The use of mesenchymal stem cell therapy offers new hopes for patients with various forms of kidney disease. The scientific rationale and current state of clinical research using mesenchymal stem cell (MSC) therapy in kidney diseases is the topic of a recent review published in the American Journal of Kidney Diseases. Co-author Dr. Luigi Biancone (LB), from the Nephrology, Dialysis, and Renal Transplantation Unit, Centre for Experimental Medical Research (CeRMS), University of Torino, Torino, Italy, discussed this review with Dr. Matthew Sparks (eAJKD), eAJKD Advisory Board member.
eAJKD: Why are you interested in this topic, and why is this important to study?
LB: Unfortunately, there are few specific therapies for patients with a wide variety of kidney diseases. Our group is interested in a promising field of research that uses MSC therapy to help repair the damaged kidney. We are hopeful that this exciting new therapy will offer patients with kidney disease a new avenue that will make a difference in long-term outcomes.
It is widely accepted that eventual tissue damage with loss of parenchymal cells is a common final outcome of chronic kidney disease of diverse etiologies. Hopefully, the repair process can counteract the loss of parenchymal cells and replace the dead or damaged cells. However, in the kidney, this repair process is frequently hampered by eventual tissue fibrosis and chronic loss of kidney function. Therapeutic strategies to optimize the repair should therefore inhibit the mechanisms involved in cellular loss, and stimulate the proliferation of new or damaged parenchymal cells. Bone marrow–derived stem cells have been proposed as an appealing therapeutic approach to avoid, or at least, limit kidney injury. In particular, mesenchymal stem cells have garnered great interest for their regenerative and immunomodulatory properties, mainly due to the release of paracrine factors.
eAJKD: Can you briefly describe MSC, and explain how these cells are identified and isolated for use?
LB: MSCs belong to a rare population of cells of mesenchymal origin first isolated from bone marrow and then from several organs. The rationale for their use in regenerative medicine is based on their ability to migrate to the site of injury, to differentiate into different cell lineages, to release factors that influence cell survival/ proliferation, and to modulate the immune response/inflammation. So far MSCs for transplantation have been harvested from bone marrow aspirates, but they may also be derived from umbilical cord blood and adipose tissue.
Different protocols for MSCs preparation and transplantation exist, and their variability may often account for the discordant results in clinical trials. In some of these, about 60-80 mL of bone marrow cell aspirate is obtained, cells are isolated by density gradient, and then cultured. Release criteria generally include microbiology and viability tests, morphologic analysis, and immune phenotyping for expression of CD73, CD90, and CD105, and absence of CD34, CD45, CD14, and CD3. At early passages, cells in culture are detached and infused at a dose of 1-2 x 106, with the number of infusions dependent upon the protocol.
eAJKD: In what specific kidney diseases do you see MSC therapy being employed initially?
LB: We believe that their potential is best initially explored in two settings: 1) as induction therapy in kidney transplantation, especially in marginal donor grafts, where the hope is that MSC therapy will help reduce delayed graft function and allow for less immunosuppression; 2) as “prophylaxis” for preventing or attenuating the development of acute tubular necrosis in high risk patients undergoing, for instance, certain surgical procedures such as coronary bypass surgery. Indeed, both these settings are currently under investigation with clinical trials. See Table 1 in the article for a list of all current trials.
eAJKD: Have there been any successes in treating kidney disease in humans with MSCs?
LB: So far, mostly anecdotal case reports or series have been published on the use of MSC. However, recent data from a large randomized prospective study on autologous MSC induction in living-related kidney transplants was published. The trial enrolled a total of 159 patients and achieved unprecedented statistical power in the field of stem cells research. The results showed that using MSCs during the induction of immunosuppression compared with anti-IL2-R antibody resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better kidney function at 1 year. In addition, kidney function recovered faster among the MSC therapy groups, with increased eGFR levels during the first month after surgery than the control group suggesting a positive impact on the ischemia-reperfusion injury. This study may represent a milestone in the field, but long-term monitoring is needed to provide more data on the efficacy and safety of this approach.
eAJKD: What are the potential side effects of using this therapy?
LB: The ongoing clinical trials in the field of MSC-based therapies in acute kidney injury and solid organ transplantation will be the platform for newly evolving stem cell therapy in the near future. However, some notes of caution must be taken into account. The heterogeneity of MSC population may generate some difficulties in the evaluating their potential in different diseases. Some complications may arise from MSC administration into the blood stream, such as pulmonary emboli or infarctions. The possibility of tumorigenesis or maldifferentiation should be also considered. Myocardial calcificationsand enhanced accumulation of fibroblasts and myofibroblasts in the lung have been reported in preclinical studies. Of note, in humans to date, no significant detrimental effects have been reported using MSC-based therapies.
eAJKD: Are any trials exploring the use of cytokines or other molecules produced by MSC in kidney injury?
LB: In the past, insulin-like growth factor I, a cytokine produced by MSCs, was tested in patients with acute kidney injury with poor results. This experience suggests that the local effect of MSCs revolves around the orchestration of several factors rather than a single cytokine. This notion supports the investigation of complex MSC products such as exosomes that may alter the local milieu by horizontal transfer of several genes.
eAJKD: When do you see MSC therapy becoming common practice in renal medicine?
LB: As stated above, long-term results are required, in particular to further define the safety profile of MSC therapy. An additional boost may derive from the use of allogeneic MSCs. If this approach is supported by positive clinical trial results, it may override several practical problems of autologous MSCs in terms of cell preparation, characterization, and safety control.
The next 3-4 years will be crucial to define whether MSC therapy is a real step forward, or just another unsustained promise.