Challenges and opportunities for stem cell therapy in patients with chronic kidney disease

Abstract

Chronic kidney disease (CKD) is a global health care burden affecting billions of individuals worldwide. The kidney has limited regenerative capacity from chronic insults, and for the most common causes of CKD, no effective treatment exists to prevent progression to end-stage kidney failure. Therefore, novel interventions, such as regenerative cell-based therapies, need to be developed for CKD. Given the risk of allosensitization, autologous transplantation of cells to boost regenerative potential is preferred. Therefore, verification of cell function and vitality in CKD patients is imperative. Two cell types have been most commonly applied in regenerative medicine. Endothelial progenitor cells contribute to neovasculogenesis primarily through paracrine angiogenic activity and partly by differentiation into mature endothelial cells in situ. Mesenchymal stem cells also exert paracrine effects, including proangiogenic, anti-inflammatory, and antifibrotic activity. However, in CKD, multiple factors may contribute to reduced cell function, including older age, coexisting cardiovascular disease, diabetes, chronic inflammatory states, and uremia, which may limit the effectiveness of an autologous cell-based therapy approach. This Review highlights current knowledge on stem and progenitor cell function and vitality, aspects of the uremic milieu that may serve as a barrier to therapy, and novel methods to improve stem cell function for potential transplantation.

Keywords: end-stage renal disease; senescence; stem cells; uremia.

Figure 1

Endothelial progenitor cell (EPC) and mesenchymal stem cell (MSC) reparative functions in chronic kidney disease. Both cell types possess the capacity to release a variety of cytokines, growth factors, and extracellular vesicles. Cells home to the injured tissue, engraft (although incorporation in kidney structures is often modest), and promote neoangiogenesis. Cumulative effects of the EPC and MSC result in multiple beneficial effects including decreased inflammation, oxidative stress, and apoptosis. Structural effects include minimization of tubular injury, tubulointerstitial fibrosis, and potentially glomerulosclerosis.

Figure 2

Causative factors for endothelial progenitor (EPC) and mesenchymal stem cell (MSC) dysfunction in chronic kidney disease (CKD). In the setting of CKD, EPC and MSC become functionally impaired, and EPC demonstrate a reduction in the number of circulating cells. Moreover, the cell vitality might decrease, demonstrated by apoptosis and cellular senescence. A variety of factors shown to contribute to these findings are listed above. IL-6: interleukin-6, CRP: C-reactive protein, RAAS: renin-angiotensin-aldosterone system, EPO: erythropoietin, ADMA: asymmetric dimethylarginine.

Figure 3

Preconditioning treatments, pharmacological agents, and other interventions with potential to improve endothelial progenitor (EPC, highlighted in tan boxes) and mesenchymal stem cell (MSC, highlighted in blue boxes) function for stem cell transplantation in chronic kidney disease. Given the EPC and MSC dysfunction in varying disease states, several studies have examined the beneficial effects of drugs and interventions that increase their function and number. HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme-A, ACEi: angiotensin-converting enzyme inhibitors, CCB: calcium channel blockers, ESA: erythropoietin stimulating agent, DPP4: dipeptidyl peptidase-4 inhibitors, PPAR: peroxisome proliferator-activated-receptor, ARB: angiotensin-2 receptor blockers. RRT: renal replacement therapy