1. Figure 1 Principal pathogenic mechanisms of
acute kidney injury in the context of sepsis or major surgery
Figure 1 | Principal pathogenic mechanisms of acute kidney injury in the context of sepsis or major surgery. In both settings, alterations in systemic and glomerular haemodynamics — arising from the vasodilatory effects of systemic inflammatory mediators or anaesthesia, decreases in actual or effective in plasma volume and myocardial depression — may cause an early decrease in glomerular filtration rate (GFR) with potential for rapid reversibility (dotted arrows). Depending on the clinical context, these changes can be associated with high, normal or low cardiac output. However, both sepsis and tissue injury in surgery result in the generation of damage-associated molecular patterns (DAMPs) — including high mobility group protein B1 (HMGB1), histones, cell-free RNA and DNA, ribonuclear proteins, S100 proteins and heat-shock proteins — or pathogen-associated molecular patterns (PAMPs) — prototypically lipopolysaccharide but also including a vast array of other bacterial-specific or viral-specific molecules. These 'molecular patterns' are recognized by Toll-like receptors (TLRs), triggering systemic and local release of pro-inflammatory mediators, such as IL-1, IL-2, IL-6, IL-8 IL-12, IL-18, transforming growth factor-β (TGFβ), tumour necrosis factor (TNF), IFNγ, C-C chemokine ligand 2 (CCL2) and CCL5. Furthermore, antimicrobial drugs that are used for the treatment of infections can contribute to nephrotoxicity (Fig. 3). The effects of DAMPs and PAMPs are combined with those of specific immune responses and the generation of other inflammatory mediators, including products of coagulation and complement activation, leading to the recruitment of a peritubular inflammatory cell infiltrate (neutrophils, monocytes, macrophages and lymphocytes). Importantly, these circulating toxins and mediators may act directly on the endothelium or may be filtered in the glomerulus, where they interact with tubular cells and cause injury. The renal inflammatory response can cause injury to the endothelium, microcirculation and tubular cells. If this damage is severe, it will lead to sustained clinical acute kidney injury (AKI) that is unresponsive to the correction of systemic haemodynamic abnormalities. Finally, during critical illness, the effects of fluid overload, elevated venous pressure and development of abdominal compartment syndrome can also contribute to the persistence of AKI by an increase in tubular pressure and reduction of glomerular perfusion.
Kellum, J. A. & Prowle, J. R. (2018) Paradigms of acute kidney injury in the intensive care setting
Nat. Rev. Nephrol. doi: /nrneph