Abstract
BACKGROUND: Bone marrow-derived early outgrowth cells (EOCs) secrete soluble factors that exert potent renoprotective effects, such that infusion of their conditioned medium recapitulates the affects of the cells themselves. OBJECTIVES: The objective of this study is to test whether the protective effect of conditioned medium infusion wanes with time and whether tachyphylaxis occurs with repeated administration. DESIGN: This is a placebo-controlled animal study. SETTING: The study was conducted at St. Michael's Hospital, Toronto, Ontario, Canada. SUBJECTS: Fischer 344 (F344) rats were used in this study. MEASUREMENTS: The following were measured: (1) urinary protein:creatinine ratio, (2) glomerular filtration rate, (3) systolic blood pressure, (4) body weight, (5) glomerular endothelial cell density, and (6) glomerular and tubulointerstitial type IV collagen deposition. METHODS: Subtotally nephrectomized F344 rats, a model of progressive chronic kidney disease, were randomized 4 weeks post-surgery to receive thrice-weekly intravenous injections of concentrated EOC-conditioned medium (EOC CM) or unconditioned medium (UCM) over 2 weeks. Three animal groups were studied, according to whether they were administered conditioned medium: once (Initial Therapy Only group), twice (Repeat Therapy group), or not at all (No Therapy group). RESULTS: Following initial therapy, EOC CM-treated animals excreted less urinary protein, a marker of renal injury, than their UCM-treated counterparts. At 10 weeks post-subtotal nephrectomy, however, mean urinary protein excretion in conditioned medium-treated animals was fourfold greater than at the completion of the initial treatment course. At this time point, conditioned medium-treated animals were randomized to receive a second course of either conditioned medium (Repeat Therapy group) or unconditioned medium (Initial Therapy Only group). At study end (14 weeks post-subtotal nephrectomy), Repeat Therapy animals demonstrated higher glomerular filtration rate, less proteinuria, preserved renal microvasculature, and diminished fibrosis when compared with the No Therapy group. Initial Therapy Only animals exhibited an intermediate effect. LIMITATIONS: Testing the effect of EOC-conditioned medium in a single model of chronic kidney disease (CKD) has limitations. CONCLUSIONS: These findings suggest that early outgrowth cell-derived factors, while renoprotective, have a limited duration of action. Repeated administration of these factors, however, is able to extend the duration of efficacy and attenuate the progression of experimental chronic kidney disease.