Current strategies and challenges in engineering a bioartificial kidney

Abstract

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.

Figure 1

(A) Photograph of retroperitoneal dissection from an E15 rat embryo showing metanephros (m) and ureteric bud (arrowhead). (B) Photograph of a developed metanephros (m) in the omentum of an adult host rat 3 weeks post-transplantation. Arrowhead shows developed ureter. Magnifications are shown. (43)

Figure 2

Transplants retrieved from the omentum of immunodeficient mice 3 weeks after transplantation. (A,D): Macroscopic views of (A) E14.5 and (D) E17.5 transplants. Scales in centimeters. The transplants contained large cysts (*). (B): Histological analysis (H&E) staining) identified primitive tubules (white arrow)., glomeruli (black arrow), newly formed blood vessels (white arrowhead), and polyglycolic acid fibers (black arrowhead) in the E14.5 transplants. (C): E14.5 cells partially differentiated into bone (†) and cartilage (‡). (E): The retrieved E17.5 transplants showed the formation of tubules and glomeruli, (F) but the E20.5 transplants showed very little kidney tissue formation (scale bars = 20 μm). (18)

Figure 3

Development of neokidney derived from human mesenchymal stem cells (hMSCs). The neo-kidney was implanted into the omentum of rats without heminephrectomies (A) and with heminephrectomies (B). After this relay culturing, hMSCs formed into an organoid (C).

Figure 4

Tissue-engineered renal units. (A) Illustration of renal unit and units retrieved three months after implantation. (B) Unseeded control. (C) Seeded with allogeneic control cells. (D) Seeded with cloned cells, showing the accumulation of urine like fluid. (22)

Figure 5

Cell seeding and whole-organ culture of decellularized rat kidneys. (a) Schematic of a cell-seeding apparatus enabling endothelial cell seeding through port A attached to the renal artery (Ra) and epithelial cell seeding through port B attached to the ureter (U) while negative pressure in the organ chamber is applied to port C, thereby generating a transrenal pressure gradient. (b) Schematic of a whole-organ culture in a bioreactor enabling tissue perfusion through port A attached to the renal artery and drainage to a reservoir through port B. K, kidney. (c) Cell-seeded decellularized rat kidney in whole-organ culture. (25)

Figure 6

Schematic of the extracorporeal perfusion circuit for renal cell therapy. Flow rates approximate those used clinically. The hemofilter perfusion PUMP system used the BBraun’s (Bethlehem, PA) Diapact System; the RAD perfusion system used an Alaris (San Diego, CA) intravenous pump for the pre-RAD ultrafiltrate line and a Minntech (Minneapolis, MN) blood pump for the post-RAD blood line. Qb, blood low; Qf, rate of fluid filtration. (29)

Figure 7

Schematic of the implantable bioartificial kidney. Arterial and venous connections depict blood flow through the device. A conduit connects the device to the bladder for waste removal. The unprecedented hydraulic permeability of the silicon nanopore membranes enables blood to flow through the device with only the arterial venous pressure differential, negating the need for an internal blood pump.

Figure 8

Nanopore membrane fabricated using silicon MEMS technology. Top left: Cross-section of membrane illustrating various structural layers (not to scale). Pores (exaggerated) are formed in the polysilicon diaphragm, which is supported by an underlying silicon substrate. Top right: SEM image of membrane showing uniformly spaced array of slit pores. Bottom left: SEM image showing membrane cross-section and non-tortuous pore geometry. Bottom right: SEM image showing close-up of 9nm slight pore and smooth surface characteristics. (32)