Molecular Mechanisms of Sepsis-Associated Acute Kidney Injury

Abstract

Sepsis-associated AKI is a complex pathologic state driven by dynamic interactions between the host and microbes. The rapid progression and the absence of a molecular clock that stages the disease timeline make precise therapeutic interventions highly challenging. In this review, we aim to refine the timeline of sepsis-associated AKI by dissecting key molecular events that drive disease progression and may inform therapeutic strategies. AKI, initiated by microbes or infection mimicry, involves the rapid and simultaneous activation of inflammatory and anti-inflammatory pathways. This energy-intensive response is further fueled by the loss of distinction between self and nonself, leading to excessive antiviral responses mediated by self-derived nucleic acids. The resulting metabolic burden overwhelms cellular functions, triggering the integrated stress response and profound translation shutdown. Although this shutdown response may be necessary for energy preservation and for priming endogenous recovery mechanisms, prolonged inhibition of translation represents a maladaptive feature of septic AKI. Despite these challenges, the kidney exhibits remarkable resilience. Recovery relies on metabolic flexibility and stress-adaptive mechanisms, such as enhanced polyamine biosynthesis and RNA editing. Meanwhile, microbes also demonstrate metabolic adaptability, enabling them to evade host defenses and exploit the host environment. Understanding this dynamic interplay along the timeline of septic AKI is essential for developing rational therapeutic strategies.

Keywords: AKI.

Figure 1:. Renal tissue responses in sepsis

Phases of tissue responses in the kidney following a systemic infection. Surviving sepsis is analogous to navigating all the steps without being ‘wiped out’ by a wave. The magnitude and duration of each phase vary depending on the type of infection, but the sequence of responses remains constant. These phases overlap, each involving a diverse array of molecular pathways and cell types.

Figure 2.. Molecular mechanisms of sepsis-associated AKI

Illustration of representative molecular pathways involved in each phase of sepsis-associated AKI. The inner circle depicts a cadre of mechanisms, while the middle and outer circles highlight select genes and systems active in each phase. The Red Queen card symbolizes concurrent microbial evolution and adaptation, which are not detailed in this diagram. Note that the size of the quadrants does not represent actual duration of each phase in sepsis. TLRs, Toll-like receptors; SG, stress granules; Pol II CTD, RNA polymerase II C-terminal domain; uORF, upstream open reading frame; CDS, coding sequence

Figure 3.. Staphylococcus aureus infection

Left: Genome structure of MRSA USA300. The region corresponding to the arginine catabolic mobile element (ACME) is magnified (blue). SCCmec: Staphylococcal Cassette Chromosome mec, which encodes methicillin resistance. speG: spermidine acetyltransferase. Middle: Representative clinical challenges encountered by nephrologists. Right: Illustration of hematogenous dissemination of S. aureus resulting in acute kidney injury (descending pyelonephritis).