Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 422

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Clinical Trials, U.S.: Kidney Disease

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Clinical Trials, U.S.: Kidney Disease

The advent of cell-based therapies has changed the traditional view regarding organs having limited capacities for regeneration. Stem cells are currently viewed as the solution to a wide range of diseases that are generally characterized with damaged or dysfunctional cells and tissues. The introduction of stem cells to specific organs of the body for differentiation, as well as replacement or repair of diseased tissues, is based on their inherent plasticity, allowing them to perform an array of cellular functions. In the area of kidney diseases and disorders, stem cells are regarded as key structures that could serve as mechanisms for their natural repair and prevent further progression of renal diseases.

For centuries, the biomedical field has considered vital organs of the body as fully differentiated groups of tissues that have no capacity for regenerating their constituent cells. However, the discovery of stem cells and their ability to self-renew has not only changed the views of organ physiology and treatment paradigms but also triggered a new biomedical field now known as regenerative medicine. For example, the increase in the functional demand of the kidney has long been considered to result in hypertrophy of renal cells. For decades, patients diagnosed with kidney failure have required renal transplants in order to continue the body’s requirement of cleansing its bodily fluids. However, initial experiments conducted several decades ago involving animal models have shown that bone marrow–derived stem cells could be used to replace damaged renal cells. This observed plasticity was thus further examined using more extensive research studies using various types of stem cells.

The Application of Stem Cells in Kidney Diseases

The potential application of cell-based therapies to kidney diseases appears to be more significant than that to other diseases because its incidence has been increasing in the past few decades. Furthermore, kidney diseases are strongly associated with various medical conditions that are also increasing in prevalence, including cardiovascular diseases, as well as metabolic syndromes including obesity and diabetes. Amid the significant improvement in treatment strategies for various chronic medical conditions, the morbidity and mortality rate of kidney disease has been constant, thus prompting the need to identify a more effective approach to its prevention and treatment. Epidemiological studies have shown that the survival rate of a patient with end-stage renal disease is significantly lower than a patient diagnosed with prostate cancer.

One of the major factors influencing the increase in the incidence and the stagnant morbidity and mortality of kidney disease is the lack of novel treatment regimens for this condition. For decades, the same therapeutic formulations for cardiovascular diseases that strongly influence the development of kidney disease have been used, which include statins, angiotensin converting-enzyme inhibitors, and aspirin. Problems relating to the utilization of these drugs have also been a problem. Treatment options for impending kidney problems stemming from cardiovascular conditions include kidney transplantations and dialysis; however, the patient outcomes often vary depending on the skills of the attending physician as well as the number of available matching kidney donors. This unmet need for an effective treatment scheme for kidney disease has thus existed for decades.

The use of bone marrow–derived stem cells for the treatment of kidney diseases has emerged from the principle that these pluripotent cells possess the capacity to promote tissue repair, particularly in cases of acute renal failure. In the case of kidney disease, renal cells undergo ischemia due to damages inflicted by toxins such as antibiotic and chemotherapeutic drugs, as well as other immune factors. The damaged nephrons are thus unable to further function in the kidney, often resulting in other systemic diseases and multiple organ failure. Acute renal failure is also associated with the loss of epithelial cells of the renal tubules, mainly through the process of necrosis. This early form of tissue damage can result in edema in a patient, together with microvascular problems relating to perfusion or inability to promote the flow of toxins out of the body.

The introduction of bone marrow–derived stem cells for the treatment of acute renal failure is expected to enhance the repair of damaged ischemic cells of the renal tubules, thus increasing patient survival. The administration of bone marrow–derived stem cells also decreases the production of interleukin-6 levels, which are strongly associated with atherosclerosis and serve as an indicator of inflammation. This reduction in cytokine production may then facilitate the shift toward tissue repair instead of utilizing the energy stores of the cells in eliciting anti-inflammatory responses.

Current Clinical Trials Using Stem Cells in Kidney Diseases

There are currently at least 300 clinical trials that are investigating specific mechanisms and effects involving the use of stem cells in the treatment of kidney diseases. In one of the most recent clinical studies, the optimal density of bone marrow–derived stem cells is being investigated in patients who are scheduled to undergo kidney transplant. Present issues involving the need to resolve problems regarding tissue rejection after organ transplant have prompted clinical scientists to launch this study. In the case of kidney transplant, patients are first administered antirejection drugs to prevent the development of graft-versus-host disease and facilitate in the acceptance of the donated kidney.

However, despite the administration of antirejection drugs, there are still some patients who experience graft rejection some time after the actual organ transplant. Furthermore, the medications employed as antirejection regimen are often toxic and can cause damage to the kidneys, development of infections, and an elevated risk for cancer. The use of stem cells is then introduced as a technique to induce graft tolerance in the patient, allowing his or her cells to recognize the presence of a new organ in the body. It is assumed that the injection of stem cells would significantly enhance tissue acceptance and, in turn, decrease the chances of tissue rejection in prospective kidney transplant recipients.

The clinical study focuses on two major factors that influence the success of kidney transplant outcomes. First, stem cells will be employed to prepare the organ recipient for the transplantation procedure, which is also known as conditioning. Second, stem cells will be administered to decrease and ultimately prevent the development of graft-versus-host disease. Classical methods of conditioning include the destruction of the patient’s immune system and replacement with new bone marrow cells that would assist in combating potential infections. Graft-versus-host disease develops when the transplanted bone marrow progenitor cells perceive the donor’s cells as foreign material and start to attack these cells; severe cases often result in death. The use of stem cells is therefore presumed to help condition the immune system of the patient to the impending organ transplant, ensuring that both patient and donor cells could coexist without cellular destruction, which is a condition known as mixed chimerism. Furthermore, the conditioning and the actual procedure of transplantation are expected to be markedly decreased in this clinical study.

In another clinical study, the ideal conditioning drug is being investigated in combination with the introduction of bone marrow–derived stem cells. Similar to the previously described clinical trial, this study aims to establish mixed chimerism, yet using the optimal conditioning drug. Current medications administered for conditioning prior to kidney transplant include sirolimus, phycophenolate mofetil, and tacrolimus.

A monoclonal antibody known as alemtuzumab has also been employed for conditioning of patients; it acts by binding and depleting T lymphocytes of the bone marrow, thus preventing the development of an immune response. In the clinical study, alemtuzumab is administered to destroy the lymphocytes of the patient right at the time of transplantation. This is then immediately followed by the introduction of bone marrow–derived stem cells that would subsequently differentiate into new T lymphocytes that are expected to recognize the new kidney as part of its own system and thus would not elicit any immune response against the transplanted organ. Other parallel clinical trials are being conducted around the United States that are investigating the use of other conditioning drugs in combination with the bone marrow–derived stem cells. These drugs include cyclosporine, fludarabine phosphate, pentostatin, and anti-interleukin-2 receptor antibody, also known as basiliximab.

There are also investigations that are currently assessing the efficacy of the combination consisting of conditioning drugs, irradiation, and the administration of bone marrow–derived stem cells in preventing the development of graft-versus-host disease in renal transplant patients.

Rhea U. Vallente

Independent Scholar

See Also: Graft Failure, Graft-Versus-Host Disease; Kidney Disease; Kidney: Cell Types Composing the Tissue; Kidney: Current Research on Isolation or Production of Therapeutic Cells; Kidney: Development and Regeneration Potential; Kidney: Major Pathologies; Kidney: Stem and Progenitor Cells in Adults.

Читать книгу The SAGE Encyclopedia of Stem Cell Research - Группа авторов - Страница 422

Clinical Trials, U.S.: Kidney Disease

The Application of Stem Cells in Kidney Diseases

Current Clinical Trials Using Stem Cells in Kidney Diseases

Further Readings