Investigating the role of human umbilical mesenchymal stromal cells as therapies in a model of renal IRI in different mouse strains

Acute kidney injury (AKI), a common complication in hospitalised patients, has been associated with a high mortality rate as well as progression to chronic kidney disease and end-stage renal failure. AKI does not have a distinct pathophysiology as the disease can be brought about by different insults from nephrotoxicity and sepsis to surgical procedures. Regardless of the initial cause, AKI is characterised by a reduction in blood flow to the kidneys and subsequent hypoxia, processes which are associated with inflammation and immune system activation. Macrophages are highly versatile cells of the immune system, ubiquitous in all tissues, and have been identified to play a central role in both the injury phase and the subsequent resolution of inflammation in animal models of kidney disease. Despite recent advances in medical treatment, currently, there is no cure for AKI, and the disease is managed with fluid therapy, dialysis and ultimately, transplantation. Over the last two decades, extensive research done within the fields of regenerative medicine and pre-clinical research has proposed mesenchymal stromal cells (MSCs) as the main therapy for the treatment of various inflammatory diseases, including AKI. MSCs have become an attractive tool for cell-based therapies due to their potent immunosuppressive and immunomodulatory functions with effects on both innate and adaptive immune cells, including monocytes and macrophages. Nevertheless, the precise mode of action of these therapies is still largely unknown. The work in this thesis aimed to characterise and compare the injury response to bilateral renal ischaemia-reperfusion injury (IRI), and on this basis, characterise and compare the regenerative response to cellular therapies following bilateral renal IRI in three different mouse strains. Throughout all the experiments within this thesis I have demonstrated that bilateral renal IRI leads to strain-dependent responses. I have employed a series of experiments that assessed renal function, weight, macrophage levels in kidneys and spleens, and cytokine levels in plasma and kidneys to characterise and compare the effect that bilateral renal IRI has on three different mouse strains – BALB/c, C56BL/6 albino and CD1. Importantly, the application of human umbilical cord (hUC) MSC therapies failed to result in an efficacious response in ameliorating kidney injury, regardless of mouse strain. Despite this observation, I was able to demonstrate that hUC-MSC treatment can marginally modulate macrophages in kidney and spleen, and influence cytokine levels in the kidney. However, these effects were not replicated across the three strains and displayed high inter-strain variability. Further work is required into the mode of action of MSCs so as to better replicate the results seen in pre-clinical studies and to translate these into the clinic

The complex interplay between kidney injury and inflammation

Abstract Acute kidney injury (AKI) has gained significant attention following patient safety alerts about the increased risk of harm to patients, including increased mortality and hospitalization. Common causes of AKI include hypovolaemia, nephrotoxic medications, ischaemia and acute glomerulonephritis, although in reality it may be undetermined or multifactorial. A period of inflammation either as a contributor to the kidney injury or resulting from the injury is almost universally seen. This article was compiled following a workshop exploring the interplay between injury and inflammation. AKI is characterized by some degree of renal cell death through either apoptosis or necrosis, together with a strong inflammatory response. Studies interrogating the resolution of renal inflammation identify a whole range of molecules that are upregulated and confirm that the kidneys are able to intrinsically regenerate after an episode of AKI, provided the threshold of damage is not too high. Kidneys are unable to generate new nephrons, and dysfunctional or repeated episodes will lead to further nephron loss that is ultimately associated with the development of renal fibrosis and chronic kidney disease (CKD). The AKI to CKD transition is a complex process mainly facilitated by maladaptive repair mechanisms. Early biomarkers mapping out this process would allow a personalized approach to identifying patients with AKI who are at high risk of developing fibrosis and subsequent CKD. This review article highlights this process and explains how laboratory models of renal inflammation and injury assist with understanding the underlying disease process and allow interrogation of medications aimed at targeting the mechanistic interplay.</jats:p