173 results on '"Humes HD"'
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2. A selective cytopheretic inhibitory device for use during cardiopulmonary bypass surgery
- Author
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Pino, CJ, primary, Lou, L, additional, Smith, PL, additional, Ding, F, additional, Pagani, FD, additional, Buffington, DA, additional, and Humes, HD, additional
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- 2012
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3. Acute Renal Failure — The Promise of New Therapies
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Humes Hd
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medicine.medical_specialty ,urogenital system ,business.industry ,Hospitalized patients ,Mortality rate ,medicine ,General Medicine ,medicine.disease ,business ,Intensive care medicine ,Acute tubular necrosis - Abstract
Acute tubular necrosis is common in acutely ill hospitalized patients, with mortality rates exceeding 50 percent.1 The regenerative capacity of kidneys damaged by acute tubular necrosis is substant...
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- 1997
4. Decision making in medicine. Limiting acute renal failure.
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Humes HD
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- 1999
5. High Energy Phosphates, Phospholipids, and Calcium in Ischemic Renal Tubular Cell Injury
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Hunt Da, Humes Hd, and Nguyen Vd
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Pathology ,medicine.medical_specialty ,Kidney ,Necrosis ,urogenital system ,business.industry ,Cell ,Acute kidney injury ,Ischemia ,urologic and male genital diseases ,medicine.disease ,Pathogenesis ,medicine.anatomical_structure ,Biochemistry ,Excretory system ,medicine ,medicine.symptom ,business ,Acute tubular necrosis - Abstract
It is becoming increasingly clear that the final common pathogenetic pathway for the development of ischemic acute renal failure is renal tubular cell injury.1,2 Acute renal failure developing from an ischemic insult occurs from tubular cell injury that produces segmental necrosis in renal tubules, so that a patchy distribution of frankly necrotic lesions appears to be the rule rather than the exception in the pathology of acute renal failure.3 The segmental, patchy renal tubular cell necrosis initiates a variety of factors responsible at the nephronal level for excretory failure of the kidney. These factors include intratubular obstruction, backleak of glomerular filtrate, and glomerular hemodynamic alterations. Ultimately, the understanding of the pathogenesis of acute tubular necrosis resides in the understanding of the biochemical alterations responsible for renal tubular cell injury. In this regard, declines in levels of high energy phosphates within the cell, alterations in cellular calcium metabolism, and degradation of membrane phospholipids appear to be metabolic derangements induced by ischemia critical in the evolution of cell injury.
- Published
- 1986
6. Immunomodulatory effects of a cell processing device to ameliorate dysregulated hyperinflammatory disease states.
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Westover AJ, Humes HD, and Pino CJ
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- Humans, Neutrophils metabolism, Neutrophils immunology, Cytokines metabolism, Cell Adhesion, Cell- and Tissue-Based Therapy methods, Calcium metabolism, Monocytes immunology, Monocytes metabolism, Immunomodulation, Inflammation metabolism, Inflammation immunology
- Abstract
Cell directed therapy is an evolving therapeutic approach to treat organ dysfunction arising from hyperinflammation and cytokine storm by processing immune cells in an extracorporeal circuit. To investigate the mechanism of action of the Selective Cytopheretic Device (SCD), in vitro blood circuits were utilized to interrogate several aspects of the immunomodulatory therapy. SCD immunomodulatory activity is due to its effects on circulating neutrophils and monocytes in a low ionized calcium (iCa, Ca
2+ ) blood circuit. Activated neutrophils adhere to the SCD fibers and degranulate with release of the constituents of their exocytotic vesicles. Adhered neutrophils in the low iCa environment display characteristics of apoptotic senescence. These neutrophils are subsequently released and returned back to circulation, demonstrating a clear potential for in vivo feedback. For monocytes, SCD treatment results in the selective adhesion of more pro-inflammatory subsets of the circulating monocyte pool, as demonstrated by both cell surface markers and cytokine secretory rates. Once bound, over time a subset of monocytes are released from the membrane with a less inflammatory functional phenotype. Similar methods to interrogate mechanism in vitro have been used to preliminarily confirm comparable findings in vivo. Therefore, the progressive amelioration of circulating leukocyte activation and immunomodulation of excessive inflammation observed in SCD clinical trials to date is likely due to this continuous autologous leukocyte processing., (© 2024. The Author(s).)- Published
- 2024
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7. Increasing Eligibility to Transplant Through the Selective Cytopheretic Device: A Review of Case Reports Across Multiple Clinical Conditions.
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Iyer SPN, Pino CJ, Yessayan LT, Goldstein SL, Weir MR, Westover AJ, Catanzaro DA, Chung KK, and Humes HD
- Abstract
A stable, minimum physiological health status is required for patients to qualify for transplant or artificial organ support eligibility to ensure the recipient has enough reserve to survive the perioperative transplant period. Herein, we present a novel strategy to stabilize and improve patient clinical status through extracorporeal immunomodulation of systemic hyperinflammation with impact on multiple organ systems to increase eligibility and feasibility for transplant/device implantation. This involves treatment with the selective cytopheretic device (SCD), a cell-directed extracorporeal therapy shown to adhere and immunomodulate activated neutrophils and monocytes toward resolution of systemic inflammation. In this overview, we describe a case series of successful transition of pediatric and adult patients with multiorgan failure to successful transplant/device implantation procedures by treatment with the SCD in the following clinical situations: pediatric hemophagocytic lymphohistiocytosis, and adult hepatorenal and cardiorenal syndromes. Application of the SCD in these cases may represent a novel paradigm in increasing clinical eligibility of patients to successful transplant outcomes., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
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- 2024
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8. New opportunity for targeting systemic inflammation in patients with heart failure through leucocyte immunomodulation.
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Pitt B, Iyer SPN, and Humes HD
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- Humans, Heart Failure immunology, Immunomodulation, Inflammation immunology, Leukocytes immunology
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- 2024
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9. Extracorporeal Immunomodulation Therapy in Acute Chronic Liver Failure With Multiorgan Failure: First in Human Use.
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Yessayan LT, Sharma P, Westover AJ, Szamosfalvi B, and Humes HD
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- Humans, Immunomodulation, Multiple Organ Failure etiology, Multiple Organ Failure therapy, Prognosis, Acute-On-Chronic Liver Failure therapy, End Stage Liver Disease complications, End Stage Liver Disease therapy
- Abstract
Two patients presented with acute on chronic liver failure and multiorgan failure and, as typical for this disorder, they presented with hyperinflammation and anticipated high mortality rates. Both cases were diagnosed with hepatorenal syndrome (HRS). Under a FDA approved Investigational Device Exemption clinical trial, they underwent treatment with an extracorporeal cell-directed immunomodulatory device, called selective cytopheretic device. Both patients showed rapid clinical improvement associated with a decline in elevated blood cytokine concentrations and diminution of activation levels of circulating leukocytes. On follow-up, one patient was alive at day 90 after treatment and undergoing liver transplantation evaluation and the other patient had a successful liver transplantation 6 days after selective cytopheretic device therapy ended. These cases represent the first in human evaluation of extracorporeal cell-directed immunomodulation therapy in acute on chronic liver failure with successful clinical outcomes in a disorder with dismal prognosis., (Copyright © ASAIO 2023.)
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- 2024
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10. Selective Cytopheretic Device Use in Continuous Kidney Replacement Therapy in Children: A Cohort Study With a Historical Comparator.
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Goldstein SL, Ollberding NJ, Askenazi DJ, Basu RK, Selewski DT, Krallman KA, Yessayan L, and Humes HD
- Abstract
Rationale and Objective: Critically ill children with acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect at circuit-ionized calcium of <0.40 mmol/L. In an adult CRRT patient study, SCD-treated patients reported improved survival or dialysis independence. We reported safety data from children who received CRRT-SCD therapy and compared outcomes with a historic pediatric CRRT cohort., Study Design: We performed 2 prospective multicenter studies to evaluate the safety and feasibility of SCD in critically ill children., Setting and Participants: Four pediatric institutions enrolled children weighing 10 kg or more with AKI and multi-organ dysfunction receiving CRRT as the standard of care with the SCD-integrated post-CRRT membrane., Exposure: Patients received CRRT-SCD with regional citrate anticoagulation for up to 7-10 days, or CRRT discontinuation, whichever came first., Analytical Approach: We reported serious adverse events among patients and CRRT-SCD-related process and outcome variables. We compared survival to intensive care unit (ICU) discharge rates between the CRRT-SCD cohort and a matched cohort from the prospective pediatric CRRT registry, using odds ratios in multivariable analysis for factors associated with prospective pediatric CRRT patient ICU mortality. To validate these crude analyses, Bayesian logistic regression was performed to assess for attributable benefit-risk assessment of the SCD., Results: Twenty-two patients received CRRT-SCD treatments. Fifteen serious adverse events were recorded; none were SCD-related. Seventeen patients survived till ICU discharge or day 60. Both multivariable and Bayesian analyses revealed a probable benefit of the addition of SCD. Fourteen of the 16 patients surviving ICU discharge reported a normal estimated glomerular filtration rate and no patient was dialysis dependent at 60 days., Limitations: The study had a few limitations, such as (1) a small sample size in the SCD-PED cohort group; (2) unchanging historic control group; and (3) adverse events were not recorded in the control group., Conclusions: The SCD therapy is feasible, safe, and demonstrates probable benefit for critically ill children who require CRRT for AKI., (© 2024 The Authors.)
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- 2024
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11. Blood Volume Analysis and Cardiorenal Syndrome: From Bench to Bedside.
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Jefferies JL, Stavish CA, Silver MA, Butler J, Humes HD, and Strobeck J
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- Humans, Cardio-Renal Syndrome physiopathology, Cardio-Renal Syndrome classification, Cardio-Renal Syndrome therapy, Blood Volume physiology, Blood Volume Determination methods
- Abstract
Background: This review delves into the intricate landscape of cardiorenal syndrome (CRS) and highlights the pivotal role of blood volume analysis (BVA) in improving patient care and outcomes., Summary: BVA offers a direct and highly accurate quantification of intravascular volume, red blood cell volume, and plasma volume, complete with patient-specific norms. This diagnostic tool enhances the precision of diuretic and red cell therapies, significantly elevating the effectiveness of conventional care., Key Messages: Our objectives encompass a comprehensive understanding of how BVA informs the evaluation and treatment of CRS, including its subtypes, pathophysiology, and clinical significance. We delve into BVA principles, techniques, and measurements, elucidating its diagnostic potential and advantages compared to commonly used surrogate measures. We dissect the clinical relevance of BVA in various CRS scenarios, emphasizing its unique contributions to each subtype. By assessing the tangible impact of BVA on patient outcomes through meticulous analysis of relevant clinical studies, we unveil its potential to enhance health outcomes and optimize resource utilization. Acknowledging the challenges and limitations associated with BVA's clinical implementation, we underscore the importance of multidisciplinary collaboration among cardiologists, nephrologists, and other clinicians. Finally, we identify research gaps and propose future directions for BVA and CRS, contributing to ongoing advancements in this field and patients affected by this complicated clinical syndrome., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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12. In vivo Assessment of a Manual Single Lumen Alternating Micro-Batch Hemodiafiltration System.
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Lanker SL, Pino CJ, Humes HD, Chawla L, and Johnston KA
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- Animals, Swine, Potassium blood, Hemodiafiltration methods, Hemodiafiltration instrumentation
- Abstract
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.)
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- 2024
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13. Rationale and Design of NEUTRALIZE-AKI: A Multicenter, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury Requiring Continuous Kidney Replacement Therapy.
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Yessayan L, Humes HD, Scribe EC, Iyer SPN, and Chung KK
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- Adult, Humans, Adolescent, Young Adult, Middle Aged, Aged, Aged, 80 and over, Treatment Outcome, Intensive Care Units, Critical Care, Critical Illness therapy, Renal Replacement Therapy, Renal Dialysis adverse effects, Acute Kidney Injury etiology
- Abstract
Introduction: NEUTRALIZE-AKI is a pivotal study to evaluate the safety and effectiveness of the selective cytopheretic device (SCD) in adult patients with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT)., Methods/design: This is a two-arm, randomized, open-label, controlled multi-center pivotal US study which will enroll 200 adult patients (age 18-80 years) in the intensive care unit with acute kidney injury requiring CKRT and at least one additional organ failure across 30 clinical centers. Eligible patients will be randomized to CKRT plus SCD therapy versus CKRT alone. Therapy will be administered for up to 10 days, with the hypothesis that the CKRT plus SCD group will demonstrate a lower mortality rate or better rate of renal recovery than the CKRT alone group by day 90. The primary outcome is a composite of dialysis dependence or all-cause mortality at day 90., Conclusion: The SCD is a cell-directed extracorporeal therapy that targets and deactivates pro-inflammatory neutrophils and monocytes, with evidence of efficacy across a variety of critically ill patient populations. Knowledge and experience from many of those studies and other AKI trials were incorporated into the design of this pivotal study, with the aim to investigate the role of effector cell immunomodulation in the intervention of AKI., (© 2023 S. Karger AG, Basel.)
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- 2024
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14. Safety Summary of the Selective Cytopheretic Device: A Review of Safety Data Across Multiple Clinical Trials in ICU Patients With Acute Kidney Injury and Multiple Organ Failure.
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Humes HD, Goldstein SL, Yessayan LT, Catanzaro DA, Scribe EC, Iyer SPN, and Chung KK
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Objectives: Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD)., Data Sources and Study Selection: The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report., Data Extraction and Data Synthesis: Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression., Conclusions: The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks., Competing Interests: Dr. Humes is a scientific advisor for SeaStar Medical and has a financial interest in the company. Drs. Goldstein and Yessayan receive consulting fees from SeaStar Medical. Drs. Catanzaro, Scribe, Iyer, and Chung are employees of SeaStar Medical., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)
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- 2023
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15. Estimating Changes in Glomerular Filtration Rate With Fluorescein Isothiocyanate-Sinistrin During Renal Replacement Therapy.
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Chan G, Pino CJ, Johnston KA, and Humes HD
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- Animals, Swine, Glomerular Filtration Rate, Fluoresceins, Renal Replacement Therapy, Isothiocyanates, Continuous Renal Replacement Therapy
- Abstract
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.)
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- 2023
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16. Transdermal Detection of MB-102 and Correlation to Meropenem Pharmacokinetics During Continuous Renal Replacement Therapy: In Vivo Results.
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Dorshow RB, Johnson JR, Shieh JJ, Riley IR, Rogers TE, Pino CJ, Johnston KA, Tang P, Nolin TD, Humes HD, and Goldstein SL
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- Animals, Swine, Meropenem pharmacokinetics, Critical Illness, Renal Replacement Therapy methods, Anti-Bacterial Agents pharmacokinetics, Continuous Renal Replacement Therapy
- Abstract
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.)
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- 2023
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17. Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human.
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Humes HD, Aaronson KD, Buffington DA, Sabbah HN, Westover AJ, Yessayan LT, Szamosfalvi B, and Pagani FD
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- Humans, Animals, Dogs, Stroke Volume, Ventricular Function, Left, Cytokines, Interleukin-6 pharmacology, Inflammation therapy, Heart Failure therapy
- Abstract
Background: Inflammation has been associated with progression and complications of chronic heart failure (HF) but no effective therapy has yet been identified to treat this dysregulated immunologic state. The selective cytopheretic device (SCD) provides extracorporeal autologous cell processing to lessen the burden of inflammatory activity of circulating leukocytes of the innate immunologic system., Aim: The objective of this study was to evaluate the effects of the SCD as an extracorporeal immunomodulatory device on the immune dysregulated state of HF. HF., Methods and Results: SCD treatment in a canine model of systolic HF or HF with reduced ejection fraction (HFrEF) diminished leukocyte inflammatory activity and enhanced cardiac performance as measured by left ventricular (LV) ejection fraction and stroke volume (SV) up to 4 weeks after treatment initiation. Translation of these observations in first in human, proof of concept clinical study was evaluated in a patient with severe HFrEFHFrEF ineligible for cardiac transplantation or LV LV assist device (LVAD) due to renal insufficiency and right ventricular dysfunction. Six hour SCD treatments over 6 consecutive days resulted in selective removal of inflammatory neutrophils and monocytes and reduction in key plasma cytokines, including tumor necrosis factor-alpha (TNF-α),), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. These immunologic changes were associated with significant improvements in cardiac power output, right ventricular stroke work index, cardiac index and LVSV index…. Stabilization of renal function with progressive volume removal permitted successful LVAD implantation., Conclusion: This translational research study demonstrates a promising immunomodulatory approach to improve cardiac performance in HFrEFHFrEF and supports the important role of inflammation in the progression of HFHF., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: HDH, DAB, AJW: Innovative Biotherapies, Inc. and SeaStar Medical, Inc., (Copyright: © 2023 Humes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2023
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18. Use of extracorporeal immunomodulation in a toddler with hemophagocytic lymphohistiocytosis and multisystem organ failure.
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Goldstein SL, Yessayan LT, Krallman KA, Collins M, Benoit S, Westover A, and Humes HD
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- Humans, Infant, Herpesvirus 4, Human, Multiple Organ Failure therapy, Multiple Organ Failure complications, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections therapy, Epstein-Barr Virus Infections diagnosis, Lymphohistiocytosis, Hemophagocytic complications, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic therapy, Pancytopenia
- Abstract
Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a dysregulated immune disorder in children, associated with Epstein-Barr virus (EBV) infection or malignancies. In severe forms, HLH presents with signs and symptoms of hyperinflammation that progress to life-threatening multiorgan failure. Intervention with an extracorporeal immunomodulatory treatment utilizing a selective cytopheretic device (SCD) could be beneficial. The SCD with regional citrate anticoagulation selectively binds the most highly activated circulating neutrophils and monocytes and deactivates them before release to the systemic circulation. Multiple clinical studies, including a multicenter study in children, demonstrate SCD therapy attenuates hyperinflammation, resolves ongoing tissue injury and allows progression to functional organ recovery. We report the first case of SCD therapy in a patient with HLH and multi-organ failure., Case Diagnosis/treatment: A previously healthy 22-month-old toddler presented with fever, abdominal distension, organomegaly, pancytopenia, and signs of hyperinflammation. EBV PCR returned at > 25 million copies. The clinical and laboratory pictures were consistent with systemic EBV-positive T-cell lymphoma with symptoms secondary to HLH. The patient met inclusion criteria for an ongoing study of integration of the SCD with a continuous kidney replacement therapy (CKRT) as part of standard of care. The patient received CKRT-SCD for 4 days with normalization of serum markers of sepsis and inflammation. The patient underwent hematopoietic stem cell transplantation 52 days after presentation and has engrafted with normal kidney function 8 months later., Conclusions: SCD treatment resulted in improvement of poor tissue perfusion reflected by rapid decline in serum lactate levels, lessened systemic capillary leak with discontinuation of vasoactive agents, and repair and recovery of lung and kidney function with extubation and removal of hemodialysis support., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)
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- 2023
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19. Immunomodulatory therapy using a pediatric dialysis system ameliorates septic shock in miniature pigs.
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Johnston KA, Pino CJ, Chan G, Ketteler SK, Goldstein SL, and Humes HD
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- Animals, Swine, Renal Dialysis, Swine, Miniature, Anticoagulants therapeutic use, Citric Acid therapeutic use, Citrates, Immunomodulation, Shock, Septic therapy, Sepsis drug therapy, Acute Kidney Injury therapy
- Abstract
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.)
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- 2023
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20. Hemolytic Uremic Syndrome-Induced Acute Kidney Injury Treated via Immunomodulation with the Selective Cytopheretic Device.
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Hambrick HR, Short K, Askenazi D, Krallman K, Pino C, Yessayan L, Westover A, Humes HD, and Goldstein SL
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- Humans, Child, Endothelial Cells, Renal Dialysis adverse effects, Escherichia coli Infections therapy, Escherichia coli Infections drug therapy, Shiga-Toxigenic Escherichia coli, Hemolytic-Uremic Syndrome complications, Hemolytic-Uremic Syndrome therapy, Acute Kidney Injury etiology, Acute Kidney Injury therapy
- Abstract
Introduction: Shiga-toxin associated-hemolytic uremic syndrome (STEC-HUS) is a severe cause of acute kidney injury (AKI) in children. Although most children recover, about 5% die and 30% develop chronic renal morbidity. HUS pathophysiology includes activated neutrophils damaging vascular endothelial cells. Therapeutic immunomodulation of activated neutrophils may alter the progression of disease. We present 3 pediatric patients treated with the selective cytopheretic device (SCD)., Methods: We describe a 12 y.o. (patient 1) and two 2 y.o. twins (patients 2 and 3) with STEC-HUS requiring continuous renal replacement therapy (CRRT) who were enrolled in two separate studies of the SCD., Results: Patient 1 presented with STEC-HUS causing AKI and multisystem organ failure and received 7 days of SCD and CRRT treatment. After SCD initiation, the patient had gradual recovery of multi-organ dysfunction, with normal kidney and hematologic parameters at 60-day follow-up. Patients 2 and 3 presented with STEC-HUS with AKI requiring dialysis. Each received 24 h of SCD therapy. Thereafter, both gradually improved, with normalization (patient 2) and near-normalization (patient 3) of kidney function at 60-day follow-up., Conclusion: Immunomodulatory treatment with the SCD was associated with improvements in multisystem stigmata of STEC-HUS-induced AKI and was well-tolerated without any device-related adverse events., (© 2023 S. Karger AG, Basel.)
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- 2023
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21. Extracorporeal Immunomodulation Treatment and Clinical Outcomes in ICU COVID-19 Patients.
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Yessayan LT, Neyra JA, Westover AJ, Szamosfalvi B, and Humes HD
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To evaluate safety and clinical outcomes of extracorporeal immunomodulation treatment with a selective cytopheretic device (SCD) in COVID-19 ICU patients with multiple organ failure., Design: Two-center, prospective, single-arm treatment clinical trial., Setting: ICUs at two academic medical centers between September 2020 and July 2021., Patients: Twenty-two COVID-10 patients in the ICU with acute respiratory distress syndrome who required mechanical ventilation. Nearly all included patients in the intervention group except one had acute kidney injury requiring continuous renal replacement therapy (CRRT). Sixteen subjects meeting enrollment criteria were selected as contemporaneous controls from a concurrent prospective registry CRRT trial., Intervention: Treatment with an SCD integrated into a continuous renal replacement extracorporeal blood circuit for up to 10 days to provide autologous leukocyte cell processing to immunomodulate the hyperinflammatory disease state of COVID-19., Measurements and Main Results: SCD treatment in COVID-19 ICU patients with multiple organ failure demonstrated an acceptable safety profile with no device-related serious adverse events. Treatment of these patients resulted in the selective removal of highly activated circulating leukocytes as determined by flow cytometry. Significant reductions were observed in the elevated plasma levels of eight cytokines and biomarkers, including interleukin (IL)6, IL15, IL10, and soluble ST2, which are predictive of mortality in COVID-19 patients. Significant improvements of leukocytosis and Po
2 /Fio2 ratios occurred during treatment not observed in the control group. SCD-treated subjects had a reduction in 60-day mortality of 50% compared with 81% in the control cohort. The subjects who received greater than 96 hours of SCD treatment, per protocol, had a further reduction in mortality to 31% ( p < 0.012)., Conclusions: Extracorporeal immunomodulation therapy with an SCD demonstrated safety without any device-related serious adverse events. As a rescue therapy in COVID-19 ICU patients progressing to multiple organ failure despite maximal pharmacologic and organ support interventions, SCD treatment resulted in improved clinical outcomes. This autologous leukocyte cell processing technology may provide a new approach in the treatment of unremitting hyperinflammation of COVID-19., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)- Published
- 2022
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22. A digital protein microarray for COVID-19 cytokine storm monitoring.
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Song Y, Ye Y, Su SH, Stephens A, Cai T, Chung MT, Han MK, Newstead MW, Yessayan L, Frame D, Humes HD, Singer BH, and Kurabayashi K
- Subjects
- Algorithms, Biomarkers blood, C-Reactive Protein analysis, COVID-19 blood, Critical Illness, Cytokine Release Syndrome immunology, Equipment Design, Ferritins analysis, Interleukin-10 blood, Interleukin-1beta blood, Interleukin-6 blood, Limit of Detection, Monitoring, Physiologic instrumentation, SARS-CoV-2, Tumor Necrosis Factor-alpha blood, COVID-19 immunology, Cytokine Release Syndrome blood, Cytokines blood, Digital Technology methods, Enzyme-Linked Immunosorbent Assay methods, Monitoring, Physiologic methods, Protein Array Analysis methods
- Abstract
Despite widespread concern regarding cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of the technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4 pg mL
-1 ), inter-assay repeatability (∼10% CV), and rapid operation providing feedback on the progress of therapy within 4 hours. This test allowed us to perform serial monitoring of two critically ill patients with respiratory failure and to support immunomodulatory therapy using the selective cytopheretic device (SCD). We also observed clear interleukin-6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as ferritin and C-reactive protein (CRP). Our data revealed large subject-to-subject variability in patients' response to COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.- Published
- 2021
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23. Use of the Selective Cytopheretic Device in Critically Ill Children.
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Goldstein SL, Askenazi DJ, Basu RK, Selewski DT, Paden ML, Krallman KA, Kirby CL, Mottes TA, Terrell T, and Humes HD
- Abstract
Introduction: Critically ill children with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect when circuit ionized calcium (iCa
2+ ) is maintained at <0.40 mmol/l with regional citrate anticoagulation (RCA). In a randomized trial of adult patients on CRRT, those treated with the SCD maintaining an iCa2+ <0.40 mmol/l had improved survival/dialysis independence. We conducted a US Food and Drug Administration (FDA)-sponsored study to evaluate safety and feasibility of the SCD in 16 critically ill children., Methods: Four pediatric intensive care units (ICUs) enrolled children with AKI and multiorgan dysfunction receiving CKRT to receive the SCD integrated post-CKRT membrane. RCA was used to achieve a circuit iCa2+ level <0.40 mmol/l. Subjects received SCD treatment for 7 days or CKRT discontinuation, whichever came first., Results: The FDA target enrollment of 16 subjects completed the study from December 2016 to February 2020. Mean age was 12.3 ± 5.1 years, weight was 53.8 ± 28.9 kg, and median Pediatric Risk of Mortality II was 7 (range 2-19). Circuit iCa2+ levels were maintained at <0.40 mmol/l for 90.2% of the SCD therapy time. Median SCD duration was 6 days. Fifteen subjects survived SCD therapy; 12 survived to ICU discharge. All ICU survivors were dialysis independent at 60 days. No SCD-related adverse events (AEs) were reported., Conclusion: Our data demonstrate that SCD therapy is feasible and safe in children who require CKRT. Although we cannot make efficacy claims, the 75% survival rate and 100% renal recovery rate observed suggest a possible favorable benefit-to-risk ratio., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)- Published
- 2020
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24. Treatment of Cytokine Storm in COVID-19 Patients With Immunomodulatory Therapy.
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Yessayan L, Szamosfalvi B, Napolitano L, Singer B, Kurabayashi K, Song Y, Westover A, and Humes HD
- Subjects
- Adult, Betacoronavirus, COVID-19, Coronavirus Infections blood, Critical Care methods, Extracorporeal Membrane Oxygenation methods, Humans, Immunomodulation, Male, Middle Aged, Pandemics, Pneumonia, Viral blood, Respiratory Distress Syndrome therapy, Respiratory Distress Syndrome virology, SARS-CoV-2, Coronavirus Infections immunology, Coronavirus Infections therapy, Critical Illness therapy, Cytapheresis methods, Interleukin-6 blood, Pneumonia, Viral immunology, Pneumonia, Viral therapy
- Abstract
Observational evidence suggests that excessive inflammation with cytokine storm may play a critical role in development of acute respiratory distress syndrome (ARDS) in COVID-19. We report the emergency use of immunomodulatory therapy utilizing an extracorporeal selective cytopheretic device (SCD) in two patients with elevated serum interleukin (IL)-6 levels and refractory COVID-19 ARDS requiring extracorporeal membrane oxygenation (ECMO). The two patients were selected based on clinical criteria and elevated levels of IL-6 (>100 pg/ml) as a biomarker of inflammation. Once identified, emergency/expanded use permission for SCD treatment was obtained and patient consented. Six COVID-19 patients (four on ECMO) with severe ARDS were also screened with IL-6 levels less than 100 pg/ml and were not treated with SCD. The two enrolled patients' PaO2/FiO2 ratios increased from 55 and 58 to 200 and 192 at 52 and 50 hours, respectively. Inflammatory indices also declined with IL-6 falling from 231 and 598 pg/ml to 3.32 and 116 pg/ml, respectively. IL-6/IL-10 ratios also decreased from 11.8 and 18 to 0.7 and 0.62, respectively. The two patients were successfully weaned off ECMO after 17 and 16 days of SCD therapy, respectively. The results observed with SCD therapy on these two critically ill COVID-19 patients with severe ARDS and elevated IL-6 is encouraging. A multicenter clinical trial is underway with an FDA-approved investigational device exemption to evaluate the potential of SCD therapy to effectively treat COVID-19 intensive care unit patients.
- Published
- 2020
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25. Metformin and Inhibition of Transforming Growth Factor-Beta Stimulate In Vitro Transport in Primary Renal Tubule Cells.
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Love H, Evans R, Humes HD, Roy S, Zent R, Harris R, Wilson M, and Fissell WH
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- Cells, Cultured, Humans, Kidney Tubules cytology, Metformin pharmacology, Receptor, Transforming Growth Factor-beta Type I antagonists & inhibitors, Transforming Growth Factor beta
- Abstract
Patient-oriented applications of cell culture include cell therapy of organ failure like chronic renal failure. Clinical deployment of a cell-based device for artificial renal replacement requires qualitative and quantitative fidelity of a cultured cell to its in vivo counterpart. Active specific apicobasal ion transport reabsorbs 90-99% of the filtered load of salt and water in the kidney. In a bioengineered kidney, tubular transport concentrates wastes and eliminates the need for hemodialysis, but renal tubule cells in culture transport little or no salt and water. We previously identified transforming growth factor-beta as a signaling pathway necessary for in vitro differentiation of renal tubule cells. Inhibition of TGF-β receptor-1 led to active inhabitable electrolyte and water transport by primary human renal tubule epithelial cells in vitro . Addition of metformin increased transport, in the context of a transient effect on 5' AMP-activated kinase phosphorylation. The signals that undermine in vitro differentiation are complex, but susceptible to pharmacologic intervention. This achievement overcomes a major hurdle limiting the development of a bioreactor of cultured cells for renal replacement therapy that encompasses not only endocrine and metabolic functions but also transport and excretion. Impact statement Clinical tissue engineering requires functional fidelity of the cultured cell to its in vivo counterpart, but this has been elusive in renal tissue engineering. Typically, renal tubule cells in culture have a flattened morphology and do not express key transporters essential to their function. In this study, we build on our prior work by using small molecules to modulate pathways affected by substrate elasticity. In doing so, we are able to enhance differentiation of these cells on conventional noncompliant substrates and show transport. These results are fundamentally enabling a new generation of cell-based renal therapies.
- Published
- 2020
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26. Experience With Pediatric Medical Device Development.
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Humes HD and Westover AJ
- Published
- 2020
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27. Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.
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Johnston KA, Westover AJ, Rojas-Pena A, Haft JW, Toomasian JM, Johnson T, Buffington DA, and Humes HD
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- Animals, Cardiopulmonary Bypass methods, Inflammation etiology, Inflammation prevention & control, Sus scrofa, Swine, Cardiopulmonary Bypass adverse effects, Cardiopulmonary Bypass instrumentation, Leukocytes, Membranes, Artificial
- Abstract
Leukocyte (LE) activation during cardiopulmonary bypass (CPB) promotes a systemic inflammatory response that contributes to organ injury and postoperative organ dysfunction. A leukocyte modulatory device (L-MOD) for use during (and after) CPB to limit leukocyte-mediated organ injury was tested in a preclinical model. Twenty-two pigs underwent 180 minutes of CPB and 5 hours postoperative observation. Pigs received no intervention (group 1, n = 9), 3 hours of therapy by incorporation of L-MOD into the CPB circuit (group 2, n = 6), or 8 hours of therapy using a femoral venovenous L-MOD circuit during and after CPB (group 3, n = 7). Leukocyte activation was increased at the end of CPB and leukocyte counts, namely neutrophils, increased postoperatively in most animals. These indices trended much lower in group 3. Systemic vascular resistance was not as reduced post-CPB for the L-MOD-treated pigs, and urine output was significantly greater for group 3 (p < 0.01). At 5 hours post-CPB, group 3 had a lower troponin-I (1.59 ± 0.68 ng/ml) than group 1 or group 2 (3.97 ± 2.63 and 3.55 ± 2.04 ng/ml, respectively, p < 0.05) and a lower urine neutrophil gelatinase-associated lipocalin (7.57 ± 3.59 ng/ml) than the average of the other groups (50.71 ± 49.17, p < 0.05). These results demonstrate the therapeutic potential of L-MOD therapy to mitigate the inflammatory response to CPB. Eight hours of venovenous L-MOD resulted in less organ injury and post-op organ dysfunction in this model.
- Published
- 2019
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28. Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung.
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Pino CJ, Westover AJ, Johnston KA, Buffington DA, and Humes HD
- Abstract
Regenerative medicine was initially focused on tissue engineering to replace damaged tissues and organs with constructs derived from cells and biomaterials. More recently, this field of inquiry has expanded into exciting areas of translational medicine modulating the body's own endogenous processes, to prevent tissue damage in organs and to repair and regenerate these damaged tissues. This review will focus on recent insights derived from studies in which the manipulation of the innate immunologic system may diminish acute kidney injury and enhance renal repair and recovery without the progression to chronic kidney disease and renal failure. The manner in which these interventions may improve acute and chronic organ dysfunction, including the heart, brain, and lung, will also be reviewed.
- Published
- 2018
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29. A case of tumor lysis syndrome and acute renal failure associated with elotuzumab treatment in multiple myeloma.
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Atchison DK and Humes HD
- Abstract
Renal dysfunction is a common comorbidity of multiple myeloma. However, tumor lysis syndrome is a rare cause of renal dysfunction in multiple myeloma. Elotuzumab is a newly US FDA-approved monoclonal antibody used in the treatment of refractory multiple myeloma. To our knowledge, elotuzumab has not been associated with a case of tumor lysis syndrome. We present the case of a patient who developed clinical tumor lysis syndrome 1 week after treatment with elotuzumab accompanied by renal failure with hyperphosphatemia, hyperkalemia, and profound hyperuricemia. His course was further complicated by significant epistaxis from the accumulation of dabigatran in acute renal failure. In spite of treatment with rasburicase and hemodiafiltration, the patient decompensated and eventually died. Risk factors for the development of tumor lysis syndrome in multiple myeloma are discussed.
- Published
- 2017
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30. Development of a wearable bioartificial kidney using the Bioartificial Renal Epithelial Cell System (BRECS).
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Johnston KA, Westover AJ, Rojas-Pena A, Buffington DA, Pino CJ, Smith PL, and Humes HD
- Subjects
- Animals, Epithelial Cells pathology, Humans, Kidney pathology, Sheep, Stem Cells pathology, Epithelial Cells metabolism, Kidney metabolism, Kidneys, Artificial, Stem Cells metabolism, Wearable Electronic Devices
- Abstract
Cell therapy for the treatment of renal failure in the acute setting has proved successful, with therapeutic impact, yet development of a sustainable, portable bioartificial kidney for treatment of chronic renal failure has yet to be realized. Challenges in maintaining an anticoagulated blood circuit, the typical platform for solute clearance and support of the biological components, have posed a major hurdle in advancement of this technology. This group has developed a Bioartificial Renal Epithelial Cell System (BRECS) capable of differentiated renal cell function while sustained by body fluids other than blood. To evaluate this device for potential use in end-stage renal disease, a large animal model was established that exploits peritoneal dialysis fluid for support of the biological device and delivery of cell therapy while providing uraemic control. Anephric sheep received a continuous flow peritoneal dialysis (CFPD) circuit that included a BRECS. Sheep were treated with BRECS containing 1 × 10
8 renal epithelial cells or acellular sham devices for up to 7 days. The BRECS cell viability and activity were maintained with extracorporeal peritoneal fluid circulation. A systemic immunological effect of BRECS therapy was observed as cell-treated sheep retained neutrophil oxidative activity better than sham-treated animals. This model demonstrates that use of the BRECS within a CFPD circuit embodies a feasible approach to a sustainable and effective wearable bioartificial kidney. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)- Published
- 2017
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31. Immunomodulatory Device Therapy in a Pediatric Patient With Acute Kidney Injury and Multiorgan Dysfunction.
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Selewski DT, Goldstein SL, Fraser E, Plomaritas K, Mottes T, Terrell T, and Humes HD
- Published
- 2017
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- View/download PDF
32. Bioengineered Renal Cell Therapy Device for Clinical Translation.
- Author
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Pino CJ, Westover AJ, Buffington DA, and Humes HD
- Subjects
- Cells, Cultured, Humans, Acute Kidney Injury therapy, Biomedical Engineering, Cell- and Tissue-Based Therapy instrumentation, Kidney cytology, Kidneys, Artificial
- Abstract
The bioartificial renal epithelial cell system (BRECS) is a cell-based device to treat acute kidney injury through renal cell therapy from an extracorporeal circuit. To enable widespread implementation of cell therapy, the BRECS was designed to be cryopreserved as a complete device, cryostored, cryoshipped to an end-use site, thawed as a complete device, and employed in a therapeutic extracorporeal hemofiltration circuit. This strategy overcomes storage and distribution issues that have been previous barriers to cell therapy. Previous BRECS housings produced by computer numerical control (CNC) machining, a slow process taking hours to produce one bioreactor, was also prohibitively expensive (>$600/CNC-BRECS); major obstacles to mass production. The goal of this study was to produce a BRECS to be mass produced by injection-molded BRECS (IM-BRECS), decreasing cost (<$20/unit), and improving manufacturing speed (hundreds of units/h), while maintaining the same cell therapy function as the previous CNC-BRECS, first evaluated through prototypes produced by stereolithography BRECS (SLA-BRECS). The finalized IM-BRECS design had a significantly lower fill volume (10 ml), mass (49 g), and footprint (8.5 cm × 8.5 cm × 1.5 cm), and was demonstrated to outperform the previous BRECS designs with respect to heat transfer, significantly improving control of cooling during cryopreservation and reducing thaw times during warming. During in vitro culture, IM-BRECS performed similarly to previous CNC-BRECS with respect to cell metabolic activity (lactate production, oxygen consumption, and glutathione metabolism) and amount of cells supported.
- Published
- 2017
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33. A bio-artificial renal epithelial cell system conveys survival advantage in a porcine model of septic shock.
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Westover AJ, Buffington DA, Johnston KA, Smith PL, Pino CJ, and Humes HD
- Subjects
- Animals, Blood Pressure, Cytokines blood, Disease Models, Animal, Escherichia coli physiology, Hematocrit, Hemodynamics, Kaplan-Meier Estimate, Kidney physiopathology, Kidney Function Tests, Shock, Septic blood, Shock, Septic physiopathology, Survival Analysis, Sus scrofa, Artificial Organs microbiology, Epithelial Cells pathology, Kidney pathology, Shock, Septic pathology
- Abstract
Renal cell therapy using the hollow fiber based renal assist device (RAD) improved survival time in an animal model of septic shock (SS) through the amelioration of cardiac and vascular dysfunction. Safety and ability of the RAD to improve clinical outcomes was demonstrated in a Phase II clinical trial, in which patients had high prevalence of sepsis. Even with these promising results, clinical delivery of cell therapy is hampered by manufacturing hurdles, including cell sourcing, large-scale device manufacture, storage and delivery. To address these limitations, the bioartificial renal epithelial cell system (BRECS) was developed. The BRECS contains human renal tubule epithelial cells derived from adult progenitor cells using enhanced propagation techniques. Cells were seeded onto trabeculated disks of niobium-coated carbon, held within cryopreservable, perfusable, injection-moulded polycarbonate housing. The study objective was to evaluate the BRECS in a porcine model of SS to establish conservation of efficacy after necessary cell sourcing and design modifications; a pre-clinical requirement to move back into clinical trials. SS was incited by peritoneal injection of E. coli simultaneous to insertion of BRECS (n=10) or control (n=15), into the ultrafiltrate biofeedback component of an extracorporeal circuit. Comparable to RAD, prolonged survival of the BRECS cohort was conveyed through stabilization of cardiac output and vascular leak. In conclusion, the demonstration of conserved efficacy with BRECS therapy in a porcine SS model represents a crucial step toward returning renal cell therapy to the clinical setting, initially targeting ICU patients with acute kidney injury requiring continuous renal replacement therapy. Copyright © 2014 John Wiley & Sons, Ltd., (Copyright © 2014 John Wiley & Sons, Ltd.)
- Published
- 2017
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34. Immunomodulatory Device Promotes a Shift of Circulating Monocytes to a Less Inflammatory Phenotype in Chronic Hemodialysis Patients.
- Author
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Szamosfalvi B, Westover A, Buffington D, Yevzlin A, and Humes HD
- Subjects
- Female, Humans, Inflammation therapy, Kidney Failure, Chronic therapy, Male, Membranes, Artificial, Monocytes metabolism, Phenotype, Flow Cytometry methods, Inflammation etiology, Monocytes immunology, Renal Dialysis adverse effects
- Abstract
Patients with end-stage renal disease (ESRD) on chronic hemodialysis (HD) suffer accelerated morbidity and mortality rates caused by cardiovascular disease and infections. Chronic inflammation plays a critical role in these poor outcomes. The activated monocyte (MO) has become a prime therapeutic target to modulate this inflammatory process. A selective cytopheretic device (SCD) was evaluated to assess its effects on the circulating MO pool. A pilot trial was undertaken in 15 ESRD patients on HD with C-reactive protein (CRP) levels greater than 5 mg/dl. An excellent safety profile was observed with no decline in leukocyte (LE) or platelet counts. The effect of SCD therapy on MO phenotypes in these patients was determined on peripheral blood MO utilizing flow cytometry. SCD therapy promoted a shift in MO phenotype from predominantly CD14 expressing MO at baseline/pre-SCD therapy to CD14 expressing MO post-SCD therapy. A significant shift in MO population phenotype afforded by a single SCD therapy session was observed (p < 0.013). In a subset of patients (n = 7) presenting with type 2 diabetes mellitus (T2D), this persistent decline in MO CD14 expression was sustained as long as 2 weeks posttherapy. These results demonstrate that the SCD therapy has the potential to modulate the chronic proinflammatory state in ESRD patients.
- Published
- 2016
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35. An Immunomodulatory Device Improves Insulin Resistance in Obese Porcine Model of Metabolic Syndrome.
- Author
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Westover AJ, Johnston KA, Buffington DA, and Humes HD
- Subjects
- Animals, Citric Acid, Disease Models, Animal, Extracorporeal Circulation methods, Inflammation, Leukocytes, Metabolic Syndrome metabolism, Neutrophils immunology, Obesity metabolism, Swine, Swine, Miniature, Immunomodulation, Insulin Resistance, Leukapheresis methods, Macrophages immunology, Metabolic Syndrome immunology, Monocytes immunology, Obesity immunology
- Abstract
Obesity is associated with tissue inflammation which is a crucial etiology of insulin resistance. This inflammation centers around circulating monocytes which form proinflammatory adipose tissue macrophages (ATM). Specific approaches targeting monocytes/ATM may improve insulin resistance without the adverse side effects of generalized immunosuppression. In this regard, a biomimetic membrane leukocyte processing device, called the selective cytopheretic device (SCD), was evaluated in an Ossabaw miniature swine model of insulin resistance with metabolic syndrome. Treatment with the SCD in this porcine model demonstrated a decline in circulating neutrophil activation parameters and monocyte counts. These changes were associated with improvements in insulin resistance as determined with intravenous glucose tolerance testing. These improvements were also reflected in lowering of homeostatic model assessment- (HOMA-) insulin resistant (IR) scores for up to 2 weeks after SCD therapy. These results allow for the planning of first-in-man studies in obese type 2 diabetic patients.
- Published
- 2016
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36. Negating Tissue Contracture Improves Volume Maintenance and Longevity of In Vivo Engineered Tissues.
- Author
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Lytle IF, Kozlow JH, Zhang WX, Buffington DA, Humes HD, and Brown DL
- Subjects
- Animals, Biocompatible Materials, Contracture etiology, Rats, Rats, Inbred F344, Silicones, Tissue Engineering methods, Contracture prevention & control, Tissue Engineering instrumentation, Tissue Scaffolds
- Abstract
Background: Engineering large, complex tissues in vivo requires robust vascularization to optimize survival, growth, and function. Previously, the authors used a "chamber" model that promotes intense angiogenesis in vivo as a platform for functional three-dimensional muscle and renal engineering. A silicone membrane used to define the structure and to contain the constructs is successful in the short term. However, over time, generated tissues contract and decrease in size in a manner similar to capsular contracture seen around many commonly used surgical implants. The authors hypothesized that modification of the chamber structure or internal surface would promote tissue adherence and maintain construct volume., Methods: Three chamber configurations were tested against volume maintenance. Previously studied, smooth silicone surfaces were compared to chambers modified for improved tissue adherence, with multiple transmembrane perforations or lined with a commercially available textured surface. Tissues were allowed to mature long term in a rat model, before analysis., Results: On explantation, average tissue masses were 49, 102, and 122 mg; average volumes were 74, 158 and 176 μl; and average cross-sectional areas were 1.6, 6.7, and 8.7 mm for the smooth, perforated, and textured groups, respectively. Both perforated and textured designs demonstrated significantly greater measures than the smooth-surfaced constructs in all respects., Conclusions: By modifying the design of chambers supporting vascularized, three-dimensional, in vivo tissue engineering constructs, generated tissue mass, volume, and area can be maintained over a long time course. Successful progress in the scale-up of construct size should follow, leading to improved potential for development of increasingly complex engineered tissues.
- Published
- 2015
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37. A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury.
- Author
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Tumlin JA, Galphin CM, Tolwani AJ, Chan MR, Vijayan A, Finkel K, Szamosfalvi B, Dev D, DaSilva JR, Astor BC, Yevzlin AS, and Humes HD
- Subjects
- Adult, Aged, Critical Care, Female, Humans, Male, Middle Aged, Renal Replacement Therapy methods, Treatment Outcome, Acute Kidney Injury therapy, Renal Dialysis, Renal Replacement Therapy instrumentation
- Abstract
Objective: Acute kidney injury (AKI) is a highly morbid condition in critically ill patients that is associated with high mortality. Previous clinical studies have demonstrated the safety and efficacy of the Selective Cytopheretic Device (SCD) in the treatment of AKI requiring continuous renal replacement therapy in the intensive care unit (ICU)., Design, Setting, Patients: A randomized, controlled trial of 134 ICU patients with AKI, 69 received continuous renal replacement therapy (CRRT) alone and 65 received SCD therapy., Results: No significant difference in 60-day mortality was observed between the treated (27/69; 39%) and control patients (21/59; 36%, with six patients lost to follow up) in the intention to treat (ITT) analysis. Of the 19 SCD subjects (CRRT+SCD) and 31 control subjects (CRRT alone) who maintained a post-filter ionized calcium (iCa) level in the protocol's recommended range (≤ 0.4 mmol/L) for greater or equal to 90% of the therapy time, 60-day mortality was 16% (3/19) in the SCD group compared to 41% (11/27) in the CRRT alone group (p = 0.11). Dialysis dependency showed a borderline statistically significant difference between the SCD treated versus control CRRT alone patients maintained for ≥ 90% of the treatment in the protocol's recommended (r) iCa target range of ≤ 0.4 mmol/L with values of, 0% (0/16) and 25% (4/16), respectively (P = 0.10). When the riCa treated and control subgroups were compared for a composite index of 60 day mortality and dialysis dependency, the percentage of SCD treated subjects was 16% versus 58% in the control subjects (p<0.01). The incidence of serious adverse events did not differ between the treated (45/69; 65%) and control groups (40/65; 63%; p = 0·86)., Conclusion: SCD therapy may improve mortality and reduce dialysis dependency in a tightly controlled regional hypocalcaemic environment in the perfusion circuit., Trial Registration: ClinicalTrials.gov NCT01400893 http://clinicaltrials.gov/ct2/show/NCT01400893.
- Published
- 2015
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38. The bioartificial kidney.
- Author
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Buffington DA, Westover AJ, Johnston KA, and Humes HD
- Subjects
- Animals, Bioartificial Organs, Bioengineering, Epithelial Cells, Humans, Kidney physiology, Renal Insufficiency therapy
- Abstract
Renal failure has an exceedingly high mortality rate despite advances in dialysis technology. Current renal replacement therapies (RRTs) restore only the filtration function of the kidney. Replacing the critical transport, metabolic, and endocrine functions of the kidney may provide more complete RRT, changing the natural history of these disease processes. Primary human renal epithelial cells (RECs) have been isolated and expanded under conditions that enhance propagation, resulting in maximum cell yield for use in bioengineered applications. These RECs demonstrate differentiated absorptive, metabolic, and endocrine functions of the kidney when tested under in vitro and preclinical ex vivo animal studies. When incorporated into bioengineered systems, RECs have proved to provide effective RRTs in both preclinical and clinical studies. These engineered "bioartificial kidneys" demonstrate metabolic activity with systemic effects and improvement of survival in patients with acute kidney injury and multiorgan failure. Results also indicate REC therapy influences systemic leukocyte activation and the balance of inflammatory cytokines, suggesting that this REC therapy may improve morbidity and mortality by altering the proinflammatory state of patients. This innovative approach for treating renal and inflammatory disease states may become a groundbreaking, transformative platform to current standard-of-care therapies, enabling the advancement of numerous lifesaving technologies., (Copyright © 2014 Mosby, Inc. All rights reserved.)
- Published
- 2014
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39. The bioartificial kidney: current status and future promise.
- Author
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Humes HD, Buffington D, Westover AJ, Roy S, and Fissell WH
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Equipment Design, Forecasting, Humans, Kidney Diseases pathology, Kidney Diseases physiopathology, Renal Replacement Therapy trends, Tissue Engineering trends, Tissue Scaffolds, Treatment Outcome, Bioartificial Organs trends, Kidney pathology, Kidney physiopathology, Kidney Diseases therapy, Kidneys, Artificial trends, Renal Replacement Therapy methods, Stem Cell Transplantation trends, Tissue Engineering methods
- Abstract
The rapid understanding of the cellular and molecular bases of organ function and disease processes will be translated in the next decade into new therapeutic approaches to a wide range of clinical disorders, including acute and chronic renal failure. Central to these new therapies are the developing technologies of cell therapy and tissue engineering, which are based on the ability to expand stem or progenitor cells in tissue culture to perform differentiated tasks and to introduce these cells into the patient either via extracorporeal circuits or as implantable constructs. Cell therapy devices are currently being developed to replace the filtrative, metabolic, and endocrinologic functions of the kidney lost in both acute and chronic renal failure. This review summarizes the current state of development of a wearable or implantable bioartificial kidney. These devices have the promise to be combined to produce a wearable or implantable bioartificial kidney for full renal replacement therapy that may significantly diminish morbidity and mortality in patients with acute or chronic kidney disease.
- Published
- 2014
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40. The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multicenter pilot study.
- Author
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Tumlin JA, Chawla L, Tolwani AJ, Mehta R, Dillon J, Finkel KW, DaSilva JR, Astor BC, Yevzlin AS, and Humes HD
- Subjects
- Acute Kidney Injury mortality, Adolescent, Adult, Aged, Aged, 80 and over, Female, Hospital Mortality, Humans, Intensive Care Units, Male, Middle Aged, Prospective Studies, Single-Blind Method, Survival Rate, Treatment Outcome, United States, Young Adult, Acute Kidney Injury therapy, Renal Replacement Therapy
- Abstract
Acute kidney injury (AKI) is characterized by deterioration in kidney function resulting in multisystem abnormalities. Much of the morbidity and mortality associated with AKI result from a systemic inflammatory response syndrome (SIRS). This study described herein is a prospective, single-arm, multicenter US study designed to evaluate the safety and efficacy of the Selective Cytopheretic Device (SCD) treatment on AKI requiring continuous renal replacement therapy (CRRT) in the ICU. The study enrolled 35 subjects. The mean age was 56.3±15. With regard to race, 71.4% of the subjects were Caucasian, 22.9% were Black, and 5.7% were Hispanic. Average SOFA score was 11.3±3.6. Death from any cause at Day 60 was 31.4%. Renal recovery, defined as dialysis independence, was observed in all of the surviving subjects at Day 60. The results of this pilot study indicate the potential for a substantial improvement in patient outcomes over standard of care therapy, which is associated with a greater than 50% 60-day mortality in the literature. The SCD warrants further study in scientifically sound, pivotal trial to demonstrate reasonable assurance of safety and effectiveness., (© 2012 Wiley Periodicals, Inc.)
- Published
- 2013
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41. Selective cytopheretic inhibitory device with regional citrate anticoagulation and portable sorbent dialysis.
- Author
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Pino CJ, Farokhrani A, Lou L, Smith PL, Johnston K, Buffington DA, and Humes HD
- Subjects
- Animals, Biomarkers blood, Disease Models, Animal, Immunotherapy methods, Leukapheresis methods, Leukocytes immunology, Materials Testing, Renal Dialysis methods, Swine, Time Factors, Uremia blood, Uremia immunology, Anticoagulants administration & dosage, Biomimetic Materials, Citric Acid administration & dosage, Extracorporeal Circulation instrumentation, Immunotherapy instrumentation, Leukapheresis instrumentation, Membranes, Artificial, Renal Dialysis instrumentation, Uremia therapy
- Abstract
Selective cytopheretic inhibitory device (SCD) therapy is an immunomodulatory treatment provided by a synthetic biomimetic membrane in an extracorporeal circuit, which has shown promise in preclinical large animal models of severe sepsis as well as in clinical trials treating patients with acute kidney injury and multiple organ failure. During SCD therapy, citrate is administered to lower ionized calcium levels in blood for anticoagulation and inhibition of leukocyte activation. Historically, citrate has been known to interfere with sorbent dialysis, therefore, posing a potential issue for the use of SCD therapy with a portable dialysis system. This sorbent dialysis SCD (sorbent SCD) would be well suited for battlefield and natural disaster applications where the water supply for standard dialysis is limited, and the types of injuries in those settings would benefit from SCD therapy. In order to explore the compatibility of sorbent and SCD technologies, a uremic porcine model was tested with the Allient sorbent dialysis system (Renal Solutions Incorporated, Fresenius Medical Care, Warrendale, PA, USA) and concurrent SCD therapy with regional citrate anticoagulation. The hypothesis to be assessed was whether the citrate load required by the SCD could be metabolized prior to recirculation from systemic blood back into the therapeutic circuit. Despite the fact that the sorbent SCD maintained urea clearance without any adverse hematologic events, citrate load for SCD therapy caused an interaction with the sorbent column resulting in elevated, potentially toxic aluminum levels in dialysate and in systemic blood. Alternative strategies to implement sorbent-SCD therapy will be required, including development of alternate urease-sorbent column binding chemistry or further changes to the sorbent-SCD therapeutic circuit along with determining the minimum citrate concentration required for efficacious SCD treatment., (© 2012, Copyright the Authors. Artificial Organs © 2012, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)
- Published
- 2013
- Full Text
- View/download PDF
42. Cell-based approaches for the treatment of systemic inflammation.
- Author
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Pino CJ, Yevzlin AS, Lee K, Westover AJ, Smith PL, Buffington DA, and Humes HD
- Subjects
- Acute Kidney Injury therapy, Humans, Immunomodulation, Multiple Organ Failure therapy, Cell- and Tissue-Based Therapy methods, Inflammation therapy, Stem Cells
- Abstract
Acute and chronic solid organ failures are costly disease processes with high mortality rates. Inflammation plays a central role in both acute and chronic organ failure, including heart, lung and kidney. In this regard, new therapies for these disorders have focused on inhibiting the mediators of inflammation, including cytokines and free radicals, with little or no success in clinical studies. Recent novel treatment strategies have been directed to cell-based rather than mediator-based approaches, designed to immunomodulate the deleterious effects of inflammation on organ function. One approach, cell therapy, replaces cells that were damaged in the acute or chronic disease process with stem/progenitor technology, to rebalance excessive inflammatory states. As an example of this approach, the use of an immunomodulatory role of renal epithelial progenitor cells to treat acute renal failure (ARF) and multiorgan failure arising from acute kidney injury is reviewed. A second therapeutic pathway, cell processing, does not incorporate stem/progenitor cells in the device, but rather biomimetic materials that remove and modulate the primary cellular components, which promote the worsening organ tissue injury associated with inflammation. The use of an immunomodulating leukocyte selective cytopheretic inhibitory device is also reviewed as an example of this cell processing approach. Both of these unconventional strategies have shown early clinical efficacy in pilot clinical trials and may transform the therapeutic approach to organ failure disorders.
- Published
- 2013
- Full Text
- View/download PDF
43. Substitution-free hemodiafiltration.
- Author
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Lee K, Pino CJ, and Humes HD
- Subjects
- Clinical Trials as Topic, Hemodiafiltration instrumentation, Hemodialysis Solutions, Hemodynamics, Hemorheology, Humans, Kidney Failure, Chronic physiopathology, Kidney Failure, Chronic therapy, Models, Biological, Pressure, Treatment Outcome, Hemodiafiltration methods
- Abstract
Hemodiafiltration (HDF) has been reported to deliver better dialysis outcomes in patients with end-stage renal disease. Technical advances now allow online-based HDF to be used on a clinical basis. However, HDF is being performed at a limited rate because of the requirement of exogenous fluid infusion, which causes safety and cost issues. Therefore, various modifications on HDF strategies have been devised to achieve the HDF without exogenous fluid infusion, which can be achieved by spontaneous fluid reinfusion. In this article, substitution-free HDF strategies are reviewed in detail, with specific attention to technical aspects of the methodology, in vivo and in vitro efficacies, and applicability to clinical use.
- Published
- 2012
- Full Text
- View/download PDF
44. Enhanced propagation of adult human renal epithelial progenitor cells to improve cell sourcing for tissue-engineered therapeutic devices for renal diseases.
- Author
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Westover AJ, Buffington DA, and Humes HD
- Subjects
- Adult, Aged, Cell Proliferation, Cell Shape, Cells, Cultured, Cryopreservation, Female, Humans, Immunohistochemistry, Male, Middle Aged, Tissue Donors, Cell Culture Techniques methods, Epithelial Cells cytology, Equipment and Supplies, Kidney cytology, Kidney Diseases therapy, Stem Cells cytology, Tissue Engineering instrumentation
- Abstract
Renal cell therapy employing cells derived from adult renal epithelial cell (REC) progenitors promises to reduce the morbidity of patients with renal insufficiency due to acute renal failure and end stage renal disease. To this end, tissue engineered devices addressing the neglected biologic component of renal replacement therapy are being developed. Because human donor tissue is limited, novel enhanced progenitor cell propagation (EP) techniques have been developed and applied to adult human kidney transplant discards from six donors. Changes include more efficient digestion and the amplification of progenitors prior to terminal epithelial differentiation promoted by contact inhibition and the addition of retinoic acid. Differentiated morphology in EP populations was demonstrated by the ability to form polarized epithelium with tight junctions, apical central cilia and expression of brush border membrane enzymes. Evaluation of lipopolysaccharide stimulated interleukin-8 secretion and γ-glutamyl transpeptisade activity in EP derived cells was used to confirm therapeutic equivalence to REC obtained using published techniques, which have previously shown efficacy in large animal models and clinical trials. Yield exceeded 10(16) cells/gram cortex from the only kidney obtained due to an anatomical defect, while the average yield from diseased kidneys ranged from 1.1 × 10(9) to 8.8 × 10(11) cells/gram cortex, representing an increase of more than 10 doublings over standard methods. Application of the EP protocol to REC expansion has solved the problem of cell sourcing as the limiting factor to the manufacture of cell based therapies targeting renal diseases and may provide a method for autologous device fabrication from core kidney biopsies., (Copyright © 2012 John Wiley & Sons, Ltd.)
- Published
- 2012
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45. Bioartificial Renal Epithelial Cell System (BRECS): A Compact, Cryopreservable Extracorporeal Renal Replacement Device.
- Author
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Buffington DA, Pino CJ, Chen L, Westover AJ, Hageman G, and Humes HD
- Abstract
Renal cell therapy has shown clinical efficacy in the treatment of acute renal failure (ARF) and promise for treatment of end-stage renal disease (ESRD) by supplementing conventional small solute clearance (hemodialysis or hemofiltration) with endocrine and metabolic function provided by cells maintained in an extracorporeal circuit. A major obstacle in the widespread adoption of this therapeutic approach is the lack of a cryopreservable system to enable distribution, storage, and therapeutic use at point of care facilities. This report details the design, fabrication, and assessment of a Bioartificial Renal Epithelial Cell System (BRECS), the first all-in-one culture vessel, cryostorage device, and cell therapy delivery system. The BRECS was loaded with up to 20 cell-seeded porous disks, which were maintained by perfusion culture. Once cells reached over 5 × 10
6 cells/disk for a total therapeutic dose of approximately 108 cells, the BRECS was cryopreserved for storage at -80°C or -140°C. The BRECS was rapidly thawed, and perfusion culture was resumed. Near precryopreservation values of cell viability, metabolic activity, and differentiated phenotype of functional renal cells were confirmed post-reconstitution. This technology could be extended to administer other cell-based therapies where metabolic, regulatory, or secretion functions can be leveraged in an immunoisolated extracorporeal circuit.- Published
- 2012
- Full Text
- View/download PDF
46. Cell-based strategies for the treatment of kidney dysfunction: a review.
- Author
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Pino CJ, Yevzlin AS, Tumlin J, and Humes HD
- Subjects
- Animals, Humans, Kidney cytology, Kidney injuries, Kidney pathology, Acute Kidney Injury therapy, Cell- and Tissue-Based Therapy methods, Kidney Failure, Chronic therapy, Tissue Engineering methods
- Abstract
Conventional treatment of acute and chronic renal diseases has focused on solute removal. Novel strategies aim to treat the multifactorial disease states of acute kidney injury and chronic kidney disease by mitigating inflammation. Cell-based technologies for the treatment of kidney dysfunction fall under two broad categories: cell therapy and cell processing. Cell therapy utilizes cells that are isolated, cultured outside of the body, and reintroduced as therapy, leveraging beneficial metabolic and synthetic functions. For example, renal tubule cells have been used to provide gluconeogenesis, ammoniagenesis, metabolism of glutathione, catabolism of important peptide hormones, growth factors, and cytokines critical to multiorgan homeostasis and immunomodulation to treat renal dysfunction. Cell processing focuses on altering the characteristics of cell populations inside the body to provide therapy. The selective cytopheretic device is an example of this novel therapeutic strategy that aims to modulate the innate immune response during organ dysfunction, additional organ injury, by binding and deactivating leukocytes. In this review, both cell therapy and cell processing approaches will be discussed in the context of acute kidney injury and chronic renal disease., (Copyright © 2012 S. Karger AG, Basel.)
- Published
- 2012
- Full Text
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47. The effects of a novel therapeutic device on acute kidney injury outcomes in the intensive care unit: a pilot study.
- Author
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Ding F, Yevzlin AS, Xu ZY, Zhou Y, Xie QH, Liu JF, Zheng Y, DaSilva JR, and Humes HD
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Device Approval, Female, Humans, Intensive Care Units, Male, Middle Aged, Pilot Projects, Prospective Studies, Renal Dialysis methods, Treatment Outcome, United States, United States Food and Drug Administration, Acute Kidney Injury therapy, Critical Care methods
- Abstract
Despite decades of improvements in the provision of renal replacement therapy, the morbidity and mortality associated with acute kidney injury (AKI) in the intensive care unit (ICU) setting remains extremely high. Much of the morbidity and mortality of this disorder is the consequence of systemic cellular damage that results from immune dysregulation. This is a prospective, single-arm, single-center study designed to evaluate the safety and efficacy of treatment with a selective cytopheretic device (SCD) on clinical outcomes in AKI requiring renal replacement therapy in the ICU. The patients enrolled in the trial were compared with historical case-matched controls with respect to age and Sequential Organ Failure Assessment (SOFA) score. The mortality for the case-matched controls was 77.78%, whereas the mortality in the SCD treatment group was 22.22% (p = 0.027). Multiple regression analysis identified treatment with SCD as the only significant variable affecting mortality among age, SOFA score, average change in urine output over the first 7 days during or after treatment. Mean total urine output in the 10 subjects receiving SCD treatment increased from a baseline of approximately 500 ml/d to more than 2,000 ml/d by day 7 of treatment. The SCD represents a novel therapeutic approach to alter the acute inflammatory response seen in AKI, and further evaluation of the safety and efficacy of the device is being evaluated in a multicenter investigation in the United States under an Food and Drug Administration (FDA) approved investigational device exemption (IDE).
- Published
- 2011
- Full Text
- View/download PDF
48. A biomimetic membrane device that modulates the excessive inflammatory response to sepsis.
- Author
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Ding F, Song JH, Jung JY, Lou L, Wang M, Charles L, Westover A, Smith PL, Pino CJ, Buffington DA, and Humes HD
- Subjects
- Animals, Immunohistochemistry, Swine, Inflammation prevention & control, Membranes, Artificial, Molecular Mimicry, Sepsis prevention & control
- Abstract
Objective: Septic shock has a clinical mortality rate approaching fifty percent. The major clinical manifestations of sepsis are due to the dysregulation of the host's response to infection rather than the direct consequences of the invading pathogen. Central to this initial immunologic response is the activation of leukocytes and microvascular endothelium resulting in cardiovascular instability, lung injury and renal dysfunction. Due to the primary role of leukocyte activation in the sepsis syndrome, a synthetic biomimetic membrane, called a selective cytopheretic device (SCD), was developed to bind activated leukocytes. The incorporation of the SCD along an extracorporeal blood circuit coupled with regional anticoagulation with citrate to lower blood ionized calcium was devised to modulate leukocyte activation in sepsis., Design: Laboratory investigation., Setting: University of Michigan Medical School., Subjects: Pigs weighing 30-35 kg., Interventions: To assess the effect of the SCD in septic shock, pigs were administered 30×10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in an extracorporeal circuit containing SCD., Measurements and Main Results: In this animal model, the SCD with citrate compared to control groups without the SCD or with heparin anticoagulation ameliorated the cardiovascular instability and lung sequestration of activated leukocytes, reduced renal dysfunction and improved survival time compared to various control groups. This effect was associated with minimal elevations of systemic circulating neutrophil activation., Conclusions: These preclinical studies along with two favorable exploratory clinical trials form the basis of an FDA-approved investigational device exemption for a pivotal multicenter, randomized control trial currently underway.
- Published
- 2011
- Full Text
- View/download PDF
49. A microfluidic bioreactor with integrated transepithelial electrical resistance (TEER) measurement electrodes for evaluation of renal epithelial cells.
- Author
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Ferrell N, Desai RR, Fleischman AJ, Roy S, Humes HD, and Fissell WH
- Subjects
- Animals, Cell Proliferation, Dogs, Electrodes, Fluorescent Antibody Technique, Humans, Membrane Proteins analysis, Phosphoproteins analysis, Staining and Labeling, Tight Junctions physiology, Tubulin analysis, Zonula Occludens-1 Protein, Bioreactors, Electric Impedance, Epithelial Cells physiology, Microfluidic Analytical Techniques methods
- Abstract
We have developed a bilayer microfluidic system with integrated transepithelial electrical resistance (TEER) measurement electrodes to evaluate kidney epithelial cells under physiologically relevant fluid flow conditions. The bioreactor consists of apical and basolateral fluidic chambers connected via a transparent microporous membrane. The top chamber contains microfluidic channels to perfuse the apical surface of the cells. The bottom chamber acts as a reservoir for transport across the cell layer and provides support for the membrane. TEER electrodes were integrated into the device to monitor cell growth and evaluate cell-cell tight junction integrity. Immunofluorescence staining was performed within the microchannels for ZO-1 tight junction protein and acetylated α-tubulin (primary cilia) using human renal epithelial cells (HREC) and MDCK cells. HREC were stained for cytoskeletal F-actin and exhibited disassembly of cytosolic F-actin stress fibers when exposed to shear stress. TEER was monitored over time under normal culture conditions and after disruption of the tight junctions using low Ca(2+) medium. The transport rate of a fluorescently labeled tracer molecule (FITC-inulin) was measured before and after Ca(2+) switch and a decrease in TEER corresponded with a large increase in paracellular inulin transport. This bioreactor design provides an instrumented platform with physiologically meaningful flow conditions to study various epithelial cell transport processes., (© 2010 Wiley Periodicals, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
50. Stem cell technology for the treatment of acute and chronic renal failure.
- Author
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Pino CJ and Humes HD
- Subjects
- Acute Kidney Injury therapy, Adult, Cell Differentiation, Embryonic Stem Cells transplantation, Hemofiltration methods, Homeostasis, Humans, Kidney cytology, Kidney pathology, Kidney physiology, Kidney Failure, Chronic therapy, Kidney Tubules physiology, Kidneys, Artificial, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells cytology, Morphogenesis, Renal Replacement Therapy methods, Ureter physiology, Ureter physiopathology, Acute Kidney Injury surgery, Kidney Failure, Chronic surgery, Stem Cell Transplantation methods
- Abstract
Acute and chronic renal failure are disorders with high rates of morbidity and mortality. Current treatment is based upon conventional dialysis to provide volume regulation and small solute clearance. There is growing recognition that renal failure is a complex disease state requiring a multifactorial therapy to address the short-comings of the conventional monofactorial approach. Kidney transplantation remains the most effective treatment, however, organ availability lags far behind demand. Many key kidney functions including gluconeogenesis, ammoniagenesis, metabolism of glutathione, catabolism of important peptide hormones, growth factors, and cytokines critical to multiorgan homeostasis and immunomodulation are provided by renal tubule cells. Therefore, cell-based therapies are promising multifactorial treatment approaches. In this review, current stem cell technologies including adult stem cells, embryonic stem cells and induced pluripotent stem cells will be discussed as cell sources for the treatment of acute and chronic renal failure., (Copyright 2010 Mosby, Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
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