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BACKGROUND: Bradycardia and asystole events are common among patients treated with maintenance hemodialysis. However, triggers of these events in patients on maintenance hemodialysis (HD), particularly during the long interdialytic period when these events cluster, are uncertain. METHODS: The Monitoring in Dialysis Study (MiD) enrolled 66 patients on maintenance HD who were implanted with loop recorders and followed for 6 months. We analyzed associations of predialysis laboratory values with clinically significant bradyarrhythmia or asystole (CSBA) during the 12 hours before an HD session. Associations with CSBA were analyzed with mixed-effect models. Adjusted negative binomial mixed-effect regression was used to estimate incidence rate ratios (IRR) for CSBA. We additionally evaluated associations of CSBA at any time during follow-up with time-averaged dialytic and laboratory parameters and associations of peridialytic parameters with occurrence of CSBA from the start of one HD session to the beginning of the next. RESULTS: There were 551 CSBA that occurred in the last 12 hours of the interdialytic interval preceding 100 HD sessions in 12% of patients and 1475 CSBA events in 23% of patients overall. We did not identify significant associations between dialytic parameters or serum electrolytes and CSBA in the last 12 hours of the interdialytic interval in adjusted analyses. Median time-averaged ultrafiltration rate was significantly higher in individuals without CSBA (9.8 versus 8, P=0.04). Use of dialysate sodium concentrations ≤135 (versus 140) mEq/L was associated with a reduced risk of CSBA from the start of one session to the beginning of next. CONCLUSIONS: Although a few factors had modest associations with CSBA in some analyses, we did not identify any robust associations of modifiable parameters with CSBA in the MiD Study. Further investigation is needed to understand the high rates of arrhythmia in the hemodialysis population.

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.

Individuals receiving long-term hemodialysis are at increased risk of developing cardiovascular disease (CVD). Traditional cardiovascular risk factors do not fully explain the high CVD risk in this population. During hemodialysis, blood interacts with the biomaterials of the hemodialysis circuit. This interaction can activate the complement system and the factor XII-driven contact system. FXII activation triggers both the intrinsic pathway of coagulation and the kallikrein-kinin pathway, resulting in thrombin and bradykinin production, respectively. The complement system plays a key role in the innate immune response, but also contributes to the pathogenesis of numerous disease states. Components of the complement pathway, including mannose binding lectin and C3, are associated with CVD risk in people with end-stage kidney disease (ESKD). Both the complement system and the factor XII-driven contact coagulation system mediate proinflammatory and procoagulant responses that could contribute to or accelerate CVD in hemodialysis recipents. This review summarizes what is already known about hemodialysis-mediated activation of the complement system and in particular the coagulation contact system, emphasizing the potential role these systems play in the identification of new biomarkers for CVD risk stratification and the development of potential therapeutic targets or innovative therapies that decrease CVD risk in ESKD patients.

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. Meth...

BACKGROUND: There is a paucity of contemporary data examining electrolyte changes during and immediately after hemodialysis (HD), and their relationship with dialysate prescriptions. The present study examines these relationships. METHODS: We analyzed patient- (n=66) and HD session-level pre- and post-dialysis laboratory data (n=1,713) over a six-month period from the Monitoring in Dialysis Study. We fit mixed effects regression models to analyze electrolyte, blood urea nitrogen, creatinine, and albumin levels immediately post-HD, accounting for pre-HD and dialysate prescriptions. In a subset of US patients (n=40), 15-minute post-HD and 30-minute post-HD values were available at one session. Predictive models were fit to estimate electrolyte levels immediately post-HD, accounting for pre-HD concentrations and dialysate prescriptions. RESULTS: Serum bicarbonate, calcium, and albumin increased (mean increase 4.9±0.3 mEq/L, 0.7±0.1 mEq/L, and 0.4±0.03 g/dL, respectively), whereas potassium, magnesium, and phosphorus decreased immediately post-HD (mean −1.2±0.1 mEq/L, −0.3±0.03 mEq/L, and −3.0±0.2 mg/dL, respectively). Hypokalemia and hypophosphatemia were present in 40% of and 67% of immediate post-HD samples, respectively. Dynamic changes were observed in electrolyte concentrations at 15- and 30-minutes post-HD, compared to immediately post-HD. CONCLUSION: We describe the magnitude of post-dialytic changes in serum electrolytes with contemporary HD, reporting a high incidence of electrolyte abnormalities post-HD, and present predictive nomograms relating electrolyte changes immediately post-HD to dialysate prescriptions. Our results may be useful for clinical care and provide insights for future research on dialysate prescriptions.

The FINE-CKD model was developed to estimate the cost-effectiveness of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).To perform internal and external validation by comparing the model estimates with trial results and outcomes from other models.Incidence rates from trials were compared with the model predictions. Statistical tests were then performed to assess whether modeled event rates aligned with trial observations. A cross-validation was also performed using the online version of the SHARP CKD-Cardiovascular Disease (SHARP CKD-CVD) model, with population characteristics from the finerenone trials analyzed. Where no finerenone data were available, the default SHARP CKD-CVD values were used. Comparison of the results considered the ranges from both models.The outcomes of the FINE-CKD model reflect the event rates observed in the trials. Based on the results of the statistical tests, the hypothesis of no difference between observed and modeled events cannot be rejected for any of the outcomes. The results of the FINE-CKD model are within the ranges from the SHARP CKD-CVD model. Disease progressions align across the models; however, incident kidney failure events in the SHARP CKD-CVD model were higher. This can be explained by simulation of more severely affected patients in the SHARP CKD-CVD model.This study demonstrates that the FINE-CKD model adequately reflects the clinical data and provides reliable extrapolation relative to the existing predictive tools while also being conservative in its approach.

Cannulation is not only one of the most common medical procedures but also fraught with complications. The skill of the clinician performing cannulation directly impacts cannulation outcomes. However, current methods of teaching this skill are deficient, relying on subjective demonstrations and unrealistic manikins that have limited utility for skills training. Furthermore, of the factors that hinders effective continuing medical education is the assumption that clinical experience results in expertise. In this work, we examine if objective metrics acquired from a novel cannulation simulator are able to distinguish between experienced clinicians and established experts, enabling the measurement of true expertise. Twenty-two healthcare professionals, who practiced cannulation with varying experience, performed a simulated arteriovenous fistula cannulation task on the simulator. Four clinicians were peer-identified as experts while the others were designated to the experienced group. The simulator tracked the motion of the needle (via an electromagnetic sensor), rendered blood flashback function (via an infrared light sensor), and recorded pinch forces exerted on the needle (via force sensing elements). Metrics were computed based on motion, force, and other sensor data. Results indicated that, with near 80% of accuracy using both logistic regression and linear discriminant analysis, the objective metrics differentiated between experts and the experienced, including identifying needle motion and finger force as two prominent features that distinguished between the groups. Furthermore, results indicated that expertise was not correlated with years of experience, validating the central hypothesis of the study. These insights contribute to structured and standardized medical skills training by enabling a meaningful definition of expertise and could potentially lead to more effective skills training methods.

In accordance with the recently released Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, there is a significant need for focused efforts on improving hemodialysis cannulation outcomes. Toward this, structured and meaningful training of our clinical personnel who cannulate in dialysis clinics is a priority. With the availability of advanced sensors and computing methods, simulators could be indispensable tools for standardized skills assessment and training. In this article we present ways in which sensor data could be used to quantify cannulation skill. As with many other medical specialties, implementation of simulator-based training holds the promise of much-needed improvement in end-stage kidney disease patient outcomes.

Advances in standards of care have extended the life expectancy of patients with kidney failure. However, options for chronic vascular access for haemodialysis — an essential part of kidney replacement therapy — have remained unchanged for decades. The high morbidity and mortality associated with current vascular access complications highlights an unmet clinical need for novel techniques in vascular access and is driving innovation in vascular access care. The development of devices, biological approaches and novel access techniques has led to new approaches to controlling fistula geometry and manipulating the underlying cellular and molecular pathways of the vascular endothelium, and influencing fistula maturation and formation through the use of external mechanical methods. Innovations in arteriovenous graft materials range from small modifications to the graft lumen to the creation of completely novel bioengineered grafts. Steps have even been taken to create new devices for the treatment of patients with central vein stenosis. However, these emerging therapies face difficult hurdles, and truly creative approaches to vascular access need resources that include well-designed clinical trials, frequent interaction with regulators, interventionalist education and sufficient funding. In addition, the heterogeneity of patients with kidney failure suggests it is unlikely that a ‘one-size-fits-all’ approach for effective vascular access will be feasible in the current environment.

BACKGROUND AND OBJECTIVES: Patients receiving maintenance hemodialysis (HD) have a high incidence of cardiac events, including arrhythmia and sudden death. Intradialytic hypotension (IDH) is a common complication of HD and is associated with development of reduced myocardial perfusion, a potential risk factor for arrhythmia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed data from the Monitoring in Dialysis study, which used implantable loop recorders to detect and continuously monitor electrocardiographic data from patients on maintenance HD (n=66 from the United States and India) over a 6-month period (n=4720 sessions). Negative binomial mixed effects regression was used to test the association of IDH(20) (decline in systolic BP >20 mm Hg from predialysis systolic BP) and IDH(0–20) (decline in systolic BP 0–20 mm Hg from predialysis systolic BP) with clinically significant arrhythmia (bradycardia≤40 bpm for ≥6 seconds, asystole≥3 seconds, ventricular tachycardia ≥130 bpm for ≥30 seconds, or patient-marked events) during HD. RESULTS: The median age of participants was 58 (25th–75th percentile, 49–66) years; 70% were male; and 65% were from the United States. IDH occurred in 2251 (48%) of the 4720 HD sessions analyzed, whereas IDH(0–20) occurred during 1773 sessions (38%). The number of sessions complicated by least one intradialytic clinically significant arrhythmia was 27 (1.2%) where IDH(20) occurred and 15 (0.8%) where IDH(0–20) occurred. Participants who experienced IDH(20) (versus not) had a nine-fold greater rate of developing an intradialytic clinically significant arrhythmia (incidence rate ratio, 9.4; 95% confidence interval, 3.0 to 29.4), whereas IDH(0–20) was associated with a seven-fold higher rate (incidence rate ratio, 7.2; 95% confidence interval, 2.1 to 25.4). CONCLUSIONS: IDH is common in patients on maintenance HD and is associated with a greater risk of developing intradialytic clinically significant arrhythmia.

Background Blood flow-induced wall shear stress (WSS) is a strong local regulator of vascular remodeling, but its effects on arteriovenous fistula (AVF) remodeling are unclear. Methods In this prospective cohort study, we used statistical mixed-effects modeling to investigate the associations between WSS and AVF remodeling in 120 participants undergoing AVF creation surgery. Postoperative magnetic resonance imaging data at 1 day, 6 weeks, and 6 months were used to derive current WSS by computational fluid dynamic simulations and to quantify subsequent changes in AVF lumen cross-sectional area at 1-mm intervals along the proximal artery and AVF vein. Results Combining artery and vein data, prior mean WSS was significantly associated with lumen area expansion. Mean WSS at day 1 was significantly associated with lumen area change from day 1 to week 6 (11% larger week-6 area per IQR increase in day-1 mean WSS, 95% CI 5%-18%; n=101), and mean WSS at 6 weeks was significantly associated with lumen area change from week 6 to month 6 (14% larger area per IQR increase, 95% CI 3%-28%; n=52). The association of mean WSS at day 1 with lumen area expansion from day 1 to week 6 differed significantly by diabetes (p=0.009): 27% (95% CI 17%-37%) larger area per IQR increase in mean WSS without diabetes, and 9% (95% CI -1-19%) with diabetes. Day-1 oscillatory shear index (OSI) was significantly associated with lumen area change from day 1 to week 6 (5% smaller area per IQR increase in OSI, 95% CI 3%-7%), and OSI at week 6 was significantly associated with lumen change from week 6 to month 6 (7% smaller area per IQR increase in OSI, 95% CI 2%-11%). WSS spatial gradient was not significantly associated with subsequent remodeling. In a joint model, WSS and OSI statistically significantly interacted in their associations with lumen area expansion in a complex nonlinear fashion. Conclusion Higher WSS and lower OSI were associated with greater lumen expansion after AVF creation surgery.

Albuminuria is useful for early screening and diagnosis of kidney impairment, especially in people with pre-diabetes or type 2 diabetes (T2D), which is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD), associated with increased mortality, poor cardiovascular outcomes, and high economic burden. Identifying patients with CKD who are most likely to progress to ESKD permits timely implementation of appropriate interventions. The early stages of CKD are asymptomatic, which means identification of CKD relies on routine assessment of kidney damage and function. Both albuminuria and estimated glomerular filtration rate are measures of kidney function. This review discusses albuminuria as a marker of kidney damage and cardiorenal risk, highlights the importance of early screening and routine testing for albuminuria in people with T2D, and provides new insights on the optimum management of CKD in T2D using albuminuria as a target in a proposed algorithm. Elevated urine albumin can be used to detect CKD in people with T2D and monitor its progression; however, obstacles preventing early detection exist, including lack of awareness of CKD in the general population, poor adherence to clinical guidelines, and country-level variations in screening and treatment incentives. With albuminuria being used as an entry criterion and a surrogate endpoint for kidney failure in clinical trials, and with novel treatment interventions available to prevent CKD progression, there is an urgent need for early screening and diagnosis of kidney function decline in people with T2D or pre-diabetes.

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.

Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications.To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD.A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review.The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.

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.

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.

Importance National initiatives have emphasized the use of autogenous arteriovenous fistulas (AVFs) for hemodialysis, but their purported benefits have been questioned. Objective To examine AVF usability, longer-term functional patency, and remedial procedures to facilitate maturation, manage complications, or maintain patency in the Hemodialysis Fistula Maturation (HFM) Study. Design, setting, and participants The HFM Study was a multicenter (n = 7) prospective National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases cohort study performed to identify factors associated with AVF maturation. A total of 602 participants were enrolled (dialysis, kidney failure: 380; predialysis, chronic kidney disease [CKD]: 222) with AVF maturation ascertained for 535 (kidney failure, 353; CKD, 182) participants. Interventions All clinical decisions regarding AVF management were deferred to the individual centers, but remedial interventions were discouraged within 6 weeks of creation. Main outcomes and measures In this case series analysis, the primary outcome was unassisted maturation. Functional patency, freedom from intervention, and participant survival were summarized using Kaplan-Meier analysis. Results Most participants evaluated (n = 535) were men (372 [69.5%]) and had diabetes (311 [58.1%]); mean (SD) age was 54.6 (13.6) years. Almost two-thirds of the AVFs created (342 of 535 [64%]) were in the upper arm. The AVF maturation rates for the kidney failure vs CKD participants were 29% vs 10% at 3 months, 67% vs 38% at 6 months, and 76% vs 58% at 12 months. Several participants with kidney failure (133 [37.7%]) and CKD (63 [34.6%]) underwent interventions to facilitate maturation or manage complications before maturation. The median time from access creation to maturation was 115 days (interquartile range [IQR], 86-171 days) but differed by initial indication (CKD, 170 days; IQR, 113-269 days; kidney failure, 105 days; IQR, 81-137 days). The functional patency for the AVFs that matured at 1 year was 87% (95% CI, 83.2%-90.2%) and at 2 years, 75% (95% CI, 69.7%-79.7%), and there was no significant difference for those receiving interventions before maturation. Almost half (188 [47.5%]) of the AVFs that matured had further intervention to maintain patency or treat complications. Conclusions and relevance The findings of this study suggest that AVF remains an accepted hemodialysis access option, although both its maturation and continued use require a moderate number of interventions to maintain patency and treat the associated complications.

Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis vascular access and their successful maturation is critical to reduce patient morbidity, mortality, cost, and improve quality of life. Peri-anastomotic venous segment stenosis is the primary cause of AVF maturation failure. The objective is to develop a software protocol for the functional analysis of arteriovenous fistula.We have developed a standard protocol for the anatomical analysis of the AVF to better understand the mechanisms involved in AVF stenosis and to identify future imaging biomarkers for AVF success or failure using non-contrast magnetic resonance imaging (MRI). The 3D model of the AVF is created using a polar dynamic programming technique. Analysis has been performed on six Yorkshire cross domestic swine, but techniques can be applied into clinical settings.Differences in AVF angles and vein curvature are associated with significant variability of venous cross-sectional area. This suggests that the pattern of stenosis is likely to be dependent upon hemodynamic profiles which are largely determined by AVF anatomical features and could play an important role in AVF maturation.This protocol enables us to visualize and study the hemodynamic profiles indirectly allowing early stratification of patients into high and low risk groups for AVF maturation failure. High risk patients could then be targeted with an enhanced process of care or future maturation enhancing therapies resulting in a much-needed precision-medicine approach to dialysis vascular access.

While access-related dysfunction is a clear driver of clinical outcomes and costs, the full impact of vascular access dysfunction on patient experience and quality of life is not fully characterized in the literature. One way to more comprehensively characterize the patient experience from the patient perspective is through patient reported outcomes (PROs). However, the limited implementation of PROs in clinical trials, patient registries, quality measurement, and other research settings has significantly constrained the patient voice in evaluation of vascular access outcomes and vascular access decision-making. To address these issues, the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and the U.S. Food and Drug Administration, assembled an interdisciplinary workgroup to enhance uptake of access-related PROs with the aims of: (1) reviewing the domains of HRQOL that are affected by vascular access, collect information on existing instruments that measure access-specific HRQOL in hemodialysis, and identify gaps in existing measures; (2) identifying and critically assessing barriers to widespread use of access-specific PRO measures; and (3) defining initiatives to overcome barriers and make recommendations for strategies to improve the use and utility of access-specific PRO measures. A consensus group process identified potential barriers to use of PRO measures in six categories: (1) PRO misperceptions, (2) patient factors, (3) regulators and payers, (4) instrument factors, (5) study design, and (6) physicians. The workgroup provided recommendations for actions to promote the widespread utilization of vascular access-related PRO measures in five categories: (1) development of vascular access-specific PRO measures, (2) ensuring comprehensive assessment when using vascular access PRO measures, (3) ensuring accessibility and applicability of vascular access PRO measures to all end stage kidney disease populations, (4) establishing universal guidelines and accepted vascular access PRO measures, and (5) engaging stakeholders across all facets.

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.

Background and Aims Vadadustat is a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylases under development to treat anemia associated with chronic kidney disease (CKD). The vadadustat phase 3 program includes four efficacy and cardiovascular safety outcome trials of vadadustat versus the erythropoiesis-stimulating agent (ESA) darbepoetin alfa. Here we describe detailed results on hematologic efficacy in two phase 3, randomized trials (the PRO2TECT trials) in adult patients with non–dialysis-dependent (NDD) CKD and anemia, in which vadadustat met prespecified noninferiority criteria compared to darbepoetin alfa, with respect to hematologic efficacy (correction/maintenance of hemoglobin [Hb] target concentrations). Method The mean screening Hb level for the ESA-untreated NDD-CKD trial (NCT02648347) had to be Results A total of 3,476 patients (1751 ESA-untreated and 1725 ESA-treated) were randomized 1:1 to vadadustat or darbepoetin alfa. In both trials, vadadustat was noninferior to darbepoetin alfa with regard to the difference of mean change in Hb concentrations between baseline and PEP, as well as between baseline and SEP. The respective proportions of patients (vadadustat vs. darbepoetin alfa) with an average Hb value within the geography-specific target range in the PEP and SEP were 50.4% versus 50.2% and 43.1% versus 43.5% in the ESA-untreated trial and 60.1% versus 60.7% and 50.7% versus 49.0% in the ESA-treated trial. The proportion of patients (vadadustat vs darbepoetin alfa) who achieved an Hb increase >1.0 g/dL from baseline to week 52 was assessed only for the ESA-untreated trial and was 87.7% (95% CI: 85.4%, 89.8%) for vadadustat versus 88.0% (95% CI: 85.6%, 90.0%) for darbepoetin alfa. Hematologic parameters at time points within the PEP and SEP are presented in Table 1. In both the ESA-untreated and ESA-treated trials, the reticulocyte count trended up from baseline through week 52 for vadadustat and trended down from baseline for darbepoetin alfa. Trends in erythrocyte mean corpuscular volume and erythrocyte mean corpuscular Hb were largely unremarkable by week 52 in both treatment groups. Conclusion Vadadustat demonstrated similar profiles across erythrocyte parameters compared with darbepoetin alfa in the treatment of adults with anemia in CKD not on dialysis, whether ESA-untreated or ESA-treated at study entry.

Haemodialysis vascular access (VA) dysfunction is a major cause of morbidity in haemodialysis (HD) patients. Primary venous outflow occlusion and restenosis after percutaneous transluminal angioplasty (PTA) are two major obstacles for the long-term use of dialysis VA. It remains unclear whether oxidative stress markers can be used as predictors for thrombotic occlusion of VA and progressive stenosis dysfunction demanding PTA. All routine HD patients at one teaching hospital participated in this study including ankle-brachial index (ABI) examinations and serum oxidative stress markers. The serum oxidative stress markers (high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase-2 (MMP-2), MMP-9, homocysteine, asymmetrical dimethylarginine (ADMA), nitrate oxidase (NO), tumour necrosis factor-α (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-1β (IL-1β), and transforming growth factor-β (TGF-β)) were measured using immunosorbent assays in 159 HD patients (83 men and 76 women, mean age: 65 ± 12 years). The participants met the following criteria: (1) received regular HD treatment for at least 6 months, without clinical evidence of acute or chronic inflammation, recent myocardial infarction, unstable angina or circulatory congestion, and (2) received an arteriovenous fistula (AVF)/arteriovenous graft (AVG: polytetrafluoroethylene, PTFE) as the current VA for more than 6 months, without interventions within the last 6 months. All the participants were followed up clinically for up to 12 months to estimate the amount of primary thrombotic occlusion and VA dysfunction demanding PTA. During the 12-month observation, 24 patients (15.1%) had primary thrombotic occlusion of VAs. Another 24 patients (15.1%) required PTA because of clinical dysfunction of access. Additionally, during the follow-up period, restenosis occurred in 12 patients (50% of 24 patients). The access types of arteriovenous grafts (AVGs) and a diagnosis of peripheral arterial occlusive disease (PAOD) were two strong predictors for acute thrombotic events of VA (hazard ratio (HR): 16.93 vs. 2.35, p &lt, 0.001 vs. 0.047). Comparing dysfunctional with non-dysfunctional VAs, up to 27.7% of patients with high levels of ADMA (&gt, 0.6207 μM, N = 65) received required PTA compared with 4.4% of those with low levels (≤0.6207 μM, N = 90, 0.001). In multivariate analysis, the plasma baseline levels of ADMA independently conferred nearly 4.55 times the risk of primary stenotic dysfunction of HD VA (HR: 4.55, 95% confidence interval: 1.20 to 17.26, p = 0.026). In conclusion, our findings suggest the role of ADMA in the development of symptomatic VA dysfunction. Additionally, PAOD severity can be used in clinical practice to predict whether acute thrombotic occlusion of VA will easily occur in HD patients.

Supplemental material, sj-pdf-1-jva-10.1177_11297298211018295 for Patient-reported outcomes in hemodialysis vascular access: A call to action by Karen Woo, Robert Fuld, Amanda Grandinetti, Jeffrey Lawson, Terry Litchfield, Mark Ohan, John Devin Peipert, Matthew B Rivara, Glenda Roberts, Prabir Roy-Chaudhury, Margo Underwood and Robert J Nordyke in The Journal of Vascular Access

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.

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.

Individuals with dialysis-dependent kidney failure experience considerable disease- and treatment-related decline in functional status and overall well-being. Despite these experiences, there have been few substantive technological advances in KRT in decades. As such, new federal initiatives seek to accelerate innovation. Historically, integration of patient perspectives into KRT product development has been limited. However, the US Food and Drug Administration recognizes the importance of incorporating patient perspectives into the total product life cycle (i.e., from product conception to postmarket surveillance) and encourages the consideration of patient-reported outcomes in regulatory-focused clinical trials when appropriate. Recognizing the significance of identifying patient-reported outcome measures (PROMs) that capture contemporary patient priorities, the Kidney Health Initiative, a public–private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a workgroup to (1) develop a conceptual framework for a health-related quality of life PROM; (2) identify and map existing PROMs to the conceptual framework, prioritizing them on the basis of their supporting evidence for use in the regulatory environment; and (3) describe next steps for identifying PROMs for use in regulatory clinical trials of transformative KRT devices. This paper summarizes the proposed health-related quality-of-life PROM conceptual framework, maps and prioritizes PROMs, and identifies gaps and future needs to advance the development of rigorous, meaningful PROMS for use in clinical trials of transformative KRT devices.