Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment

Sadudee Peerapornratana, Carlos L Manrique-Caballero, Hernando Gómez, John A Kellum, Sadudee Peerapornratana, Carlos L Manrique-Caballero, Hernando Gómez, John A Kellum

Abstract

Sepsis-associated acute kidney injury (S-AKI) is a frequent complication of the critically ill patient and is associated with unacceptable morbidity and mortality. Prevention of S-AKI is difficult because by the time patients seek medical attention, most have already developed acute kidney injury. Thus, early recognition is crucial to provide supportive treatment and limit further insults. Current diagnostic criteria for acute kidney injury has limited early detection; however, novel biomarkers of kidney stress and damage have been recently validated for risk prediction and early diagnosis of acute kidney injury in the setting of sepsis. Recent evidence shows that microvascular dysfunction, inflammation, and metabolic reprogramming are 3 fundamental mechanisms that may play a role in the development of S-AKI. However, more mechanistic studies are needed to better understand the convoluted pathophysiology of S-AKI and to translate these findings into potential treatment strategies and add to the promising pharmacologic approaches being developed and tested in clinical trials.

Keywords: epidemiology; inflammation; metabolic reprogramming; microvascular dysfunction; prevention; sepsis-associated acute kidney injury; sepsis-induced acute kidney injury; treatment.

Conflict of interest statement

DISCLOSURE

JAK discloses grant support and consulting fees from Astute Medical, Baxter, bioMerieux, BioPorto, and NxStage. All the other authors declared no competing interests.

Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1 |. Clinical course and outcomes…
Figure 1 |. Clinical course and outcomes of sepsis-associated acute kidney injury (S-AKI).
The exact onset of kidney injury in sepsis is unknown. Patients who present with sepsis should be suspected for AKI, and, vice versa, those who present with AKI should be suspected for sepsis as well. AKI may present simultaneously with sepsis at hospital admission (a) or develop during hospitalization (b). In the latter case, it is still possible to prevent AKI by optimal resuscitation and appropriate sepsis treatment. Novel biomarkers have an established role in the early recognition of AKI at this point. Once S-AKI is diagnosed, close monitoring and timely organ support should be done together to prevent further kidney injury. However, S-AKI is still associated with an extremely high risk of in-hospital death. The survivors have various clinical trajectories and outcomes. S-AKI is able to reverse early during the first week after being documented and is associated with a good prognosis. Some patients may experience 1 or more episodes of relapse after the initial reversal of AKI during hospitalization. This emphasizes that close monitoring and avoidance of nephrotoxic insults are mandatory along the clinical course of S-AKI even after early reversal or recovery. Patients with complete recovery of S-AKI may be discharged with good health; however, they still carry the risk of chronic kidney disease (CKD) and other consequences, including recurrent sepsis (dotted lines). Those patients who do not completely recover by 7 days after being documented AKI will be classified as having acute kidney disease (AKD), which may recover later or progress to CKD and is associated with adverse long-term outcomes. Further research regarding the potential role of biomarkers for the prediction of renal recovery is needed. S-AKI survivors who are discharged from the hospital should be followed up in the long term with optimal care by a nephrologist to monitor progression to CKD and other long-term consequences. CVD, cardiovascular disease; ED, emergency department.
Figure 2 |. Microcirculatory and inflammatory alterations.
Figure 2 |. Microcirculatory and inflammatory alterations.
Sepsis-associated acute kidney injury can occur in the absence of overt signs of hypoperfusion and clinical signs of hemodynamic instability. Several theories involving microcirculatory, including hemodynamic, changes and inflammation have been proposed to explain the dissociation between the structural findings and the altered renal function observed during sepsis-associated acute kidney injury. Glomerular filtration rate is correlated with the glomerular blood flow and the intraglomerular pressure (Pc). Glomerular shunting and constriction of the efferent arteriole result in a Pc decrease with the subsequent decline in glomerular filtration rate and urine output. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) released after the invasion of infectious pathogens have the ability to bind to a family of receptors known as pattern recognition receptors, especially Toll-like receptors (TLRs), which are expressed on the surface of immune cells, endothelial cells, and tubular epithelial cells (TECs). These result in a downstream cascade of signals and an increased synthesis of proinflammatory cytokines, reactive oxygen species (ROS), oxidative stress, and endothelial activation. Endothelial activation promotes rolling and adhesion of leucocytes and platelets, resulting in increased risk of thrombi formation and flow continuity alterations (intermittent or no flow). Also, endothelial activation is associated with increased vascular permeability and leakage, causing interstitial edema and increasing oxygen diffusion distance to the TECs. In addition to these endothelia and flow alterations, DAMPs and PAMPs can also directly affect TECs. It has been demonstrated that TECs also expressed TLRs on their surface. DAMPs and PAMPs are small enough to be filtered in the glomeruli and then to be exposed to TLR present on the TEC surface, resulting in increased production of ROS, oxidative stress, and mitochondrial damage. APCs, antigen-presenting cells; RBCs, red blood cells.
Figure 3 |. Metabolic reprogramming.
Figure 3 |. Metabolic reprogramming.
During sepsis-associated acute kidney injury (AKI), a reprioritization of energy occurs that seeks to meet metabolic vital needs prioritizing survival at the expense of cell function. Multiple highly consuming adenosine triphosphate (ATP) functions are downregulated to save energy, including protein synthesis and ion transportation, especially in the proximal tubular epithelial cells (TECs) and cellular replication. In addition to this shutdown of nonvital functions, experimental studies have suggested that TECs may reprogram their metabolism switching to aerobic glycolysis and oxidative phosphorylation to fulfill energy requirements during sepsis. Preservation of functional mitochondrial poll is necessary to carry out all the metabolic changes. During sepsis, mitochondria enter a series of quality control processes such as mitophagy and biogenesis to preserve the mitochondrial pool to confer protection and fulfill the necessary energetic requirements. ACC, acetyl coenzyme A carboxylase α; AMPKα, adenosine monophosphate kinase α; C-Myc, cell Myc gen; Cpt1, carnitine palmitoyltransferase 1; FA, frataxin; FAO, fatty acid oxidation; G0–G2, phases of the cell cycle; Gluc, glucose; GO, golgin; HIF-1α, hypoxia-inducible factor-1α; IGFBP7, insulin-like growth factor binding protein 7; LDH, lactic acid dehydrogenase; mTORC1, mammalian target of rapamycin complex 1; PDH, pyruvate dehydrogenase; PDHK, pyruvate dehydrogenase kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; PKM2, pyruvate kinase isozyme M2; Sirt, sirtuins; TIMP-2, tissue inhibitor of metalloproteinase-2; TNF, tumor necrosis factor.

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