with the slit-membrane–associated adaptor protein CD2AP. In zebrafish larvae, knockdown of nostrin alters the glomerular filtration barrier function, inducing proteinuria and leading to ultrastructural morphological changes on the endothelial and epithelial side and of the glomerular basement membrane of the glomerular capillary loop. We conclude that NOSTRIN expression is an important factor for the integrity of the glomerular filtration barrier. Disease-related alteration of NOSTRIN expression may not only affect the vascular endothelium and, therefore, contribute to endothelial cell dysfunction but might also contribute to the development of podocyte disease and proteinuria.

The vast majority of arteriovenous grafts (AVG) have been constructed using expanded polytetrafluoroethylene (ePTFE). While ePTFE grafts have the advantage of being relatively inexpensive and easy to manufacture, distribute, ship, and store, their primary patency rates are disappointing when compared with the native AVF. Though use of arteriovenous fistulas (AVF) in the United States has increased substantially, approximately 25% of hemodialysis patients continue to use AVG as their vascular access. We present here a comprehensive review of biological grafts and their use in hemodialysis vascular access. In this review, we discuss the use of synthetics and then explore the evolution of biological grafts over the past 20 years, their clinical impact, and future challenges in widespread clinical use in hemodialysis patients. Provided are in depth descriptions of currently used nonbiological arteriovenous grafts and the recent approaches in increasing the patency of synthetic grafts. Recent technological advances using tissue-engineered AVGs have shown promise for patients receiving hemodialysis and their potential to provide an attractive, viable option for vascular access have been discussed.

Cardiovascular implantable electronic devices (CIEDs) are frequently utilized for management of cardiac dysrhythmias in patients with chronic kidney disease or end-stage renal disease receiving hemodialysis. The survival benefit from use of implantable cardioverter defibrillators in patients with CKD or ESRD is not as clear as in the general population, particularly when used for primary prevention of sudden cardiac death. Transvenous CIED leads are associated with central vein stenosis resulting in significant adverse consequences for existing or future arteriovenous access. Venous hypertension from CIED lead-related central vein stenosis is a challenging clinical problem and may require repeated percutaneous interventions, replacement of the CIED, or creation of alternative arteriovenous access. Infections associated with transvenous CIED leads are more frequent and associated with worse outcomes in patients with renal disease. Epicardial CIED leads or other nontransvenous devices may reduce complications of both central venous stenosis and endovascular infection in these vulnerable patients. Consensus recommendations are offered for avoidance and management of complications arising from the use of CIEDs and arteriovenous hemodialysis access.

The StenTec™ Gauge provides a method to determine the static intra-access pressure ratio (P(Ia Ratio) ) within a fistula or graft. The StenTec Gauge estimates the peak systolic pressure within the fistula or graft by measurement of the distance that the blood-air interface progresses into the tubing of the fistula needle, after the needle is inserted "dry" into the fistula or graft and before the cap is removed from the tubing. The peak systolic pressure is graphically compared with the systolic arterial blood pressure of the patient, to determine P(Ia Ratio) . For best accuracy, the StenTec Gauge should be chosen that best matches the internal volume of the fistula needle tubing (2.3-2.6 ml for 12-inch tubing and 3.6 ml for 16-inch tubing) and the approximate elevation of the city in which it is used (0-1000, 1000-3000, and 3000-6000 feet above sea level). In this article, we explain the rationale for this method of surveillance, evidence for accuracy of the StenTec Gauge, and the correlation of changes in the P(Ia Ratio) to the development of stenosis in a fistula or graft.

Error-free chromosome segregation depends on timely activation of the multi-subunit E3 ubiquitin ligase APC/C. Activation of the APC/C initiates chromosome segregation and mitotic exit by targeting critical cell-cycle regulators for destruction. The APC/C is the principle target of the mitotic checkpoint, which prevents segregation while chromosomes are unattached to spindle microtubules. We now report the identification and characterization of APC16, a conserved subunit of the APC/C. APC16 was found in association with tandem-affinity-purified mitotic checkpoint complex protein complexes. APC16 is a bona fide subunit of human APC/C: it is present in APC/C complexes throughout the cell cycle, the phenotype of APC16-depleted cells copies depletion of other APC/C subunits, and APC16 is important for APC/C activity towards mitotic substrates. APC16 sequence homologues can be identified in metazoans, but not fungi, by four conserved primary sequence stretches. We provide evidence that the C. elegans gene K10D2.4 and the D. rerio gene zgc:110659 are functional equivalents of human APC16. Our findings show that APC/C is composed of previously undescribed subunits, and raise the question of why metazoan APC/C is molecularly different from unicellular APC/C.

Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.

Physically diverse carbon nanostructures are increasingly being studied for potential applications in cancer chemotherapy. However, limited knowledge exists on the effect of their shape in tuning the biological outcomes when used as nanovectors for drug delivery. In this study, we evaluated the effect of doxorubicin-conjugated single walled carbon nanotubes (CNT-Dox) and doxorubicin-conjugated spherical polyhydroxylated fullerenes or fullerenols (Ful-Dox) on angiogenesis. We report that CNTs exert a pro-angiogenic effect in vitro and in vivo. In contrast, the fullerenols or doxorubicin-conjugated fullerenols exerted a dramatically opposite antiangiogenic activity in zebrafish and murine tumor angiogenesis models. Dissecting the angiogenic phenotype into discrete cellular steps revealed that fullerenols inhibited endothelial cell proliferation, while CNTs attenuated the cytotoxic effect of doxorubicin on the endothelial cells. Interestingly, CNT promoted endothelial tubulogenesis, a late step during angiogenesis. Further, mechanistic studies revealed that CNTs, but not fullerenols, induced integrin clustering and activated focal adhesion kinase and downstream phosphoinositide-3-kinase (PI3K) signaling in endothelial cells, which can explain the distinct angiogenic outcomes. The results of the study highlight the function of physical parameters of nanoparticles in determining their activity in biological settings.

Background— Therapeutic vasculogenesis is an emerging concept that can potentially be harnessed for the management of ischemic pathologies. The present study elucidates the potential coregulation of vasculogenesis by the heparan sulfate glycosaminoglycan–rich cell-surface glycome and the transcriptome. Methods and Results— Differentiation of embryonic stem cells into endothelial cells in an in vitro embryoid body is paralleled by an amplification of heparan sulfate glycosaminoglycan sulfation, which correlates with the levels of the enzyme N -deacetylase/ N -sulfotransferase 1 (NDST1). Small hairpin RNA–mediated knockdown of NDST1 or modification of heparan sulfate glycosaminoglycans in embryonic stem cells with heparinases or sodium chlorate inhibited differentiation of embryonic stem cells into endothelial cells. This was translated to an in vivo zebrafish embryo model, in which the genetic knockdown of NDST1 resulted in impaired vascularization characterized by a concentration-dependent decrease in intersegmental vessel lumen and a large tail-vessel configuration, which could be rescued by use of exogenous sulfated heparan sulfate glycosaminoglycans. To explore the cross talk between the glycome and the transcriptome during vasculogenesis, we identified by microarray and then validated wild-type and NDST1 knockdown–associated gene-expression patterns in zebrafish embryos. Temporal analysis at 3 developmental stages critical for vasculogenesis revealed a cascade of pathways that may mediate glycocalyx regulation of vasculogenesis. These pathways were intimately connected to cell signaling, cell survival, and cell fate determination. Specifically, we demonstrated that forkhead box O3A/5 proteins and insulin-like growth factor were key downstream signals in this process. Conclusions— The present study for the first time implicates interplay between the glycome and the transcriptome during vasculogenesis, revealing the possibility of harnessing specific cellular glyco-microenvironments for therapeutic vascularization.

Group IVA phospholipase A2 [cytosolic phospholipase A2α (cPLA2α)] is a key mediator of inflammation and tumorigenesis. In this study, by using a combination of chemical inhibition and genetic approaches in zebrafish and murine cells, we identify a mechanism by which cPLA2α promotes cell proliferation. We identified 2 cpla2α genes in zebrafish, cpla2αa and cpla2αb, with conserved phospholipase activity. In zebrafish, loss of cpla2α expression or inhibition of cpla2α activity diminished G1 progression through the cell cycle. This phenotype was also seen in both mouse embryonic fibroblasts and mesangial cells. G1 progression was rescued by the addition of arachidonic acid or prostaglandin E2 (PGE2), indicating a phospholipase-dependent mechanism. We further show that PGE2, through PI3K/AKT activation, promoted Forkhead box protein O1 (FOXO1) phosphorylation and FOXO1 nuclear export. This led to up-regulation of cyclin D1 and down-regulation of p27Kip1, thus promoting G1 progression. Finally, using pharmacologic inhibitors, we show that cPLA2α, rapidly accelerated fibrosarcoma (RAF)/MEK/ERK, and PI3K/AKT signaling pathways cooperatively regulate G1 progression in response to platelet-derived growth factor stimulation. In summary, these data indicate that cPLA2α, through its phospholipase activity, is a critical effector of G1 phase progression through the cell cycle and suggest that pharmacological targeting of this enzyme may have important therapeutic benefits in disease mechanisms that involve excessive cell proliferation, in particular, cancer and proliferative glomerulopathies.—Naini, S. M., Choukroun, G. J., Ryan, J. R., Hentschel, D. M., Shah, J. V., Bonventre, J. V. Cytosolic phospholipase A2α regulates G1 progression through modulating FOXO1 activity.

Kidney injury molecule 1 (KIM-1), an epithelial phagocytic receptor, is markedly upregulated in the proximal tubule in various forms of acute and chronic kidney injury in humans and many other species. Whereas acute expression of KIM-1 has adaptive anti-inflammatory effects, chronic expression may be maladaptive in mice. Here, we characterized the zebrafish Kim family, consisting of Kim-1, Kim-3, and Kim-4. Kim-1 was markedly upregulated in kidney after gentamicin-induced injury and had conserved phagocytic activity in zebrafish. Both constitutive and tamoxifen-induced expression of Kim-1 in zebrafish kidney tubules resulted in loss of the tubule brush border, reduced GFR, pericardial edema, and increased mortality. Kim-1-induced kidney injury was associated with reduction of growth of adult fish. Kim-1 expression led to activation of the mammalian target of rapamycin (mTOR) pathway, and inhibition of this pathway with rapamycin increased survival. mTOR pathway inhibition in KIM-1-overexpressing transgenic mice also significantly ameliorated serum creatinine level, proteinuria, tubular injury, and kidney inflammation. In conclusion, persistent Kim-1 expression results in chronic kidney damage in zebrafish through a mechanism involving mTOR. This observation predicted the role of the mTOR pathway and the therapeutic efficacy of mTOR-targeted agents in KIM-1-mediated kidney injury and fibrosis in mice, demonstrating the utility of the Kim-1 renal tubule zebrafish models.

We report the isolation of TRIP‐Br1, a transcriptional regulator that interacts with the PHD‐bromodomain of co‐repressors of Kruppel‐associated box (KRAB)‐mediated repression, KRIP‐1(TIF1β) and TIF1α, as well as the co‐activator/adaptor p300/CBP. TRIP‐Br1 and the related protein TRIP‐Br2 possess transactivation domains. Like MDM2, which has a homologous transactivation domain, TRIP‐Br proteins functionally contact DP‐1, stimulating E2F‐1/DP‐1 transcriptional activity. KRIP‐1 potentiates TRIP‐Br protein co‐activation of E2F‐1/DP‐1. TRIP‐Br1 is a component of a multiprotein complex containing E2F‐1 and DP‐1. Co‐expression of the retinoblastoma gene product (RB) abolishes baseline E2F‐1/DP‐1 transcriptional activity as well as TRIP‐Br/KRIP‐1 co‐activation, both of which are restored by the adenovirus E1A oncoprotein. These features suggest that TRIP‐Br proteins function at E2F‐responsive promoters to integrate signals provided by PHD‐ and/or bromodomain‐ containing transcription factors. TRIP‐Br1 is identical to the cyclin‐dependent kinase 4 (cdk4)‐binding protein p34 SEI‐1 , which renders the activity of cyclin D/cdk4 resistant to the inhibitory effect of p16 INK4a during late G 1 . TRIP‐Br1(p34 SEI‐1 ) is differentially overexpressed during the G 1 and S phases of the cell cycle, consistent with a dual role for TRIP‐Br1(p34 SEI‐1 ) in the regulation of cell cycle progression through sequential effects on the transcriptional activity of E2F‐responsive promoters during G 1 and S phases.

The vast majority of arteriovenous grafts (AVG) have been constructed using expanded polytetrafluoroethylene (ePTFE). While ePTFE grafts have the advantage of being relatively inexpensive and easy to manufacture, distribute, ship, and store, their primary patency rates are disappointing when compared with the native AVF. Though use of arteriovenous fistulas (AVF) in the United States has increased substantially, approximately 25% of hemodialysis patients continue to use AVG as their vascular access. We present here a comprehensive review of biological grafts and their use in hemodialysis vascular access. In this review, we discuss the use of synthetics and then explore the evolution of biological grafts over the past 20 years, their clinical impact, and future challenges in widespread clinical use in hemodialysis patients. Provided are in depth descriptions of currently used nonbiological arteriovenous grafts and the recent approaches in increasing the patency of synthetic grafts. Recent technological advances using tissue-engineered AVGs have shown promise for patients receiving hemodialysis and their potential to provide an attractive, viable option for vascular access have been discussed.

Cardiovascular implantable electronic devices (CIEDs) are frequently utilized for management of cardiac dysrhythmias in patients with chronic kidney disease or end-stage renal disease receiving hemodialysis. The survival benefit from use of implantable cardioverter defibrillators in patients with CKD or ESRD is not as clear as in the general population, particularly when used for primary prevention of sudden cardiac death. Transvenous CIED leads are associated with central vein stenosis resulting in significant adverse consequences for existing or future arteriovenous access. Venous hypertension from CIED lead-related central vein stenosis is a challenging clinical problem and may require repeated percutaneous interventions, replacement of the CIED, or creation of alternative arteriovenous access. Infections associated with transvenous CIED leads are more frequent and associated with worse outcomes in patients with renal disease. Epicardial CIED leads or other nontransvenous devices may reduce complications of both central venous stenosis and endovascular infection in these vulnerable patients. Consensus recommendations are offered for avoidance and management of complications arising from the use of CIEDs and arteriovenous hemodialysis access.

Summary Dialysis vascular access dysfunction is currently a huge clinical problem. We believe that comprehensive academic-based dialysis vascular access programs that go all the way from basic and translational science investigation to clinical research to a dedicated curriculum and opportunities in vascular access for nephrologists in training are essential for improving dialysis vascular access care. This paper reviews the fundamental concepts and requirements for us to move toward this vision.

Purpose The maturation of an arteriovenous fistula (AVF) requires remodeling of the arterial inflow and the venous outflow limbs to sustain flows sufficient to support hemodialysis. However, factors influencing remodeling of AVF are poorly understood. We hypothesized that AVF remodeling was an endothelium-dependent process. Methods This is a prospective cohort study of patients (n=25) undergoing autologous AVF formation. Brachial artery vasoreactivity studies were performed pre-operatively to assess endothelium-dependent, flow-mediated vasodilation (FMD). High-resolution ultrasound was used to assess venous and arterial diameters intraoperatively, and at 3 months. Results The mean age was 64.5 ± 13.6 yrs. Twelve patients (48%) had diabetes. The mean FMD for the entire cohort was (mean ± SEM) 5.82 ± 0.9%, (range) 0–17.3%. The vein increased in size 3.19 ± .28 to 6.11 ± .41 mm, 108.4 ± 17.9%, p=.0001, while the artery increased from 3.29 ± .14 to 4.48 ± .30 mm, 20.47 ± 10.8%, p=.013. There was a significant positive correlation between the degree of arterial and venous remodeling, r=.52, p=.023. Brachial artery FMD most strongly correlated with the magnitude of arterial remodeling, r=.47, p=.038. Patients with diabetes failed to undergo venous remodeling to the same extent as did those without diabetes, 59.2 ± 24.4% vs. 141.5 ± 25.4%, p=.04. Conclusion Impairment of endothelial function is associated with decreased arterial remodeling and final venous lumen diameter attained at 3 months. Further investigation is needed to determine whether modulation of endothelial function in this cohort can improve AVF maturation.

Our study, for the first time, implicates the interplay between the glycome and the transcriptome during vasculogenesis, and opens up the possibility of harnessing the right matrix for therapeutic vascularization.

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a hallmark of human cancer, occurring in a majority of tumors. Activation of this pathway is critical for transformation and also for the angiogenic switch, which is a key step for tumor progression. The objective of this study was to engineer a PI3K inhibitor-loaded biodegradable nanoparticle and to evaluate its efficacy. Here we report that a nanoparticle-enabled targeting of the PI3K pathway results in inhibition of downstream Akt phosphorylation, leading to inhibition of proliferation and induction of apoptosis of B16/F10 melanoma. It, however, failed to exert a similar activity on MDA-MB-231 breast cancer cells, resulting from reduced internalization and processing of nanoparticles in this cell line. Excitingly, the nanoparticle-enabled targeting of the PI3K pathway resulted in inhibition of endothelial cell proliferation and tubulogenesis, two key steps in tumor angiogenesis. Furthermore, it inhibited both B16/F10- and MDA-MB-231-induced angiogenesis in a zebrafish tumor xenotransplant model. Our study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.

The kidney and vasculature are intimately linked both functionally and during development, when nephric and blood/vascular progenitor cells occupy adjacent bands of mesoderm in zebrafish and frog embryos. Developmental mechanisms that underlie the differentiation of kidney versus blood/vascular lineages remain unknown. The odd skipped related1 (osr1)gene encodes a zinc-finger transcription factor that is expressed in the germ ring mesendoderm and subsequently in the endoderm and intermediate mesoderm,prior to the expression of definitive kidney or blood/vascular markers. Knockdown of osr1 in zebrafish embryos resulted in a complete,segment-specific loss of anterior kidney progenitors and a compensatory increase in the number of angioblast cells in the same trunk region. Histology revealed a subsequent absence of kidney tubules, an enlarged cardinal vein and expansion of the posterior venous plexus. Altered kidney versus vascular development correlated with expanded endoderm development in osr1knockdowns. Combined osr1 loss of function and blockade of endoderm development by knockdown of sox32/casanova rescued anterior kidney development. The results indicate that osr1 activity is required to limit endoderm differentiation from mesendoderm; in the absence of osr1, excess endoderm alters mesoderm differentiation, shifting the balance from kidney towards vascular development.

Gene array-type experiments have identified large numbers of genes thought to be important for the integrity of the glomerular slit diaphragm. Confirmation of individual proteins has been limited by the expenses and time involved in generating transgenic or knockout mice for each candidate. We present a functional screening assay based on the clearance of a 70-kDa fluorescent dextran in another vertebrate system that is rapid and low in cost. In the pronephric glomerulus of larval zebrafish, we have demonstrated quantifiable loss of slit diaphragm integrity in a zebrafish model of puromycin aminonucleoside (PA) toxicity. In addition, after knockdown of CD2-associated protein (CD2AP) and podocin, two well-characterized genetic contributors to podocyte differentiation in mammals, we observed glomerular loss of serum macromolecules similar to that seen in mammalian kidneys with inborn mutations in these genes. Increased filtration of 70-kDa FITC-labeled dextran correlates with effacement of podocyte foot processes in ultrastructural analysis. These findings document the value of the zebrafish model in genomics and pharmacological screening applications.

Limited knowledge exists on the role of the extracellular ‘glyco’ matrix on neovascularization. In this study, we integrated our novel glycome-sequencing platform with a chemical-genetic approach t...

Kidney disease in the 21(st) century affects increasing numbers of individuals. We continue to be challenged by our lack of understanding of the pathophysiology of acute and chronic renal disease including genetic diseases involving the kidney. Rodent knockout animals or inbred strains have greatly contributed to our understanding of many monogenetic and complex diseases. Non-rodent animal models of disease have become more attractive since genomic data has become available for a variety of organisms that offer distinct advantages over mice and rats for ease in conducting high-throughput chemical or mutagenesis screens. It is thus timely to examine the physiology and pathophysiology of the kidney or kidney equivalents in these organisms to evaluate their relevance as models for human disease. In addition to organisms whose small size and accessibility facilitate large scale screening approaches, larger animals at the other end of the spectrum offer unique physiological advantages in both size equivalency to humans as well as, in some cases, physiological and pathophysiological responses that closely mimic those of humans. Here we review a selected number of non-rodent experimental models of kidney diseases, focusing on recent advances in the use of the worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster, the zebrafish Danio rerio, the little skate Leucoraja erinacea, the MGH miniature swine, merino cross sheep, and the cow Bos taurus to study kidney disease.