In the United States alone, 1 in 7 or 37 million people are estimated to suffer from Chronic Kidney Disease. The population affected often falls under the bracket of “low-income”, making the cost of dialysis, even with insurance- exorbitant- lying anywhere from approximately $10000 to $90000. With dialysis and transplants currently being the primary effective cures for this progressive, end-game disease, research is being conducted in multi-disciplinary fields. Research with mesenchymal stem cells has taken center stage in the past decade, which is the main focus of this paper. By analyzing treatment options and various stem cell research documents, it can be concluded that mesenchymal stem cells carry renotrophic characteristics, making them ideal for regeneration purposes. Mesenchymal Stem Cells are adult stem cells derived from sources like the umbilical cord, bone marrow, and fat tissue, dissolving ethical problems. I have investigated possible solutions, including using laser technology to build organs and gene therapy to combat the absence of the p53 gene. While there needs to be much more testing and research, my paper addresses possible options that would provide a more efficient, cost- and time-effective treatment option for those suffering from Chronic Kidney Disease.
Over the progression of Chronic Kidney Disease, your nephrons degenerate rapidly, causing irreversible damage. Chronic Kidney Disease(CKD) is defined by the degeneration of your kidney, resulting in a glomerular filtration rate(GFR) of less than 60 mL/min per 1.73 m^2 of blood for at least three consecutive months. More than 1 in 7 Americans and 8-16% of people worldwide suffer from CKD, according to CDC reports. More often than not, the diagnosis doesn’t occur until the disease has progressed to more advanced stages due to the obscurity of symptoms, resulting in less reliable treatment. Tests to diagnose CKD are taken on urine samples to detect protein. Excessive amounts of protein in urine samples suggest extensive renal damage. Healthy kidneys filter proteins which are larger molecules to be reabsorbed into the bloodstream. As the kidneys degenerate, cell and nephron count quickly decline, and necessary molecules are excreted via the urine .
Figure 2. Healthy vs. Unhealthy Kidney. Figure 2 shows the difference between a healthy and a damaged kidney.
Figure 2.1 shows a healthy kidney that filters the urine and wastes out but keeps the necessary nutrients in the bloodstream. Figure 2.2 shows that the glomerulus of the kidney degenerates and lets the protein leave the body via urine.
Some recognizable symptoms like edema-fluid congregating in your extremities and urination problems are unlikely to present in the early stages and general symptoms like itchiness, dry skin, weight loss, and fatigue are more common, but unlikely to be reported. Due to this, the speed and occurrence of progression is immense. But there are options for the future that may provide viable treatment pathways . Stem Cell research has been a developing field. Scientists have succeeded in creating a rat kidney using human induced pluripotent endothelial cells. They have also used micro-vesicles that are exosomes from mesenchymal stem cells as a therapeutic treatment for the disease . Mesenchymal stem cells have unique renotrophic characteristics, as well as an invisibility to the immune system that has been proven both beneficial and a barrier when it comes to building an artificial organ and injecting treatment into patients .
Figure 1. eGFR rate. This figure shows the range of eGFR that determines the level of kidney disease progression. The lower the level of eGFR(mL/min), the more damaged the kidney.
eGFR is an estimated blood test that determines how well your kidneys function.
What are Stem Cells, and Why are they Revolutionary?
Stem cells are undifferentiated cells from which other cells form. These cells can be made into cells with specialized functions in laboratory settings, just as they are naturally differentiated in the body. Fundamental mechanisms are changed to divert the purpose from multiplication to specialization. Transcription factors based on protein codes determine the cell type, changing cell morphology, membrane potential, metabolism, stimulus, and other determining factors. Stem Cells are challenging to come by, especially those that are pluripotent, and can differentiate into a wide range of cell types. Adult stem cells have been found in organs like the brain, bone marrow, skeletal muscle, skin, gut, liver, and more. There are multiple types of stem cells depending on differentiation ability and source. Mesenchymal cells have a valuable ability of self-division, making them ideal for breeding and growth . Mesenchymal stem cells have unique immunosuppressive characteristics as well as cancerous tendencies due to an abnormality in the p53 gene, the gene responsible for tumor detection and suppression . The last type are induced pluripotent, the type used for the rat kidney, these are human cells extracted from parts of the body and forced to revert into stem cells in a laboratory. Stem cell research has a promising future, scientists have figured out how to breed cardiac cells in space as it is quicker than on land . There has been success in the development of a rat kidney using human-induced pluripotent stem cell-derived endothelial cells . This gives hope that one of the most deadly diseases, heart disease, may have a pathway for treatment.
Mesenchymal Stem Cells
Mesenchymal Stem Cells are stem cells that are your body’s organic defense as cells and nephrons are damaged inside the kidney, making these types ideal for an artificial kidney. They help protect and heal the organ . These cells have been incorporated into dialysis machines, and even transfused into humans to help aid the progression of CKD. Micro-vesicles from MSCs show significant progress in healing and reversing a damaged kidney. These micro-vesicles have proved more effective than the mesenchymal stem cells in some aspects . Exosomes from umbilical cords help protect against renal oxidative stress and apoptosis which can help strengthen the kidney and prevent nephron degeneration . Through similar trials, these transfusions have helped stunt the decay, even as factors of amount and source must be considered . As a result of the immunosuppressive characteristics of the mesenchymal stem cells, making them practically invisible to the immune system, there is a propensity towards tumor pathogenesis, signaling that undetected cancer and malignant tumor growth could be a possibility, specifically osteosarcoma. Cancer cells evade the gene due to mutations in the p53 gene due to external sources or a completely random occurrence .
Figure 3. Kidney Anatomy. Figure 3 is a figure of the kidney, as each portion of the organ helps filter the blood. Significant damage during CKD occurs to the nephrons in the glomerulus. When building an artificial kidney, everything needs to be as accurate as possible to ensure everything functions properly with other organs.
Architecture of an Artificial Kidney
The main problem with mesenchymal stem cells is the propensity to develop cancerous tumors. The P53 gene can be solved using various treatment options, like waiting for random mutations among cell DNA and RNA structures and using gene therapy as an expedited process. Gene therapy primarily introduces cellular material into cells to compensate for abnormalities or the lack of specific genes. In this case, the p53 gene is missing in mesenchymal stem cells. With the gene introduced to the body through a vector such as an adenovirus, we can help supplement stem cells' apoptosis and tumor-battling function . There have been studies in which gene therapy via the p53 gene has been used to combat neck and head cancers. The adenovirus works by introducing the genes right into the DNA of the cell . Here another problem arises in relation to the existing architecture of the artificial organ. The main problem with building organs is their architecture. More than a few millimeters thick can cause failure. Polymers must aggregate correctly. The kidney comprises multiple types of cells: glomerular endothelial, podocytes, mesangial, and tubule epithelium cells . For an artificial kidney to function similarly to an actual replacement, the structure of the kidney would need to be as similar as possible to the original. All biochemical messengers and cell interactions must be precise, making the procedure and thought of building a 3D organ much more challenging. Scientists have used near-infrared lasers to bind proteins like collagen and fibrin by using chemicals like aldehydes and alkylamines . The scaffold was able to send and receive messages appropriately. However, this experiment was used on rodents, human cells would complicate the procedure and require more specialization, but in theory, this could work for many organs in various species .
As of now, significant research shows that mesenchymal stem cells, which are universal in the immune system, have a promising future in many organs, not just the kidney. As mesenchymal cells have a significant proclivity to developing malignant tumors, they require regulation and constant treatment during transfusion or organ replacement. If kidney degeneration hasn’t progressed to extreme levels, I believe that investing in therapeutic treatments using micro-vesicles could prove beneficial. By using gene therapy to include the p53 gene in mesenchymal stem cells, we can effectively combat that. There is more research and testing to be done when constructing the organ, but experimenting with constructive proteins like collagen and fibrin, and many others since ,the kidney is extremely complicated. The usage of lasers, stem cell therapy, and mesenchymal stem cells provide an opportunity to create an artificial kidney that could reform treatment plans for those suffering from Chronic Kidney Disease.
Braam B;Verhaar MC;Blankestijn P;Boer WH;Joles JA; (2003). Technology insight: Innovative options for end-stage renal disease--from kidney refurbishment to Artificial Kidney2. Nature clinical practice. Nephrology. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/17895933/
Ciampi, O., Bonandrini, B., Derosas, M., Conti, S., Rizzo, P., Benedetti, V., Figliuzzi, M., Remuzzi, A., Benigni, A., Remuzzi, G., & Tomasoni, S. (2019, May 29). Engineering the vasculature of decellularized rat kidney scaffolds using human induced pluripotent stem cell-derived endothelial cells. Nature News. Retrieved January 13, 2023, from https://www.nature.com/articles/s41598-019-44393-y
F;, V. J. F. A. Q. J. A. S. (n.d.). P53 as the focus of gene therapy: Past, present and future. Current drug targets. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/29336259/
Gura V;Macy AS;Beizai M;Ezon C;Golper TA;, V. G. (n.d.). Technical breakthroughs in the wearable artificial kidney (WAK). Clinical journal of the American Society of Nephrology : CJASN. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/19696219/
Han Y;Li X;Zhang Y;Han Y;Chang F;Ding J; (n.d.). Mesenchymal stem cells for regenerative medicine. Cells. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/31412678/
He J;Wang Y;Lu X;Zhu B;Pei X;Wu J;Zhao W;, J. H. (n.d.). Micro-vesicles derived from bone marrow stem cells protect the kidney both in vivo and in vitro by microrna-dependent repairing. Nephrology (Carlton, Vic.). Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/25907000/
IS;, L. H. Y. H. (n.d.). Double-edged sword of mesenchymal stem cells: Cancer-promoting versus therapeutic potential. Cancer science. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/28756624/
KG;, K. J. P. J. J. A. G. (n.d.). Creating a wearable artificial kidney: Where are we now? Expert review of medical devices. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/26076370/
Levey AS;Coresh J;Balk E;Kausz AT;Levin A;Steffes MW;Hogg RJ;Perrone RD;Lau J;Eknoyan G; ; (n.d.). National Kidney Foundation Practice Guidelines for chronic kidney disease: Evaluation, classification, and stratification. Annals of internal medicine. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/12859163/
Orlando G;Booth C;Wang Z;Totonelli G;Ross CL;Moran E;Salvatori M;Maghsoudlou P;Turmaine M;Delario G;Al-Shraideh Y;Farooq U;Farney AC;Rogers J;Iskandar SS;Burns A;Marini FC;De Coppi P;Stratta RJ;Soker S; (n.d.). Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies. Biomaterials. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/23680364/
Parsley, J. (2021, January 12). The universe of Universal Stem Cells: Rewards vs risks. A Closer Look at Stem Cells. Retrieved January 13, 2023, from https://www.closerlookatstemcells.org/2021/01/12/the-universe-of-universal-stem-cells-rewards-vs-risks/
Y;, L. X. L. W. F. X. X. (n.d.). The immunogenicity and immune tolerance of pluripotent stem cell derivatives. Frontiers in immunology. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/28626459/
Y;, M. A. N. M. N. (n.d.). Regenerative Medicine for the kidney: Renotropic factors, renal stem/progenitor cells, and stem cell therapy. BioMed research international. Retrieved January 13, 2023, from https://pubmed.ncbi.nlm.nih.gov/24895592/