In Vivo Assessment of a Manual Single Lumen Alternating Micro-Batch Hemodiafiltration (mSLAMB) System.

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 (RRT). METHODS: Using a porcine model, uremic toxins and exogenous fluorescent tracer concentrations were successfully lowered within just 1 hour of treatment. RESULTS: With a maximal dialysate flow, mSLAMB can achieve decreases in serum potassium concentration of > 0.5 mmol/L/ hr. With the mSLAMB hemodiafiltration system, micro-batch processing was also successful in removing up to 250mL 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.

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.

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.

Extracorporeal Immunomodulation Therapy in Acute Chronic Liver Failure With Multiorgan Failure: First in Human Use.

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.

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.

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.

Hemolytic Uremic Syndrome-Induced Acute Kidney Injury Treated via Immunomodulation with the Selective Cytopheretic Device.

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.

Estimating Changes in Glomerular Filtration Rate With Fluorescein Isothiocyanate-Sinistrin During Renal Replacement Therapy.

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.

Transdermal Detection of MB-102 and Correlation to Meropenem Pharmacokinetics During Continuous Renal Replacement Therapy: In Vivo Results.

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.

Translation of immunomodulatory therapy to treat chronic heart failure: Preclinical studies to first in human.

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.

Use of extracorporeal immunomodulation in a toddler with hemophagocytic lymphohistiocytosis and multisystem organ failure.

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.

Immunomodulatory therapy using a pediatric dialysis system ameliorates septic shock in miniature pigs.

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.

Extracorporeal Immunomodulation Treatment and Clinical Outcomes in ICU COVID-19 Patients.

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 Po2/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.

Use of the Selective Cytopheretic Device in Critically Ill Children.

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 (iCa2+) 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.

A digital protein microarray for COVID-19 cytokine storm monitoring.

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.

Treatment of Cytokine Storm in COVID-19 Patients With Immunomodulatory Therapy.

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.

Novel Leukocyte Modulator Device Reduces the Inflammatory Response to Cardiopulmonary Bypass.

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.

Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung.

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.

Development of a wearable bioartificial kidney using the Bioartificial Renal Epithelial Cell System (BRECS).

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 × 108 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.