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Guilpin A, Magnin M, Aigle A, Ayoub J, Schuhler T, Lac R, Marchal T, Brichart T, Hammed A, Louzier V. Temporary bilateral clamping of renal arteries induces ischemia-reperfusion: A new pig model of acute kidney injury using total intravenous anesthesia. Physiol Rep 2025; 13:e70203. [PMID: 39895016 PMCID: PMC11788332 DOI: 10.14814/phy2.70203] [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: 09/26/2024] [Revised: 12/18/2024] [Accepted: 01/06/2025] [Indexed: 02/04/2025] Open
Abstract
Ischemia-reperfusion (IR) is a leading cause of acute kidney injury (AKI), and pigs are commonly used in preclinical AKI models. However, existing models often vary in the methods used to induce ischemia, and the resulting AKI tends to be mild-to-moderate. Moreover, follow-up is often performed under volatile anesthesia, which, in contrast to total intravenous anesthesia (TIVA), can induce malignant hyperthermia and cause hemodynamic instability. Here we present a novel surgical model of IR-induced AKI using bilateral renal artery clamping under TIVA. Anesthesia was induced via TIVA with diazepam, ketamine, and morphine. After retroperitoneal exposure, the renal arteries were isolated and clamped with a plastic tube for 90 min, followed by 8 h of reperfusion. The IR group (n = 6) was compared with a Sham group (n = 5) that underwent the same procedure without IR. The IR group developed moderate-to-severe AKI as evidenced by reduced glomerular filtration, a 158% increase in plasma creatinine versus 21% in the Sham group, and elevated neutrophil gelatinase-associated lipocalin levels (+280% in IR vs. 0% in Sham), indicating tubular injury. Histopathology confirmed these findings. Thus, this preclinical model successfully induced moderate-to-severe AKI in pigs. The TIVA anesthetic protocol offered several advantages compared to halogenated gas anesthesia.
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Affiliation(s)
- Axel Guilpin
- MexBrainVilleurbanneFrance
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
| | - Mathieu Magnin
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
- Université de Lyon, VetAgro Sup, Unité de Physiologie, Pharmacodynamie et ThérapeutiqueMarcy l'EtoileFrance
| | | | - Jean‐Yves Ayoub
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
| | - Timothée Schuhler
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
| | - Romain Lac
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
| | - Thierry Marchal
- Université de Lyon, VetAgro Sup, Pole de Pathologie VétérinaireMarcy l'EtoileFrance
| | | | - Abdessalem Hammed
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
| | - Vanessa Louzier
- Université de Lyon, UR APCSe Agressions Pulmonaires et Circulatoires Dans le Sepsis, VetAgro SupMarcy l'EtoileFrance
- Université de Lyon, VetAgro Sup, Unité de Physiologie, Pharmacodynamie et ThérapeutiqueMarcy l'EtoileFrance
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Liu J, Chen R, Zhou S, Guo Z, Su L, Cao L, Li Y, Zhang X, Luo F, Xu R, Gao Q, Lin Y, Xu X, Nie S. Acute kidney injury is associated with liver-related outcomes in patients with hepatitis B virus infection: a retrospective cohort study. BMC Nephrol 2025; 26:12. [PMID: 39780049 PMCID: PMC11715857 DOI: 10.1186/s12882-024-03925-z] [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: 03/04/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND The effects of acute kidney injury (AKI) on liver-related outcomes in patients with hepatitis B virus (HBV) infection remain unclear. The study aimed to evaluate the association between AKI with liver-related mortality and complications in patients with HBV infection. METHODS The multicenter, retrospective cohort study included Chinese adults with HBV infection from 24 regional central hospitals between January 2000 and December 2022. AKI was defined as a ≥ 26.5 μmol/l increase in serum creatinine concentration within 48 h, or a ≥ 50% increase over the baseline within 7 days. The primary outcome was post-discharge liver-related mortality, while the secondary outcome was a composite of new-onset liver cirrhosis and hepatocellular carcinoma. Cox proportional hazard model was employed for analyses. RESULTS Of the 86,204 inpatients with HBV infection and without liver cancer or cirrhosis at baseline, 4407(5.1%) patients experienced AKI. During a mean follow-up of 4.6 ± 2.4 years, 334 (0.4%) patients died of liver-related events. After adjustment, AKI during hospitalization was significantly associated with a higher risk of liver-related mortality after discharge (adjusted hazard ratio (HR), 1.78; 95% confidence intervals (CI), 1.26-2.51, P = 0.001), especially in those with severe AKI. Similarly, AKI was associated with a higher risk of cirrhosis or new-onset hepatocellular carcinoma (adjusted HR, 1.33; 95%CI, 1.10-1.60, P = 0.004). The association between AKI and liver-related outcomes remained consistent across different subgroups. CONCLUSIONS AKI during hospitalization was associated with substantial increased risk of liver-related mortality and incident liver-related complication. Our findings highlight the importance of monitoring AKI in patients with HBV infection for tailoring personalized treatments.
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Affiliation(s)
- Jiao Liu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Ruixuan Chen
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Shiyu Zhou
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Zhixin Guo
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Licong Su
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Lisha Cao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Yanqin Li
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Xiaodong Zhang
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Fan Luo
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Ruqi Xu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Qi Gao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Yuxin Lin
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China
| | - Xin Xu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China.
| | - Sheng Nie
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, 1838 N Guangzhou Ave, Guangzhou, 510515, China.
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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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Lin Y, Li P, Zhang Y, Gao Q, Su L, Li Y, Xu R, Cao Y, Gao P, Luo F, Chen R, Zhang X, Nie S, Xu X. Incidence, risk factors, and outcomes of acute liver injury in hospitalized adults with acute kidney injury: a large multicenter study. Hepatol Int 2024; 18:1756-1769. [PMID: 38698184 DOI: 10.1007/s12072-023-10627-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 12/08/2023] [Indexed: 05/05/2024]
Abstract
BACKGROUND Acute kidney injury (AKI) and acute liver injury (ALI) were associated with poor outcomes during hospitalization, respectively. However, the clinical outcome of AKI combined with ALI (AKI-ALI) remains unknown. The current study aimed to describe AKI-ALI's incidences, risk factors, and outcomes. METHODS The study population included patients aged 18-99 years with enough serum creatinine and liver testing hospitalized at 19 medical centers throughout China between 2000 and 2021. AKI was defined by Kidney Disease Improving Global Outcomes and ALI was defined by the change of liver enzymes based on Asia Pacific Association of Study of Liver consensus guidelines. Cox proportional hazard model was used to identify risk factors for AKI-ALI, and a time-dependent Cox proportional hazard regression model was used to estimate the association between AKI-ALI and in-hospital mortality. RESULTS Among the 18,461 patients with AKI, 1689 (9.1%) combined with ALI. Male patients or those who have used nonsteroidal anti-inflammatory drugs or vasopressors, and who have heart failure or shock, with higher AST or GGT values, were associated with an increased risk of AKI-ALI. Compared with AKI-nonALI, patients with AKI-ALI were at higher risk of in-hospitalized mortality (hazard ratio [HR] 1.76, 95% confidence interval [CI] 1.54, 2.00). In addition, a stronger association between AKI-ALI and in-hospital mortality was found in those with lower AKI grades (p for interaction = 0.037). CONCLUSIONS ALI was not uncommon among patients with AKI, especially in patients who used vasopressors and had shock. This study highlights the association between AKI-ALI and a significantly increased risk of mortality. It suggests that dynamic monitoring of liver function is essential, particularly in patients with AST and GGT exceeding the normal upper limit, to improve the in-hospital prognosis of AKI patients.
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Affiliation(s)
- Yuxin Lin
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pingping Li
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuping Zhang
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qi Gao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Licong Su
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanqin Li
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruqi Xu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yue Cao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Peiyan Gao
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fan Luo
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruixuan Chen
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaodong Zhang
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng Nie
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Xin Xu
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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Jia X, Liu H, Yin G, Xiang W, Zhao H, Zhang X, Tang X, Cheng X, Kuo CF, Liu C, Wang W, Lu N. Arctium lappaL. polysaccharides alleviate oxidative stress and inflammation in the liver and kidney of aging mice by regulating intestinal homeostasis. Int J Biol Macromol 2024; 280:135802. [PMID: 39306181 DOI: 10.1016/j.ijbiomac.2024.135802] [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: 07/06/2024] [Revised: 08/21/2024] [Accepted: 09/18/2024] [Indexed: 11/20/2024]
Abstract
Arctium lappa L. polysaccharide (ALP) is a prominent bioactive compound renowned for its multifaceted functional properties, including anti-inflammatory, antioxidant, antifibrotic, immunomodulatory, and pro-apoptotic effects. This study evaluated the aging-delaying effect of ALP and its mechanisms using a D-galactose (D-gal)-induced aging model. After an 8-week treatment, ALP significantly ameliorated D-gal-induced inflammation and oxidative stress in the liver, kidneys, and intestines. Notably, ALP administration led to a marked reduction of the pathogenic bacterium Desulfovibrio and a substantial increase in the beneficial bacterium Muribaculum. These microbial shifts were associated with upregulated expression of intestinal tight junction proteins and intestinal mucins, leading to enhanced intestinal barrier integrity. Consequently, the leakage of enterotoxins and inflammatory mediators was effectively reduced. The findings indicate that ALP alleviates tissue inflammation and oxidative stress, while also delaying aging in mice. This effect is achieved through the regulation of intestinal ecological homeostasis and the repair of the intestinal immune barrier.
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Affiliation(s)
- Xueyan Jia
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Haoming Liu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Guoliang Yin
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Wen Xiang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi 214041, China
| | - Haotian Zhao
- Sports & Health Research Institute, Jiangnan University, Wuxi 214122, China
| | - Xuan Zhang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
| | - Xue Tang
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Sports & Health Research Institute, Jiangnan University, Wuxi 214122, China
| | - Xiangrong Cheng
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Sports & Health Research Institute, Jiangnan University, Wuxi 214122, China
| | - Chia-Feng Kuo
- Department of Food Science, Nutrition, and Nutraceutical Biotechnology, Shih Chien University, Taipei 222, Taiwan
| | - Chang Liu
- School of Sport Science, Beijing Sport University, Beijing 100084, China
| | - Wei Wang
- Beiler Anti-aging, Wuxi Xinbiao Medical Examination Co., Ltd, Wuxi 214091, China
| | - Naiyan Lu
- School of Food Science and Technology, Jiangnan University, Wuxi 214122, China; Sports & Health Research Institute, Jiangnan University, Wuxi 214122, China
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6
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Borges A, Bento L. Organ crosstalk and dysfunction in sepsis. Ann Intensive Care 2024; 14:147. [PMID: 39298039 DOI: 10.1186/s13613-024-01377-0] [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: 03/30/2024] [Accepted: 09/10/2024] [Indexed: 09/21/2024] Open
Abstract
Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Sepsis-associated organ dysfunction involves multiple inflammatory mechanisms and complex metabolic reprogramming of cellular function. These mechanisms cooperate through multiple organs and systems according to a complex set of long-distance communications mediated by cellular pathways, solutes, and neurohormonal actions. In sepsis, the concept of organ crosstalk involves the dysregulation of one system, which triggers compensatory mechanisms in other systems that can induce further damage. Despite the abundance of studies published on organ crosstalk in the last decade, there is a need to formulate a more comprehensive framework involving all organs to create a more detailed picture of sepsis. In this paper, we review the literature published on organ crosstalk in the last 10 years and explore how these relationships affect the progression of organ failure in patients with septic shock. We explored these relationships in terms of the heart-kidney-lung, gut-microbiome-liver-brain, and adipose tissue-muscle-bone crosstalk in sepsis patients. A deep connection exists among these organs based on crosstalk. We also review how multiple therapeutic interventions administered in intensive care units, such as mechanical ventilation, antibiotics, anesthesia, nutrition, and proton pump inhibitors, affect these systems and must be carefully considered when managing septic patients. The progression to multiple organ dysfunction syndrome in sepsis patients is still one of the most frequent causes of death in critically ill patients. A better understanding and monitoring of the mechanics of organ crosstalk will enable the anticipation of organ damage and the development of individualized therapeutic strategies.
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Affiliation(s)
- André Borges
- Intensive Care Unit of Hospital de São José, Unidade de Urgência Médica, Rua José António Serrano, Lisbon, 1150-199, Portugal.
- NOVA Medical School, Campo dos Mártires da Pátria 130, Lisbon, 1169-056, Portugal.
| | - Luís Bento
- Intensive Care Unit of Hospital de São José, Unidade de Urgência Médica, Rua José António Serrano, Lisbon, 1150-199, Portugal
- NOVA Medical School, Campo dos Mártires da Pátria 130, Lisbon, 1169-056, Portugal
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7
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Han YK, Lim HJ, Jang G, Jang SY, Park KM. Kidney ischemia/reperfusion injury causes cholangiocytes primary cilia disruption and abnormal bile secretion. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167225. [PMID: 38749218 DOI: 10.1016/j.bbadis.2024.167225] [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: 02/29/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 06/17/2024]
Abstract
BACKGROUND Acute kidney injury (AKI) causes distant liver injury, to date, which causes poor outcomes of patients with AKI. Many studies have been performed to overcome AKI-associated liver injury. However, those studies have mainly focused on hepatocytes, and AKI-induced liver injury still remains a clinical problem. Here, we investigated the implication of cholangiocytes and their primary cilia which are critical in final bile secretion. Cholangiocyte, a lining cell of bile ducts, are the only liver epithelial cell containing primary cilium (a microtubule-based cell surface signal-sensing organelle). METHODS Cystathione γ-lyase (CSE, a transsulfuration enzyme) deficient and wild-type mice were subjected to kidney ischemia followed by reperfusion (KIR). Some mice were administered with N-acetyl-cysteine (NAC). RESULTS KIR damaged hepatocytes and cholagiocytes, disrupted cholangiocytes primary cilia, released the disrupted ciliary fragments into the bile, and caused abnormal bile secretion. Glutathione (GSH) and H2S levels in the livers were significantly reduced by KIR, resulting in increased the ratio oxidized GSH to total GSH, and oxidation of tissue and bile. CSE and cystathione β-synthase (CBS) expression were lowered in the liver after KIR. NAC administration increased total GSH and H2S levels in the liver and attenuated KIR-induced liver injuries. In contrast, Cse deletion caused the reduction of total GSH levels and worsened KIR-induced liver injuries, including primary cilia damage and abnormal bile secretion. CONCLUSIONS These results indicate that KIR causes cholangiocyte damage, cholangiocytes primary cilia disruption, and abnormal bile secretion through reduced antioxidative ability of the liver.
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Affiliation(s)
- Yong Kwon Han
- Department of Anatomy, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea
| | - Hui Jae Lim
- Department of Anatomy, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea; Department of Biomedical Science and BK21 Plus, The Graduate School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea
| | - GiBong Jang
- Department of Anatomy, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea; Department of Biomedical Science and BK21 Plus, The Graduate School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea
| | - Se Young Jang
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea
| | - Kwon Moo Park
- Department of Anatomy, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea; Cardiovascular Research Institute, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea; Department of Biomedical Science and BK21 Plus, The Graduate School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea.
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8
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Gui Y, Yu Y, Wang W, Wang Y, Lu H, Mozdzierz S, Eskander K, Lin YH, Li H, Tian XJ, Liu S, Zhou D. Proteome characterization of liver-kidney comorbidity after microbial sepsis. FASEB J 2024; 38:e23597. [PMID: 38581235 PMCID: PMC11537479 DOI: 10.1096/fj.202302520r] [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: 12/06/2023] [Revised: 03/05/2024] [Accepted: 03/25/2024] [Indexed: 04/08/2024]
Abstract
Sepsis is a life-threatening condition that occurs when the body responds to an infection but subsequently triggers widespread inflammation and impaired blood flow. These pathologic responses can rapidly cause multiple organ dysfunction or failure either one by one or simultaneously. The fundamental common mechanisms involved in sepsis-induced multiple organ dysfunction remain unclear. Here, employing quantitative global and phosphoproteomics, we examine the liver's temporal proteome and phosphoproteome changes after moderate sepsis induced by cecum ligation and puncture. In total, 4593 global proteins and 1186 phosphoproteins according to 3275 phosphosites were identified. To characterize the liver-kidney comorbidity after sepsis, we developed a mathematical model and performed cross-analyses of liver and kidney proteome data obtained from the same set of mice. Beyond immune response, we showed the commonly disturbed pathways and key regulators of the liver-kidney comorbidity are linked to energy metabolism and consumption. Our data provide open resources to understand the communication between the liver and kidney as they work to fight infection and maintain homeostasis.
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Affiliation(s)
- Yuan Gui
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Yanbao Yu
- Department of Chemistry & Biochemistry, University of Delaware, Newark, DE, USA
| | - Wenjia Wang
- Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yuanyuan Wang
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Hanyue Lu
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Sarah Mozdzierz
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Kirollos Eskander
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Yi-Han Lin
- National Center for Advancing Translational Sciences, MD, USA
| | - Hanwen Li
- Departments Statistics, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Xiao-Jun Tian
- School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA
| | - Silvia Liu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dong Zhou
- Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA
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Hidayati EL, Fahlevi R, Puspitasari HA, Tartila, Puspaningtyas NW, Primacakti F, Saraswati M, Miranda ME, Prawira Y, Prayitno A, Pardede SO, Putri ND. Emerging progressive atypical acute kidney injury in young children linked to ethylene glycol and diethylene glycol intoxication. Pediatr Nephrol 2024; 39:897-904. [PMID: 37755463 DOI: 10.1007/s00467-023-06157-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 08/31/2023] [Accepted: 08/31/2023] [Indexed: 09/28/2023]
Abstract
BACKGROUND There had been a sudden surge of unusually severe and rapidly progressing acute kidney injury (AKI) incidence in Indonesia since August 2022 which did not correspond to the rise of COVID-19 incidence. We suspected this was related to ethylene glycol (EG) and diethylene glycol (DEG) intoxication. This study is aimed at describing the clinical and laboratory characteristics of AKI related to D(EG) intoxication in order to spread awareness of the possibility of intoxication in cases of rapidly progressing AKI with unknown etiology. METHODS We conducted a cross-sectional study by collecting secondary data from the pediatric AKI registry at a national referral hospital in Jakarta, Indonesia. Data on children admitted from January to November 2022 with diagnosis of stage 3 AKI based on KDIGO criteria were included. Data regarding demographics, symptoms prior to anuria, laboratory results, infection panel including COVID-19 status, treatment administered, and mortality were analyzed. RESULTS Sixteen patients tested positive for EG and DEG, all with history of consuming syrup-based medications. High anion gap metabolic acidosis was observed in majority of patients with mean pH 7.33 ± 0.07 and mean anion gap 15.6 ± 7.8 mEq/L. No patient had high osmolal gap (mean osmolal gap 3.46 ± 4.68). One deceased patient, who had kidney biopsy performed, showed severe damage and calcium oxalate crystals in the kidney tissue. Mortality was recorded in six patients (37.5%). CONCLUSION Careful history taking of patient's clinical course, including consumption of syrup-based medications and laboratory findings, might aid clinicians to establish a working diagnosis of D(EG) intoxication without needing to wait for blood toxicology test. Early diagnosis and therapy are crucial to prevent substantial mortality.
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Affiliation(s)
- Eka Laksmi Hidayati
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia.
| | - Reza Fahlevi
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Henny Adriani Puspitasari
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Tartila
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Niken Wahyu Puspaningtyas
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Fitri Primacakti
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Meilania Saraswati
- Department of Pathological Anatomy, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Monik Ediana Miranda
- Department of Pathological Anatomy, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Yogi Prawira
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Ari Prayitno
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Sudung Oloan Pardede
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
| | - Nina Dwi Putri
- Department of Child Health, Faculty of Medicine Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
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10
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Khajepour F, Mahmoodpoor F, Jafari E, Kakaei F, Bahraminia F, Aghajani S, Vahed SZ, Bagheri Y. Prazosin Protects the Liver Against Renal Ischemia/Reperfusion Injury in Rats. Drug Res (Stuttg) 2023. [PMID: 36940722 DOI: 10.1055/a-2015-7976] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
Acute kidney injury (AKI) is a common subsequent problem after many medical conditions. AKI is associated with distant organ dysfunction where systemic inflammation and oxidative stress play major roles. In this study, the effect of Prazosin, an α1-Adrenergic receptor antagonist, was investigated on the liver injury induced by kidney ischemia-reperfusion (I/R) in rats. Male adult Wistar rats (n=21) were divided into three groups: sham, kidney I/R, and kidney I/R pre-treated with Prazosin (1 mg/kg). Kidney I/R was induced by vascular clamping of the left kidney for 45 min to reduce the blood flow. Oxidative and antioxidant factors along with apoptotic (Bax, Bcl-2, caspase3), and inflammatory (NF-κβ, IL-1β, and IL-6) factors were measured in the liver at protein levels. Prazosin could reserve liver function (p<0.01) and increase glutathione level (p<0.05) after kidney I/R significantly. Malonil dialdehyde (MDA), a lipid peroxidation marker, was diminished more significantly in Prazosin-treated rats compared to the kidney I/R group (p<0.001). Inflammatory and apoptotic factors were diminished by Prazosin pre-treatment in the liver tissue (p<0.05). Pre-administration of Prazosin could preserve liver function and decrease its inflammatory and apoptotic factors under kidney I/R conditions.
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Affiliation(s)
- Fatemeh Khajepour
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Fariba Mahmoodpoor
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Persian Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Elmira Jafari
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Farzad Kakaei
- Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farina Bahraminia
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Shadi Aghajani
- Faculty of Veterinary Medicine, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | | | - Yasin Bagheri
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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11
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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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12
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Chang SN, Park JG, Kang SC. Therapeutic propensity of ginsenosides Rg1 and Rg3 in rhabdomyolysis-induced acute kidney injury and renohepatic crosstalk in rats. Int Immunopharmacol 2023; 115:109602. [PMID: 36580761 DOI: 10.1016/j.intimp.2022.109602] [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: 10/12/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Ginseng is a traditional herbal medicine used for thousands of years in Southeast Asian countries because of its medicinal properties. Ginsenosides Rg1 and Rg3 have demonstrated therapeutic properties against a broad spectrum of diseases. PURPOSE Here in this study, we investigated the therapeutic efficacy of Rg1 and Rg3 in alleviating glycerol-induced acute kidney injury, also known as rhabdomyolysis-induced acute kidney injury (RAKI). METHODS AKI was induced in male Wistar rats through intramuscular injection of 10 mL/kg glycerol and simultaneous oral treatment of ginsenosides Rg1 and Rg3 for 3 days. We also evaluated the therapeutic potential of Rg1 and Rg3 on human embryonic kidney epithelial (HEK-293). Cell viability and LDH assay were performed on HEK-293 cells to evaluate the toxicity of Rg1 and Rg3. Evaluation of important kidney damage markers such as creatinine and blood urea nitrogen (BUN) was carried out at different time points from the rat serum. Histopathological analysis was performed on kidney tissues. We also performed experiments such as ELISA assay, immunohistochemistry, immunofluorescence staining, COMET assay, western blotting, TUNEL assay, and flow cytometry to obtain results. RESULTS Rg1 and Rg3 significantly downregulated the expression of kidney damage markers such as creatinine and BUN in a dose-dependent manner. Histopathological analysis revealed damage across the glomerulus, tubules, and collecting duct rendering the kidney dysfunctional in glycerol treatment groups. However, Rg1 and Rg3 treated groups showed a significant reduction in tubular necrosis at both 10 and 20 mg/kg. There was also a sharp downregulation of oxidative and ER stress markers. Additionally, we observed nuclear translocation of Nrf2 which were more prominent in kidney tissues. Rg1 and Rg3 were also able to mitigate apoptotic cell death in vitro and in vivo evaluated through immunofluorescence staining for p53, TUNEL assay, flow cytometry, and immunoblotting for intrinsic apoptosis markers. CONCLUSION In summary, we conclude that Rg1 and Rg3 exhibited natural therapeutic remedy against AKI.
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Affiliation(s)
- Sukkum Ngullie Chang
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea.
| | - Jae Gyu Park
- Advanced Bio Convergence Center (ABCC), Pohang Technopark Foundation, Pohang 37668, Republic of Korea.
| | - Sun Chul Kang
- Department of Biotechnology, Daegu University, Gyeongsan, Gyeongbuk 38453, Republic of Korea.
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13
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Deng S, Zhang Y, Xin Y, Hu X. Vagus nerve stimulation attenuates acute kidney injury induced by hepatic ischemia/reperfusion injury in rats. Sci Rep 2022; 12:21662. [PMID: 36522408 PMCID: PMC9755310 DOI: 10.1038/s41598-022-26231-w] [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: 08/07/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatic ischemia/reperfusion (I/R) injury, caused by limited blood supply and subsequent blood supply, is a causative factor resulting in morbidity and mortality during liver transplantation and liver resection. Hepatic I/R injury frequently contributes to remote organ injury, such as kidney, lung, and heart. It has been demonstrated that vagus nerve stimulation (VNS) is effective in remote organ injury after I/R injury. Here, our aim is to investigate the potential action of VNS on hepatic I/R injury-induced acute kidney injury (AKI) and explore its underlying mechanisms. To test this hypothesis, male Sprague-Dawley rats were randomly assigned into three experimental groups: Sham group (sham operation, n = 6); I/R group (hepatic I/R with sham VNS, n = 6); and VNS group (hepatic I/R with VNS, n = 6). VNS was performed during the entire hepatic I/R process. Our results showed that throughout the hepatic I/R process, VNS significantly regulated the expression levels of various iconic factors and greatly enhanced the protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) in the kidneys. These findings suggested that VNS may ameliorate hepatic I/R injury-induced AKI by suppressing inflammation, oxidative stress, and apoptosis probably through activating the Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Simin Deng
- grid.216417.70000 0001 0379 7164Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011 Hunan China
| | - Yifeng Zhang
- grid.216417.70000 0001 0379 7164Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011 Hunan China
| | - Ying Xin
- grid.216417.70000 0001 0379 7164Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011 Hunan China
| | - Xinqun Hu
- grid.216417.70000 0001 0379 7164Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011 Hunan China
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14
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Li X, Yuan F, Zhou L. Organ Crosstalk in Acute Kidney Injury: Evidence and Mechanisms. J Clin Med 2022; 11:jcm11226637. [PMID: 36431113 PMCID: PMC9693488 DOI: 10.3390/jcm11226637] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/31/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022] Open
Abstract
Acute kidney injury (AKI) is becoming a public health problem worldwide. AKI is usually considered a complication of lung, heart, liver, gut, and brain disease, but recent findings have supported that injured kidney can also cause dysfunction of other organs, suggesting organ crosstalk existence in AKI. However, the organ crosstalk in AKI and the underlying mechanisms have not been broadly reviewed or fully investigated. In this review, we summarize recent clinical and laboratory findings of organ crosstalk in AKI and highlight the related molecular mechanisms. Moreover, their crosstalk involves inflammatory and immune responses, hemodynamic change, fluid homeostasis, hormone secretion, nerve reflex regulation, uremic toxin, and oxidative stress. Our review provides important clues for the intervention for AKI and investigates important therapeutic potential from a new perspective.
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15
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Yang M, Luo S, Yang J, Chen W, He L, Liu D, Zhao L, Wang X. Crosstalk between the liver and kidney in diabetic nephropathy. Eur J Pharmacol 2022; 931:175219. [PMID: 35987257 DOI: 10.1016/j.ejphar.2022.175219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 08/09/2022] [Accepted: 08/14/2022] [Indexed: 11/26/2022]
Abstract
Diabetic nephropathy (DN) is a serious complication of diabetes, and its pathogenesis has not been fully elucidated. Recently, communication between organs has gradually become a new focus in the study of diseases pathogenesis, and abnormal interorgan communication has been proven to be involved in the occurrence and progression of many diseases. As an important metabolic organ in the human body, the liver plays an important role in maintaining homeostasis in humans. The liver secretes a series of proteins called hepatokines that affect adjacent and distal organs through paracrine or endocrine signaling pathways. In this review, we summarize some of the hepatokines identified to date and describe their roles in DN to discuss the possibility that the liver-renal axis is potentially useful as a therapeutic target for DN. We summarize the important hepatokines identified thus far and discuss their relationship with DN. We propose for the first time that the "liver-renal axis" is a potential therapeutic target in individuals with DN.
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Affiliation(s)
- Ming Yang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shilu Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jinfei Yang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wei Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Di Liu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Li Zhao
- Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, China
| | - Xi Wang
- Department of Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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16
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Deng S, Zhang Y, Xin Y, Hu X. Vagus Nerve Stimulation Attenuates Acute Kidney Injury Induced by Hepatic Ischemia/Reperfusion Injury by Suppressing Inflammation, Oxidative Stress, and Apoptosis in Rats.. [DOI: 10.21203/rs.3.rs-1937916/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Abstract
Hepatic ischemia reperfusion (I/R) injury, caused by limited blood supply and subsequent blood supply, is a causative factor resulting in morbidity and mortality during liver transplantation (LT) and liver resection. Hepatic I/R injury frequently contributes to remote organ injury, such as kidney, lung, and heart. It has been demonstrated that vagus nerve stimulation (VNS) is effective in remote organ injury after ischemia reperfusion injury. Here, our aim is to investigate the potential action of VNS on hepatic I/R injury-induced acute kidney injury (AKI) and explore its underlying mechanisms. To test this hypothesis, male Sprague-Dawley rats were randomly assigned into three experimental groups: Sham group (sham operation, n=6); I/R group (hepatic I/R with sham VNS, n=6); and VNS group (hepatic I/R with VNS, n=6). VNS was performed during the entire hepatic I/R process. Our results showed that throughout the hepatic I/R process, VNS significantly reduced inflammation, oxidative stress, and apoptosis, and greatly enhanced the protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) in the kidneys. These findings suggest that VNS may ameliorate hepatic I/R injury-induced AKI by suppressing inflammation, oxidative stress, and apoptosis probably through activating the Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Simin Deng
- Second Xiangya Hospital of Central South University
| | - Yifeng Zhang
- Second Xiangya Hospital of Central South University
| | - Ying Xin
- Second Xiangya Hospital of Central South University
| | - Xinqun Hu
- Second Xiangya Hospital of Central South University
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17
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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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18
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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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19
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Awad AS, Elariny HA, Sallam AS. Colchicine attenuates renal ischemia-reperfusion-induced liver damage: implication of TLR4/NF-κB, TGF-β, and BAX and Bcl-2 gene expression. Can J Physiol Pharmacol 2022; 100:12-18. [PMID: 34411492 DOI: 10.1139/cjpp-2021-0007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemia-reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules, has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Forty rats were divided randomly into four groups: sham group, colchicine-treated group, IRI group, and colchicine-treated + IRI group. Treatment with colchicine significantly reduced hepatic toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) transcription factor, myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-alpha (TNF-α) contents; downregulated BCL2 associated X apoptosis regulator (BAX) gene expression, transforming growth factor-β (TGF-β) content, and upregulated hepatic B cell lymphoma 2 (Bcl-2) gene expression as compared with the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.
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Affiliation(s)
- Azza Sayed Awad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Egypt
| | - Hemat A Elariny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Egypt
| | - Amany Said Sallam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, Egypt
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20
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Early Hypertransaminasemia after Kidney Transplantation: Significance and Evolution According to Donor Type. J Clin Med 2021; 10:jcm10215168. [PMID: 34768688 PMCID: PMC8584479 DOI: 10.3390/jcm10215168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/29/2021] [Accepted: 11/01/2021] [Indexed: 11/21/2022] Open
Abstract
Early hypertransaminasemia after kidney transplantation (KT) is frequent. It has been associated with the crosstalk produced between the liver and the kidney in ischemia-reperfusion situations. However, the influence of the donor type has not been evaluated. We present a retrospective study analyzing the increase in serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) during the first three months post-KT in 151 recipients who received thymoglobulin as induction therapy, either from brain-death donors (DBD, n = 75), controlled circulatory death donors (cDCD, n = 33), or uncontrolled DCD (uDCD, n = 43). Eighty-five KT recipients from DBD who received basiliximab were included as controls. From KT recipients who received thymoglobulin, 33.6/43.4% presented with an increase in AST/ALT at 72 h post-KT, respectively. Regarding donor type, the percentage of recipients who experienced 72 h post-KT hypertransaminasemia was higher in uDCD group (65.1/83.7% vs. 20.3/26% in DBD and 20.7/27.6% in cDCD, p < 0.001). Within the control group, 9.4/12.9% of patients presented with AST/ALT elevation. One month after transplant, AST/ALT values returned to baseline in all groups. The multivariate analysis showed that uDCD recipients had 6- to 12-fold higher risk of developing early post-KT hypertransaminasemia. Early post-KT hypertransaminasemia is a frequent and transient event related to the kidney donor type, being more frequent in uDCD recipients.
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21
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Gordeeva AE, Kurganova EA, Novoselov VI. The Hepatoprotective Effect of Peroxiredoxin 6 in Ischemia–Reperfusion Kidney Injury. Biophysics (Nagoya-shi) 2021. [DOI: 10.1134/s0006350921050067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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22
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Bodine SC, Brooks HL, Bunnett NW, Coller HA, Frey MR, Joe B, Kleyman TR, Lindsey ML, Marette A, Morty RE, Ramírez JM, Thomsen MB, Yosten GLC. An American Physiological Society cross-journal Call for Papers on "Inter-Organ Communication in Homeostasis and Disease". Am J Physiol Lung Cell Mol Physiol 2021; 321:L42-L49. [PMID: 34010064 PMCID: PMC8321848 DOI: 10.1152/ajplung.00209.2021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 05/13/2021] [Accepted: 05/15/2021] [Indexed: 12/17/2022] Open
Affiliation(s)
- Sue C Bodine
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Heddwen L Brooks
- Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, New York University, New York, New York
| | - Hilary A Coller
- Molecular Biology Interdepartmental Program, University of California, Los Angeles, California
- Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California
- Department of Biological Chemistry, University of California, Los Angeles, California
| | - Mark R Frey
- The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California
- Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, California
- Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Bina Joe
- Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio
- Center for Hypertension and Personalized Medicine, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio
| | - Thomas R Kleyman
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Merry L Lindsey
- Department of Cellular and Integrative Physiology, Center for Heart and Vascular Research, University of Nebraska Medical Center, Omaha, Nebraska
- Research Service, VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - André Marette
- Department of Medicine, Faculty of Medicine, Cardiology Axis of the Québec Heart and Lung Institute, Hôpital Laval, Laval University, Quebec City, Québec, Canada
- Institute of Nutrition and Functional Foods, Laval University, Quebec City, Québec, Canada
| | - Rory E Morty
- Department of Translational Pulmonology and the Translational Lung Research Center Heidelberg, University Hospital Heidelberg, member of the German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, Justus Liebig University Giessen, member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Jan-Marino Ramírez
- Department of Neurological Surgery, University of Washington Medical Center, Seattle, Washington
- Center on Human Development and Disability, University of Washington, Seattle, Washington
- Center for Integrative Brain Research at the Seattle Children's Research Institute, University of Washington, Seattle, Washington
| | - Morten B Thomsen
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Gina L C Yosten
- Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri
- Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri
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23
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Zhong J, Yang HC, Yermalitsky V, Shelton EL, Otsuka T, Wiese CB, May-Zhang LS, Banan B, Abumrad N, Huang J, Cavnar AB, Kirabo A, Yancey PG, Fogo AB, Vickers KC, Linton MF, Davies SS, Kon V. Kidney injury-mediated disruption of intestinal lymphatics involves dicarbonyl-modified lipoproteins. Kidney Int 2021; 100:585-596. [PMID: 34102217 DOI: 10.1016/j.kint.2021.05.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 04/06/2021] [Accepted: 05/06/2021] [Indexed: 12/24/2022]
Abstract
Kidney disease affects intestinal structure and function. Although intestinal lymphatics are central in absorption and remodeling of dietary and synthesized lipids/lipoproteins, little is known about how kidney injury impacts the intestinal lymphatic network, or lipoproteins transported therein. To study this, we used puromycin aminoglycoside-treated rats and NEP25 transgenic mice to show that proteinuric injury expanded the intestinal lymphatic network, activated lymphatic endothelial cells and increased mesenteric lymph flow. The lymph was found to contain increased levels of cytokines, immune cells, and isolevuglandin (a highly reactive dicarbonyl) and to have a greater output of apolipoprotein AI. Plasma levels of cytokines and isolevuglandin were not changed. However, isolevuglandin was also increased in the ileum of proteinuric animals, and intestinal epithelial cells exposed to myeloperoxidase produced more isolevuglandin. Apolipoprotein AI modified by isolevuglandin directly increased lymphatic vessel contractions, activated lymphatic endothelial cells, and enhanced the secretion of the lymphangiogenic promoter vascular endothelial growth factor-C by macrophages. Inhibition of isolevuglandin synthesis by a carbonyl scavenger reduced intestinal isolevuglandin adduct level and lymphangiogenesis. Thus, our data reveal a novel mediator, isolevuglandin modified apolipoprotein AI, and uncover intestinal lymphatic network structure and activity as a new pathway in the crosstalk between kidney and intestine that may contribute to the adverse impact of kidney disease on other organs.
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Affiliation(s)
- Jianyong Zhong
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hai-Chun Yang
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
| | - Valery Yermalitsky
- Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
| | - Elaine L Shelton
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Tadashi Otsuka
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Carrie B Wiese
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Linda S May-Zhang
- Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
| | - Babak Banan
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Naji Abumrad
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jiansheng Huang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ashley B Cavnar
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Annet Kirabo
- Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
| | - Patricia G Yancey
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Agnes B Fogo
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kasey C Vickers
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - MacRae F Linton
- Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Sean S Davies
- Department of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
| | - Valentina Kon
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
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24
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Todorović Z, Đurašević S, Stojković M, Grigorov I, Pavlović S, Jasnić N, Tosti T, Macut JB, Thiemermann C, Đorđević J. Lipidomics Provides New Insight into Pathogenesis and Therapeutic Targets of the Ischemia-Reperfusion Injury. Int J Mol Sci 2021; 22:2798. [PMID: 33801983 PMCID: PMC7999969 DOI: 10.3390/ijms22062798] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 11/16/2022] Open
Abstract
Lipids play an essential role in both tissue protection and damage. Tissue ischemia creates anaerobic conditions in which enzyme inactivation occurs, and reperfusion can initiate oxidative stress that leads to harmful changes in membrane lipids, the formation of aldehydes, and chain damage until cell death. The critical event in such a series of harmful events in the cell is the unwanted accumulation of fatty acids that leads to lipotoxicity. Lipid analysis provides additional insight into the pathogenesis of ischemia/reperfusion (I/R) disorders and reveals new targets for drug action. The profile of changes in the composition of fatty acids in the cell, as well as the time course of these changes, indicate both the mechanism of damage and new therapeutic possibilities. A therapeutic approach to reperfusion lipotoxicity involves attenuation of fatty acids overload, i.e., their transport to adipose tissue and/or inhibition of the adverse effects of fatty acids on cell damage and death. The latter option involves using PPAR agonists and drugs that modulate the transport of fatty acids via carnitine into the interior of the mitochondria or the redirection of long-chain fatty acids to peroxisomes.
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Affiliation(s)
- Zoran Todorović
- School of Medicine, University of Belgrade, 11129 Belgrade, Serbia; (M.S.); (J.B.M.)
- University Medical Centre “Bežanijska kosa”, 11080 Belgrade, Serbia
| | - Siniša Đurašević
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (S.Đ.); (N.J.); (J.Đ.)
| | - Maja Stojković
- School of Medicine, University of Belgrade, 11129 Belgrade, Serbia; (M.S.); (J.B.M.)
| | - Ilijana Grigorov
- Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (I.G.); (S.P.)
| | - Slađan Pavlović
- Institute for Biological Research “Siniša Stanković”—National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; (I.G.); (S.P.)
| | - Nebojša Jasnić
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (S.Đ.); (N.J.); (J.Đ.)
| | - Tomislav Tosti
- Faculty of Chemistry, University of Belgrade, 11000 Belgrade, Serbia;
| | - Jelica Bjekić Macut
- School of Medicine, University of Belgrade, 11129 Belgrade, Serbia; (M.S.); (J.B.M.)
- University Medical Centre “Bežanijska kosa”, 11080 Belgrade, Serbia
| | - Christoph Thiemermann
- Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK;
| | - Jelena Đorđević
- Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia; (S.Đ.); (N.J.); (J.Đ.)
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25
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Soliman E, Shewaikh SM, Fahmy A, Elshazly S. Entacapone scavenges peroxynitrite and protects against kidney and liver injuries induced by renal ischemia/reperfusion in rats. Int Urol Nephrol 2021; 53:1713-1721. [PMID: 33675481 DOI: 10.1007/s11255-021-02827-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 02/24/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute kidney injury (AKI), secondary to renal ischemia/reperfusion (I/R), is a serious problem associated with high mortality. The pathophysiology of AKI after renal I/R involves peroxynitrite production; hence, scavenging this metabolite may rescue AKI. Entacapone is a catechol-O-methyl transferase (COMT) inhibitor which elicits antioxidant activity by scavenging peroxynitrite. Therefore, we hypothesized that the peroxynitrite scavenging activity of entacopone protects against AKI after renal I/R injury in rats. METHODS Male Wistar rats were given either entacapone or a well-known peroxynitrite scavenger (FeTPPS) daily for 10 days before I/R procedures. I/R was induced by occluding both renal pedicles for 45 min followed by reperfusion for 24 h. RESULTS Pre-treatment with either entacapone or FeTPPS improved renal function as indicated by a significant reduction in serum creatinine and urea when compared to I/R group (P < 0.05). I/R injury increased renal levels of NO (4-folds, P < 0.05), iNOS (4-folds, P < 0.05), and 3-nitrotyrosine (5-folds, P < 0.05) compared to sham control. These effects were abrogated in animals pre-treated with entacapone or FeTPPS before being subjected to I/R (P < 0.05). In addition, entacapone or FeTPPS significantly inhibited I/R-induced elevation in renal TNF-α levels (78% and 58%, respectively) and caspase-3 activity (72% and 56%, respectively) indicating the reduction of both inflammation and apoptosis in the kidney (P < 0.05). The two drugs also improved kidney and liver functions in rats with renal I/R injury. CONCLUSION Our study showed that entacapone and FeTPPS protected against AKI and remote liver damage associated with renal I/R and this effect might be due to scavenging peroxynitrite and reducing nitrosative stress.
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Affiliation(s)
- Eman Soliman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
| | - Samar M Shewaikh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Ahmed Fahmy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
| | - Shimaa Elshazly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt
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26
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Marants R, Qirjazi E, Lai KB, Szeto CC, Li PKT, Li F, Lee TY, McIntyre CW. Exploring the Link Between Hepatic Perfusion and Endotoxemia in Hemodialysis. Kidney Int Rep 2021; 6:1336-1345. [PMID: 34013112 PMCID: PMC8116762 DOI: 10.1016/j.ekir.2021.02.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/25/2021] [Accepted: 02/01/2021] [Indexed: 01/18/2023] Open
Abstract
Introduction The liver receives gut-derived endotoxin via the portal vein, clearing it before it enters systemic circulation. Hemodialysis negatively impacts the perfusion and function of multiple organs systems. Dialysate cooling reduces hemodialysis-induced circulatory stress and protects organs from ischemic injury. This study examined how hemodialysis disrupts liver hemodynamics and function, its effect on endotoxemia, and the potential protective effect of dialysate cooling. Methods Fifteen patients were randomized to receive either standard (36.5°C dialysate temperature) or cooled (35.0°C) hemodialysis first in a two-visit crossover trial. We applied computed tomography (CT) liver perfusion imaging to patients before, 3 hours into and after each hemodialysis session. We measured hepatic perfusion and perfusion heterogeneity. Hepatic function was measured by indocyanine green (ICG) clearance. Endotoxin levels in blood throughout dialysis were also measured. Results During hemodialysis, overall liver perfusion did not significantly change, but portal vein perfusion trended towards increasing (P = 0.14) and perfusion heterogeneity significantly increased (P = 0.038). In addition, ICG clearance decreased significantly during hemodialysis (P = 0.016), and endotoxin levels trended towards increasing during hemodialysis (P = 0.15) and increased significantly after hemodialysis (P = 0.037). Applying dialysate cooling trended towards abrogating these changes but did not reach statistical significance compared to standard hemodialysis. Conclusion Hemodialysis redistributes liver perfusion, attenuates hepatic function, and results in endotoxemia. Higher endotoxin levels in end-stage renal disease (ESRD) patients may result from the combination of decreased hepatic clearance function and increasing fraction of liver perfusion coming from toxin-laden portal vein during hemodialysis. The protective potential of dialysate cooling should be explored further in future research studies.
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Affiliation(s)
- Raanan Marants
- Department of Medical Biophysics, Western University, London, Ontario, Canada.,Robarts Research Institute, Western University, London, Ontario, Canada
| | - Elena Qirjazi
- The Lilibeth Caberto Kidney Clinical Research Unit, London Health Sciences Centre, London, Ontario, Canada.,Division of Nephrology, Alberta Health Sciences, Calgary, Alberta, Canada
| | - Ka-Bik Lai
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Cheuk-Chun Szeto
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Philip K T Li
- Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Fiona Li
- Department of Medical Biophysics, Western University, London, Ontario, Canada.,Robarts Research Institute, Western University, London, Ontario, Canada.,Lawson Health Research Institute, London, Ontario, Canada
| | - Ting-Yim Lee
- Department of Medical Biophysics, Western University, London, Ontario, Canada.,Robarts Research Institute, Western University, London, Ontario, Canada.,Lawson Health Research Institute, London, Ontario, Canada
| | - Christopher W McIntyre
- Department of Medical Biophysics, Western University, London, Ontario, Canada.,The Lilibeth Caberto Kidney Clinical Research Unit, London Health Sciences Centre, London, Ontario, Canada.,Lawson Health Research Institute, London, Ontario, Canada.,Division of Nephrology, London Health Sciences Centre, London, Ontario, Canada
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27
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Bonavia A, Stiles N. Renohepatic crosstalk: a review of the effects of acute kidney injury on the liver. Nephrol Dial Transplant 2021; 37:1218-1228. [PMID: 33527986 DOI: 10.1093/ndt/gfaa297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Indexed: 12/13/2022] Open
Abstract
Several theories regarding acute kidney injury (AKI)-related mortality have been entertained, although mounting evidence supports the paradigm that impaired kidney function directly and adversely affects the function of several remote organs. The kidneys and liver are fundamental to human metabolism and detoxification, and it is therefore hardly surprising that critical illness complicated by hepatorenal dysfunction portends a poor prognosis. Several diseases can simultaneously impact the proper functioning of the liver and kidneys, although this review will address the impact of AKI on liver function. While evidence for this relationship in humans remains sparse, we present supportive studies and then discuss the most likely mechanisms by which AKI can cause liver dysfunction. These include 'traditional' complications of AKI (uremia, volume overload and acute metabolic acidosis, among others) as well as systemic inflammation, hepatic leukocyte infiltration, cytokine-mediated liver injury and hepatic oxidative stress. We conclude by addressing the therapeutic implications of these findings to clinical medicine.
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Affiliation(s)
- Anthony Bonavia
- Department of Anesthesiology and Perioperative Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.,Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA
| | - Nicholas Stiles
- Department of Anesthesiology and Perioperative Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
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28
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Bagheri Y, Aghajani S, Hosseinzadeh M, Hoshmandan F, Abdollahpour A, Vahed SZ. Protective effects of Gamma Oryzanol on distant organs after kidney ischemia-reperfusion in rats: A focus on liver protection. Hum Exp Toxicol 2020; 40:1022-1030. [PMID: 33325270 DOI: 10.1177/0960327120979014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Acute kidney injury (AKI) is the main clinical concern resulted from ischemia-reperfusion injury (IRI). Ample clinical data indicates that AKI is associated with distant organ dysfunctions and poor patients' outcomes. Oxidative stress and inflammation have a critical role in the pathogenesis of organ injuries following IRI. The objectives of this study were to determine the impact of Gamma Oryzanol (GO), extracted from rice bran oil, on distant organs in rats after IRI. METHODS Twelve out of 24 Wistar rats were treated by one dosage of GO (100mg/kg) 1 h before I/R induction through both oral gavage and intraperitoneal injection. Then, the AKI model rats were induced by IRI. Oxidative stress and antioxidant protein levels were assessed in the brain, heart, and liver tissues in the experimental groups. Furthermore, the effects of GO on IRI-induced liver dysfunction, apoptosis, and inflammation were measured by Western blot. RESULTS GO pretreatment could significantly restore the levels and activity of antioxidant proteins in the brain, heart, and liver tissues (P < 0.05). Moreover, GO pretreatment could decrease the inflammatory cytokine (IL-1, IL-6, and TNF-α) in the liver (P < 0.01). By reducing Bax/Bcl-2 ratio and down-regulating caspase-3, GO could significantly diminish apoptosis in the liver tissue after the kidney I/R (P < 0.01). Additionally, GO could significantly diminish the deterioration of liver function in the kidney I/R model. CONCLUSION GO protects distant organs against renal IRI-induced oxidative stress. Furthermore, it ameliorates liver function and remarkably exerts anti-oxidative, anti-inflammatory, and anti-apoptotic roles in the liver as an important detoxifying organ.
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Affiliation(s)
- Yasin Bagheri
- Young Researchers and Elite Club, 201583Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Shadi Aghajani
- Faculty of Veterinary Medicine, 201583Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Mahla Hosseinzadeh
- Faculty of Veterinary Medicine, 201583Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Farid Hoshmandan
- Faculty of Veterinary Medicine, 201583Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Abdollah Abdollahpour
- Faculty of Veterinary Medicine, 201583Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Sepideh Zununi Vahed
- Kidney Research Center, 48432Tabriz University of Medical Sciences, Tabriz, Iran
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29
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Lei G, Wang G, Zhang C, Chen Y, Yang X. Using Machine Learning to Predict Acute Kidney Injury After Aortic Arch Surgery. J Cardiothorac Vasc Anesth 2020; 34:3321-3328. [DOI: 10.1053/j.jvca.2020.06.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/01/2020] [Accepted: 06/03/2020] [Indexed: 01/01/2023]
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30
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Kaur J, Kaur T, Sharma AK, Kaur J, Yadav HN, Pathak D, Singh AP. Fenofibrate attenuates ischemia reperfusion-induced acute kidney injury and associated liver dysfunction in rats. Drug Dev Res 2020; 82:412-421. [PMID: 33226649 DOI: 10.1002/ddr.21764] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 11/10/2020] [Accepted: 11/10/2020] [Indexed: 01/09/2023]
Abstract
Ischemia/reperfusion (I/R) is one of the common reasons for acute kidney injury (AKI) and we need to develop effective therapies for treating AKI. We investigated the role of fenofibrate against I/R-induced AKI and associated hepatic dysfunction in rats. In male wistar albino rats, renal pedicle occlusion for 40 min and 24 h reperfusion resulted in AKI. I/R-induced AKI was demonstrated by measuring serum creatinine, creatinine clearance, urea, uric acid, potassium, fractional excretion of sodium and urinary microproteins. Oxidative stress in rat kidneys was quantified by assaying superoxide anion generation, thiobarbituric acid reactive substances, and reduced glutathione levels. AKI-induced hepatic damage was quantified by assaying serum aminotransferases, alkaline phosphatase and bilirubin levels. Moreover, serum cholesterol, high density lipoprotein and triglycerides were quantified. Hematoxylin-eosin staining of renal and hepatic tissues was done and the kidney and liver injury scores were determined. Immunohistology of endothelial nitric oxide synthase (eNOS) was done in rat kidneys. Fenofibrate was administered for 1 week before subjecting rats to AKI. In separate group, the nitric oxide synthase inhibitor, L-nitroarginine methyl ester (L-NAME) was administered prior to fenofibrate treatment. In I/R group, significant alteration in the serum/urine parameters indicated AKI and hepatic dysfunction along with marked increase in kidney and liver injury scores. Treatment with fenofibrate attenuated AKI and associated hepatic dysfunction. Moreover, I/R-induced decrease in renal eNOS expression was abrogated by fenofibrate. Pre-treatment with L-NAME abolished fenofibrate mediated reno- and hepato-protective effects. In conclusion, fenofibrate attenuates I/R-induced AKI and associated hepatic dysfunction putatively through modulation of eNOS expression.
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Affiliation(s)
- Jashanpreet Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Tajpreet Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India.,Department of Pharmacology, Khalsa College of Pharmacy, Amritsar (INDIA), India
| | - Ashwani Kumar Sharma
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Japneet Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Harlokesh Narayan Yadav
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.,Department of Veterinary Anatomy, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, India
| | | | - Amrit Pal Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
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Abstract
Physical trauma can affect any individual and is globally accountable for more than one in every ten deaths. Although direct severe kidney trauma is relatively infrequent, extrarenal tissue trauma frequently results in the development of acute kidney injury (AKI). Various causes, including haemorrhagic shock, rhabdomyolysis, use of nephrotoxic drugs and infectious complications, can trigger and exacerbate trauma-related AKI (TRAKI), particularly in the presence of pre-existing or trauma-specific risk factors. Injured, hypoxic and ischaemic tissues expose the organism to damage-associated and pathogen-associated molecular patterns, and oxidative stress, all of which initiate a complex immunopathophysiological response that results in macrocirculatory and microcirculatory disturbances in the kidney, and functional impairment. The simultaneous activation of components of innate immunity, including leukocytes, coagulation factors and complement proteins, drives kidney inflammation, glomerular and tubular damage, and breakdown of the blood-urine barrier. This immune response is also an integral part of the intense post-trauma crosstalk between the kidneys, the nervous system and other organs, which aggravates multi-organ dysfunction. Necessary lifesaving procedures used in trauma management might have ambivalent effects as they stabilize injured tissue and organs while simultaneously exacerbating kidney injury. Consequently, only a small number of pathophysiological and immunomodulatory therapeutic targets for TRAKI prevention have been proposed and evaluated.
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32
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Shang Y, Madduma Hewage S, Wijerathne CUB, Siow YL, Isaak CK, O K. Kidney Ischemia-Reperfusion Elicits Acute Liver Injury and Inflammatory Response. Front Med (Lausanne) 2020; 7:201. [PMID: 32582723 PMCID: PMC7280447 DOI: 10.3389/fmed.2020.00201] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/24/2020] [Indexed: 12/20/2022] Open
Abstract
Ischemia-reperfusion (IR) is a common risk factor that causes acute kidney injury (AKI). AKI is associated with dysfunction of other organs also known as distant organ injury. The liver function is often compromised in patients with AKI and in animal models. However, the underlying mechanisms are not fully understood. Inflammatory response plays an important role in IR-induced tissue injury. Although increased proinflammatory cytokines have been detected in the kidney and the distant organs after renal IR, their original sources remain uncertain. In the present study, we investigated the acute effect of renal IR on hepatic inflammatory cytokine expression and the mechanism involved. Sprague-Dawley rats that were subjected to renal IR (ischemia for 45 min followed by reperfusion for 1 h or 6 h) had increased plasma levels of creatinine, urea, and transaminases, indicating kidney and liver injuries. There was a significant increase in the expression of proinflammatory cytokine mRNA (MCP-1, TNF-α, IL-6) in the kidney and liver in rats with renal IR. This was accompanied by a significant increase in proinflammatory cytokine protein levels in the plasma, kidney, and liver. Activation of a nuclear transcription factor kappa B (NF-κB) was detected in the liver after renal IR. The inflammatory foci and an increased myeloperoxidase (MPO) activity were detected in the liver after renal IR, indicating hepatic inflammatory response and leukocyte infiltration. These results suggest that renal IR can directly activate NF-κB and induce acute production of proinflammatory cytokines in the liver. Renal IR-induced hepatic inflammatory response may contribute to impaired liver function and systemic inflammation.
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Affiliation(s)
- Yue Shang
- St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.,Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada
| | - Susara Madduma Hewage
- St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
| | - Charith U B Wijerathne
- St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.,Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada
| | - Yaw L Siow
- St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.,Agriculture and Agri Food Canada, St. Boniface Hospital Research Centre, Winnipeg, MB, Canada
| | - Cara K Isaak
- St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
| | - Karmin O
- St. Boniface Hospital Research Centre, Winnipeg, MB, Canada.,Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada.,Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
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Husain‐Syed F, Rosner MH, Ronco C. Distant organ dysfunction in acute kidney injury. Acta Physiol (Oxf) 2020; 228:e13357. [PMID: 31379123 DOI: 10.1111/apha.13357] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/13/2019] [Accepted: 07/31/2019] [Indexed: 12/28/2022]
Abstract
Acute kidney injury (AKI) is a common complication in critically ill patients and it is associated with increased morbidity and mortality. Epidemiological and clinical data show that AKI is linked to a wide range of distant organ injuries, with the lungs, heart, liver, and intestines representing the most clinically relevant affected organs. This distant organ injury during AKI predisposes patients to progression to multiple organ dysfunction syndrome and ultimately, death. The strongest direct evidence of distant organ injury occurring in AKI has been obtained from animal models. The identified mechanisms include systemic inflammatory changes, oxidative stress, increases in leucocyte trafficking and the activation of proapoptotic pathways. Understanding the pathways driving AKI-induced distal organ injury are critical for the development and refinement of therapies for the prevention and attenuation of AKI-related morbidity and mortality. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury.
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Affiliation(s)
- Faeq Husain‐Syed
- Division of Nephrology, Pulmonology, and Critical Care Medicine, Department of Internal Medicine II University Hospital Giessen and Marburg Giessen Germany
- Department of Nephrology, Dialysis and Transplantation, International Renal Research Institute of Vicenza (IRRIV) San Bortolo Hospital Vicenza Italy
| | - Mitchell H. Rosner
- Department of Medicine University of Virginia Health System Charlottesville Virginia
| | - Claudio Ronco
- Department of Nephrology, Dialysis and Transplantation, International Renal Research Institute of Vicenza (IRRIV) San Bortolo Hospital Vicenza Italy
- Department of Medicine Università degli Studi di Padova Padova PD Italy
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Lim AKH, Arumugananthan C, Lau Hing Yim C, Jellie LJ, Wong EWW, Junckerstorff RK. A Cross-Sectional Study of the Relationship between Serum Creatine Kinase and Liver Biochemistry in Patients with Rhabdomyolysis. J Clin Med 2019; 9:jcm9010081. [PMID: 31905634 PMCID: PMC7019809 DOI: 10.3390/jcm9010081] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/20/2019] [Accepted: 12/22/2019] [Indexed: 12/20/2022] Open
Abstract
Abnormal liver function tests are commonly observed with rhabdomyolysis, but the nature of this association is not fully defined. This study aims to determine the functional relationship between serum creatine kinase, as a marker of rhabdomyolysis severity, and liver biochemistry. We used linear regression to model the relationship between liver biochemistry and peak serum creatine kinase. A total of 528 patients with a median age of 74 years were included. The distribution of creatine kinase, bilirubin, alkaline phosphatase, alanine aminotransferase, and γ-glutamyl transferase were significantly skewed, and these variables were log-transformed prior to regression. There was a positive linear correlation between log-alanine aminotransferase and log-creatine kinase. In the multiple regression analysis, log-creatine kinase, age, acute kidney injury stage, and chronic liver disease were independently associated with log-alanine aminotransferase. This model explained 46% of the variance of log-alanine aminotransferase. We found no correlation between the log-creatine kinase and the log-bilirubin, log-alkaline phosphatase, or log-γ-glutamyl transferase. Serum alanine aminotransferase was not associated with inpatient mortality but a higher creatine kinase-alanine aminotransferase ratio was associated with lower odds of mortality. In conclusion, an isolated elevation in alanine aminotransferase can occur in rhabdomyolysis, and it may be possible to anticipate the level of increase based on the peak creatine kinase.
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Affiliation(s)
- Andy K. H. Lim
- General Medicine, Monash Health, Clayton, Victoria 3168, Australia; (C.A.); (C.L.H.Y.); (L.J.J.); (E.W.W.W.); (R.K.J.)
- Department of Medicine, Monash University, Clayton, Victoria 3168, Australia
- Correspondence:
| | - Chitherangee Arumugananthan
- General Medicine, Monash Health, Clayton, Victoria 3168, Australia; (C.A.); (C.L.H.Y.); (L.J.J.); (E.W.W.W.); (R.K.J.)
| | - Corinne Lau Hing Yim
- General Medicine, Monash Health, Clayton, Victoria 3168, Australia; (C.A.); (C.L.H.Y.); (L.J.J.); (E.W.W.W.); (R.K.J.)
| | - Lucy J. Jellie
- General Medicine, Monash Health, Clayton, Victoria 3168, Australia; (C.A.); (C.L.H.Y.); (L.J.J.); (E.W.W.W.); (R.K.J.)
| | - Elena W. W. Wong
- General Medicine, Monash Health, Clayton, Victoria 3168, Australia; (C.A.); (C.L.H.Y.); (L.J.J.); (E.W.W.W.); (R.K.J.)
| | - Ralph K. Junckerstorff
- General Medicine, Monash Health, Clayton, Victoria 3168, Australia; (C.A.); (C.L.H.Y.); (L.J.J.); (E.W.W.W.); (R.K.J.)
- Department of Medicine, Monash University, Clayton, Victoria 3168, Australia
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35
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Raj D, Tomar B, Lahiri A, Mulay SR. The gut-liver-kidney axis: Novel regulator of fatty liver associated chronic kidney disease. Pharmacol Res 2019; 152:104617. [PMID: 31881272 DOI: 10.1016/j.phrs.2019.104617] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 12/09/2019] [Accepted: 12/21/2019] [Indexed: 12/12/2022]
Abstract
Increased interest in understanding the liver-kidney axis in health and disease during the last decade unveiled multiple recent evidence that suggested a strong association of fatty liver diseases with chronic kidney disease (CKD). Low-grade systemic inflammation is thought to be the major contributing factor to the pathogenesis of CKD associated with fatty liver. However, other contributing factors largely remained unclear, for example, gut microbiota and intestinal barrier integrity. Homeostasis of the gut microbiome is very crucial for the health of an individual. Imbalance in the gut microbiota leads to various diseases like fatty liver disease and CKD. On the contrary, disease conditions can also distinctly change gut microbiota. In this review, we propose the pathogenic role of the gut-liver-kidney axis in the development and progression of CKD associated with chronic fatty liver diseases, either non-alcoholic fatty liver disease or non-alcoholic steatohepatitis in experimental models and humans. Further, we discuss the therapeutic potential and highlight the future research directions for therapeutic targeting of the gut-liver-kidney axis.
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Affiliation(s)
- Desh Raj
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India
| | - Bhawna Tomar
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Amit Lahiri
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India
| | - Shrikant R Mulay
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110001, India.
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36
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Đurašević S, Stojković M, Bogdanović L, Pavlović S, Borković-Mitić S, Grigorov I, Bogojević D, Jasnić N, Tosti T, Đurović S, Đorđević J, Todorović Z. The Effects of Meldonium on the Renal Acute Ischemia/Reperfusion Injury in Rats. Int J Mol Sci 2019; 20:ijms20225747. [PMID: 31731785 PMCID: PMC6888683 DOI: 10.3390/ijms20225747] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 11/01/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our results showed that meldonium decreased animal body mass gain, food and water intake, and carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1, causing manganese superoxide dismutase expression and activity to increase, as well as lipid peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex changes in renal lipidomics. Taken together, our results have confirmed that meldonium pre-treatment protects against I/R-induced oxidative stress and apoptosis/necrosis.
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Affiliation(s)
- Siniša Đurašević
- Faculty of Biology, University of Belgrade, 11158 Belgrade, Serbia; (N.J.); (J.Đ.)
- Correspondence: ; Tel.: +381-63-367108
| | - Maja Stojković
- School of Medicine, University of Belgrade, 11129 Belgrade, Serbia; (M.S.); (L.B.); (Z.T.)
| | - Ljiljana Bogdanović
- School of Medicine, University of Belgrade, 11129 Belgrade, Serbia; (M.S.); (L.B.); (Z.T.)
| | - Slađan Pavlović
- Institute for Biological Research “Siniša Stanković”–National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (S.P.); (S.B.-M.); (I.G.); (D.B.)
| | - Slavica Borković-Mitić
- Institute for Biological Research “Siniša Stanković”–National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (S.P.); (S.B.-M.); (I.G.); (D.B.)
| | - Ilijana Grigorov
- Institute for Biological Research “Siniša Stanković”–National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (S.P.); (S.B.-M.); (I.G.); (D.B.)
| | - Desanka Bogojević
- Institute for Biological Research “Siniša Stanković”–National Institute of Republic of Serbia, University of Belgrade, 11060 Belgrade, Serbia; (S.P.); (S.B.-M.); (I.G.); (D.B.)
| | - Nebojša Jasnić
- Faculty of Biology, University of Belgrade, 11158 Belgrade, Serbia; (N.J.); (J.Đ.)
| | - Tomislav Tosti
- Faculty of Chemistry, University of Belgrade, 11158 Belgrade, Serbia;
| | - Saša Đurović
- Institute of General and Physical Chemistry, University of Belgrade, 11158 Belgrade, Serbia;
| | - Jelena Đorđević
- Faculty of Biology, University of Belgrade, 11158 Belgrade, Serbia; (N.J.); (J.Đ.)
| | - Zoran Todorović
- School of Medicine, University of Belgrade, 11129 Belgrade, Serbia; (M.S.); (L.B.); (Z.T.)
- University Medical Centre “Bežanijska kosa”, University of Belgrade, 11080 Belgrade, Serbia
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37
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Faria J, Ahmed S, Gerritsen KGF, Mihaila SM, Masereeuw R. Kidney-based in vitro models for drug-induced toxicity testing. Arch Toxicol 2019; 93:3397-3418. [PMID: 31664498 DOI: 10.1007/s00204-019-02598-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 10/15/2019] [Indexed: 12/18/2022]
Abstract
The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs' microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.
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Affiliation(s)
- João Faria
- Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Sabbir Ahmed
- Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands
| | - Karin G F Gerritsen
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
| | - Silvia M Mihaila
- Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.,Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
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N-Acetylcysteine Attenuates the Increasing Severity of Distant Organ Liver Dysfunction after Acute Kidney Injury in Rats Exposed to Bisphenol A. Antioxidants (Basel) 2019; 8:antiox8100497. [PMID: 31640182 PMCID: PMC6826922 DOI: 10.3390/antiox8100497] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/11/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023] Open
Abstract
Distant organ liver damage after acute kidney injury (AKI) remains a serious clinical setting with high mortality. This undesirable outcome may be due to some hidden factors that can intensify the consequences of AKI. Exposure to bisphenol A (BPA), a universal chemical used in plastics industry, is currently unavoidable and can be harmful to the liver. This study explored whether BPA exposure could be a causative factor that increase severity of remote liver injury after AKI and examined the preventive benefit by N-acetylcysteine (NAC) in this complex condition. Male Wistar rats were given vehicle, BPA, or BPA + NAC for 5 weeks then underwent 45 min renal ischemia followed by 24 h reperfusion (RIR), a group of vehicle-sham-control was also included. RIR not only induced AKI but produced liver injury, triggered systemic oxidative stress as well as inflammation, which increasing severity upon exposure to BPA. Given NAC to BPA-exposed rats diminished the added-on effects of BPA on liver functional impairment, oxidative stress, inflammation, and apoptosis caused by AKI. NAC also mitigated the abnormalities in mitochondrial functions, dynamics, mitophagy, and ultrastructure of the liver by improving the mitochondrial homeostasis regulatory signaling AMPK-PGC-1α-SIRT3. The study demonstrates that NAC is an effective adjunct for preserving mitochondrial homeostasis and reducing remote effects of AKI in environments where BPA exposure is vulnerable.
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Capalbo O, Giuliani S, Ferrero-Fernández A, Casciato P, Musso CG. Kidney-liver pathophysiological crosstalk: its characteristics and importance. Int Urol Nephrol 2019; 51:2203-2207. [PMID: 31549285 DOI: 10.1007/s11255-019-02288-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 09/15/2019] [Indexed: 12/16/2022]
Abstract
The kidney plays a crucial role in controlling the blood volume and pressure, electrolyte and acid-base balance, erythropoietin secretion, as well as renin-angiotensin-aldosterone system activity. All these renal activities have important repercussion in the organism, explaining why morbidity and mortality rates are high in patients with significant renal dysfunction. In this sense, there are renal-induced liver damages in acute kidney injury, as well as liver-induced renal damages in hepatic disease. Ischemia, reperfusion, cytokine outflow, pro-inflammatory cascades, metabolic acidosis, oxidative stress, and changes in enzymatic and metabolic pathways provide the bases for this bidirectional kidney-liver damage. In conclusion, knowing the characteristics of this kidney-liver crosstalk is crucial for handling the complications induced by this vicious circle.
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Affiliation(s)
- Olivia Capalbo
- Human Physiology Department, Instituto Universitario Del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Sofía Giuliani
- Human Physiology Department, Instituto Universitario Del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Alberta Ferrero-Fernández
- Human Physiology Department, Instituto Universitario Del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Paola Casciato
- Hepatology Section, Internal Medicine Division, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Carlos G Musso
- Human Physiology Department, Instituto Universitario Del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
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Mohammadi M, Najafi H, Mohamadi Yarijani Z, Vaezi G, Hojati V. Piperine pretreatment attenuates renal ischemia-reperfusion induced liver injury. Heliyon 2019; 5:e02180. [PMID: 31463384 PMCID: PMC6706586 DOI: 10.1016/j.heliyon.2019.e02180] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 05/09/2019] [Accepted: 07/25/2019] [Indexed: 01/09/2023] Open
Abstract
Background Remote organ injury is one of the complications which are developed following ischemia-reperfusion induced acute kidney injury (AKI), dramatically increasing its mortality rate. The aim of the present study was to investigate the effect of piperine pretreatment on liver dysfunction following ischemia-reperfusion induced AKI. Materials and methods Acute kidney injury was induced by 30 min-bilateral renal ischemia followed by 24 h of reperfusion. To investigate liver damages, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) enzymes were measured in plasma. In order to study oxidative stress, malondialdehyde (MDA) and ferric reducing antioxidant power (FRAP) levels were measured. Furthermore, the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA along with infiltration of leukocytes in the liver tissue was measured for inflammation assessment. Histopathological damages were studied through measuring the extent of cellular fibrosis, sinusoidal dilatation, and vascular congestion in liver tissue. Results Following acute kidney injury, AST, ALT, and ALP levels in plasma, MDA level and ICAM-1 expression in the liver tissue, infiltration of leukocytes into the interstitium, and hepatic histopathologic damages increased significantly, while FRAP decreased. Pretreatment with piperine at 10 and 20 mg/kg body weight was able to improve these damages, such that some of them reached its value in the sham group, though piperine in the 20 mg/kg was more effective. Conclusions The results of this study suggest that ischemia-reperfusion induced AKI result in hepatic damages, and pretreatment with piperine can prevent development of these damages through its antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Maryam Mohammadi
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Houshang Najafi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeynab Mohamadi Yarijani
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gholamhasan Vaezi
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
| | - Vida Hojati
- Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran
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41
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Organ crosstalk: the potent roles of inflammation and fibrotic changes in the course of organ interactions. Inflamm Res 2019; 68:825-839. [PMID: 31327029 DOI: 10.1007/s00011-019-01271-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/10/2019] [Accepted: 07/10/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Organ crosstalk can be defined as the complex and mutual biological communication between distant organs mediated by signaling factors. Normally, crosstalk helps to coordinate and maintain homeostasis, but sudden or chronic dysfunction in any organ causes dysregulation in another organ. Many signal molecules, including cytokines and growth factors, are involved in the metabolic dysregulation, and excessive or inappropriate release of these molecules leads to organ dysfunction or disease (e.g., obesity, type 2 diabetes). AIM AND METHOD The aim of this review is to reveal the impact of organ crosstalk on the pathogenesis of diseases associated with organ interactions and the role of inflammatory and fibrotic changes in the organ dysfunction. After searching in MEDLINE, PubMed and Google Scholar databases using 'organ crosstalk' as a keyword, studies related to organ crosstalk and organ interaction were compiled and examined. CONCLUSION The organ crosstalk and the functional integration of organ systems are exceedingly complex processes. Organ crosstalk contributes to metabolic homeostasis and affects the inflammatory response, related pathways and fibrotic changes. As in the case of interactions between adipose tissue and intestine, stimulation of inflammatory mechanisms plays an active role in the development of diseases including insulin resistance, obesity, type 2 diabetes and hepatic steatosis. The increased level of knowledge about the 'crosstalk' between any organ and distant organs will facilitate the early diagnosis of the disease as well as the management of the treatment practices in the short- and long-term organ dysfunction.
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42
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Lee S, Park S, Kang MW, Yoo HW, Han K, Kim Y, Lee JP, Joo KW, Lim CS, Kim YS, Kim H, Kim DK. Long-term impact of dialysis-requiring AKI during the perioperative period of liver transplantation on postdischarge outcomes. Clin Transplant 2019; 33:e13649. [PMID: 31230386 DOI: 10.1111/ctr.13649] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 06/05/2019] [Accepted: 06/15/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND Patients undergoing liver transplantation (LT) are prone to dialysis-requiring acute kidney injury (AKI-D). However, long-term prognoses among them need further investigation, as overall survival after LT is improving. METHODS A nationwide, population-based cohort study was conducted using the data of Korean National Health Insurance System between 2006 and 2015. The patients who received dialysis during the perioperative period of LT were in the AKI-D group, and the control group included those who did not undergo dialysis. RESULTS Among the 6879 patients who underwent LT, 968 were in the AKI-D group. All-cause mortality [adjusted hazard ratio (HR): 1.52 (1.26-1.83), P < 0.001], end-stage renal disease (ESRD) progression [adjusted HR: 2.93 (2.34-3.66), P < 0.001], and ICU readmission [adjusted HR: 1.70 (1.44-2.01), P < 0.001] within and after 90 days from discharge were increased in the AKI-D group. When analyzed among those who recovered from dialysis at discharge, overall outcomes were similar to those of the AKI-D group, except the long-term mortality. CONCLUSIONS AKI-D during the perioperative period of LT was associated with worse mortality, ESRD progression, and ICU readmission risk. The results of renal-recovered patients could indicate clinicians that achievement of dialysis independence is important to gain favorable long-term postdischarge survival.
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Affiliation(s)
- Soojin Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sehoon Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Min Woo Kang
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hai-Won Yoo
- Department of Preventive Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Kyungdo Han
- Department of Medical Statistics, College of Medicine, Catholic University of Korea, Seoul, Korea
| | - Yaerim Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Jung Pyo Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Kwon Wook Joo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Chun Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Korea.,Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyeongsu Kim
- Department of Preventive Medicine, Konkuk University School of Medicine, Seoul, Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.,Kidney Research Institute, Seoul National University College of Medicine, Seoul, Korea
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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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Blanco VE, Hernandorena CV, Scibona P, Belloso W, Musso CG. Acute Kidney Injury Pharmacokinetic Changes and Its Impact on Drug Prescription. Healthcare (Basel) 2019; 7:healthcare7010010. [PMID: 30646533 PMCID: PMC6473374 DOI: 10.3390/healthcare7010010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/06/2019] [Accepted: 01/08/2019] [Indexed: 12/17/2022] Open
Abstract
Acute kidney injury (AKI) is a common problem in hospitalized patients that is associated with significant morbid-mortality. The impact of kidney disease on the excretion of drugs eliminated by glomerular filtration and tubular secretion is well established, as well as the requirement for drug dosage adjustment in impaired kidney function patients. However, since impaired kidney function is associated with decreased activity of several hepatic and gastrointestinal drug-metabolizing enzymes and transporters, drugs doses adjustment only based on kidney alteration could be insufficient in AKI. In addition, there are significant pharmacokinetics changes in protein binding, serum amino acid levels, liver, kidney, and intestinal metabolism in AKI, thus the determination of plasma drug concentrations is a very useful tool for monitoring and dose adjustment in AKI patients. In conclusion, there are many pharmacokinetics changes that should be taken into account in order to perform appropriate drug prescriptions in AKI patients.
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Affiliation(s)
- Victoria E Blanco
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Potosí 4234, C1199AC CABA Buenos Aires, Argentina.
| | - Carolina V Hernandorena
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Potosí 4234, C1199AC CABA Buenos Aires, Argentina.
| | - Paula Scibona
- Pharmacology Division, Internal Medicine Department, Hospital Italiano de Buenos Aires, C1199 ABH Buenos Aires, Argentina.
| | - Waldo Belloso
- Pharmacology Division, Internal Medicine Department, Hospital Italiano de Buenos Aires, C1199 ABH Buenos Aires, Argentina.
| | - Carlos G Musso
- Human Physiology Department, Instituto Universitario del Hospital Italiano de Buenos Aires, Potosí 4234, C1199AC CABA Buenos Aires, Argentina.
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Abstract
Inflammation is an adaptive process to the noxious stimuli that the human body is constantly exposed to. From the local inflammatory response to a full-blown systemic inflammation, a wide complex sequence of events occurs. Persistent immunosuppression and catabolism may ensue, until multiple organ failure finally sets in. And since clinically useful and specific biomarkers are lacking, diagnosis may come late. A thorough understanding of these events (how they begin, how they evolve, and how to modulate them) is imperative, but as yet poorly studied. This review aims to consolidate current knowledge of these events so that the management of these patients is not only evidence-based, but also built on an understanding of the inner workings of the human body in health and in disease.
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Affiliation(s)
- Miguel Lourenço Varela
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal.
- Intensive Care Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal.
| | - Mihail Mogildea
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal
| | - Ignacio Moreno
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal
| | - Ana Lopes
- Internal Medicine 1, Hospital de Faro, Centro Hospitalar Universitário do Algarve, Rua Leão Penedo, Faro, 8000-386, Portugal
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Elshazly S, Soliman E. PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury. Toxicol Appl Pharmacol 2018; 362:86-94. [PMID: 30393147 DOI: 10.1016/j.taap.2018.10.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 10/16/2018] [Accepted: 10/24/2018] [Indexed: 01/09/2023]
Abstract
Remote organ damage is the major cause of death in patients with acute kidney injury (AKI) due to renal ischemia reperfusion (IR). Liver is one of the vital organs which are profoundly affected by AKI. The present study aims to investigate the role of peroxisome proliferator activator receptor gamma (PPARγ) in liver damage induced by IR injury in rats. Renal IR was induced by right nephrectomy, occlusion of left renal pedicle for 45 min to induce ischemia, and then reperfusion for 6 or 24 h. The PPARγ agonist, pioglitazone, was given orally for 7 days before renal IR procedure. Animals receiving pioglitazone showed improvement in renal and hepatic functions when compared to IR groups. Renal IR increased renal, hepatic and serum levels of tumor necrosis factor-α (TNF-α) and induced apoptotic cell death in liver. These effects were diminished with pioglitazone. In addition, pioglitazone reduced renal IR-induced oxidative stress in liver. Pioglitazone reduced malondialdehyde (MDA) content and NADPH oxidase mRNA expression and induced further increase in nuclear factor erythroid 2-related factor 2 (Nrf2) expression when compared to IR groups. Furthermore, pioglitazone increased the expression of PPARγ target genes such as renal and hepatic PPARγ1 (Pparg1), hepatic hemoxygenase-1 (Hmox1), and hepatic thioredoxin (TRx). Histological profiles for kidney and liver were also ameliorated with pioglitazone. Hence, PPARγ is a potential target to protect liver in patients with renal IR injury.
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Affiliation(s)
- Shimaa Elshazly
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Eman Soliman
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
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Morello J, Derks RJE, Lopes SS, Steenvoorden E, Monteiro EC, Mayboroda OA, Pereira SA. Zebrafish Larvae Are a Suitable Model to Investigate the Metabolic Phenotype of Drug-Induced Renal Tubular Injury. Front Pharmacol 2018; 9:1193. [PMID: 30459607 PMCID: PMC6232664 DOI: 10.3389/fphar.2018.01193] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 09/28/2018] [Indexed: 12/04/2022] Open
Abstract
Prevention and treatment of drug-induced renal injury (DIRI) rely on the availability of sensitive and specific biomarkers of early kidney injury and predictive animal models of human pathophysiology. This study aimed to evaluate the potential of zebrafish larvae as translational model in metabolic profiling of DIRI. Zebrafish larvae were exposed to the lethal concentration for 10% of the larvae (LC10) or ½ LC10 of gentamicin, paracetamol and tenofovir as tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). Metabolites were extracted from whole larvae and analyzed by liquid chromatography-mass spectrometry. Principal component analysis showed that drug exposition to the LC10 of paracetamol, TFV, and TDF was the main source of the variance of the data. To identify the metabolites responsible for the toxic effects of the drugs, partial least squares discriminant analyses were built between the LC10 and ½ LC10 for each drug. Features with variable importance in projection> 1.0 were selected and Venn diagrams were built to differentiate between the common and drug specific metabolites of DIRI. Creatine, tyrosine, glutamine, guanosine, hypoxanthine were identified as common metabolites, adenosine and tryptophan as paracetamol-specific and xanthine and oxidized glutathione as tenofovir-specific. Those metabolic changes can be associated with alterations in energy metabolism, xenobiotic detoxification and protein catabolism, all described in the human pathophysiology of DIRI. Thus, zebrafish proved to be a suitable model to characterize the metabolic changes associated with DIRI. This information can be useful to early diagnose DIRI and to improve our knowledge on the mechanisms of DIRI.
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Affiliation(s)
- Judit Morello
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Rico J E Derks
- Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, Netherlands
| | - Susana S Lopes
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Evelyne Steenvoorden
- Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, Netherlands
| | - Emilia C Monteiro
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Oleg A Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Centre, Leiden, Netherlands.,Department of Chemistry, Tomsk State University, Tomsk, Russia
| | - Sofia A Pereira
- CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
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Merath K, Chen Q, Bagante F, Akgul O, Idrees JJ, Dillhoff M, Cloyd JM, Pawlik TM. Synergistic Effects of Perioperative Complications on 30-Day Mortality Following Hepatopancreatic Surgery. J Gastrointest Surg 2018; 22:1715-1723. [PMID: 29916105 DOI: 10.1007/s11605-018-3829-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 05/22/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Data on the interaction effect of multiple concurrent postoperative complications relative to the risk of short-term mortality following hepatopancreatic surgery have not been reported. The objective of the current study was to define the interaction effect of postoperative complications among patients undergoing HP surgery on 30-day mortality. METHODS Using the ACS-NSQIP Procedure Targeted Participant Use Data File, patients who underwent HP surgery between 2014 and 2016 were identified. Hazard ratios (HRs) for 30-day mortality were estimated using Cox proportional hazard models. Two-way interaction effects assessing combinations of complications relative to 30-day mortality were calculated using the relative excess risk due to interaction (RERI) in separate adjusted Cox models. RESULTS Among 26,824 patients, 10,886 (40.5%) experienced at least one complication. Mortality was higher among patients who experienced at least one complication versus patients who did not experience a complication (3.0 vs 0.1%, p < 0.001). The most common complications were blood transfusion (16.9%, n = 4519), organ space infection (12.2%, n = 3273), and sepsis/septic shock (8.2%, n = 2205). Combinations associated with additive effect on mortality included transfusion + renal dysfunction (RERI 12.3, 95% CI 5.2-19.4), pulmonary dysfunction + renal dysfunction (RERI 60.9, 95% CI 38.6-83.3), pulmonary dysfunction + cardiovascular complication (RERI 144.1, 95% CI 89.3-199.0), and sepsis/septic shock + renal dysfunction (RERI 11.5, 95% CI 4.4-18.7). CONCLUSION Both the number and specific type of complication impacted the incidence of postoperative mortality among patients undergoing HP surgery. Certain complications interacted in a synergistic manner, leading to a greater than expected increase in the risk of short-term mortality.
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Affiliation(s)
- Katiuscha Merath
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Qinyu Chen
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Fabio Bagante
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA.,Department of Surgery, University of Verona, Verona, Italy
| | - Ozgur Akgul
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Jay J Idrees
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Mary Dillhoff
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Jordan M Cloyd
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA. .,Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA.
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50
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Hobson C, Lysak N, Huber M, Scali S, Bihorac A. Epidemiology, outcomes, and management of acute kidney injury in the vascular surgery patient. J Vasc Surg 2018; 68:916-928. [PMID: 30146038 PMCID: PMC6236681 DOI: 10.1016/j.jvs.2018.05.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 05/13/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Conventional clinical wisdom has often been nihilistic regarding the prevention and management of acute kidney injury (AKI), despite its being a frequent and morbid complication associated with both increased mortality and cost. Recent developments have shown that AKI is not inevitable and that changes in management of patients can reduce both the incidence and morbidity of perioperative AKI. The purpose of this narrative review was to review the epidemiology and outcomes of AKI in patients undergoing vascular surgery using current consensus definitions, to discuss some of the novel emerging risk stratification and prevention techniques relevant to the vascular surgery patient, and to describe a standardized perioperative pathway for the prevention of AKI after vascular surgery. METHODS We performed a critical review of the literature on AKI in the vascular surgery patient using the PubMed and MEDLINE databases and Google Scholar through September 2017 using web-based search engines. We also searched the guidelines and publications available online from the organizations Kidney Disease: Improving Global Outcomes and the Acute Dialysis Quality Initiative. The search terms used included acute kidney injury, AKI, epidemiology, outcomes, prevention, therapy, and treatment. RESULTS The reported epidemiology and outcomes associated with AKI have been evolving since the publication of consensus criteria that allow accurate identification of mild and moderate AKI. The incidence of AKI after major vascular surgery using current criteria is as high as 49%, although there are significant differences, depending on the type of procedure performed. Many tools have become available to assess and to stratify the risk for AKI and to use that information to prevent AKI in the surgical patient. We describe a standardized clinical assessment and management pathway for vascular surgery patients, incorporating current risk assessment and preventive strategies to prevent AKI and to decrease its complications. Patients without any risk factors can be managed in a perioperative fast-track pathway. Those patients with positive risk factors are tested for kidney stress using the urinary biomarker TIMP-2•IGFBP7, and care is then stratified according to the result. Management follows current Kidney Disease: Improving Global Outcomes guidelines. CONCLUSIONS AKI is a common postoperative complication among vascular surgery patients and has a significant impact on morbidity, mortality, and cost. Preoperative risk assessment and optimal perioperative management guided by that risk assessment can minimize the consequences associated with postoperative AKI. Adherence to a standardized perioperative pathway designed to reduce risk of AKI after major vascular surgery offers a promising clinical approach to mitigate the incidence and severity of this challenging clinical problem.
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Affiliation(s)
- Charles Hobson
- Department of Surgery, Malcom Randall VAMC, Gainesville, Fla; Department of Health Services Research, Management and Policy, University of Florida, Gainesville, Fla
| | - Nicholas Lysak
- Department of Surgery, College of Medicine, University of Florida, Gainesville, Fla
| | - Matthew Huber
- Department of Medicine, College of Medicine, University of Florida, Gainesville, Fla
| | - Salvatore Scali
- Department of Surgery, Malcom Randall VAMC, Gainesville, Fla; Department of Surgery, College of Medicine, University of Florida, Gainesville, Fla
| | - Azra Bihorac
- Department of Medicine, College of Medicine, University of Florida, Gainesville, Fla; Precision and Intelligent Systems in Medicine (PrismaP), University of Florida, Gainesville, Fla.
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