From Molecules to Mechanisms: Developing Adverse Outcome Pathways for Tubular Necrosis and Crystalline Nephropathies

Abstract

This thesis focuses on the development of Adverse Outcome Pathways for kidney injury, with specific emphasis on tubular necrosis and crystalline nephropathies. The kidney is a major target organ for drug- and chemical-induced toxicity because of its role in filtration, secretion, reabsorption, and concentration of substances in the tubular fluid. However, kidney injury is often complex and may result from multiple interacting biological processes. A better mechanistic understanding of how early molecular and cellular changes lead to adverse effects at the tissue and organ level is therefore important for toxicology, drug safety, and the advancement of more human-relevant testing strategies. Adverse Outcome Pathways provide an organised framework for organising biological knowledge. They describe how a molecular initiating event can trigger a sequence of measurable key events that ultimately result in an adverse outcome. In this thesis, existing scientific evidence was collected, evaluated and organised to describe the mechanistic pathways underlying tubular necrosis and crystalline nephropathies. Tubular necrosis is characterised by severe injury and death of tubular epithelial cells. It is associated with mitochondrial dysfunction, oxidative stress, disturbed cellular energy metabolism, impaired transport functions, inflammation, and disruption of tubular integrity. Crystalline nephropathies are kidney disorders in which crystals form or accumulate within the kidney. These crystals may obstruct tubules, injure epithelial cells, promote inflammation, and contribute to progressive kidney dysfunction. The work presented in this thesis identifies and structures key biological events involved in these forms of kidney injury. It highlights how early disturbances at the molecular and cellular level can be connected to later pathological changes in kidney tissue and function. By evaluating the available evidence for these connections, the thesis also identifies areas where mechanistic knowledge is relatively strong, as well as uncertainties and knowledge gaps that call for further study. Overall, this thesis demonstrates that Adverse Outcome Pathways can be useful for organising and interpreting mechanistic evidence in kidney toxicology. The developed pathways may support a more transparent assessment of nephrotoxic hazards and inform testing strategies that better leverage human-relevant models and non-animal approaches. In doing so, the thesis contributes to the broader transition from descriptive toxicity assessment towards mechanism-based safety evaluation.