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

The application of stem cell-derived secretome in regenerative therapies offers the key advantage that instead of the stem cells, only their effective paracrine compounds are in vivo delivered. Ideally, the secretome can be steered by the culture conditions of the stem cells. So far, most studies use stem cells cultured on stiff plastic substrates, not representative of their native 3D environment. In this study, cells are cultured inside synthetic polyisocyanide (PIC)-based hydrogels, which are minimal, tailorable, and highly reproducible biomimetic matrices. Secretome analysis of human adipose-derived stem cells (multiplex, ELISA) displays that matrix manipulation is a powerful tool to direct the secretome composition. As an example, cells in nonadherent PIC gels secrete increased levels of IL-10 and the conditioned media from 3D culture accelerate wound closure. In all, our PIC-based approach opens the door to dedicated matrix design to engineer the secretome for custom applications.

The construction of scaffolds and subsequent incorporation of cells and biologics have been widely investigated to regenerate damaged tissues. Scaffolds act as a template to guide tissue formation, and their characteristics have a considerable impact on the regenerative process. Whereas many technologies exist to induce specific two-dimensional (2D) morphologies into biomaterials, the introduction of three-dimensional (3D) micromorphologies into individual pore walls of scaffolds produced from biological molecules such as collagen poses a challenge. We here report the use of dicarboxylic acids to induce specific micromorphologies in collagen scaffolds and evaluate their effect on cellular migration and differentiation. Insoluble type I collagen fibrils were suspended in monocarboxylic and dicarboxylic acids of different concentrations, and unidirectional and random pore scaffolds were constructed by freezing and lyophilization. The application of various acids and concentrations resulted in variations in 3D micromorphologies, including wall structure, wall thickness, and pore size. The use of dicarboxylic acids resulted in acid-specific micromorphologies, whereas monocarboxylic acids did not. Dicarboxylic acids with an odd or even number of C-atoms resulted in frayed/fibrillar or smooth wall structures, respectively, with varying appearances. The formation of micromorphologies was concentration-dependent. In vitro analysis indicated the cytocompatibility of scaffolds, and micromorphology-related cell behavior was indicated by enhanced myosin staining and myosin heavy chain gene expression for C2C12 myoblasts cultured on scaffolds with frayedlike micromorphologies compared to those with smooth micromorphologies. In conclusion, porous collagen scaffolds with various intrawall 3D micromorphologies can be constructed by application of dicarboxylic acids, superimposing the second level of morphology to the overall scaffold structure. Acid crystal formation is key to the specific micromorphologies observed and can be explained by the odd/even theory for dicarboxylic acids. Scaffolds with a 3D micrometer-defined topography may be used as a screening platform to select optimal substrates for the regeneration of specific tissues.

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.