Bioengineered Kidney Tubules Efficiently Clear Uremic Toxins in Experimental Dialysis Conditions

Patients with end-stage kidney disease (ESKD) suffer from high levels of protein-bound uremic toxins (PBUTs) that contribute to various comorbidities. Conventional dialysis methods are ineffective in removing these PBUTs. A potential solution could be offered by a bioartificial kidney (BAK) composed of porous membranes covered by proximal tubule epithelial cells (PTECs) that actively secrete PBUTs. However, BAK development is currently being hampered by a lack of knowledge regarding the cytocompatibility of the dialysis fluid (DF) that comes in contact with the PTECs. Here, we conducted a comprehensive functional assessment of the DF on human conditionally immortalized PTECs (ciPTECs) cultured as monolayers in well plates, on Transwell® inserts, or on hollow fiber membranes (HFMs) that form functional units of a BAK. We evaluated cell viability markers, monolayer integrity, and PBUT clearance. Our results show that exposure to DF did not affect ciPTECs’ viability, membrane integrity, or function. Seven anionic PBUTs were efficiently cleared from the perfusion fluid containing a PBUTs cocktail or uremic plasma, an effect which was enhanced in the presence of albumin. Overall, our findings support that the DF is cytocompatible and does not compromise ciPTECs function, paving the way for further advancements in BAK development and its potential clinical application.</p

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

New mixed matrix membrane for the removal of urea from dialysate solution

Urea removal is one of the biggest challenges in dialysate regeneration in Wearable Artificial Kidney (WAK) devices. In this work, a new Mixed Matrix Membrane (MMM) is developed for urea removal in WAK applications. The MMM consists of polystyrene-based ninhydrin particles within a polyethersulfone/polyvinylpyrrolidone polymer blend matrix. The MMM is prepared via dry-wet spinning technique and characterized in terms of its morphology via electron microscopy and clean water permeance. Urea removal is studied both in static and in dynamic conditions. Thanks to the good dispersion of small size ninhydrin particles (size < 63 µm), the MMM removed under static conditions, at 70 °C, 2.1 ± 0.1 mmol of urea per grams of particles at 24 h, while urea removal by the particles in suspension reached 1.7 ± 0.1 mmol/g under the same conditions. Importantly, in continuous recirculation experiments, performed at 70 °C using a laboratory scale module, the MMM removed 3.4 ± 0.3 mmol of urea per grams of particles, in 4 h, due to the high particle accessibility by urea within the membrane. Based on these results it is estimated that only 215 g of MMM are needed for removing the daily produced urea from spent dialysate (400 mmol) making MMM suitable for application to WAK, where miniaturization and lightweight are required

New mixed matrix membrane for the removal of urea from dialysate solution

Urea removal is one of the biggest challenges in dialysate regeneration in Wearable Artificial Kidney (WAK) devices. In this work, a new Mixed Matrix Membrane (MMM) is developed for urea removal in WAK applications. The MMM consists of polystyrene-based ninhydrin particles within a polyethersulfone/polyvinylpyrrolidone polymer blend matrix. The MMM is prepared via dry-wet spinning technique and characterized in terms of its morphology via electron microscopy and clean water permeance. Urea removal is studied both in static and in dynamic conditions. Thanks to the good dispersion of small size ninhydrin particles (size < 63 µm), the MMM removed under static conditions, at 70 °C, 2.1 ± 0.1 mmol of urea per grams of particles at 24 h, while urea removal by the particles in suspension reached 1.7 ± 0.1 mmol/g under the same conditions. Importantly, in continuous recirculation experiments, performed at 70 °C using a laboratory scale module, the MMM removed 3.4 ± 0.3 mmol of urea per grams of particles, in 4 h, due to the high particle accessibility by urea within the membrane. Based on these results it is estimated that only 215 g of MMM are needed for removing the daily produced urea from spent dialysate (400 mmol) making MMM suitable for application to WAK, where miniaturization and lightweight are required

Drugs commonly applied to kidney patients may compromise renal tubular uremic toxins excretion

In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake.We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equippedwithOAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay.We show that selected ARBs and furosemide significantly reduced fluorescein uptake,with the highest potency forARBs. Thiswas exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function

New mixed matrix membrane for the removal of urea from dialysate solution

Urea removal is one of the biggest challenges in dialysate regeneration in Wearable Artificial Kidney (WAK) devices. In this work, a new Mixed Matrix Membrane (MMM) is developed for urea removal in WAK applications. The MMM consists of polystyrene-based ninhydrin particles within a polyethersulfone/polyvinylpyrrolidone polymer blend matrix. The MMM is prepared via dry-wet spinning technique and characterized in terms of its morphology via electron microscopy and clean water permeance. Urea removal is studied both in static and in dynamic conditions. Thanks to the good dispersion of small size ninhydrin particles (size < 63 µm), the MMM removed under static conditions, at 70 °C, 2.1 ± 0.1 mmol of urea per grams of particles at 24 h, while urea removal by the particles in suspension reached 1.7 ± 0.1 mmol/g under the same conditions. Importantly, in continuous recirculation experiments, performed at 70 °C using a laboratory scale module, the MMM removed 3.4 ± 0.3 mmol of urea per grams of particles, in 4 h, due to the high particle accessibility by urea within the membrane. Based on these results it is estimated that only 215 g of MMM are needed for removing the daily produced urea from spent dialysate (400 mmol) making MMM suitable for application to WAK, where miniaturization and lightweight are required

Drugs commonly applied to kidney patients may compromise renal tubular uremic toxins excretion

In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake.We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equippedwithOAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay.We show that selected ARBs and furosemide significantly reduced fluorescein uptake,with the highest potency forARBs. Thiswas exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function

From portable dialysis to a bioengineered kidney

Introduction: Since the advent of peritoneal dialysis (PD) in the 1970s, the principles of dialysis have changed little. In the coming decades, several major breakthroughs are expected. Areas covered: Novel wearable and portable dialysis devices for both hemodialysis (HD) and PD are expected first. The HD devices could facilitate more frequent and longer dialysis outside of the hospital, while improving patient’s mobility and autonomy. The PD devices could enhance blood purification and increase technique survival of PD. Further away from clinical application is the bioartificial kidney, containing renal cells. Initially, the bioartificial kidney could be applied for extracorporeal treatment, to partly replace renal tubular endocrine, metabolic, immunoregulatory and secretory functions. Subsequently, intracorporeal treatment may become possible. Expert commentary: Key factors for successful implementation of miniature dialysis devices are patient attitudes and cost-effectiveness. A well-functioning and safe extracorporeal blood circuit is required for HD. For PD, a double lumen PD catheter would optimize performance. Future research should focus on further miniaturization of the urea removal strategy. For the bio-artificial kidney (BAK), cost effectiveness should be determined and a general set of functional requirements should be defined for future studies. For intracorporeal application, water reabsorption will become a major challenge