The kidney's primary function is to remove waste products and excess fluid from the blood and to regulate electrolyte and acid/base homeostasis. Acute renal failure (ARF) is characterized by a rapid deterioration in kidney function, resulting in a failure to maintain fluid, electrolyte and acid-base homoeostasis. Chronic renal failure (CRF) is characterized by a gradual loss of renal function over time. In the most severe stage of CRF, called end-stage renal disease (ESRD), kidney function is compromised to a degree that is incompatible with life unless renal replacement therapy (RRT) is instituted, i.e., dialysis or renal transplantation. Therapeutic options for ARF patients are limited, with the mainstay of treatment being RRT as well. In these patients, although dialysis is life-saving, it is only a temporary solution and does not replace all kidney functions. At the same time, the shortage of available organs for transplantation limits the second option. Therefore, research directed toward new therapeutic alternatives is required.
Supplementary cell introduction into a damaged adult kidney aims to facilitate repair and regeneration processes. Such cell-based therapies hold promise to repair or delay renal disease progression through cell engraftment, permanent cell incorporation into healing renal tubules or through trophic effects, via paracrine secretion of growth factors and therapeutic proteins. Stem cells present prime candidates for cell-based therapies, since they can potentially replace damaged cells when administered peripherally.
Several stem cell sources have been proposed as therapeutically relevant. Although embryonic stem cells (ESCs) have the highest potential of developing into all tissue types, their use in clinical application is restricted, due to a risk of teratoma formation. Induced pluripotent stem cells (iPSCs) present an alternative to ESCs, and provide the benefits of their autologous source, when compared to ESCs. However, no ongoing clinical trial(s) using ESCs or iPSCs for kidney disorders have been documented at clinicaltrials.gov.
Mesenchymal stem cells (MSCs) have been most widely used in experimental models of ARF due to their differentiation potential and their immunologic characteristics. MSCs secrete a broad spectrum of “trophic” growth factors, cytokines, chemokines, anti-inflammatory factors and possess immunomodulatory functions. Furthermore, they can enhance the proliferation of endogenous stem cells and thus engage them in tissue repair. Human MSCs have been shown to be renoprotective in SCID mice with acute kidney injury (AKI). Endothelial precursor cells (EPCs) are highly effective in improving kidney function by repairing microvascular injury and correcting hemodynamics in animals with AKI. MSCs displayed a similar vasculoprotective effect in early post-AKI in rats.
Umbilical cord blood-derived MSCs, amniotic fluid stem cells, menstrual blood stem cells, and adipose-derived stem cells all share characteristics with bone marrow–derived MSCs and can be exploited toward renal damage repair. Stem cells originating from amniotic fluid have been shown to be beneficial in the treatment of cisplatinum-induced experimental AKI, and adipose-derived stem cells are renoprotective in ischemia-reperfusion injury–induced AKI in rats.
At present, only bone marrow–derived hematopoietic stem cells (HSCs) and MSCs, gave rise to major efforts to exploit their characteristics in clinical applications.
Renal Bio-Replacement Therapy
Bio-replacement therapy involves application of cell therapy via an extracorporeal circuit, allowing immune-isolation of the cell device, eliminating immune-rejection concerns, and enabling the use of allogeneic cells. This strategy uses hemofiltration as a working substitute for glomerular filtration, where metabolic and secretory functions of proximal tubule cells are replaced through the application of a renal tubule assist device (RAD). This approach has shown considerable promise after testing in animal models and in phase I/II clinical trials in ARF patients. But a follow-up phase IIb study was suspended after an interim analysis which revealed a high survival rate of patients treated with sham control RAD without cells. These findings initiated development of two therapeutic approaches: an cell-free device approach, called the selective cytopheretic device (SCD), and a new cell-based device, called the bioartificial renal epithelial cell system (BRECS).
Current efforts to achieve full reconstitution of renal function have focused on the expansion of primary kidney cells in culture and their structure organization on scaffolds for either subcutaneous implantation or for use in extracorporeal perfusion systems.
Despite the marked advances and the great promise of cell therapy in kidney regeneration, a large gap still exists between scientific knowledge and its clinical translation to safe, effective stem cell-based therapies.