Presentation Authors: Daniel Sun*, Paurush Babbar, Mei Kuang, Danli Lin, Jesse KcKenney, Margot Damaser, Bradley Gill, Cleveland, OH
Introduction: Renal artery clamping during partial nephrectomy causes ischemia-reperfusion injury (IRI), which can lead to acute kidney injury and exacerbate chronic kidney disease. No therapies to prevent renal IRI exist, and while the trophic and anti-inflammatory effects of mesenchymal stem cells (MSCs) show promise, cellular therapy in the setting of malignancy raises concern. This study investigated the use and optimal route of administration of acellular MSC-conditioned culture media (CCM) for improving recovery of kidney function after IRI in a rat model.
Methods: Donor rat bone marrow MSC colonies were used to produce CCM, as previously published. First, to assess the utility of CCM, 39 male Sprague-Dawley rats underwent right nephrectomy. After a 2-week recovery, the left renal hilum was clamped for 45 minutes to produce IRI. Five minutes prior to clamping, rats received 300ÂµL of intravenous normal saline (n=13), non-conditioned plain media (n=13), or CCM (n=13). Serum creatinine (SCr) was measured at days 2, 5 and 7 post-ischemia. Next, to determine the optimal route of CCM administration, a second cohort underwent the same surgeries and received, intravenous CCM (n=13), subcutaneous CCM (n=13), intra-(renal)arterial CCM (n=13), or no treatment (n=13). SCr was measured at days 5, 7, 9, and 14 post-ischemia with kidneys excised on day 14 for histopathology. Quantitative values are presented as mean percent change in SCr from baseline Â± standard error. Basic comparative statistics were performed with p-values < 0.05 considered statistically significant.
Results: By day 7 post-ischemia, CCM compared to saline or plain media resulted in significantly lower SCr relative to baseline (115% Â± 8% v 147% Â± 12%, p=0.04; 115% Â± 8% v 151% Â± 12%, p=0.02; respectively). By day 14 post-ischemia, either intra-arterial CCM or subcutaneous CCM compared to no treatment resulted in significantly lower SCr relative to baseline (114% Â± 7% v 224% Â± 48%, p=0.03; 117% Â± 12% v 224% Â± 48%, p=0.03; respectively). A similar trend in SCr relative to baseline was noted for intravenous CCM compared to no treatment (148% Â± 21% v 224% Â± 48%, p=0.05). Compared to no treatment, CCM-treated kidneys contained less tubular dilation and loss of cellular structure indicating ischemic injury.
Conclusions: When given before renal ischemia, the acellular secretome of mesenchymal stem cells improves recovery of renal function following ischemia-reperfusion injury. This improvement occurs despite route of administration, suggesting the therapy functions by a systemic effect.