Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

Donor-Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure.

Cardiovascular disease is the cause of death in ≈50% of hemodialysis patients. Accumulation of uremic solutes in systemic circulation is thought to be a key driver of the endothelial dysfunction that underlies elevated cardiovascular events. A challenge in understanding the mechanisms relating chronic kidney disease to cardiovascular disease is the lack of in vitro models that allow screening of the effects of the uremic environment on the endothelium. Here, a method is described for microfabrication of human blood vessels from donor cells and perfused with donor serum. The resulting donor-derived microvessels are used to quantify vascular permeability, a hallmark of endothelial dysfunction, in response to serum spiked with pathophysiological levels of indoxyl sulfate, and in response to serum from patients with chronic kidney disease and from uremic pigs. The uremic environment has pronounced effects on microvascular integrity as demonstrated by irregular cell-cell junctions and increased permeability in comparison to cell culture media and healthy serum. Moreover, the engineered microvessels demonstrate an increase in sensitivity compared to traditional 2D assays. Thus, the devices and the methods presented here have the potential to be utilized to risk stratify and to direct personalized treatments for patients with chronic kidney disease.

A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes.

In FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine albumin-to-creatinine ratio of 30-5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67-0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7-2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30-300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64-0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.

Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease.

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

Drug-coated balloons and dialysis vascular access: is there light at the end of the tunnel . . .

This commentary uses the negative results of the PAVE (Paclitaxel-coated Balloons and Angioplasty of Arteriovenous Fistulas) study to (i) discuss the role of drug-coated balloons in the armamentarium of therapies for dialysis vascular access stenosis and (ii) suggest a more patient centered, individualized, and precision medicine-based approach for the future care of patients with dialysis vascular access dysfunction.

Analyses of hemodialysis arteriovenous fistula geometric configuration and its associations with maturation and reintervention.

OBJECTIVE: An arteriovenous fistula (AVF) is the preferred vascular access for chronic hemodialysis; however, the rates of AVF maturation failure and reintervention remain high. We investigated the AVF geometric parameters and their associations with AVF physiologic maturation and reintervention in a prospective multicenter study. METHODS: From 2011 to 2016, patients undergoing vein end-to-artery side upper extremity AVF creation surgery were recruited. Contrast-free dark blood and phase-contrast magnetic resonance imaging (MRI) scans were performed using 3.0T scanners to obtain the AVF lumen geometry and flow rates, respectively, at postoperative day 1, week 6, and month 6. The arteriovenous anastomosis angle, nonplanarity, and tortuosity of the fistula were calculated according to the lumen centerlines. AVFs were considered physiologically matured if, using the week 6 MRI data, the flow rate was ≥500 mL/min and the minimum vein lumen diameter was ≥5 mm. The associations of these geometric parameters with AVF maturation and reintervention due to perianastomotic and mid-vein stenosis within 1 year were assessed. RESULTS: A total of 111 patients had a usable day 1 MRI scan, with most having upper arm AVFs (n = 73). Compared with the forearm AVFs, upper arm AVFs had greater anastomosis angles (P < .001), larger deviations from a plane (nonplanarity; P = .002), and more prominent tortuosity (P = .038) at day 1. These parameters significantly increased between day 1 and week 6 in upper arm AVFs. In contrast, significant changes in these parameters in forearm AVFs were not observed. The rate of maturation was 54% and 86% for forearm and upper arm AVFs, respectively. None of the geometric parameters at day 1 were associated with AVF maturation in either location. The rate of reintervention was 24% and 30% for forearm and upper arm AVFs, respectively, with a larger nonplanarity angle at day 1 associated with less reintervention (30° ± 15° vs 21° ± 10°; P = .034) in upper arm AVFs only. This relationship was unchanged after adjusting for age, sex, race, dialysis status, or diabetes. CONCLUSIONS: In our study, upper arm fistulas had a larger anastomosis angle, were more nonplanar, and had more tortuous veins than forearm fistulas. For upper arm fistulas, a larger nonplanarity angle is associated with a lower rate of reintervention within 1 year. Once confirmed, vascular surgeons could consider increasing the nonplanarity angle by incorporating a tension-free gentle curvature in the proximal segment of the mobilized vein to reduce reinterventions when creating an upper arm fistula.

Early Adventitial Activation and Proliferation in a Mouse Model of Arteriovenous Stenosis: Opportunities for Intervention.

BACKGROUND: Arteriovenous fistula (AVF) stenosis remains an important cause of AVF maturation failure, for which there are currently no effective therapies. We examined the pattern and phenotype of cellular proliferation at different timepoints in a mouse model characterized by a peri-anastomotic AVF stenosis. METHODS: Standard immunohistochemical analyses for cellular proliferation and macrophage infiltration were performed at 2, 7 and 14 d on our validated mouse model of AVF stenosis to study the temporal profile, geographical location and cellular phenotype of proliferating and infiltrating cells in this model. RESULTS: Adventitial proliferation and macrophage infiltration (into the adventitia) began at 2 d, peaked at 7 d and then declined over time. Surprisingly, there was minimal macrophage infiltration or proliferation in the neointimal region at either 7 or 14 d, although endothelial cell proliferation increased rapidly between 2 d and 7 d, and peaked at 14 d. CONCLUSIONS: Early and rapid macrophage infiltration and cellular proliferation within the adventitia could play an important role in the downstream pathways of both neointimal hyperplasia and inward or outward remodelling.

The Lutonix AV Randomized Trial of Paclitaxel-Coated Balloons in Arteriovenous Fistula Stenosis: 2-Year Results and Subgroup Analysis.

PURPOSE: To present final, 2-year results of a randomized trial comparing paclitaxel-coated vs uncoated balloon angioplasty following vessel preparation with ultra-high-pressure percutaneous transluminal angioplasty (PTA) in hemodialysis arteriovenous fistulae (AVFs). MATERIALS AND METHODS: Twenty-three sites enrolled 285 subjects with dysfunctional AVFs located in the arm. Before 1:1 randomization, successful vessel preparation was achieved (full waist effacement, < 30% residual stenosis). Follow-up was clinically driven except for a 6-month office visit. RESULTS: Ninety-six of 141 subjects in the drug-coated balloon (DCB) arm and 111 of 144 in the control arm completed the study. Target lesion primary patency (TLPP) rates for the DCB and control groups were 58% ± 4 vs 46% ± 4 (P = .02) at 9 months, 44% ± 5 vs 36% ± 4 (P = .04) at 12 months, 34% ± 5 vs 28% ± 4 (P = .06) at 18 months, and 27% ± 4 vs 24% ± 4 (P = .09) at 24 months, respectively. Mean time to TLPP event for subjects with an event was longer for DCBs (322 vs 207 d; P < .0001). Fewer interventions were needed to maintain target lesion patency in the DCB group at 9 months (P = .02) but not at 12 (P = .08), 18 (P = .13), or 24 months (P = .19). The noninferiority safety target was met at all intervals (P < .01). Mortality did not differ between groups (P = .27). Post hoc analyses showed equivalent DCB effect in all subgroups. CONCLUSIONS: Two-year results demonstrate long-term safety and variable efficacy of DCB angioplasty in AVFs.

A coming of age for vascular access research: the good, the bad, and the ugly!

Dialysis vascular access dysfunction remains an important clinical problem with a very significant morbidity, mortality, and socio-economic cost. Despite the magnitude of the clinical problem, there are currently no truly effective therapies for vascular access dysfunction. Through a high-quality scientific investigation, Liang et al. have identified a number of novel biological pathways responsible for "mouse" arteriovenous fistula stenosis. We hope that the identification of these druggable pathways (targets) will allow for the development of new and effective therapies for vascular access dysfunction, through the creation of an innovation substrate for dialysis vascular access.

Costs Attributable to Arteriovenous Fistula and Arteriovenous Graft Placements in Hemodialysis Patients with Medicare coverage.

INTRODUCTION: Hemodialysis (HD) in end-stage renal disease (ESRD) patients requires vascular access (VA) through an arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG), or a central venous catheter. While AVF or AVG is commonly used for HD, the economic implications of AVF versus AVG use have not been fully established. We describe the healthcare resource utilization and costs of AVF and AVG use for incident ESRD patients in the United States. METHODS: This observational cohort study of AVF and AVG placements used data from the United States Renal Data System to identify and follow access placements. AVF and AVG placements after ESRD onset for incident patients from 2012 to 2014 with continuous Medicare primary coverage were included. All-cause and access-related Medicare costs were averaged over the placement lifetime and expressed as per dialysis-month costs. RESULTS: The analysis included 38,035 AVF placements and 12,789 AVG placements. Total all-cause monthly costs for AVF averaged USD 8,508; mean monthly costs were USD 3,027 for inpatient (IP), USD 3,139 for outpatient (OP), USD 1,572 for physician services, and USD 770 for other care settings. Access-related monthly costs averaged USD 1,699 and represented 20% of all-cause charges for AVFs. Mean all-cause monthly costs for AVG were USD 9,605; by setting monthly costs were USD 3,811 for IP, USD 3,034 for OP, USD 1,881 for physician services and USD 879 for other care settings. Access-related monthly costs averaged USD 2,656 and represented 28% of all-cause charges for AVGs. DISCUSSION/CONCLUSIONS: This study indicates that costs due to VA are a significant burden on Medicare budgets and on patients. The factors driving access-related utilization and costs merit attention in future research. Both optimizing process of care and discovery innovation may significantly accelerate better stewardship of available healthcare resources.

Clinical Outcomes of Arteriovenous Access in Incident Hemodialysis Patients with Medicare Coverage, 2012-2014.

BACKGROUND: Chronic hemodialysis requires a mode of vascular access through an arteriovenous fistula (AVF), a prosthetic arteriovenous graft (AVG), or a central venous catheter (CVC). AVF is recommended over AVG or CVC due to increased patency and decreased intervention rates for those that mature. AVG are preferred over CVC due to decreased infection and mortality risk. The aims of this study were to evaluate the lifespan of AVF and AVG in maturation, sustained access use, and abandonment. METHODS: The United States Renal Data System (USRDS), Medicare claims, and CROWNWeb were used to identify access placements. Patients with a first end-stage renal disease (ESRD) service from January 1, 2012 to June 30, 2014 with continuous coverage with Medicare as primary payer and ≥1 AVF or AVG placed after ESRD onset were included. Maturation was defined as the first use of the access for hemodialysis recorded in CROWNWeb. Sustained access use was defined as 3 consecutive months of use without catheter placement or replacement. Accesses that were never used at any time post-placement were considered abandoned. RESULTS: The cohort included 38,035 AVF placements and 12,789 AVG placements. Sixty-nine percent of AVF and 72% of AVG matured. Fifty-two percent of AVF and 51% of AVG achieved sustained access use. One quarter of AVF and 14% of AVG were abandoned without use as recorded in CROWNWeb. CONCLUSION: Although considered the gold standard for vascular access, only half of AVF and AVG placements achieved sustained access use. The USRDS database has inherent limitations but provides useful clinical insight into maturation, sustained use, and abandonment.

Clinical and Economic Benefits of Stent Grafts in Dysfunctional and Thrombosed Hemodialysis Access Graft Circuits in the REVISE Randomized Trial.

PURPOSE: To compare reinterventions and associated costs to maintain arteriovenous graft hemodialysis access circuits after rescue with percutaneous transluminal angioplasty (PTA), with or without concurrent Viabahn stent grafts, over 24 months. MATERIALS AND METHODS: This multicenter (n = 30 sites) study evaluated reintervention number, type, and cost in 269 patients randomized to undergo placement of stent grafts or PTA alone. Outcomes were 24-month average cumulative number of reinterventions, associated costs, and total costs for all patients and in 4 groups based on index treatment and clinical presentation (thrombosed or dysfunctional). RESULTS: Over 24 months, the patients in the stent graft arm had a 27% significant reduction in the average number of reinterventions within the circuit compared to the PTA arm (3.7 stent graft vs 5.1 PTA; P = .005) and similar total costs ($27,483 vs $28,664; P = .49). In thrombosed grafts, stent grafts significantly reduced the number of reinterventions (3.7 stent graft vs 6.2 PTA; P = .022) and had significantly lower total costs compared to the PTA arm ($30,329 vs $37,206; P = .027). In dysfunctional grafts, no statistical difference was observed in the number of reinterventions or total costs (3.7 stent graft vs 4.4 PTA; P = .12, and $25,421 stent graft and $22,610 PTA; P = .14). CONCLUSIONS: Over 24 months, the use of stent grafts significantly reduced the number of reinterventions for all patients, driven by patients presenting with thrombosed grafts. Compared to PTA, stent grafts reduced overall treatment costs for patients presenting with thrombosed grafts and had similar costs for stenotic grafts.

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation.

BACKGROUND: The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. METHODS: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. RESULTS: Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. CONCLUSIONS: Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.

Relationship between dialytic parameters and reviewer confirmed arrhythmias in hemodialysis patients in the monitoring in dialysis study.

BACKGROUND: Hemodialysis patients have high rates of sudden death, but relationships between serum electrolytes, the dialysis prescription, and intra-dialytic shifts in fluid and electrolyte with arrhythmia are uncertain. METHODS: We analyzed sixty-six hemodialysis patients who underwent loop recorder implantation with continuous electrocardiographic monitoring, weekly to bi-weekly testing of pre- and post-dialysis electrolytes, and detailed capture of dialysis prescription and flow sheet data for 6 months. The incidence rate ratio (IRR) of reviewer confirmed arrhythmias (RCA) during dialysis through 8 h after dialysis and associations with serum chemistries and dialytic parameters were assessed using adjusted, negative-binomial regression. RESULTS: Among 66 individuals with a mean age of 56 years, 12,480 events were detected in 64 (97%) patients. RCA nadired 12-24 h after dialysis and increased during the final 12 h of the inter-dialytic interval through the first 8 h after dialysis. Higher pre-dialysis serum magnesium concentration was associated with lower incidence rate ratio for arrythmia (IRR per 1 mg/dL increase 0.49, 95% CI; 0.25, 0.94), as was dialysate calcium concentration > 2.5 mEq/L vs. 2.5 mEq/L (IRR 0.52, 95% CI: 0.39, 0.70). Neither intradialytic serum potassium nor weight change were significantly associated with RCA rate. However, there was effect modification such that arrhythmia rate was maximal with concurrently high intradialytic volume and potassium removal (Pinteraction = 0.01). CONCLUSIONS: Intra and post-dialytic arrhythmias are common in hemodialysis. Additional studies designed to further elucidate whether modification of the serum magnesium concentration, dialysate calcium concentration, and the extent of intradialytic potassium and fluid removal reduces the risk of per-dialytic arrhythmia are warranted. TRIAL REGISTRATION: Clinicaltrials.gov NCT01779856. Prospectively registered on January 22, 2013.

Prediction of Arteriovenous Fistula Clinical Maturation from Postoperative Ultrasound Measurements: Findings from the Hemodialysis Fistula Maturation Study.

BACKGROUND: The utility of early postoperative ultrasound measurements in predicting arteriovenous fistula (AVF) clinical maturation is uncertain. METHODS: We investigated the relationships of ultrasound parameters with AVF clinical maturation in newly created AVF, measured at 1 day and 2 and 6 weeks, in 602 participants of a multicenter, observational cohort study. A backward elimination algorithm identified ultrasound measurements that independently predicted unassisted and overall AVF maturation. Candidate variables included AVF blood flow, diameter, and depth, upper arm arterial diameter, presence of stenosis, presence of accessory veins, seven case-mix factors (age, sex, black race, AVF location, diabetes, dialysis status, and body mass index), and clinical center. We evaluated the accuracy of the resulting models for clinical prediction. RESULTS: At each ultrasound measurement time, AVF blood flow, diameter, and depth each predicted in a statistically significant manner both unassisted and overall clinical maturation. Moreover, neither the remaining ultrasound parameters nor case-mix factors were associated with clinical AVF maturation after accounting for blood flow, diameter, and depth, although maturation probabilities differed among clinical centers before and after accounting for these parameters. The crossvalidated area under the receiver operating characteristic curve for models constructed using these three ultrasound parameters was 0.69, 0.74, and 0.79 at 1 day and 2 and 6 weeks, respectively, for unassisted AVF clinical maturation and 0.69, 0.71, and 0.76, respectively, for overall AVF maturation. CONCLUSIONS: AVF blood flow, diameter, and depth moderately predicted unassisted and overall AVF clinical maturation. The other factors considered did not further improve AVF maturation prediction.

Primary outcomes of the Monitoring in Dialysis Study indicate that clinically significant arrhythmias are common in hemodialysis patients and related to dialytic cycle.

Sudden death is one of the more frequent causes of death for hemodialysis patients, but the underlying mechanisms, contribution of arrhythmia, and associations with serum chemistries or the dialysis procedure are incompletely understood. To study this, implantable loop recorders were utilized for continuous cardiac rhythm monitoring to detect clinically significant arrhythmias including sustained ventricular tachycardia, bradycardia, asystole, or symptomatic arrhythmias in hemodialysis patients over six months. Serum chemistries were tested pre- and post-dialysis at least weekly. Dialysis procedure data were collected at every session. Associations with clinically significant arrhythmias were assessed using negative binomial regression modeling. Sixty-six patients were implanted and 1678 events were recorded in 44 patients. The majority were bradycardias (1461), with 14 episodes of asystole and only one of sustained ventricular tachycardia. Atrial fibrillation, although not defined as clinically significant arrhythmias, was detected in 41% of patients. With thrice-weekly dialysis, the rate was highest during the first dialysis session of the week and was increased during the last 12 hours of each inter-dialytic interval, particularly the long interval. Among serum and dialytic parameters, only higher pre-dialysis serum sodium and dialysate calcium over 2.5 mEq/L were independently associated with clinically significant arrhythmias. Thus, clinically significant arrhythmias are common in hemodialysis patients, and bradycardia and asystole rather than ventricular tachycardia may be key causes of sudden death in hemodialysis patients. Associations with the temporal pattern of dialysis suggest that modification of current dialysis practices could reduce the incidence of sudden death.

Relationships Between Clinical Processes and Arteriovenous Fistula Cannulation and Maturation: A Multicenter Prospective Cohort Study.

BACKGROUND: Half of surgically created arteriovenous fistulas (AVFs) require additional intervention to effectively support hemodialysis. Postoperative care and complications may affect clinical maturation. STUDY DESIGN: Hemodialysis Fistula Maturation (HFM) Study, a 7-center prospective cohort study. SETTING & PARTICIPANTS: 491 patients with single-stage AVFs who had neither thrombosis nor AVF intervention before a 6-week postoperative ultrasonographic examination and who required maintenance hemodialysis. PREDICTORS: Postoperative care processes and complications. OUTCOMES: Attempted cannulation, successful cannulation, and unassisted and overall clinical maturation as defined by the HFM Study criteria. RESULTS: AVF cannulation was attempted in 443 of 491 (90.2%) participants and was eventually successful in 430 of these 443 (97.1%) participants. 263 of these 430 (61.2%) reached unassisted and 118 (27.4%) reached assisted AVF maturation (overall maturation, 381/430 [88.6%]). Attempted cannulation was less likely in patients of surgeons with policies for routine 2-week versus later-than-2-week first postoperative visits (OR, 0.21; 95% CI, 0.06-0.70), routine second postoperative follow-up visits (OR, 0.39; 95% CI, 0.15-0.97), and a routine clinical postoperative ultrasound (OR, 0.28; 95% CI, 0.14-0.55). Attempted cannulation was also less likely among patients undergoing procedures to assist maturation (OR, 0.51; 95% CI, 0.27-0.98). Unassisted maturation was more likely for patients treated in facilities with access coordinators (OR, 1.91; 95% CI, 1.17-3.12), but less likely after precannulation nonstudy ultrasounds (OR per ultrasound, 0.42 [95% CI, 0.26-0.68]) and initial unsuccessful cannulation attempts (OR per each additional attempt, 0.90 [95% CI, 0.83-0.98]). Overall maturation was less likely with infiltration before successful cannulation (OR, 0.44; 95% CI, 0.22-0.89). Among participants receiving maintenance hemodialysis before AVF surgery, unassisted and overall maturation were less likely with longer intervals from surgery to initial cannulation (ORs for each additional month of 0.81 [95% CI, 0.76-0.88] and 0.93 [95% CI, 0.89-0.98], respectively) and from initial to successful cannulation (ORs for each additional week of 0.87 [95% CI, 0.81-0.94] and 0.88 [95% CI, 0.83-0.94], respectively). LIMITATIONS: Surgeons' management policies were assessed only by questionnaire at study onset. Most participants received upper-arm AVFs, planned 2-stage AVFs were excluded, and maturation time windows were imposed. Some care processes may have been missed and the observational design limits causal attribution. CONCLUSIONS: Multiple processes of care and complications are associated with AVF maturation outcomes.

Comparison of hemodialysis arteriovenous fistula blood flow rates measured by Doppler ultrasound and phase-contrast magnetic resonance imaging.

OBJECTIVE: The objective of this study was to compare blood flow rates measured by Doppler ultrasound (DUS) and phase-contrast magnetic resonance imaging (MRI) in patients having a hemodialysis arteriovenous fistula (AVF) and to identify scenarios in which there was significant discordance between these two approaches. METHODS: Blood flow rates in the proximal artery (PA) and draining vein (DV) of newly created upper extremity AVFs were measured and compared using DUS and phase-contrast MRI at 1 day, 6 weeks, and 6 months postoperatively. RESULTS: Blood flow rates in the PA measured by DUS (1155 ± 907 mL/min, mean ± standard deviation) and by MRI (1170 ± 657 mL/min) were not statistically different (P = .812) based on 78 data pairs from 49 patients. DV DUS flow (1277 ± 995 mL/min) and MRI flow (1130 ± 655 mL/min) were also not statistically different (P = .071) based on 64 data pairs. In both PA and DV, the two methods substantially agreed with each other (Cohen κ: PA, 0.66; DV, 0.67) when flow rates were put into four clinically relevant categories (<300, 300-599, 600-1499, and ≥1500 mL/min). The Bland-Altman analyses of DUS and MRI flow identified six and four outliers for PA and DV, respectively. Seven outliers had higher DUS than MRI flow, with all DUS scan sites having a large lumen or significant local curvature; the other three had lower DUS flow, partly due to an underestimation of lumen diameter by DUS. CONCLUSIONS: DUS and MRI flow rates are generally comparable in both PA and DV. When DUS is used for flow measurements, careful attention to accurate lumen diameter measurements is needed and scan sites with marked curvature should be avoided. Our result may improve the accuracy of DUS-measured AVF blood flow rate.

Effect of Anti-Hypertensive Medication History on Arteriovenous Fistula Maturation Outcomes.

BACKGROUND: The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis. However, approximately half of AVFs fail to mature. The use of angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) exerts favorable endothelial effects and may promote AVF maturation. We tested associations of ACE-I and ARBs, CCBs, beta-blockers, and diuretics with the maturation of newly created AVFs. METHODS: We evaluated 602 participants from the Hemodialysis Fistula Maturation Study, a multi-center, prospective cohort study of AVF maturation. We ascertained the use of each medication class within 45 days of AVF creation surgery. We defined maturation outcomes by clinical use within 9 months of surgery or 4 weeks of initiating hemodialysis. RESULTS: Unassisted AVF maturation failure without intervention occurred in 54.0% of participants, and overall AVF maturation failure (with or without intervention) occurred in 30.1%. After covariate adjustment, CCB use was associated with a 25% lower risk of overall AVF maturation failure (95% CI 3%-41% lower) but a non-significant 10% lower risk of unassisted maturation failure (95% CI 23% lower to 5% higher). ACE-I/ARB, beta-blocker, and diuretic use was not significantly associated with AVF maturation outcomes. None of the antihypertensive medication classes were associated with changes in AVF diameter or blood flow over 6 weeks following surgery. CONCLUSIONS: CCB use may be associated with a lower risk of overall AVF maturation failure. Further studies are needed to determine whether CCBs might play a causal role in improving AVF maturation outcomes.

The pathogenesis of hemodialysis vascular access failure and systemic therapies for its prevention: Optimism unfulfilled.

In patients receiving hemodialysis, the provision of safe and effective vascular access using an arteriovenous fistula or graft is regarded as a critical priority by patients and health professionals. Vascular access failure is associated with morbidity and mortality, such that strategies to prevent these outcomes are essential. Inadequate vascular remodeling and neointimal hyperplasia resulting in stenosis and frequently thrombosis are critical to the pathogenesis of access failure. Systemic medical therapies with pleiotropic effects including antiplatelet agents, omega-3 polyunsaturated fatty acids (fish oils), statins, and inhibitors of the renin-angiotensin-aldosterone system (RAAS) may reduce vascular access failure by promoting vascular access maturation and reducing stenosis and thrombosis through antiproliferative, antiaggregatory, anti-inflammatory and vasodilatory effects. Despite such promise, the results of retrospective analyses and randomized controlled trials of these agents on arteriovenous fistula and graft outcomes have been mixed. This review describes the current understanding of the pathogenesis of arteriovenous fistula and graft failure, the biological effects of antiplatelet agents, fish oil supplementation, RAAS blockers and statins that may be beneficial in improving vascular access survival, results from clinical trials that have investigated the effect of these agents on arteriovenous fistula and graft outcomes, and it explores future therapeutic approaches combining these agents with novel treatment strategies.