Identification of inflammatory clusters in long-COVID through analysis of plasma biomarker levels.

Mechanisms underlying long COVID remain poorly understood. Patterns of immunological responses in individuals with long COVID may provide insight into clinical phenotypes. Here we aimed to identify these immunological patterns and study the inflammatory processes ongoing in individuals with long COVID. We applied an unsupervised hierarchical clustering approach to analyze plasma levels of 42 biomarkers measured in individuals with long COVID. Logistic regression models were used to explore associations between biomarker clusters, clinical variables, and symptom phenotypes. In 101 individuals, we identified three inflammatory clusters: a limited immune activation cluster, an innate immune activation cluster, and a systemic immune activation cluster. Membership in these inflammatory clusters did not correlate with individual symptoms or symptom phenotypes, but was associated with clinical variables including age, BMI, and vaccination status. Differences in serologic responses between clusters were also observed. Our results indicate that clinical variables of individuals with long COVID are associated with their inflammatory profiles and can provide insight into the ongoing immune responses.

First-in-human evaluation of a biological regenerative vascular conduit for hemodialysis access.

INTRODUCTION: The long-term survival and low complication rate of autogenous fistulas for hemodialysis access is often offset by early thrombosis and slow or failed maturation leading to the use of central venous catheters. A regenerative material may have the potential to overcome these limitations. A completely biological acellular vascular conduit was investigated in this first-in-human clinical study. METHODS: With approval of the ethics board and patients' informed consent, five subjects were enrolled based on predetermined inclusion criteria. Five patients underwent implant of a novel acellular, biological tissue conduit (TRUE AVC™) in the upper arm in a curved configuration between brachial artery and axillary vein. After maturation, standard dialysis was commenced through the new access. Patients were followed up to 26 weeks with ultrasound and physical exam. Serum samples were evaluated for an immune response to the novel allogeneic human tissue implant. RESULTS: This new tissue conduit handled well surgically, with properties similar to that of native human vein. Post procedure conduit flow was excellent in all cases, averaging 1098 ± 388 ml/min at week 4 and remaining stable through 1248 ± 355 ml/min at 26 weeks. Surgical site healing was normal with no edema or erythema by week 4. Six-month primary assisted patency was 80% and secondary patency was 100%. Prescribed dialysis was successfully delivered without infection, and there was no significant change in conduit diameter. Serum testing showed no increase in PRA or IgG specific to the TRUE AVC. One implant required intervention at 5 months with thrombectomy and covered stent procedure. CONCLUSION: This first-in-human 6-month study with favorable patency and low complication rate establishes the initial safety and feasibility of this novel biological tissue conduit for dialysis access in patients with end-stage kidney disease. Its mechanical durability and lack of immune response establishes TRUE AVC as a potential regenerative material for clinical use.

ASDIN white paper: Management of cephalic arch stenosis endorsed by the American Society of Diagnostic and Interventional Nephrology.

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).

Novel classification of proximal forearm perforator vein in the planning and creation of percutaneous and surgical Gracz-type arteriovenous fistulae.

BACKGROUND: The perforator vein determines whether it is feasible to create a percutaneous (pAVF) or surgical "Gracz-type" arteriovenous fistula (sAVF). Creating a standard anatomic classification of the antecubital region is beneficial to both the selection of the appropriate device and/or procedure and technical outcomes. Accordingly, an analysis of a large cohort of patients undergoing pAVF/sAVF was performed, focusing on perforator vein anatomical suitability, and a novel anatomical classification of the antecubital region was developed and proposed. METHODS: Between August 2018 and July 2022, chronic or end-stage kidney disease patients as well as patients anticipated an initiation of apheresis, who were referred for vascular access planning, underwent a standardized evaluation of upper extremities. A vessel mapping summary detailing the vasculature and the access creation plan was completed, indicating the anatomical suitability for sAVF and pAVF (Ellipsys and WavelinQ) techniques. RESULTS: Of 524 patients, 36.5% were female (average age 65 years). 53.2% were on dialysis, 41.6% had diabetes, and 13.2% had a previously failed permanent dialysis access. The anatomy for successful pAVF creation was judged to be suitable in 54% of patients for an Ellipsys-pAVF, and 29.8% for WavelinQ-pAVF. Of the WavelinQ group, 54.4% had suitable anatomy for ulnar, 26.9% for radial, and 18.6% for both ulnar/radial anastomoses. Additionally, 60.7% had suitable anatomy for pAVF creation with at least one of the systems, while 22.5% were suited for both types of pAVF-systems. 80.3% were candidates for creation of a Gracz-AVF. CONCLUSION: Overall, we found that about 60% of patients are likely candidates for a pAVF, with 80% being candidates for creation of a Gracz-AVF. Male patients have significantly higher suitability for most types of AVF creation, and younger patients are more suitable for Ellipsys-pAVF and RCAVFs. Most importantly, a universal classification of perforator vein was developed, which is indispensable in modern vascular access planning.

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling.

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as ß-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher ß-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, ß-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Metabolic Changes in Peripheral Blood Mononuclear Cells Isolated From Patients With End Stage Renal Disease.

As numerous complex pathologies stem from cellular energy dysfunction, we aimed to elucidate mitochondrial function and associated stress pathologies in kidney disease in a cohort of hemodialysis patients with end-stage kidney disease (ESKD). The bioenergetics study was conducted using peripheral blood mononuclear cells (PBMCs) of ESKD patients (n = 29) and healthy controls (no ESKD, n = 10). PBMCs were isolated from whole blood and seeded into assay plates to detect changes in oxidative phosphorylation and glycolysis. The bioenergetics analysis (i.e., mitochondrial stress test) was performed using Seahorse XFe24 flux analyzer. We observed significant reduction in mitochondrial respiration in patient PBMCs in terms of fundamental bioenergetics parameters such as basal respiration, ATP turnover, maximal respiration and spare respiratory capacity. These findings were correlated with the expression levels of proteins coordinating cellular energy status and regulating mitochondrial dynamics. Our data demonstrates an association between mitochondrial oxygen consumption of PBMCs and ESKD. AMPK activity, its downstream effector PGC-1α and mitochondrial fission/fusion proteins are partially responsible for the decrease in oxidative phosphorylation of PBMCs isolated from ESKD patients. We propose a link between mitochondrial dysfunction and ESKD and a role for mitochondria as a potential site for therapeutic interventions.

International Comparisons of Native Arteriovenous Fistula Patency and Time to Becoming Catheter-Free: Findings From the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Optimizing vascular access use is crucial for long-term hemodialysis patient care. Because vascular access use varies internationally, we examined international differences in arteriovenous fistula (AVF) patency and time to becoming catheter-free for patients receiving a new AVF. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,191 AVFs newly created in 2,040 hemodialysis patients in 2009 to 2015 at 466 randomly selected facilities in the Dialysis Outcomes and Practice Patterns Study (DOPPS) from the United States, Japan, and EUR/ANZ (Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom, Australia, and New Zealand). PREDICTORS: Demographics, comorbid conditions, dialysis vintage, body mass index, AVF location, and country/region. OUTCOMES: Primary/cumulative AVF patency (from creation), primary/cumulative functional patency (from first use), catheter dependence duration, and mortality. ANALYTICAL APPROACH: Outcomes estimated using Cox regression. RESULTS: Across regions, mean patient age ranged from 61 to 66 years, with male preponderance ranging from 55% to 66%, median dialysis vintage of 0.3 to 3.2 years, with 84%, 54%, and 32% of AVFs created in the forearm in Japan, EUR/ANZ, and United States, respectively. Japan displayed superior primary and cumulative patencies due to higher successful AVF use, whereas cumulative functional patency was similar across regions. AVF patency associations with age and other patient characteristics were weak or varied considerably between regions. Catheter-dependence following AVF creation was much longer in EUR/ANZ and US patients, with nearly 70% remaining catheter dependent 8 months after AVF creation when AVFs were not successfully used. Not using an arteriovenous access within 6 months of AVF creation was related to 53% higher mortality in the subsequent 6 months. LIMITATIONS: Residual confounding. CONCLUSIONS: Our findings highlight the need to reevaluate practices for optimizing long-term access planning and achievable AVF outcomes, especially AVF maturation. New AVFs that are not successfully used are associated with long-term catheter exposure and elevated mortality risk. These findings highlight the importance of selecting the best access type for each patient and developing effective clinical pathways for when AVFs fail to mature successfully.

Efficacy and safety associated with the use of the Surfacer® Inside-Out® Access Catheter System: Results from a prospective, multicenter Food and Drug Administration-approved Investigational Device Exemption study.

PURPOSE: Thoracic central venous obstruction is commonly associated with the use of central venous catheters. The Surfacer System to Facilitate Access in Venous Occlusions Study was an Food and Drug Administration-approved US Investigational Device Exemption study designed to evaluate the performance and safety of the Surfacer System when used to facilitate central venous access in patients with thoracic central venous obstruction. METHODS: Thirty patients were enrolled in this prospective, multicenter, single-arm study between December 2017 and May 2019. Device performance and adverse events were collected peri-procedurally and at discharge. Enrollment included 15 female and 15 male subjects with a mean age of 55.5 ± 12.9 (range: 30-79) years. Twenty-eight patients (93.3%) required central venous access for hemodialysis access. Locations of thoracic central venous obstruction were graded from 1 to 4 based on severity and extension of venous occlusions. Seven patients (23.3%) had type 1, 6 (20.0%) type 2, 16 (53.3%) type 3, and 1 (3.3%) type 4 obstruction. RESULTS: Successful central venous catheter placement was achieved in 27 of 30 patients (90.0%). The procedure was discontinued in three (10.0%) due to tortuous anatomy discovered intraprocedurally. All 27 patients with successful CVC placement achieved adequate catheter patency and tip positioning with a mean overall procedural time and time to achieve central venous access with the Surfacer System being 44.1 ± 30.6 and 19.1 ± 25.1 min, respectively. There were no device-related adverse events or catheter malposition. CONCLUSION: The results of the SAVEUS Study confirm the safety and efficacy of the Surfacer System and the Inside-Out procedure when used for the placement of right-sided central venous access in patients with thoracic central venous obstruction.

Reduced myocardial blood flow reserve in kidney transplant candidates may hamper risk stratification.

BACKGROUND: Vasodilator nuclear stress testing is frequently ordered for risk stratification prior to kidney transplantation. Since 82Rb-positron emission tomography-computed tomography can measure myocardial blood flow (MBF), the response to vasodilator stress can be verified rendering the results of the scan more reliable. METHODS: We reviewed the MBF response to dipyridamole infusion in 328 patients with end-stage kidney disease (ESKD) prior to transplant (188 hemodialysis-HD, 120 peritoneal dialysis-PD, and 20 pre-dialysis patients-CKD5) and in 100 controls with normal kidney function. A stress/rest MBF ratio ≥ 2 was considered an adequate response to dipyridamole. Coronary artery calcium (CAC) was measured on CT. RESULTS: Inadequate MBF response was seen in 36%-HD, 21%-PD, 45%-CKD5 vs. 23%-controls (p = 0.006). Univariable predictors of poor MBF response in ESKD patients were age, diabetes mellitus, and CAC (all p < 0.03) while serum hemoglobin was borderline significant (p = 0.052). Multivariable predictors of a poor MBF response were age (p = 0.002) and lower serum hemoglobin (p = 0.014). Ischemia was identified in 8% of ESKD patients and 24% of controls (p < 0.001). CONCLUSIONS: ESKD patients are less likely to respond appropriately to vasodilator stress compared to patients with normal renal function and had a lower incidence of ischemia despite a high pre-test probability of disease. Physicians performing vasodilator stress without MBF measurement should be aware of the high probability of a false negative response.

ASDIN white paper: Assessment and management of hemodialysis access-induced distal ischemia by interventional nephrologists.

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.

Patient selection, education, and cannulation of percutaneous arteriovenous fistulae: An ASDIN White Paper.

End-stage kidney disease patients who are candidates for surgical arteriovenous fistula creation commonly experience obstacles to a functional surgical arteriovenous fistula, including protracted wait time for creation, poor maturation, and surgical arteriovenous fistula dysfunction that can result in significant patient morbidity. The recent approval of two endovascular devices designed to create a percutaneous arteriovenous fistula enables arteriovenous fistula creation to be placed in the hands of interventionalists, thereby increasing the number of arteriovenous fistula providers, reducing wait times, and allowing the patient to avoid surgery. Moreover, current studies demonstrate that patients with percutaneous arteriovenous fistula experience improved time to arteriovenous fistula maturation. Yet, in order to realize the potential advantages of percutaneous arteriovenous fistula creation within our hemodialysis patient population, it is critical to select appropriate patients, ensure adequate patient and dialysis unit education, and provide sufficient instruction in percutaneous arteriovenous fistula cannulation and monitoring. In this White Paper by the American Society of Diagnostic and Interventional Nephrology, experts in interventional nephrology, surgery, and interventional radiology convened and provide recommendations on the aforementioned elements that are fundamental to a functional percutaneous arteriovenous fistula.

Association Between Type of Vascular Access Used in Hemodialysis Patients and Subsequent Kidney Transplant Outcomes.

RATIONALE & OBJECTIVE: Vascular access type (arteriovenous fistula [AVF] vs arteriovenous graft [AVG] vs central venous catheter [CVC]) associates with clinical outcomes in patients with end-stage kidney disease undergoing hemodialysis. Whether a similar association exists with outcomes after kidney transplantation is unknown. We hypothesized that AVGs would associate with worse outcomes, perhaps owing to persistent subclinical inflammation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Using US registry data merged with electronic health records of a large dialysis organization (2006-2011), we selected patients receiving a first-ever kidney transplant after undergoing more than 30 days of hemodialysis. EXPOSURE: Hemodialysis access used during the patient's last pretransplantation hemodialysis session. OUTCOMES: Patients were followed up from kidney transplantation for all-cause mortality, kidney allograft loss from any cause, and allograft loss not from death. ANALYTICAL APPROACH: Time-to-event analysis including Kaplan-Meier plots and Cox proportional hazards regression estimated cause-specific HRs and 95% CIs. RESULTS: Among 9,291 patients who underwent kidney transplantation between 2006 and 2011, a total of 65.3% used an AVF, 20.4% used an AVG, and 14.3% used a CVC for hemodialysis before transplantation. Multivariable regression models adjusted for demographic variables, comorbid conditions, transplant characteristics, and laboratory parameters identified no independent associations between vascular access type and all-cause mortality (HRAVG, 1.13 [95% CI, 0.97-1.33]; HRCVC, 1.00 [95% CI, 0.83-1.21]). Similarly, AVG and CVC use were not independently associated with all-cause allograft loss compared with AVF use (HRAVG, 1.13 [95% CI, 1.00-1.28]; HRCVC, 1.12 [95% CI, 0.96-1.29]). CVC use was associated with 30% higher risk for allograft loss from causes other than death compared with AVF use (HRCVC, 1.30 [95% CI, 1.06-1.57]), but AVGs were not (HRAVG, 1.17 [95% CI, 0.98-1.39]). LIMITATIONS: Nonrandomized exposure leading to potential residual confounding. CONCLUSIONS: No association was found for AVG use before kidney transplantation with mortality, all-cause allograft loss, and allograft loss from all causes other than death, compared with AVF use. The association of CVC use with allograft loss from causes other than death requires further investigation.

Medicare Costs Associated With Arteriovenous Fistulas Among US Hemodialysis Patients.

BACKGROUND: An arteriovenous fistula (AVF) is the recommended vascular access for hemodialysis (HD). Previous studies have not examined the resources and costs associated with creating and maintaining AVFs. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Elderly US Medicare patients initiating hemodialysis therapy during 2010 to 2011. PREDICTOR: AVF primary and secondary patency and nonuse in the first year following AVF creation. OUTCOMES: Annualized vascular access costs per patient per year. RESULTS: Among patients with only a catheter at HD therapy initiation, only 54% of AVFs were successfully used for HD, 10% were used but experienced secondary patency loss within 1 year of creation, and 83% experienced primary patency loss within 1 year of creation. Mean vascular access costs per patient per year in the 2.5 years after AVF creation were $7,871 for AVFs that maintained primary patency in year 1, $13,282 for AVFs that experienced primary patency loss in year 1, $17,808 for AVFs that experienced secondary patency loss in year 1, and $31,630 for AVFs that were not used. Similar patterns were seen among patients with a mature AVF at HD therapy initiation and patients with a catheter and maturing AVF at HD therapy initiation. Overall, in 2013, fee-for-service Medicare paid $2.8 billion for dialysis vascular access-related services, ∼12% of all end-stage renal disease payments. LIMITATIONS: Lack of granularity with certain billing codes. CONCLUSIONS: AVF failure in the first year after creation is common and results in substantially higher health care costs. Compared with patients whose AVFs maintained primary patency, vascular access costs were 2 to 3 times higher for patients whose AVFs experienced primary or secondary patency loss and 4 times higher for patients who never used their AVFs. There is a need to improve AVF outcomes and reduce costs after AVF creation.

Recommended Clinical Trial End Points for Dialysis Catheters.

Central venous catheters are used frequently in patients on hemodialysis as a bridge to a permanent vascular access. They are prone to frequent complications, including catheter-related bloodstream infection, catheter dysfunction, and central vein obstruction. There is a compelling need to develop new drugs or devices to prevent central venous catheter complications. We convened a multidisciplinary panel of experts to propose standardized definitions of catheter end points to guide the design of future clinical trials seeking approval from the Food and Drug Administration. Our workgroup suggests diagnosing catheter-related bloodstream infection in catheter-dependent patients on hemodialysis with a clinical suspicion of infection (fever, rigors, altered mental status, or unexplained hypotension), blood cultures growing the same organism from the catheter hub and a peripheral vein (or the dialysis bloodline), and absence of evidence for an alternative source of infection. Catheter dysfunction is defined as the inability of a central venous catheter to (1) complete a single dialysis session without triggering recurrent pressure alarms or (2) reproducibly deliver a mean dialysis blood flow of >300 ml/min (with arterial and venous pressures being within the hemodialysis unit parameters) on two consecutive dialysis sessions or provide a Kt/V≥1.2 in 4 hours or less. Catheter dysfunction is defined only if it persists, despite attempts to reposition the patient, reverse the arterial and venous lines, or forcefully flush the catheter. Central vein obstruction is suspected in patients with >70% stenosis of a central vein by contrast venography or the equivalent, ipsilateral upper extremity edema, and an existing or prior history of a central venous catheter. There is some uncertainty about the specific criteria for these diagnoses, and the workgroup has also proposed future high-priority studies to resolve these questions.