The clinical challenge:
At least 8% (approximately 40 million people) of the European population currently has a degree of chronic kidney disease (CKD), placing them at a moderate to high risk to develop kidney failure. This figure is increasing each year and if the present trend continues, the number of people with CKD will double over the next decade.
CKD carries a very high mortality risk, and for example in Australia, overall there has been a 23% increase in deaths from kidney disease over the past 10 years, killing more people each year than breast cancer (2,799), prostate cancer (3,111) or even road accidents (1,417). The drivers for this increasing prevalence are an aging population and the shift from acute cardiovascular mortality to chronic cardiovascular morbidity (heart and kidney failure, diabetes).
To cope with these increases, national governments would need to spend 3-5% of their annual healthcare budgets on renal replacement therapies in the next years (25 billion per annum for the EU zone and Australia together). This does not include the wider costs of additional medical expenses, decreased quality of life and life expectancy, increased morbidity and reduced capacity to work. The development of novel strategies for treatment is therefore fundamental to averting this huge medical and societal problem.
The scientific challenge:
CKD results in renal failure due to the development of progressive fibrosis. STELLAR will develop strategies that lead to regeneration of injured kidney tissue instead of fibrosis. Members of the consortium have shown that not only resolution of fibrosis but also full restoration of function of injured kidneys can be induced in CKD.
The repair process can be stimulated by the presence of mesenchymal stromal cells (MSCs). More recently resident kidney MSCs (kMSCs) have been identified in both animal and human tissue which might play a role in the regeneration and functional repair of damaged kidney epithelium and endothelium. Within the consortium, assessment of the functional importance of these cell types in kidney repair in vivo, and their interdependence in the repair process, will to be determined.
Members of the consortium have shown considerable promise in the treatment of CKD with non-renal MSCs in both preclinical and clinical settings, it is clear that these cells do not directly contribute to formation of new epithelial cells. The consortium will investigate whether kMSCs, which possess most MSC features but also show some epithelial differentiation potential, may be prefered over allogeneic bone marrow (bm) or umbilical cord derived MSC as a source of cells for clinical trails in kidney disease and for the treatment of CKD. Addressing this hypothesis and investigating the potential mechanisms involved will be a major priority, as will be investigations into the interplay between these endogenous MSCs and kidney epithelial progenitors.
To assess in vivo outcomes, the consortium will also focus on the discovery of biomarkers that reflect the regenerative properties of these cells in order to translate this work into the clinical arena.
Via the European partners, and building on pre-existing FP7 sponsored private public collaborations, isolation methods for kMSCs from human material are being developed. The combination of these work plans and skill sets will enable this team to develop this knowledge into a therapeutic cell therapy for CKD.
The four scientific workpackages within STELLAR are:
- To functionally compare kMSCs with bone narrow derived MSC and umbilical cord derived MSCs in vitro.
- To discover the mechanisms of action by which kMSCs control the biology of kidney repair in vivo, particularly with respect to the response of the proposed resident epithelial stem cells.
- To validate the safety and efficacy of (k)MSC-based therapy in relevant preclinical rodent models of proliferative , proteinuric non-proliferative kidney disease and interstitial kidney disease.
- To develop standardized characterization, quality control and good manufacturing practice (GMP) of MSCs, with a special emphasis on maintaining the kMSC phenotype during expansion in a closed system bioreactor.