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Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 44109

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Prof. Dr. Andreas von Knethen

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Guest Editor

Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy–Experimental Unit, University Hospital Frankfurt, Theodor-Stern-Kai 7, Building 9B, 3rd Floor, 60590 Frankfurt, Germany
Interests: sepsis; ARDS; macrophages; T cells; Nrf2; PPARgamma; mouse sepsis models
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Special Issue Information

Dear Colleagues,

It is my pleasure to announce that I will be acting as Guest Editor for a Special Issue of IJMS entitled “Sepsis: From Molecular Mechanisms and Pathophysiology to Novel Therapeutic Approaches”. Considering antibiosis, eradication of the focus, and intensive care supply as the only treatment regimens for patients suffering from sepsis, it is obvious that new therapies are mandatory. Because the anamneses of patients are very heterogeneous, characterizing mechanistic details associated with sepsis initiation or progression will be helpful to set up new therapy approaches. Therefore, manuscripts elucidating molecular mechanisms in vitro or in vivo in preclinical models as well as studies from patients providing insights into new therapy concepts to prevent or treat sepsis progression are welcome. Based on this research topic, a combination of original research manuscripts and review articles in the field of the origin of sepsis and deviated therapies is planned.

Review and original articles that cover, but are not limited to, the following topics are welcome:

Cell culture studies, characterizing and/or identifying new factors involved in sepsis development;
The role of immune cell subpopulations in sepsis progression;
Animal models providing mechanistic insights of underlying principles leading to sepsis;
Therapeutic approaches to prevent or cure sepsis and future perspectives;
Definition of new sepsis biomarkers;
Characterization of putative subgroups of sepsis patients with a similar origin of sepsis.

Prof. Dr. Andreas von Knethen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

animal models
therapy concept
biomarkers
sepsis
immune suppression
epigenetics

Related Special Issue

Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches in International Journal of Molecular Sciences (9 articles)

Published Papers (12 papers)

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Research

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11 pages, 1855 KiB

Open AccessArticle

Relationship among Low T3 Levels, Type 3 Deiodinase, Oxidative Stress, and Mortality in Sepsis and Septic Shock: Defining Patient Outcomes

by Josi Vidart, Luiza Axelrud, André Cardoso Braun, Rafael Aguiar Marschner and Simone Magagnin Wajner

Int. J. Mol. Sci. 2023, 24(4), 3935; https://doi.org/10.3390/ijms24043935 - 15 Feb 2023

Cited by 3 | Viewed by 1657

Abstract

Low T3 syndrome occurs frequently in patients with sepsis. Type 3 deiodinase (DIO3) is present in immune cells, but there is no description of its presence in patients with sepsis. Here, we aimed to determine the prognostic impact of thyroid hormones levels (TH), measured on ICU admission, on mortality and evolution to chronic critical illness (CCI) and the presence of DIO3 in white cells. We used a prospective cohort study with a follow-up for 28 days or deceased. Low T3 levels at admission were present in 86.5% of the patients. DIO3 was induced by 55% of blood immune cells. The cutoff value of 60 pg/mL for T3 displayed a sensitivity of 81% and specificity of 64% for predicting death, with an odds ratio of 4.89. Lower T3 yielded an area under the receiver operating characteristic curve of 0.76 for mortality and 0.75 for evolution to CCI, thus displaying better performance than commonly used prognostic scores. The high expression of DIO3 in white cells provides a novel mechanism to explain the reduction in T3 levels in sepsis patients. Further, low T3 levels independently predict progression to CCI and mortality within 28 days for sepsis and septic shock patients. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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14 pages, 2762 KiB

Open AccessArticle

Rhamnetin, a Natural Flavonoid, Ameliorates Organ Damage in a Mouse Model of Carbapenem-Resistant Acinetobacter baumannii-Induced Sepsis

by Hyeju Lee, Manigandan Krishnan, Minju Kim, Young Kyung Yoon and Yangmee Kim

Int. J. Mol. Sci. 2022, 23(21), 12895; https://doi.org/10.3390/ijms232112895 - 25 Oct 2022

Cited by 8 | Viewed by 1591

Abstract

In sepsis, the persistence of uncontrolled inflammatory response of infected host cells eventually leads to severe lung and organ failure and, ultimately, death. Carbapenem-resistant Acinetobacter baumannii (CRAB), causative bacteria of sepsis and lung failure in acute cases, belongs to a group of critical pathogens that cannot be eradicated using the currently available antibiotics. This underlines the necessity of developing new modes of therapeutics that can control sepsis at the initial stages. In this study, we investigated the anti-inflammatory activities in vitro and in vivo and the antiseptic effects of rhamnetin, a naturally occurring flavonoid. We found that among its isoforms, the potency of rhamnetin was less explored but rhamnetin possessed superior anti-inflammatory activity with least cytotoxicity. Rhamnetin showed significant anti-inflammatory effects in lipopolysaccharide-, CRAB-, and Escherichia coli (E. coli)-stimulated mouse macrophages by inhibiting the release of interleukin-6 and nitric oxide. In a mouse model of sepsis infected with clinically isolated CRAB or E. coli, rhamnetin significantly reduced the bacterial burden in the organs. In addition, normalized pro-inflammatory cytokine levels in lung lysates and histological analysis of lung tissue indicated alleviation of lung damage. This study implies that a potent natural product such as rhamnetin could be a future therapeutic for treating carbapenem-resistant gram-negative sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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8 pages, 366 KiB

Open AccessArticle

Time to Effective Therapy Is an Important Determinant of Survival in Bloodstream Infections Caused by Vancomycin-Resistant Enterococcus spp

by Alessandro Russo, Alice Picciarella, Roberta Russo, Gabriella d’Ettorre and Giancarlo Ceccarelli

Int. J. Mol. Sci. 2022, 23(19), 11925; https://doi.org/10.3390/ijms231911925 - 7 Oct 2022

Cited by 4 | Viewed by 1332

Abstract

Enterococcal bloodstream infections (EBSI) caused by vancomycin-resistant enterococci (VRE) are associated with a significant rate of unfavorable outcomes. No definitive data have been reported about the association between delayed antibiotic therapy and mortality. In this prospective observational study in three large hospitals in Italy (from August 2016 to April 2021), all consecutive hospitalized patients with a confirmed diagnosis of hospital-acquired monomicrobial BSI caused by VRE—with no evidence of endocarditis—were analyzed. Cox regression analysis showed that risk factors independently associated with 30-day mortality were age (HR 2.98, CI95% 1.44–6.81, p = 0.002), chronic kidney disease (HR 5.21, CI95% 1.48–22.23, p = 0.001), oncologic disease (HR 2.81, CI95% 1.45–19.8, p = 0.005), and intensive care unit admission (HR 3.71, CI95% 2.23–7.99, p < 0.001). Conversely, early effective therapy was associated with survival (HR 0.32, CI95% 0.38–0.76, p < 0.001). The administration of early effective antibiotic therapy within 48 h from blood culture collection was associated with 30-day mortality rates lower than 33%. Time from blood culture collection to appropriate therapy was an independent predictor of 30-day mortality in patients with EBSI caused by VRE. Based on these data, clinicians should start effective antibiotic therapy as soon as possible, preferably within the first 48 h from blood culture collection. Treatment strategies allowing the early delivery of in vitro active antibiotics are urgently needed, especially in critically ill patients at risk of VRE bacteremia. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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22 pages, 4518 KiB

Open AccessArticle

Acute Endotoxemia-Induced Respiratory and Intestinal Dysbiosis

by Evy Goossens, Jianhui Li, Chana Callens, Nathalie Van Rysselberghe, Hannele Kettunen, Juhani Vuorenmaa, Natalia Garcia Gonzalez, Claude Libert, Richard Ducatelle and Filip Van Immerseel

Int. J. Mol. Sci. 2022, 23(19), 11602; https://doi.org/10.3390/ijms231911602 - 1 Oct 2022

Cited by 5 | Viewed by 1969

Abstract

Systemic inflammatory response syndrome (SIRS) is a severe condition characterized by systemic inflammation, which may lead to multiple organ failure, shock and death. SIRS is common in burn patients, pancreatitis and sepsis. SIRS is often accompanied by intestinal dysbiosis. However, the mechanism, role and details of microbiome alterations during the early phase of acute SIRS are not completely understood. The current study aimed to characterize the dynamic alterations of both the intestinal and respiratory microbiome at two timepoints during the early phase of acute SIRS (4 and 8 h after LPS) and link these to the host response in a mouse model of a LPS-induced lethal SIRS. Acute SIRS had no effect on the microbiome in the large intestine but induced a rapid dysbiosis in the small intestine, which resembled the microbiome alterations commonly observed in SIRS patients. Later in the disease progression, a dysbiosis of the respiratory microbiome was observed, which was associated with the MMP9 expression in the lungs. Although similar bacteria were increased in both the lung and the small intestine, no evidence for a gut-lung translocation was observed. Gut dysbiosis is commonly observed in diseases involving inflammation in the gut. However, whether the inflammatory response associated with SIRS and sepsis can directly cause gut dysbiosis was still unclear. In the current study we provide evidence that a LPS-induced SIRS can directly cause dysbiosis of the small intestinal and respiratory microbiome. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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9 pages, 2022 KiB

Open AccessArticle

Inhibitory Activities of Rare Ginsenoside Rg4 on Cecal Ligation and Puncture-Induced Sepsis

by Go Oun Kim, Nayeon Kim, Gyu Yong Song and Jong-Sup Bae

Int. J. Mol. Sci. 2022, 23(18), 10836; https://doi.org/10.3390/ijms231810836 - 16 Sep 2022

Cited by 4 | Viewed by 1852

Abstract

Sepsis is an uncontrolled response to inflammatory infection and is associated with high levels of mortality and morbidity. Rg4 is a rare ginsenoside mainly found in the leaves of Panax ginseng C. A. Meyer and the major protopanaxatriol-type ginsenoside of black ginseng. In this study, we determined whether Rg4 affects cecal ligation and puncture (CLP)-induced sepsis. Animals were separated into the following six groups: control group, CLP-operated group, CLP plus maslinic acid (MA), and CLP plus Rg4 (5, 10, or 15 mg/kg). Survival rate, body weight changes, inflammatory cytokines, and histological analyses were assessed. Human endothelial cells were activated with the high-mobility group box 1 (HMGB1) protein and Rg4. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were used to assess inflammation and gene expression, respectively. After CLP surgery, the Rg4-administered group exhibited a higher survival rate and body weight compared with the untreated control group. Rg4 treatment reduced cytokine levels, including tumor necrosis factor (TNF)-α and interleukin (IL)-1β, as well as nitric oxide (NO) levels and renal inflammation. After Rg4 treatment of HMGB1-activated cells, the expressions of toll-like receptor (TLR) 4 and TNF-α were decreased, and the activation of phosphoinositide 3-kinase (PI3K)/AKT signaling increased cell viability. In summary, Rg4 inhibited inflammation and exhibited a protective effect against CLP-induced sepsis, thereby reinforcing cell survival against septic responses. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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17 pages, 3214 KiB

Open AccessArticle

Rapid Synergistic Biofilm Production of Pseudomonas and Candida on the Pulmonary Cell Surface and in Mice, a Possible Cause of Chronic Mixed Organismal Lung Lesions

by Pornpimol Phuengmaung, Jiradej Mekjaroen, Wilasinee Saisorn, Tanittha Chatsuwan, Poorichaya Somparn and Asada Leelahavanichkul

Int. J. Mol. Sci. 2022, 23(16), 9202; https://doi.org/10.3390/ijms23169202 - 16 Aug 2022

Cited by 10 | Viewed by 1837

Abstract

Due to the possible co-presence of Pseudomonas aeruginosa and Candida albicans (the most common nosocomial pathogens) in lungs, rapid interkingdom biofilm production is possible. As such, PA+CA produced more dominant biofilms on the pulmonary epithelial surface (NCI-H292) (confocal fluorescent extracellular matrix staining) with dominant psl upregulation, as demonstrated by polymerase chain reaction (PCR), after 8 h of experiments than PA alone. With a proteomic analysis, rhamnosyltransferase RhlB protein (Psl-associated quorum-sensing protein) was found to be among the high-abundance proteins in PA+CA than in PA biofilms, supporting psl-mediated biofilms in PA+CA on the cell surface. Additionally, PA+CA increased supernatant cytokines (IL-8 and IL-13, but not TNF-α, IL-6, and IL-10) with a similar upregulation of TLR-4, TLR-5, and TLR-9 (by PCR) compared with PA-stimulated cells. The intratracheal administration of PA+CA induced a greater severity of sepsis (serum creatinine, alanine transaminase, serum cytokines, and histology score) and prominent biofilms (fluorescent staining) with psl upregulation (PCR). In comparison with PA+CA biofilms on glass slides, PA+CA biofilms on biotic surfaces were more prominent (fluorescent staining). In conclusion, PA+CA induced Psl-predominant biofilms on the pulmonary cell surface and in mice with acute pneumonia, and these biofilms were more prominent than those induced by PA alone, highlighting the impact of Candida on rapid interkingdom biofilm production. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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12 pages, 2886 KiB

Open AccessArticle

Renin as a Marker of Tissue Perfusion, Septic Shock and Mortality in Septic Patients: A Prospective Observational Study

by Patrycja Leśnik, Lidia Łysenko, Małgorzata Krzystek-Korpacka, Ewa Woźnica-Niesobska, Magdalena Mierzchała-Pasierb and Jarosław Janc

Int. J. Mol. Sci. 2022, 23(16), 9133; https://doi.org/10.3390/ijms23169133 - 15 Aug 2022

Cited by 8 | Viewed by 1483

Abstract

Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the host’s response to an infection, where the dominant mechanism is tissue hypoperfusion. Currently, the marker used to define tissue disorders is lactate levels, which may be elevated in other disease states as well. Renin is an essential hormone for the proper functioning of the renin-angiotensin-aldosterone (RASS) system. It is secreted in the glomerular apparatus in response to hypoperfusion. This study aimed to assess the usefulness of renin as a marker of tissue hypoperfusion in patients with sepsis and septic shock. A final group of 48 patients treated for sepsis and septic shock in the intensive care unit was included. Blood samples for renin quantification were collected in the morning as a part of routine blood analysis on the first, third, and fifth days. Sepsis was diagnosed in 19 patients (39.6%), and septic shock was diagnosed in 29 patients (60.4%). There was no significant difference in renin concentration between patients who received and did not receive continuous renal replacement therapy (CRRT) on any study day. Therefore, all samples were analyzed together in subsequent analyses. There was a significant difference in renin concentration between sepsis survivors and non-survivors on the third (31.5 and 119.9 pg/mL, respectively) and fifth (18.2 and 106.7 pg/mL, respectively) days. As a survival marker, renin was characterized by 69% and 71% overall accuracy if determined on the third and fifth days, respectively. There was a significant difference in renin concentration between sepsis and septic shock patients on the first (45.8 and 103.4 pg/mL, respectively) and third (24.7 and 102.1 pg/mL, respectively) days. At an optimal cut-off of 87 pg/mL, renin had very good specificity and a positive likelihood ratio. Renin was a strong predictor of mortality in patients with sepsis and septic shock. Further, the level of renin in patients with septic shock was significantly higher than in patients with sepsis. In combination with the assessment of lactate concentration, renin seems to be the optimal parameter for monitoring tissue hypoperfusion and could be helpful for septic shock diagnosis, as well as for identifying candidate patients for CRRT. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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Review

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12 pages, 632 KiB

Open AccessReview

Advances in Rodent Experimental Models of Sepsis

by Lun Cai, Elizabeth Rodgers, Nick Schoenmann and Raghavan Pillai Raju

Int. J. Mol. Sci. 2023, 24(11), 9578; https://doi.org/10.3390/ijms24119578 - 31 May 2023

Cited by 7 | Viewed by 2402

Abstract

In the development of therapeutic strategies for human diseases, preclinical experimental models have a key role. However, the preclinical immunomodulatory therapies developed using rodent sepsis were not successful in human clinical trials. Sepsis is characterized by a dysregulated inflammation and redox imbalance triggered by infection. Human sepsis is simulated in experimental models using methods that trigger inflammation or infection in the host animals, most often mice or rats. It remains unknown whether the characteristics of the host species, the methods used to induce sepsis, or the molecular processes focused upon need to be revisited in the development of treatment methods that will succeed in human clinical trials. Our goal in this review is to provide a survey of existing experimental models of sepsis, including the use of humanized mice and dirty mice, and to show how these models reflect the clinical course of sepsis. We will discuss the strengths and limitations of these models and present recent advances in this subject area. We maintain that rodent models continue to have an irreplaceable role in studies toward discovering treatment methods for human sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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15 pages, 1524 KiB

Open AccessReview

Antithrombin as Therapeutic Intervention against Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation: Lessons Learned from COVID-19-Associated Coagulopathy

by Christian J. Wiedermann

Int. J. Mol. Sci. 2022, 23(20), 12474; https://doi.org/10.3390/ijms232012474 - 18 Oct 2022

Cited by 4 | Viewed by 2062

Abstract

Recent research has contributed significantly to our understanding of the pathogenesis of acute disseminated intravascular coagulation. COVID-19 can be considered as a new underlying condition of disseminated intravascular coagulation. In this narrative review, current evidence is presented regarding biomarker differences between sepsis-induced and COVID-19-associated coagulopathies, supporting the importance of acquired antithrombin deficiency in the early differential diagnosis of septic coagulopathy and its potential impact on treatment with endogenous anticoagulants. Establishing new scoring systems for septic coagulopathy in combination with endogenous anticoagulant biomarker activities may allow for the identification of those in the heterogeneous population of sepsis patients who are more likely to benefit from targeted specific treatment interventions. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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30 pages, 1000 KiB

Open AccessReview

Cytokine Storm—Definition, Causes, and Implications

by Dominik Jarczak and Axel Nierhaus

Int. J. Mol. Sci. 2022, 23(19), 11740; https://doi.org/10.3390/ijms231911740 - 3 Oct 2022

Cited by 61 | Viewed by 6580

Abstract

The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators). Usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death. Not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies. Due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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34 pages, 5803 KiB

Open AccessReview

Pathophysiology of Sepsis and Genesis of Septic Shock: The Critical Role of Mesenchymal Stem Cells (MSCs)

by Matthieu Daniel, Yosra Bedoui, Damien Vagner, Loïc Raffray, Franck Ah-Pine, Bérénice Doray and Philippe Gasque

Int. J. Mol. Sci. 2022, 23(16), 9274; https://doi.org/10.3390/ijms23169274 - 17 Aug 2022

Cited by 12 | Viewed by 11766

Abstract

The treatment of sepsis and septic shock remains a major public health issue due to the associated morbidity and mortality. Despite an improvement in the understanding of the physiological and pathological mechanisms underlying its genesis and a growing number of studies exploring an even higher range of targeted therapies, no significant clinical progress has emerged in the past decade. In this context, mesenchymal stem cells (MSCs) appear more and more as an attractive approach for cell therapy both in experimental and clinical models. Pre-clinical data suggest a cornerstone role of these cells and their secretome in the control of the host immune response. Host-derived factors released from infected cells (i.e., alarmins, HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (e.g., LPS, peptidoglycans) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of cytokines/chemokines and growth factors that influence, respectively, immune cell recruitment and stem cell mobilization. However, the way in which MSCs exert their beneficial effects in terms of survival and control of inflammation in septic states remains unclear. This review presents the interactions identified between MSCs and mediators of immunity and tissue repair in sepsis. We also propose paradigms related to the plausible roles of MSCs in the process of sepsis and septic shock. Finally, we offer a presentation of experimental and clinical studies and open the way to innovative avenues of research involving MSCs from a prognostic, diagnostic, and therapeutic point of view in sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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14 pages, 1348 KiB

Open AccessReview

Sepsis and Acute Kidney Injury: A Review Focusing on the Bidirectional Interplay

by Yu-Ming Chang, Yu-Ting Chou, Wei-Chih Kan and Chih-Chung Shiao

Int. J. Mol. Sci. 2022, 23(16), 9159; https://doi.org/10.3390/ijms23169159 - 15 Aug 2022

Cited by 19 | Viewed by 8376

Abstract

Although sepsis and acute kidney injury (AKI) have a bidirectional interplay, the pathophysiological mechanisms between AKI and sepsis are not clarified and worthy of a comprehensive and updated review. The primary pathophysiology of sepsis-associated AKI (SA-AKI) includes inflammatory cascade, macrovascular and microvascular dysfunction, cell cycle arrest, and apoptosis. The pathophysiology of sepsis following AKI contains fluid overload, hyperinflammatory state, immunosuppression, and infection associated with kidney replacement therapy and catheter cannulation. The preventive strategies for SA-AKI are non-specific, mainly focusing on infection control and preventing further kidney insults. On the other hand, the preventive strategies for sepsis following AKI might focus on decreasing some metabolites, cytokines, or molecules harmful to our immunity, supplementing vitamin D3 for its immunomodulation effect, and avoiding fluid overload and unnecessary catheter cannulation. To date, several limitations persistently prohibit the understanding of the bidirectional pathophysiologies. Conducting studies, such as the Kidney Precision Medicine Project, to investigate human kidney tissue and establishing parameters or scores better to determine the occurrence timing of sepsis and AKI and the definition of SA-AKI might be the prospects to unveil the mystery and improve the prognoses of AKI patients. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 2.0)

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