Abstract
Background:
Chronic kidney disease (CKD) has a high prevalence (~14% of the population) and is associated with a significantly increased risk of cardiovascular disease and a 15-fold higher rate of mortality than the general population. Current therapies slow disease progression but do not repair organ damage, leading to end-stage renal disease. Stem cell therapy has the potential to promote repair via neovascularization and antifibrotic effects. We tested the renal reparative capacity of allogeneic mesenchymal stem cells (MSCs) and kidney ckit+ stem cells (c-kit) in an established swine model of CKD.
Methods:
Yorkshires pigs (n=27) underwent 5/6 nephrectomy via renal artery embolization and 4-weeks later received either: MSC (10х10
6
), c-kit (10х10
6
), combination (MSC+c-kit; 1:1 ratio [5х10
6
each]), or placebo (each n=5). Allogeneic cell therapy was delivered via the patent renal artery of the remnant kidney. Kidney functional parameters and renal MRI were measured at baseline, and at 4- and 12-weeks (euthanasia) post-embolization.
Results:
The CKD model was validated from baseline to 4 weeks by an increased creatinine: (Δ1.1 ± 0.15 mg/dl; p<0.0001), BUN (Δ13.50 ± 2.99mg/dl; p=0.0003), and urine protein/creatinine ratio (Δ0.311mg/g; p=0.018), and decreased GFR (Δ49.82 ±6.41 ml/min; p=0.0002). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. After 12 weeks, there was a significant difference in MAP between groups (p=0.04), with an increase in the placebo group (19.97± 8.65 mmHg, p=0.08). BUN and creatinine levels improved in all of the groups from 4-12 weeks. GFR also improved in all the groups, but with the greatest effect in the combination group (76± 23.83ml/min; p= 0.03) from 4-12 weeks. Urine protein/creatinine ratio did not change in placebo but decreased in cell treated groups. There was no evidence of immune rejection as evaluated in a complete body necropsy.
Conclusion:
Allogeneic MSCs and kidney-derived stem cells are safe in a CKD swine model. The combination of stem cells was shown to be more efficacious in improving kidney function. These novel findings have important implications for the advancement of cell therapy for CKD.