Sepsis-Associated Acute Kidney Injury

Abstract

Sepsis-associated acute kidney injury (S-AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is characterized by rapid deterioration of renal function associated with sepsis. The pathophysiology of S-AKI remains incompletely understood, so most therapies remain reactive and nonspecific. Possible pathogenic mechanisms to explain S-AKI include microcirculatory dysfunction, a dysregulated inflammatory response, and cellular metabolic reprogramming. In addition, several biomarkers have been developed in an attempt to improve diagnostic sensitivity and specificity of S-AKI. This article discusses the current understanding of S-AKI, recent advances in pathophysiology and biomarker development, and current preventive and therapeutic approaches.

Keywords: AKI; Biomarkers; Inflammation; Metabolic reprogramming; Microcirculation; Sepsis.

Fig. 1.

Inflammatory response and microcirculatory dysfunction. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) are inflammatory mediators derived from bacteria and host immune cells, respectively. These inflammatory mediators bind to pattern recognition receptors (PRRs) expressed on the surface of innate immune cells, endothelial cells, and renal TECs initiating a downstream cascade of signals. This cascade increases the synthesis of proinflammatory cytokines, reactive oxygen species (ROS), oxidative stress, and endothelial activation by nitric oxide and nitric oxide synthase (iNOS) upregulation. During inflammation, DAMPs and PAMPs are filtered in the glomeruli. Once in the tubule, these bind the Toll-like receptor (TLRs) present in the apical membrane of the TEC. In addition, some evidence suggests that TECs are also exposed to the inflammatory mediators present in the peritubular circulation, creating a double-hit effect. Moreover, the inflammatory response can also injure the TECs by increasing the oxidative stress and producing ROS. Microcirculatory dysfunction is the result of a series of events that lead to an impaired delivery of oxygen and nutrients to the tissue. Endothelial activation provoked by the inflammatory response results in a cascade of events that lead to shedding of the glycocalyx, increased leukocyte migration, and endothelial permeability. In addition, microcirculatory dysfunction is characterized by a heterogeneous flow, reduced number of capillaries with continuous flow, with an associated increase of capillaries with sluggish or no flow. Sluggish and no flow, a result of the increased expression of adhesion molecules on the inflammatory and endothelial cells, facilitate the migration of neutrophils and macrophage to the interstitial space. Furthermore, the areas with sluggish flow have increased production of ROS and oxidative stress, manifested by TEC apical vacuolization.16,35,49 APC, antigen-presenting cell; RBC, red blood cell. (Adapted from: Peerapornratana, S., Manrique-Caballero, C. L., Gó mez, H. & Kellum, J. A. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney international 96, 1083–1099, https://doi.org/10.1016/j.kint.2019.05.026 (2019).)

Figure 2.. Metabolic Reprogramming

In the early metabolic response to S-AKI, renal tubular epithelial cells undergo a proinflammatory phase (acute anabolic phase) metabolism in which the Akt/mammalian target of rapamycin complex 1 (mTORC1)/Hypoxia Inducible Factor (HIF)-1α complex drives the induction of aerobic glycolysis by increasing the expression of glycolytic enzymes (e.g. lactate dehydrogenase [LDH], PKM2 and pyruvate dehydrogenase kinase [PDHK]). HIF-1α promotes the conversion of pyruvate to lactate and, along with PDHK, inhibit the conversion of lactate into acetyl-CoA hindering the induction of the Krebs cycle and decreasing OXPHOS. In the late anti-inflammatory (adaptive catabolic phase) OXPHOS, metabolic pathways are reestablished. This is driven by adenosine monophosphate-activated protein kinase (AMPK) activation, Sirt1 and Sirt6. AMPK activates Sirt1 and Sirt6. Sirt6 will block the activity of HIF-1α switching back from aerobic glycolysis to OXPHOS. is induced by the decrease in ATP levels. AMPK activates peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC)-1α and with CPT-1 will stimulate fatty acid oxidation and oxidative metabolism. Furthermore, PGC1α along with AMPK will induce mitochondrial biogenesis.^,, Adopted and adapted from: Gómez, H., Kellum, J. A. & Ronco, C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nature Reviews Nephrology 13, 143, doi:10.1038/nrneph.2016.186 (2017).

Figure 3.. Metabolic Adaptive Response to Sepsis: Prioritizing Cell Survival

As consequence of the early metabolic reprogramming that TEC undergoes during sepsis, non-vital functions such as cell replication, protein synthesis and ion transportation are put in ‘stand-by’, and the limited amount of ATP available is redirected toward vital functions, prioritizing cell survival at the expense of cell function. Active transport pumps such as Na⁺/K⁺ ATPase are engulfed by the cell to limit the spend of ATP. Additionally, one of the most cell energy-consuming processes is cell replication. TEC have intrinsic mechanisms that allow to detect if the cell possesses enough ATP to undergo a complete cell cycle. If this is not the case it would shut down cell replication, resulting in elevation of cycle arrest biomarkers (i.e. IGFBP7 and TIMP2). Finally, to restore TEC oxidative metabolism and normal TEC metabolism, a healthy pool of mitochondria is required. During sepsis, mitochondrial population is severely injured. As a protective mechanism, mitochondrial quality control processes such as mitophagy and biogenesis are activated as a mechanism to restore the mitochondrial pool and switch back to OXPHOS. Adopted and adapted from: Peerapornratana, S., Manrique-Caballero, C. L., Gómez, H. & Kellum, J. A. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney international 96, 1083–1099, doi:10.1016/j.kint.2019.05.026 (2019).

Fig. 4.

Proposed diagnostic approach to S-AKI and AKI as a sepsis-defining event. aSepsis-3 Q18 criteria7: patient with suspected or documented infection who has a total SOFA score greater than or equal to 2. bKDIGO criteria.11 Stage 1 AKI: increase in serum creatinine level 1.5 to 1.9 times baseline or increase in serum creatinine level greater than or equal to 0.3 mg/dL within 48 hours or urine output less than 0.5 mL/kg/h for 6 to 12 hours. Stage 2 AKI: increase in serum creatinine level 2.0 to 2.9 times baseline or urine output less than 0.5 mL/kg/h for greater than or equal to 12 hours. Stage 3 AKI: increase in serum creatinine level greater than or equal to 3.0 times baseline, or increase in serum creatinine level greater than or equal to 4.0 mg/dL, or urine output less than 0.3 mL/kg/h for greater than or equal to 24 hours, or anuria for greater than or equal to 12 hours, or need for initiation of RRT. ED, emergency department; ICU, intensive care unit.