Translational Nephrology: Taking Aim at Tubular Debris

Abstract

Acute kidney injury is characterized by a rapid decline in renal function, which results in the accumulation of metabolic waste and toxins. Changes that result in decreased renal blood flow or the presence of toxic chemicals (e.g. metabolic by-products from medications) within the blood can cause stress to the tubular cells within the kidney, whose task is to reabsorb metabolites before they are excreted in the urine. If the stress persists, tubular cells will die. The loss of cells within the tubules decreases the kidneys capacity for reabsorption, and the debris produced by dying cells can result in blockage of the tubules, resulting in decreased flow. The combination of these factors within the nephrons, decreased flow, increased renal protein, high salt, and low pH create ideal conditions for cast formation, which can further complicate matters. Therefore, mechanisms are needed to ensure efficient clearance of debris in order to initiate repair and restore kidney function. In their recent paper, Arai et al. (Nat. Med. 2016; 22: 183-193), have identify one such mechanism involving the Apoptosis Inhibitor of Macrophages protein (AIM). In the blood of healthy individuals, AIM can be found in complexes with IgM. The presence of inflammation induces the release of AIM, which then enters into the tubules within the kidney to mark debris for disposal by phagocytes. Activated tubular cells, which are undergoing proliferation in order to replace lost cells, upregulate a receptor that binds AIM-tagged debris. The receptor is called Kidney Injury Molecule 1 (KIM-1) and bestows upon the surviving tubular cells the ability to repair tubular function much like a do-it-yourself (DIY) kit. Best of all, it appears that the application of recombinant AIM during AKI may be of therapeutic benefit for improving kidney function. Keywords Mechanisms of acute Kidney InjuryAcute kidney injury (AKI) represents a global health problem associated with high morbidity and mortality. AKI has multiple causes, including reduced renal blood flow (ischemia), nephrotoxicity, as well as urinary tract obstruction. Despite its diverse causes, the common element is tubular cell damage, which induces inflammation. If left untreated, fibrosis develops that progresses to chronic kidney disease (CKD) and ultimately ends in renal failure. Unfortunately, aside from renal replacement therapy and kidney transplantation, no reliable treatment exists that improves survival and restores kidney function [1]. While animal models, such as ischemia-reperfusion injury and nephrotoxicity, have provided detailed insight into the mechanisms of damage, they have so far done little to improve therapy; until now. The kidney's primary function is to remove metabolic waste products from the blood; however it also plays an important role in homeostasis, regulating the levels of electrolytes, maintaining the acid-base balance, as well as regulating blood pressure. Filtration of the blood occurs within the glomeruli. Nitrogenous wastes are secreted in the urine, w...