Three-Dimensional Kidney-on-a-Chip Assessment of Contrast-Induced Kidney Injury: Osmolality and Viscosity

Abstract

Increased viscosity of concentrated contrast media (CM) in the renal tubules can perturb renal hemodynamics and have a detrimental effect on tubular epithelial cells. However, the effects of viscosity on contrast-induced nephropathy (CIN) remain poorly understood. Conventional in vitro culture studies do not reflect the rheological properties of CM. Therefore, we investigated the effects of CM viscosity on renal tubules using a kidney-on-a-chip and two different types of CM. Renal proximal tubule epithelial cells (RPTEC) were cultured in a three-dimensional microfluidic culture platform under bidirectional fluid shear stress. We treated the RPTEC with two types of CM: low- (LOCM, iopromide) and iso-osmolar contrast media (IOCM, iodixanol). Renal tubular cell injury induced by LOCM and IOCM was examined under different iodine concentrations (50–250 mgI/mL) and shear-stress conditions. LOCM showed a significant dose-dependent cytotoxic effect, which was significantly higher than that of IOCM under static and low-to-moderate shear stress conditions. However, high shear-stress resulted in reduced cell viability in IOCM; no difference between IOCM and LOCM was found under high shear-stress conditions. The cytotoxic effects were pronounced at a mean shear stress of 1 dyn/cm2 or higher. The high viscosity of IOCM slowed the fluid flow rate and augmented fluid shear-stress. We suggest an alternative in vitro model of CIN using the three-dimensional kidney-on-a-chip. Our results indicate a vital role of viscosity-induced nephrotoxicity under high shear-stress conditions, contrary to the findings of conventional in vitro studies.

Development of Drug Efficacy Testing Platform for Glomerulonephritis

“…Using the 3D-MOTIVE chip, we simultaneously cultured podocytes and endothelial cells on the membrane of the insert module ( Figure 1 ). A rocker machine was employed to ensure continuous perfusion, allowing for the bidirectional flow of the medium [ 5 ]. A comparative analysis of the morphological changes in podocyte differentiation was conducted between culturing podocytes alone on a 2D plate and co-culturing them on the GFB-mimicking chip ( Figure 2 ).…”

“…The medium inside the insert was then replaced with a 1:1 mixture of CIHP-1 and RFP-HGMVEC media. The glomeruli tissue chip produced through this process was continuously perfused on an Organo Flow L rocker (Mimetas, Gaithersburg, MD, USA #MI-OFPR-L) to establish a bidirectional flow [ 5 ]. This flow was initiated by adjusting the rocker to an angle of 7° with an interval of 8 min, resulting in a mean flow rate of 2.02 μL/min and a mean shear of 1.3 × 10 −6 N/cm 2 .…”

“…Due to this limitation, we aimed to create a GFB-mimicking chip by applying physiological shear stress using the 3D-multi-organ tissue interdisciplinary value escalation (3D-MOTIVE) chip introduced in our previous study [ 4 ]. As reported, the incorporation of physiological fluidic shear stress allows us to address the shortcomings of traditional models [ 5 , 6 ]. We fabricated a GFB-mimicking chip and through this chip, we replicated the MN model to assess the efficacy of tacrolimus in treating MN, with a specific focus on its impact on glomerular damage associated with podocytopathies.…”

Models for barrier understanding in health and disease in lab-on-a-chips

“…Kim and coworkers conducted an analysis of a three-dimensional kidney-on-a-chip model to assess the physicochemical factors of contrast media in contrast media-induced nephropathy (CIN) 93 . The novel CIN model accurately reflected in vivo situations under shear-stress conditions.…”