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Haemodialysis is life sustaining but expensive, provides limited removal of uraemic solutes, is associated with poor patient quality of life and has a large carbon footprint. Innovative dialysis technologies such as portable, wearable and implantable artificial kidney systems are being developed with the aim of addressing these issues and improving patient care. An important challenge for these technologies is the need for continuous regeneration of a small volume of dialysate. Dialysate recycling systems based on sorbents have great potential for such regeneration. Novel dialysis membranes composed of polymeric or inorganic materials are being developed to improve the removal of a broad range of uraemic toxins, with low levels of membrane fouling compared with currently available synthetic membranes. To achieve more complete therapy and provide important biological functions, these novel membranes could be combined with bioartificial kidneys, which consist of artificial membranes combined with kidney cells. Implementation of these systems will require robust cell sourcing; cell culture facilities annexed to dialysis centres; large-scale, low-cost production; and quality control measures. These challenges are not trivial, and global initiatives involving all relevant stakeholders, including academics, industrialists, medical professionals and patients with kidney disease, are required to achieve important technological breakthroughs.Portable, wearable and implantable artificial kidney systems require compact and efficient dialysate regeneration systems and novel membranes for improved toxin removal and long-term patency. Here, the authors discuss efforts to overcome these challenges and future perspectives for achieving miniaturized dialysis.

In vitro models serve as indispensable tools for advancing our understanding of biological processes, elucidating disease mechanisms, and establishing screening platforms for drug discovery. Kidneys play an instrumental role in the transport and elimination of drugs and toxins. Nevertheless, despite the well-documented inter-individual variability in kidney function and the multifaceted nature of renal diseases—spanning from their origin, trigger and which segment of the kidney is affected—to presentation, progression and prognosis, few studies take into consideration the variable of sex. Notably, the inherent disparities between female and male biology warrants a more comprehensive representation within in vitro models of the kidney. The omission of sex as a fundamental biological variable carries the substantial risk of overlooking sex-specific mechanisms implicated in health and disease, along with potential differences in drug responsiveness and toxicity profiles between sexes. This review emphasizes the importance of incorporating cellular, biological and functional sex-specific features of renal activity in health and disease in in vitro models. For that, we thoroughly document renal sex-specific features and propose a strategic experimental framework to integrate sex-based differences into human kidney in vitro models by outlining critical design criteria to elucidate sex-based features at cellular and tissue levels. The goal is to enhance the accuracy of models to unravel renal mechanisms, and improve our understanding of their impact on drug efficacy and safety profiles, paving the way for a more comprehensive understanding of patient-specific treatment modalities. Plain English Summary Understanding the differences in kidney function between males and females is crucial for developing safer and more effective drugs and drug dosing strategies. Sex differences arise from a combination of hormonal, anatomical, and genetic factors. However, many current kidney models used in research fail to accurately replicate these distinctions, hindering our understanding of kidney health, disease and drug effectiveness. To address this gap, this review delves into the existing knowledge about sex-related variations in kidney function and disorders. Additionally, it examines the limitations of current kidney models and suggests a framework for sex-inclusive kidney research. By doing so, the review provides critical insights and suggestions to develop improved models that enhance our understanding of kidney diseases and aid in drug discovery and safety assessments. Ultimately, this will lead to more efficient and secure drug development processes. Highlights Sex as a crucial variable: The review underscores the vital role of sex as a variable in kidney models, impacting current understanding of renal diseases and drug responses. Sexual dimorphism in kidney function: The review explores the origin of sexual dimorphism in kidney function through the lens of sex differences in kidney growth, transporter machinery, renal RAAS system, sex hormone receptors and inflammatory response, addressing clinical implications for nephrotoxicity screens, kidney diseases and hormone therapy. Proposal of a strategic framework: By highlighting a cohesive experimental framework, the review guides the development of more accurate kidney in vitro models, integrating sex-based distinctions for improved physiological and pathological studies. Implication for broader research: Beyond kidneys, the review advocates acknowledging and exploring sex-based disparities in the broader biomedical research field, crucial for a comprehensive understanding and the development of patient-specific treatments.

This review outlines the evolutionary journey from traditional two-dimensional (2D) cell culture to the revolutionary field of organ-on-a-chip technology. Organ-on-a-chip technology integrates microfluidic systems to mimic the complex physiological environments of human organs, surpassing the limitations of conventional 2D cultures. This evolution has opened new possibilities for understanding cell–cell interactions, cellular responses, drug screening, and disease modeling. However, the design and manufacture of microchips significantly influence their functionality, reliability, and applicability to different biomedical applications. Therefore, it is important to carefully consider design parameters, including the number of channels (single, double, or multi-channels), the channel shape, and the biological context. Simultaneously, the selection of appropriate materials compatible with the cells and fabrication methods optimize the chips’ capabilities for specific applications, mitigating some disadvantages associated with these systems. Furthermore, the success of organ-on-a-chip platforms greatly depends on the careful selection and utilization of cell resources. Advances in stem cell technology and tissue engineering have contributed to the availability of diverse cell sources, facilitating the development of more accurate and reliable organ-on-a-chip models. In conclusion, a holistic perspective of in vitro cellular modeling is provided, highlighting the integration of microfluidic technology and meticulous chip design, which play a pivotal role in replicating organ-specific microenvironments. At the same time, the sensible use of cell resources ensures the fidelity and applicability of these innovative platforms in several biomedical applications.

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.

Protein-bound uremic toxins (PBUTs) are associated with the progression of chronic kidney disease (CKD) and its associated morbidity and mortality. The conventional dialysis techniques are unable to efficiently remove PBUTs due to their plasma protein binding. Therefore, novel approaches are being developed, but these require validation in animals before clinical trials can begin. We conducted a systematic review to document PBUT concentrations in various models and species. The search strategy returned 1163 results for which abstracts were screened, resulting in 65 full-text papers for data extraction (rats (n = 41), mice (n = 17), dogs (n = 3), cats (n = 4), goats (n = 1), and pigs (n = 1)). We performed descriptive and comparative analyses on indoxyl sulfate (IS) concentrations in rats and mice. The data on large animals and on other PBUTs were too heterogeneous for pooled analysis. Most rodent studies reported mean uremic concentrations of plasma IS close to or within the range of those during kidney failure in humans, with the highest in tubular injury models in rats. Compared to nephron loss models in rats, a greater rise in plasma IS compared to creatinine was found in tubular injury models, suggesting tubular secretion was more affected than glomerular filtration. In summary, tubular injury rat models may be most relevant for the in vivo validation of novel PBUT-lowering strategies for kidney failure in humans.

Cell macroencapsulation devices (CMD) offer a promising solution for organ function replacement by shielding implanted cells from the host immune system while allowing the exchange of nutrients and waste products. Developing efficient CMD necessitates optimizing vascular integration, membrane permeability, and cellular functionality using robust preclinical models. In this study, we adapted the chick chorioallantoic membrane (CAM) model to develop and evaluate CMD. Semipermeable membranes were integrated into the CAM, with vascularization modulated through growth factors and extracellular matrix manipulation. Human kidney tubular epithelial cells were cultured on these vascularized membranes to assess cell viability, polarization, and functionality, including selective transport and barrier integrity. The membranes integrated successfully into the CAM and supported functional vascularization, demonstrating selective permeability by facilitating the exchange of low-molecular-weight compounds while preventing the infiltration of larger proteins and cells, thereby creating an immune-isolated environment. Kidney tubular epithelial cells remained viable, polarized, and functionally active, showcasing selective compound transport and robust barrier integrity. These findings underscore the CAM model's utility in evaluating vascular integration, membrane permeability, and epithelial cell functionality, all critical parameters for CMD development. The CAM model provides a rapid, cost-effective platform for CMD assessment, significantly accelerating their development and potential clinical translation. This approach holds particular promise for applications targeting kidney diseases characterized by compromised transport functions, offering a pathway toward more effective therapeutic solutions.

Background Ischemia/reperfusion injury is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal stromal cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy; however, their full potential in treating AKI remains unknown. Methods In this study, we employed an in vitro model of chemically induced ischemia using antimycin A combined with 2-deoxy- d -glucose to induce ischemic injury in proximal tubule epithelial cells. Afterwards we evaluated the effects of MSC secretome, CM or EVs obtained from adipose tissue, bone marrow, and umbilical cord, on ameliorating the detrimental effects of ischemia. To assess the damage and treatment outcomes, we analyzed cell morphology, mitochondrial health parameters (mitochondrial activity, ATP production, mass and membrane potential), and overall cell metabolism by metabolomics. Results Our findings show that ischemic injury caused cytoskeletal changes confirmed by disruption of the F-actin network, energetic imbalance as revealed by a 50% decrease in the oxygen consumption rate, increased oxidative stress, mitochondrial dysfunction, and reduced cell metabolism. Upon treatment with MSC secretome, the morphological derangements were partly restored and ATP production increased by 40–50%, with umbilical cord-derived EVs being most effective. Furthermore, MSC treatment led to phenotype restoration as indicated by an increase in cell bioenergetics, including increased levels of glycolysis intermediates, as well as an accumulation of antioxidant metabolites. Conclusion Our in vitro model effectively replicated the in vivo-like morphological and molecular changes observed during ischemic injury. Additionally, treatment with MSC secretome ameliorated proximal tubule damage, highlighting its potential as a viable therapeutic option for targeting AKI.

Chronic kidney disease (CKD) is a major healthcare burden that takes a toll on the quality of life of many patients. Emerging evidence indicates that a substantial proportion of these patients carry a genetic defect that contributes to their disease. Any effort to reduce the percentage of patients with a diagnosis of nephropathy heading towards kidney replacement therapies should therefore be encouraged. Besides early genetic screenings and registries, in vitro systems that mimic the complexity and pathophysiological aspects of the disease could advance the screening for targeted and personalized therapies. In this regard, the use of patient-derived cell lines, as well as the generation of disease-specific cell lines via gene editing and stem cell technologies, have significantly improved our understanding of the molecular mechanisms underlying inherited kidney diseases. Furthermore, organs-on-chip technology holds great potential as it can emulate tissue and organ functions that are not found in other, more simple, in vitro models. The personalized nature of the chips, together with physiologically relevant read-outs, provide new opportunities for patient-specific assessment, as well as personalized strategies for treatment. In this review, we summarize the major kidney-on-chip (KOC) configurations and present the most recent studies on the in vitro representation of genetic kidney diseases using KOC-driven strategies.

The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs’ microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumulate in plasma in tubular dysfunction. We here hypothesize that PBUT clearance may be a sensitive tubular function marker, and tested this in a DKD mouse model and in type 2 diabetic patients. Among the PBUTs with the highest OAT affinity (i.e., indoxyl sulfate (IS), hippuric acid (HA) and kynurenic acid (KA)), plasma concentrations were higher and urinary excretions were lower 6 and 8 months after DKD induction in mice. These parameters correlated better with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers. In patients, the clearance of IS, HA, KA and p -cresyl sulfate (PCS) was associated with urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), independent of eGFR. In multiple regression analysis, additionally adjusted for relevant risk factors for tubular injury, the clearance of IS, HA and PCS remained significantly associated with urinary NGAL. In conclusion, IS, HA, KA and PCS clearance may represent a biomarker of kidney tubular function in DKD.