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Introduction: The manual single lumen alternating micro-batch hemodiafiltration (mSLAMB) system is a closed-loop dialysis system designed to provide kidney support in emergency situations (e.g., fluid overload, hyperkalemia, acidemia). If done repeatedly in small batches and at high flow rates, this system was found to achieve clearance levels comparable to traditional renal replacement therapy., Methods: Using a porcine model, uremic toxins and exogenous fluorescent tracer concentrations were successfully lowered within just 1 h of treatment., Results: With a maximal dialysate flow, mSLAMB can achieve decreases in serum potassium concentration of >0.5 mmol/L/h. With the mSLAMB hemodiafiltration system, micro-batch processing was also successful in removing up to 250 mL of ultrafiltrate in 8 cycles., Conclusion: This process could create a better fluid balance allowing for administering therapeutic fluids such as sodium bicarbonate in the clinic. Electrolyte imbalance and volume overload remain severe life-threatening emergencies in low resource settings; therefore, mSLAMB should be explored further due to its modest vascular access requirements, low cost, and ability to be performed without electricity or batteries., (© 2024 S. Karger AG, Basel.)

Background: The 2018 United Network for Organ Sharing (UNOS) heart transplant policy change (PC) sought to improve waitlist risk stratification to decrease waitlist mortality and promote geographically broader sharing for high-acuity patients awaiting heart transplantation. Our analysis sought to determine the effect of the UNOS PC on outcomes in patients waiting for, or who have received, a heart-kidney transplantation., Methods: We analyzed adult (≥18 years old), first-time, heart-only and heart-kidney transplant candidates and recipients from the UNOS Registry. Patients were divided into pre-PC (PRE: October 18, 2016-May 30, 2018) and post-PC (POST: October 18, 2018-May 30, 2020) groups for comparison. Competing risks analysis (subdistribution and cause-specific hazards analyses) was performed to assess for differences in waitlist death/deterioration or heart transplantation. One-year post-transplant survival was assessed with Kaplan-Meier and Cox analyses. We included an interaction term (policy era × heart ± kidney) in our analyses to evaluate the effect of PC on outcomes in heart-kidney patients., Results: One-year post-transplant survival was similar (p = 0.83) for PRE heart-kidney and heart-only recipients, but worse (p < 0.001) for POST heart-kidney vs heart-only recipients. There was a policy-era interaction between heart-kidney and heart-only recipients (HR 1.92[1.04,3.55], p = 0.038) indicating a detrimental effect of policy on 1-year survival in POST vs PRE heart-kidney recipients. No added beneficial effect of PC on waitlist outcomes in heart-kidney vs heart-only candidates was observed., Conclusions: There was no added policy-era benefit on waitlist outcomes for heart-kidney candidates when compared to heart-only candidates. POST heart-kidney recipients experienced worse 1-year survival compared to PRE heart-kidney recipients with no policy effect on heart-only recipients., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The 2018 adult heart allocation policy sought to improve waitlist risk stratification, reduce waitlist mortality, and increase organ access. This system prioritized patients at greatest risk for waitlist mortality, especially individuals requiring temporary mechanical circulatory support (tMCS). Posttransplant complications are significantly higher in patients on tMCS before transplantation, and early posttransplant complications impact long-term mortality. We sought to determine if policy change affected early posttransplant complication rates of rejection, infection, and hospitalization., Methods: We included all adult, heart-only, single-organ heart transplant recipients from the UNOS registry with pre-policy (PRE) individuals transplanted between November 1, 2016, and October 31, 2017, and post-policy (POST) between November 1, 2018, and October 31, 2019. We used a multivariable logistic regression analysis to assess the effect of policy change on posttransplant rejection, infection, and hospitalization. Two COVID-19 eras (2019-2020, 2020-2021) were included in our analysis., Results: The majority of baseline characteristics were comparable between PRE and POST era recipients. The odds of treated rejection (p = 0.8), hospitalization (p = 0.69), and hospitalization due to rejection (p = 0.76) and infection (p = 0.66) were similar between PRE and POST eras; there was a trend towards reduced odds of rejection (p = 0.08). In both COVID eras, there was a clear reduction in rejection and treated rejection with no effect on hospitalization for rejection or infection. Odds of all-cause hospitalization was increased in both COVID eras., Conclusions: The UNOS policy change improves access to heart transplantation for higher acuity patients without increasing early posttransplant rates of treated rejection or hospitalization for rejection or infection, factors which portend risk for long-term posttransplant mortality., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Excreted exclusively by the kidneys, fluorescein isothiocyanate (FITC)-sinistrin can be used to measure glomerular filtration rate (GFR) and is detectable transdermally. Determination of changes in native kidney GFR (NK-GFR) in patients with acute kidney injury, particularly during continuous renal replacement therapy, improves clinical decision-making capability. To test feasibility of measuring changes in NK-GFR during CRRT with FITC-sinistrin, in vitro circuits (n = 2) were utilized to simultaneously clear FITC-sinistrin by removal of ultrafiltrate at varying rates, simulating kidney function, and by dialysis at a constant rate. Clearance calculated by fluorescence-measuring devices on the circuit showed good agreement with clearance calculated from assay of fluid samples ( R2 = 0.949). In vivo feasibility was studied by dialyzing anesthetized pigs (n = 3) and measuring FITC-sinistrin clearance during progression from normal, to unilaterally, then bilaterally nephrectomized. FITC-sinistrin clearance was reduced in vitro , when ultrafiltrate was decreased or with successive nephrectomies in vivo . Transdermal readers showed 100% sensitivity in detecting a decrease in NK-GFR in pigs with a bias of 6.5 ± 13.4% between transdermal-derived GFR (tGFR) and plasma-measured methods determining proportional changes in clearance. Clearance of FITC-sinistrin by dialysis remained consistent. In patients receiving a constant dialysis prescription, transdermal measurement of FITC-sinistrin can detect relative changes in NK-GFR., Competing Interests: Disclosures: C.J.P., K.A.J., and H.D.H. are employees of Innovative BioTherapies (IBT). IBT is wholly owned by H.D.H. G.C. has no conflicts of interest to report., (Copyright © ASAIO 2023.)

Critically ill patients undergoing continuous renal replacement therapy (CRRT) have medical conditions requiring extensive pharmacotherapy. Continuous renal replacement therapy impacts drug disposition. Few data exist regarding drug dosing requirements with contemporary CRRT modalities and effluent rates. The practical limitations of pharmacokinetic studies requiring numerous plasma and effluent samples, and lack of generalizability of observations from specific CRRT prescriptions, highlight gaps in bedside assessment of CRRT drug elimination and individualized dosing needs. We employed a porcine model using transdermal fluorescence detection of the glomerular filtration rate fluorescent tracer agent MB-102, with the aim to assess the relationship between systemic exposure of MB-102 and meropenem during CRRT. Animals underwent bilateral nephrectomies and received intravenous bolus doses of MB-102 and meropenem. Once MB-102 equilibrated in the animal, CRRT was initiated. Continuous renal replacement therapy prescriptions comprised four combinations of blood pump (low versus high) and effluent (low versus high) flow rates. Changes in transdermal detected MB-102 clearance occurred immediately with a change in CRRT rates. Blood side meropenem clearance mirrored transdermal MB-102 clearance ( r2 : 0.95-0.97, p value all <0.001). We suggest transdermal MB-102 clearance provides real-time personalized assessment of drug elimination and could optimize prescription of drugs for critically ill patients requiring CRRT., Competing Interests: Disclosure: R.B.D., J.R.J., J.-J.S., I.R.R., and T.E.R. are employees of MediBeacon Inc. The other authors have no conflicts of interest to report., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASAIO.)

NR2F2 is expressed in endothelial cells (ECs) and Nr2f2 knockout produces lethal cardiovascular defects. In humans, reduced NR2F2 expression is associated with cardiovascular diseases including congenital heart disease and atherosclerosis. Here, NR2F2 silencing in human primary ECs led to inflammation, endothelial-to-mesenchymal transition (EndMT), proliferation, hypermigration, apoptosis-resistance, and increased production of reactive oxygen species. These changes were associated with STAT and AKT activation along with increased production of DKK1. Co-silencing DKK1 and NR2F2 prevented NR2F2-loss-induced STAT and AKT activation and reversed EndMT. Serum DKK1 concentrations were elevated in patients with pulmonary arterial hypertension (PAH) and DKK1 was secreted by ECs in response to in vitro loss of either BMPR2 or CAV1, which are genetic defects associated with the development of PAH. In human primary ECs, NR2F2 suppressed DKK1, whereas its loss conversely induced DKK1 and disrupted endothelial homeostasis, promoting phenotypic abnormalities associated with pathologic vascular remodeling. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating chronic vascular diseases associated with EC dysfunction. NEW & NOTEWORTHY NR2F2 loss in the endothelial lining of blood vessels is associated with cardiovascular disease. Here, NR2F2 -silenced human endothelial cells were inflammatory, proliferative, hypermigratory, and apoptosis-resistant with increased oxidant stress and endothelial-to-mesenchymal transition. DKK1 was induced in NR2F2 -silenced endothelial cells, while co-silencing NR2F2 and DKK1 prevented NR2F2-loss-associated abnormalities in endothelial signaling and phenotype. Activating NR2F2 or blocking DKK1 may be useful therapeutic targets for treating vascular diseases associated with endothelial dysfunction.

Background: Childhood cancer survivors are vulnerable to long-term treatment-related health conditions, which can lead to poor quality of life. Little data exist on the overall health of long-term Australian and New Zealand childhood cancer survivors or on survivors' motivations for attending survivorship clinics., Methods: This study administers a cross-sectional questionnaire to long-term survivors ≥5 years from their primary diagnosis. We compared participant-reported number of late effects by a cancer diagnosis, and identified clinical (eg, treatment) and demographic (eg, age) factors that were associated with late effects burden and engagement in cancer survivorship care., Results: A total of 634 participants completed questionnaires (48% male, mean age = 21.7 years). Most participants (79%) reported at least one cancer-related late effect, most commonly fatigue (40%) and memory/learning difficulties (34%). Brain tumor survivors reported a higher total number of late effects than survivors with other diagnoses (mean = 5.7 vs. 3.2, P < .001). Participants' most commonly reported motivators for engaging in care were to understand problems that may occur later in life because of their cancer and/or treatment (98.5%) and to get reassurance about one's health (97.4%). The proportion of survivors endorsing each motivating factor was similar across cancer diagnoses, with the exception of learning more about insurance and pensions (highest in brain tumor survivors = 80%). In multivariable analyses, survivors were more likely to report being engaged in survivorship care if they were younger (P < .001), less time had elapsed since their diagnosis (P < .001), or they reported a higher number of motivating factors (P = .016)., Conclusion: Survivors report a range of health problems decades after treatment completion. Understanding the burden of late effects, and motivators for seeking survivorship care to manage these health problems, is important for ensuring that tailored interventions or services are available to meet the needs of this growing population and to design effective models of survivorship care., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Application of the immunomodulatory selective cytopheretic device (SCD) to enhance renal replacement therapy and improve outcomes of acute kidney injury in pediatric patients is impeded by safety concerns. Therapy using a pediatric hemodialysis system could overcome these limitations., Methods: Yucatan minipigs (8-15 kg) with induced septic shock underwent continuous hemodiafiltration with the CARPEDIEM™ pediatric hemodialysis system using regional citrate anticoagulation (RCA) with or without SCD (n = 5 per group). Circuit function plus hemodynamic and hematologic parameters were assessed for 6 h., Results: SCD was readily integrated into the CARPEDIEM™ system and treatment delivered for 6 h without interference with pump operation. SCD-treated pigs maintained higher blood pressure (p = 0.009) commensurate with lesser degree of lactic acidosis (p = 0.008) compared to pigs only receiving hemodiafiltration. Renal failure occurred in untreated pigs while urine output was sustained with SCD therapy. Neutrophil activation levels and ss-SOFA scores at 6 h trended lower in the SCD-treated cohort., Conclusions: SCD therapy under RCA was safely administered using the CARPEDIEM™ pediatric hemodialysis system for up to 6 h and no circuit compatibility issues were identified. Sepsis progression and organ dysfunction was diminished with SCD treatment in this model supportive of therapeutic benefit of this immunomodulatory therapy., Impact: SCD therapy with regional citrate anticoagulation has the potential to be administered safely to patients weighing <20 kg using the Carpediem renal replacement therapy platform. Use of a renal replacement therapy platform designed specifically for neonates/infants overcomes safety concerns for delivery of SCD treatment in this population. SCD therapy using the Carpediem renal replacement therapy platform retained the suggestive efficacy seen in larger children and adults to reduce organ injury and dysfunction from sepsis., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)