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Lee K, Jang HR, Rabb H. Lymphocytes and innate immune cells in acute kidney injury and repair. Nat Rev Nephrol 2024; 20:789-805. [PMID: 39095505 DOI: 10.1038/s41581-024-00875-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2024] [Indexed: 08/04/2024]
Abstract
Acute kidney injury (AKI) is a common and serious disease entity that affects native kidneys and allografts but for which no specific treatments exist. Complex intrarenal inflammatory processes driven by lymphocytes and innate immune cells have key roles in the development and progression of AKI. Many studies have focused on prevention of early injury in AKI. However, most patients with AKI present after injury is already established. Increasing research is therefore focusing on mechanisms of renal repair following AKI and prevention of progression from AKI to chronic kidney disease. CD4+ and CD8+ T cells, B cells and neutrophils are probably involved in the development and progression of AKI, whereas regulatory T cells, double-negative T cells and type 2 innate lymphoid cells have protective roles. Several immune cells, such as macrophages and natural killer T cells, can have both deleterious and protective effects, depending on their subtype and/or the stage of AKI. The immune system not only participates in injury and repair processes during AKI but also has a role in mediating AKI-induced distant organ dysfunction. Targeted manipulation of immune cells is a promising therapeutic strategy to improve AKI outcomes.
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Affiliation(s)
- Kyungho Lee
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Cell and Gene Therapy Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hye Ryoun Jang
- Division of Nephrology, Department of Medicine, Samsung Medical Center, Cell and Gene Therapy Institute, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hamid Rabb
- Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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2
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Wang Q, Xiao J, Wei S, Yang X, Li J, Zuo Y, Hu Z. Remote liver ischemic preconditioning protects against renal ischemia/reperfusion injury via phosphorylation of extracellular signal-regulated kinases 1 and 2 in mice. PLoS One 2024; 19:e0308977. [PMID: 39159207 PMCID: PMC11332924 DOI: 10.1371/journal.pone.0308977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/02/2024] [Indexed: 08/21/2024] Open
Abstract
Perioperative acute kidney injury (AKI), which is mainly mediated by renal ischemia‒reperfusion (I/R) injury, is commonly observed in clinical practice. However, effective measures for preventing and treating this perioperative complication are still lacking in the clinic. Thus, we designed this study to examine whether remote liver ischemic preconditioning (RLIPC) has a protective effect on damage caused by renal I/R injury. In a rodent model, 30 mice were divided into five groups to assess the effects of RLIPC and ERK1/2 inhibition on AKI. The groups included the sham-operated (sham), kidney ischemia and reperfusion (CON), remote liver ischemic preconditioning (RLIPC), CON with the ERK1/2 inhibitor U0126 (CON+U0126), and RLIPC with U0126 (RLIPC+U0126). RLIPC consisted of 4 liver ischemia cycles before renal ischemia. Renal function and injury were assessed through biochemical assays, histology, cell apoptosis and protein phosphorylation analysis. RLIPC significantly mitigated renal dysfunction, tissue damage, inflammation, and apoptosis caused by I/R, which was associated with ERK1/2 phosphorylation. Furthermore, ERK1/2 inhibition with U0126 negated the protective effects of RLIPC and exacerbated renal injury. To summarize, we demonstrated that RLIPC has a strong renoprotective effect on kidneys post I/R injury and that this effect may be mediated by phosphorylation of ERK1/2.
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Affiliation(s)
- Qifeng Wang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junshen Xiao
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shichao Wei
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xi Yang
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiaxue Li
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yunxia Zuo
- Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhaoyang Hu
- Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Baker PR, Li AS, Griffin BR, Gil HW, Orlicky DJ, Fox BM, Park B, Sparagna GC, Goff J, Altmann C, Elajaili H, Okamura K, He Z, Stephenson D, D'Alessandro A, Reisz JA, Nozik ES, Sucharov CC, Faubel S. Disruption in glutathione metabolism and altered energy production in the liver and kidney after ischemic acute kidney injury in mice. Sci Rep 2024; 14:13862. [PMID: 38879688 PMCID: PMC11180093 DOI: 10.1038/s41598-024-64586-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 06/11/2024] [Indexed: 06/19/2024] Open
Abstract
Acute kidney injury (AKI) is a systemic disease that affects energy metabolism in various remote organs in murine models of ischemic AKI. However, AKI-mediated effects in the liver have not been comprehensively assessed. After inducing ischemic AKI in 8-10-week-old, male C57BL/6 mice, mass spectrometry metabolomics revealed that the liver had the most distinct phenotype 24 h after AKI versus 4 h and 7 days. Follow up studies with in vivo [13C6]-glucose tracing on liver and kidney 24 h after AKI revealed 4 major findings: (1) increased flux through glycolysis and the tricarboxylic (TCA) cycle in both kidney and liver; (2) depleted hepatic glutathione levels and its intermediates despite unchanged level of reactive oxygen species, suggesting glutathione consumption exceeds production due to systemic oxidative stress after AKI; (3) hepatic ATP depletion despite unchanged rate of mitochondrial respiration, suggesting increased ATP consumption relative to production; (4) increased hepatic and renal urea cycle intermediates suggesting hypercatabolism and upregulation of the urea cycle independent of impaired renal clearance of nitrogenous waste. Taken together, this is the first study to describe the hepatic metabolome after ischemic AKI in a murine model and demonstrates that there is significant liver-kidney crosstalk after AKI.
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Affiliation(s)
- Peter R Baker
- Division of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, 13123 East 16th Avenue, Box 300, Aurora, CO, 80045, USA
| | - Amy S Li
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Benjamin R Griffin
- Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hyo-Wook Gil
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - David J Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Benjamin M Fox
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Bryan Park
- Division of Pulmonary Sciences and Critical Care, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Genevieve C Sparagna
- Division of Cardiology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Jared Goff
- Division of Cardiology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Christopher Altmann
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Hanan Elajaili
- Division of Pediatric Critical Care, Department of Pediatrics, University of Colorado Anschutz Medical Campus, 12700 E 19th Ave, Aurora, CO, B13180045, USA
| | - Kayo Okamura
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Zhibin He
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Daniel Stephenson
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA
| | - Julie A Reisz
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, 12801 East 17th Avenue, Aurora, CO, 80045, USA
| | - Eva S Nozik
- Division of Pediatric Critical Care, Department of Pediatrics, University of Colorado Anschutz Medical Campus, 12700 E 19th Ave, Aurora, CO, B13180045, USA
| | - Carmen C Sucharov
- Division of Cardiology, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, CO, 80045, USA
| | - Sarah Faubel
- Division of Renal Diseases and Hypertension, Department of Internal Medicine, University of Colorado Anschutz Medical Campus, Mail Stop C281, 12700 East 19th Avenue, Aurora, CO, 80045, USA.
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Chen T, Chang C, Hou B, Qiu L, Sun H, Zhu X. Research progress in the role of gut microbiota in acute kidney injury. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2024; 49:385-391. [PMID: 38970512 PMCID: PMC11208396 DOI: 10.11817/j.issn.1672-7347.2024.230526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Indexed: 07/08/2024]
Abstract
Acute kidney injury (AKI) remains a global public health problem with high incidence, high mortality rates, expensive medical costs, and limited treatment options. AKI can further progress to chronic kidney disease (CKD) and eventually end-stage renal disease (ESRD). Previous studies have shown that trauma, adverse drug reactions, surgery, and other factors are closely associated with AKI. With further in-depth exploration, the role of gut microbiota in AKI is gradually revealed. After AKI occurs, there are changes in the composition of gut microbiota, leading to disruption of the intestinal barrier, intestinal immune response, and bacterial translocation. Meanwhile, metabolites of gut microbiota can exacerbate the progression of AKI. Therefore, elucidating the specific mechanisms by which gut microbiota is involved in the occurrence and development of AKI can provide new insights from the perspective of intestinal microbiota for the prevention and treatment of AKI.
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Affiliation(s)
- Tianxiao Chen
- Department of Basic Medicine, Wuxi Medical College, Jiangnan University, Wuxi Jiangsu 214122, China.
| | - Chang Chang
- Department of Basic Medicine, Wuxi Medical College, Jiangnan University, Wuxi Jiangsu 214122, China
| | - Bao Hou
- Department of Basic Medicine, Wuxi Medical College, Jiangnan University, Wuxi Jiangsu 214122, China
| | - Liying Qiu
- Department of Basic Medicine, Wuxi Medical College, Jiangnan University, Wuxi Jiangsu 214122, China
| | - Haijian Sun
- Department of Basic Medicine, Wuxi Medical College, Jiangnan University, Wuxi Jiangsu 214122, China
| | - Xuexue Zhu
- Department of Basic Medicine, Wuxi Medical College, Jiangnan University, Wuxi Jiangsu 214122, China.
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Luo H, Wen J, Yang H, Ran Q, Hou Y. Allograft function predicts mortality in kidney transplant recipients with severe COVID-19: a paradoxical risk factor. Front Immunol 2024; 15:1335148. [PMID: 38415244 PMCID: PMC10896886 DOI: 10.3389/fimmu.2024.1335148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/29/2024] [Indexed: 02/29/2024] Open
Abstract
Introduction Kidney transplant recipients (KTRs) are at a higher risk of severe coronavirus disease (COVID-19) because of their immunocompromised status. However, the effect of allograft function on the prognosis of severe COVID-19 in KTRs is unclear. In this study, we aimed to analyze the correlation between pre-infection allograft function and the prognosis of severe COVID-19 in KTRs. Methods This retrospective cohort study included 82 patients who underwent kidney transplantation at the Sichuan Provincial Peoples Hospital between October 1, 2014 and December 1, 2022 and were diagnosed with severe COVID-19. The patients were divided into decreased eGFR and normal eGFR groups based on the allograft function before COVID-19 diagnosis (n=32 [decreased eGFR group], mean age: 43.00 years; n=50 [normal eGFR group, mean age: 41.88 years). We performed logistic regression analysis to identify risk factors for death in patients with severe COVID-19. The nomogram was used to visualize the logistic regression model results. Results The mortality rate of KTRs with pre-infection allograft function insufficiency in the decreased eGFR group was significantly higher than that of KTRs in the normal eGFR group (31.25% [10/32] vs. 8.00% [4/50], P=0.006). Pre-infection allograft function insufficiency (OR=6.96, 95% CI: 1.4633.18, P=0.015) and maintenance of a mycophenolic acid dose >1500 mg/day before infection (OR=7.59, 95% CI: 1.0853.20, P=0.041) were independent risk factors, and the use of nirmatrelvir/ritonavir before severe COVID-19 (OR=0.15, 95% CI: 0.030.72, P=0.018) was a protective factor against death in severe COVID-19. Conclusions Pre-infection allograft function is a good predictor of death in patients with severe COVID-19. Allograft function was improved after treatment for severe COVID-19, which was not observed in patients with non-severe COVID-19.
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Affiliation(s)
- Han Luo
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Jingyu Wen
- Department of Medical Insurance, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Hongji Yang
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial Peoples Hospital, Chengdu, China
| | - Qing Ran
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yifu Hou
- Department of Organ Transplantation, Sichuan Provincial Peoples Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province & Organ Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial Peoples Hospital, Chengdu, China
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Komaru Y, Bai YZ, Kreisel D, Herrlich A. Interorgan communication networks in the kidney-lung axis. Nat Rev Nephrol 2024; 20:120-136. [PMID: 37667081 DOI: 10.1038/s41581-023-00760-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/08/2023] [Indexed: 09/06/2023]
Abstract
The homeostasis and health of an organism depend on the coordinated interaction of specialized organs, which is regulated by interorgan communication networks of circulating soluble molecules and neuronal connections. Many diseases that seemingly affect one primary organ are really multiorgan diseases, with substantial secondary remote organ complications that underlie a large part of their morbidity and mortality. Acute kidney injury (AKI) frequently occurs in critically ill patients with multiorgan failure and is associated with high mortality, particularly when it occurs together with respiratory failure. Inflammatory lung lesions in patients with kidney failure that could be distinguished from pulmonary oedema due to volume overload were first reported in the 1930s, but have been largely overlooked in clinical settings. A series of studies over the past two decades have elucidated acute and chronic kidney-lung and lung-kidney interorgan communication networks involving various circulating inflammatory cytokines and chemokines, metabolites, uraemic toxins, immune cells and neuro-immune pathways. Further investigations are warranted to understand these clinical entities of high morbidity and mortality, and to develop effective treatments.
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Affiliation(s)
- Yohei Komaru
- Department of Medicine, Division of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Yun Zhu Bai
- Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Daniel Kreisel
- Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
- Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Andreas Herrlich
- Department of Medicine, Division of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
- VA Saint Louis Health Care System, John Cochran Division, St. Louis, MO, USA.
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Okamura K, Lu S, He Z, Altmann C, Montford JR, Li AS, Lucia MS, Orlicky DJ, Weiser-Evans M, Faubel S. IL-6 mediates the hepatic acute phase response after prerenal azotemia in a clinically defined murine model. Am J Physiol Renal Physiol 2023; 325:F328-F344. [PMID: 37471421 PMCID: PMC10511171 DOI: 10.1152/ajprenal.00267.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 06/09/2023] [Accepted: 07/13/2023] [Indexed: 07/22/2023] Open
Abstract
Prerenal azotemia (PRA) is a major cause of acute kidney injury and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of glomerular filtration rate (GFR) that returns to baseline with resuscitation. Adult male C57BL/6J wild-type (WT) and IL-6-/- mice were studied. Intraperitoneal furosemide (4 mg) or vehicle was administered at time = 0 and 3 h to induce PRA from volume loss. Resuscitation began at 6 h with 1 mL intraperitoneal saline for four times for 36 h. Six hours after furosemide administration, measured glomerular filtration rate was 25% of baseline and returned to baseline after saline resuscitation at 48 h. After 6 h of PRA, plasma interleukin (IL)-6 was significantly increased, kidney and liver histology were normal, kidney and liver lactate were normal, and kidney injury molecule-1 immunofluorescence was negative. There were 327 differentially regulated genes upregulated in the liver, and the acute phase response was the most significantly upregulated pathway; 84 of the upregulated genes (25%) were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included serum amyloid A2, serum amyloid A1, lipocalin 2, chemokine (C-X-C motif) ligand 1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in wild-type PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of PRA that includes IL-6-mediated upregulation of the hepatic acute phase response.NEW & NOTEWORTHY Prerenal azotemia (PRA) accounts for a third of acute kidney injury (AKI) cases yet is rarely studied in preclinical models. We developed a clinically defined murine model of prerenal azotemia characterized by a 75% decrease in measured glomerular filtration rate (GFR), return of measured glomerular filtration rate to baseline with resuscitation, and absent tubular injury. Numerous systemic effects were observed, such as increased plasma interleukin-6 (IL-6) and upregulation of the hepatic acute phase response.
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Affiliation(s)
- Kayo Okamura
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Sizhao Lu
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Zhibin He
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Chris Altmann
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - John R Montford
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Renal Section, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado, United States
| | - Amy S Li
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - M Scott Lucia
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - David J Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Mary Weiser-Evans
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
| | - Sarah Faubel
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
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Wang Y, Zhang Y, Shou S, Jin H. The role of IL-17 in acute kidney injury. Int Immunopharmacol 2023; 119:110307. [PMID: 37182383 DOI: 10.1016/j.intimp.2023.110307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/28/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
Acute kidney injury (AKI) is a common clinical kidney disease with a high mortality rate. AKI is caused by a variety of factors, including sepsis, ischemia, and nephrotoxic drugs, and can progress to chronic kidney disease and end-stage renal disease. Numerous studies have suggested that cytokines can be used as therapeutic targets for AKI. IL-17 is a pro-inflammatory cytokine that not only participates in the host defense and the development of autoimmune diseases but also is linked to AKI due to a variety of factors. This review will give an overview of the structure, signaling pathways, and biological functions of IL-17, as well as its role in AKI, to show that IL-17 is a potential target for the prevention and treatment of AKI.
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Affiliation(s)
- Yali Wang
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, PR China
| | - Yan Zhang
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, PR China
| | - Songtao Shou
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, PR China
| | - Heng Jin
- Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, PR China.
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Matsuura R, Doi K, Rabb H. Acute kidney injury and distant organ dysfunction-network system analysis. Kidney Int 2023; 103:1041-1055. [PMID: 37030663 DOI: 10.1016/j.kint.2023.03.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/24/2023] [Accepted: 03/24/2023] [Indexed: 04/10/2023]
Abstract
Acute kidney injury (AKI) occurs in about half of critically ill patients and associates with high in-hospital mortality, increased long-term mortality post-discharge and subsequent progression to chronic kidney disease. Numerous clinical studies have shown that AKI is often complicated by dysfunction of distant organs, which is a cause of the high mortality associated with AKI. Experimental studies have elucidated many mechanisms of AKI-induced distant organ injury, which include inflammatory cytokines, oxidative stress and immune responses. This review will provide an update on evidence of organ crosstalk and potential therapeutics for AKI-induced organ injuries, and present the new concept of a systemic organ network to balance homeostasis and inflammation that goes beyond kidney-crosstalk with a single distant organ.
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Affiliation(s)
- Ryo Matsuura
- Department of Nephrology and Endocrinology, the University of Tokyo Hospital
| | - Kent Doi
- Department of Emergency and Critical Care Medicine, the University of Tokyo Hospital.
| | - Hamid Rabb
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine
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Li B, Chen M, Zeng Y, Luo S. Correlation between perioperative dexmedetomidine administration and postoperative acute kidney injury in hypertensive patients undergoing non-cardiac surgery. Front Pharmacol 2023; 14:1143176. [PMID: 37063282 PMCID: PMC10090366 DOI: 10.3389/fphar.2023.1143176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
Background: Previous studies have suggested that dexmedetomidine may have a protective effect on renal function. However, it is currently unclear whether perioperative dexmedetomidine administration is associated with postoperative acute kidney injury (AKI) incidence risk in hypertensive patients undergoing non-cardiac surgery.Methods: This investigation was a retrospective cohort study. Hypertensive patients undergoing non-cardiac surgery in Third Xiangya Hospital of Central South University from June 2018 to December 2019 were included. The relevant data were extracted through electronic cases. The univariable analysis identified demographic, preoperative laboratory, and intraoperative factors associated with acute kidney injury. Multivariable stepwise logistic regression was used to assess the association between perioperative dexmedetomidine administration and postoperative acute kidney injury after adjusting for interference factors. In addition, we further performed sensitivity analyses in four subgroups to further validate the robustness of the results.Results: A total of 5769 patients were included in this study, with a 7.66% incidence of postoperative acute kidney injury. The incidence of postoperative acute kidney injury was lower in the dexmedetomidine-administered group than in the control group (4.12% vs. 8.06%, p < 0.001). In the multivariable stepwise logistic regression analysis, perioperative dexmedetomidine administration significantly reduced the risk of postoperative acute kidney injury after adjusting for interference factors [odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.36–0.87, p = 0.010]. In addition, sensitivity analysis in four subgroups indicated parallel findings: i) eGRF <90 mL/min·1.73/m2 subgroup (OR = 0.40, 95% CI: 0.19–0.84, p = 0.016), ii) intraoperative blood loss <1000 mL subgroup (OR = 0.58, 95% CI: 0.36–0.94, p = 0.025), iii) non-diabetes subgroup (OR = 0.51, 95% CI: 0.29–0.89, p = 0.018), and iv) older subgroup (OR = 0.55, 95% CI: 0.32–0.93, p = 0.027).Conclusion: In conclusion, our study suggests that perioperative dexmedetomidine administration is associated with lower risk and less severity of postoperative acute kidney injury in hypertensive individuals undergoing non-cardiac surgery. Therefore, future large-scale RCT studies are necessary to validate this benefit.
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Affiliation(s)
- Bo Li
- Operation Center, Third Xiangya Hospital, Central South University, Changsha, China
| | - Minghua Chen
- Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Youjie Zeng
- Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Siwan Luo
- Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Siwan Luo,
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11
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Cui C, Wang X, Li L, Wei H, Peng J. Multifaceted involvements of Paneth cells in various diseases within intestine and systemically. Front Immunol 2023; 14:1115552. [PMID: 36993974 PMCID: PMC10040535 DOI: 10.3389/fimmu.2023.1115552] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/02/2023] [Indexed: 03/14/2023] Open
Abstract
Serving as the guardians of small intestine, Paneth cells (PCs) play an important role in intestinal homeostasis maintenance. Although PCs uniquely exist in intestine under homeostasis, the dysfunction of PCs is involved in various diseases not only in intestine but also in extraintestinal organs, suggesting the systemic importance of PCs. The mechanisms under the participation of PCs in these diseases are multiple as well. The involvements of PCs are mostly characterized by limiting intestinal bacterial translocation in necrotizing enterocolitis, liver disease, acute pancreatitis and graft-vs-host disease. Risk genes in PCs render intestine susceptible to Crohn’s disease. In intestinal infection, different pathogens induce varied responses in PCs, and toll-like receptor ligands on bacterial surface trigger the degranulation of PCs. The increased level of bile acid dramatically impairs PCs in obesity. PCs can inhibit virus entry and promote intestinal regeneration to alleviate COVID-19. On the contrary, abundant IL-17A in PCs aggravates multi-organ injury in ischemia/reperfusion. The pro-angiogenic effect of PCs aggravates the severity of portal hypertension. Therapeutic strategies targeting PCs mainly include PC protection, PC-derived inflammatory cytokine elimination, and substituting AMP treatment. In this review, we discuss the influence and importance of Paneth cells in both intestinal and extraintestinal diseases as reported so far, as well as the potential therapeutic strategies targeting PCs.
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Affiliation(s)
- Chenbin Cui
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Xinru Wang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Lindeng Li
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Hongkui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China
- The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, China
- *Correspondence: Jian Peng,
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12
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Amin SN, Sakr HI, El Gazzar WB, Shaltout SA, Ghaith HS, Elberry DA. Combined saline and vildagliptin induced M2 macrophage polarization in hepatic injury induced by acute kidney injury. PeerJ 2023; 11:e14724. [PMID: 36815993 PMCID: PMC9933746 DOI: 10.7717/peerj.14724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 12/19/2022] [Indexed: 02/15/2023] Open
Abstract
Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into "classically activated macrophages" (M1) and "alternatively activated macrophages" (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-α (TNF-α), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI+Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline+Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway.
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Affiliation(s)
- Shaimaa N. Amin
- Department of Anatomy, Physiology, and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan,Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hader I. Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt,Department of Medical Physiology, Medicine Program, Batterjee Medical College, Jeddah, Saudi Arabia
| | - Walaa B. El Gazzar
- Department of Anatomy, Physiology, and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa, Jordan,Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Sherif A. Shaltout
- Department of Pharmacology, Public health, and Clinical Skills, Faculty of Medicine, The Hashemite University, Zarqa, Jordan,Department of Pharmacology, Faculty of Medicine, Benha University, Benha, Egypt
| | | | - Dalia A. Elberry
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
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13
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Mineralocorticoid Receptor Antagonism Attenuates Multiple Organ Failure after Renal Ischemia and Reperfusion in Mice. Int J Mol Sci 2023; 24:ijms24043413. [PMID: 36834824 PMCID: PMC9965387 DOI: 10.3390/ijms24043413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Renal ischemia reperfusion (IR) injury is a major cause of acute kidney injury (AKI) that is often complicated by multiple organ failure of the liver and intestine. The mineralocorticoid receptor (MR) is activated in patients with renal failure associated with glomerular and tubular damage. We thus investigated whether canrenoic acid (CA), a mineralocorticoid receptor (MR) antagonist, protects against AKI-induced hepatic and intestinal injury, suggesting the underlying mechanisms. Mice were divided into five groups: sham mice, mice subjected to renal IR, and mice pretreated with canrenoic acid (CA; 1 or 10 mg/kg) 30 min prior to renal IR. At 24 h after renal IR, the levels of plasma creatinine, alanine aminotransferase and aldosterone were measured, and structural changes and inflammatory responses of the kidney, liver, and intestine were analyzed. We found that CA treatment reduced plasma creatinine levels, tubular cell death and oxidative stress induced by renal IR. CA treatment also decreased renal neutrophil infiltration and inflammatory cytokine expression and inhibited the release of high-mobility group box 1 induced by renal IR. Consistently, CA treatment reduced renal IR-induced plasma alanine transaminase, hepatocellular injury and neutrophil infiltration, and inflammatory cytokine expression. CA treatment also decreased small intestinal cell death, neutrophil infiltration and inflammatory cytokine expression induced by renal IR. Taken together, we conclude that MR antagonism by CA treatment protects against multiple organ failure in the liver and intestine after renal IR.
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14
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Wallaeys C, Garcia‐Gonzalez N, Libert C. Paneth cells as the cornerstones of intestinal and organismal health: a primer. EMBO Mol Med 2022; 15:e16427. [PMID: 36573340 PMCID: PMC9906427 DOI: 10.15252/emmm.202216427] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/24/2022] [Accepted: 09/29/2022] [Indexed: 12/28/2022] Open
Abstract
Paneth cells are versatile secretory cells located in the crypts of Lieberkühn of the small intestine. In normal conditions, they function as the cornerstones of intestinal health by preserving homeostasis. They perform this function by providing niche factors to the intestinal stem cell compartment, regulating the composition of the microbiome through the production and secretion of antimicrobial peptides, performing phagocytosis and efferocytosis, taking up heavy metals, and preserving barrier integrity. Disturbances in one or more of these functions can lead to intestinal as well as systemic inflammatory and infectious diseases. This review discusses the multiple functions of Paneth cells, and the mechanisms and consequences of Paneth cell dysfunction. It also provides an overview of the tools available for studying Paneth cells.
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Affiliation(s)
- Charlotte Wallaeys
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Natalia Garcia‐Gonzalez
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
| | - Claude Libert
- Center for Inflammation Research‐VIBGhentBelgium,Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
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15
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Eyraud D, Creux M, Lastennet D, Lemoine L, Vaillant JC, Savier E, Vézinet C, Scatton O, Granger B, Puybasset L, Loncar Y. Restrictive intraoperative fluid intake in liver surgery and postoperative renal function: A propensity score matched study. Clin Res Hepatol Gastroenterol 2022; 46:101899. [PMID: 35257960 DOI: 10.1016/j.clinre.2022.101899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Postoperative acute kidney injury (AKI) is a common complication in hepatic surgery. In hepatic surgery, relative hypovolemia may help to limit blood loss, but the consequences of restrictive fluid intake are unknown. The goal of this study was to determine the influence of intraoperative fluid intake on the incidence of AKI and its consequences. METHODS Data from 397 consecutive patients who underwent liver resection were prospectively recorded and retrospectively analyszed. We compared the incidence of postoperative acute kidney failure in patients given restrictive (≤ 5 mL/kg/h) versus liberal (> 5 mL/kg/h) fluid therapy. We calculated a 1:1 match propensity score using logistic regression to estimate the likelihood of patients receiving restrictive or liberal intraoperative fluid intakes. The association between the intraoperative fluid intake strategy and occurrence of postoperative AKI were tested using a Cox frailty model on the database of matched patients. RESULTS Postoperative AKI was diagnosed in 133 of the 397 patients. Fluid intake strategy was restrictive for 121 patients and liberal for 276 patients. After propensity score matching to balance confounding factors, the liberal strategy was associated with a significantly lower risk for postoperative AKI compared to the restrictive strategy (Hazard Ratio 0.40 [0.29; 0.56], P<0.001). Patients with postoperative AKI had longer hospital stays and higher mortality. There were no cases of further blood loss in the liberal fluid intake group. CONCLUSIONS A restrictive fluid intake strategy is a risk factor for developing postoperative AKI, with serious consequences, without reducing blood loss in liver surgery.
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Affiliation(s)
- Daniel Eyraud
- Department of Anesthesiology and Critical Care, GRC 29, DREAM DMU, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Paris, France; Department of Digestive, HPB Surgery, and Liver Transplantation, University Hospitals Pitié-Salpêtrière Charles-Foix, Sorbonne University, Paris, France.
| | - Marine Creux
- Department of Anesthesiology and Critical Care, GRC 29, DREAM DMU, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Paris, France
| | - Diane Lastennet
- Department of Biostatistics Public Health and Medical Informatics, University Hospitals Pitié-Salpêtrière Charles-Foix, Sorbonne University, Paris, France
| | - Louis Lemoine
- Department of Anesthesiology and Critical Care, GRC 29, DREAM DMU, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Paris, France
| | - Jean Christophe Vaillant
- Department of Digestive, HPB Surgery, and Liver Transplantation, University Hospitals Pitié-Salpêtrière Charles-Foix, Sorbonne University, Paris, France
| | - Eric Savier
- Department of Digestive, HPB Surgery, and Liver Transplantation, University Hospitals Pitié-Salpêtrière Charles-Foix, Sorbonne University, Paris, France
| | - Corinne Vézinet
- Department of Anesthesiology and Critical Care, GRC 29, DREAM DMU, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Paris, France
| | - Olivier Scatton
- Department of Digestive, HPB Surgery, and Liver Transplantation, University Hospitals Pitié-Salpêtrière Charles-Foix, Sorbonne University, Paris, France
| | - Benjamin Granger
- Department of Biostatistics Public Health and Medical Informatics, University Hospitals Pitié-Salpêtrière Charles-Foix, Sorbonne University, Paris, France
| | - Louis Puybasset
- Department of Anesthesiology and Critical Care, GRC 29, DREAM DMU, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Paris, France
| | - Yann Loncar
- Department of Anesthesiology and Critical Care, GRC 29, DREAM DMU, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne University, Paris, France
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16
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Chang YM, Chou YT, Kan WC, Shiao CC. Sepsis and Acute Kidney Injury: A Review Focusing on the Bidirectional Interplay. Int J Mol Sci 2022; 23:ijms23169159. [PMID: 36012420 PMCID: PMC9408949 DOI: 10.3390/ijms23169159] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/06/2022] [Accepted: 08/12/2022] [Indexed: 11/25/2022] Open
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.
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Affiliation(s)
- Yu-Ming Chang
- Division of Nephrology, Department of Internal Medicine, Camillian Saint Mary’s Hospital Luodong, Yilan 26546, Taiwan
| | - Yu-Ting Chou
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan
| | - Wei-Chih Kan
- Department of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan
- Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan
- Correspondence: (W.-C.K.); (C.-C.S.)
| | - Chih-Chung Shiao
- Division of Nephrology, Department of Internal Medicine, Camillian Saint Mary’s Hospital Luodong, Yilan 26546, Taiwan
- Saint Mary’s Junior College of Medicine, Nursing and Management, Yilan 26546, Taiwan
- Correspondence: (W.-C.K.); (C.-C.S.)
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17
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Potnuru PP, Ganduglia C, Schaefer CM, Suresh M, Eltzschig HK, Jiang Y. Impact of cesarean versus vaginal delivery on the risk of postpartum acute kidney injury: A retrospective database controlled study in 116,876 parturients. J Clin Anesth 2022; 82:110915. [PMID: 35969987 DOI: 10.1016/j.jclinane.2022.110915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 10/31/2022]
Abstract
STUDY OBJECTIVE The rate of cesarean delivery is increasing globally but the risk of perioperative organ injury associated with cesarean delivery is not well defined. The objective of this study was to determine the risk of postpartum acute kidney injury, a peripartum complication defined by an acute decrease in kidney function, associated with cesarean delivery compared to vaginal delivery. SETTING Population-based discharge database. PATIENTS The Optum Clinformatics® Data Mart was queried for parturients that underwent cesarean or vaginal delivery between January 2016 to January 2018. Using a propensity score model based on 27 antepartum characteristics, we generated a final matched cohort of 116,876 parturients. INTERVENTION/EXPOSURE Cesarean delivery as the mode of delivery. MEASUREMENTS The risk of acute kidney injury associated with each delivery mode and the effect of acute kidney injury on the length of hospital stay for parturients. MAIN RESULTS The matched cohort consisted of 116,876 deliveries, with 58,438 cases in each group. In the cesarean delivery group, the incidence of postpartum acute kidney injury was 24.5 vs. 7.9 per 10,000 deliveries in the vaginal delivery group (adjusted odds ratio = 3; 95% CI, 2.13-4.22; P < .001). The median of the length of hospital stay [interquartile range] was longer by 50% in parturients who developed postpartum acute kidney injury after vaginal delivery (3 [2-4] days vs. those who did not, 2 [2, 3] days; P < .001) and by 67% after cesarean delivery (5 [4-7] days vs. 3 [3, 4] days; P < .001). CONCLUSIONS Cesarean delivery is associated with a significantly increased risk of postpartum acute kidney injury as compared to vaginal delivery. The development of postpartum acute kidney injury is associated with prolonged length of hospital stay.
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Affiliation(s)
- Paul P Potnuru
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
| | - Cecilia Ganduglia
- School of Public Health, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
| | - Caroline M Schaefer
- School of Public Health, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
| | - Maya Suresh
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
| | - Holger K Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA
| | - Yandong Jiang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX 77030, USA.
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18
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Sharma N, Sircar A, Anders HJ, Gaikwad AB. Crosstalk between kidney and liver in non-alcoholic fatty liver disease: mechanisms and therapeutic approaches. Arch Physiol Biochem 2022; 128:1024-1038. [PMID: 32223569 DOI: 10.1080/13813455.2020.1745851] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Liver and kidney are vital organs that maintain homeostasis and injury to either of them triggers pathogenic pathways affecting the other. For example, non-alcoholic fatty liver disease (NAFLD) promotes the progression of chronic kidney disease (CKD), vice versa acute kidney injury (AKI) endorses the induction and progression of liver dysfunction. Progress in clinical and basic research suggest a role of excessive fructose intake, insulin resistance, inflammatory cytokines production, activation of the renin-angiotensin system, redox imbalance, and their impact on epigenetic regulation of gene expression in this context. Recent developments in experimental and clinical research have identified several biochemical and molecular pathways for AKI-liver interaction, including altered liver enzymes profile, metabolic acidosis, oxidative stress, activation of inflammatory and regulated cell death pathways. This review focuses on the current preclinical and clinical findings on kidney-liver crosstalk in NAFLD-CKD and AKI-liver dysfunction settings and highlights potential molecular mechanisms and therapeutic targets.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Anannya Sircar
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India
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19
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Hepokoski M, Singh P. Mitochondria as mediators of systemic inflammation and organ cross talk in acute kidney injury. Am J Physiol Renal Physiol 2022; 322:F589-F596. [PMID: 35379000 PMCID: PMC9054254 DOI: 10.1152/ajprenal.00372.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Acute kidney injury (AKI) is a systemic inflammatory disease that contributes to remote organ failures. Multiple organ failure is the leading cause of death due to AKI, and lack of understanding of the mechanisms involved has precluded the development of novel therapies. Mitochondrial injury in AKI leads to mitochondrial fragmentation and release of damage-associated molecular patterns, which are known to active innate immune pathways and systemic inflammation. This review presents current evidence suggesting that extracellular mitochondrial damage-associated molecular patterns are mediators of remote organ failures during AKI that have the potential to be modifiable.
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Affiliation(s)
- Mark Hepokoski
- 1Veterans Affairs San Diego Healthcare System, San Diego, California,2Division of Pulmonary and Critical Care Medicine, University of California, San Diego, California
| | - Prabhleen Singh
- 1Veterans Affairs San Diego Healthcare System, San Diego, California,3Division of Nephrology and Hypertension, University of California, San Diego, California
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20
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Kraus AC, De Miguel C. Hyperoxia and Acute Kidney Injury: A Tale of Oxygen and the Kidney. Semin Nephrol 2022; 42:151282. [PMID: 36404211 PMCID: PMC9825666 DOI: 10.1016/j.semnephrol.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Although oxygen supplementation is beneficial to support life in the clinic, excessive oxygen therapy also has been linked to damage to organs such as the lung or the eye. However, there is a lack of understanding of whether high oxygen therapy directly affects the kidney, leading to acute kidney injury, and what molecular mechanisms may be involved in this process. In this review, we revise our current understanding of the mechanisms by which hyperoxia leads to organ damage and highlight possible areas of investigation for the scientific community interested in novel mechanisms of kidney disease. Overall, we found a significant need for both animal and clinical studies evaluating the role of hyperoxia in inducing kidney damage. Thus, we urge the research community to further investigate oxygen therapy and its impact on kidney health with the goal of optimizing oxygen therapy guidelines and improving patient care.
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Affiliation(s)
- Abigayle C Kraus
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - Carmen De Miguel
- Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
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21
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Chou YT, Kan WC, Shiao CC. Acute Kidney Injury and Gut Dysbiosis: A Narrative Review Focus on Pathophysiology and Treatment. Int J Mol Sci 2022; 23:ijms23073658. [PMID: 35409017 PMCID: PMC8999046 DOI: 10.3390/ijms23073658] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/10/2022] Open
Abstract
Acute kidney injury (AKI) and gut dysbiosis affect each other bidirectionally. AKI induces microbiota alteration in the gastrointestinal (GI) system, while gut dysbiosis also aggravates AKI. The interplay between AKI and gut dysbiosis is not yet well clarified but worthy of further investigation. The current review focuses on the pathophysiology of this bidirectional interplay and AKI treatment in this base. Both macrophages and neutrophils of the innate immunity and the T helper type 17 cell from the adaptive immunity are the critical players of AKI-induced gut dysbiosis. Conversely, dysbiosis-induced overproduction of gut-derived uremic toxins and insufficient generation of short-chain fatty acids are the main factors deteriorating AKI. Many novel treatments are proposed to deter AKI progression by reforming the GI microbiome and breaking this vicious cycle. Data support the benefits of probiotic treatment in AKI patients, while the results of postbiotics are mainly limited to animals. Prebiotics and synbiotics are primarily discussed in chronic kidney disease patients rather than AKI patients. The effect of adsorbent treatment seems promising, but more studies are required before the treatment can be applied to patients. Immune therapy and some repurposed drugs such as allopurinol are prospects of future treatments and are worth more discussion and survey.
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Affiliation(s)
- Yu-Ting Chou
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan;
| | - Wei-Chih Kan
- Department of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan 71004, Taiwan
- Department of Biological Science and Technology, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan
- Correspondence: (W.-C.K.); (C.-C.S.)
| | - Chih-Chung Shiao
- Division of Nephrology, Department of Internal Medicine, Camillian Saint Mary’s Hospital Luodong, Yilan 265, Taiwan
- Saint Mary’s Junior College of Medicine, Nursing and Management, Yilan 26647, Taiwan
- Correspondence: (W.-C.K.); (C.-C.S.)
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22
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Platt E, Klootwijk E, Salama A, Davidson B, Robertson F. Literature review of the mechanisms of acute kidney injury secondary to acute liver injury. World J Nephrol 2022; 11:13-29. [PMID: 35117976 PMCID: PMC8790308 DOI: 10.5527/wjn.v11.i1.13] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/12/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
People exposed to liver ischaemia reperfusion (IR) injury often develop acute kidney injury and the combination is associated with significant morbidity and mortality. Molecular mediators released by the liver in response to IR injury are the likely cause of acute kidney injury (AKI) in this setting, but the mediators have not yet been identified. Identifying the mechanism of injury will allow the identification of therapeutic targets which may modulate both liver IR injury and AKI following liver IR injury.
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Affiliation(s)
- Esther Platt
- Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom
| | - Enriko Klootwijk
- Department of Renal Medicine, University College London, London NW3 2PF, United Kingdom
| | - Alan Salama
- Department of Renal Medicine, University College London, London NW3 2PF, United Kingdom
| | - Brian Davidson
- Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom
| | - Francis Robertson
- Division of Surgery and Interventional Science, University College London, London NW3 2QG, United Kingdom
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23
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Herrlich A. Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury. FEBS Lett 2021; 596:620-637. [PMID: 34932216 DOI: 10.1002/1873-3468.14262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/08/2021] [Accepted: 12/09/2021] [Indexed: 11/07/2022]
Abstract
Homeostasis and health of multicellular organisms with multiple organs depends on interorgan communication. Tissue injury in one organ disturbs this homeostasis and can lead to disease in multiple organs, or multiorgan failure. Many routes of interorgan crosstalk during homeostasis are relatively well known, but interorgan crosstalk in disease still lacks understanding. In particular, how tissue injury in one organ can drive injury at remote sites and trigger multiorgan failure with high mortality is poorly understood. As examples, acute kidney injury can trigger acute lung injury and cardiovascular dysfunction; pneumonia, sepsis or liver failure conversely can cause kidney failure; lung transplantation very frequently triggers acute kidney injury. Mechanistically, interorgan crosstalk after tissue injury could involve soluble mediators and their target receptors, cellular mediators, in particular immune cells, as well as newly identified neuro-immune connections. In this review, I will focus the discussion of deleterious interorgan crosstalk and its mechanistic concepts on one example, acute kidney injury-induced remote lung injury.
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Affiliation(s)
- Andreas Herrlich
- Division of Nephrology, Department of Medicine, Washington University in St. Louis, MO, USA
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Lai HJ, Zhan YQ, Qiu YX, Ling YH, Zhang XY, Chang ZN, Zhang YN, Liu ZM, Wen SH. HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage. Surgery 2021; 170:239-248. [PMID: 33745733 DOI: 10.1016/j.surg.2021.01.042] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 01/18/2021] [Accepted: 01/24/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Ischemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. METHODS Intestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti-high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. RESULTS Significant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti-high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. CONCLUSION These results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.
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Affiliation(s)
- Han-Jin Lai
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ya-Qing Zhan
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yu-Xin Qiu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yi-Hong Ling
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
| | - Xu-Yu Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ze-Nan Chang
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Yi-Nan Zhang
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Zi-Meng Liu
- Department of Critical Care Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
| | - Shi-Hong Wen
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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Secretory Sorcery: Paneth Cell Control of Intestinal Repair and Homeostasis. Cell Mol Gastroenterol Hepatol 2021; 12:1239-1250. [PMID: 34153524 PMCID: PMC8446800 DOI: 10.1016/j.jcmgh.2021.06.006] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 12/18/2022]
Abstract
Paneth cells are professional secretory cells that classically play a role in the innate immune system by secreting antimicrobial factors into the lumen to control enteric bacteria. In this role, Paneth cells are able to sense cues from luminal bacteria and respond by changing production of these factors to protect the epithelial barrier. Paneth cells rely on autophagy to regulate their secretory capability and capacity. Disruption of this pathway through mutation of genes, such as Atg16L1, results in decreased Paneth cell function, dysregulated enteric microbiota, decreased barrier integrity, and increased risk of diseases such as Crohn's disease in humans. Upon differentiation Paneth cells migrate downward and intercalate among active intestinal stem cells at the base of small intestinal crypts. This localization puts them in a unique position to interact with active intestinal stem cells, and recent work shows that Paneth cells play a critical role in influencing the intestinal stem cell niche. This review discusses the numerous ways Paneth cells can influence intestinal stem cells and their niche. We also highlight the ways in which Paneth cells can alter cells and other organ systems.
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Yang J, Meng M, Pan C, Qian L, Sun Y, Shi H, Shen Y, Dou W. Intravoxel Incoherent Motion and Dynamic Contrast-Enhanced Magnetic Resonance Imaging to Early Detect Tissue Injury and Microcirculation Alteration in Hepatic Injury Induced by Intestinal Ischemia-Reperfusion in a Rat Model. J Magn Reson Imaging 2021; 54:751-760. [PMID: 33749079 PMCID: PMC8451931 DOI: 10.1002/jmri.27604] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/21/2022] Open
Abstract
Background Intravoxel incoherent motion (IVIM) can provide quantitative information about water diffusion and perfusion that can be used to evaluate hepatic injury, but it has not been studied in hepatic injury induced by intestinal ischemia–reperfusion (IIR). Dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) can provide perfusion data, but it is unclear whether it can provide useful information for assessing hepatic injury induced by IIR. Purpose To examine whether IVIM and DCE‐MRI can detect early IIR‐induced hepatic changes, and to evaluate the relationship between IVIM and DCE‐derived parameters and biochemical indicators and histological scores. Study Type Prospective pre‐clinical study. Population Forty‐two male Sprague–Dawley rats. Field Strength/Sequence IVIM‐diffusion‐weighted imaging (DWI) using diffusion‐weighted echo‐planar imaging sequence and DCE‐MRI using fast spoiled gradient recalled‐based sequence at 3.0 T. Assessment All rats were randomly divided into the control group (Sham), the simple ischemia group, the ischemia–reperfusion (IR) group (IR1h, IR2h, IR3h, and IR4h) in a model of secondary hepatic injury caused by IIR, and IIR was induced by clamping the superior mesenteric artery for 60 minutes and then removing the vascular clamp. Advanced Workstation (AW) 4.6 was used to calculate the imaging parameters (apparent diffusion coefficient [ADC], true diffusion coefficient [D], perfusion‐related diffusion [D*] and volume fraction [f]) of IVIM. OmniKinetics (OK) software was used to calculate the DCE imaging parameters (Ktrans, Kep, and Ve). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed with an automatic biochemical analyzer. Superoxide dismutase (SOD) activity was assessed using the nitro‐blue tetrazolium method. Malondialdehyde (MDA) was determined by thiobarbituric acid colorimetry. Histopathology was performed with hematoxylin and eosin staining. Statistical Tests One‐way analysis of variance (ANOVA) and Bonferroni post‐hoc tests were used to analyze the imaging parameters and biochemical indicators among the different groups. Pearson correlation analysis was applied to determine the correlation between imaging parameters and biochemical indicators or histological score. Results ALT and MDA reached peak levels at IR4h, while SOD reached the minimum level at IR4h (all P < 0.05). ADC, D, D*, and f gradually decreased as reperfusion continued, and Ktrans and Ve gradually increased (all P < 0.05). The degrees of change for f and Ve were greater than those of other imaging parameters at IR1h (all P < 0.05). All groups showed good correlation between imaging parameters and SOD and MDA (r[ADC] = 0.615, −0.666, r[D] = 0.493, −0.612, r[D*] = 0.607, −0.647, r[f] = 0.637, −0.682, r[Ktrans] = −0.522, 0.500, r[Ve] = −0.590, 0.665, respectively; all P < 0.05). However, the IR groups showed poor or no correlation between the imaging parameters and SOD and MDA (P [Ktrans and MDA] = 0.050, P [D and SOD] = 0.125, P [the remaining imaging parameters] < 0.05). All groups showed a positive correlation between histological score and Ktrans and Ve (r = 0.775, 0.874, all P < 0.05), and a negative correlation between histological score and ADC, D, f, and D* (r = −0.739, −0.821, −0.868, −0.841, respectively; all P < 0.05). For the IR groups, there was a positive correlation between histological score and Ktrans and Ve (r = 0.747, 0.802, all P < 0.05), and a negative correlation between histological score and ADC, D, f, and D* (r = −0.567, −0.712, −0.715, −0.779, respectively; all P < 0.05). Data Conclusion The combined application of IVIM and DCE‐MRI has the potential to be used as an imaging tool for monitoring IIR‐induced hepatic histopathology. Level of Evidence 1 Technical Efficacy Stage 2
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Affiliation(s)
- Jiaxing Yang
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
- Graduate CollegeDalian Medical UniversityDalianChina
| | - Mingzhu Meng
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
| | - Changjie Pan
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
| | - Liulan Qian
- Department of Science and EducationChangzhou Second People's HospitalChangzhouChina
| | - Yangyang Sun
- Department of PathologyChangzhou Second People's HospitalChangzhouChina
| | - Haifeng Shi
- Department of RadiologyChangzhou Second People's HospitalChangzhouChina
| | - Yong Shen
- Department of Enhanced ApplicationGE Healthcare ChinaBeijingChina
| | - Weiqiang Dou
- Department of MR ResearchGE Healthcare ChinaBeijingChina
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Jo SK. Kidney-Gut Crosstalk in AKI. KIDNEY360 2021; 2:886-889. [PMID: 35373056 PMCID: PMC8791352 DOI: 10.34067/kid.0007722020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 02/19/2021] [Indexed: 02/04/2023]
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Yu J, He X, Wei A, Liu T, Zhang Q, Pan Y, Hao Z, Yang L, Yuan Y, Zhang Z, Zhang C, Hao C, Liu Z, Li W. HPS1 Regulates the Maturation of Large Dense Core Vesicles and Lysozyme Secretion in Paneth Cells. Front Immunol 2020; 11:560110. [PMID: 33224134 PMCID: PMC7674556 DOI: 10.3389/fimmu.2020.560110] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
HPS1, a BLOC-3 subunit that acts as a guanine nucleotide exchange factor of Rab32/38, may play a role in the removal of VAMP7 during the maturation of large dense core vesicles of Paneth cells. Loss of HPS1 impairs lysozyme secretion and alters the composition of intestinal microbiota, which may explain the susceptibility of HPS-associated inflammatory bowel disease. Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding tendency, and other chronic organ lesions due to defects in tissue-specific lysosome-related organelles (LROs). For some HPS subtypes, such as HPS-1, it is common to have symptoms of HPS-associated inflammatory bowel disease (IBD). However, its underlying mechanism is largely unknown. HPS1 is a subunit of the BLOC-3 complex which functions in the biogenesis of LROs. Large dense core vesicles (LDCVs) in Paneth cells of the intestine are a type of LROs. We here first report the abnormal LDCV morphology (increased number and enlarged size) in HPS1-deficient pale ear (ep) mice. Similar to its role in melanosome maturation, HPS1 plays an important function in the removal of VAMP7 from LDCVs to promote the maturation of LDCVs. The immature LDCVs in ep mice are defective in regulated secretion of lysozyme, a key anti-microbial peptide in the intestine. We observed changes in the composition of intestinal microbiota in both HPS-1 patients and ep mice. These findings provide insights into the underlying mechanism of HPS-associated IBD development, which may be implicated in possible therapeutic intervention of this devastating condition.
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Affiliation(s)
- Jiaying Yu
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.,University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Xin He
- University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Aihua Wei
- Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Teng Liu
- Department of Dermatology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Qin Zhang
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Ying Pan
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Zhenhua Hao
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Lin Yang
- University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yefeng Yuan
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Zhao Zhang
- University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Chang Zhang
- University of Chinese Academy of Sciences, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Chanjuan Hao
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Zhihua Liu
- Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
| | - Wei Li
- Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
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Sharma N, Gaikwad AB. Ameliorative effect of AT2R and ACE2 activation on ischemic renal injury associated cardiac and hepatic dysfunction. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2020; 80:103501. [PMID: 32979558 DOI: 10.1016/j.etap.2020.103501] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 09/12/2020] [Accepted: 09/17/2020] [Indexed: 06/11/2023]
Abstract
This study explored the role of the depressor arm of renin-angiotensin system (RAS) on ischemic renal injury (IRI)-associated cardio-hepatic sequalae under non-diabetic (ND) and diabetes mellitus (DM) conditions. Firstly, rats were injected with Streptozotocin (55 mg/kg i.p.) to develop DM. ND and DM rats underwent Bilateral IRI followed by 24 h of reperfusion. Further, ND and DM rats were subjected to AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator- Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or its combination therapy. As results, IRI caused cardio-hepatic injuries via altered oxidant/anti-oxidant levels, elevated inflammatory events, and altered protein expressions of ACE, ACE2, Ang II, Ang-(1-7) and urinary AGT. However, concomitant therapy of AT2R agonist and ACE2 activator exerts a protective effect in IRI-associated cardio-hepatic dysfunction as evidenced by inhibited oxidative stress, downregulated inflammation, and enhanced cardio-hepatic depressor arm of RAS under ND and DM conditions.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
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Sabapathy V, Venkatadri R, Dogan M, Sharma R. The Yin and Yang of Alarmins in Regulation of Acute Kidney Injury. Front Med (Lausanne) 2020; 7:441. [PMID: 32974364 PMCID: PMC7472534 DOI: 10.3389/fmed.2020.00441] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 07/06/2020] [Indexed: 12/16/2022] Open
Abstract
Acute kidney injury (AKI) is a major clinical burden affecting 20 to 50% of hospitalized and intensive care patients. Irrespective of the initiating factors, the immune system plays a major role in amplifying the disease pathogenesis with certain immune cells contributing to renal damage, whereas others offer protection and facilitate recovery. Alarmins are small molecules and proteins that include granulysins, high-mobility group box 1 protein, interleukin (IL)-1α, IL-16, IL-33, heat shock proteins, the Ca++ binding S100 proteins, adenosine triphosphate, and uric acid. Alarmins are mostly intracellular molecules, and their release to the extracellular milieu signals cellular stress or damage, generally leading to the recruitment of the cells of the immune system. Early studies indicated a pro-inflammatory role for the alarmins by contributing to immune-system dysregulation and worsening of AKI. However, recent developments demonstrate anti-inflammatory mechanisms of certain alarmins or alarmin-sensing receptors, which may participate in the prevention, resolution, and repair of AKI. This dual function of alarmins is intriguing and has confounded the role of alarmins in AKI. In this study, we review the contribution of various alarmins to the pathogenesis of AKI in experimental and clinical studies. We also analyze the approaches for the therapeutic utilization of alarmins for AKI.
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Affiliation(s)
| | | | | | - Rahul Sharma
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine (CIIR), University of Virginia, Charlottesville, VA, United States
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Han SJ, Kim M, Novitsky E, D'Agati V, Lee HT. Intestinal TLR9 deficiency exacerbates hepatic IR injury via altered intestinal inflammation and short-chain fatty acid synthesis. FASEB J 2020; 34:12083-12099. [PMID: 32738096 DOI: 10.1096/fj.202000314r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 06/22/2020] [Accepted: 06/28/2020] [Indexed: 12/13/2022]
Abstract
Mice deficient in intestinal epithelial TLR9 develop small intestinal Paneth cell hyperplasia and higher Paneth cell IL-17A levels. Since small intestinal Paneth cells and IL-17A play critical roles in hepatic ischemia reperfusion (IR) injury, we tested whether mice lacking intestinal TLR9 have increased hepatic IR injury. Mice lacking intestinal TLR9 had profoundly increased liver injury after hepatic IR compared to WT mice with exacerbated hepatocyte necrosis, apoptosis, neutrophil infiltration, and inflammatory cytokine generation. Moreover, we observed increased small intestinal inflammation and apoptosis after hepatic IR in intestinal TLR9 deficient mice. As a potential explanation for increased hepatic IR injury, fecal short-chain fatty acids butyrate and propionate levels were lower in intestinal TLR9 deficient mice. Suggesting a potential therapy for hepatic IR, exogenous administration of butyrate or propionate protected against hepatic IR injury in intestinal TLR9 deficient mice. Mechanistically, butyrate induced small intestinal IL-10 expression and downregulated the claudin-2 expression. Finally, IL-10 neutralization abolished the protective effects of butyrate against hepatic IR injury. Our studies show intestinal TLR9 deficiency results in exacerbated hepatic IR injury with increased small intestinal apoptosis and inflammation. Furthermore, short-chain fatty acids butyrate and propionate protect against hepatic IR injury and intestinal apoptosis/inflammation in intestinal TLR9 deficient mice.
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Affiliation(s)
- Sang Jun Han
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Mihwa Kim
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Ella Novitsky
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Vivette D'Agati
- Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - H Thomas Lee
- Anesthesiology Research Laboratories, Department of Anesthesiology, Columbia University, New York, NY, USA
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Risk of incident bleeding after acute kidney injury: A retrospective cohort study. J Crit Care 2020; 59:23-31. [PMID: 32485439 DOI: 10.1016/j.jcrc.2020.05.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/07/2020] [Accepted: 05/13/2020] [Indexed: 12/20/2022]
Abstract
PURPOSE End-stage kidney disease (ESKD) causes bleeding diathesis; however, whether these findings are extrapolable to acute kidney injury (AKI) remains uncertain. We assessed whether AKI is associated with an increased risk of bleeding. METHODS Single-center retrospective cohort study, excluding readmissions, admissions <24 h, ESKD or kidney transplants. The primary outcome was the development of incident bleeding analyzed by multivariate time-dependent Cox models. RESULTS In 1001 patients, bleeding occurred in 48% of AKI and 57% of non-AKI patients (p = .007). To identify predictors of incident bleeding, we excluded patients who bled before ICU (n = 488). In bleeding-free patients (n = 513), we observed a trend toward higher risks of bleeding in AKI (22% vs. 16%, p = .06), and a higher risk of bleeding in AKI-requiring dialysis (38% vs. 17%, p = .01). Cirrhosis, AKI-requiring dialysis, anticoagulation, and coronary artery disease were associated with bleeding (HR 3.67, 95%CI:1.33-10.25; HR 2.82, 95%CI:1.26-6.32; HR 2.34, 95%CI:1.45-3.80; and HR 1.84, 95%CI:1.06-3.20, respectively), while SOFA score and sepsis had a protective association (HR 0.92 95%CI:0.84-0.99 and HR 0.55, 95%CI:0.34-0.91, respectively). Incident bleeding was not associated with mortality. CONCLUSIONS AKI-requiring dialysis was associated with incident bleeding, independent of anticoagulant administration. Studies are needed to better understand how AKI affects coagulation and clinical outcomes.
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Han SJ, Williams RM, D'Agati V, Jaimes EA, Heller DA, Lee HT. Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury. Kidney Int 2020; 98:76-87. [PMID: 32386967 DOI: 10.1016/j.kint.2020.01.036] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/24/2020] [Accepted: 01/31/2020] [Indexed: 12/12/2022]
Abstract
We developed an innovative therapy for ischemic acute kidney injury with discerning kidney-targeted delivery of a selective Toll-like receptor 9 (TLR9) antagonist in mice subjected to renal ischemia reperfusion injury. Our previous studies showed that mice deficient in renal proximal tubular TLR9 were protected against renal ischemia reperfusion injury demonstrating a critical role for renal proximal tubular TLR9 in generating ischemic acute kidney injury. Herein, we used 300-400 nm polymer-based mesoscale nanoparticles that localize to the renal tubules after intravenous injection. Mice were subjected to sham surgery or 30 minutes renal ischemia and reperfusion injury after receiving mesoscale nanoparticles encapsulated with a selective TLR9 antagonist (unmethylated CpG oligonucleotide ODN2088) or mesoscale nanoparticles encapsulating a negative control oligonucleotide. Mice treated with the encapsulated TLR9 antagonist either six hours before renal ischemia, at the time of reperfusion or 1.5 hours after reperfusion were protected against ischemic acute kidney injury. The ODN2088-encapsulated nanoparticles attenuated renal tubular necrosis, inflammation, decreased proinflammatory cytokine synthesis. neutrophil and macrophage infiltration and apoptosis, decreased DNA fragmentation and caspase 3/8 activation when compared to the negative control nanoparticle treated mice. Taken together, our studies further suggest that renal proximal tubular TLR9 activation exacerbates ischemic acute kidney injury by promoting renal tubular inflammation, apoptosis and necrosis after ischemia reperfusion. Thus, our studies suggest a potential promising therapy for ischemic acute kidney injury with selective kidney tubular targeting of TLR9 using mesoscale nanoparticle-based drug delivery.
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Affiliation(s)
- Sang Jun Han
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA
| | - Ryan M Williams
- Department of Molecular Pharmacology & Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Biomedical Engineering, City College of New York, New York, New York, USA
| | - Vivette D'Agati
- Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York, USA
| | - Edgar A Jaimes
- Renal Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Daniel A Heller
- Department of Molecular Pharmacology & Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
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Gumbert SD, Kork F, Jackson ML, Vanga N, Ghebremichael SJ, Wang CY, Eltzschig HK. Perioperative Acute Kidney Injury. Anesthesiology 2020; 132:180-204. [PMID: 31687986 PMCID: PMC10924686 DOI: 10.1097/aln.0000000000002968] [Citation(s) in RCA: 162] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Perioperative organ injury is among the leading causes of morbidity and mortality of surgical patients. Among different types of perioperative organ injury, acute kidney injury occurs particularly frequently and has an exceptionally detrimental effect on surgical outcomes. Currently, acute kidney injury is most commonly diagnosed by assessing increases in serum creatinine concentration or decreased urine output. Recently, novel biomarkers have become a focus of translational research for improving timely detection and prognosis for acute kidney injury. However, specificity and timing of biomarker release continue to present challenges to their integration into existing diagnostic regimens. Despite many clinical trials using various pharmacologic or nonpharmacologic interventions, reliable means to prevent or reverse acute kidney injury are still lacking. Nevertheless, several recent randomized multicenter trials provide new insights into renal replacement strategies, composition of intravenous fluid replacement, goal-directed fluid therapy, or remote ischemic preconditioning in their impact on perioperative acute kidney injury. This review provides an update on the latest progress toward the understanding of disease mechanism, diagnosis, and managing perioperative acute kidney injury, as well as highlights areas of ongoing research efforts for preventing and treating acute kidney injury in surgical patients.
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Affiliation(s)
- Sam D. Gumbert
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Felix Kork
- Department of Anaesthesiology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany
| | - Maisie L. Jackson
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Naveen Vanga
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Semhar J. Ghebremichael
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Christy Y. Wang
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
| | - Holger K. Eltzschig
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030
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Han SJ, Lee HT. Mechanisms and therapeutic targets of ischemic acute kidney injury. Kidney Res Clin Pract 2019; 38:427-440. [PMID: 31537053 PMCID: PMC6913588 DOI: 10.23876/j.krcp.19.062] [Citation(s) in RCA: 170] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 07/13/2019] [Accepted: 07/17/2019] [Indexed: 12/19/2022] Open
Abstract
Acute kidney injury (AKI) due to renal ischemia reperfusion (IR) is a major clinical problem without effective therapy and is a significant and frequent cause of morbidity and mortality during the perioperative period. Although the pathophysiology of ischemic AKI is not completely understood, several important mechanisms of renal IR-induced AKI have been studied. Renal ischemia and subsequent reperfusion injury initiates signaling cascades mediating renal cell necrosis, apoptosis, and inflammation, leading to AKI. Better understanding of the molecular and cellular pathophysiological mechanisms underlying ischemic AKI will provide more targeted approach to prevent and treat renal IR injury. In this review, we summarize important mechanisms of ischemic AKI, including renal cell death pathways and the contribution of endothelial cells, epithelial cells, and leukocytes to the inflammatory response during ischemic AKI. Additionally, we provide some updated potential therapeutic targets for the prevention or treatment of ischemic AKI, including Toll-like receptors, adenosine receptors, and peptidylarginine deiminase 4. Finally, we propose mechanisms of ischemic AKI-induced liver, intestine, and kidney dysfunction and systemic inflammation mainly mediated by Paneth cell degranulation as a potential explanation for the high mortality observed with AKI.
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Affiliation(s)
- Sang Jun Han
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY, USA
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Ducray HAG, Globa L, Pustovyy O, Roberts MD, Rudisill M, Vodyanoy V, Sorokulova I. Prevention of excessive exercise-induced adverse effects in rats with Bacillus subtilis BSB3. J Appl Microbiol 2019; 128:1163-1178. [PMID: 31814258 PMCID: PMC7079029 DOI: 10.1111/jam.14544] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/21/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Aims To characterize efficacy of the Bacillus subtilis BSB3 (BSB3) strain in the prevention of excessive exercise‐induced side effects and in maintaining stability of the gut microbiota. Methods and Results Rats were pretreated by oral gavage with B. subtilis BSB3 (BSB3) or with phosphate‐buffered saline (PBS) twice a day for 2 days, and were either exposed forced treadmill running or remained sedentary. Histological analysis of intestine, immunofluorescence staining of tight junction (TJ) proteins, serum lipopolysaccharide and intestinal fatty acid‐binding protein assay, culture‐based analysis and pyrosequencing for the gut microbiota were performed for each rat. Forced running resulted in a substantial decrease in intestinal villi height and total mucosa thickness, the depletion of Paneth cells, an inhibition of TJ proteins expression. Short‐term treatment of rats with BSB3 before running prevented these adverse effects. Culture‐based analysis of the gut microbiota revealed significant elevation of pathogenic microorganisms only in treadmill‐exercised rats pretreated with PBS. High‐throughput 16S rRNA gene sequencing also revealed an increase in pathobionts in this group. Preventive treatment of animals with BSB3 resulted in predominance of beneficial bacteria. Conclusions BSB3 prevents excessive exercise‐associated complications by beneficial modulation of the gut microbiota. Significance and Impact of the Study Our study shows a new application of beneficial bacteria for prevention the adverse effects of excessive exercise.
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Affiliation(s)
- H A G Ducray
- Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, AL, USA
| | - L Globa
- Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, AL, USA
| | - O Pustovyy
- Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, AL, USA
| | - M D Roberts
- School of Kinesiology, Auburn University, Auburn, AL, USA
| | - M Rudisill
- School of Kinesiology, Auburn University, Auburn, AL, USA
| | - V Vodyanoy
- Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, AL, USA
| | - I Sorokulova
- Department of Anatomy, Physiology and Pharmacology, Auburn University, Auburn, AL, USA
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Han SJ, Kim M, D'Agati VD, Lee HT. Norepinephrine released by intestinal Paneth cells exacerbates ischemic AKI. Am J Physiol Renal Physiol 2019; 318:F260-F272. [PMID: 31813250 DOI: 10.1152/ajprenal.00471.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrated larger increases in portal venous norepinephrine levels compared with plasma norepinephrine in mice, consistent with an intestinal source of norepinephrine release after renal ischemia and reperfusion. We demonstrated that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrated mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts expressed significantly higher norepinephrine levels after ischemic AKI compared with sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induced norepinephrine release in the small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with the selective α-adrenergic antagonists yohimbine and phentolamine protected against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation, and apoptosis and less hepatic dysfunction. Taken together, we identify Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.
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Affiliation(s)
- Sang Jun Han
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - Mihwa Kim
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - Vivette Denise D'Agati
- Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
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Lai Y, Deng J, Wang M, Wang M, Zhou L, Meng G, Zhou Z, Wang Y, Guo F, Yin M, Zhou X, Jiang H. Vagus nerve stimulation protects against acute liver injury induced by renal ischemia reperfusion via antioxidant stress and anti-inflammation. Biomed Pharmacother 2019; 117:109062. [PMID: 31177065 DOI: 10.1016/j.biopha.2019.109062] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 05/31/2019] [Accepted: 05/31/2019] [Indexed: 10/26/2022] Open
Abstract
OBJECTIVE Renal ischemia reperfusion (I/R) is not an isolated event; however, it results in remote organ dysfunction. Vagus nerve stimulation (VNS) has shown protective effects against renal I/R injury via an anti-inflammatory mechanism. This study aimed to investigate whether VNS could attenuate liver injury induced by renal I/R and identify the underlying mechanisms. METHODS Eighteen healthy male Sprague-Dawley rats (200-250 g) were equally divided into three groups: sham group (sham surgery without I/R or VNS), I/R group (renal I/R) and VNS group (renal I/R plus VNS). The I/R model was established by excising the right kidney and then clamping the left renal pedicle with an occlusive nontraumatic microaneurysm clamp for 45 min followed by a 6-h reperfusion. The rats in the VNS group received spontaneous left cervical VNS with renal ischemia and reperfusion. At the end of the experiment, blood and liver tissues were collected to detect liver function, oxidative stress and inflammatory parameters. Additionally, TUNEL staining, real-time PCR, western blotting and hematoxylin and eosin staining of liver tissues were performed to assess liver injury and the underlying mechanisms. RESULTS Kidney and liver function was severely damaged in the I/R group compared to the sham group. However, VNS significantly protected kidney and liver function. Rats treated with VNS revealed decreases in oxidative enzymes, apoptosis and levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in serum and liver compared with rats in the I/R group. Rats in the VNS group also showed increased antioxidant stress responses compared to rats in the I/R group. CONCLUSION VNS exerts protective effects against liver injury from renal I/R via inhibiting oxidative stress and apoptosis, downregulating inflammatory cytokines and enhancing antioxidative capability in the liver, and may become a promising adjuvant therapeutic strategy for treating liver injury induced by acute renal injury.
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Affiliation(s)
- Yanqiu Lai
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Jielin Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Meng Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Liping Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Guannan Meng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Zhen Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Yuhong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Fuding Guo
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Ming Yin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Xiaoya Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China.
| | - Hong Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China.
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Han SJ, Li H, Kim M, D’Agati V, Lee HT. Intestinal Toll-like receptor 9 deficiency leads to Paneth cell hyperplasia and exacerbates kidney, intestine, and liver injury after ischemia/reperfusion injury. Kidney Int 2019; 95:859-879. [DOI: 10.1016/j.kint.2018.10.035] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 10/09/2018] [Accepted: 10/24/2018] [Indexed: 01/02/2023]
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Teixeira JP, Ambruso S, Griffin BR, Faubel S. Pulmonary Consequences of Acute Kidney Injury. Semin Nephrol 2019; 39:3-16. [DOI: 10.1016/j.semnephrol.2018.10.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Risk of de novo infection following acute kidney injury: A retrospective cohort study. J Crit Care 2018; 48:9-14. [PMID: 30121515 DOI: 10.1016/j.jcrc.2018.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 07/16/2018] [Accepted: 08/06/2018] [Indexed: 01/09/2023]
Abstract
PURPOSE Recent studies suggest that acute kidney injury (AKI) can affect distant organ function and increase non-renal complications. We determined whether AKI is associated with an increased risk of incident infections. MATERIAL AND METHODS We conducted a one-year single-center retrospective cohort study, excluding patients readmitted to the ICU or for <24 h, on chronic dialysis, and kidney transplant recipients. The primary outcome was the development of incident infections analyzed by multivariate time-dependent Cox models. RESULTS Of the 1001 included patients, infections were more frequent in those with AKI (62% vs. 37% without AKI; p < .001). To characterize predictors of incident infections, we excluded patients with an infection until ICU admission (n = 244). Patients with AKI presented infections more often than without AKI (44% vs. 20%; p < .001). AKI, chronic obstructive pulmonary disease, and mechanical ventilation (MV) were associated with incident infections (HR 1.62, 95%CI:1.15-2.30, HR 1.51, 95%CI 1.04-2.18 and HR 2.14, 95%CI:1.48-3.09, respectively) while age, MV, higher fluid balance, and AKI were independent predictors of mortality. CONCLUSIONS AKI was associated with incident in-hospital infections. However, newly occurring infections were not associated with an increased risk of mortality. Further studies are needed to understand how AKI affects distant organ function and associated clinical outcomes.
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Lee SA, Cozzi M, Bush EL, Rabb H. Distant Organ Dysfunction in Acute Kidney Injury: A Review. Am J Kidney Dis 2018; 72:846-856. [PMID: 29866457 DOI: 10.1053/j.ajkd.2018.03.028] [Citation(s) in RCA: 164] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 03/25/2018] [Indexed: 01/09/2023]
Abstract
Acute kidney injury (AKI) is common in critically ill patients and is associated with increased morbidity and mortality. Dysfunction of other organs is an important cause of poor outcomes from AKI. Ample clinical and epidemiologic data show that AKI is associated with distant organ dysfunction in lung, heart, brain, and liver. Recent advancements in basic and clinical research have demonstrated physiologic and molecular mechanisms of distant organ interactions in AKI, including leukocyte activation and infiltration, generation of soluble factors such as inflammatory cytokines/chemokines, and endothelial injury. Oxidative stress and production of reactive oxygen species, as well as dysregulation of cell death in distant organs, are also important mechanism of AKI-induced distant organ dysfunction. This review updates recent clinical and experimental findings on organ crosstalk in AKI and highlights potential molecular mechanisms and therapeutic targets to improve clinical outcomes during AKI.
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Affiliation(s)
- Sul A Lee
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Yonsei University College of Medicine, Seoul, South Korea
| | - Martina Cozzi
- Department of Nephrology and Dialysis, Azienda Sanitaria Universitaria Integrata di Trieste, Trieste, Italy
| | - Errol L Bush
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Hamid Rabb
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
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Choi YJ, Zhou D, Barbosa ACS, Niu Y, Guan X, Xu M, Ren S, Nolin TD, Liu Y, Xie W. Activation of Constitutive Androstane Receptor Ameliorates Renal Ischemia-Reperfusion-Induced Kidney and Liver Injury. Mol Pharmacol 2018; 93:239-250. [PMID: 29351922 PMCID: PMC5801556 DOI: 10.1124/mol.117.111146] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 01/05/2018] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) is associate with high mortality. Despite evidence of AKI-induced distant organ injury, a relationship between AKI and liver injury has not been clearly established. The goal of this study is to investigate whether renal ischemia-reperfusion (IR) can affect liver pathophysiology. We showed that renal IR in mice induced fatty liver and compromised liver function through the downregulation of constitutive androstane receptor (CAR; -90.4%) and inhibition of hepatic very-low-density lipoprotein triglyceride (VLDL-TG) secretion (-28.4%). Treatment of mice with the CAR agonist 1,4-bis[2-(3,5 dichloropyridyloxy)] benzene (TCPOBOP) prevented the development of AKI-induced fatty liver and liver injury, which was associated with the attenuation of AKI-induced inhibition of VLDL-TG secretion. The hepatoprotective effect of TCPOBOP was abolished in CAR-/- mice. Interestingly, alleviation of fatty liver by TCPOBOP also improved the kidney function, whereas CAR ablation sensitized mice to AKI-induced kidney injury and lethality. The serum concentrations of interleukin-6 (IL-6) were elevated by 27-fold after renal IR, but were normalized in TCPOBOP-treated AKI mice, suggesting that the increased release of IL-6 from the kidney may have mediated the AKI responsive liver injury. Taken together, our results revealed an interesting kidney-liver organ cross-talk in response to AKI. Given the importance of CAR in the pathogenesis of renal IR-induced fatty liver and impaired kidney function, fatty liver can be considered as an important risk factor for kidney injury, and a timely management of hepatic steatosis by CAR activation may help to restore kidney function in patients with AKI or kidney transplant.
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Affiliation(s)
- You-Jin Choi
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Dong Zhou
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Anne Caroline S Barbosa
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Yongdong Niu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Xiudong Guan
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Meishu Xu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Songrong Ren
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Thomas D Nolin
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Youhua Liu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences (Y.-J.C., A.C.S.B., Y.N, M.X., S.R., W.X.), Department of Pathology, School of Medicine (D.Z., Y.L.), Center for Clinical Pharmaceutical Sciences, Department of Pharmacy and Therapeutics, School of Pharmacy (T.D.N), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, China (Y.N.); and Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (X.G.)
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Dysbiosis of intestinal microbiota and decrease in paneth cell antimicrobial peptide level during acute necrotizing pancreatitis in rats. PLoS One 2017; 12:e0176583. [PMID: 28441432 PMCID: PMC5404871 DOI: 10.1371/journal.pone.0176583] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Intestinal barrier dysfunction plays an important role in acute necrotizing pancreatitis (ANP) and intestinal microbiota dysbiosis was involved in intestinal barrier failure. Paneth cells protect intestinal barrier and are associated with intestinal microbiota. Here, we investigated changes in intestinal microbiota and antimicrobial peptides of Paneth cells in ileum during ANP. METHODS Rats with ANP were established by retrograde injection of 3.5% sodium taurocholate into biliopancreatic duct and sacrificed at 24h and 48h, respectively. Injuries of pancreas and distal ileum were evaluated by histopathological score. Intestinal barrier function was assessed by plasma diamine oxidase activity (DAO) and D-lactate. Systemic and intestinal inflammation was evaluated by TNFα, IL-1β and IL-17A concentration by ELISA, respectively. 16S rRNA high throughput sequencing on fecal samples was used to investigate the changes in intestinal microbiota in the ANP group at 48h. Lysozyme and α-defensin5 were measured by real-time PCR, western blot and immunofluoresence. RESULTS ANP rats had more severe histopathological injuries in pancreas and distal ileum, injured intestinal barrier and increased expression of TNFα, IL-1β and IL-17A in plasma and distal ileum compared with those of the sham-operated (SO) group. Principal component analysis (PCA) showed structural segregation between the SO and ANP groups. Operational taxonomic unit (OTU) number and ACE index revealed decreased microbiota diversity in the ANP group. Taxonomic analysis showed dysbiosis of intestinal microbiota structure. At phyla level, Saccharibacteria and Tenericutes decreased significantly. At genus level, Escherichia-Shigella and Phascolarctobacterium increased significantly, while Candidatus_Saccharimonas, Prevotellaceae_UCG-001, Lachnospiraceae_UCG-001, Ruminiclostridium_5 and Ruminococcaceae_UCG-008 decreased significantly. Lysozyme and α-defensin5 mRNA expression levels decreased significantly in ANP group at 48h. Protein expression of lysozyme decreased in ANP groups at 24h and 48h. Meanwhile, the relative abundance of Escherichia-Shigella correlated inversely with the decrease in lysozyme. CONCLUSION The disorder in intestinal microbiota and decreases of Paneth cell antimicrobial peptides might participate in the pathogenesis of intestinal barrier dysfunction during ANP.
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Altmann C, Ahuja N, Kiekhaefer CM, Andres Hernando A, Okamura K, Bhargava R, Duplantis J, Kirkbride-Romeo LA, Huckles J, Fox BM, Kahn K, Soranno D, Gil HW, Teitelbaum I, Faubel S. Early peritoneal dialysis reduces lung inflammation in mice with ischemic acute kidney injury. Kidney Int 2017; 92:365-376. [PMID: 28318621 DOI: 10.1016/j.kint.2017.01.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 01/10/2017] [Accepted: 01/12/2017] [Indexed: 01/18/2023]
Abstract
Although dialysis has been used in the care of patients with acute kidney injury (AKI) for over 50 years, very little is known about the potential benefits of uremic control on systemic complications of AKI. Since the mortality of AKI requiring renal replacement therapy (RRT) is greater than half in the intensive care unit, a better understanding of the potential of RRT to improve outcomes is urgently needed. Therefore, we sought to develop a technically feasible and reproducible model of RRT in a mouse model of AKI. Models of low- and high-dose peritoneal dialysis (PD) were developed and their effect on AKI, systemic inflammation, and lung injury after ischemic AKI was examined. High-dose PD had no effect on AKI, but effectively cleared serum IL-6, and dramatically reduced lung inflammation, while low-dose PD had no effect on any of these three outcomes. Both models of RRT using PD in AKI in mice reliably lowered urea in a dose-dependent fashion. Thus, use of these models of PD in mice with AKI has great potential to unravel the mechanisms by which RRT may improve the systemic complications that have led to increased mortality in AKI. In light of recent data demonstrating reduced serum IL-6 and improved outcomes with prophylactic PD in children, we believe that our results are highly clinically relevant.
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Affiliation(s)
- Chris Altmann
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Nilesh Ahuja
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Carol M Kiekhaefer
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Ana Andres Hernando
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Kayo Okamura
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Rhea Bhargava
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Jane Duplantis
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | | | - Jill Huckles
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Benjamin M Fox
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Kashfi Kahn
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Danielle Soranno
- Department of Pediatrics and Bioengineering, University of Colorado Denver, Aurora, Colorado, USA
| | - Hyo-Wook Gil
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA; Department of Internal Medicine, Soonchunhyang University, Cheonan Hospital, Cheonan, Republic of Korea
| | - Isaac Teitelbaum
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA
| | - Sarah Faubel
- University of Colorado Denver, Internal Medicine, Renal, Aurora, Colorado, USA.
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de Jong PR, González-Navajas JM, Jansen NJG. The digestive tract as the origin of systemic inflammation. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2016; 20:279. [PMID: 27751165 PMCID: PMC5067918 DOI: 10.1186/s13054-016-1458-3] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Failure of gut homeostasis is an important factor in the pathogenesis and progression of systemic inflammation, which can culminate in multiple organ failure and fatality. Pathogenic events in critically ill patients include mesenteric hypoperfusion, dysregulation of gut motility, and failure of the gut barrier with resultant translocation of luminal substrates. This is followed by the exacerbation of local and systemic immune responses. All these events can contribute to pathogenic crosstalk between the gut, circulating cells, and other organs like the liver, pancreas, and lungs. Here we review recent insights into the identity of the cellular and biochemical players from the gut that have key roles in the pathogenic turn of events in these organ systems that derange the systemic inflammatory homeostasis. In particular, we discuss the dangers from within the gastrointestinal tract, including metabolic products from the liver (bile acids), digestive enzymes produced by the pancreas, and inflammatory components of the mesenteric lymph.
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Affiliation(s)
- Petrus R de Jong
- Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. .,Sanford Burnham Prebys Medical Discovery Institute, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
| | - José M González-Navajas
- Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Hospital General Universitario de Alicante, Alicante, Spain.,Alicante Institute of Health and Biomedical Research (ISABIAL - FISABIO Foundation), Alicante, Spain
| | - Nicolaas J G Jansen
- Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
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Rabadi M, Kim M, D'Agati V, Lee HT. Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion. Am J Physiol Renal Physiol 2016; 311:F437-49. [PMID: 27335376 PMCID: PMC5008675 DOI: 10.1152/ajprenal.00254.2016] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 06/13/2016] [Indexed: 11/22/2022] Open
Abstract
We previously demonstrated that renal peptidyl arginine deiminase-4 (PAD4) is induced after renal ischemia and reperfusion (I/R) injury and exacerbates acute kidney injury (AKI) by increasing the renal tubular inflammatory response. Here, we tested whether genetic ablation of PAD4 attenuates renal injury and inflammation after I/R in mice. After renal I/R, PAD4 wild-type mice develop severe AKI with large increases in plasma creatinine, neutrophil infiltration, as well as significant renal tubular necrosis, apoptosis, and proinflammatory cytokine generation. In contrast, PAD4-deficient mice are protected against ischemic AKI with reduced real tubular neutrophil infiltration, renal tubular necrosis, and apoptosis. In addition, hepatic injury and inflammation observed in PAD4 wild-type mice after renal I/R are significantly attenuated in PAD4-deficient mice. We also show that increased renal tubular PAD4 expression after renal I/R is associated with translocation of PAD4 from the nucleus to the cytosol. Consistent with PAD4 cytosolic translocation, we show increased renal tubular cytosolic peptidyl-citrullination after ischemic AKI. Mechanistically, recombinant PAD4 treatment increased nuclear translocation of NF-κB in cultured human as well as murine proximal tubule cells that is inhibited by a PAD4 inhibitor (2-chloroamidine). Taken together, our studies further support the hypothesis that renal tubular PAD4 plays a critical role in renal I/R injury by increasing the renal tubular inflammatory response and neutrophil infiltration after renal I/R perhaps by interacting with the proinflammatory transcription factor NF-κB in the cytosol and promoting its nuclear translocation.
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Affiliation(s)
- May Rabadi
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and
| | - Mihwa Kim
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and
| | - Vivette D'Agati
- Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York
| | - H Thomas Lee
- Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and
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Faubel S, Shah PB. Immediate Consequences of Acute Kidney Injury: The Impact of Traditional and Nontraditional Complications on Mortality in Acute Kidney Injury. Adv Chronic Kidney Dis 2016; 23:179-85. [PMID: 27113694 DOI: 10.1053/j.ackd.2016.02.007] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 02/20/2016] [Accepted: 02/23/2016] [Indexed: 01/20/2023]
Abstract
Acute kidney injury (AKI) that requires renal replacement therapy is associated with a mortality rate that exceeds 50% in the intensive care unit, which is greater than other serious illnesses such as acute lung injury and myocardial infarction. Much information is now available regarding the complications of AKI that contribute to mortality and may be usefully categorized as "traditional" and "nontraditional". Traditional complications are the long-recognized complications of AKI such as hyperkalemia, acidosis, and volume overload, which may be typically corrected with renal replacement therapy. "Nontraditional" complications include complications such as sepsis, lung injury, and heart failure that may arise due to the effects of AKI on inflammatory cytokines, immune function, and cell death pathways such as apoptosis. In this review, we discuss both traditional and nontraditional complications of AKI with a focus on factors that contribute to mortality, considering both pathophysiology and potential remedies. Because AKI is the most common inpatient consult to nephrologists, it is essential to be aware of the complications of AKI that contribute to mortality to devise appropriate treatment strategies to prevent and manage AKI complications with the ultimate goal of reducing the unacceptably high mortality rate of AKI.
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Minor Postoperative Increases of Creatinine Are Associated with Higher Mortality and Longer Hospital Length of Stay in Surgical Patients. Anesthesiology 2016; 123:1301-11. [PMID: 26492475 DOI: 10.1097/aln.0000000000000891] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Surgical patients frequently experience postoperative increases in creatinine levels. The authors hypothesized that even small increases in postoperative creatinine levels are associated with adverse outcomes. METHODS The authors examined the association of postoperative changes from preoperative baseline creatinine with all-cause in-hospital mortality and hospital length of stay (HLOS) in a retrospective analysis of surgical patients at a single tertiary care center between January 2006 and June 2012. RESULTS The data of 39,369 surgical patients (noncardiac surgery n = 37,345; cardiac surgery n = 2,024) were analyzed. Acute kidney injury (AKI)-by definition of the Kidney Disease: Improving Global Outcome group-was associated with a five-fold higher mortality (odds ratio [OR], 4.8; 95% CI, 4.1 to 5.7; P < 0.001) and a longer HLOS of 5 days (P < 0.001) after adjusting for age, sex, comorbidities, congestive heart failure, preoperative hemoglobin, preoperative creatinine, exposure to radiocontrast agent, type of surgery, and surgical AKI risk factors. Importantly, even minor creatinine increases (Δcreatinine 25 to 49% above baseline but < 0.3 mg/dl) not meeting AKI criteria were associated with a two-fold increased risk of death (OR, 1.7; 95% CI, 1.3 to 2.4; P < 0.001) and 2 days longer HLOS (P < 0.001). This was more pronounced in noncardiac surgery patients. Patients with minor creatinine increases had a five-fold risk of death (OR, 5.4; 95% CI, 1.5 to 20.3; P < 0.05) and a 3-day longer HLOS (P < 0.01) when undergoing noncardiac surgery. CONCLUSIONS Even minor postoperative increases in creatinine levels are associated with adverse outcomes. These results emphasize the importance to find effective therapeutic approaches to prevent or treat even mild forms of postoperative kidney dysfunction to improve surgical outcomes.
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Doi K, Rabb H. Impact of acute kidney injury on distant organ function: recent findings and potential therapeutic targets. Kidney Int 2016; 89:555-64. [PMID: 26880452 DOI: 10.1016/j.kint.2015.11.019] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 11/03/2015] [Accepted: 11/18/2015] [Indexed: 12/18/2022]
Abstract
Acute kidney injury (AKI) is a common complication in critically ill patients and subsequently worsens outcomes. Although many drugs to prevent and treat AKI have shown benefits in preclinical models, no specific agent has been shown to benefit AKI in humans. Moreover, despite remarkable advances in dialysis techniques that enable management of AKI in hemodynamically unstable patients with shock, dialysis-requiring severe AKI is still associated with an unacceptably high mortality rate. Thus, focusing only on kidney damage and loss of renal function has not been sufficient to improve outcomes of patients with AKI. Recent data from basic and clinical research have begun to elucidate complex organ interactions in AKI between kidney and distant organs, including heart, lung, spleen, brain, liver, and gut. This review serves to update the topic of organ cross talk in AKI and focuses on potential therapeutic targets to improve patient outcomes during AKI-associated multiple organ failure.
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Affiliation(s)
- Kent Doi
- Department of Emergency and Critical Care Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hamid Rabb
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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