The Role of a Bioengineered Artificial Kidney in Renal Failure

Renal failure continues to carry substantial burden of morbidity and mortality in both acute and chronic forms, despite advances in transplantation and dialysis. There is evidence to suggest that the kidney has metabolic, endocrine, and immune effects transcending its filtration functions, even beyond secretion of renin and erythropoietin. Our laboratory has developed experience in the tissue culture of renal parenchymal cells, and has now been able to demonstrate the metabolic activity of these cells in an extracorporeal circuit recapitulating glomerulotubular anatomy. We have observed active transport of sodium, glucose, and glutathione. We describe the design and initial preclinical testing of the bioartificial kidney, as well as future directions of our research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71995/1/j.1749-6632.2001.tb03841.x.pd

Hemocompatibility of Silicon-Based Substrates for Biomedical Implant Applications

Silicon membranes with highly uniform nanopore sizes fabricated using microelectromechanical systems (MEMS) technology allow for the development of miniaturized implants such as those needed for renal replacement therapies. However, the blood compatibility of silicon has thus far been an unresolved issue in the use of these substrates in implantable biomedical devices. We report the results of hemocompatibility studies using bare silicon, polysilicon, and modified silicon substrates. The surface modifications tested have been shown to reduce protein and/or platelet adhesion, thus potentially improving biocompatibility of silicon. Hemocompatibility was evaluated under four categories—coagulation (thrombin–antithrombin complex, TAT generation), complement activation (complement protein, C3a production), platelet activation (P-selectin, CD62P expression), and platelet adhesion. Our tests revealed that all silicon substrates display low coagulation and complement activation, comparable to that of Teflon and stainless steel, two materials commonly used in medical implants, and significantly lower than that of diethylaminoethyl (DEAE) cellulose, a polymer used in dialysis membranes. Unmodified silicon and polysilicon showed significant platelet attachment; however, the surface modifications on silicon reduced platelet adhesion and activation to levels comparable to that on Teflon. These results suggest that surface-modified silicon substrates are viable for the development of miniaturized renal replacement systems

Current strategies and challenges in engineering a bioartificial kidney.

Renal replacement therapy was an early pioneer in both extra-corporeal organ replacement and whole organ transplantation. Today, the success of this pioneering work is directly demonstrated in the millions of patients worldwide successfully treated with dialysis and kidney transplantation. However, there remain significant shortcomings to current treatment modalities that limit clinical outcomes and quality of life. To address these problems, researchers have turned to using cell-based therapies for the development of a bioartificial kidney. These approaches aim to recapitulate the numerous functions of the healthy kidney including solute clearance, fluid homeostasis and metabolic and endocrine functions. This review will examine the state-of-the-art in kidney bioengineering by evaluating the various techniques currently being utilized to create a bioartificial kidney. These promising new technologies, however, still need to address key issues that may limit the widespread adoption of cell therapy including cell sourcing, organ scaffolding, and immune response. Additionally, while these new methods have shown success in animal models, it remains to be seen whether these techniques can be successfully adapted for clinical treatment in humans

Orbital Shear Stress Regulates Differentiation and Barrier Function of Primary Renal Tubular Epithelial Cells

Primary cells cultured in vitro gradually lose features characteristic of the in vivo phenotype. Culture techniques that help maintain cell-specific phenotype are advantageous for development of tissue engineered and bioartificial organs. Here we evaluated the phenotype of primary human renal tubular epithelial cells subjected to fluid shear stress by culturing the cells on an orbital shaker. Transepithelial electrical resistance (TEER), cell density, and gene and protein expression of proximal tubule-specific functional markers were measured in cells subjected to orbital shear stress. Cells cultured on an orbital shaker had increased TEER, higher cell density, and enhanced tubular epithelial specific gene and protein expression. This is likely due at least in part to the mechanical stress applied to the apical surface of the cells although other factors including increased nutrient and oxygen delivery and improved mixing could also play a role. These results suggest that orbital shaker culture may be a simple approach to augmenting the differentiated phenotype of cultured renal epithelial cells

Optimal design of perturbations for individual two-compartment pharmacokinetic analysis

<p>We consider the optimal design of pharmacokinetic studies in patients that receive intermittent hemodialysis and intravenous antibiotic. Hemodialysis perturbs the pharmacokinetic system, providing additional opportunity for study. Designs that allocate measurements to occur exclusively during hemodialysis are shown to be viable alternatives to conventional designs, where all measurements occur outside of hemodialysis. Furthermore, hybrid designs with both conventional and intradialytic measurements have nearly double the efficiency of conventional designs. Convex optimal design and Monte Carlo techniques were used to simultaneously optimize hemodialysis event characteristics and sampling times, accounting for population pharmacokinetic heterogeneity. We also present several related methodological innovations.</p

A distributed solute model : An extended two-pore model with application to the glomerular sieving of ficoll

One of the many unresolved questions regarding the permeability of the glomerular filtration barrier is the reason behind the marked difference in permeability between albumin and polysaccharide probe molecules such as Ficoll and dextran of the same molecular size. Although the differences in permeability have been mainly attributed to charge effects, we have previously shown that this would require a highly charged filtration barrier, having a charge density that is ~10 times more than that on the albumin molecule. In this article, the classic two-pore model was extended by introducing size distributions on the solute molecules, making them conformationally flexible. Experimental sieving data for Ficoll from the rat glomerulus and from precision-made silicon nanopore membranes were analyzed using the model. For the rat glomerulus a small-pore radius of 36.2 Å and a geometric standard deviation (gSD) for the Ficoll size-distribu-tion of 1.16 were obtained. For the nanopore membranes, a gSD of 1.24 and a small-pore radius of 43 Å were found. Interestingly, a variation of only ~16% in the size of the polysaccharide molecule is sufficient to explain the difference in permeability between albumin and Ficoll. Also, in line with previous data, the effects of applying a size distribution on the solute molecule are only evident when the molecular size is close to the pore size. Surely there is at least some variation in the pore radii, and, likely, the gSD obtained in the current study is an overestimation of the “true” variation in the size of the Ficoll molecule