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Critical Care Nephrology and Acute Kidney Injury The Pathophysiology of Sepsis-Associated AKI Shuhei Kuwabara, Eibhlin Goggins, and Mark D Okusa Abstract Sepsis-associated AKI is a life-threatening complication that is associated with high morbidity and mortality in patients who are critically ill Although it is clear early supportive interventions in sepsis reduce mortality, it is less clear that they prevent or ameliorate sepsis-associated AKI This is likely because specific mechanisms underlying AKI attributable to sepsis are not fully understood Understanding these mechanisms will form the foundation for the development of strategies for early diagnosis and treatment of sepsis-associated AKI Here, we summarize recent laboratory and clinical studies, focusing on critical factors in the pathophysiology of sepsis-associated AKI: microcirculatory dysfunction, inflammation, NOD-like receptor protein inflammasome, microRNAs, extracellular vesicles, autophagy and efferocytosis, inflammatory reflex pathway, vitamin D, and metabolic reprogramming Lastly, identifying these molecular targets and defining clinical subphenotypes will permit precision approaches in the prevention and treatment of sepsis-associated AKI CJASN 17: 1050–1069, 2022 doi: https://doi.org/10.2215/CJN.00850122 Introduction Historically, Lewis Thomas was responsible for a paradigm shift in our concept of sepsis by changing the focus from pathogens to the pathologic dysregulated host response that serves as the basis for the clinical expression of the systemic inflammatory response syndrome (1) In 1991, the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference on sepsis and organ failure defined sepsis as infection-induced systemic inflammatory response syndrome (2) In 2016, with the Third International Census Definition for Sepsis and Septic Shock, sepsis was defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection (3) Thus, the focus shifted from an emphasis on the hyperactive immune response or cytokine storm in which fluids and a vasopressor were necessary for hemodynamic support, to the importance of organ damage, a condition that complicates clinical management and increases mortality The standard management approaches in sepsis (fluid resuscitation, vasopressors, parental antibiotics, or implementing Surviving Sepsis Campaign Care bundles) are associated with a reduction of hospital mortality (4) The time of sepsis bundle protocol initiation is critical (5) When the 3-hour bundle of care (blood cultures, broad-spectrum antibiotic agents, and lactate measurement) was initiated within hours after arrival in the emergency department and completed within 12 hours, the longer time to completion of the bundle was associated with higher mortality Although early initiation of a care bundle was associated with reduced mortality, it is not clear whether implementing these management strategies reduces sepsis-associated AKI A recent study of Surviving 1050 Copyright © 2022 by the American Society of Nephrology Sepsis Campaign Care bundles was disappointing in terms of reducing sepsis-associated AKI (6) Thus, a better understanding of the pathophysiology of sepsisassociated AKI and improved clinical trial design are needed Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia Correspondence: Dr Mark D Okusa, University of Virginia, PO Box 800133, Charlottesville, VA 22908 Email: mdo7y@ virginia.edu Epidemiology Sepsis accounts for about 50% of all patients with AKI in the intensive care unit (ICU) and is the leading cause of death in the ICU (7–9) Mortality from sepsisassociated AKI cannot be explained solely by loss of kidney function, rather AKI-induced multiorgan dysfunction, including lung, heart, brain, liver, and intestine, contributes to the overall mortality in sepsisassociated AKI (10) The mortality of patients with AKI in ICU and non-ICU settings increases with the number of failed organ systems (11) Compared with AKI with nonseptic etiologies, the pathophysiology of sepsis-associated AKI is complex because the AKI episode is also a leading cause of sepsis (12) When sepsis develops after AKI, the prognosis is poor, the hospital stay is longer, and mortality rates are higher (13) Although timely administration of antibiotics is one of the most effective interventions to reduce mortality in patients who are septic, its role in sepsis-associated AKI is unclear (6) because antibiotics are often associated with nephrotoxicity in sepsis-associated AKI (14–17) Furthermore, established approaches for septic shock (e.g., fluid management, antibiotics, and vasopressors) have failed to improve outcomes in sepsisassociated AKI (18) Failure of clinical trials focusing on single targets such as inflammatory cytokines (TNF-a and IL-1b) (19–21) may partly be due to the failed recognition www.cjasn.org Vol 17 July, 2022 Potential targets for diagnosis and treatment of sepsis-associated AKI found in preclinical studies Target Disease Model Intervention Outcome Nonseptic AKI Rat, IRI — FoxD1 pericytes Nonseptic AKI Pericyte ablation (56) Gli11 pericytes Nonseptic AKI Pericyte ablation Kidney injury " (57) SA-AKI Mouse, diphtheria toxin Mouse, diphtheria toxin Mouse, CLP Pericyte density #, vascular congestion " Kidney injury " Inhibition Vascular leakage #, survival " (58) SA-AKI SA-AKI Mouse, CLP Swine, LPS Inhibition — Vascular leakage ", survival # Pericyte-to-myofibroblast transdifferentiation " (59) (60) SA-AKI SA-AKI Nonseptic AKI SA-AKI SA-AKI Mouse, LPS Mouse, CLP Mouse, cisplatin Mouse, LPS Rat, fecal peritonitis Inhibition Inhibition Inhibition Inhibition Inhibition Vascular leakage ", survival # Kidney injury # Kidney injury ! Kidney injury # Kidney IL-1b # (61) (69) (70) (71) (72) Nonseptic AKI SA-AKI Mouse, IRI Mouse, LPS, CLP Activation — (98) (92) SA-AKI SA-AKI Mouse, LPS Human, LPS-induced HK-2 cells (in vitro) — Inhibition/activation Kidney injury " miR-452 " before kidney injury miR-762 ", miR-144–3p " Inflammation and apoptosis #/" SA-AKI Rat, CLP Nonseptic AKI Mouse SA-AKI Mouse, CLP SA-AKI Mouse, CLP SA-AKI Mouse, CLP Brain-derived extracellular vesicles Extracellular vesicles secreted on thorax trauma M2 macrophage-derived extracellular vesicles Endothelial progenitor cellderived extracellular vesicles Extracellular vesicles from adipose tissue-derived mesenchymal stem cells Sepsis Sepsis SA-AKI SA-AKI Mouse, LPS Mouse, CLP Mouse, LPS Human, LPS-induced HK-2 cells (in vitro) Mouse, CLP Mouse, IRI Microcirculatory dysfunction and pericyte loss Neural glial 21 pericytes Friend leukemia virus integration miR-145a PDGFRb1 pericytes NLRP3 inflammasome Sirtuin NLRP3 NLRP3 Panx1 P2X7 miRNAs miR-494 miR-452 miR-762, miR-144–3p miR-34–5b Unknown Thioredoxin-interacting protein Lysine (K)-specific demethylase 6B Unknown Autophagy and efferocytosis LC3 LC3 Atg7 Sirtuin p53 AIM SA-AKI Nonseptic AKI Inhibition Activation Inhibition Activation/inhibition Deacetylation Inhibition/activation (55) (99) (93) Kidney injury " (109) Kidney injury " (110) Kidney injury # (111) Kidney injury # (112) Kidney injury # (113) Survival # Survival ", lung injury # Kidney injury " Inflammation and apoptosis #/" Kidney injury # Kidney injury "/# (117) (118) (122) (123) (124) (132) Pathophysiology of Sepsis-Associated AKI, Kuwabara et al Extracellular vesicles Unknown Reference CJASN 17: 1050–1069, July, 2022 Table 1051 1052 CJASN Table (Continued) Target Cholinergic anti-inflammatory pathway Vagus nerve Vagus nerve Cholinergic antiinflammatory pathway Cholinergic antiinflammatory pathway Vitamin D Vitamin D receptor Vitamin D Vitamin D receptor Vitamin D receptor Metabolic reprogramming and mitochondrial function PPARg coactivator-1a Drp1 PINK1/PARK2 STING cGAS Mitochondrial reactive oxygen species Drp1 Disease Model Intervention Outcome Reference Sepsis Nonseptic AKI Nonseptic AKI Mouse, LPS Mouse, IRI Mouse, IRI Plasma TNF-a # Kidney injury # Kidney injury # (144) (144,145) (146) SA-AKI Mouse, CLP Activation Activation Activation by pulsed ultrasound Activation by pulsed ultrasound Kidney injury # (147) SA-AKI SA-AKI Nonseptic AKI Nonseptic AKI Mouse, LPS Mouse, LPS Mouse, cisplatin Mouse, IRI Inhibition/activation Deprivation Activation/Inhibition Activation Kidney injury "/# Kidney injury " Kidney injury #/" Kidney injury # (153) (154) (158) (159) SA-AKI Nonseptic AKI SA-AKI Nonseptic AKI SA-AKI SA-AKI Mouse, LPS Mouse, IRI Mouse, LPS, CLP Mouse, cisplatin Mouse, CLP, LPS Mouse, CLP Inhibition Inhibition Inhibition Inhibition Inhibition Antioxidation by SS-31 SA-AKI Mouse, LPS Inhibition by Mdivi-1 " # " # # # (168) (170) (171) (172) (173) (174) Kidney injury # (76) Kidney Kidney Kidney Kidney Kidney Kidney injury injury injury injury injury injury IRI, ischemia-reperfusion injury; FoxD1, forkhead box D1; SA-AKI, sepsis-associated AKI; CLP, cecal ligation puncture; miRNA, microRNA; PDGFRb, platelet-derived growth factor receptor b; NLRP3, NOD-like receptor protein 3; Panx1, pannexin-1; LC3, microtubule-associated protein light chain 3; Atg7, autophagy-related gene 7; AIM, apoptosis inhibitor of macrophage; Drp1, dynamin-related protein 1; PINK1, PTEN-induced kinase 1; PARK2, Parkin RBR E3 ubiquitin protein ligase; STING, stimulator of interferon genes; cGAS, cyclic GMPAMP synthase; SS-31, Szeto-Schiller-31 CJASN 17: 1050–1069, July, 2022 Pathophysiology of Sepsis-Associated AKI, Kuwabara et al that sepsis is a heterogeneous disorder Investigators are recognizing that subphenotypes exist (22) that could permit stratification and enrichment of populations to specific targeted interventions In adult respiratory distress syndrome, interventions for the most part have proven ineffective However, it is important to consider that adult respiratory distress is a heterogeneous syndrome that is characterized by subphenotypes In two randomized clinical trials, systemic paralysis and heavy sedation (23) or prone position (24) resulted in favorable outcomes in a severe phenotype of adult respiratory distress syndrome on the basis of PaO2/FiO2 ratio (24) Recently, Chaudhary et al used deeplearning techniques and identified three distinct subphenotypes of patients with sepsis-associated AKI by analyzing routinely measured laboratory tests and vital signs (25) These three clusters differed with regard to comorbidities, laboratory tests, vital signs, and mortality Thus sepsisassociated AKI is a complex syndrome consisting of subphenotypes Prognostic enrichment may reduce this heterogeneous population to more homogeneous populations of patients with sepsis-associated AKI to improve the efficacy of targeted therapeutic interventions The pathophysiology of sepsis-associated AKI has been reviewed recently (26–29); in this review, we discuss newly identified targets that further expand our understanding of the fundamental mechanisms of sepsis-associated AKI from the perspective of microcirculatory dysfunction, inflammation, and metabolic reprogramming (Table 1) Lastly, we Pathogens 1053 describe the relationship between sepsis-associated AKI and coronavirus disease 2019 (COVID-19) Overview of Sepsis-Associated AKI Activation and Suppression of the Immune System An overview of the pathogenesis of sepsis-associated AKI is depicted in Figure After bacterial infection, a hyperactive dysregulated innate immune response leads to a cascade of proinflammatory molecules activating the complement system, and cellular innate immunity that contributes to sepsis-associated AKI Cell death pathways and immune cells are activated, leading to infiltration of T cells, macrophages, and neutrophils, and amplification of tissue injury (30–32) Early events trigger innate immunity through the host response to danger-associated molecular patterns (DAMPs; normally endogenous “hidden” intracellular molecules that are released by dying or damaged cells and activate the immune system) or pathogen-associated molecular patterns (small molecular motifs, including LPS, flagellin, double-stranded RNA, and CpG DNA) (33), which are ligands for pattern recognition receptors, such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I–like receptors (34,35) Early deaths are a result of a hyperinflammatory “cytokine storm” response leading to circulatory collapse, lactic acidosis, and hypercatabolism Both the initial degree of inflammatory response and early deaths depend on a number of factors, including patient comorbid • Age • Gender • Genetic background • Comorbid conditions PAMPs DAMPs AKI Sepsis • MicroRNAs • Extracellular vesicles • Autophagy/efferocytosis • Inflammatory reflex pathway • Vitamin D • Metabolic reprogramming Cytokine storm • Macrocirculatory dysfunction • Microcirculatory dysfunction • Pericyte loss • NOD-like receptor protein inflammasome • MicroRNAs • Extracellular vesicles • Metabolic reprogramming • Mitochondrial damage • Nephrotoxins Figure | Overview of the pathophysiology of sepsis-associated AKI Key factors that provide pro- or anti-inflammatory effects on the kidneys during sepsis contribute to the pathophysiology of sepsis-associated AKI DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns 1054 CJASN Pericyte Normal peritubular capillary flow Endothelium Macrophage Normoxic capillary Monocyte Proximal capillary Region of hypoxia Neutrophil Lymphocyte Red blood cell Hypoxic capillary Region of hypoxia Platelet Cell adhesion molecule Myofibroblast Pericyte detachment Pericyte-to-myofibroblast transdifferentiation Immune cell infiltration Leukostasis Figure | Microcirculatory dysfunction and pericyte loss A possible model of microcirculatory dysfunction resulting from activation of adhesion molecules leading to leukostasis, degranulation of leukocytes, and release of chemokines, cytokines, and reactive oxygen species Endothelial injury and pericyte loss develop during sepsis-associated AKI Leukostasis leads to regions of hypoxia and further injury During sepsis, detachment of pericytes and pericyte-to-myofibroblast transdifferentiation are promoted in the capillaries around the proximal tubules, which could further induce immune cell infiltration into the interstitial space, leukostasis, and hypoxia, even in the early phase of infection These events might be a leading cause of microcirculatory abnormalities and subsequent kidney injury conditions, genetic background, and inflammatory factors such as pathogen virulence and bacterial burden (36) Subsequently, there is mitochondrial dysfunction (37), apoptosis (38), and other forms of regulated cell-death pathways, such as ferroptosis, necroptosis, and pyroptosis (39) Events later in sepsis-associated AKI include organ crosstalk and pronounced immunosuppression (10,36,40,41) Spleens and lungs, harvested 30–180 minutes after death from patients who had multiple organ failures (circulatory, hepatic, renal), and succumbed in the ICU, had immune cells with decreased production of pro- and anti-inflammatory cytokines (41,42) Reduced cytokine secretion including TNF-a, IL-6, and IL-10, and increased regulatory T cells, a feature of T cell exhaustion, were observed in the spleen (42) Lung epithelial cells also showed a severe increase in ligands or molecules for inhibitory receptors, such as programmed cell death ligand (42); binding to its target inhibitory receptor, PD-1, dampens the immune response These results characterize a condition of profound immunosuppression and evidence for T cell exhaustion in the late phase of sepsis (41,42) and provide the rationale for immunotherapy and the use of immune checkpoint inhibitors in patients with sepsis-associated immunosuppression (41) However, effective immunotherapeutic strategies regulating inflammation during sepsis have not been established in clinical use, but are underway (43) CJASN 17: 1050–1069, July, 2022 Pathophysiology of Sepsis-Associated AKI, Kuwabara et al 1055 Paracrine signaling? PAMPs, DAMPs Panx1 P2X7 Inflammation P2X7 TLR ATP Changes in mitochondrial function and energy metabolism? Pro-IL-1E IL-1E Caspase-1 NLRP3 inflammasome Figure | NOD-like receptor protein (NLRP3) inflammasome NLRP3 inflammasome plays a central role in the promotion of inflammatory responses during sepsis Pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) activate the NLRP3 inflammasome, which might be mediated by the disturbance of mitochondrial homeostasis and metabolic reprogramming The extracellular release of ATP through pannexin-1 (Panx1) and its binding to the P2X7 receptor also promotes the maturation of IL-1b in the kidney TLR, toll-like receptor Microcirculatory Dysfunction and Pericyte Loss Previously, sepsis-associated AKI was thought to be due to a disorder of macrocirculation in which hypotension and decreased kidney blood flow (RBF) resulted in acute tubular necrosis (44) The predominant causal feature in sepsisassociated AKI was thought to be generalized arterial vasodilation associated with a decrease in systemic vascular resistance (45) In sepsis-associated AKI, decreased RBF is a consistent finding in rodent models, but there is now substantial evidence that global RBF is preserved or even increased during the development of kidney injury in large animals and humans (28,46,47) In systematic analysis, RBF was increased in three human studies of sepsis, but decreased in 62% of 159 animal studies or had either no change or increased in 38% of these animal studies (48) These observations emphasize mechanisms of injury despite maintained RBF incuding the importance of the microcirculation Microvascular function is a major contributor to the microcirculation (26), and, despite maintenance of sustained RBF, altered microcirculatory flow may lead to altered kidney tissue hypoperfusion Using intravital video microscopy, Wu et al demonstrated that peritubular capillary flow was compromised in LPS-induced sepsis (49) Peritubular capillary flow decreased by 88%, intermittent flow increased by 400%, and no flow increased by approximately 300% Using multiparametric photo-acoustic microscopy, a novel tool that can measure real-time changes in microhemodynamics and oxygen metabolism, our group showed that sepsis induced an acute and significant reduction in peritubular capillary oxygen saturation of hemoglobin, concomitant with a marked reduction in kidney ATP levels (50) These intravital studies demonstrate that sepsis altered microvascular flow, resulting in tissue hypoxia and compromised bioenergetics The microvascular dysfunction is heterogeneous and relates to patchy areas of leukostasis, with associated changes in oxygen extraction (metabolic rate of oxygen) (49,50) These studies show local microvascular dysfunction and patchy areas of oxygen saturation, likely related to endothelial dysfunction and inflammatory and other oxidative factors (51) Although much has been written about the inflamed local microenvironment and its contribution to microvascular dysfunction during sepsis (29,49,50,52) (Figure 2), an understanding of the contribution of pericytes to the pathophysiology of sepsis-associated AKI is still lacking Pericytes, which intermittently surround capillary endothelial cells to maintain microvascular homeostasis including blood flow and vascular permeability, are considered the main source of myofibroblasts in CKD with progressive fibrosis (53,54) One study using a rat AKI model demonstrated that pericyte density in the kidney medulla decreased after ischemia-reperfusion, which induced vascular congestion (55) Using a genetic model to selectively ablate 90% of kidney pericytes but no other cell lineages, 1056 CJASN there was worsening AKI, lipid accumulation, and apoptosis of tubule epithelial cells (56) Detachment of Gli11 cells, a major subset of pericytes, from endothelial cells after AKI was associated with endothelial cell damage and reduced capillary number (57) These results suggest pericytes could be implicated in the heterogeneity of microcirculatory abnormalities during the progression of sepsis-associated AKI (Figure 2), as supported by recently identified molecular mechanisms underlying sepsis-associated dysfunction of kidney pericytes For instance, the transcriptional factor Friend leukemia virus integration as a target of miR-145a promoted kidney pericyte loss and vascular leakage via activation of NF-kB signaling in a murine cecal ligation puncture model (58,59) In a swine model of LPS-induced AKI, pericyte-to-myofibroblast transdifferentiation was observed within hours after LPS challenge and might be mediated by the secretion of LPS-binding protein and subsequent stimulation of TLR4 signaling in pericytes (60) Moreover, global sirtuin (which controls key metabolic pathways by activating mitochondrial enzymes involved in the respiratory chain, in ATP production, and in both the citric acid and urea cycles) knockout mice exhibited increased vascular permeability in the lung, heart, kidney, and brain after LPS treatment (61) Angiopoietins/Tie-2 and hypoxia-inducible factor-2a/Notch3 signaling were identified as downstream pathways of sirtuin 3, leading to LPSinduced pericyte loss in the lung; the same pathways may function in the kidney Further investigation of the relationship between pericyte-mediated regulation of microvasculature and GFR reduction during the development of sepsis is necessary to better understand sepsis-associated AKI Inflammation NOD-Like Receptor Protein Inflammasome Disruption of the innate immune system has profound effects on sepsis-induced organ dysfunction (27,30,62) In response to infection, pathogen-associated molecular patterns and DAMPs bind to TLRs on the cell surface and promote the release of proinflammatory cytokines (33,63–66) In addition to these factors, the cytoplasmic NOD-like receptor protein (NLRP3) inflammasome is integral to the inflammatory cascade in sepsis-associated AKI (65–77) (Figure 3) The NLRP3 inflammasome activates caspase-1 facilitating the maturation of IL-1b and IL-18, which exacerbates inflammation (65,66,78,79) In a mouse model of sepsis, NLRP3 knockout reduced caspase1 and IL-1b/IL-18 levels in the kidney and attenuated kidney injury (69) In contrast, a protective effect of NLRP3 knockout was not observed in a cisplatin-induced AKI model (70), suggesting that the activation of NLRP3 inflammasome during the development of kidney injury may be context dependent Furthermore, recent investigations have shown that cellular energy metabolism, especially in ATP metabolism, is pivotal for regulating the NLRP3 inflammasome (71,72) Pannexin-1, a transmembrane channel for the transport of ATP and other small molecules, was highly expressed in the kidney tissue of LPS-treated mice and patients with sepsis-associated AKI, and its inhibition prevented the activation of the NLRP3 inflammasome (71) The administration of an ATP-gated P2X7 receptor antagonist (A-438079) also decreased kidney IL-1b in a rat model of sepsis (72) Because extracellular ATP released from pannexin-1 or from injured cells can stimulate P2X7 as a DAMP (66,67), pannexin-1 and P2X7 could play a role in the transduction of inflammatory signaling to neighboring cells Modulators of the NLRP3 inflammasome (sirtuin 1, sirtuin 3, parkin, and dynamin-related protein 1) in experimental models of murine sepsis were mostly associated with mitochondrial function, the main source of ATP (73–77) In summary, the NLRP3 inflammasome is central to the inflammatory cascade in sepsis-activated innate immunity and should be considered as an important target for therapeutic intervention in sepsis-associated AKI MicroRNAs Emerging evidence suggests that microRNAs (miRNAs), small noncoding RNAs composed of about 22 nucleotides, are critical for the pathophysiology of both sepsis and AKI (80–84) miRNAs repress target protein expression at the post-transcriptional level, which controls cellular functions such as cell development, differentiation, metabolism, inflammatory responses, and cell death (80–84) The clinical importance of miRNAs is the emergence of their role in disease states including sepsis-associated AKI Previously, clinical studies unsuccessfully targeted single molecules (e.g., TNF-a), but we now know that a single RNA makes more than one protein Thus, one miRNA candidate has the ability to regulate entire pathogenic biologic pathways (85), potentially rendering the candidate miRNA more effective Recent clinical studies have identified several miRNAs that are increased or decreased in patients with sepsis-associated AKI (86–96) (Table 2) Several miRNAs (miR-4321, -4270, -15a–5p, -15b–5p, and -16–5p) are involved in the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin signaling pathway (87,94), emphasizing the importance of cellular metabolic processes in the development of sepsis-associated AKI During kidney ischemia-reperfusion injury, miR-494 increased in the urine before the rise in creatinine and exacerbated inflammation by inhibiting activating transcription factor (ATF3) (97,98) Liu et al also showed increased miR-452, a target gene of NF-kB, in the serum and urine before kidney dysfunction in LPS- and cecal ligation puncture–induced AKI murine models (92) Tod et al found changes in miRNAs in sepsis-associated AKI from miRNA microarray analysis of LPS-treated mice (99) In the early phase (at 1.5 and hours after LPS injection), the most elevated miRNA in the kidney was miR-762, whereas the expression of miR-144–3p was significantly increased in the late phase (at 24 hours after LPS injection) Subsequent proteome analysis revealed that downstream targets of miR-762 and miR-144–3p might be the secretion-associated Ras-related GTPase 1B and aquaporin-1, respectively Similarly, miR-34–5b, which was elevated in the serum of patients with sepsis-associated AKI, suppressed the expression of aquaporin-2 in tubular epithelial cells (93) These observations indicate that miR-494, miR-452, and miR-762 could be early predictors of sepsisassociated AKI pathogenesis, and regulation of aquaporin expression by miR-144–3p and miR-34–5b might be critical for the homeostasis of kidney microcirculation Although miRNAs are not Food and Drug Administration approved CJASN 17: 1050–1069, July, 2022 Table Pathophysiology of Sepsis-Associated AKI, Kuwabara et al 1057 MicroRNAs in sepsis-associated AKI MicroRNA Increased miR-107 Sample Control Target Pathway Reference CECs Healthy volunteers, nonseptic AKI, septic non-AKI DUSP7 (86) miR-4321 Serum Healthy volunteers, septic non-AKI AKT1, mTOR, NOX5 (87) miR-4270 Serum Healthy volunteers, septic non-AKI PPARGC1A, AKT3, NOX5, PIK3C3, WNT1 (87) miR-29a Serum Septic non-AKI Unknown (88) miR-10a-5p Serum Septic non-AKI Unknown (88) miR-26b Urine Septic non-AKI Unknown (89) miR-210 Plasma Healthy volunteers Unknown (90) miR-494 Plasma Healthy volunteers Unknown (90) miR-152–3p Serum Healthy volunteers ERRFI1, STAT3 (91) miR-452 Serum, Urine Healthy volunteers, septic non-AKI Unknown (92) miR-34b–5p Serum Healthy volunteers AQP2 (93) Plasma Healthy volunteers Unknown (90) miR-15a–5p Serum Healthy volunteers, septic non-AKI mTOR signaling (94) miR-15b–5p Serum Healthy volunteers, septic non-AKI mTOR signaling (94) miR-16–5p Serum Healthy volunteers, septic non-AKI PI3K/AKT/mTOR signaling (94) miR-376b Urine Healthy volunteers, septic non-AKI NFKBIZ (95) miR-150–5p Serum Healthy volunteers MEKK3/JNK pathway (96) Decreased miR-205 Title of the Reference MiR-107 induces TNF-a secretion in endothelial cells causing tubular cell injury in patients with septic AKI Differentially expressed miRNAs in sepsis-induced AKI target oxidative stress and mitochondrial dysfunction pathways Differentially expressed miRNAs in sepsis-induced AKI target oxidative stress and mitochondrial dysfunction pathways Predictive value of miRNA-29a and miRNA-10a–5p for 28-day mortality in patients with sepsisinduced AKI Predictive value of miRNA-29a and miRNA-10a–5p for 28-day mortality in patients with sepsisinduced AKI Urinary miR-26b as a potential biomarker for patients with sepsisassociated AKI: a Chinese population-based study Expression patterns and prognostic value of miR-210, miR-494, and miR-205 in middle-aged and old patients with sepsis-induced AKI Expression patterns and prognostic value of miR-210, miR-494, and miR-205 in middle-aged and old patients with sepsis-induced AKI A novel role of the miR-152–3p/ ERRFI1/STAT3 pathway modulates the apoptosis and inflammatory response after AKI Discovery and validation of miR-452 as an effective biomarker for AKI in sepsis miR-34b–5p promotes renal cell inflammation and apoptosis by inhibiting AQP2 in sepsis-induced AKI Expression patterns and prognostic value of miR-210, miR-494, and miR-205 in middle-aged and old patients with sepsis-induced AKI The miR-15a–5p-XIST-CUL3 regulatory axis is important for sepsis-induced AKI The miR-15a–5p-XIST-CUL3 regulatory axis is important for sepsis-induced AKI The miR-15a–5p-XIST-CUL3 regulatory axis is important for sepsis-induced AKI The negative feedback loop of NFkB/miR-376b/NFKBIZ in septic AKI MiR-150–5p protects against septic acute kidney injury via repressing the MEKK3/JNK pathway miRNA, microRNA; CECs, circulating endothelial cells; DUSP7, dual-specificity phosphatase 7; AKT1, AKT serine/threonine kinase 1; mTOR, mammalian target of rapamycin; NOX5, NADPH oxidase; PPARGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; WNT1, WNT family member 1; ERRFI1, ERBB receptor feedback inhibitor 1; STAT3, signal transducer and activator of transcription 3; AQP2, aquaporin-2; PI3K, phosphatidylinositol-3-kinase; NFKBIZ, NF-kB inhibitor z; MEKK3, mitogen-activated protein kinase 3; JNK, c-Jun N-terminal kinase 1058 CJASN Roles Origins ATF3 ? Diagnosis Septic damage Extracellular vesicles Components Brain (neurons and astrocytes) ? Function Plasma after thorax trauma Apoptotic bodies M2 macrophages/ endothelial progenitor cells Exosomes VCAM-1, E-selectin, cytokines, etc miR-93-5p Therapy Adipose tissue-derived mesenchymal stem cells Microvesicles ? Multivesicular body DNA/RNA microRNA Protein Figure | Extracellular vesicles Shown here are examples of sepsis-associated AKI-associated extracellular vesicles that are identified from recent studies The origins of extracellular vesicles are heterogeneous Extracellular vesicles provide diagnostic, functional, and therapeutic roles in sepsis-associated AKI Urinary exosomes (smaller extracellular vesicles) containing activating transcription factor (ATF3) are upregulated in patients with sepsis-associated AKI and are an example of an extracellular vesicle biomarker in AKI Brain- and plasmaderived (on thorax trauma) extracellular vesicles promote kidney inflammation, an example of extracellular vesicle functional role In addition, extracellular vesicles from M2 macrophages, endothelial progenitor cells, and adipose tissue-derived mesenchymal stem cells induce an anti-inflammatory effect on the kidney The latter also indicates a regenerative or therapeutic role VCAM-1, vascular cell adhesion molecule for clinical intervention, miRNA candidate drugs are in clinical development in phase and phase trials (100) Extracellular Vesicles There is a growing interest in extracellular vesicles as potential biomarkers and bioregulators of kidney diseases (101–106) (Figure 4) Extracellular vesicles are lipid bilayerenclosed particles that can be released from most cell types and contain a variety of molecules, such as DNAs, RNAs, miRNAs, proteins, lipids, and other cytosolic components They can be classified into three types according to their biogenesis and size: exosomes (30–100 nm), microvesicles (100–1000 nm), and apoptotic bodies (50–5000 nm) The biologic characteristics of extracellular vesicles vary across the cell types of origins, thus extracellular vesicles can have not only diagnostic value, but also functional (e.g., proinflammatory) and therapeutic (e.g., anti-inflammatory) effects on neighboring cells or distant organs Changes in extracellular vesicle counts and their components have been detected during sepsis, AKI (103–106), and sepsisassociated AKI For example, compared with healthy volunteers and patients who are septic without AKI, patients with sepsis-associated AKI showed higher levels of urinary extracellular vesicles containing ATF3 in the early phase of sepsis (107) This increase is not consistent with the fact that ATF3 expression is repressed by miR-494, and urinary miR-494 was elevated during AKI (97,98); however, the finding that miRNAs contribute to the determination of extracellular vesicle release and intracellular retention (108) may be the key to clarifying the relationship between miR494 and exosomal ATF3 Lin et al demonstrated the functional effect of brain-derived extracellular vesicles (mainly from neurons and astrocytes) on kidney tissue in sepsis; treatment with brain-derived extracellular vesicles exacerbated sepsis-induced injury and apoptosis in the kidney of rats (109) Moreover, Seibold et al suggested that extracellular vesicles secreted on thorax trauma are strongly associated with sepsis and biochemical markers of AKI (110) The authors further showed the thorax trauma–responding extracellular vesicles might originate from endothelial cells and contain endothelial activators, such as vascular cell adhesion molecule 1, E-selectin, and cytokines (110) In contrast, there is some evidence for therapeutic roles of extracellular vesicles during sepsis-associated AKI In a murine sepsis model, miR-93–5p–expressing extracellular vesicles derived from M2 (anti-inflammatory) macrophages and endothelial progenitor cells protected the kidney against injury (111,112) In addition, extracellular vesicles from adipose tissue–derived mesenchymal stem cells reduced sepsis-induced kidney cell injury, but the principal component of extracellular vesicles responsible for the protection of the kidneys has not been identified (113) Cell-based therapies for clinical disorders have led the way to extracellular vesicle research and the potential for the use of extracellular vesicles therapeutically Extracellular vesicles therapies offer a number of advantages over cellbased therapies, including less immunogenicity, longer shelf CJASN 17: 1050–1069, July, 2022 Pathophysiology of Sepsis-Associated AKI, Kuwabara et al Autophagy Efferocytosis Sirtuin tio n mTOR signaling IgM-AIM De ac et y la PI3K signaling 1059 BCR p53 PI3k/Akt pathway ULK1 complex PI3K mTOR Deacetylation Sirtuin Glomerulus MAPK/ERK pathway Cytosolic components Filtered AIM Dying cell Shed KIM-1 Initiation Elongation ATG12 ATG12 Maturation LC3-III LC3-II ATG10 ATG16 ATG7 ATG7 ATG3 ATG12 system Cleavage LC3-I ATG4 ATG5 ATG16 ATG5 Autophagosome ATG8 system Engulfment Recovery from septic damage Figure | Autophagy and efferocytosis Boosting autophagy or efferocytosis has the potential to protect kidney cells against septic damage Autophagic flux consists of a variety of proteins such as ATG12-ATG5-ATG16L system and the microtubule-associated protein light chain (MAP1LC3 [LC3]) system Among these factors, LC3 and autophagy-related gene (Atg7), which are involved in the maturation of an autophagosome, are suggested to ameliorate lung and kidney injury during sepsis, respectively Sirtuin and deacetylated p53 by sirtuin facilitate the elongation of a phagophore, and their activation also leads to kidney protection As well as autophagy, efferocytosis can provide anti-inflammatory effects via the removal of dying cells During AKI, apoptosis inhibitor of macrophage (AIM) dissociated from IgM is filtered through the glomerulus followed by the binding with dying cells The complex of AIM and dying cells then interact with kidney injury molecule–1 (KIM-1) expressed on the tubular cells Cells engulf these complexes, which attenuates sepsis-induced damage BCR, B cell receptor; PI3K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin; ULK1, unc-51 like autophagy activating kinase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal–regulated kinase life, lack of replication, and reduced tumor risk (114) Despite these advantages, there are still gaps in our knowledge that require continued investigations; for example, we need to better understand precise cell targeting properties and targeting uptake mechanisms to deliver to specific intracellular sites Furthermore, because extracellular vesicles are a heterogeneous population, extracellular vesicle subphenotypes could offer distinct therapeutic advantages (114) Autophagy and Efferocytosis Autophagy is a conserved process by which damaged internal organelles and cytoplasmic components, such as mitochondria, are processed by lysosomal degradative pathways to facilitate cell survival; a successful and limited autophagy response triggers an anti-inflammatory response and tissue repair (115,116) (Figure 5) The autophagosome complex consists of serine/threonine protein kinases ULK1, ULK2, the class III phosphatidylinositol-3–kinase complex, two ubiquitin-like conjugation systems, the ATG12-ATG5ATG16L system, and the microtubule-associated protein light chain (MAP1LC3 [LC3]) system (115,116) Mice that are deficient in the autophagy LC3 gene are more susceptible to sepsis-induced mortality (117) LC3 overexpression improved survival and reduced lung injury through increased autophagosome clearance (118) Autophagy is activated during sepsis and AKI (119,120) and plays a protective role in sepsis-associated AKI (121) Mei et al., using both pharmacologic inhibitors and mouse models, demonstrated a critical role of autophagy in sepsis-associated AKI (122) Chloroquine, an inhibitor of autophagy, worsened LPS-induced AKI Furthermore, proximal tubule-specific autophagy-related gene knockout mice displayed more severe kidney damage 24 hours after LPS treatment compared with wild-type mice In addition, overexpression of the stress-responsive histone deacetylase, sirtuin 6, induces autophagy, inhibits apoptosis, and has a protective effect in kidney tubule cells after LPS treatment (123) Pretreatment with the autophagy agonist, rapamycin, attenuated kidney tubule damage in a mouse sepsis model, whereas administration of the autophagy inhibitors, 3-MA and chloroquine, 1060 CJASN Brain C1 neurons NTS Other C1 target areas DMV Jugular/nodose ganglia Electrical VNS Sympathetic preganglionic neuron Efferent vagus nerve Afferent vagus nerve Ultrasound Celiac/suprarenal ganglia Peripheral organ Spleen Macrophages ChAT-positive T cells Splenic nerve NE E2-adrenergic receptor ACh Anti-inflammation D7nAChR Figure | Inflammatory reflex pathway The original description of the inflammatory reflex consisted of afferent vagus nerve fibers transmitting danger signals to the nucleus tractus solitarius (NTS) from the periphery, efferent vagus nerve arising in the dorsal motor nucleus of the vagus (DMV), splenic nerve, norepinephrine (NE) release in the spleen, activation of choline acetyltransferase (ChAT)–positive T cells expressing b2-adrenergic receptors, and activation of a7 nicotinic acetylcholine receptors (a7nAChRs) on macrophages, leading to suppression of proinflammatory cytokine release and reduced inflammation and/or tissue injury Recent studies have shown that the reflex is much more complicated than previously thought For example, in addition to activation of the cholinergic anti-inflammatory pathway (CAP) by a vagal preganglionic efferent pathway, stimulation of brainstem C1 neurons, which protects kidneys from ischemia-reperfusion injury (IRI), elicits activation of the CAP via a sympathetic efferent pathway (191) that involves known C1 projections to sympathetic preganglionic neurons These innervate sympathetic ganglia, such as the celiac and suprarenal ganglia, or via other C1 projections in the brain that would stimulate a sympathetic pathway (145,191) Either electrical vagus nerve stimulation (144,145) or pulsed ultrasound (146,147) is thought to activate the inflammatory reflex pathway and attenuate inflammation and AKI and sepsis-associated AKI Dashed lines represent unconfirmed pathways, and solid lines represent confirmed pathways a7nAChR, alpha nicotinic acetylcholine receptors; ACh, acetylcholine significantly worsened kidney injury (124) Additionally, Sun et al clarified the role of p53, which has been previously shown to play a role in various forms of AKI during sepsis-associated AKI (124,125) Although the expression of p53 protein did not change in HK-2 cells (a human cell line derived from normal proximal tubular epithelial cells) or in the kidney cortex, there was an increase in p53 translocation from the nucleus to the cytoplasm, along with an increase in p53 acetylation in sepsis models (124) Deacetylation of p53 by sirtuin promoted autophagy and alleviated kidney damage in septic mice (124) Efferocytosis refers to the clearance of dead or dying cells by professional or nonprofessional phagocytes (126–128) (Figure 5) Apoptosis, necroptosis, pyroptosis, or ferroptosis are types of programmed cell death, depending on specific conditions; once activated, cellular clearance is necessary Dying cells need to be removed quickly to prevent the release of DAMPs, which exacerbate inflammation resulting in worsening tissue damage (126–128) For apoptotic cells, exposure of phosphatidylserine on cell membranes leads to engulfment by phagocytic cells Inflammatory mediators released by dying cells during AKI (primarily proximal tubule cells) attract infiltrating immune cells and exacerbate tissue injury Specific molecules that are involved in the recognition of necrotic cells by phagocytes assist in resolution of AKI Apoptosis inhibitor of macrophage (AIM) is a member of the scavenger receptor cysteine-rich domain superfamily Most circulating AIM is bound to IgM pentamers, which prevents its kidney excretion (129–131) However, during AKI, AIM dissociates from IgM, through unknown mechanisms, and is filtered through the glomerulus (132) AIM then accumulates on necrotic cell debris within the kidney proximal tubules and binds to kidney injury molecule–1 (KIM-1), a well-known urinary biomarker of tubular injury (132–134) This interaction enhances KIM-1–mediated phagocytic removal of the debris In AIM knockout mice, there CJASN 17: 1050–1069, July, 2022 Physiological condition Pathophysiology of Sepsis-Associated AKI, Kuwabara et al Early phase of sepsis SS-31 Late phase of sepsis ? Glycolysis Septic damage 1061 Glycolysis OXPHOS OXPHOS PGC-1D Proximal tubule Recovery Mitochondrial biogenesis ? Glycolysis OXPHOS PINK1/PARK2 Mitophagy Mdivi-1 Drp1 Mitochondrial fission Severe injury ? cGAS-STING Inflammation Figure | Overview of metabolic reprogramming and mitochondrial function in sepsis-associated AKI The principal pathway of energy production in kidney cells switches from oxidative phosphorylation (OXPHOS) to glycolysis in the early stage of sepsis A functional changes in mitochondria in this phase may determine the extent of kidney injury in the later stage Mitochondrial biogenesis through PPARg coactivator-1a (PGC-1a) and the removal of damaged mitochondrial via mitophagy mediated by the PTEN-induced kinase (PINK1)/Parkin RBR E3 ubiquitin protein ligase (PARK2) may allow cells to return to using OXPHOS, followed by the recovery from injury In contrast, abnormal mitochondrial dynamics, such as an increase in dynamin-related protein (Drp1), exacerbate sepsis-associated AKI In response to the mitochondrial damage, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is also activated, which accelerates inflammation in kidney cells Lastly, Szeto-Schiller-31 (SS-31; antioxidant) and Mdivi-1 (Drp1 inhibitor) have potential as therapeutic drugs for sepsis-associated AKI via the attenuation of mitochondrial damage is a decrease in necrotic cell clearance and persistent kidney inflammation after AKI, leading to higher mortality due to progressive kidney dysfunction Recombinant AIM resulted in removal of debris, with improved kidney pathology after AKI (132) These results suggest the potential therapeutic benefit of enhancing efferocytosis of dying cells to improve outcomes in sepsis-associated AKI (135) Inflammatory Reflex Pathway Neuroimmunomodulation plays a key role during inflammation (136,137) Inflammatory signals in peripheral tissues are transmitted by afferent fibers of vagus nerve toward the central nervous system, which activates the cholinergic antiinflammatory pathway through vagus efferent fibers (138–140) (Figure 6) Various studies have demonstrated that an anti-inflammatory effect of that pathway is mediated by splenic nerve, CD41 T cells expressing choline acetyltransferase, and a7 nicotinic acetylcholine receptor–positive macrophages in the spleen (136–143) Recently, Inoue et al showed that electrical vagus nerve stimulation significantly reduced plasma TNF-a levels elicited by LPS administration and protected the kidney from ischemia-reperfusion injury (144) Furthermore, the precise neural circuits involved in vagus nerve stimulation–induced kidney protection were identified; efferent or afferent stimulation was adequate to protect the kidney, and afferent vagus nerve stimulation activated the C1 neurons (in the medulla oblongata)–sympathetic nervous system–splenic nerve–spleen–kidney axis (145) We also found that pulsed ultrasound activates the cholinergic anti-inflammatory pathway and ameliorates mouse kidney damage in both an ischemia-reperfusion 1062 CJASN A Drug X 90 patients - no benefit drug exposure 10 patients - benefit B Drug X Genomics RNA-Seq Proteomics Metabolomics Biomarkers Clinical data Drug Y Drug Z 10/10 benefit 10/10 benefit 10/10 benefit Figure | Precision approach to therapies in sepsis-associated AKI Ineffective therapies in sepsis-associated AKI are due to the complexity of pathogenesis and the heterogeneity of the critically ill population (A) Traditionally, clinical trials randomly assign this heterogeneous group to a therapeutic intervention with limited success (B) Enrichment approaches through genomics, RNA sequencing, proteomics, metabolomics, and biomarkers will identify molecular endophenotypes, and clinical and laboratory parameters may identify subphenotypes that are responsive to specific targeted interventions (theoretical Drug X, Y, and Z) yielding greater likelihood of treatment response The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) Kidney Precision Medicine Project (KPMP) focuses in part on obtaining kidney biopsies safely in patients with AKI to interrogate molecular targets and identify endophenotypes injury model and a sepsis model of AKI (146,147) These findings indicate that strategies for the activation of the inflammatory reflex pathway have great potential to attenuate ischemic AKI and sepsis-associated AKI There are ongoing clinical trials evaluating the protective effect of vagus nerve stimulation on inflammatory diseases (e.g., rheumatoid arthritis [148] and inflammatory bowel diseases [149]) and the approved clinical usage of ultrasound devices Pulsed ultrasound using Food and Drug Administration–approved parameters is portable and nonpharmacologic, thus avoiding off-target side effects Vitamin D The main circulating metabolite of vitamin D is 25hydroxyvitamin D, which serves as a marker for evaluation of vitamin D status and is metabolized in the kidney by the enzyme 25-hydroxyvitamin D-1a–hydroxylase to its active form, 1,25-dihydroxyvitamin D (150,151) Accumulating evidence suggests an association between vitamin D actions and anti-inflammation in the kidney (152–154) In humans, vitamin D deficiency is highly prevalent in patients who are critically ill and has been associated with increased rates of sepsis, an observation that provides the rationale for its use in sepsis-associated AKI (155) In preclinical studies, vitamin D and its receptor are also considered to be a therapeutic target for kidney injury (156,157) In a murine LPSinduced AKI model, genetic deletion of vitamin D receptor induced higher levels of serum creatinine, proinflammatory cytokines, such as TNF-a and IL-1b in the cortex, and tubular cell apoptosis than littermate controls (153) These alterations during LPS-induced AKI have also been observed in mice fed a vitamin D–deficient diet (154) Furthermore, pretreatment with vitamin D analogs (paricalcitol, calcitriol, and cholecalciferol) before exposure to various causes of AKI including LPS, cisplatin, and ischemia-reperfusion protects kidneys against injury in these experimental preclinical models and could serve as a potentially promising therapeutic approach (153,154,158,159) Despite the results of animal studies, a randomized clinical trial in patients who are critically ill with sepsis demonstrated that a single administration of calcitriol to patients who were septic failed to decrease plasma proinflammatory cytokines and urinary neutrophil gelatinase-associated lipocalin and KIM-1 within 48 hours compared with patients who were placebo treated (160) Although it is essential to take into account the fact that both low and high doses of vitamin D can be a risk factor for AKI (161), vitamin D administration in the early stage of sepsis might be important to prevent sepsis-associated AKI Additional studies are necessary to determine the role of vitamin D in sepsis-associated AKI Metabolic Reprogramming and Mitochondrial Function Metabolic reprogramming during sepsis-associated AKI can have a major effect on outcomes, but this process CJASN 17: 1050–1069, July, 2022 remains incompletely understood (162,163) As a key player in energy production, mitochondria contributes importantly to the pathophysiology of sepsis-associated AKI (164) (Figure 7) Under physiologic conditions, proximal tubule cells use aerobic respiration for ATP production; however, early in sepsis, cells switch to using glycolysis (162,163,165,166) This shift can serve a few functions Aerobic glycolysis can provide sufficient energy for vital functions to avoid cell death, while also allowing for the reallocation of energy to critical processes including macromolecule synthesis Additionally, this can reduce mitochondrial damage caused by reactive oxygen species production during oxidative phosphorylation This early metabolic switch is followed by a late anti-inflammatory catabolic phase in which tubule cells return to using oxidative phosphorylation Using a sepsis model in mice, mitochondrial oxygen consumption in proximal tubules hours after sepsis was decreased, whereas mitochondrial content and biogenesis markers were increased (167) After 24 hours, these markers were decreased, and mitochondria displayed high respiratory capacity Moreover, the enhancement of mitochondrial biogenesis through PPARg coactivator-1a may be essential during recovery from sepsis-associated AKI (168) These differing metabolic adaptations in early and late sepsis-associated AKI are crucial and can determine the extent of damage, including organ dysfunction and progression to CKD Recent studies have identified potential mechanisms of mitochondrial damage during sepsisassociated AKI (169–173) There appears to be an increase in mitochondrial fragmentation, mediated by an upregulation of the mitochondrial fission gene, dynamin-related protein 1, during sepsis (169) In support of this finding, proximal tubule-specific deletion of dynamin-related protein attenuated kidney ischemia-reperfusion injury, inflammation, and programmed cell death and promoted epithelial recovery; loss of dynamin-related protein preserved mitochondrial structure and reduced oxidative stress in injured kidneys (170) Dysfunctional mitochondria are normally removed by selective mitochondrial autophagy Activation of the PTEN-induced kinase 1/ Parkin RBR E3 ubiquitin protein ligase pathway of mitophagy is protective in experimental models of sepsisassociated AKI (171) Mitochondrial damage also activates the cyclic GMP-AMP synthase–stimulator of interferon genes pathway (172), and the severity of sepsis-induced AKI was lessened in cyclic GMP-AMP synthase– deficient mice (173) Furthermore, the Szeto-Schiller-31 peptide, an antioxidant, improves mitochondrial function and ameliorates AKI In a sepsis model, Szeto-Schiller-31 restored creatinine and blood urea nitrogen and reversed the sepsis-induced increase in reactive oxygen species and decrease in ATP levels (174) Another approach has focused on targeting mitochondrial dynamics In an LPSinduced sepsis-associated AKI model, the administration of Mdivi-1, a dynamin-related protein inhibitor, improved mitochondrial function and reduced NLRP3 inflammasome-mediated pyroptosis in tubular epithelial cells (76) Together, metabolic reprogramming associated with the disturbance of mitochondrial homeostasis is clearly an important feature during sepsis-associated AKI, and strategies targeting mitochondrial function may hold therapeutic promise in sepsis-associated AKI Pathophysiology of Sepsis-Associated AKI, Kuwabara et al 1063 Relationship between Sepsis-Associated AKI and COVID-19 In January 2020, the World Health Organization declared COVID-19 a public health emergency Kidney involvement is a common manifestation of the disease, and 25% of patients hospitalized for COVID-19 develop AKI (175,176) Studies have shown similarities between sepsis-associated AKI and COVID-19–associated AKI (177,178) For example, in both diseases, only modest tubular and glomerular damage is seen, despite profound changes in kidney function A recent study compared morphologic and molecular characteristics from postmortem samples of patients with sepsis-associated AKI and COVID-19–associated AKI (179) The transcriptional analysis demonstrated that both had enrichment of pathways involved in inflammation compared with nonseptic AKI Morphologic characteristics were also similar However, important distinctions exist Although a cytokine storm has been described in COVID19, a meta-analysis found that patients with sepsis had 27 times higher mean IL-6 concentrations than patients with COVID-19 (180) Another study found that levels of TNF-a, IL-8, and IL-6 were lower in patients with COVID-19 than in patients with sepsis (181) Additionally, thrombi and intravascular coagulation are features of COVID-19– associated AKI not commonly seen in sepsis-associated AKI, and concentrations of D-dimer (a fibrin degradation product after blood clot degradation) are five times higher in patients who have COVID-19 and are critically ill (180) Despite these differences, it is likely that what we have learned regarding the management of sepsis-associated AKI can be applied to COVID-19–associated AKI Clinical Implications Translating preclinical research into clinical care has been a major hurdle in improving treatment for AKI (182) Although we recognize the importance of timely administration of care bundles (5), the effect on AKI requires consideration of additional approaches and factors First, we need to better understand the pathophysiology of sepsisassociated AKI In addition to traditional targets such as TNF-a and IL-1b, development of novel pharmacologic agents and nonpharmacologic approaches (i.e., activating the inflammatory reflex pathway [146,147]) and targeting unique pathways will be important (Figure 1) Second, it is important to realize that patients with sepsis may have AKI unrelated to sepsis For example, antibiotics are universally administered to patients who are septic, resulting in nephrotoxic AKI Third, the pathogenesis is complex and, although preclinical studies utilizing various animal models may be useful, it also introduces additional complexities When examining activated gene sets from a mouse model of prerenal and intrinsic AKI, functionally unrelated signal transduction pathways were identified and were localized in different cell types in the kidney (183,184) Compared with AKI with nonseptic etiologies, the pathophysiology of sepsis-associated AKI is complex; microarray studies using various rodent models of AKI showed that the LPS-induced sepsis-associated AKI had the largest number of uniquely altered genes compared with nonseptic AKI (185) Most of these genes were 1064 CJASN associated with mitochondria, whereas unique genes in an ischemia-reperfusion–induced AKI model were enriched with oxidative stress and that in a cisplatin-induced model were ribosomal genes (185) This study underscores the complexity of the pathogenesis of AKI and the difficulty in its study, as different models affect unique gene expression patterns Last, it is important to identify relevant human molecular targets, evaluate their efficacy in relevant animal models (186), and validate results in well-designed clinical trials (187) The National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) Kidney Precision Medicine Project focuses in part on obtaining kidney biopsies safely in patients with AKI and on interrogating molecular targets and endophenotypes (188) Enrichment approaches through molecular and clinical phenotypes may lead to improved therapeutic precision and identify those groups with a greater likelihood of responding to treatment (22,189,190) (Figure 8) Disclosures E Goggins reports receiving research funding from the University of Virginia Medical Scientist Training Program M.D Okusa reports consultancy agreements with HemoShear and Janssen; receiving research funding from AM Pharma/Pfizer and an National Institutes of Health (NIH) research grant; receiving honoraria from UpToDate; having patents or royalties with University of Virginia Patent Office; serving in an advisory or leadership role for NIDDH/NIDDK DSMB; and having other interests or relationships with the John Bower Foundation The remaining author has nothing to disclose 11 Funding This work was supported by NIH/NIDDK grants R01 DK085259 and R01 DK123248 (to M Okusa) and Uehara Memorial Foundation Research Fellowship (to S Kuwabara, 202030018), and the Medical Scientist Training Program (NIH/NIGMS grant T32 GM007267 support for E Goggins) 14 Acknowledgments The authors would like to acknowledge the careful editing by Drs Diane Rosin and Uta Erdbr€ uegger (Division of Nephrology) and advice from members of the Okusa laboratory Some of the illustrations were created with BioRender.com Author Contributions M Okusa conceptualized the study, was responsible for the funding acquisition, and provided supervision; 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(B) Enrichment approaches through genomics, RNA sequencing, proteomics, metabolomics, and biomarkers will identify molecular endophenotypes, and clinical and laboratory parameters may identify... candidate has the ability to regulate entire pathogenic biologic pathways (85), potentially rendering the candidate miRNA more effective Recent clinical studies have identified several miRNAs that are