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.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) were tested by several groups for their potential applicability in surgically induced CRF. A single injection of BM-MSCs was sufficient to reduce interstitial fibrosis and glomerulosclerosis in 5/6 renal mass reduction induced in rats. However, functional restoration was only temporarily achieved. However, another group showed that weekly administration of BM-MSCs, ameliorated functional renal parameters and led to a more significant morphological improvements. Donor cells only temporarily integrated into kidney tissue, leading the authors to conclude that protective effects of BM-MSCs were mediated by paracrine mechanisms, and that these effects are more effectively sustained by repeated stem cell delivery. Adriamycin-induced nephropathy is another experimental model of human primary focal segmental glomerulosclerosis and characterized by podocyte injury followed by glomerulosclerosis, tubulointerstitial inflammation, and fibrosis. In this model, BM-MSC treatment failed to modify clinical parameters, such as proteinuria and serum creatinine, leading the authors to conclude that BM-MSCs lack true regenerative potential under the tested conditions.
Controversy exists regarding the ability of MSCs to contribute to renal regeneration. Various modes of cell therapy delivery have been attempted in distinct models of experimental CRF, but with a limited success.
Several clinical trials have assessed the use of MSCs in immunoregulatory cell therapy, as an adjunct to immunosuppressive treatment in renal transplantation. The ONE study applies this novel supplementation of cell therapy to human clinical organ transplantation. This project aims to develop various immunoregulatory cell products to be administered to organ transplant recipients, allowing for a direct comparison of the safety, clinical practicality and therapeutic efficacy between the products.
A study using BM-derived CD34+ endothelial progenitor cells (EPCs) demonstrated their immunomodulatory paracrine effects in 5/6 nephrectomized mice. EPC injection led to a reduction in cellular infiltrates, downregulation of pro-inflammatory cytokines and adhesion molecules, and an increase in angiogenic signaling.
Tengion is currently conducting a phase 1 clinical trial to assess the safety and to determine the optimal conditions for delivery of Neo-Kidney Augment (NKA), implanted into a recipient kidney. NKA is comprised of expanded autologous, selected renal cells (SRC), formulated in a gelatin-based hydrogel. Therapeutic intervention with NKA is intended to delay the need for RRT, which is currently inevitable in patients with CRF. Proof of principle for SRC as the biologically active component of NKA, was established in multiple models of CRF.
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.