Introduction
In the United States, there are currently over 750,000 patients with end-stage renal disease (ESRD). Around the world, 2.6 million people receive renal replace-ment therapy in the form of dialysis or a kidney transplant, with the number expected to double by 2030. Willem Kolff’s invention of the dialysis machine in 1943 and Belding Scribner’s subsequent development of the arteriove-nous fistula in 1960 revolutionized kidney care. Recent exciting developments in kidney research have the potential to transform treatment beyond dialysis and trans-plantation. Here, we highlight five emerging approaches for ESRD.
Wearable and Bioartificial kidneys
The wearable artificial kidney and implantable bioartificial kidney each have the potential to provide continuous dialysis throughout the day. They are expected to contribute to higher toxin clearance with more cardiovascular stability as well as improved quality of life. The wearable artificial kidney is a miniaturized wearable hemodialysis device with continuous dialysis capacity. The latest version is a belt-like device weighing up to 5 kg that is connected to blood vessels through catheters (Figure 1A). the implantable bioartificial kidney is a hybrid device that combines a mechanical blood filter made with a silicon membrane and a bioreactor containing engineered renal tubular epithelial cells. The implantable bioartificial kidney is designed to attach directly to the systemic circulation and is controlled by the patient’s blood pressure, thus eliminating the need for electrical pumps, with filtered waste removed directly into the bladder (Figure 1A). A major concern with the implantable bioartificial kidney will be the durability and clotting of the blood filter, as patients may need frequent surgery to manipulate or change the device.
Kidney-on-a-chip
An organ-on-a-chip is an advanced microfluidics-based cell culture platform designed to mimic organ physiology. Continuous flow through a microfluidics system provides a physiological cell microenvironment, which allows long-term culturing while maintaining cell phenotypes (Figure 1B).
This chip-based technique in nephrology medicine has been used to reproduce tubular structures or glomeruli. A number of different glomerulus-on-a-chip and tubule-on-a-chip models have been tested for drug screening, disease modeling, and in vivo regenerative medicine applications. An improved glomerulus-on-a-chip model that recapitulates the human glomerular filtration barrier has been developed from human podocytes and glomerular endothelial cells that are not separated by an artificial membrane, allowing direct cellular communication. This model reproduced selective permeability with differential clearance of albumin and inulin. Given the availability of both tubule-on-a-chip and glomerulus- on-a-chip models, future studies to develop next-generation chips combining both elements to generate a functional nephron that recapitulates both filtration and reabsorption are warranted.
Growing a kidney from stem cell derived
organoids
The discovery of induced pluripotent stem cells (iPSCs) has enabled the use of human PSCs and led to the development of innovative protocols for human organoid research. Since the introduction of induction protocols for human iPSCs-derived kidney precursor cells, the kidney organoid field has flourished. A recent advance in 3D bioprinting technologies further facilitated improvement in kidney organoid technologies by allowing the fabrication of tissue in an automated and spatially controlled fashion (Figure 1B). These advances improved the quality of organoids and also provided high throughput and reproducibility. Encouraging preliminary data suggest a potential use of kidney organoids as kidney disease models. These advances improved the quality of organoids and also provided high throughput and reproducibility. Encouraging preliminary data suggest a potential use of kidney organoids as kidney disease models. However, sophisticated analyses using single-cell RNA-Seq revealed that current organoids are limited to developing kidneys that do not mature beyond the second trimester stage. Thus, to model various adult human kidney diseases and for use of regenerative medicine, further research is required to generate more mature organoids. Thus, current kidney organoid systems do not model adult human kidneys, and further research is required to generate more mature organoids. Recent advances in understanding human kidney development through cutting-edge technologies such as single-cell RNA-Seq are expected to enable the development of more mature organoids in the future.
Immunotolerance protocol for kidney
transplant
The main current approach for tolerance induction is based on mixed chimerism induction through donor bone marrow transplantation or donor-derived hematopoietic stem cell transplantation. Although the number of study participants has been limited, multiple centers recently reported successful discontinuation of maintenance immunosuppression with favorable safety. Another promising approach is regulatory cell–based therapy, which takes advantage of their tolerogenic effect. In a recent single-arm multicenter clinical trial (The ONE Study), 40% of patients were successfully weaned to tacrolimus monotherapy over the 60-week period by use of cell-based medical products containing Tregs, DCs, or macrophages. In a recent single-arm multicenter clinical trial (The ONE Study), 40% of patients were successfully weaned to tacrolimus monotherapy over the 60-week period by use of cell-based medical products containing Tregs, DCs, or macrophages. The study group showed a favorable safety profile, with fewer infectious complications compared with the standard of care group. Randomized, controlled clinical trials based on this study are currently underway (ISRCTN11038572). Using nanoparticles for selective delivery of donor alloantigens or immunosuppressants to antigen-presenting cells has also been proposed as a strategy to induce immune tolerance in transplantation. Nanomaterials per se are known to not induce activation of antigen-presenting cells and can be easily customized, enabling delivery of their therapeutic cargo with minimal immunogenicity and high uptake.
Xenotransplantation
Xenotransplantation using domestic pigs has been considered a promising future strategy to alleviate the organ shortage. Since humans have preformed antibodies against porcine xenoantigens, which cause hyperacute rejection,
triple-knockout pigs lacking three major xenoantigens (αGal, Neu5Gc, and SDa) were developed and are now used as a xenotransplantation model. Based on the triple-knockout pig model, additionally advanced genetically engineered pigs that have protective human transgenes, including those for costimulatory molecules and coagulation pathway and complement cascades, are currently available and expected to further improve xenotransplantation outcomes (Figure 1C). With remarkable advances in gene-editing technologies through the CRISPR/Cas9 technique, xenotransplantation outcomes in nonhuman primates have been continually improved, achieving recipient survival beyond one year.
Ethical, social, and religious concerns regarding xenotransplantation also need to be addressed in future studies. If xenotransplantation becomes clinically available, educational strategies for the general public and potential kidney transplant patient candidates and their families are likely to be required for its successful application.
Discussion
Given the steadily increasing number of patients with ESRD, we have a pressing need for discoveries and therapeutic innovations. Clinical application of the technologies for ESRD will require more time, resources, and effort, however, they have the potential to make dramatic improvements in the care of patients with kidney failure.
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