Metabolic mechanisms of acute proximal tubular injury

Damage to the proximal tubule (PT) is the most frequent cause of acute kidney injury (AKI) in humans. Diagnostic and treatment options for AKI are currently limited, and a deeper understanding of pathogenic mechanisms at a cellular level is required to rectify this situation. Metabolism in the PT is complex and closely coupled to solute transport function. Recent studies have shown that major changes in PT metabolism occur during AKI and have highlighted some potential targets for intervention. However, translating these insights into effective new therapies still represents a substantial challenge. In this article, in addition to providing a brief overview of the current state of the field, we will highlight three emerging areas that we feel are worthy of greater attention. First, we will discuss the role of axial heterogeneity in cellular function along the PT in determining baseline susceptibility to different metabolic hits. Second, we will emphasize that elucidating insult specific pathogenic mechanisms will likely be critical in devising more personalized treatments for AKI. Finally, we will argue that uncovering links between tubular metabolism and whole-body homeostasis will identify new strategies to try to reduce the considerable morbidity and mortality associated with AKI. These concepts will be illustrated by examples of recent studies emanating from the authors' laboratories and performed under the auspices of the Swiss National Competence Center for Kidney Research (NCCR Kidney.ch).

Automated summary

Damage to the proximal tubule is the most common cause of acute kidney injury in humans. Current diagnostic and treatment options are limited, and a deeper understanding of pathogenic mechanisms at a cellular level is needed. Recent studies have shown significant changes in proximal tubule metabolism during acute kidney injury, highlighting potential targets for intervention. This article emphasizes the current state of the field and highlights three emerging areas worthy of attention: axial heterogeneity in determining baseline susceptibility, insult specific pathogenic mechanisms, and the link between tubular metabolism and whole-body homeostasis.