Experimental models of acute kidney injury for translational research

Abstract

Preclinical models of human disease provide powerful tools for therapeutic discovery but have limitations. This problem is especially apparent in the field of acute kidney injury (AKI), in which clinical trial failures have been attributed to inaccurate modelling performed largely in rodents. Multidisciplinary efforts such as the Kidney Precision Medicine Project are now starting to identify molecular subtypes of human AKI. In addition, over the past decade, there have been developments in human pluripotent stem cell-derived kidney organoids as well as zebrafish, rodent and large animal models of AKI. These organoid and AKI models are being deployed at different stages of preclinical therapeutic development. However, the traditionally siloed, preclinical investigator-driven approaches that have been used to evaluate AKI therapeutics to date rarely account for the limitations of the model systems used and have given rise to false expectations of clinical efficacy in patients with different AKI pathophysiologies. To address this problem, there is a need to develop more flexible and integrated approaches, involving teams of investigators with expertise in a range of different model systems, working closely with clinical investigators, to develop robust preclinical evidence to support more focused interventions in patients with AKI.

Fig. 1 ∣. Rodent models of cardiorenal syndrome type 1.

a ∣ The most common cause of cardiorenal syndrome type 1 (CRS-1) is acute myocardial infarction, which can be modelled using coronary artery ligation. The left anterior descending artery is commonly suture ligated, resulting in severe acute heart failure that does not resolve. Acute renal effects include a reduction in glomerular filtration rate (GFR) with accompanying increases in blood urea nitrogen (BUN) and serum creatinine levels. Late outcomes include tubulointerstitial fibrosis. b ∣ Cardiac arrest and cardiopulmonary resuscitation is a model of whole-body ischaemia–reperfusion that models cardiac arrest-induced CRS-1. The arrest time can be varied to titrate injury. The model results in severe AKI with near-zero GFR, increased serum and kidney tissue biomarkers of injury such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), renal inflammation with infiltrating macrophages and an increase in tissue transforming factor-β1 (TGFβ1) in the first 24 h. Late outcomes include reduced GFR and tubulointerstitial fibrosis. c ∣ Cardiopulmonary bypass is a component of cardiac surgery that itself induces CRS-1. In rodent models of cardiopulmonary bypass, tubing is placed in the aorta and vena cava and connected to a pump and membrane oxygenator for circulation. This model requires considerable surgical expertise and a thoracotomy. Time on the pump can be varied. Acute renal effects include acute tubular necrosis with increased BUN and serum creatinine as well as podocyte injury and inflammation (demonstrated by increased interleukin (IL)-1β and IL-6). Studies with prolonged survival reporting late outcomes are rare.

Fig. 2 ∣. Individualized therapeutic development plans for AKI.

A multidisciplinary, team science approach in which multiple, complementary models of acute kidney injury (AKI) are selected based on their ability to recapitulate molecular and cellular pathophysiology in patients with distinct AKI phenotypes, as well as the therapeutic development stage, is needed to capture the heterogeneity of human disease and optimize the development of effective therapeutics for these patients. Results from these animal model studies will provide iterative feedback for therapeutic development.