Cell-based therapies for chronic kidney disease

Abstract

Chronic kidney disease (CKD) may lead to end-stage renal failure, requiring renal replacement strategies. Development of new therapies to reduce progression of CKD is therefore a major global public health target. The aim of this thesis was to investigate whether cell-based therapies have the potential to reduce progression of CKD. The effect of bone marrow cell (BMC) therapy on the progression of CKD in a rat model of established CKD was studied. Administration of a single renal artery injection of 50*106 healthy BMC in established CKD effectively reduced progression of renal injury and that this effect was durable. Healthy BMC therapy decreased hypertension, uremia, proteinuria and anemia, improved renal function and decreased renal damage. These findings suggest that therapy with healthy BMCs can be used to reduce renal disease progression and has long-lasting effects. However, for clinical application, use of autologous BMC would be preferable to prevent rejection. Therefore, we studied the effect of CKD-derived BMCs in our model of established CKD. We found that CKD BMCs were less effective compared to healthy BMCs, implying that this approach may not be suitable for clinical application in this form. Therefore, dysfunction of CKD BMCs needs to be reversed. In CKD nitric oxide (NO)-availability is reduced and such reduced NO-availability may also play a role in BMC dysfunction in CKD. Pravastatin, a lipid-lowering drug, is known to exert pleiotropic effects including improved NO-availability, anti-inflammatory and anti-oxidant effects and improved migration towards damaged cells. The effect of ex vivo short term (2h) pre-treatment of CKD BMC with pravastatin on their subsequent in vivo therapeutic effect on the progression of renal failure in established CKD was studied. We also studied the effects of systemic in vivo treatment of CKD rats with pravastatin. We demonstrated that CKD BMC dysfunction could be reversed by short-term ex vivo pre-treatment with pravastatin and that this short-term pre-treatment effect resulted in better renal function and less renal damage in CKD rats treated with pravastatin-treated CKD BMC compared to untreated CKD BMC recipients. In contrast, two weeks of systemic exposure by oral pravastatin had no beneficial effects on renal function or renal injury in CKD rats. Pravastatin treatment of CKD BMC significantly decreased expression of the pro-inflammatory and pro-apoptotic cytokine LIX (CXCL5) and increased expression of promigratory thymus chemokine (CXCL7). In all our studies the number of cells that we could trace after six weeks was very low and we did not see incorporation in epithelial or endothelial structures,suggesting a major role for paracrine factors. We studied the effects of mesenchymal stem cell (MSC) derived conditioned medium (CM) in our model of established CKD. Our study showed that administration of MSC-derived CM decreased progression of CKD. Exosomes were not the reno-protective component in the conditioned medium. We conclude that cell-based therapies can decrease the progression of CKD, that dysfunction of CKD BMC can be reversed, and that paracrine factors appear to play an important role.