Sepsis associated acute kidney injury

• Norwegian landrace pigs 25-25 kg
• Monitored with invasive arterial, pulmonary artery, renal vein catheters
• Continous iohexol infusion (mGFR)
• E. coli infusion for 3 hrs
• 7 hours follow up
• Repeated blood and urine sampling
• Tissue samples before euthanasia

Background: Sepsis impairs proximal renal tubular epithelial cell (PTEC) function, and this impairment contributes to the pathophysiology of sepsis-associated acute kidney injury (SA-AKI). By closely replicating in vivo conditions, primary human PTEC offer superior biological relevance for studying SA-AKI. The purpose of this scoping review was to identify and investigate experiments, where human primary PTEC have been used to study sepsis-related factors.

Methods: A comprehensive literature search strategy was developed, and our reported items adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) checklist. Peer-reviewed articles published in English or Scandinavian languages between 1946 and 2024 were included.

Results: The literature search provided 292 results. Twelve studies were included, out of which only two were published after 2010. Eight studies used human primary PTEC isolated from healthy tissue during tumor nephrectomy, while four studies used primary PTEC purchased from commercially available providers. Experimental methods were heterogenous. The included studies applied E. coli porine, E. coli, Staphylococcal enterotoxin B, cytokines and lipopolysaccharide with differing dosages, exposure lengths, and combinations.

Conclusions: Although human primary PTEC more closely resembles the in vivo environment in human kidneys, their use in sepsis and SA-AKI research remains remarkably limited, leading to substantial research gaps in the field. In addition, there is significant heterogeneity in the methodologies employed across existing studies. Standardizing and expanding the use of primary PTECs in future in vitro research could be pivotal for unraveling novel and relevant insights into the pathophysiology of SA-AKI.

Molecules that are freely filtrated at the glomerulus and completely reabsorbed by the proximal tubules may be utilized as functional renal biomarkers and thus provide a sensitive method to detect AKI at an early stage.

Lithium is an alkali metal found in trace substances in human blood (13). Lithium is not bound to plasma proteins, thus it passes the glomerular membrane in its entirety. Lithium is not actively reabsorbed, it is passively reabsorbed, but at the same rate as the active reabsorption of sodium and water in the proximal tubule. It is known to be almost completely reabsorbed in parallel, but passively, with sodium and water in the proximal tubule of the kidney, and as the closest approximator to direct measurement of sodium reabsorption in this segment. What is not reabsorbed here is assumed to be excreted in urine, giving a reasonably estimation of sodium reabsorption in the proximal renal tubule. 

In the current study we hypothesized that proximal tubule function is impaired in the early stages of SA-AKI. The aim for study was to measure endogenous lithium renal clearance in patients with SA-AKI and in patients with non- AKI sepsis.

• At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli.
• Such metabolic reprogramming, was originally referred to as the Warburg effect in cancer
• Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during sepsis associated acute kidney injury
• We aim to study metabolic reprogramming in a large animal model of SA-AKI